Oxetanes in Drug Discovery

Diss.ETHNo.
17929
OxetanesinDrugDiscovery
Adissertationsubmittedtothe
SwissFederalInstituteofTechnologyZurich
forthedegreeof
DoctorofSciences
Presentedby
GeorgWuitschik
Dipl.Chem.TUMnchen
bornJanuary051980inBadTlz,Germany
CitizenoftheFederalRepublicofGermany
Acceptedontherecommendationof
Prof.Dr.ErickM.Carreira,examiner
Prof.Dr.FranoisDiederich,coexaminer
Prof.Dr.KlausMller,coexaminer
Zrich,2008
Acknowledgments
AtfirstandforemostIwouldliketothankmysupervisorsProfessorDr.ErickM.Carreira,
Professor Dr. Klaus Mller and Dr. Mark RogersEvans. They gave me the freedom, trust,
guidanceandresourcesthisprojectandImyselfneededtoflourish.Theirinputincountless
discussionsandmailconversationschangedmeandgavemeaglimpseofwhatitmeansto
beascientist.
IamgratefultoProfessorDr.FranoisDiederichforacceptingthecoexaminationofmy
thesisandhistrustinandsupport oftheproject.Dr.AlecFettesandJohannesBurkhardI
wanttothankforcriticallyreadingthismanuscriptandtherebysubstantiallyimprovingit.I
wouldalsoliketothankAlecforadvertisingthisplacetomeandhissupportasafriend.The
othermembersoftheCarreiragroupIalsowanttothankforprovidingagoodworkingat
mosphere,beingpatientwithcomputerproblemsandlisteningtooxetanetalks.Professor
Dr.JeffManthorphe,ProfessorDr.JrmeWaser,Dr.AlexSzpilman,andProfessorDr.Karl
GademannIwanttothankfortheirhelpintheearlydaysofmyPhD.Ialsowanttothank
pastandpresentmembersofmylab,Dr.YannBethuel,Dr.ChikakoOgawa,TobiasBrtsch,
Damien Barbaras, Dr. Thomas Fessard, Roger Geisser, Dr. Pablo Barrio and Lukas Kreis for
thegoodcollaborationandfriendlyatmosphere.IwouldliketothankDr.FlorianKleinbeck
forhisfriendshipingoodaswellasinbadtimes.Forbeingacrazygirlwithgoodtasteoftea,
musicandsheepIwanttothankFangLiZhang.
DuringmytimeinthegroupIwasfortunatetohaveMoritzMrkiasanapprenticeatmy
sideforthreeyears,whomIthankforhisworkanddedicationtoovercomethechallenges
alongtheway.IhopehehasbenefitedasmuchfromourcollaborationasIdidbeinghissu
pervisor.InthatrespectImgratefulforthesupportMoritzandIexperiencedfromtheteam
oftheLehrlabor,ProfessorDr.JrgBorschbergandDieterSchorno.Iamthankfulforhaving
had these superb students who propelled the project forward with their input and hard
work:LuziBarandun,RomanMarty,MaurizioBernasconiandAndreasBuckl.IwishJohannes
Burkhardgoodluckasmysuccessorontheprojectandhopehewillenjoyworkingonitas
muchasIdid.
Computers were all but a minor component of my time in this group and so I want to
thankAstridVolmerforsharingtheresponsibilityofbeingsystemadministratorwithme,for
herdedicationandwilltomovethingsforward,andforheradviceasafriend.
Obviously this thesis would not have been possible without the excellent infrastructure
andtechnicalstaffoftheETHZrich.IwouldliketomentionespeciallyDr.BerndSchweizer
(xraystructures),theteamoftheSchalter,theglasswarecleaning,theMSaswellasthe
combustionanalysisservice.IwouldalsoliketothankFranziskaPeyerforhelpingmewhen
everIneededsomethingandherfriendliness.
This work would not have been possible without the strong and sustained support of a
numberofpeopleofRoche,whonotonlymeasuredthecompounds,butalsowereextreme
ly helpful in interpreting and understanding the results. In particular I would like to thank
AndrAlker,Dr.HolgerFischer,Dr.ManfredKansy,PiaWarga,IsabelleParrilla,Dr.Stefanie
Bendels,Dr.LiudmilaPolonchuk,FrankSenner,BjrnWagner,Dr.FranzSchuler,Dr.Thierry
GodelandDr.JosefSchneider.Iwanttothankmysupervisorsforenablingmetocometo
Rocheforthreemonthstoapplytheoxetanechemistryinarealproject.ImgratefultoDr.
MarkRogersEvans,myhostatRocheandhiscoworkerDidierRombach,aswellasOlivier
GavelleandDr.RainerMartin.
TheF.HoffmannLaRocheAGishighlyacknowledgedforfundingthisworkbyprovidinga
scholarship.
iii
GewidmetmeinenEltern
iv
Publications
1. Trost,B.M.;Yang,H.B.;Wuitschik,G.,ARucatalyzedtandemalkyneenonecoupl
ing/Michael addition: Synthesis of 4methylene2,6cistetrahydropyrans. Org. Lett.
2005,7,(21),476164.
2. Wuitschik, G.; RogersEvans, M.; Mller, K.; Fischer, H.; Wagner, B.; Schuler, F.; Po
lonchuk, L.; Carreira, E. M., Oxetanes as Promising Modules in Drug Discovery. An
gew.Chem.,Int.Ed.2006,45,773639
3. Wuitschik,G.,Carreira,E.M.,RogersEvansM.,Mller,K.,Oxetan3one:chemistry
andsynthesisinProcessChemistryinthePharmaceuticalIndustry(Eds.:K.Gadama
setti,T.Braish),CRCPressLLC,BocaRaton,Fla,2008,pp.21729.
4. Wuitschik, G.; RogersEvans, M.; Buckl, A.; Bernasconi, M.; Mrki, M.; Godel, T.;
Fischer,H.;Wagner,B.;Parrilla,I.;Schuler,F.;Schneider,J.;Alker,A.;Schweizer,W.
B.;Mller,K.;Carreira,E.M.,SpirocyclicOxetanes:SynthesisandProperties.Angew.
Chem.,Int.Ed.2008,47,451215
PosterandOralPresentations
March17,2008
PresentationatSyngentaCPMuenchwilenAG
December19,2007
PresentationatRaTTMeeting,F.HoffmannLaRoche,Basel
March1821,2007
PosterPresentationatFrontiersinMedicinalChemistry,Berlin,Germany
January27,2007
PresentationatNovartisAG,Basel
December8,2006
PresentationatF.HoffmannLaRoche,Basel
August2631,2006
PresentationatLSYRSummerSchool2006,Moltai,Lithuania
vi
TableofContents
Abstract_____________________________________________________________________ix
Zusammenfassung____________________________________________________________xii
ListofAbbreviationsandAcronyms______________________________________________xv
Introduction _________________________________________________________1
1.1
StucturalPropertiesofOxetanes:__________________________________________ 3
1.2
RingOpeningReactionsofOxetanes_______________________________________ 6
1.3
TendencyofOxetanetoFormRadicals _____________________________________ 8
1.4
PreparationofOxetanes________________________________________________ 10
1.5
PharmacologicallyRelevantOxetanes_____________________________________ 12
IdeaandTheoreticalConcept___________________________________________19
2.1
OxetanesasLipoNeutralBulkIncrease____________________________________ 19
2.2
OxetanesasCarbonylAnalogues _________________________________________ 24
2.3
SpirocyclicOxetanesasaMimicforOxaHeterocycles________________________ 28
2.4
SyntheticAccesstoOxetanes____________________________________________ 31
MainPart,Chemistry_________________________________________________39
3.1
PreparationofOxetan3one ____________________________________________ 39
3.1.1
RouteviaKetalCleavage______________________________________________________41
3.1.2
OxidationofOxetan3ol______________________________________________________45
3.2
AdditionstoOxetan3one ______________________________________________ 50
3.2.1
3Aryloxetan3ols___________________________________________________________50
3.2.2
3Fluorooxetanes___________________________________________________________52
3.2.3
3Aryloxetanes______________________________________________________________54
3.2.4
3Aminooxetanes ___________________________________________________________57
3.3
OxetanesBearingaQuaternaryCenter ____________________________________ 59
3.4
1,4AdditiontoMichaelAcceptors________________________________________ 60
3.4.1
PreparationofAcceptors _____________________________________________________61
3.4.2
ConjugateAdditions _________________________________________________________62
vii
3.5
ChemistrystartingwithTribromopentaerythritol____________________________ 67
3.6
SelectiveOpeningof2,6dioxaspiro[3.3]heptane____________________________ 71
3.7
FollowupReactions____________________________________________________ 74
3.7.1
CompoundsoftheOpenChainSeries ___________________________________________74
3.7.2
OxetaneAnaloguesofSibutramine _____________________________________________77
3.7.3
SpirocyclicOxetanes_________________________________________________________79
3.7.4
ReactionsofSulfone93.______________________________________________________83
3.8
ReagentCompatibilityofOxetanes _______________________________________ 85
PhysicochemicalandPharmacologicalProfileofOxetanes___________________87
4.1
MeasuredProperties___________________________________________________ 90
4.1.1
StructuralConsiderations_____________________________________________________90
4.1.2
AcidDissociationConstantpKa_________________________________________________95
4.1.3
Lipophilicity________________________________________________________________98
4.1.4
AqueousSolubility__________________________________________________________100
4.1.5
MetabolicStability__________________________________________________________102
4.1.6
ChemicalStability __________________________________________________________105
4.2
OxetanesasgemdimethylAnalogues____________________________________ 105
4.2.1
StructuralConsiderations____________________________________________________106
4.2.2
AqueousSolubilityandLipophilicity____________________________________________107
4.2.3
Metabolicstability__________________________________________________________109
4.2.4
hERGChannel_____________________________________________________________110
4.2.5
AmphiphilicityandPhospholipidosis ___________________________________________112
4.3
OxetanesasCarbonylAnalogues ________________________________________ 114
4.3.1
4.3.2
InfluenceonpKa ___________________________________________________________116
4.3.3
LipophilicityandAqueousSolubility____________________________________________117
4.3.4
MetabolicandChemicalStability______________________________________________119
4.4
SpirocyclicOxetanesasMorpholineAnalogues_____________________________ 120
4.4.1
4.4.2
InfluenceonpKa ___________________________________________________________122
4.4.3
SolubilityandLipophilicity____________________________________________________122
4.4.4
Metabolicstability__________________________________________________________124
4.5
Applications_________________________________________________________ 125
viii
ConclusionandOutlook______________________________________________129
ExperimentalSection ________________________________________________131
6.1
GeneralMethods_____________________________________________________ 131
6.2
PreparationofOxetan3one ___________________________________________ 140
6.2.1
PreparationofOxetan3onevia3,3Dimethoxyoxetane ___________________________140
6.2.2
PreparationofOxetan3onebyOxidationofOxetan3ol __________________________147
6.3
PreparationofMichaelAcceptors _______________________________________ 148
6.4
PreparationofOxetanesoftheOpenChainScaffold________________________ 154
6.5
PreparationofOxetanesoftheCyclicScaffolds ____________________________ 167
6.6
PreparationofNonpublishedOxetanes___________________________________ 181
6.6.1
3Aryloxetan3ols__________________________________________________________181
6.6.2
3Aryl3fluorooxetanes _____________________________________________________187
6.6.3
3Aryloxetanes____________________________________________________________189
6.6.4
3Phenyl3aminooxetanes___________________________________________________190
6.6.5
ConjugateAdditionProducts _________________________________________________192
6.6.5.1
AdditionstoAcrylate89 ________________________________________________192
6.6.5.2
AdditionstoNitroolefin96 ______________________________________________195
6.6.5.3
AdditionstoAldehyde90 _______________________________________________198
6.6.5.4
AdditionstoPhenylsulfone93____________________________________________198
6.6.6
2Oxa6azaspiro[3.3]heptanes________________________________________________201
6.6.7
SibutramineAnalogues______________________________________________________207
6.7
PreparationofAnalogues ______________________________________________ 216
6.7.1
MethyleneAnalogues_______________________________________________________216
6.7.2
GemdimethylAnalogues ____________________________________________________219
6.7.2.1
OpenChainScaffold ___________________________________________________219
6.7.2.2
CyclicScaffolds________________________________________________________224
6.7.3
CarbonylAnalogues_________________________________________________________232
CurriculumVitae _______________________________________________________239
ix
Abstract
Manydrugcandidatesthatdisplayinvitroactivityalsoshareundesiredfeaturessuchas
high lipophilicity or metabolic liabilities that rule out their further development. In many
cases,theseproblemscanbetracedbacktothepresenceofcertainfunctionalgroupsthat
areknowntohaveadetrimentalinfluenceonthesolubility,chemicalormetabolicstability
ofagivenscaffold.Wereasonedthatoxetanesmightbeabletosubstitutesomeofthese.
Fromastructuralpointofview,3,3disubstitutedoxetanescanbedescribedasacombi
nation of steric bulk exhibited by its methylene groups and the polarity introduced by the
etherealoxygen.Therefore,anoxetaneposesamorehydrophilicalternativetobulkyfunc
tionalitiessuchasgemdimethylgroups.Moleculescontainingcarbonylgroupsinturnoften
displayundesirablechemicalreactivityatorinproximitytothecarbonylfunction.Anoxe
tane,beinglesselectrophilicandlackingtheabilitytostabilizeadjacentnegativechargescan
beanalternative.Furthermore,aclassofspirocyclicoxetanesmightbeabletoreplacemor
pholine,anoftencounteredheterocycleinmedicinalchemistrybyvirtueoftheirstructural
andphysicochemicalsimilarity.Interestingly,neitherofthesepotentialapplicationsofoxe
taneshadbeeninvestigatedbefore,noristheremuchprecedencefortheiruseinmedicinal
chemistry.
Wereasonedthatinordertobepracticallyrelevant,theoxetanemotifhadtobeeasily
accessible in various structural contexts. A building block strategy was pursued to achieve
thisgoal.Startingfromoxetan3one,awiderangeofoxetanecontainingcompoundscould
be made. This structural diversity is a result of the flexibility, inherent to the chemistry of
oxetan3oneandevenmoretotheMichaelacceptorsderivedfromit.
Theseroutesallowedustopreparetwodistinctseriesofmoleculesinwhichtheoxetane
wasembeddedatdifferentpositionsofthescaffold. The compounds shownbelowonthe
leftwerecomparedwiththeirgemdimethylcounterparts.
xi
Themembersofthespirocyclicseriesontherightwereinadditiontothatalsomatched
withtherespectivecarbonylandmorpholineanalogues.Theaqueoussolubility,lipophilicity,
metabolicstabilityandotherparametersweremeasuredthenforallthesecompoundsatF.
HoffmannLaRoche.
Theresultsclearlyshowthattheintegrationofanoxetanecanhaveadramaticinfluence
onthephysicoandbiochemicalpropertiesoftheunderlyingscaffold.Whencomparedwith
theirgemdimethylcounterparts,oxetanesarelesslipophilic,moresolubleandinmostcas
esalsometabolicallymorestable.Thereplacementofacarbonylgroupwithanoxetanecan
leadtosignificantchangesintheconformationalpreference,basicity,lipophilicityandme
tabolicstabilityoftheunderlyingscaffold.Thisreplacementseemstobeattractiveinsitua
tions where the carbonyl compound shows chemical or metabolic instability, undesirable
reactivity or when a nonplanar conformation is desired. Some of the spirocyclic oxetanes
seem to even exceed morpholine in their ability to solubilize a given scaffold while at the
sametimebeinglesspronetometabolicdegradation.
TheresultsofthisworkhavenotonlybeensuccessfullyappliedtovariousprojectsofF.
HoffmannLa Roche, but also by several other pharmaceutical companies. Taken together
ourdatamakeacaseforamoregeneraluseofthisunderrepresentedstructuralmotifin
drugdiscoveryandbeyond.
We are deeply indebted to F. HoffmannLa Roche, Basel for its commitment to initiate
andsupportthisproject.
xii
Zusammenfassung
Viele Verbindungen, welche Aktivitt in vitro zeigen, weisen Eigenschaften wie hohe
LipophilieodermetabolischeInstabilittauf,dieeineWeiterentwicklungunmglichmachen.
InvielenFllenlassensichdieseProblemeaufdasVorhandenseinbestimmterfunktioneller
Gruppen zurckfhren, deren abtrglicher Einfluss auf die wssrige Lslichkeit und
metabolischeStabilittbekanntist.OxetaneknnteneinigedieserGruppenersetzen.
AusSichtihrerStruktur,knnen3,3disubstituierteOxetanebeschriebenwerdenalseine
Kombination des sterischen Anspruchs der beiden Methylengruppen und der Hydrophilie
des polaren Ethersauerstoffs. Daher stellen Oxetane eine polare Alternative zu sterisch
anspruchsvollen Funktionalitten wie geminalen Dimethylgruppen dar. Im Gegensatz dazu
besitzen Molekle, die Carbonylgruppen enthalten oft eine unerwnschte chemische
Reaktivitt an oder um die Carbonylgruppe herum. Ein Oxetan vermeidet dies durch seine
reduzierte Elektrophilie und durch das Fehlen jenes elektronenarmen Systems, durch
welches benachbarte negative Ladungen stabilisiert wrden. Darberhinaus ist eine
bestimmteKlassespirozyklischerOxetaneaufgrundhnlicherStrukturundEigenschaftenin
derLage,deninderMedizinalchemieoftverwendetenBausteinMorpholinzuersetzen.
Um aber praktische Relevanz zu erlangen, mssen verschiedenste Oxetane synthetisch
einfachzugnglichsein.WirentschiedenunsfreineHerangehensweise,inderBausteine,
welchebereitseinOxetanenthaltenmiteinemMoleklgerstverbundenunddanachweiter
funktionalisiert wrden. Ausgehend von Oxetan3on konnte so eine breite Palette von
Oxetanen dargestellt werden. Diese Vielfalt resultiert aus der Flexibilitt der Chemie von
Oxetan3onundmehrnochderderdavonabgeleitetenMichaelakzeptoren.
xiii
Darauf aufbauend konnten wir zwei Klassen von Moleklen herstellen, in welchen der
EinflussvonOxetanenanverschiedenenStellendesMoleklgerstesstudiertwurde.Inder
unten links gezeigten Klasse von Moleklen konnten die Eigenschaften des Oxetans mit
jenendergeminalenDimethylgruppeverglichenwerden.
xiv
Die Spirozyklen rechts wiederum, ermglichten zustzlich noch den Vergleich mit den
entprechenden Carbonylanaloga und Morpholin. Fr all diese Verbindungen wurden dann
bei F. HoffmannLa Roche Schlsselparameter wie zum Beispiel wssrige Lslichkeit,
Lipophilie,metabolischeStabilittbestimmt.
DieErgebnissedieserUntersuchungenzeigendeutlich,dassdieIntegrationeinesOxetans
dramatische Auswirkungen auf die physiko wie auch biochemischen Parameter des
zugrundeliegenden Moleklgersts haben kann. Im Vergleich mit ihren geminalen
Dimethylpendants sind Oxetane weniger lipophil, besser wasserlslich und in den meisten
Fllen auch metabolisch stabiler. Der Austausch einer Carbonylgruppe gegen ein Oxetan
fhrt in der Regel zu signifikanten nderungen der Konformation, der Basizitt, der
Lipophilie und der metabolischen Stabilitt. Diese Substitution kommt infrage fr Flle, in
denen die Carbonylverbindung instabil, oder wenn eine nderung der Konformation
erwnschtist.EinigespirozyklischeOxetaneandererseits,scheinenmehrnochalsMorpholin
in der Lage zu sein, die Wasserlslichkeit einer Verbindung zu erhhen bei gleichzeitig
verringerterAnflligkeitzumetabolischemAbbau.
DieResultatedieserArbeitwurdennichtnurinverschiedenenProjektenbeiF.Hoffmann
LaRoche, sondern auch von mehreren anderen Firmen erfolgreich angewandt. Unsere
ErgebnisselegendenGrundsteinfreinebreitereAnwendungdieserunterreprsentierten
SubstanzklasseinderMedizinalchemieunddarberhinaus.
WirsindF.HoffmannLaRoche,BaselfrdasgrosseEngagement,dasfrInitiierungund
vorallemdieDurchfhrungdiesesProjektesunerlsslichwarzugrossemDankverpflichtet.
ListofAbbreviationsandAcronyms
xv
degree
ngstrom
Ac
acetyl
AIBN
2,2azobisisobutyronitrile
aq.
aqueous
atm
atmosphere
Bn
benzyl
bp
boilingpoint
br
broad
Bu
butyl
Bz
benzoyl
degreecentigrade
calcd
calculated
CAM
cericammoniummolybdate
cat.
catalytic
Clint
internalmetabolicclearance
cm1
reciprocalcentimeters
cod
cyclooctadiene
Cy
cyclohexyl
NMRchemicalshiftinppmdownfieldfromastandard
xvi
day,doublet
DAST
diethylaminosulfurtrifluoride
DIBALH
diisobutylaluminumhydride
DMAP
4N,Ndimethylaminopyridine
DMF
N,Ndimethylformamide
DMSO
dimethylsulfoxide
dppa
diphenylphosphorylazide
ECG
electrocardiogram
EI
electronimpactionization
ent
reversalofstereocenters
equiv.
equivalent
ESI
electronsprayionization
Et
ethyl
etal.
andothers
FT
Fouriertransformation
gram
gem
geminal
hour,human
hERG
humanEtheragogoRelatedGene
HPLC
highperformanceliquidchromatography
HR
highresolution
xvii
Hz
Hertz
iso
IBX
2iodoxybenzoicacid
IR
infrared
couplingconstant,Joule
kcal
kilocalorie
KHMDS
potassium1,1,1,3,3,3hexamethyldisilazide
LDA
lithiumdiisopropylamide
LiDBB
lithiumDitertbutylbiphenyl
logD
intrinsiclipophilicity
logP
lipophilicity
multiplet,mouse
meta
moleculeion
molar
mbar
millibar
Me
methyl
mg
milligram
MHz
megahertz
min
minute
ml
milliliter
xviii
mp
meltingpoint
microliter
mmol
millimole
micromole
mol%
molepercent
Ms
methylsulfonyl
MS
molecularsieves,massspectrometry
nAl2O3
neutralaluminumoxide
NMO
NmethylmorpholineNoxide
NMR
nuclearmagneticresonance
vibrationfrequencyincm1
ortho
para
PCC
pyridiniumchlorochromate
pH
negativedecadiclogarithmofhydrogenionconcentration
Ph
phenyl
pKa
negativedecadiclogarithmoftheaciddissociationconstant
ppm
partspermillion
Pr
propyl
pyr
pyridine
quartet
quant.
quantitative
Rf
retentionfactor
rt
roomtemperature
singlet,second
triplet
tert
temperature,tesla
TBAB
tetranbutylammoniumbromide
TBAF
tetranbutylammoniumfluoride
TEMPO
2,2,6,6tetramethylpiperidine1oxylradical
TES
triethylsilyl
TFA
trifluoroaceticacid
THF
tetrahydrofuran
TLC
thinlayerchromatography
TMS
trimethylsilyl
Ts
4methylphenylsulfonyl
TPAP
tetranpropylammoniumperruthenate
UV
ultraviolet
w%
weightpercent
benzyloxycarbonyl
xix
OXETANESINDRUGDISCOVERY
Introduction
Foranactivecompoundtobecomeadrug,affinitytoitstargetisaprerequisite,but
notbyitselfsufficient.Factorslikeaqueoussolubility,lipophilicity,membranepermeabili
ty,metabolicstability,toxicityandsideeffectsdeterminethefateofacompoundmuch
morethanmerebindingconstants.
Picture 1: Drug candidate facing resistance on the way to the market.1

The acceptable ranges for these properties are tight, because of the attrition risk a
deviationposesfortheclinicaldevelopmentofadrugcandidate.Asclinicalstudiesand
registrationabsorbthemajorityofcostsinthedrugdiscoveryanddevelopmentprocessit
iscriticaltoanticipatewhichcompoundsareworththeeffortofclinicalstudiesandreject
othersbeforehand.2
Thus,physicochemicalandpharmacokineticpropertiesareprofiledonaroutinebasis
earlyinthediscoveryprocess,andareoptimizedtogetherwithtargetaffinity.Asaresult,
1
DrawingbyDr.SimonaCeccarelli,F.HoffmannLaRocheBasel.
2
K.H.Bleicher,H.J.Bhm,K.Mller,A.I.Alanine,Nat.Rev.DrugDiscov.2003,2,369.Severalempirical
setsofruleshavebeenproposedinordertopredictthedruglikenessofagivencompound,Lipinskis
RuleofFivebeingthemostwellknown(C.A.Lipinski,F.Lombardo,B.W.Dominy,P.J.Feeney,Adv.Drug
Del.Rev.2001,46,3.).
Introduction
thepercentagetowhichpharmacokineticsandbioavailabilityareresponsibleforattrition
ofacompoundinclinicaldevelopmenthasdeclinedfrom39%in1991to10%in2000.3In
agivenstructuralcontext,problemslikelowsolubility,chemicalormetabolicinstability,
orsideeffectscanoftenbetracedbacktothepresenceofcertainfunctionalgroups.
Picture 2: Selection of functional groups that can have detrimental effects on properties
relevant to medicinal chemistry.4
Forsuchfunctionalitiesitwouldbedesirabletohavealternativesatonesdisposalthat
relievetheindividualproblemwhilstretainingtheessentialstructuralfeaturesofthere
I.Kola,J.Landis,Nat.Rev.DrugDiscov.2004,3,711.
4
Intermsofchemicalstability,Picture2listsfunctionalitiesthatbecauseoftheirinherentreactivityareto
beavoided.Esterscanbesaponifiedandsulfurcontainingfunctionalitiesoxidized.Inmanycasesthepres
enceofepoxides,acylating/alkylatingagents,Michaelacceptors,aldehydesmakesamoleculesusceptible
towards nucleophilic attack. Stereocenters next to a carbonyl function can undergo epimerization, inter
convertingforexampleinthecaseofthalidomideitstwoenantiomersoneofwhichisextremelyteratogen
ic.Linkedtochemicalstabilityisthesusceptibilityofsomefunctionalgroupstoundergooxidativemetabolic
degradation, noteworthy in this respect being electronrich aromatic rings, aliphatic groups and amines.
Othermembersofthisgroupcanbeenzymaticallyhydrolyzed.Nonpolarfunctionalitiessummarizedinthe
bottomrightnotonlydecreaseaqueoussolubility,morelipophilicmoleculeswerealsoshowntobemore
pronetometabolicdegradation(K.A.S.Algailany,J.B.Houston,J.W.Bridges,Biochem.Pharmacol.1978,
27,783.).Sideeffectsoftenresultfrominherentchemicalreactivity,theformationofreactivemetabolites
(electronricharomatics),amphiphilicityorthepresenceofphotochemicallysensitivegroups.
Introduction
spectivemolecularentity.Thiswouldmakeiteasiertooptimizeactivityandpharmacoki
neticpropertiesconcurrently.
Despitetheneedforareservoiroffunctionalgroupstoavoidtheproblemsshownin
Picture 2, the number of commonly used structural moieties is small. A recent study
foundthatamongthe800,000differentframeworksfoundforthecompoundsrecorded
intheCASregistry,halfofthemcanbeassignedto143differentframeworks.5Thisshows
hownarrowlyfocusedscientificinterestistoasmallnumberofscaffolds.Ananalysisofa
commercialdrugdatabasepointsinthesamedirection;here,halfofthe5120drugscould
bedescribedbythe32mostfrequentlyoccurringframeworks.6Thislackofstructuraldi
versity among test compounds has already been identified earlier as a potential bottle
neckinthedrugdiscoveryprocess.7
Oxetanes are clearly one of the neglected frameworks of organic, but also medicinal
chemistry.8 Although earlier lack of interest itself was not the justification for our re
search, the previously reported physical and structural properties of oxetanes made us
believethat3,3disubstitutedoxetanescouldhelpaddressspecificrecurringproblemsin
drugdiscovery,pertinenttosomeofthefunctionalgroupsshowninPicture2.Itwasfar
fromclear,howeverwhetherthephysicochemicalproperties,thechemicalreactivityand
syntheticaccessibilityofoxetaneswouldwarranttheirextensiveuseindrugdiscovery.
1.1 StucturalPropertiesofOxetanes
Foroxetanestobeusefulformedicinalchemistry,theirstructuralimpactandproperty
modulationeffectsneedtobewelldefinedandpredictable.Furthermore,itisimportant
toknowhowpolarthisstructuralmotifisandwhatconsequencesthesmallringsizehas
onthepolarityoftheetherealoxygenanditsabilitytoformhydrogenbonds.
Analysisofthestructureofoxetanesrevealssomeinterestingfeatures.Incontrastto
whatisobservedwithcyclobutane,theringisessentiallyplanarasdeterminedbymicro
5
A.H.Lipkus,Q.Yuan,K.A.Lucas,S.A.Funk,W.F.Bartelt,R.J.Schenck,A.J.Trippe,J.Org.Chem.2008,
73,4443.
6
G.W.Bemis,M.A.Murcko,J.Med.Chem.1996,39,2887.
7
M.D.Burke,E.M.Berger,S.L.Schreiber,Science2003,302,613.
8
7,727 articles found in Scifinder Scholar contain the concept oxetanes, 377,866 epoxides and 65,197
(SearchdonewithScifinderScholar,May2,2008).
Introduction
wavespectroscopy.9 The replacement of a methylene unit by an oxygen atom reduces

the otherwise unfavorable eclipsing interactions which are minimized by outofplane
distortion in cyclobutane. More recent crystallographic studies showed that oxetane is
puckeredatlowtemperatures(Figure1)inthecrystallinestate(10.7(90Kdata)and8.7
(140 K data) respectively).10 Introduction of substituents increases eclipsing interactions
and therefore also often leads to puckered structures.11 As the CO bonds (1.45 ) are
shorterthantheCCbonds(1.55),thebondanglesaresmaller(CCC85)andbigger
(OCC92,COC92)than90inoxetane.12
Figure 1: Comparison of the puckering angles between cyclobutane13 and oxetane.

Severalobservationsindicatethatamongcyclicethers,oxetanesdisplaythemostLew
isbasic oxygen. The equilibrium constant of hydrogenbond formation was determined
bymeasuringIRspectraofmixturesoftherespectiveetherand4fluorophenol.14
W.D.Gwinn,Discuss.Faraday.Soc.1955,43.;J.Fernandez,R.J.Myers,W.D.Gwinn,J.Chem.Phys.1955,
23,758.Theupperboundaryforpuckeringoftheoxetaneringatambienttemperaturewasdeterminedto
be020.
10
P.Luger,J.Buschmann,J.Am.Chem.Soc.1984,106,7118.
11
Forexamplesofpuckeredoxetanes,see:a)J.H.Noordik,J.M.Cillissen,ActaCrystallogr.,Sect.C:Cryst.
Struct.Commun.1981,10,345.b)G.Holan,C.Kowala,J.Wunderli,J.Chem.Soc.,Chem.Commun.1973,34.
12
S.I.Chan,W.D.Gwinn,J.Zinn,J.Chem.Phys.1961,34,1319.Thestructuraldatainthispublicationwas
obtained by microwave spectroscopy, differences from Xray data (puckered oxetane, see Ref. 10) are
small.
13
T.Ueda,T.Shimanou,J.Chem.Phys.1968,49,470.
14
M.Berthelot,F.Besseau,C.Laurence,Eur.J.Org.Chem.1998,925.Theequilibriumconcentrationswere
determinedbymeasuringtheabsorbancesoftheOHstretchingof4fluorophenolfordifferentinitialbase
concentrations.
Introduction
4Fphenol
1.5
Iodine
logK
1.3
1.1
0.9
log
0.7
0
Diagram 1: Strength of association with 4-fluorophenol and iodine in cyclic ethers against
ring-size.14,17
The maximum of hydrogenbonding strength among cyclic ethers results from two
competingeffects.Withsmallerringsize,theCOCanglediminishes,exposingtheoxy
genlonepairsmoretopotentialacceptors;consequentlytheabilityforhydrogenbonding
increases.15Forsmallrings,thescharacterinthehybridizationoftheoxygenlonepairs
increases, making them less available for hydrogen bonding. Several studies suggest,
howeverthatonlyforthreememberedringsasignificantchangeinhybridizationofthe
oxygenlonepairsoccurs,thusmakingoxetanesthebestacceptorsforhydrogenbondsin
theseries.16
Oxetanealsoformscomplexeswithiodine17andwithdinitrogenpentoxide18.Incase
ofiodine,acomparisonofthebindingconstants(Diagram1)ofoxetanewithpropylene
oxide and tetrahydrofuran reveals that the difference in binding strength is more pro
nouncedthanincaseofhydrogenbonds.Thismightbearesultofthehigherstericde
mandofiodinecomparedtoaproton,highlightingtheaccessibilityoftheelectronpairs
inoxetane.Astudyconductedontheaqueoussolubilityofisomericcyclicethersshowed
that among tetrahydropyran and 1, or 2methyltetrahydrofuran, 3,3dimethyloxetane
wasthemostsolublecompound.19Theoutstandingabilityofoxetanestoformhydrogen
bondsand donateelectrondensityisofinterestforpharmaceuticalapplications,asthe
incorporationofanoxetanemightmaketheunderlyingscaffoldmorewatersoluble.
15
L.Bellon,R.W.Taft,J.L.M.Abboud,J.Org.Chem.1980,45,1166.
16
a)R.West,L.S.Whatley,M.K.T.Lee,D.L.Powell,J.Am.Chem.Soc.1964,86,3227.b)E.Lippert,H.
Prigge,JustusLiebigsAnn.Chem.1962,659,81.
17
M.Brandon,M.Tamres,S.Searles,J.Am.Chem.Soc.1960,82,2129.InDiagram1thepointforiodine
withn=0referstopropyleneoxide.
18
H.H.Sisler,P.E.Perkins,J.Am.Chem.Soc.1956,78,1135.
19
G.M.Bennett,W.G.Philip,J.Chem.Soc.1928,1937.
Introduction
1.2 RingOpeningReactionsofOxetanes
It is far from clear whether oxetanes are chemically stable enough to be practically
usefulinmedicinalchemistry.Assmallsaturatedheterocycles,oxetanesdisplaychemical
aswellasphysicalcharacteristicswhoseoriginscanbetracedbacktotheirinherentring
strain.Inoxetaneitself,thestrainenergyhasbeendeterminedtobe106kJ/mol,only1
kJ/mollessthanforoxiraneand20kJ/molmorethantetrahydrofuran.
Oxetanes undergo polymerization in solvents such as chloromethane catalyzed by a
varietyofLewisacids,formingpolyethersofhighmolecularweight.Thepolymerof3,3
bis(chloromethyl)oxetane has found wide application under the brand names Penta
plastorPenton.20
Oxetaneundergoeshydrolysiscatalyzedbysulphuricorperchloricacidinaqueousdio
xanealmostasrapidlyasethyleneoxide.Inthepresenceofbase,however,ringopening
oftrimethyleneoxideisveryslow:Oxiranehydrolysesthreeordersofmagnitudefaster
thanoxetaneunderalkalineconditions.21Theoreticalstudiescarriedoutontheoriginof
thisreactivitydifferenceputforwarddifferentpossibleexplanations.Hozetal.conclude
that in case of threemembered oxirane more strain is released in the transition state
leading to a lower activation energy than in fourmembered rings.22 For the closely re
lated case of cyclopropane vs. cyclobutane, Houk et al. point out that for three
membered rings the transition state has aromatic character stabilizing it compared to
fourmemberedringsdisplayingatransitionstatewithantiaromaticcharacter.23
20
A.C.Farthing,R.J.W.Reynolds,J.Polym.Sci.1954,12,503.
21
J.G.Pritchard,F.A.Long,J.Am.Chem.Soc.1958,80,4162.Forkineticstudiesonthemechanismofacid
catalyzedringopeningofoxetane,see:M.Lajunen,J.M.Koskinen,ActaChem.Scand.1994,48,788.
22
a)J.L.Wolk,M.Sprecher,H.Basch,S.Hoz,Org.Biomol.Chem.2004,2,1065.b)J.L.Wolk,T.Hoz,H.
Basch,S.Hoz,J.Org.Chem.2001,66,915.c)A.Sella,H.Basch,S.Hoz,J.Am.Chem.Soc.1996,118,416.
Hozrejectspreviouslymadeclaims(H.D.Banks,J.Org.Chem.2003,68,2639.)thatthereactivitydifference
canbetracedbacktodifferentdegreesofstabilizationofthereactingcenterspartialpositivechargebythe
leavingalkoxide.
23
D.Sawicka,K.N.Houk,J.Mol.Model.2000,6,158.
Introduction
Scheme 1: Ring-opening reaction of oxetanes:24 a) LiO(tBuO)C=CH2, BF3OEt2; b)

RCCLi, BF3OEt2; c) ArH, AlCl3; d) RLi or RMgX; e) TMSCN, ZnI2; f)
RHC=CHAlR3Li, BF3OEt2 or H2C=CHMgX; g) allylTMS, TiCl4; h) 1. Li, cat
DBB, 2. RCHO; i) LiAlH4; j) R2NH or R2NMgX; k) HX; l) ROH, cat. H2SO4; m)
BF3OEt2, BF3, AlCl3 or PCl5; n) RCOCl
Duetothis reactivitydifferencetowardsnucleophiles,ringopeningreactionsofoxe
tanesoftenrequiretheuseofstrongLewisacids(seeScheme1)orhightemperaturesto
occur.Additionally,oxetaneswithsubstitutionatthe3positiondisplayreducedsuscepti
bility to ring opening, because any ring cleavage via nucleophilic displacement reaction
wouldsufferfromunfavorablenonbondedinteractionsthatareanalogoustothoseob
servedatneopentyliccenters.
24
a)M.Yamaguchi,K.Shibato,I.Hirao,TetrahedronLett.1984,25,1159.b)M.Yamaguchi,Y.Nobayashi,I.
Hirao,TetrahedronLett.1983,24,5121.c)S.Searles,J.Am.Chem.Soc.1954,76,2313.d)S.Searles,J.Am.
Chem.Soc.1951,73,124.e)S.A.Carr,W.P.Weber,Synth.Commun.1985,15,775.f)A.Alexakis,D.Ja
chiet,Tetrahedron1989,45,6197.orS.Julia,C.Gueremy,Bull.Soc.Chim.Fr.1965,2994.g)S.A.Carr,W.P.
Weber,J.Org.Chem.1985,50,2782.h)B.Mudryk,T.Cohen,J.Org.Chem.1989,54,5657.i)S.Searles,K.
A.Pollart,E.F.Lutz,J.Am.Chem.Soc.1957,79,948.Openingof3,3disubstitutedoxetanesismuchslower
thaninlesssubstitutedoxetanes(S.Searles,E.F.Lutz,J.Am.Chem.Soc.1959,81,3674.)j)S.Searles,V.P.
Gregory,J.Am.Chem.Soc.1954,76,2789.k)S.Searles,Jr.,Chem.HeterocyclicCompds.(ArnoldWeissberg
er,editor.Interscience)1964,19,983.l)S.Searles,C.F.Butler,J.Am.Chem.Soc.1954,76,56.m)A.R.Ka
tritzky,C.W.Rees,inComprehensiveHeterocyclicChemistry,PergamonPressplc,Oxford(UK),1984,p.382.
n)C.G.Derick,D.W.Bissell,J.Am.Chem.Soc.1916,38,2478.
Introduction
Beingkineticallymorestablethanepoxidestowardnucleophilicringopening,oxetanes
shouldalsobelesspronetoreactwithendogenousnucleophileslikeglutathione(GSH)25
oramines.Oxetanesshouldalsobemorecompatiblewithchemicalreagentsandsynthet
icproceduresthanepoxides.Althoughnotmuchisknownabouttheproclivityofsubsti
tutedoxetanestoundergoacidinducedringopening,stronglyacidicconditionsmightbe
problematicdespitethefactthatsubstitutionlowersringstrain26andshieldstheoxetane
sterically24ifromattack.
1.3 TendencyofOxetanetoFormRadicals
Oxidative primary metabolism relies mainly on the cytochrome P450 (CYP) enzyme
family.27Membersofthisfamilysharehemeboundironoxocomplexesascommonoxi
dantintheiractivesites.Ithasbeensuggestedthatinmanycasestheinitialandoften
ratelimiting step of metabolism is the abstraction of H to form a radical, making posi
tionsinmoleculesthatgiverisetomorestableradicalsmoresusceptibletowardsmeta
bolism.28 By virtue of thestabilizing interaction of an electron pair on the ether oxygen
with an unpaired electron in alphaposition, the homolytic bond dissociation energy is
reduced and radicals are formed more easily.29 Therefore cyclic ethers should be good
substratesforCYPs.30Amongthefewexampleshowever,wheremetabolicdataonoxe
tanecontainingcompoundshasbeenpublished,nonedocumentsoxidativeattackonthe
2position of the oxetane ring.31 Oxetane was found to react under thermal conditions
withdimethylazodicarboxylateviaaproposedradicalintermediate:32
25
ForareviewonGSHadducts,see:I.A.Blair,CurrentDrugMetabolism2006,7,853.
26
B.Ringner,S.Sunner,H.Watanabe,ActaChem.Scand.1971,25,141.Thisisprobablyaresultofreduced
stericrepulsionbetweensubstituentsatthe3positionthemselves,andbetweenthemandthemethylene
groupsinthering.
27
For a review about the P450 gene superfamily and their evolution, see: F. J. Gonzalez, D. W. Nebert,
TrendsGenet.1990,6,182.
28
F.P.Guengerich,G.P.Miller,I.H.Hanna,H.Sato,M.V.Martin,J.Biol.Chem.2002,277,33711.
29
Oneprominentconsequenceistheformationofperoxidesinmanycyclicaswellasacyclicethersunder
theinfluenceofoxygenandlight.
30
THFismetabolizedinthebodytohydroxybutyricacidviatheintermediary2hydroxytetrahydrofuran.
B.Cartigny,N.Azaroual,M.Imbenotte,N.Sadeg,F.Testart,J.Richecoeur,G.Vermeersch,M.Lhermitte,J.
Anal.Toxicol.2001,25,270.
31
Search done in MDL Drug Metabolite Database on May 12 2008. Hits where the oxetane ring was
cleaved,canmainlybeattributedtohydrolysis.
32
G.Ahlgren,TetrahedronLett.1974,2779.Noyieldgiven.Therelatedreactionofoxetanewithdimethyl
acetylenedicarboxylatewasreportedbythesameauthor:G.Ahlgren,J.Org.Chem.1973,38,1369.
Introduction
MeO2 C
MeO2 C
H
N
N
MeO2C
MeO2C
NH
N
HN CO2Me
MeO2 C N
Scheme 2: Hydrazination of oxetane under thermal conditions.32

Studies comparing the relative rates with which different cyclic ethers participate in
radicalreactionsyielddifferentresultsdependingonthetypeofreactionandanalytical
techniqueemployed.
100
Oxygenuptake
relativeRate
80
Chlorination
60
Reactionwith
40
20
0
Oxirane
Oxetane
THF
THP
Dioxane
Diagram 2: Relative reaction rates of a variety of substrates standardized for oxetane.33

Forthereactionwithoxygentherateofoxygenconsumptionwasmeasuredirrespec
tiveofthedifferentreactionpathways.34Ithasfurthermorebeensuggestedthattheini
tial step in the photooxidation of ethers is the absorption of light by a chargetransfer
complexofmolecularoxygenwithether.Theformationofthischargetransfercomplex
would then depend on the donor ability of the respective ether.35 Therefore the rate
wouldnotbesolelydeterminedbythestabilityoftheetherradical.
33
Oxygenuptakeincaseofepoxidesreferstopropyleneoxide.
34
N.Kulevsky,C.T.Wang,V.I.Stenberg,J.Org.Chem.1969,34,1345.5mLoftherespectiveetherwere
saturatedwithoxygenandtheamountofoxygenabsorbedcalculatedfromthepressureabovetheether.
Noerrormarginsaregivenandtheauthorsdonotstatewhetherthepressureabovetheliquidreferstothe
partialpressureofoxygenorthetotalpressure(inwhichcasecorrectionswouldhavetobemadeforthe
differentpartialetherpressures).
35
V.I.Stenberg,R.D.Olson,C.T.Wang,N.Kulevsky,J.Org.Chem.1967,32,3227.
10
Introduction
Incaseofthechlorination,theformationoftheparticularchloroetherwasmeas
ured,36whereasforthereactionwithSO4thetimedependentconsumptionoftheradical
was photometricallymonitored.37 Here, the oxetane wasfound to be less reactive than
tetrahydrofuranandtetrahydropyran.38
Theratewithwhichcyclicethersparticipateinaradicalchainreactiondependslargely
onthereactionchosen,andseeminglydoesnotallowforrankingtheirpropensitytoform
radicals.Fromthisdataitisthereforenotclear,howlikelytheoxetaneinagivenmole
culewillbeatargetofmetabolicoxidation,notleastasfactorsotherthanradicalstability
seemtoplayanimportantrole.
1.4 PreparationofOxetanes
Only a small number of oxetanes is commercially available (see Picture 6) which re
flectsthelimitedusethesecompoundshavefoundinthedifferentfieldsofchemistry.8
Lackingcommercialsupplies,resilientsyntheticaccessroutestowardsahostoffunctio
nalizedoxetaneshavetobeprovidedforawidespreaduseindrugdiscovery.
Oxetane,theparentheterocyclehasfirstbeenreportedbyReboulin1878,whopre
pareditbyreactionof3chloropropanolwithaqueousbase.39Thisclassofsaturatedoxy
gen heterocycles has been made in a variety of different ways. Those that have found
repeated use in the literature include intramolecular versions of the Williamson ether
synthesis,theadditionofsulfoniumylidstoaldehydes,andthePaternoBchicycloaddi
tion.
36
C.Walling,M.J.Mintz,J.Am.Chem.Soc.1967,89,1515.
37
R. E. Huie, C. L. Clifton, S. A. Kafafi, J. Phys. Chem. 1991, 95, 9336. The radical was prepared by laser
inducedphotolysisofS2O82.
38
The authors also provide calculated CH bond dissociation energies (oxetane: 387.4 kJ/mol, THF: 388.2
kJ/mol, THP: 390.4 kJ/mol), but cannot explain the discrepancy between the calculation (AM1) and the
experimentalfindings.
39
M.Reboul,Ann.Chim.(Paris)1878,14,496.
Introduction
11
Scheme 3: Common ways to prepare oxetanes.

Amongthese,theWilliamsonethersynthesisisthemostgeneral.40Itisinterestingto
notethattherateofclosureofdifferentandchloroalcoholsinaqueousbasediffers
considerably,withepoxideformationfromchlorohydrinfavoredbytwoordersofmag
nitudeoverthehomolog.41Itisoftenthecasethatformationofbyproductsaswellasa
variety of intermolecular reactions effectively compete with the desired ring formation,
thusloweringtheyield.42OnenotablesidereactionistheGrobfragmentationofthe
haloalcoxideintoanaldehydeandanalkenethatdependingonthesubstratecancom
pletelydisrupttheformationofthecorrespondingoxetane:43
Scheme 4: Grob fragmentation as side reaction competing with ring closure. 44
40
S.Searles,Jr.,Chem.HeterocyclicCompds.(ArnoldWeissberger,editor.Interscience)1964,19,983.
41
G.Forsberg,ActaChem.Scand.1954,8,135.
42
a)G.Forsberg,ActaChem.Scand.1954,8,135.b)L.Ruzicka,Helv.Chim.Acta1926,9,230.
43
W.Fischer,C.A.Grob,Helv.Chim.Acta1978,61,2336.
44
S.Searles,R.G.Nickerson,W.K.Witsiepe,J.Org.Chem.1959,24,1839.S.Searles,M.J.Gortatowski,J.
Am.Chem.Soc.1953,75,3030.Theauthorsclaimthattherateoffragmentationcorrelateswiththether
modynamicstabilityofthealkeneformed,thusk1/k2:R=Ph>Alkyl>H.
12
Introduction
The onepot conversion of aldehydes or ketones with sulfoxonium ylides to give 2

substitutedoxetanesprovidesanalternateroute.45Thisreactionisconsideredtoproceed
via an epoxide intermediate that subsequently undergoes ring opening by a second
equivalent of the ylide. The resulting alkoxy sulfonium ylide then participates in an
intramolecular displacement reaction to furnish a 2substituted oxetane (Scheme 3).46
ThesameclassofsubstitutedoxetanescanbeaccessedviathePaternoBchireaction.47
Thiscycloadditionreactionbetweenanaldehydeoraketoneandanelectronrichalkene
affordsregioselectivelythecorrespondingoxetanesingoodyield.48Animportantdiffer
ence between the various approaches is that in the Williamson ether synthesis stereo
chemicalissuesareaddressedseparatelyfromtheringclosingevent.Bycontrast,inthe
processeswhichcommencewithcarbonylsubstratescontrolmustbeexercisedoverthe
generationofstereocentersduringtheringclosurestep.
The latter two methods necessarily lead to oxetanes thatincorporatesubstitution at
C2 and are therefore not suitable for the preparation of 3,3disubstuted oxetanes, the
focusofthisproject.AlthoughtheremainingapproachinvolvingintramolecularWilliam
son ether synthesis provides access to 3,3disubstitued oxetanes, its efficiency is highly
substratedependant which is problematic for the de novo construction of the oxetane
ringonanexistingscaffold.
1.5 PharmacologicallyRelevantOxetanes
Likeeveryfunctionalgroupnewlyintroducedtodrugdiscovery,oxetanesfacetherisk
of unknown general incompatibilities, for example with respect to metabolism or toxic
effects. Any precedence of oxetanes in pharmacological applications therefore helps to
reduce this risk. Not much is known, however about the pharmacological properties of
oxetanes.
45
S.C.Welch,A.S.C.P.Rao,J.Am.Chem.Soc.1979,101,6135.
46
A.O.Fitton,J.Hill,D.E.Jane,R.Millar,SynthesisStuttgart1987,1140.
47
G.Bchi,C.G.Inman,E.S.Lipinsky,J.Am.Chem.Soc.1954,76,4327.
48
T.Bach,SynthesisStuttgart1998,683.
Introduction
13
Early studies in rats involving 3,3diethyloxetane and other simple oxetanes revealed
their anesthetic, sedative and anticonvulsant properties.49 Conformationally restrained
oxetanederivativesofcytidine1andthymidine2havebeeninvestigatedfortheiruseas
partofantisenseoligonuclotides(AON).
Scheme 5: Oxetane analogues (1,2) of Cytidine and Thymidine used for Antisense oligonuclotides50
The resulting AONRNA heterodimers were only slightly less stable as measured by
their melting temperature (Tm). While the AONRNA heterodimers still were substrates
of RNAase H, they showed increased stability towards degradation by nucleases.50Oxe
tanes also have been used as transitionstate mimics for Renin, an aspartate protease
importantinbloodpressureregulation.51
Scheme 6: Oxetanes as transition-state analogues for Renin, an aspartate protease51
49
H. T. Gier, S. Searles, J. Med. Pharmaceut. Ch. 1959, 1, 355. Zarudii et al. found a variety of 3,3
disubstitutedoxetanestopossessbroncholyticactivityincats(F.S.Zarudii,D.N.Lazareva,E.S.Kurmaeva,
O.B.Chalova,T.K.Kiladze,E.A.Kantor,D.L.Rakhmankulov,Pharm.Chem.J.(Engl.Transl.)1985,19,108.).
Inarecentstudy,theanestheticpropertiesofsomefluorinatedoxetaneswereexaminedandfoundtohave
noadvantagecomparedtocommonlyusedanesthetics(E.I.Eger,II,D.Lemal,M.J.Laster,M.Liao,K.Jan
kowska,A.Raghavanpillai,A.V.Popov,Y.Gan,Y.Lou,Anesth.Analg.2007,104,1090.).
50
a)P.I.Pradeepkumar,J.Chattopadhyaya,J.Chem.Soc.,PerkinTrans.22001,2074.b)P.I.Pradeepku
mar,N.V.Amirkhanov,J.Chattopadhyaya,Org.Biomol.Chem.2003,1,81.
51
S.H.Rosenberg,K.P.Spina,H.Stein,J.Cohen,W.R.Baker,H.D.Kleinert,Bioorg.Med.Chem.1994,2,
927. Despite the high binding affinity the authors state that lack of oral availability and high molecular
weightnecessitatefurtherdevelopment.IncaseofCarbapenemantibiotics,thereplacementofatetrahy
drofuranwithanoxetanebroughtnoimprovementinactivity(S.M.Sakya,T.W.Strohmeyer,P.Bitha,S.A.
Lang,Y.I.Lin,Bioorg.Med.Chem.Lett.1997,7,1805.).
14
Introduction
Incaseofthedihydroxyisoster3itisbelievedthatthediolinteractswithbothaspar
tateresiduesintheactivesite.52Theauthors,howeverdonotprovidearationalforthe
increasedbindingaffinityofoxetane5comparedtotetrahydrofuran4.
Allmarketeddrugscontainingtheoxetaneringarederivedfromonefamilyofnatural
products.53 Taxol (6, first commercially developed by BristolMyersSquibb) was iso
lated54 from the bark of the western yew (Taxus brevifolia) and is, together with the
structurallyrelatedDocetaxel(7,firstmarketedbyChugaiPharmaceuticalsasTaxotere),
presentlyusedincancerchemotherapy.
Scheme 7: Marketed drugs containing oxetanes53

Bothcompoundsactbyinterferingwithnormalmicrotubulebreakdownduringcelldi
vision.55ThestructuralconsequencesoftheoxetaneinTaxolwassubjectofacomputa
tionalstudy,fromwhichitwasconcludedthattheoxetaneleadstotherigidificationof
theoverallstructure56andactsasahydrogenbondacceptorpartnerforathreonineOH
in the putative binding pocket.57 Replacement of the oxetane in taxol with azetidine,
52
S.Thaisrivongs,D.T.Pals,L.T.Kroll,S.R.Turner,F.S.Han,J.Med.Chem.1987,30,976.Forareview
aboutdifferenttransitionstatemimicsofRenin,see:W.J.Greenlee,Med.Res.Rev.1990,10,173.
53
ProusScienceIntegrity,SearchonMay62008
54
M.C.Wani,H.L.Taylor,M.E.Wall,P.Coggon,A.T.Mcphail,J.Am.Chem.Soc.1971,93,2325.
55
V.Farina,Editor,TheChemistryandPharmacologyofTaxolanditsDerivatives.[In:Pharmacochem.Libr.,
1995:22],1995.
56
T.C.Boge,M.Hepperle,D.G.VanderVelde,C.W.Gunn,G.L.Grunewald,G.I.Georg,Bioorg.Med.Chem.
Lett.1999,9,3041.
57
M.Wang,B.Cornett,J.Nettles,D.C.Liotta,J.P.Snyder,J.Org.Chem.2000,65,1059.
Introduction
15
thietane,andselenetaneinvariablyresultedinloweractivity.58However,theroleofthe
oxetanemoietyremainscontroversialregardingthebioactivityofTaxol(6).
Oxetanes are found embedded only in a few natural products, many of them being
terpenoids(Figure2).OxetanocinA(8)wasfirstisolated59fromthesoilbacteriumBacil
lus megaterium NK840218. It inhibits the reverse transcriptase of HIV by mimicking
adenosinewhichtriggeredconsiderablecommercialandsyntheticinterest.60Thrombox
aneA2(9)isacompoundpredominantlysynthesizedbyplateletsandpromotesvasocon
striction,plateletaggregation,andbronchoconstriction.Ithasaplasmahalflifeofonly30
seconds,beforetheoxetaneringhydrolysestogiveinactiveThromboxaneB2.61Merrilac
toneA(10)wasfirstisolatedfromIlliciummerrillianum.62Itstimulatesthegrowthofrat
neuronsandbecauseofthatanditscomplex,condensedpolycyclicstructureseveraltotal
syntheseshavebeenpublishedinrecentyears.63
MitrephoroneA(12)hasbeenisolatedfromMitrephoraglabraandwasfoundtobe
cytotoxic for a variety of cancer cell lines.64 Oxetin (11) has been isolated from the fer
mentationbrothofStreptomycessp.OM2317andwasfoundtohaveherbicidalaswell
asantibacterialeffects;furtherinvestigationofitsbiologicalactivityisongoing.65
58
a)A.A.L.Gunatilaka,F.D.Ramdayal,M.H.Sarragiotto,D.G.I.Kingston,D.L.Sackett,E.Hamel,J.Org.
Chem.1999,64,2694.b)R.MarderKarsenti,J.Dubois,L.Bricard,D.Guenard,F.GueritteVoegelein,J.Org.
Chem.1997,62,6631.
59
N.Shimada,S.Hasegawa,T.Harada,T.Tomisawa,A.Fujii,T.Takita,J.Antibiot.1986,39,1623.
60
Forareviewonitsbiologicalactivity,see:a)H.Hoshino,N.Shimizu,N.Shimada,T.Takita,T.Takeuchi,J.
Antibiot.1987,40,1077.b)J.Seki,N.Shimada,K.Takahashi,T.Takita,T.Takeuchi,H.Hoshino,Antimicrob.
AgentsChemother.1989,33,773.Norbeckpublishedin1988thefirsttotalsynthesisof()OxetanocinA:D.
W.Norbeck,J.B.Kramer,J.Am.Chem.Soc.1988,110,7217.
61
S.M.Roberts,F.Scheinmann,Editors,NewSyntheticRoutestoProstaglandinsandThromboxanes,1982.
62
J.M.Huang,R.Yokoyama,C.S.Yang,Y.Fukuyama,TetrahedronLett.2000,41,6111.
63
a) V.B. Birman, S. J.Danishefsky, J.Am. Chem.Soc. 2002,124,2080.b) G. Mehta, S. R. Singh, Angew.
Chem.,Int.Ed.Engl.2006,45,953.c)S.J.Danishefsky,Asymm.Synth.2007,251.d)M.Inoue,N.Lee,S.
Kasuya,T.Sato,M.Hirama,M.Moriyama,Y.Fukuyama,J.Org.Chem.2007,72,3065.e)W.He,J.Huang,X.
Sun,A.J.Frontier,J.Am.Chem.Soc.2008,130,300.
64
C.Li,D.Lee,T.N.Graf,S.S.Phifer,Y.Nakanishi,J.P.Burgess,S.Riswan,F.M.Setyowati,A.M.Saribi,D.
D.Soejarto,N.R.Farnsworth,J.O.Falkinham,D.J.Kroll,A.D.Kinghorn,M.C.Wani,N.H.Oberlies,Org.
Lett.2005,7,5709.
65
S.Omura,M.Murata,N.Imamura,Y.Iwai,H.Tanaka,A.Furusaki,T.Matsumoto,J.Antibiot.1984,37,
1324.
16
Introduction
Figure 2: Natural products containing oxetanes

Maoyecrystal I (13) was isolated from Isidon japonicus and shows cytotoxic proper
ties.66 Dictyoxetane (14) is a diterpenoid first isolated from the brown algae Dictyoata
dichotoma.67Itspolycyclicethercorehastriggeredconsiderablesyntheticinterest.68Bra
dyoxetin(15)wasfoundtobeanimportantchemicalsignalforBradyrhizobiumjaponicum
involvedinsymbioticgeneregulation.69
Thereareanthropogenicsmallmolecules(Figure3)thatalsoincorporateoxetanerings
both as scaffold (EDO) and sidechain (oxasulfuron). The insecticide EDO (16, 2,2bis(4
ethoxyphenyl)3,3dimethyloxetane) is 25 times more potent than DDT, and also active
against DDTresistant strains of Musca domestica. In contrast to the notorious environ
mentallypersistentDDT,EDO(16)isbiodegradable.70
66
Q.B.Han,J.X.Zhang,Y.Lu,Y.S.Wu,Q.T.Zheng,H.D.Sun,PlantaMed.2004,70,581.Aderivativein
whichtheoxetaneringwascleavedmethanolyticallyshowednocytotoxicity.
67
K.C.Pullaiah,R.K.Surapaneni,C.B.Rao,K.F.Albizati,B.W.Sullivan,D.J.Faulkner,C.H.He,J.Clardy,J.
Org.Chem.1985,50,3665.
68
a)J.Reinecke,H.M.R.Hoffmann,ChemEur.J.1995,1,368.b)K.A.Marshall,A.K.Mapp,C.H.Heath
cock,J.Org.Chem.1996,61,9135.c)J.Wittenberg,W.Beil,H.M.R.Hoffmann,TetrahedronLett.1998,39,
8259.d)S.Proemmel,R.Wartchow,H.M.R.Hoffmann,Tetrahedron2002,58,6199.
69
J.Loh,R.W.Carlson,W.S.York,G.Stacey,Proc.Natl.Acad.Sci.U.S.A.2002,99,14446.
70
G.Holan,Nature(London)1971,232,644.
Introduction
17
Figure 3: Oxetane-containing pesticides

Oxasulfuron(17)71actsbyinhibitingthebiosynthesisofvalineandisoleucineincells.It
is used, for example, in the cultivation of soybeans to keep weeds under control. This
agrochemical is effective because crop rapidly metabolizes.72 At the end of 2007 its
productionwasstoppedduetoresistancedevelopmentinthetargetedweeds.73Norbor
nane18wasfoundtobeapotentherbicideandplantgrowthregulator.74
Apart from using an oxetane, because it accidentally fits the structural binding re
quirements of a given target best, oxetanes might be beneficial in a broader context.
What makes oxetanespotentiallyattractive for drug discovery is their high polarity and
outstandingabilityamongcyclicetherstoactasanacceptorforhydrogenbondsanddo
nate electron density.14, 17 Oxetanes are not as prone toward ring opening as epoxides,
oftenrequiringactivationbyacid.Notmuchcanbepredicted,howeverforthesuscepti
bilityofoxetanestowardoxidativemetabolicdegradationanditisnotclearwhetherthey
are metabolically and chemically stable enough. Furthermore, the current state of syn
theticmethodologyforthepreparationofoxetanesdoesnotallowforawidespreaduse
ofoxetanesindrugdiscovery.
71
W.Meyer,EP92810027,1992.
72
M.K.Koeppe,H.M.Brown,AgroFoodInd.HiTech1995,6,9.
73
personalcommunication,SyngentaAG,2008
74
S.B.Soloway,P.Vogel,C.H.AubinleDrian,J.E.Powell,U.S.Patent86916334,1986.
IdeaandTheoreticalConcept
19
Oxetanesarenotwellprecedentedinmedicinalchemistryandsystematicstudieson
their physicochemical and pharmacological properties have, to the best of our know
ledge,notbeenundertakensofar.Asaconsequence,oxetanederivativesareusuallynot
coveredbypatentclaims.Thisneglectofoxetanechemistrymightbeduetothepaucity
ofsyntheticmethodsfortheirefficientpreparation,butisneverthelesssurprising.Even
moreso,astheirpolarityandoutstandingabilityamongcyclicetherstodonateelectron
densityarewelldocumented.
Equation 1: An oxetane is the sum of its bulky and polar nature.

Oxetanes can be seen as a combination of two characteristics; they unite steric bulk
withpolarity.Therefore,certainstericallydemandingfunctionalitiesmightbereplaceable
byanoxetane.Whileitsmethylenegroupsprovidestericbulk,thepresenceofthepolar
oxygenanditsabilitytoaccepthydrogenbondscouldrendertheoxetaneanalternative
forcommonlyusedmorelipophilicbulkygroups.
Someoftencounteredpolarfunctionalities,ontheotherhanddisplayinherentchemi
calreactivitythatisundesirableinthecontextofdrugdiscovery.Therelativeinertnessof
the oxetane scaffold may help to remedy the shortcomings of these more widely used
functionalgroups.
2.1 OxetanesasLipoNeutralBulkIncrease
In medicinal chemistry,steric bulk fulfills different purposes. It is often utilized to fill
receptor pockets in the form of tbutyl and isopropyl groups. Both can be subsumed
20
under the term gemdimethyl groups. More than 10% of all launched drugs contain at
least one gemdimethyl group, highlighting its relevance for drug discovery.75 By that,
gemdimethylgroupsareslightlymorecommonthancarboxylicesters.76
14
iPr
65
gemdim.
tBu
iPrylidene
96
164
total:339
Diagram 3: Launched drugs containing different forms of gem-dimethyl groups.77

Thepresenceofageminallysubstitutedcenterinachainincreasestherateofcycliza
tioncomparedtowhatisfoundfortheunsubstitutedmolecule.Thisobservationiscom
monly referred to as the ThorpeIngold effect.78 For the formation of three or four79
memberedrings,themaincontributiontothiseffectstemsfromthestericrepulsionbe
tweenthegeminalsubstituents,whichleadstoacompressionofthebondanglebetween
the remaining substituents.80 In larger rings, the contribution of this was found to be
small,81heretheeffectpredominantlystemsfromachangeintheconformationaldistri
butionoftheopenchainform:82
75
Prous Science Integrity, May 16 2008: Search for all compounds having Launched as development
statusassociatedwithit.Totalnumberoflaunchedcompoundsis3094.
76
Prous Science Integrity, May 16 2008: Search for all compounds having Launched as development
statusandcontainingthesubstructureofacarboxylicester.Numberofcompoundsfound:333
77
ProusScienceIntegrity,May162008:Substructuresearchforallcompoundswiththegivenmotifwhich
havelaunchedasdevelopmentstatus.
78
R.M.Beesley,C.K.Ingold,J.F.Thorpe,J.Chem.Soc.1915,107,1080.
79
J.Jager,T.Graafland,H.Schenk,A.J.Kirby,J.B.F.N.Engberts,J.Am.Chem.Soc.1984,106,139.
80
Insmallringsystemsthisaccordinglydecreasestheringstrain.Foratheoreticalstudywithcyclobutanes,
see:A.L.Ringer,D.H.Magers,J.Org.Chem.2007,72,2533.Anexperimentaldeterminationofringstrainin
oxetaneswasreportedbyRingneretal.(B.Ringner,S.Sunner,H.Watanabe,ActaChem.Scand.1971,25,
141.).
81
M.E.Jung,J.Gervay,J.Am.Chem.Soc.1991,113,224.
82
ThisexplanationfortheThorpeIngoldeffectwasfirstsuggestedbyBruiceandPandit,andrecentlyad
vanced by Jung et al. a) T. C. Bruice, U. K. Pandit, J. Am. Chem. Soc. 1960, 82, 5858. b) M. E. Jung, M.
Kiankarimi,J.Org.Chem.1998,63,2968.(alsoseeRef.81)
21
Figure 4: Effect of geminal substitution on the distribution between antiperiplanar ( ap)

and synclinal (+sc, -sc) conformations.83
In case of cyclization reactions this leads to a higher relative population of reactive
conformations, in which R and R reside close to each other. For a drug candidate the
presence of a geminally substituted center within a chain results in equipopulated con
formationswithrespecttorotationaroundthebondsconnectingtothegeminallysubsti
tutedcarbon.
Theintroductionofsterichindranceoftenblockschemical84ormetabolic85liabilitiesof
nearby functional groups. Also in case of metabolically unstable methylene groups it is
commonpracticetoblockthembytheintroductionofagemdimethylunit.86
83
Calculated for 298.15 K, assuming the gaucheinteraction between R and R to be equivalent to 0.9
kcal/mol(R=R=Me).
84
a) Magnin et al. reported the protection of an (acylamino)nitrile from hydrolysis by introduction of
sterick bulk in theaminonitrile part. D. R.Magnin, J. A.Robl, R.B. Sulsky,D. J.Augeri, Y. T. Huang, L.M.
Simpkins,P.C.Taunk,D.A.Betebenner,J.G.Robertson,B.E.AbboaOffei,A.Y.Wang,M.Cap,L.Xin,L.
Tao,D.F.Sitkoff,M.F.Malley,J.Z.Gougoutas,A.Khanna,Q.Huang,S.P.Han,R.A.Parker,L.G.Hamann,J.
Med.Chem.2004,47,2587.b)Foranexample,whereanimidazolineisprotectedfromhydrolyisbybulky
substituents,see:M.vonRauch,M.Schlenk,R.Gust,J.Med.Chem.2004,47,915.
85
a)P.M.Manoury,J.L.Binet,J.Rousseau,F.M.Lefevreborg,I.G.Cavero,J.Med.Chem.1987,30,1003.b)
Foranexample,wherestericbulkreducedsusceptibilitytowardsimidecleavage,see:A.D.Borthwick,D.E.
Davies,P.F.Ertl,A.M.Exall,T.M.Haley,G.J.Hart,D.L.Jackson,N.R.Parry,A.Patikis,N.Trivedi,G.G.
Weingarten, J. M. Woolven, J. Med. Chem. 2003, 46, 4428. c) Addition of steric bulk can help to reduce
glucuronidation(phaseIImetabolism):P.Madsen,A.Ling,M.Plewe,C.K.Sams,L.B.Knudsen,U.G.Sidel
mann,L.Ynddal,C.L.Brand,B.Andersen,D.Murphy,M.Teng,L.Truesdale,D.Kiel,J.May,A.Kuki,S.H.
Shi,M.D.Johnson,K.A.Teston,J.Feng,J.Lakis,K.Anderes,V.Gregor,J.Lau,J.Med.Chem.2002,45,5755.
22
However, for a typical small molecule in medicinal chemistry the replacement of hy

drogensbymethylgroupsleadstoasignificantincreaseofitslipophilicitywhichinturn
may adversely affect its physicochemical and pharmacokinetic properties.87 Moreover,
thegemdimethylgroupcanbecomeatargetofmetabolicdegradationitself.88Asearch
in the MDL Metabolite Database reveals how prevalent oxidative attack on gem
dimethylgroupsis:89
H 3 C CH 3
R
H 3C CH 3
R
H3C
R
H
CH 3
R'
OH
H 3C
R
531 hits
99
H 3 C CH 3
R
OH
298 hits
OH
Me
H 3C
R
x=
OH
105 hits
253
R'
176
Diagram 4: Hydroxylation of gem-dimethyl containing compounds.89

Alltheseapplicationsofstericbulkcurrentlyrelyonapooloffunctionalitiesthatlike
thegemdimethylgrouphavehighlipophilicityasacommoncharacteristic.Itisnotin
escapable,howeverthattheintroductionofstericbulkcomesalongwithincreasedlipo
philicityandthusreducedaqueoussolubility.Quitethecontrary,highlipophilicityisun
desirableinmostcases.87Therefore,astable,small,andlesslipophilicmolecularmodule
withreducedsusceptibilitytometabolicattackwouldbeaveryinterestingalternative.
Theoxetanemightbeabletofillthisrole,replacingagemdimethylgroup.Anoxetane
mightthusintroducestericbulkandatthesametimereducelipophilicity.
86
Forexamples,see:a)J.L.Duffy,T.A.Rano,N.J.Kevin,K.T.Chapman,W.A.Schleif,D.B.Olsen,M.Stahl
hut,C.A.Rutkowski,L.C.Kuo,L.X.Jin,J.H.Lin,E.A.Emini,J.R.Tata,Bioorg.Med.Chem.Lett.2003,13,
2569.b)S.Ahmad,L.M.Doweyko,S.Dugar,N.Grazier,K.Ngu,S.C.Wu,K.J.Yost,B.C.Chen,J.Z.Gougou
tas,J.D.DiMarco,S.J.Lan,B.J.Gavin,A.Y.Chen,C.R.Dorso,R.Serafino,M.Kirby,K.S.Atwal,J.Med.
Chem.2001,44,3302.
87
For the proposed evolutionary origin of the preference of P450class enzymes for lipophilic molecules,
see:F.J.Gonzalez,D.W.Nebert,TrendsGenet.1990,6,182.Forquantitativecorrelationofmetabolicsta
bilitywithlipophilicity,referto:a)B.Testa,P.Crivori,M.Reist,P.A.Carrupt,Perspect.DrugDiscoveryDes.
2000,19,179.b)K.A.S.Algailany,J.B.Houston,J.W.Bridges,Biochem.Pharmacol.1978,27,783.c)A.L.
Upthagrove,W.L.Nelson,DrugMetab.Dispos.2001,29,1377.
88
R.B.Bambal,R.P.Hanzlik,Arch.Biochem.Biophys.1996,334,59.
89
MDLMetaboliteDatabase,July2006:SubstructuresearchformetabolicoxidationasshowninDiagram
4.
23
metabolically at risk
Me
R1
metabolic attack
metabolically robust ?
O
Me
R2
R1
R2
nonpolar
R1
R2
polar
Figure 5: Oxetanes as a replacement for gem-dimethyl groups.

Thinking of the oxetane as an oxygenbridged gemdimethyl group is an apparent
analogy. In addition to that, the vanderWaals calculated volumes of oxetane and pro
panearealmostidentical.Thisisinlinewiththeexperimentalfindingthatthepartialmo
lar volumes of oxetane (61.4 cm3mol1) in water is even smaller than that of propane
(70.7cm3mol1).90
Picture 3: Replacement of a methylene group with an oxetane is expected to lead to a decrease in logP.
90
a)J.C.Moore,R.Battino,T.R.Rettich,Y.P.Handa,E.Wilhelm,J.Chem.Eng.Data1982,27,22.b)J.T.
Edward,P.G.Farrell,F.Shahidi,J.Chem.Soc.Lond.FaradayTrans.11977,73,705.
24
In terms of lipophilicity, substitution of a methylene unitwith a gemdimethyl group

typicallyleadstoanincreaseofabout1logPunit.Onecandissectthereplacementinto
two discrete steps and add the accompanying changes in logP in order to estimate the
influencetheinsertionoftheetherealoxygenwouldhave.
Theintroductionofacyclobutylgroupmaybeexpectedtoleadtoanincreaseoflipo
philicityby1.5units.Ifthereplacementofamethylenegroupincyclobutanebyoxygen
hasthesameimpactasincyclopentane(logP=2.5),thenonthisbasistheeffectofthe
oxygenintroductioncanbeestimated.Indeed,thiswouldpredictthatthereplacementof
amethylenegroupwithanoxetanewouldlowerlipophilicitywhileincreasingstericbulk.
2.2 OxetanesasCarbonylAnalogues
Urea was one of the first organic compounds to be made without the help of vital
forcethatistosaythemetabolicapparatusofalivingorganism.91Carbonylcompounds,
urea being one of the simplest, are indispensable for the existence of the biology we
knowof.Notonlyaretheirelectronicpropertiesresponsibleforthestructureofnucleic
acidsandproteins,buttheirreactivitymakesthemcornerstonesofmetabolicprocesses
in nature. This also turns them into one of the workhorses of organic chemistry. Their
proclivitytowardsnucleophilicattack92aswellastheirabilitytostabilizecarbanions93
triggeredearlymilestonesinorganicsynthesisandtremendousscientificinterestintheir
chemistry thereafter. With ample methods available to make and manipulate carbonyl
compounds,theybecameroutineconstituentsofanthropogenicproductsfrompolymers
to drugs. Some incarnations of carbonyl groups like aldehydes, sterically accessible
Michaelacceptors94 or acyl halides, however are rarely or not found in drug discovery
becauseoftheirinherentreactivity.Butevenwithmorestablefunctionalitieslikeesters,
amidesorketonesthereareliabilitiesassociatedthatarerootedintheirubiquityinna
ture.
91
F.Whler,Ann.Phys.1828,37,330.
92
V.Grignard,C.R.Hebd.SeancesAcad.Sci.1900,130,1322.
93
S.Reformatsky,Ber.1887,20,1210.
94
Vinylsubstitutedcarbonylcompoundslikeacrylamidesarenotpresentinmarketeddrugs(ProusScience
Integrity,May172008).
25
Amides
739
250
Carbox.Acids
403
125
333
Esters
85
Ketones
261
65
Thioesters
Aldehydes
total
chiral
200
400
600
800
95
Diagram 5: Prevalence of carbonyl groups in marketed drugs.
Because of their widespread presence, organisms have developed enzymes that can
hydrolyzeestersandamidesorreduceketoneswhicharepartofdrugmolecules.While
sometimesdesired,forexampleforthereleaseoftheactivecompoundfromaprodrug
thesetransformationsoftenleadtofasterdegradationinthebodyandthustolowerex
positionofthetargettothedrug.Moreover,therelativeeaseofdeprotonationincar
bonylcompoundsrendersstereogeniccentersatthispositionsensitivetowardsepimeri
zation(refertoDiagram5forthecommonnessofepimerizablestereogeniccentersalpha
totherespectivecarbonylfunctionality).
VantHoffprovidedaveryinfluentialrationalforthestereochemistryoforganiccom
poundsbypostulatingatetrahedralcoordinationsphereforcarboninallitscompounds,
alsotheonescontainingmultiplebonds.96Theatomwouldberepresentedbyatetrahe
dron with its substituents attached to its vertices. Atoms, connected through a double
bondwouldsharetwoverticesoroneedge,respectively.
95
ProusScienceIntegrity,May172008:Compoundsweresearchedassubstructureswithhighestdevel
opmentstatusbeingLaunched.Chiralcompoundsadditionallyrequiredahydrogenalphatothecarbonyl
functionalityandthecarbonatomtobeastereogeniccenterwithdefinedconfiguration.
96
J.H.vantHoff,Arch.Neerl.Sci.ExactesNat.1874,9,445
26
Picture 4: Vant Hoff representation of a carbonyl group.97

While nowadays multiple bonds are rationalized differently,98 better accounting for
the spectroscopic characteristics of these molecules, vant Hoffs and Paulings bent
bond model99 are revealing in how one can think of carbonyl compounds as related to
oxetanes.IfthetwoverticessharedbythetetrahedraofoxygenandcarboninPicture4
arereplacedbymethylenegroups,thevantHoffrepresentationofthecarbonylbecomes
anoxetane.
Picture 5: Structural comparison of a carbonyl group with an oxetane. 100

AsidebysidecomparisonofthetwofunctionalitiesrevealsthesimilarCCCbondan
glesandtheidenticalrelativespatialorientationoftheoxygenlonepairs.Themaindif
ferencebetweenanoxetaneandacarbonylgroupconsistsinthedistancetheyplacethe
oxygenatomawayfromthechain.Thiswillleadtoincompatibilitywithsometargetsthat
97
Pictureadaptedfromref.99a.
98
E.Hckel,Z.Physik,1930,60,423.
99
a)L.Pauling,J.Am.Chem.Soc.1931,53,1367.b)W.E.Palke,J.Am.Chem.Soc.1986,108,6543.c)K.B.
Wiberg,Acc.Chem.Res.1996,29,229.
100
The bond angles shown may vary with the substitution pattern. Models were generated using Chem
Bio3D11.0UltraandoptimizedusingMM2forcefieldalgorithm.
27
do not tolerate the spatial requirements of an oxetane. In other cases larger volume
occupancyanddeeperoxygenplacementmightbeadvantageousatareceptorpocket.101
3
2.5
logKHB
2
1.5
1
0.5
0
MeCHO HCOOEt MeOAc Acetone Oxetane AcNHMe AcNMe2
Diagram 6: Affinity to act as an acceptor for hydrogen bonds for oxetane and different
carbonyl compounds.102
A comparison of the hydrogen bonding avidity of oxetane with different carbonyl
compounds shows that only electronrich amides are better acceptors for hydrogen
bonds.103 The examples shown in Figure 6 highlight the different benefits an oxetane
might have when replacing a carbonyl group. Acetyl choline (19)104, cocaine (20)105 or
peptidescanundergoenzymaticcleavage;thecorrespondingoxetaneanalogueshowever
wouldbestabletowardshydrolysisandmightofferlongerhalflifetimeswhileretaining
potency.
101
The conformational aspects of a carbonyl with its attendant substituents and an oxetane have to be
cautiouslyexamined.Thisisparticularlyevidentinthecaseofesters,lactones,amides,orlactams,where
thereplacementofthecarbonylgroupbyanoxetaneuniteliminatestheconjugationintheformerand
mayresultinsubstantiallynonplanararrangementsinthelatter.
102
DatatakenfromRef.103.ForadefinitionoflogKHB,seeDiagram1.Foradescriptonofthemethodused
todeterminelogKHB,seeRef.14.
103
For the Hbonding affinitiy of oxetanes, see: M. Berthelot, F. Besseau, C. Laurence, Eur. J. Org. Chem.
1998,925.Forrelatedstudieswithavarietyofcarbonylcompounds,see:a)F.Besseau,M.Lucon,C.Lau
rence,M. Berthelot, J. Chem. Soc., PerkinTrans. 2 1998, 101.b) F.Besseau, C. Laurence,M. Berthelot, J.
Chem.Soc.,PerkinTrans.21994,485.c)J.Y.Lequestel,C.Laurence,A.Lachkar,M.Helbert,M.Berthelot,J.
Chem.Soc.,PerkinTrans.21992,2091.
104
Acetylcholineisanimportantneurotransmitter.Afterreleaseintothesynapticcleftitissaponifiedby
acetylcholinesterase.Theoxetaneversionmightmaintaintheabilitytofunctionasaneurotransmittersta
bletowardsacetylcholinesterase,orcompetewiththenaturalsubstrateforbindingtotheenzymeandthus
prolongthelifetimeofnaturalacetylcholine.
105
Cocaineismainlymetabolizedbyhydrolysisofthemethylesterintobenzoylecgoninewhichisthenex
cretedviatheurine.
28
Figure 6: Possible applications for oxetanes as a carbonyl surrogate.

Pyruvate(22)isacentralintermediateinenergymetabolismandeitherundergoesde
carboxylationorreductionoftheketogroup.Inthecaseofthymine(23),switchingtoan
oxetanemighthaveanimpactforitsrecognitionasasubstratebyDNApolymeraseorits
abilitytosupportproperbasepairingwhenintegratedintoaDNAstrand.Oxetanesmay
thereforenotonlybeconsideredasasurrogateforacarbonylgroupindenovostructural
designofdrugcandidates,butalsoinmarketeddrugsornaturallyoccurringcompounds,
whereattackonoraroundthecarbonylmoietyisimportantfordegradation.
2.3 SpirocyclicOxetanesasaMimicforOxaHeterocycles
Morpholinehasfoundwidespreaduseasabuildingblockinmedicinalchemistry.Itis
often used to raise aqueous solubility of the underlying scaffold. The morpholine ring,
however is regularly target of oxidative metabolism. There are 17 marketed drugs sub
stancesthatcontainthemorpholinesubunit.For4ofthesenometabolicdatahasbeen
published,oftheresidual13compounds8showoxidativedegradationofthemorpholine
ring.106
106
ProusScienceIntegrity,May212008:Substructuresearchforlaunchedcompoundscontainingamor
pholineunit.a)D.McKillop,A.D.McCormick,G.S.Miles,P.J.Phillips,K.J.Pickup,N.Bushby,M.Hutchison,
Xenobiotica2004,34,983b)S.K.Balani,S.M.Pitzenberger,M.S.Schwartz,H.G.Ramjit,W.J.Thompson,
Drug Metab. Dispos. 1995, 23, 185. c) T. Hayashi, M. Aoyama, M. Fukuda, M. Ohki, T. Kishikawa, Chem.
Pharm. Bull. 1979, 27, 317. d) P. N. Giraldi, G. P. Tosolini, E. Dradi, G. Nannini, R. Longo, G. Meinardi, G.
Monti, I. D. Carneri, Biochem. Pharmacol. 1971, 20, 339. e) A. Betts, F. Atkinson, I. Gardner, D. Fox, R.
Webster, K. Beaumont, P. Morgan, Drug Metab. Dispos. 2007, 35, 1435. f) R. Jauch, E. Griesser, G.
Oesterhelt,W.Arnold,W.Meister,W.H.Ziegler,T.W.Guentert,ActaPsychiatr.Scand,Suppl1990,360,87.
g)R.T.Coutts,F.Jamali,F.Malek,A.Peliowski,N.N.Finer,Xenobiotica1991,21,1407.
29
S N
N
N
H
OH
Bu
N
H
HN
N
Cl
O
Moclobemide
Timolol
O 2N
H
N
Moracizine
Me
N
Nimorazole
N
O
H
N
N
Gefitinib
N O
Linezolid
N
N+
Cl
N
MeO
O
O
O
N
N
O
O
= N-Oxide formation
Molsidomine
= Oxidation and/or ring cleavage
Me
N
N
Emorfazone
Scheme 8: Marketed drugs containing a morpholine liable to metabolic oxidation.106

A more detailed analysis shows that in the discovery process morpholinecontaining
compoundsareunderrepresentedinmarketeddrugsandcompoundsintheclinic.Whe
reas 1.8% of all molecules in biological testing contain a morpholine, only 0.6% of all
launcheddrugssharethismoiety.
2.00%
1.60%
1.20%
0.80%
0.40%
0.00%
Biological Preclinical Clinical
Testing
PhaseI
PhaseI/II PhaseII
PhaseIII Launched
Diagram 7: Ratio of drug candidates containing a morpholine in the substructure and all
compounds.107
107
ProusScienceIntegrity,May212008onhighestphasereachedwithmorpholineassubstructureornot.
30
Itcanbeseenthatespeciallybeforeenteringclinicalstudiesadisproportionatenum
berofmorpholinecontainingcompoundsisrejected.Drawingconclusionshoweverfrom
thisdataisnotstraightforward.Althoughmorpholineisliabletowardsmetabolicdegra
dationandthismightbethecauseofrejectioninsomecases,itdoesnotprovethatmor
pholineisariskfactorfordrugcandidates.
Asthepopulationofmoleculesinbiologicaltestingforwhichtheintegrationofamor
pholineisconsidered,isprobablybiasedtowardsmoleculeswithscaffoldsthathavehigh
lipophilicityand/orclearance,thisgroupwould havehadahigherattritionriskanyway.
Butevenwiththiscaveatmorpholinecontainingcompoundsfaceadisproportionallyhigh
riskofattritionbeforeenteringtheclinicandthereforeanalternativestructurallysimi
lar,ifpossiblewouldbedesirable.Awholerangeofspirocyclicoxetanesmightbesuited
forthispurpose.
O
O
O
N
R 25
O
N
24
R
N
R 26
O
N
R 28
N
R 32
O
N
R 31
N
27
R
N
O
R 30
O
N
R 29
Scheme 9: Spirocyclic oxetanes (R = piperonyl) as a substitute for morpholine.108

Thesespirooxetanespositiontheoxygenatominthemolecularsymmetryplaneatan
extendeddistancefromthenitrogenatom(24,25)withsimilar(25)ordecreasedlateral
108
Overlayofsubstituteda2oxa6azaspiro[3.3]heptaneandamorpholineontheleftdonebyProf.Klaus
MllerwithMoloc(P.R.Gerber,K.Mller,J.CompAided.Mol.Design1995,9,251;forfurtherinformation,
seewww.moloc.ch).
31
bulk(24).Others(2630)placetheoxygenatareclinedanglefromthesymmetryplaneof
theparentmorpholine,resultinginareductionofsymmetrywithoutintroducingchirality.
Allspirocyclespitthehydrophilicoxetaneagainstthe6memberedringetherinmor
pholine and the potential advantage of the oxetane might partially compensate for the
lipophilicity introduced by additional methylene groups in compounds (26, 27, 2931)
Additionally,whereasthehydrogenbondingabilityoftheoxygeninmorpholineisdam
penedbythepresenceoftheelectronwithdrawingnitrogenatom,compounds24to27
mightbenefitfromtheadditionalbondseparationofthetwoelectronegativeatoms.All
spirocyclic systems are not reported in the literature except for some 2oxa6
azaspiro[3.3]heptanes109aswellasaderivativeof2oxa7azaspiro[3.5]nonane,110butno
systematicelucidationofthepropertiesofthesecompoundshasemerged.
2.4 SyntheticAccesstoOxetanes
Practicalaccessroutesareimperativeforpossibleapplicationofoxetanes.Evenifoxe
tanesshowedgreatpotentialassurrogatesformorpholine,gemdimethylgroups,orcar
bonylfunctionalities,oxetaneswillnotbeusediftheyarenotsufficientlyconvenientto
prepare.Goodroutesmustallowforoxetanestobeengraftedonavarietyofstructurally
diverse chemical surroundings in short sequences, high yield and with broad functional
grouptolerance.Amongcommonsyntheticmethods,howeveronlytheWilliamsonether
synthesisissuitedtoprovideoxetaneswithoutsubstitutionalphatotheringoxygen.111
Side reactions, highly substratedependant yields make the application of this method
difficultinthesettingofdrugdiscoverywhichischaracterizedbystructurallydiversecon
texts.
Therearetwostrategicallydistinctapproachestomakeoxetanes.Onereliesonapre
cursor that does not contain an oxetane. This could be any cyclic as well as acyclic
109
a)J.Hoste,F.Govaert,Bull.Soc.Chim.Belg.1949,58,157.b)R.K.Khazipov,N.L.Izbitskaya,T.K.Ki
ladze,O.B.Chalova,E.S.Kurmaeva,E.A.Kantor,Izv.Vyssh.Uchebn.Zaved.,NeftGaz1984,27,86.c)F.S.
Zarudii,D.N.Lazareva,E.S.Kurmaeva,O.B.Chalova,T.K.Kiladze,E.A.Kantor,D.L.Rakhmankulov,Pharm.
Chem.J.(Engl.Transl.)1985,19,108.d)C.G.Krespan,J.Org.Chem.1975,40,1205.
110
a)J.L.CastroPineiro,K.Dinnell,J.M.Elliott,G.J.Hollingworth,D.E.Shaw,C.J.Swain,(MerckSharp&
DohmeLimited,UK).WO2001087838,2001,p.199pp;b)N.Watanabe,N.Karibe,K.Miyazaki,F.Ozaki,A.
Kamada,S.Miyazawa,Y.Naoe,T.Kaneko,I.Tsukada,T.Nagakura,H.Ishihara,K.Kodama,H.Adachi,(Eisai
Co.,Ltd.,Japan).WO9942452,1999,p.148pp.
111
Seechapter1.4.
32
intermediate,butforreasonsoutlinedinchapter1.4,itwouldlikelybeasubstrateofthe
Williamsonethersynthesis.Forthisapproachtowork,substantialimprovementsofsyn
theticmethodologyhavetobeaccomplished,increasingitsyieldandbreadth.Thiscan,
butneednothappenwithintheframeoftheWilliamsonethersynthesis.
If the precursor already contains an oxetane, the problem of ring closure might be
solvedfortheparticularcase,ordeferrabletoacommercialsupplier.Asmallsetofoxe
taneswouldthenbeusedasbuildingblocksthat,onceattachedtoascaffold,wouldbe
amenabletosyntheticmodification.
Scheme 10: Building-block approach (top) in comparison with methodology involving latestage cyclization.
Wereasonedthatthedenovodevelopmentofanew,broadlyapplicableringclosing
methodology has low chances of success, moreover as not only the ring closing event
itself has to be controlled, but also as routes to suitable precursors have to be estab
lished.Forthebuildingblockapproach,howeversuitablysubstitutedoxetaneshavetobe
identified,preparedinusefulquantityandefficiency,andmethodologyfortheirfunctio
nalizationdeveloped.Thisapproachhastheimportantadvantagetopotentiallyreduce
the work load for the applying chemist down to the integration and modification of an
offtheshelfreagent.Additionally,asthemodificationoftheoxetanehappensattheend
ofthesyntheticsequence,chemicaldiversityiseasiertogeneratethanintheotherap
proach.
33
Commerciallyavailableoxetanesareonepotentialsourceofbuildingblocks.Thereare
howevernotmanyoxetanescommerciallyavailableandmostwhicharederivedfroma
smallsetofstructurallysimilarcompounds.
Picture 6: Commercially available oxetanes by december 2006.112

Only a few of these compounds, highlighted in Picture 6, might be used as building
blocks.Thesehoweverwillnotprovideaccesstothewidespectrumofoxetanes,neces
saryforthebroadaimofthisstudy.
Amongtheoxetanesknownintheliterature,oxetan3oneseemedtobeagoodcan
didateforabuildingblock.Asaketone,itreactswithavarietyofnucleophiles,andthe
additionproductsareamenabletofurtherfunctionalization.
112
ScifinderScholar.Substructuresearchforoxetanesbearingnosubstituentsin2and4position.
34
ref.113a
ref.113b
ref.113c
ref.113d
Figure 7: Reactions of oxetane-3-one in the literature.113

Literatureprecedent,albeitsparse,indicatesthattheketonefunctionalityisamenable
tofunctionalizationwithoutopeningoftheoxetaneringandthatatleastundercertain
conditions the addition products can be manipulated further. Therefore, oxetan3one
waschosentobeinvestigatedfirstasabuildingblock.
Severalsynthesesofoxetan3one(33)havebeenreportedintheliterature.Oxetan3
one was first isolated by Marshall et al. in 1952 from a complex mixture as its 2,4
dinitrophenylhydrazone.114
O 2N
NO2
O
Cl
CH2N2
Cl
Et 2O
K2CO3
Cl
N2
MeOH/H 2O
O
N2
-N2
NH
N
O
Equation 2: Preparation of oxetan-3-one from chloroacetyl chloride.114
113
a)P.Yates,A.G.Szabo,TetrahedronLett.1965,6,485.b)A.P.Kozikowski,A.H.Fauq,Synlett1991,783.
c)G.H.Berezin,US3449369,1969.d)M.D.T.Moldes,G.Costantino,M.Marinozzi,R.Pellicciari,Farmaco
2001,56,609.Forareviewaboutthepreparationofoxetan3onesandtheirchemistry,see:Y.Dejaegher,
N.M.Kuz'menok,A.M.Zvonok,N.DeKimpe,Chem.Rev.2002,102,29.
114
J.R.Marshall,J.Walker,J.Chem.Soc.1952,467.
35
The first synthesis of oxetan3one in pure form and significant quantities was re
ported in a patent from DuPont, wherein oxetan3one was investigated as a potential
solventforcyanoethylcellulose.115
Scheme 11: DuPont route to oxetan-3-one.115

This synthesis of oxetan3one commences with the DielsAlder adduct 41 of diethyl
methylenemalonate and anthracene. Diester reduction, generation of the bissulfonate
42,followedbyringclosurefurnishedoxetane43.Inasubsequentstep,oxetane43un
dergoes retroDielsAlder reaction at 340355 C to release 3methylene oxetane (44).
Thislowboilingliquidcanbedistilledfromthereactionmixture.Theauthorshighlighted
thefactthat3methyleneoxetaneneedstobehandledunderinertgasatmosphere,be
causeitveryeasilyundergoesautoxidationtoformaperoxide.116Thesafetyissuesalong
withthenumberandnatureofthestepsrequiredinthissequencerenderinourestima
tiontheapproachunsuitablefortheproductionofpreparativeamountsofoxetan3one.
Adifferentroutetooxetan3onereliesontheoxidationofoxetan3ol:
115
116
G.H.Berezin,US3297719,1967.
D.E.Applequist,J.D.Roberts,J.Am.Chem.Soc.1956,78,4012.
36
ref.117a
ref.117b
Scheme 12: Oxidation of oxetan-3-ol (45).117

Whereastheoxidationofoxetan3ol(45)withCollinsreagent(CrO3py2)wasdoneon
a preparative scale, the formation of oxetan3one (33) was the unexpected product of
the attempted preparation of oxet2ene from the tosylate of oxetan3ol (45). In both
casestheauthorshadtoresorttopreparativeGCtopurifythecompound,asthedistilla
tiveseparationfrompyridinewasfoundtobenotpossibleinthefirstcase.Oppenauer
oxidation failed to give product, as well as dichromate or permanganatebased me
thods.117a Oxidation with pyridinium chlorochromate (PCC) also furnishes oxetan3one
(33).118
Attheoutsetoftheproject,oxetan3olwasnotavailablecommerciallyinsignificant
quantities.119Therefore,whenponderingdifferentroutestooxetan3one,theprepara
tionofoxetan3olhastobetakenintoaccount.AprocedurepublishedbyBaumetal.120
laidthefoundationfortheoptimizedrouteusedbySyngenta121toprepareoxetan3olas
partofthesynthesisoftheherbicideOxasulfuron(seeChapter1.5).
117
a)J.A.Wojtowicz,R.J.Polak,J.Org.Chem.1973,38,2061.b)A.P.Kozikowski,A.H.Fauq,Synlett1991,
783.
118
Ref. 117b. No supporting information is provided. Under the conditions reported, pyridine should be
released into the reaction mixture and thus distillative purification of the product might face the same
problemsreportedinref.117a.
119
IndicatedthroughsearchforcommerciallyavailablechemicalsinScifinderScholar.Oxetan3olisnow
commerciallyavailablefromavarietyofsuppliers.
120
K.Baum,P.T.Berkowitz,V.Grakauskas,T.G.Archibald,J.Org.Chem.1983,48,2953.
121
W.Stutz,R.Waditschatka,K.Winter,M.VonFrieling,R.Gressly,B.Jau,S.Buerki,EP751136,1997.
37
Scheme 13: Preparation of oxetan-3-ol (45) on industrial scale.121

Theprocedurestartswiththeopeningofepichlorohydrine(47)with2ethylbutyricac
id, followed by acetalization of the resulting secondary alcohol 48. Chloroester 49 can
thenbecyclizedbytreatmentwithbase.Cleavageoftheprotectinggroupfurnishesoxe
tan3olinanoverallyieldof70.5%.
Whereasadequatesupplyroutesofoxetan3onemightbemandatoryforfutureap
plicationsofoxetanesinthedrugdiscoveryprocess,alleffortsspenttodevelopascalable
synthesismightberenderedworthless,iftheseessentialquestionswerenotansweredin
theaffirmativebefore:
1. Does the integration of an oxetane have a positive influence on thelipophilicity
andsolubilityoftheunderlyingscaffold?
2. Areoxetaneschemicallyandmetabolicallysufficientlystable?
3. Isoxetan3onetherightstartingpointtomakesubstitutedoxetanes?
Anegativeanswertothefirsttwoquestionswouldprobablyhavestoppedtheproject
immediately.Therefore,firstpriorityhadtobethepreparationofafewprototypicoxe
tanesfromoxetan3oneandmeasurementoftheirproperties.
MainPart,Chemistry
39
MainPart,Chemistry
Inordertotestthehypothesesregardingstructuralanalogiesofoxetanes,anumberof
compoundshavetobemade.Ideally,theirpreparationwouldnotonlydelivertherespec
tiveoxetaneinsufficientquantities,butalsohelpexplorethechemistryofoxetan3one
anddemonstrateitsusefulnessandversatility.Weenvisionedtwoprincipalpathsleading
tosubstitutedoxetanes(Figure8):
Figure 8: Proposed buildup of oxetanes starting from oxetan-3-one

Directnucleophilicattackonoxetan3onewouldprovideoxetan3olswhichafterac
tivation could be further functionalized by nucleophilic substitution. In a second ap
proach,theketonewouldbetransformedintoaMichaelacceptorthatcouldthenbea
substratefor1,4additionsofappropriatenucleophiles.
Both routes carry potentially problematic steps that lack precedence. Therefore, the
preparation of oxetan3one should becapable of providing significant quantities to ex
ploreitsusefulnessasastartingmaterial.Butuntilthisisestablished,thesynthesischo
senneednotbeamenabletoscaleuporoptimizedwithrespecttocost.
3.1 PreparationofOxetan3one
We felt that the existing routes to oxetan3one discussed in chapter 2.4 were not
practical for our purposes. The procedure by DuPont115 involved 6 steps, included
3methyleneoxetaneasanunstableintermediate116andaretroDielsAlderreactionthat
seemeddifficulttoaccomplishwithstandardlaboratoryequipment.
40
MainPart,Chemistry
Scheme 14: Preparation of oxetan-3-one by DuPont.115

Further attempts to prepare oxetan3ol (45) as described by Baum et al.120 did not
providesignificantquantitiesofthismaterial.Ringclosuretooxetane53resultedinvari
able yields, complex product mixtures, and produced large volumes of an aqueous salt
solutionthatmadescaleupdifficult.
Scheme 15: Preparation of oxetan-3-ol from epichlorohydrine.120

Theoxidationofoxetan3olwasknowntofailwithvariousmethodsotherthanCr(VI)
basedreagents,andtheprocedurewithCollinsreagent122necessitatesseparationofthe
122
J.C.Collins,W.W.Hess,Org.Synth.1988,509,644.
MainPart,Chemistry
41
productfromcodistillingpyridinebypreparativeGC.123Theidentificationofabetteroxi
dation procedure, the optimization of its reaction conditions and subsequent workup
would have to rely on the availability of larger quantities of oxetan3ol.124 As those
seemed difficult to obtain, we decided to investigate a shorter route which would not
involveoxidation.
3.1.1 RouteviaKetalCleavage
Startingfromknown125dihydroxyacetonedimethylketal(55),aonepotringclosure,126
precedent for the preparation of 3,3disubstituted oxetanes, would lead to 3,3
dimethoxyoxetane(56).Thiswouldyieldoxetan3oneupondeprotection.
Scheme 16: Proposed synthesis of oxetan-3-one starting from commercial dihydroxyacetone dimer (54).
This synthesis would have the advantage of providing access to oxetan3one (33) in
three steps from cheap commercial starting materials. The yields reported for the ring
closure by Picard et al. range from 68 to 84%.127 Literature precedence existed for the
cleavageofsteroidalketal57togivethecorrespondingoxetan3one58withdilutesul
furicacid.128
123
Othermethodsunsuccessfullytriedinclude:Oppenaueroxidation,permanganateanddichromate(J.A.
Wojtowicz,R.J.Polak,J.Org.Chem.1973,38,2061.).
124
Itwasexpectedthatduetothehydrophilicityandvolatility(bp106C,ref.123)ofoxetan3one,only
lowboilingsolventsandnonaqueousworkupwerepermissible.Distillationwouldthenbeusedforpurifi
cation.
125
a)E.L.Ferroni,V.DiTella,N.Ghanayem,R.Jeske,C.Jodlowski,M.O'Connell,J.Styrsky,R.Svoboda,A.
Venkataraman, B. M. Winkler, J. Org. Chem. 1999, 64, 4943. b) F. Charmantray, L. El Blidi, T. Gefflaut, L.
Hecquet,J.Bolte,M.Lemaire,J.Org.Chem.2004,69,9310.
126
P.Picard,D.Leclercq,J.P.Bats,J.Moulines,SynthesisStuttgart1981,550.
127
Theclosestexamplereported,a3,3dialkyloxetanewaspreparedin72%yield(ref.126).
128
W.S.Allen,S.Bernstein,M.Heller,R.Littell,J.Am.Chem.Soc.1955,77,4784.
42
MainPart,Chemistry
Equation 3: Proposed cleavage of dioxolane 57 to give oxetan-3-one 58.128

Basedonitsinfraredspectrum,howeverotherauthorsproposedadifferentstructure
for 58 in which the oxetane ring rearranged under the acidic reaction conditions.129
Therefore, it remained to be explored whether oxetan3one itself is stable under the
acidicconditionsemployedtocleavetheketalin3,3dimethoxyoxetane.
Following the literature procedure,125 dihydroxyacetone dimethylketal (55) was pre
paredinquantitativeyieldfromcommercialdihydroxyacetonedimer.Initialattemptsto
prepare3,3dimethoxyoxetaneshowedthattheringclosureisslowundertheconditions
ofthegeneralprocedurereportedbyPicardetal.126
Figure 9: Slow ring closure of -tosylatolithioxide 60.

Afterheatingat60Cfor4h,thereactionyieldedproduct56andmonotosylate59in
a ratio of 1/1 upon workup. We reasoned that cyclization of the corresponding sodium
alkoxide would be faster. If however only the second portion of nBuLi is replaced with
sodium hydride, the reaction does not significantly accelerate.130 When nBuLi is substi
tutedwithsodiumhydrideinbothdeprotonationsteps,theselectivityfortheformation
129
a)R.Hirschmann,G.A.Bailey,G.I.Poos,R.Walker,J.M.Chemerda,J.Am.Chem.Soc.1956,78,4812.b)
J.E.Herz,J.Fried,P.Grabowich,E.F.Sabo,J.Am.Chem.Soc.1956,78,4812.
130
Thisisprobablyduetoasaltmetathesis:Theinitiallyformedsodiumalkoxidereactswithlithiumtosy
late present in the mixture to give the thermodynamically more stable, but less reactive lithium alkoxide
andsodiumtosylate.
MainPart,Chemistry
43
ofmonotosylate59isreduced.131Therefore nBuLihastobeemployedtopreparemono
tosylate59.Simpleaqueousworkupremoveslithiumsaltsandsetsthestageforthecycli
zationofmonotosylate59.Uponadditionofsodiumhydride3,3dimethoxyoxetane(56)
isobtainedin37%yieldafterdistillation.132Withthiscompoundinhand,theketalclea
vagecouldbeexamined.Itwasfoundthat3,3dimethoxyoxetane(56)isstableundera
varietyofacidicconditions:133
Table 1: Screening of conditions for ketal cleavage.
Entry
Conditions
Result
1134
aq.H2SO4,CH2Cl2,0C
noreaction
aq.H2SO4,acetone,rt
noreaction
aq.H2SO4,THF,rt
noreaction
4128
aq.H2SO4,MeOH,reflux
noreaction
aq.H2SO4,acetone,reflux
tracesofproduct
aq.H2SO4,THF,rt
noreaction
2.5equivpTSAH2O,25equivglyoxalicacidH2O,CH2Cl2,rt
7%conversion
135
Amberlyst15,acetone/H2O,rt
noreaction
136
15%H2SO4onSiO2,CH2Cl2,rt
noreaction
137
MontmorilloniteK10,CH2Cl2,rt
7%conversion
10
MontmorilloniteK10,CH2Cl2,reflux,26h,0.08M
12%conversion
MontmorilloniteK10,CH2Cl2,reflux,26h,0.03M
44%conversion
7
8
137
11
131
If nBuLiisusedforthefirstdeprotonation,almostnobistosylateisformedonsmallscalewhichisinline
withtheobservationsmadeinref.126.Ifsodiumhydrideisusedinstead,theratioofbistosylatetomono
tosylateisapproximately4/5.
132
Basedondihydroxyacetonedimer.Typically,onebatchdelivers45gof3,3dimethoxyoxetane.Intotal,
476gof3,3dimethoxyoxetanewereprepared.
133
The oxonium species that are formed as intermediates during the ketal cleavage are destabilized the
electronwithdrawingeffectoftheringoxygen.Formationofasp2centeratthe3positionoftheoxetanein
intermediatesaswellastheproductalsoincreasesringstrain(seepage60forfurtherexplanation).
134
R.Breslow,J.Pecoraro,T.Sugimoto,Org.Synth.1988,509,361.
135
G.M.Coppola,Synthesis1984,1021.
136
F.Huet,A.Lechevallier,M.Pellet,J.M.Conia,SynthesisStuttgart1978,63.
137
E.C.L.Gautier,A.E.Graham,A.McKillop,S.P.Standen,R.J.K.Taylor,TetrahedronLett.1997,38,1881.
44
MainPart,Chemistry
Aqueous acid in various solvents and at different temperatures resulted only in one
caseintracesofoxetan3oneasdeterminedby 1HNMRanalysisofthecrudeproducts.
Using montmorillonite K10138 as an acid catalyst however gave some conversion after
prolonged refluxing in methylene chloride. Further optimization of this lead result
showedthatneithertheamount139northetypeofclay140usedhadaninfluenceonthe
conversion.Thereactionintetralin(bp207C)at80Cstoppedat54%conversion,com
pleteextractionofoxetan3onefromthesolventbydistillationfailedandsignificantde
compositionoccurred.Inacetone,noconversionwasobserved.Therefore,itwasdecided
tostickwithmethylenechlorideasalowboilingsolvent.
Theprogressofthereactioncanbefollowedby1HNMR,141anditwasfoundthatmax
imumconversionisreachedusuallyafter60to70hofreflux.Increaseofsubstratecon
centrationfrom0.02 Mto0.1 Mresultedinadropofconversionfrom92%to26%.Addi
tionof0.5equivalentsofwaterledtodecreasedconversion,probablybypartiallydeacti
vatingthemontmorilloniteclay.Additionof5molecularsievesalsodidnotallowusto
increaseconcentrationwithoutreducedconversion.142Onlargerscaleanduponfurther
optimizationsregardingworkupanddistillationprotocol,theketalcleavageprovides62%
isolatedyieldofoxetan3one.
Theoverallyieldover4stepsis23%withdistillationof3,3dimethoxyoxetane(56)and
oxetan3oneastheonlypurificationsteps.Inourlaboratoriesmorethan108gofoxe
tan3onewereproducedwiththisroute.Oneofthecommercialsuppliersisnowusing
thisrouteonascalelargerthan100g.143
138
MontmorilloniteK10isalayeredsilicatethatisactivatedbycalcinationandwashingwithmineralacid.It
findswideuseasasolidBrnstedacidcatalyst.Forareview,see:A.Cornelis,P.Laszlo,Synlett1994,155.or
P.Laszlo,Acc.Chem.Res.1986,19,121.
139
IncreasingtheamountofMontmorilloniteK10from0.3g/mmolto1.5g/mmolsubstratedidnotbring
significantimprovementofconversion(59%insteadof5057%).
140
MontmorilloniteK10canactasanionexchangerandintercalatecationslikeFe3+orTi4+.Theresulting
clays are often observed to be more acidic than the parent Montmorillonite K10 and also found use for
cleavingunreactiveketals(T.Kawabata,M.Kato,T.Mizugaki,K.Ebitani,K.Kaneda,Chem.Lett.2003,32,
648.P.Laszlo,A.Mathy,Helv.Chim.Acta1987,70,577.).Whenusedforthepreparationofoxetan3one,
howevertheseshowedapproximatelythesameconversionasnonmodifiedMontmorilloniteK10.
141
samplestakendirectlyfromthereactionmixture,noevaporation,1HNMR,64scans,linebroadening0.3
to0.5aswindowfunction.
142
Dryaswellashydratedmolecularsievesweretriedwithnoeffect.
143
Privatecommunication,Dr.MarkRogersEvans.Fortheothersuppliers,seeref.172.
MainPart,Chemistry
45
Scheme 17: Preparation of oxetan-3-one (33) from dihydroxy acetone dimer (54).
Despite that, the large amounts of methylene chloride needed in the last step make
thepreparationofoxetan3oneviathisroutelaboriousanddifficult,whichmayobstruct
theapplicationofoxetanesindrugdiscovery.Adifferentapproachhadtobedeveloped
aftertheinitialrouteviatheketalcleavagehadprovidedenoughoxetan3onetovalidate
itsusefulnessasabuildingblock.
3.1.2 OxidationofOxetan3ol
Themainreasonnottoinvestigatealternativemethodsfortheoxidationofoxetan3
olwasthedifficultpreparationofthiscompound.Thesituationchangedhoweverupon
publicationofourinitialstudyonoxetanes,144whenSyngentashowedinterestinapplying
thechemistrytotheirprojects.AsSyngentaproducedlargeamountsofoxetan3olinthe
synthesisoftheirherbicideoxasulfuron,theysuppliedconsiderableamountsofoxetan3
oltoinvestigateanimprovedoxidationprocedure.
Syngenta chemists unsuccessfully tried DessMartin145 and Swern146 oxidations befo
rehand, facing problems in the isolation of oxetan3one. Its polar nature and volatility
contributesignificantlytothecriteriaagoodoxidationprocedureleadingtooxetan3one
shouldfulfill:
144
G.Wuitschik,M.RogersEvans,K.Mller,H.Fischer,B.Wagner,F.Schuler,L.Polonchuk,E.M.Carreira,
Angew.Chem.,Int.Ed.2006,45,7736.
145
Forareview,see:T.Wirth,U.H.Hirt,SynthesisStuttgart1999,1271.
146
Forareview,see:T.T.Tidwell,SynthesisStuttgart1990,857.
46
MainPart,Chemistry
Onlylowboilingsolventsarepermissible.
Aqueous workup should be avoided as well as expensive, toxic or explosive rea

gents.
Thereactionshouldbehighyieldingandeasytoexecute.
Itwasfoundthatoxetan3olisoxidizedunderanumberofconditions147.Purification
andisolationofoxetan3one,howeverwasarecurrentproblem.
Table 2: Screening of conditions for the oxidation of oxetan-3-ol to oxetan-3-one.
Entry
Conditions
148
1
CrO3/Et2O,0Ctorta
2149
CrO3,TBAC,KCla
149
3
CrO3,TBAC,NaOAca
4150
PCC,4MS,rta
150
5
PCC,nAl2O3a
6150
PCC,Celitea
151
7
TPAP,NMO(1.5equiv)a
8152
TPAP,O2 a
153
9
TEMPO,H5IO6a
10154
TEMPO,Oxone,TBABa
155
11
IBX,EtOAc,reflux
12155
IBX,rt a
155
13
IBX,refluxa
IBX,acetone,reflux
14155
156
15 DMSO,P4O10,NEt3,5Ca
Yield(NMR)
n.d.b
n.d.b
n.d.b
n.d.b
n.d.b
n.d.b
47%c
~34%(10h)c
0%c
0%c
89%(3d)c
34%(3d)c
85%,(64h)c
83%(3d)c
63%(45min)c
Comment
nocompletion,sluggish
slow,sluggish
nocompletion,slow
fast(15min),clean,difficultpurification
slow
slow
fast(5min),sidereactions
slow,catalystdies
decomposition
noreaction
slow,highboilingsolvent
veryslow
veryslow
slow
fast,cheap
CH2Cl2 used as solvent. b broad signals in the NMR, probably due to the presence of Cr
species. cYieldofproductinthereactionmixturewasdeterminedbycomparingtheintegralsof
oxetan3onewithtetralinwhichwasaddedasaninternalstandard.
147
Foranexcellentbookonoxidationsofalcoholstoketonesandaldehydes,see:G.Tojo,M.Fernndez,
OxidationofAlcoholstoAldehydesandKetones,SpringerUS,2006.
148
S.J.Flatt,G.W.J.Fleet,B.J.Taylor,SynthesisStuttgart1979,815.
149
G.Gelbard,T.Brunelet,C.Jouitteau,TetrahedronLett.1980,21,4653.
150
J.Herscovici,M.J.Egron,K.Antonakis,J.Chem.Soc.,PerkinTrans.11982,1967.
151
Forareview,see:S.V.Ley,J.Norman,W.P.Griffith,S.P.Marsden,SynthesisStuttgart1994,639.
152
R.Lenz,S.V.Ley,J.Chem.Soc.,PerkinTrans.11997,3291.
153
S.S.Kim,K.Nehru,Synlett2002,616.
154
C.Bolm,A.S.Magnus,J.P.Hildebrand,Org.Lett.2000,2,1173.
155
J.D.More,N.S.Finney,Org.Lett.2002,4,3001.
156
D.F.Taber,J.C.Amedio,K.Y.Jung,J.Org.Chem.1987,52,5621.
MainPart,Chemistry
47
Chromiumbasedreagentswereinvestigatedfirstastheyareclosesttotheliterature
precedence(Table2,entries16).157Whereaschromium(VI)oxideindifferentvariations
led to slow reactions and the formation of byproducts, pyridinium chlorochromate158
whencombinedwith4molecularsievesasacatalyst150gaveveryfastandcleanconver
sion to product. Removal of the chromium salts produced as a byproduct proved to be
difficulthowever.AttemptstobindthechromiumsaltstoCeliteorbyfiltrationthrough
silicageldidnotcompletelyeliminatechromiumfromthecrudeproduct.Thepresenceof
highvalencychromiuminthecrudeproductwouldposeafirehazardwhenattemptingto
performdistillationofthismaterialatlargerscale.Additionally,hexavalentchromiumis
toxicandhasbeenfoundtobecarcinogenic.159
In the case of the Ley oxidation,151 use of Nmethyl morpholine Noxide (NMO) as a
stoichiometric cooxidant resulted in a rapid reaction, but the yield was low as judged
from the crude NMR. Furthermore, Nmethyl morpholine (bp 115 C), produced in stoi
chiometric amounts as a byproduct would probably be difficult to separate from the
product(bp106C)withoutaqueousworkup.ReplacementofNMOwithoxygenresulted
inaslowreactionwhichstoppedat30%conversion.
Reactionofoxetan3olwithIBX(oIodoxybenzoicacid)(Table2,entries1114),albeit
slow, furnishes clean product upon simple filtration and evaporation due to the virtual
insolubilityofIBXinthereactionmedia.Thisadvantagehoweverisbalancedwithserious
drawbacksofIBXasanoxidantonlargerscale.IBXbehavesasanexplosivewithproper
tiessimilartoTNT.160ThesensitivityofIBXtowardsdetonationonimpactorheatgreatly
depends on its purity.161 This makes preparation and handling of larger quantities dan
gerous,especiallywhenprocedureslikeinthiscasewouldenvisionrefluxingforatleast3
daysinthepresenceof1.5equivalentsofIBX.162
157
a)OxidationwithPCC:A.P.Kozikowski,A.H.Fauq,Synlett1991,783.b)OxidationwithCollinsreagent
(CrO32C5H5N):J.A.Wojtowicz,R.J.Polak,J.Org.Chem.1973,38,2061.
158
E.J.Corey,J.W.Suggs,TetrahedronLett.1975,2647.
159
Foranexcellentoverview,see:D.Michaels,C.Monforton,P.Lurie,Environ.Health2006,5,5.
160
J.B.Plumb,D.J.Harper,Chem.Eng.News1990,68,3.
161
a)D.B.Dess,J.C.Martin,J.Am.Chem.Soc.1991,113,7277.b)BoeckmanJr.,R.K.;Shao,P.;Mullins,J.
J.;Org.Synth.2000,77,141.
162
Ona1molescale,420gofIBXwouldbeneededtoperformthereaction.
48
MainPart,Chemistry
Amongthenumerousothermethodsfoundintheliteratureforoxidizingasecondary
alcoholtoaketone,147aDMSObasedmethodcaughtourattentionthatcouldpotentially
fulfillalltheconditionspreviouslyhighlighted.Avarietyofdehydratingagents163canbe
used to activate DMSO, the most well known probably being dicyclohexylcarbodiimide
(DCC)164inthePfitznerMoffattoxidationandoxalylchloride165intheSwernmodification
ofthePfitznerMoffatoxidation.Muchlessusedinthatrespectisphosphorouspentox
ide,firstproposedbyOnoderaetal.166(latermodificationbyTaberetal.167).Application
of the original conditions described in the paper gave oxetan3one in a clean reaction
andreasonableyieldasjudgedbycomparisonwithaninternalstandardinthe 1HNMR.
Thisapproachwaspursuedfurthernotonlybecauseofthecheapandratherinnocuous
startingmaterial,butalsobecauseoftheeaseofimplementation,avoidinglowtempera
turesandspecialequipment.
Theoriginalprocedurehadtobeadaptedinseveralrespectstofitthespecialrequire
mentsofoxetan3olasasubstrate.Withoutneedingamechanicalstirrer,themolarityof
thereactioncanbeincreasedfrom0.2 Mto1.7 Minoxetan3ol.168Inordertofacilitate
distillation, lowboiling solvents should be used and components such as triethylamine
withsimilarboilingpointsasoxetan3oneeliminatedbeforedistillation.
163
Foranoverview,see:G.Tojo,M.Fernndez,inOxidationofAlcoholstoAldehydesandKetones,Springer
US,2006,pp.97.
164
K.E.Pfitzner,J.G.Moffatt,J.Am.Chem.Soc.1963,85,3028.
165
OftenalsoreferredtoastheSwernoxidation(K.Omura,D.Swern,Tetrahedron1978,34,1651.).
166
a) K. Onodera, S. Hirano, N. Kashimur, J. Am. Chem. Soc. 1965, 87, 4651. b) K. Onodera, S. Hirano, N.
Kashimur,T.Yajima,TetrahedronLett.1965,4327.
167
D.F.Taber,J.C.Amedio,K.Y.Jung,J.Org.Chem.1987,52,5621.Themaindifferencetotheworkof
Onoderaistheintroductionofabase,triethylaminethatspeedsupthereactionsignificantly.
168
Furtherincreaseinconcentrationmightbepossible,butmechanicalstirringmightbenecessaryasvis
cosityofthereactionmixtureincreasesandtherebyheatreleasetothesurroundingicebathbecomesslow.
Higher concentrations are important, because theamounts of solvents handled,distilled anddisposed of
becomesmaller,improvingyieldandpracticability.
MainPart,Chemistry
49
Equation 4: Optimization of reagent stoichiometry leads to a reduction of starting materials in the crude product.
Therefore,theamountofreagentsneededtobeoptimizedtoreducethepresenceof
excess triethylamine and DMSO in the reaction medium. The optimized ratios reflect
morecloselythetheoreticalstoichiometryofthereactionasgiveninEquation4.169More
importantly,neithertriethylaminenorDMSOisfoundinthecrudeproductafterworkup.
Duetothehydrophilicityofoxetan3one,ananhydrousworkupprocedurehadtobe
developed.170Itwasfoundthatupondilutingthereactionmixturewithanequalvolume
of diethylether, the ammonium phosphates produced separate from the organic phase
whichcanbedecantedandfilteredthroughaplugofsilicagel.Thefiltrateisthendistilled
withoutfurtherpurificationtoyieldoxetan3onein48%isolatedyield.171
Morethan190gofoxetan3onehavebeenpreparedviathisroute,usuallyinbatches
ofonemol.Oxetan3onecanbestoredinthefreezerwithoutnoticeabledecomposition.
Oxetan3one is now commercially available from several companies,172 which should
facilitateitsuseindrugdiscoveryandspurtheexplorationofitschemistry.
169
Interestingly,theamountofphosphorouspentoxideismorethantwiceashighaspredictedforthecase
showninEquation4whenallbutoneoftheavailablephosphorousanhydridebondsareusedtopropelthe
reaction.Astheenergyreleaseduponcleavageoftheanhydridebonddependsonthechemicalnatureof
the given polyphosphate (see different hydrolysis enthalpies in ATP), this result may indicate that only a
certainextentoftheanhydridebondscontainedinP4O10cansupportthereaction.
170
Normalaqueousworkupunderacidicconditionswasreportedinref.167.
171
Reaction monitoring and workup by NMR with an internal standard reveals that the loss of material
largelyhappensduringthereaction.Betweenendofthereactionandbeginningofdistillationyielddrops
by fourpercentage points (two different internal standards used, oneadded tothe reaction mixture and
oneafterfiltration).Duringdistillationthreepercentagepointsofthetotalyieldarelostcomparedwiththe
isolated yield of oxetan3one. It is important to use appropriate columns and avoid bath temperatures
higherthan56Cinthedistillationtopreventproductfromdistillingover.
172
Atthestartoftheproject,oxetan3onewasnotcommerciallyavailable(ScifinderScholar).Itwasfirst
introduced to the market by Molbridge in February 2007. Since then Chemgenx, Parkway Scientific and
ResearchSupportInternationalalsostartedofferingoxetan3onecommercially.
50
MainPart,Chemistry
3.2 AdditionstoOxetan3one
According to literature precedence, oxetan3one shares many of the chemical fea
turesoflessstrainedandlesselectrondeficientketones(seeFigure7).Itcanbehydro
genatedtooxetan3ol173,addsGrignardreagents,174itsoximeisknown173aswellasthe
stable2,4dinitrophenylhydrazone175andaStreckeradduct.176Thisprecedencelaidthe
foundationforourownefforts.
3.2.1 3Aryloxetan3ols
Grignardreagentsaswellasaryllithiumcompoundscleanlyaddtooxetan3one(33)
to give the respective oxetan3ols in good yields. While oxetan3ols might be useful
themselves in supplanting their gemdimethyl counterparts or carboxylic acids, the hy
droxyfunctionservesasaconvenienthandleforfurtherreactions.
Scheme 18: Oxetan-3-ols, structural analogues and starting points for further
derivatization.
Table 3 summarizes the oxetan3ols made by addition of organometallic species to
oxetan3one.Theproductsareusuallycrystallinesolidsthatcanbestoredatroomtem
peraturewithoutnoticeabledecomposition.
173
G. H. Berezin, US 3449369, 1969. In this patent the hydrogenation of oxetan3one oxime to 3amino
oxetaneisreported.
174
P.Yates,A.G.Szabo,TetrahedronLett.1965,6,485.
175
K.A.Marshall,A.K.Mapp,C.H.Heathcock,J.Org.Chem.1996,61,9135.
176
A.P.Kozikowski,A.H.Fauq,Synlett1991,783.
MainPart,Chemistry
51
Table 3: 3-Aryloxetan-3-ols made by addition of organometal reagents to oxetan-3-one.
Entry
RM
Product
Yield
PhLi
87%
2177
3pyrMgClLiCl
83%
4MeOPhMgBr
77%
4BrPhMgBr
79%
quant.
80%
68%
80%
71%
10
73%
177
Grignardreagentpreparedviamagnesiumhalogenexchange(A.Krasovskiy,P.Knochel,Angew.Chem.,
Int.Ed.2004,43,3333.).
52
MainPart,Chemistry
The free alcohol functionality in these compounds can then be used for substitution
reactions. A number of compound classes are accessible this way, including 3fluoro
oxetanes,3chlorooxetanes,3alkoxyoxetanes.
3.2.2 3Fluorooxetanes
Replacement of the tertiary alcohol with a fluorine atom results in 3fluorooxetanes.
This class of compounds could serve as a polar group with a steric demand between t
butylandisopropylgroups.178
Scheme 19: Significance of 3-fluorooxetanes and their preparation of oxetan-3-ols by

treatment with DAST.
Diethylaminosulfur trifluoride (DAST) and bis(2methoxyethyl)aminosulfur trifluoride
(Deoxofluor)arestandardreagentsfortheconversionofalcohols,ketonesandcarboxylic
acids into their fluorinated counterparts.179 Although substitution reactions at the 3
position of the oxetane were expected to be difficult because of steric hindrance, ring
strainandelectrondeficiencyoftheoxetane,thisreactionwenttocompletionafterless
than1minuteat78CinthepresenceofoneequivalentofDAST(Table4,entry1).
178
gemdimethylgroupsandanoxetanehavesimilarstericdemand,asestimatedbytheirvanderWaals
volumesandpartialmolarvolumesinwater(seeref.309).IfoneassignsVtobethechangeinstericde
manduponreplacementofahydrogenwithamethylgroup,thenthereplacementofahydrogenwitha
fluorineatomresultsinachangeof1/3V.
179
For examples of the conversion of tertiary alcohols into the respective fluorides with DAST, see: a) D.
Guijarro,P.Martinez,M.Yus,Tetrahedron2003,59,1237.b)G.C.B.Harriman,J.Shao,J.R.Luly,Tetrahe
dronLett.2000,41,8853.c)K.Hirano,H.Yorimitsu,K.Oshima,Org.Lett.2004,6,4873.Forareviewabout
the usage of Deoxofluor and its advantages to DAST, see: R. P. Singh, J. n. M. Shreeve, J. Fluorine Chem.
2002,116,23.
MainPart,Chemistry
53
Table 4: Conversion of 3-aryloxetan-3-ols into the corresponding fluorinated compounds.
Entry
StartingMaterial
Product
Yield
47%
40%
43%
Theconsistentlylowyieldcanonlybeexplainedbylossesduringthereactiontoavery
polarbyproductthatcannotbeextractedintotheorganicphase,asthecrudeNMRinall
casesshowsproductofgoodpurity.EvidencecollectedatRochehoweversuggeststhat
theefficiencyofthereactionincreaseswiththeabilityofthearylsubstituenttodonate
electrondensity.180
180
IfthearylsubstituentisaBocprotectedaniline,almostquantitativeyieldsofthecorrespondingfluoro
oxetaneswereobtained.
54
MainPart,Chemistry
Equation 5: Preparation of 3-chloro-3-phenyloxetane (75) and formation of 2phenylpropenal181 as byproduct.

In a similar reaction182, 3phenyloxetan3ol (62) was converted into 3chloro3
phenyloxetane(75).Atelevatedtemperaturesandinthepresenceofanaminebase,the
intermediatemesylateortheproductcouldundergoeliminationtogive3phenyloxet2
ene which then undergoes electrocyclic ring opening leading to the observed 2
phenylpropenal(76).
3.2.3 3Aryloxetanes
Dehydroxylation of 3aryloxetan3ols would provide 3aryl oxetanes, analogues of
isopropyl groups, a very common functionality in medicinal chemistry. Following a
known183procedureforthedehydroxylationofbenzylicalcoholsunderacidicconditions
inthepresenceoftriethylsilaneasahydridedonor,3(pmethoxyphenyl)oxetan3ol(64)
couldbereducedingoodyieldwithoutaccompanyingringopening.
Equation 6: Dehydroxylation of 3-(p-methoxyphenyl)oxetan-3-ol (64).

Thisinitialpositiveresultfortheelectrondonatingpanisylresiduecouldhowevernot
begeneralizedtoothersubstrates.184Forlesselectronricharylsubstituents,noreaction
occurs or decomposition upon prolonged exposure or heating. Therefore, conditions
werescreenedtofindanalternativeprocedure.
181
ThiscompoundwasidentifiedbycomparisonofitsNMRspectrumwithliteraturedata(R.H.Newman
Evans,R.J.Simon,B.K.Carpenter,J.Org.Chem.1990,55,695.)
182
Adaptedfromaliteratureprocedure:E.Bacque,J.M.Paris,S.LeBitoux,Synth.Commun.1995,25,803.
183
J.Pataki,R.G.Harvey,J.Org.Chem.1987,52,2226.
184
Neither3phenyloxetan3ol,nor3(2,4dimethylphenyl)oxetan3olgaveanyproductunderabovecon
ditions.
MainPart,Chemistry
55
Table 5: Screening of conditions for the hydro-dehydroxylation of 3-phenyloxetan-3-ol.
Entry
Conditions
Comment
185
OH
Pd/C,H2,EtOH,4d
noreaction
OH
Pd/C,HCO2H,EtOH,4d
noreaction
OH
Pd(OH)2/C,H2,HCO2H,EtOH,2d
noreaction
OH
Pd/C,H2,AcOH,70C,15h
noreaction
186
OC(S)SMe
Lauroylperoxide, PrOH,reflux
decomposition
187
Cl
Bu3SnH,AIBN,PhMe,reflux
noreaction
Cl
Pd(OH)2/C,H2,MeOH,12h
decomposition
188
OH
5%InCl3,Ph2SiHCl,80Corrt,1d
decomposition
189
OC(O)CO2Me
Bu3SnH,AIBN,PhMe,reflux
alcoholrecovered
190
Cl
LiAlH4,rt
decomposition
191
OH
Pd(OH)2/C,H2,TFAA,THF,2d
decomposition
192
12
OH
1.NaI,TMSCl,2.AcOH,Zn
H2C=C(Ph)CH2OH193(34%)
13
10
11
OH
Et3SiH,TFA,rt,4d
decomposition
183
OH
Et3SiH,F3CSO3H,CH2Cl2
decomposition
194
15
OH
Pd/C,cyclohexene,AlCl3,75C,60h
rec.sm,decomposition
16
OTs(78)
Pd(OH)2/C,H2,EtOAc,4d
decomposition
17
OH
P2I4,PhMe,reflux
decomposition
18
OTs(78)
LiAlH4,0C,Et2O,45min
68%
19
OH
1.NaH2.pTsCl,3.LiAlH4,THF,0C
20
OH
1.NaH2.pTsCl(3.LiAlH4)Et2O,0C
14
195
185
27%,22%
noreaction197
196
S.Mitsui,Y.Kudo,M.Kobayashi,Tetrahedron1969,25,1921.
186
B.QuicletSire,S.Z.Zard,TetrahedronLett.1998,39,9435.
187
S.Lesniak,Pol.J.Chem.1995,69,1484.
188
M.Yasuda,Y.Onishi,M.Ueba,T.Miyai,A.Baba,J.Org.Chem.2001,66,7741.
189
N.S.Li,J.A.Piccirilli,J.Org.Chem.2003,68,6799.
190
S.Miyano,N.Mibu,M.Irie,S.Fujii,F.Fujisaki,N.Abe,K.Sumoto,J.Chem.Soc.,PerkinTrans.11987,
313.
191
a)M.Tanaka,K.Chiba,M.Okita,T.Kaneko,K.Tagami,S.Hibi,Y.Okamoto,H.Shirota,M.Goto,etal.,J.
Med.Chem.1992,35,4665.b)D.L.Varie,TetrahedronLett.1990,31,7583.
192
T.Morita,Y.Okamoto,H.Sakurai,SynthesisStuttgart1981,32.
193
identified by comparison of NMR with literature: M. G. Organ, A. P. Murray, J. Org. Chem. 1997, 62,
1523.
194
G.A.Olah,G.K.S.Prakash,SynthesisStuttgart1978,397.
195
H.Suzuki,H.Tani,H.Kubota,N.Sato,J.Tsuji,A.Osuka,Chem.Lett.1983,247.
196
Compound79isfullycharacterizedandtheresultwasreproduced.Theanalogous4Bromobutylether
wasobtainedupontreatmentoftosylate78withMeMgBrinTHF.
197
Reactiontothetosylatedidnotproceedindiethylether.
56
MainPart,Chemistry
Thevastmajorityofmethodsknownforthedeoxygenationofabenzylicalcoholfailed
to give product and resulted either in recovery of starting material or decomposition.
Treatmentoftosylate78withlithiumaluminumhydrideindiethyletherat0Chowever
gavethereducedproductinacceptableyield(Table5,entry18).Astosylate78wasmade
bysequentialtreatmentofthealcoholwithsodiumhydrideandpTsClinTHF,itseemed
obvioustotryaonepotdeoxygenationofalcohol62.Whenthesequencewasperformed
indiethylether,noformationoftosylate78wasobserved,probablyduetoinsolubilityof
thesodiumalkoxideof62indiethylether.198
Equation 7: Formation of n-butyl ether 79 suggests SN1-pathway for the hydrodetosylation of 78.
WhenthesolventforthereductionwaschangedtoTHF,howevernbutylether79was
formedasabyproduct.196Thisindicatedthatupontreatmentoftosylate78withlithium
aluminum hydride which acted as a Lewis acid, heterolytic bond cleavage occurred to
form carbocation 80. This was then trapped by Lewisbasic THF or quenched by LiAlH4.
When the less basic diethylether was used in place of THF, the corresponding oxonium
ion was probably formed to a lesser extent.199 This sequence has been applied to the
preparationof3aryloxetane81.
198
Forother,morelipophilicoxetanols(videinfra),thetosylationalsoproceededindiethylether.
199
Additionally,theoxoniumionderivedfromdiethyletherisstericallymorehindered,sothatitstrapping
withLiAlH4mightresultinformationofproductratherthanhydrideattackondiethylether.
MainPart,Chemistry
57
Equation 8: One-pot preparation of 3-aryloxetane 81 from its corresponding alcohol 70.

Inthiscase,tosylateformationindiethylethersucceeds200andthereductionproceeds
smoothlyat78C.Athighertemperaturesandprolongedreactiontimes,openingofthe
oxetane ring in the product resulted in lower yields. The substrate dependency of this
sequenceleavesroomfortheapplicationofothermethodsorbuildingblocksthatoffer
morereliableaccesstothisclassofcompounds.
3.2.4 3Aminooxetanes
Benzylicaminesandbenzamidesarecommonmotifsamongmarketeddrugs.201Given
theirprevalenceinmedicinalchemistryitwouldbedesirabletohaveamethodavailable
forthepreparationoftheiroxetaneanaloguesfromoxetan3one(33).
Scheme 20: 3-Amino-3-aryloxetanes, structural analogues and starting points for further
derivatization.
Two approaches to this compound class were selected to be examined first, nucleo
philic displacement and addition to a C=N double bond. Several attempts to displace a
200
Theintermediarytosylatecouldnotbeisolatedasithydrolyzedimmediatelyduringaqueousworkupto
thealcohol70.
201
5.2%ofalldrugsonthemarket(163total)containabenzylicamineand3.2%(100total)abenzamide.
(Prous Science Integrity, June 202008: Search for all compounds containing the respective substructure
andhavingLaunchedasdevelopmentstatusassociatedwithit.Totalfound:3114)
58
MainPart,Chemistry
leavinggroupwithsodiumindolamideinvariablyledtodecomposition.202Additionreac
tions of phenyl lithium to oxetan3one N,Ndimethylhydrazone also yielded no prod
uct.203
The known preparation of amino acid 36204 (see Figure 7) from oxetan3one (33)
inspired us to use amino nitriles derived from oxetan3one as precursors for
3aminooxetanes.InthesocalledBruylantsreaction,arylmagnesiumhalidesreactwith
aminonitrilestogivethecorrespondingarylamine.205
Equation 9: Preparation of 3-amino-3-aryloxetanes from aminonitriles.

Aminonitrile 82 can be prepared in high yield by treatment of oxetan3one with di
benzylamineandtrimethylsilylcyanideinaceticacid.Aprocedurepublishedforstructu
rally similar azetidines was used as a starting point for the optimization of the reaction
conditions.206HighconcentrationoftheGrignardreagentaswellasaswitchfromdiethyl
ethertoTHFisimportantforthereactiontoproceedtocompletion.Ahighconcentration
of Lewis acidic Grignard reagent might help the formation of the intermediary iminium
ion. High salt concentrations in the solution also raise its dielectric constant, promoting
theheterolyticCCNbondcleavagebystabilizingtheresultingionpair.207
202
TheleavinggroupstriedwerechlorideandtosylateinTHForDMFassolvents.AsseeninEquation5,the
amidebaseprobablyratherledtoeliminationthansubstitutiononthestericallyhinderedcenter.
203
Preparationofthehydrazoneadaptedfromaliteratureprocedure(D.A.Evans,S.L.Bender,J.Morris,J.
Am.Chem.Soc.1988,110,2506.).Attemptsusingpublishedmethodsforthepreparationtosyliminesdid
not work for oxetan3one: a) M. Gordon, R. Wright, Synthesis 1984, 1058. b) F. Chemla, V. Hebbe, J. F.
Normant,SynthesisStuttgart2000,75.
204
A.P.Kozikowski,A.H.Fauq,Synlett1991,783.
205
P.Bruylants,Bull.Soc.Chim.Belges,1924,33,467.
206
E.Bacque,J.M.Paris,S.LeBitoux,Synth.Commun.1995,25,803.
207
Attemptstopreformtheiminiumionbytreatingtheaminonitrile82withAgBF4(C.Agami,F.Couty,G.
Evano, Org. Lett. 2000, 2, 2085.) prior to the addition of PhMgBr invariably led to incompleteconversion
andcomplexreactionmixtures.
MainPart,Chemistry
59
Equation 10: Bruylants reaction of aminonitrile 82 and hydrogenolytic deprotection to

give 3-amino-3-phenyloxetane (84).
The resulting amine 83 could then be debenzylated easily to give 3amino3
phenyloxetane(84).Noreductionto3phenyloxetanewasnotobserved.208
3.3 OxetanesBearingaQuaternaryCenter
Oxetaneswouldbeconfinedtoasmallnicheindrugdiscovery,iftheirsyntheticpres
ence was limited to terminal positions (3hydro or 3fluorooxetanes) or dependent on
heteroatomlinkages(3hydroxyor3aminooxetanes).Trueflexibilityandcompetitiveness
wouldonlyarisefromthepotentialabilitytosubstituteanymethylene,gemdimethylor
carbonylgroupbyanoxetane.Inmanycases,thisimpliesintroductionoftheoxetaneunit
atinternallocationsofamolecularstructure,renderingthedevelopmentofmethodology
toaccessoxetanesbearingaquaternarycenterimportant.
Different approaches were considered to prepare this compound class. A direct way
wouldbethesubstitutionofaleavinggroupXincompound85withacarbonnucleophile.
As an alternative, nucleophilic addition reaction might be performed on Michael accep
torslikecompound87.
Figure 10: Preparation of quaternary centers by substitution or conjugate addition.
208
SeeTable5forthestabilityof3phenyloxetan3olundertowardshydrogenolysis.Examplesforhydro
genolyticcleavageofbenzylicamineswithsubstitutionanalogoustooxetane84couldnotbefoundinthe
literature(searchinBeilsteinandScifinderScholar,July2008).
60
MainPart,Chemistry
Effortstoreactavarietyofelectrophiles85withdifferentcarbonnucleophilesdidnot
result in the formation of appreciable amounts of substitution product.209 Therefore, it
wasdecidedtopursuetherouteviaconjugateadditionto3alkylideneoxetanes87.
3.4 1,4AdditiontoMichaelAcceptors
Arecurrentchallengeinthechemistryof3substitutedoxetanesseemstobetheirre
luctancetoundergonucleophilicsubstitution.Thetransitionstateofanucleophilicsubs
titution (Picture 7, left) is characterized by steric hindrance, electron deficiency and in
creasedringstrain.
Nu
Picture 7: Comparison of the transition state of a nucleophilic substitution with conjugate

addition onto a Michael acceptor.
Theseimpedimentsthatrendernucleophilicsubstitutionsdifficultfostertheconjugate
addition to compounds of the type shown in Picture 7 on the right. Here, the strained
planar geometry which raises the energy of the SNtransition state is preformed in the
reagent.Thesp2hybridized3positionoftheoxetanesuffersfromabondanglecontrac
tionofapproximately30imposedbythesmallring.Attackonthe3positionoftheoxe
tane changes the hybridization to sp3, reducing the deviation from the preferred bond
angletoapproximately20.210Theinductiveeffectoftheoxetaneoxygenwhichobstructs
thebuildupofpartialpositivechargeintheSNtransitionstatepromotesthe1,4addition
toalkylideneoxetanes,makingthe3positioninoxetanesmoreelectrophilic.
209
NeitherRuppertsreagent(TMSCF3/CsF)normethylmagnesiumiodidegaveanyproduct.Cyanideasa
nucleophileonlyyieldedsmallamountsofmixturesofnitrileandisonitrile.Attemptstolithiate3chloro3
phenyloxetanewithLiDBBonlyresultedintheformationeliminationproductH2C=C(Ph)CH2OH193.
210
Thispositiveapproximationtothepreferredbondgeometryisbalancedbyadditionaleclipsinginterac
tionsbetweenthesubstituentsonthe3positionoftheoxetaneanditsadjacentmethylenegroups.
MainPart,Chemistry
61
3.4.1 PreparationofAcceptors
Precedence for the preparation of this compound class from oxetan3one (33) is
sparse. The preparation of ester 39 via HornerWadsworthEmmons reaction indicated
howeverthattheirsynthesiswaspossible.211
Equation 11: Preparation of the ,unsaturatedester39byHWEreaction.211

Itwasfoundthatanumberofdifferentmembersofthiscompoundclasscaneasilybe
prepared. Commercially available, resonancestabilized ylides react cleanly to give the
correspondingunsaturatedester89,aldehyde90,methylketone91andnitrile92ingood
yield.212HornerWadsworthEmmonsreactionprovidesaccesstothephenylsulfone93,
ketone94andphosphonate95.Condensationofoxetan3onewithnitromethaneyields
thecorrespondingnitroalkene96.
211
212
M.D.T.Moldes,G.Costantino,M.Marinozzi,R.Pellicciari,Farmaco2001,56,609.
Workupwasperformedbyfilteringthereactionmixturesthroughaplugofsilicagel.
62
MainPart,Chemistry
Figure 11: Michael-acceptors prepared from oxetan-3-one.

Allcompoundsshownosignsofdecompositionwhenstoredinthefreezer.213Onlyin
onecase,vigorousandspontaneousdecompositionofanimpuresampleofaldehyde90
wasobserved.214
3.4.2 ConjugateAdditions
Thecompoundsshownabovereactwithabroadvarietyofheteroatomaswellascar
bonnucleophiles.Often,completeselectivityof1,4over1,2additionisseen.Acompari
sonofester89withthecorresponding3,3dimethylacrylate98highlightsthereactivity
ofthiscompoundclass.
213
Sulfone93isstablealsoatambienttemperature.
214
Tracesofbasepresentinthematerialwhichhadbeenrecoveredfromareactionmixturemighthave
triggeredpolymerization.
MainPart,Chemistry
63
CO2Et
O
MeNO2, 0.2 equiv DBU
EtO2C
MeCN, rt, < 4 h
O
97
89
CO2Et
Me
Me
MeNO2, 1.0 equiv DBU

MeCN, 60 C, 36 60 h
NO2
EtO2C
Me
98
92%
NO2
Me
85%
99
Equation 12: Conjugate addition of nitromethane to ester 89 and its gem-dimethyl analogue 98.215
Thisreactivitytowardsnucleophilicadditionallowsforthepreparationofawiderange
ofproducts.Beingabletovarybothelectrophileandnucleophileprovidesflexibleroutes
towards oxetanes with quaternary substitution. Comprehensive exploration of this vast
unchartedareaofchemicalspaceisnotwithinthegraspofthisprojectandhasnotbeen
itsgoal.Wefocusedratheronharnessingthepowerofthismethodologyfortheprepara
tion of specific structures and thereby demonstrating its value and practical relevance.
Thefollowingschemescontainanoverviewofthedifferentnucleophilesexplored.Many
of the products were then used to prepare the prototypic analogues, the physico and
biochemicalpropertiesofwhichwereprofiledthereafter.
215
Fiveequivalentsofnitromethanewereusedinbothreactions.Dataforthesecondreactiontakenfrom:
R.A.Bunce,R.E.Drumright,Org.Prep.Proced.Int.1987,19,471.
64
MainPart,Chemistry
Scheme 21: Addition products derived from ester 89.

ThecompoundsshowninScheme21includeavarietyoffunctionalgroupsandstruc
tural motives. Carbon and heteroatom, neutral and anionic nucleophiles add across the
doublebondofteninhighyield.Theabilitytoutilizearylandvinylboronicacidsasacar
bonnucleophileinasimpleprocedure216andtherebytapintothevastreservoirofcom
mercially available boronic acids should make the preparation of this type of oxetanes
alsoamenabletoparallelsynthesis.
216
The rhodiumcatalyzed addition of boronic acids to Michael acceptors was pioneered by Hayashi and
Miyaura.Forkeypublications,see:a)M.Sakai,H.Hayashi,N.Miyaura,Organometallics1997,16,4229.b)
Y.Takaya,M.Ogasawara,T.Hayashi,M.Sakai,N.Miyaura,J.Am.Chem.Soc.1998,120,5579.
MainPart,Chemistry
65
Scheme 22: Addition products derived from nitro compound 96.
Scheme 23: Addition products derived from aldehyde 90.217
217
The aldehyde group in particular possesses inherent reactivity that makes it necessary to quench the
additionproductsofaminesinsitueitherbyreductionorolefination.Itisknownthataminoaldehydes
66
MainPart,Chemistry
Theseschemeshighlightthestructuraldiversitythatemergesfromtheselectedaccep
tors. A grouping by product instead of starting material better visualizes the different
classesofoxetanesaccessiblethroughthispathway.
Picture 8: Selection of addition products accessible through oxetan-3-one.

Thedifferentclassesofoxetanesthatcanbemadefromoxetan3onearegroupedin
Picture8accordingtothedistanceoftheclosestheteroatomtotheoxetanecore.Some
ofthetargetstructuresweenvisionedtopreparehowevercanbemademoreefficiently
fromadifferentsetofstartingmaterials.Thecompoundclassesaccessiblethroughthem
complementthechemistryshownsofar.
have a high propensity to undergo polymerization (A. Chesney, I. E. Marko, Synth. Commun. 1990, 20,
3167.).
MainPart,Chemistry
67
3.5 ChemistrystartingwithTribromopentaerythritol
AnarticlebyHosteandGovaertappearedin1949,detailingonthepreparation2oxa
6azaspiro[3.3]heptane derivatives from 3,3bis(bromomethyl)oxetane (119).218 Other
articlesfollowedthatalsousednucleophilicdisplacementin3,3bis(halomethyl)oxetanes
tobuildupthisclassofspirocycles.219
ref.218
ref.219a
Scheme 24: Preparation of substituted 2-oxa-6-azaspiro[3.3]heptanes from 3,3bis(halomethyl)oxetanes.

Azetidine24belongstothisgroupofspirocyclesanditwasthereforedecidedtobuild
itupusingchemistryrelatedtotheoneshowninScheme24.Itwouldbeadvantageous
tohavetheunsubstituted2oxa6azaspiro[3.3]heptane(124)availableasabuildingblock
inordertocircumventapplyingtheharshconditionsofitspreparationtotheactualscaf
foldsofinterest.
218
J.Hoste,F.Govaert,Bull.Soc.Chim.Belg.1949,58,157.
219
a)F.S.Zarudii,D.N.Lazareva,E.S.Kurmaeva,O.B.Chalova,T.K.Kiladze,E.A.Kantor,D.L.Rakhmanku
lov,Pharm.Chem.J.(Engl.Transl.)1985,19,108.b)R.K.Khazipov,N.L.Izbitskaya,T.K.Kiladze,O.B.Cha
lova, E. S. Kurmaeva, E. A. Kantor, Izv. Vyssh. Uchebn. Zaved., Neft Gaz 1984, 27, 86. A 2oxa6
azaspiro[3.3]heptane was also used as a synthetic intermediate for the preparation of 2,6
diazaspiro[3.3]heptanes(C.G.Overberger,Y.Okamoto,V.Bulacovschi,Macromolecules1975,8,31.).Kres
panreportstheisolationofa2oxa6azaspiro[3.3]heptanederivativeasabyproduct(C.G.Krespan,J.Org.
Chem.1975,40,1205.).
68
MainPart,Chemistry
Scheme 25: Envisioned preparation of 2-oxa-6-azaspiro[3.3]heptane (124) as a starting

point for the synthesis of substituted 2-oxa-6-azaspiro[3.3]heptanes.
Therefore, conditions220 that were reported to yield 1alkylazetidines from a primary
amineand1,3dibromopropanewereprobedfortheirefficiencywiththestericallymore
hindered3,3bis(bromomethyl)oxetane(119)221.Inallcases,thereactionswerefoundto
beslow222andtheproductscouldbeisolatedonlyinsmallyield.
ref.220a
ref.220b
ref.220c
Scheme 26: Screening of

azaspiro[3.3]heptanes.220
220
conditions
for
the
preparation
of
2-oxa-6-
a)F.S.Zarudii,D.N.Lazareva,E.S.Kurmaeva,O.B.Chalova,T.K.Kiladze,E.A.Kantor,D.L.Rakhmanku
lov,Pharm.Chem.J.(Engl.Transl.)1985,19,108.b)F.H.Tsai,C.G.Overberger,R.Zand,Biopolymers1990,
30,1039.c)D.Zhao,C.Y.Chen,F.Xu,L.Tan,R.Tillyer,M.E.Pierce,J.R.Moore,Org.Synth.2000,77,12.
221
Thismaterialwaspreparedfromcommercialtribromopentaerythritol(123):C.G.Overberger,Y.Okamo
to,V.Bulacovschi,Macromolecules1975,8,31.
222
Allreactionstriedshowedresidual3,3bis(bromomethyl)oxetaneevenafterrefluxing/heatingforseveral
days.
MainPart,Chemistry
69
Hydrogenolyticdeprotectionofeithercompound125or126wasplannedtogiverise
tothefreeamine.Asvariationoftheparametersfortheringclosuredidnotresultinsub
stantialimprovementsofyields223,itwasdecidedtousethehighyieldingpreparationof
sulfonamide 120 as a starting point and investigate the cleavage of the sulfonamide
bond.224
Scheme 27: Preparation of tosyl amide 129 from commercial tribromopentaerythritol.225

Insteadofsulfanilamide,ptosylamidewaschosenasanucleophile,asmostcasesof
sulfonamide cleavages in the literature refer to this protecting group. The initially em
ployedtwostepsynthesisforthepreparationoftosylamide129couldbeturnedintoa
onepotprocedurebyvirtueofthesimilarityofthereactionconditionsofthetwosteps
involved.Thepureproduct129issimplyisolatedbyevaporationofethanol,followedby
stirringwithaqueousKOHinwhichexcessptosylamidedissolves.
Commonconditionsforthedeprotectionoftosylamidesincludeboilinginstrongmin
eralacid226orthereductivecleavage227withanalkalimetal.Amorerecentstudyfound
that Ntosylaziridines can be deprotected with magnesium in methanol.228 This method
223
Increaseintimeandreactiontemperaturedidnotgiveanyimprovement.
224
ThisworkwascarriedoutbyAndreasBucklaspartofhisSemesterarbeit.
225
Tribromopentaerythritol is used as a flame retardant for polymers: a) S. Ezra, S. Feinstein, I. Bilkis, E.
Adar,J.Ganor,Environ.Sci.Technol.2005,39,505.b)R.Borms,P.Georlette,Kunststoffe2001,91,195.
226
Foranexample,see:S.Varghese,D.Gupta,T.Baran,A.Jiemjit,S.D.Gore,R.A.Casero,P.M.Woster,J.
Med.Chem.2005,48,6350.
227
Forthesulfonamidecleavagewithalkalimetalsofazetidines,see:a)H.Takikawa,T.Maeda,M.Seki,H.
Koshino,K.Mori,J.Chem.Soc.,PerkinTrans.11997,97.b)D.Enders,J.Gries,Z.S.Kim,Eur.J.Org.Chem.
2004,4471.
228
D.A.Alonso,P.G.Andersson,J.Org.Chem.1998,63,9455.
70
MainPart,Chemistry
wasinvestigatedfirstbecauseofitssimplicityandthepotentialbenefitswithrespectto
scaleup and purification. Indeed, initial attempts showed conversion to product which
was trapped and isolated from the reaction mixture by benzoylation. This proofof
conceptclearedthewaytooptimizeboththereactionconditionsandtheisolationofthe
product.Itspolarityandvolatilityaswellastheproductionofmagnesiumsaltsduringthe
reactionpresentedachallengeforthedevelopmentofthesimpleandscalableisolation
andpurificationoftheproduct.
Scheme 28: Optimized procedure for the preparation of oxalate 130 from tosyl amide 129.
Severaladditiveswerescreenedtoprecipitatethemagnesiumsaltsfromthereaction
sothatthecrudemixturecanbefiltered.229OnlyNa2SO410H2Ohoweverwassuccessful
inprovidingfilterableprecipitates.Thissimplemethodinvolvesonlyfiltrationsaspurifica
tionstepsandisamenabletoscaleup.Thesynthesishasbeenreproducedsuccessfullyin
thelaboratoriesofRocheBaselandNovartis.
Oxalate 130 can also be utilized directly in acylation, alkylation and Buchwald
Hartwig230 reactions. In all cases, the free amine is liberated in situ by the presence of
base. This stable salt 130 thereby represents a convenient source 2oxa6
azaspiro[3.3]heptane(124).231
229
Tartaric acid, oxalic acid and different salts of EDTA were tried without success to obtain precipitates
thatwerefilterable.
230
Procedureadaptedfrom:S.Surprenant,W.D.Lubell,J.Org.Chem.2006,71,848.
231
2oxa6azaspiro[3.3]heptane can be isolated andcharacterized,butdecomposesupon storage atam
bienttemperature.
MainPart,Chemistry
71
Scheme 29: Use of oxalate 130 as a reagent in the amination of benzoyl chloride, benzyl
halides and an aryl bromide.
3.6 SelectiveOpeningof2,6Dioxaspiro[3.3]heptane
A molecule closely related to 2oxa6azaspiro[3.3]heptane (124) is 2,6
dioxaspiro[3.3]heptane(140).ThisspirocyclicoxetanehasfirstbeenobtainedbyBacker
andKeuning232in1934bytreatmentofdibromopentaerythritol(139)233withbaseinhot
ethanol.
232
H.J.Backer,K.J.Keuning,Recl.Trav.Chim.PaysBas1934,53,798.Theinitiallylowyieldofthistrans
formationwasthenoptimizedbyAbdunNuretal.(A.R.AbdunNur,C.S.Issidorides,J.Org.Chem.1962,
27,67.).Followingthatprocedure,themaximumyieldobtainedinourhandswas23%.
233
Dibromopentaerythritol(139) is commercially available and used as a flame retardant for polymers. A
studyinmicedocumenteditscancerogenicproperties:J.K.Dunnick,J.E.Heath,D.R.Farnell,J.D.Prejean,
J.K.Haseman,M.R.Elwell,Toxicol.Pathol.1997,25,541.
72
MainPart,Chemistry
Scheme 30: Preparation of 2,6-dioxaspiro[3.3]heptane (140) from dibromopentaerythritol

(139).232
We reasoned that there might be the possibility to attack selectively one of the two
rings with a nucleophile and thereby use 2,6dioxaspiro[3.3]heptane (140) as a building
blockforthepreparationofoxetanes.Interestingly,thiscompoundiscrystallineandcrys
talssuitableforsinglecrystalxrayanalysiswereobtained.234
Picture 9: x-ray structure of 2,6-dioxaspiro[3.3]heptane (140).

BothoxetaneringsareplanarandtheCCCvalenceangleis85whichissimilarto
whatisobservedinotheroxetanes.235Insolution,2,6dioxaspiro[3.3]heptane(140)hasa
dipolemomentof0.79D236onthebasisofwhichapuckeringangleof22waspredicted
forbothrings.237Theonlyexplanationforthemeasureddipolemomentmightbeafun
damentalchangeinstructuralpreferenceuponsolvation.238
234
Beingcomparableinstructureto1,4dioxanewhichisaliquidatstandardconditionsandhavingneither
aresultingdipolemomentinthesolidstatenorthepossibilitytoformhydrogenbonds,itisnotclearwhy
2,6dioxaspiro[3.3]heptane(140)isasolid(mp8990C,ref.232)ratherthanaliquid.
235
RefertoPicture11forcomparison.
236
H.Cohen,Recl.Trav.Chim.PaysBas1934,53,1139.
237
B.A.Arbousow,Bull.Soc.Chim.Fr.1960,1311.
238
This would mean that ceteris paribus andbased on thecalculation inref. 237, in solution a puckering
angleofapproximately22inbothringsshouldbefound.
MainPart,Chemistry
73
Picture 10: View along the trajectory of attack of a nucleophile on 2,6-spirocycle 140 (left)
and 3-ethyl-3-(hydroxymethyl)oxetane (141, right).239
Shown in Picture 10 on the left is the view along the likely trajectory along which a
nucleophilewouldattack.Thepictureontheright239reflectsthesituationafteropening
ofoneofthetworings.Intheconformationwhichislikelyadopted,240themethylgroup
andthenewlyformedalcohol241shieldtheremainingoxetanefromfurtherattack.There
fore,selectivityshouldincreasewithincreasingbulkofthenucleophilebeingused.242
O
MgBr
OH
Et 2 O, 0 C to rt
140
O
+
O
10%
Li+
OH
O tBu
BF3 OEt 2 , -95 to -78 C
140
O
144
142/143 = 1/1
OH
143
142
-
OH
cat. CuI
CO 2t Bu
75%
Scheme 31: Comparison of selectivities observed using an allyl cuprate243 versus a ester
lithium enolate244.
239
Structure of 3ethyl3(hydroxymethyl)oxetane (141) was calculated using the semiempiric AM1 algo
rithmoftheGamessPlugininChem3D11.0.
240
For an explanation, why this conformation is likely to be adopted and not the one where the methyl
groupandthealcoholcometorestbetweenthetwoarmsoftheoxetane,refertoDiagram9.
241
Inthereactionmixture,thealcoholisboundtometalpartoftheformernucleophileanditssolvateshell.
Therefore, the steric demand of a hydroxyl group insufficiently reflects the situation and merely poses a
lowerboundaryforthetruestericbulk.
242
Abiggernucleophilewouldnotonlybemoreselectiveforthestericallylesshinderedspirocycle140,but
alsolendmoresterichindrancetothemonoopenedproduct.
243
Adaptedfromaprocedurepublishedforoxetane:C.Huynh,F.Derguiniboumechal,G.Linstrumelle,Te
trahedronLett.1979,1503.Whenthereactionwasstoppedafter24h,NMRofthecrudematerialshowed
thepresenceofstartingmaterialinaratioofp/sm2/1.
74
MainPart,Chemistry
Thedifferenceinnucleophilicityandsize245mighthelpexplainthedifferentselectivi
tiesobservedinbothreactionsinadditiontothehighertemperaturesinthefirstexample
andthepresenceofaLewisacidinthesecond.Othernucleophileslikearyllithiumcom
poundsmightalsobesuited.Thecompoundclassestherebyaccessibleofferconvenient
handlesfortheirfurtherfunctionalizationandarecomplementarytowhatcanbemade
byconjugateaddition.
3.7 FollowupReactions
Although the sole availability of methodology to prepare oxetanes is sufficient for
themtobeappliedindrugdiscovery,itisimportanttorelatetheirpropertiestothefunc
tional groups they are planned to replace. A comparison between specific examples of
oxetanesandtheirgemdimethyl,carbonylormorpholinecounterpartshadthereforeto
beperformed.Inordertoachievethat,anumberofdiscretecompoundsweremadeand
their properties measured. The routes leading to these do not necessarily expand the
knowledgeofoxetanechemistry,butdemonstrateitsapplicability.
3.7.1 CompoundsoftheOpenChainSeries
ShowninFigure12isthescaffoldontowhichtheoxetaneunitshouldbegrafted.The
synthesis of all of these compounds relies on conjugate additions to Michael acceptors
andwasthedrivingforcetodeveloptheirchemistry.
Figure 12: Locations in which the oxetane should be integrated in the initial series.
244
Adaptedfromaprocedurepublishedforoxetane:M.Yamaguchi,K.Shibato,I.Hirao,TetrahedronLett.
1984,25,1159.
245
Althoughthetbutylgroupseemstobefarawayfromthereactioncenter,itisplausiblethatthelithium
alkoxideof144presentinthereactionmixtureplacesthetbutylgroupclosetotheincomingnucleophile
allowingthecarbonyloftheestertocoordinatetothelithium.
MainPart,Chemistry
75
The difficulty in case of compound 145 was to introduce the methyl group. Initial
1,4addition to ester 89 gives compound 146 in good yield. Removal of the ester is
accomplishedbyreductionfollowedbydecarbonylation246withWilkinsonscatalyst.
Scheme 32: Preparation of 3-aryl-3-methyloxetane 145.

ThenecessityhowevertousestoichiometricamountsofWilkinsonscatalystrenders
thismethodunattractiveonlargerscale.Therefore,amethoddevelopedbyOConnoret
al. in which the rhodium catalyst is regenerated by reaction with dppa was tried for a
simplersubstrate.247
Scheme 33: Decarbonylation of aldehyde 114 with catalytic amounts of Wilkinsons

catalyst.247
Aldehyde114waspreparedbyconjugateadditiontoacrolein90andwasalsousedin
thesynthesisofcompound148.Thereitwascondensedwithnitromethane;248theresult
ingnitroolefinwasthenreducedandreductivelyalkylatedtogivecompound148in20%
yieldover4steps.
Scheme 34: Preparation of compound 148.
246
B.Danieli,G.Lesma,D.Passarella,A.Silvani,J.Org.Chem.1998,63,3492.
247
J.M.O'Connor,J.Ma,J.Org.Chem.1992,57,5075.
248
Adaptedfromaliteratureprocedure:C.Palomo,J.M.Aizpurua,F.P.Cossio,J.M.Garcia,M.C.Lopez,M.
Oiarbide,J.Org.Chem.1990,55,2070.
76
MainPart,Chemistry
Conjugateadditionofacupratetoacrylate89providedester101.249Reductiontothe
correspondingaldehydeandreductiveaminationthengavethefinalproduct.250

Compound150carriesanitrogenbetatotheoxetane,sonitroolefin96waschosento
bethestartingpointforitspreparation.Conjugateadditionofstyrylboronicacid151pro
videsthenitrocompound152whichisthenhydrogenatedandreductivelyalkylated.

Thepreparationofcompound153involvestheconjugateadditionofdimethylamineto
acrolein90.251Theintermediaryaminoaldehyde113isthentrappedwithphosphorous
ylide154andtheresultingstyrenehydrogenatedtogivethefinalproduct.

Thesolepurposeinallcaseswasthepreparationofsufficientamountsofpurecom
poundforthemeasurementofkeypropertiesrelevantindrugdiscovery.Therefore,the
249
Adaptedfromaliteratureprocedure:D.M.Barnes,J.Ji,M.G.Fickes,M.A.Fitzgerald,S.A.King,H.E.
Morton, F. A.Plagge, M. Preskill, S. H.Wagaw,S. J.Wittenberger, J. Zhang, J.Am. Chem.Soc.2002,124,
13097.
250
Procedureusedforthereductiveamination:C.J.Ohnmacht,J.S.Albert,P.R.Bernstein,W.L.Rumsey,B.
B.Masek,B.T.Dembofsky,G.M.Koether,D.W.Andisik,D.Aharony,Bioorg.Med.Chem.2004,12,2653.
ThelowyieldcaninpartbeattributedtodifficultiesinpurifyingthisproductbychromatographyonnAl2O3.
251
Procedureadaptedfrom:A.Chesney,I.E.Marko,Synth.Commun.1990,20,3167.
MainPart,Chemistry
77
yieldsofthesetransformationswerenotoptimized.Innoneofthereactionsabove,by
productsresultingfromopeningoftheoxetaneringwerefound.
3.7.2 OxetaneAnaloguesofSibutramine
Sibutramine (155) and its metabolites belong to a class of compounds called seroto
ninereuptakeinhibitors(SNRI).Sibutramineenhancesbothsatietyandmetabolism.252It
represents an interesting target for the introduction of an oxetane, because of its re
portedsitesofmetabolicoxidation.253
Figure 13: Sibutramine (sites of metabolic attack are marked with arrows) and proposed
oxetane analogues 156 and 157.
Itwasenvisionedtoreplaceeitherthecyclobutaneortheisopropylgroupwithanoxe
taneandtestthesecompoundsfortheirmetabolicstabilityandactivityinvitro.Thesyn
thesisofcompound156commencedwiththeadditionpchlorophenyllithiumtonitroole
fin96in35%yield(seeScheme22).
Scheme 38: Preparation of compound 156.254

252
K.EunJoo,P.EunKyung,S.KweeHyun,HumanExp.Toxicol.2005,24,109.
253
B.Z.Lu,C.Senanayake,N.S.Li,Z.X.Han,R.P.Bakale,S.A.Wald,Org.Lett.2005,7,2599.
254
ThisworkwasdonebyRomanMartyaspartofhisSemesterarbeit.ItbuildsuponworkdonebyLuzi
BarandunduringhisSiRopwork.
78
MainPart,Chemistry
Nitrocompound110couldbetransformedintonitrile158applyingknownmethodol
ogy.255Subsequenttreatmentofnitrile158withisobutylmagnesiumbromideatelevated
temperatureintolueneandreductionoftheadditionproductinsituwithsodiumboro
hydrideprovidedprimaryamine159ingoodyield.256
Scheme 39: Attempted preparation of compound 157.257

Forthesynthesisofcompound157,ketone94waspreparedfromoxetan3one(see
Figure11)viaHornerWadsworthEmmonsreaction.Afterhydrogenationofthedouble
bond,itwasenvisionedtointroducetheaminebyreductiveamination258orbynucleo
philicdisplacement(showninScheme39).Bothapproachesfailedhowevertogiveprod
uct. Since the activity and metabolic stability of compound 156 were both poor, it was
decidednottofollowuponcompound157.
The chemistry en route to these molecules nevertheless includes several interesting
transformations.Theclassof3aryl3cyanooxetanesforexamplemightserveasasurro
gatefortbutylgroupsandisusefulasabuildingblockforadditionreactions.Thesameis
true for the preparation of 3alkyloxetanes like alcohol 160 through hydrogenation and
theirstabilitytowardssodiumborohydride.
255
C.Czekelius,E.M.Carreira,Angew.Chem.,Int.Ed.Engl.2005,44,612
256
FollowingaprocedureforthesynthesisofSibutramineitself:J.E.Jeffery,F.Kerrigan,T.K.Miller,G.J.
Smith,G.B.Tometzki,J.Chem.Soc.,PerkinTrans.11996,2583.
257
Conditions for the Mitsunobu reaction were adapted from: A. Miyadera, K. Satoh, A. Imura, Chem.
Pharm.Bull.2000,48,563.
258
Forarelatedexample,see:P.S.Baran,J.M.Richter,J.Am.Chem.Soc.2004,126,7450.
MainPart,Chemistry
79
3.7.3 SpirocyclicOxetanes
Whereastheseriesofcompoundsdescribedaboveweremerelymadeforthepurpose
of measurement, the spirocyclic oxetanes shown below were also intended to serve as
buildingblocksinthefuture.Thishasconsequencesforthesyntheticefficienciesandthe
stepcountthatshouldbeachievedintheirpreparation.Contrarytotheopenchaincase,
with these compounds it would be possible to study conformationally locked oxetanes.
The piperonyl group was chosen as a substituent to facilitate spectroscopic readout.
Thesecompoundsmaybecategorizedindifferentmanners,butfromasyntheticpointof
view it makes most sense to group them according to the distance between the ring
nitrogenandtheoxetane.Hence,compoundsbearingthenitrogenalphatotheoxetane
all derive from conjugate additions of an amine nucleophile to appropriate Michael
acceptors.
O
162
EtO2C
H2N
HO
H
N
then LiAlH4, 0 C
O
89
O
O
106
CBr4, PPh3
NEt3, MeCN
70%
28
O
72%
Scheme 40: Preparation of azetidine 28.259

Conjugateadditionofpiperonylaminetoacrylate89,followedbyreductionfurnishes
aminoalcohol106.Appelreaction260thenyieldsazetidine28.261
Scheme 41: Preparation of pyrrolidine 29.

259
ThisroutewasdevelopedaspartoftheSemesterarbeitofMaurizioBernasconi.
260
Procedureadaptedfrom:H.Suga,N.Tanimoto,A.J.Sinskey,S.Masamune,J.Am.Chem.Soc.1994,116,
11197.
261
Attemptstobuildupthe6oxa1azaspiro[3.3]heptanesystembyconjugateadditionofazidetoacrolein
90werenotsuccessful.
80
MainPart,Chemistry
Pyrrolidine29waspreparedinasimilarmannerby1,4additionofpiperonylamineto
acrolein90.Theintermediaryaminoaldehydewastrappedbyreactingitwithmethy
lentriphenylphosphorane (163).251 The low yield probably stems from competing 1,2
additionofpiperonylaminetothealdehydeandconcomitantsidereactionsoftheresult
ing hemiaminal or imine.262 Homoallylic amine 115 then underwent mercurymediated
hydroaminationtogivethefinalproductinlowyield.263
Scheme 42: Preparation of piperidine 30.

Contrarytowhatwasseenforpiperonylamineandinaccordancewiththeobservation
incaseofdimethylamine264,Nallylpiperonylamine(164)addedcleanlytoacrolein90.265
Subsequent trapping with methylentriphenylphosphorane (163) yielded diene 165.251
262
Abyproductcouldbeisolatedin2%yieldfromthisreactionthatmostlikelystemsfromtherearrange
mentoftheNpiperonylimineofacrolein90:
263
Procedureadaptedfrom:J.Blid,P.Brandt,P.Somfai,J.Org.Chem.2004,69,3043.Thereactionwith
lessreactiveHg(OAc)2(accordingto:N.S.Karanjule,S.D.Markad,V.S.Shinde,D.D.Dhavale,J.Org.Chem.
2006,71,4667.)insteadofHg(O2CCF3)2stoppedatlowconversion.
264
RefertoScheme37fordetails.
265
Theincreaseinreactiontimefrom50minfordimethylamineto5dincaseofNallylpiperonylamine
(164)likelystemsfromincreasedstericdemandandreducednucleophilicityofthelatter.
MainPart,Chemistry
81
Ringclosing metathesis executed on the in situ protonated amine 165 then gave 3,4
dehydropiperidine166266whichwashydrogenatedtothefinalproduct30.Interestingly,
significantamountsofsecondaryamine167wereformedaswell.267
Spirocyclesinthisseriesthatcontaintheoxetaneinbetapositiontothenitrogenare
only partially derived from oxetan3one. In two out of three cases, other approaches
yieldedtherespectiveproductmoreeasily.
O
168
O
NH2
O
OO
130
H
O
NaHB(OAc)3
CH2Cl2, rt
O
24
73%
Scheme 43: Preparation of compound 24.268

Withtheavailabilityofoxalatesalt130inlargequantities(seechapter3.5),azetidine
24couldbepreparedbyreductivealkylationwithpiperonal(168).269
266
Procedure adapted from: D. L. Wright, J. P. Schulte, M. A. Page, Org. Lett. 2000, 2, 1847. In situ
hydrogenation(J.Louie,C.W.Bielawski,R.H.Grubbs,J.Am.Chem.Soc.2001,123,11312.)ofthealkene
afterthemetathesisdidnotgiveanyproduct.
267
Itisnotclearbywhatmechanismthesideproductisformed.Itmightresultfromtheinsertionofrho
diumintotheCNbond(facilitatedbytracesofacid)togiveanallylrhodiumspecieswhichisthenhydro
genated.
268
ThiscompoundwaspreparedbyAndreasBucklaspartofhisSemesterarbeit.Procedureadaptedfrom:
B.Poulain,D.Horvath,B.Bonnet,C.Eckhoff,B.Chapelain,M.C.Bodinier,B.Deprez,J.Med.Chem.2001,
44,3378.
269
Procedureadaptedfrom:S.P.Khanapure,D.S.Garvey,D.V.Young,M.Ezawa,R.A.Earl,R.D.Gaston,X.
Q.Fang,M.Murty,A.Martino,M.Shumway,M.Trocha,P.Marek,S.W.Tam,D.R.Janero,L.G.Letts,J.
Med.Chem.2003,46,5484.
82
MainPart,Chemistry
Scheme 44: Preparation of pyrrolidine 26.

Conjugate addition of nitromethane to acrylate 89 gave nitroester 103 in excellent
yield. This compound was then reduced to the corresponding aldehyde270 which was
reductively cyclized to give crude spiropyrrolidine 169. Reductive alkylation then fur
nishedthefinalproduct26.
Scheme 45: Preparation of piperidine 27.

The preparation of hydroxyester 144 through selective ring opening of spirooxetane
140hasbeendiscussedextensivelyonpage71.Reduction,mesylationandaminationof
ester144thenresultsinpiperidine27.
270
Thisaldehydecanalsobeobtainedfromthereactionofacetaldehydewithnitroolefin96inthepresence
ofcatalyticamountsofpyrrolidinein46%yield.Duetosidereactions,howevertheyieldsinthisreaction
arenotveryreproducibleandtheproductisdifficulttoisolate.
MainPart,Chemistry
83

Piperidine25inwhichtheoxetaneispositionedgammatothenitrogenwasmadeina
fivestep sequence that did not require any purification of intermediates. The route
commencedwiththeconjugateadditionofdimethylmalonate(170)toacrylate89,fol
lowed by Krapcho demethoxycarbonylation.271 Subsequent reduction, mesylation and
aminationyieldedtheproduct25.
3.7.4 ReactionsofSulfone93.
The,unsaturatedsulfone93hasthepotentialtobecomeaverypowerfulbuilding
block. There is abundant methodology known that provides ways to reductively cleave
thesulfoneundermildconditions.272Moreover,itmightbeusedasahandlefortheJulia
olefinationanditsvariations.273
Figure 14: Nucleophilic additions to ,-unsaturated sulfone 93 and follow-up reactions.
271
Procedureadaptedfrom:F.Matsuda,S.Terashima,Tetrahedron1988,44,4721.
272
a)I.Das,T.K.Pal,C.G.Suresh,T.Pathak,J.Org.Chem.2007,72,5523.b)D.Diez,M.T.Beneitez,I.S.
Marcos, N. M. Garrido, P. Basabe, J. G. Urones, Tetrahedron: Asymmetry 2002, 13, 639. c) T. Kimura, T.
Nakata,TetrahedronLett.2007,48,43.d)G.H.Lee,E.B.Choi,E.Lee,C.S.Pak,TetrahedronLett.1993,34,
4541.
273
a) M. Julia, J. M. Paris, Tetrahedron Lett. 1973, 4833. b) P. J. Kocienski, B. Lythgoe, I. Waterhouse, J.
Chem.Soc.,PerkinTrans.11980,1045.Forareviewofsulfonechemistry,see:B.M.Trost,Bull.Chem.Soc.
Jpn.1988,61,107.
84
MainPart,Chemistry
Afewpreliminaryresultsindicatethatcarbonaswellasheteroatomnucleophilescan
addto,unsaturatedsulfone93.Desulfonationbystirringwithmagnesiuminmethanol
then gave the corresponding 3methyloxetanes. While 3aryl3methyloxetanes are also
accessiblebydecarbonylationoftherespectivealdehydeswithWilkinsonscatalyst(see
page 74), the possibility to prepare 3amino3methyloxetanes in one pot constitutes a
verysimplemethodfortheintroductionofanoxetaneontoascaffold.
Scheme 47: Additions to ,-unsaturated sulfone 93 and consecutive reductive sulfone

cleavage.
Foradditionproductslike181and183,decompositionwasobservedunderthesecon
ditions, maybe due to elimination.274 Further experiments might solve this problem by
addingcatalyticamountsofmercury(II)salts272dtothereactionorbyswitchingtoRaney
Nickel272b,c as a reductant. Attempts to use sulfone 172 in order to couple it with
274
Theexperimentsinwhichdecompositionwasobservedhavenucleophilesincommonthatarerelatively
goodleavinggroups.
MainPart,Chemistry
85
piperonal(168)inaJuliareaction,failedtogiveproduct.Alikelysolutiontothiscouldbe
touse2pyridylsulfone184asanacceptor.
Scheme 48: Addition products of 2-pyridylsulfone 184 and their proposed ability to undergo JuliaKocienski olefination.
Thistypeofsulfoneshasbeenreportedtoundergorhodiumcatalyzedconjugateaddi
tionsofarylboronicacidsandalsoonestepolefinations,followingtheJuliaKocienski275
protocol.276
3.8 ReagentCompatibilityofOxetanes
Manyofthereagentsusedinthecourseofthisworkcouldinprincipleposeathreatto
the integrity of the oxetane ring by their inherent acidity and/or nucleophilicity. There
fore,itisimportanttoknowwhichreactionconditionsaretoleratedbytheoxetanemoie
ty.Thefollowingtablecontainsacompilationofconditionsthatwerefoundtobetole
ratedorleadtodecompositioninoneorseveralcases.
Table 6: Compatibility of oxetanes to different reaction conditions.277
Reflux
RMgX,NaOH,RNH2,AcOH,Krapcho
rt
NaBH4,BH3THF,aqueousacid
NaBH4,BH3THF
0C
LiAlH4,TFA/Et3SiH,H3PO4(often)
sometimes:TFA/Et3SiH,H3PO4
Reflux
rt
0C
78C
aqueousHCl
intramolecularnucleophilesa
HClindioxane
often:TFA/Et3SiH,H3PO4
LiAlH4(slowopening)
alkoxidesorcarboxylates,iftheyareadequatelypositionedtoformafivememberedring
275
a)P.R.Blakemore,W.J.Cole,P.J.Kocienski,A.Morley,Synlett1998,26.b)J.B.Baudin,G.Hareau,S.A.
Julia,O.Ruel,TetrahedronLett.1991,32,1175.
276
P.Mauleon,J.C.Carretero,Org.Lett.2004,6,3195.
277
Onlyconditionsarelistedthatmightcauseconcernofringopeningbecauseoftheacidityornucleophi
licityofthereagentsinvolved.
86
MainPart,Chemistry
3,3Disubstitutedoxetanesareingeneralmoreresistanttodecompositionthanmono
substitutedones.Stronganhydrousacidisproblematicforbothgroupsandcanleadto
decomposition for example when trying to cleave a Boc group. Other commonly used
reagentslikestrongbaseorreducingagentsarewelltolerated.
Theinitialconcernsthatoxetaneswouldbetoounstabletowithstandcommonlyused
synthetic methods can thereby be dispelled. The synthetic data collected clearly show
that the building block approach for the preparation of oxetanes is viable, that abroad
varietyofcompoundclassescanbegenerated,andthatthesecanbefurtherelaborated
tomorecomplexstructures.
PhysicochemicalandPharmacologicalProfileofOxetanes
87
AbroadrangeofpropertieswasmeasuredforanumberofoxetanesatF.HoffmannLa
Roche AG in Basel. For some of them, the respective gemdimethyl or carbonyl com
pounds were also submitted in order to shed light on the hypothesized analogies with
oxetanes.Initially,aseriesofcompoundswasinvestigatedinwhichtheoxetanemoiety
wasintegratedatdifferentpositionsofthescaffoldshowninScheme49.
gemMe2
185
186
187
188
189
Oxetane
145
148
149
150
153
Scheme 49: Linear scaffold of which oxetane and gem-dimethyl derivatives were prepared
(indicated by the arrows).
Manyoftheproblemsencounteredindrugdiscoverycumulateinthescaffoldshown
in Scheme 49. It is highly lipophilic, poorly soluble and features different positions for
metabolicattack.278Furthermore,thecombinationofaterminalbasicamineandtheli
pophilicarylatedchainshouldrenderthemoleculeamphiphilic279andasubstrateofthe
hERGreceptor.280 By that, this scaffold represents a group of molecules for which the
integrationofanoxetanemightbeconsidered.Therespectiveoxetanederivativeswould
278
AmetabolitedeterminationatRocheforcompound185showedthatitsmainmetabolitesarethecor
respondingNoxide,abenzylicalcoholandaprimaryalcoholresultingfromattackonthetbutylgroup.
279
Forthedetaileddiscussionofamphiphilicityanditsrelevancetodrugdiscovery,refertoChapter4.2.4.
280
ForthedetaileddiscussionofthehERGreceptoranditsrelevancetodrugdiscovery,refertoChapter
4.2.4.
88
highlighttheabilityoftheoxetanetoinfluencethesepropertiesdependingonthestruc
turalcontext.
Scheme 50: Cyclic scaffolds for which oxetane, gem-dimethyl and carbonyl derivatives
were prepared (indicated by the arrows).
The series of spirocyclic oxetanes shown in Scheme 50 was chosen to serve several
purposes. A comparison of the oxetanes with the corresponding carbonyl compounds
wouldgiveanindicationastowhethertheanalogyonpapertranslatesintosimilarphysi
cochemicalproperties.Additionally,thesespirocyclicoxetanesarerelatedtomorpholine
32.Thepiperonylgroupwasselectedinordertofacilitatethemeasurementsthatdepend
onUVabsorptionforsignalreadout.Incasetheirpropertieswerepromising,thespiro
cyclicoxetanesofthisseriescouldcontrarytothefirstlinearscaffolddirectlyserveas
buildingblocksthemselves,easilyattachabletoreallifeexamples.
Table 7: Compilation of the physicochemical and biochemical properties measured.281
281
No.
LogD[a]
(LogP)[b]
gem-Me2
190
0.8 (3.1)
290
0 / 16
oxetane
24
0.5 (1.2)
24000
3/7
8.0
n.d.
Sol.
[c]
Clint (h/m)
[d]
pKa
[e]
9.6
carbonyl
205
n.d.[f]
n.d. [f]
n.d. [f]
gem-Me2
191
2.3 (4.4)
220
23 / 31
9.5
oxetane
25
1.0 (2.0)
1400
6 / 22
8.3
carbonyl
206
1.2 (1.6)
4000
120 / 88
7.5
gem-Me2
192
1.4 (3.7)
40
10 / 39
9.7
oxetane
26
0.7 (1.5)
730
2 / 27
8.1
carbonyl
207
-0.1 (-0.1)
4100
100 / 580
6.1
gem-Me2
193
2.3 (4.3)
13
31 / 89
9.4
oxetane
27
1.7 (2.3)
2000
16 / 55
7.9
carbonyl
208
0.1 (0.5)
2100
120 / 120
7.6
gem-Me2
194
0.1 (2.8)
380
7 / 14
10.1
oxetane
28
1.3 (1.3)
1400
21 / 26
6.2
carbonyl
209
1.1 (1.1)
2100
5 / 190
[f]
Measurements performed at F. HoffmannLa Roche, Basel by: Dr. Manfred Kansy, Pia Warga, Isabelle
Parrilla,Dr.StefanieBendels,Dr.HolgerFischer,FrankSenner,BjrnWagnerandDr.FranzSchuler.
89
No.
LogD[a]
(LogP)[b]
Sol.
gem-Me2
195
0.9 (3.5)
oxetane
29
carbonyl
[c]
Clint (h/m)
pKa
[d]
[e]
41
0 / 13
10.0
1.9 (1.9)
2100
31 / 74
6.3
210
1.2 (1.2)
1500
5 / 16
gem-Me2
196
1.1 (3.9)
30
0 / 18
10.2
oxetane
30
2.2 (2.4)
750
19 / 230
7.0
carbonyl
211
1.6 (1.6)
6200
8 /39
31
1.6 (1.8)
>2600
15 / 41
7.1
x=3
197
0.9 (3.1)
450
8 /18
9.6
x=2
198
0.2 (2.5)
580
6 / 18
9.7
x=1
199
-0.1 (2.1)
2500
0 / 11
9.5
32
1.5 (1.6)
8000
9 /8
7.0
gem-Me2
185
1.8 (4.3)
<1
16 / 417
9.9
oxetane
145
0.8 (3.3)
4400
0 / 43
9.9
CH2
200
1.8 (4.3)
52
37 / 523
9.9
gem-Me2
201
2.3 (4.4)
220
13 / 502
9.8
oxetane
148
1.7 (3.9)
270
0 / 147
9.6
gem-Me2
202
n.d. (n.d.)[g]
21 / 502
9.5
oxetane
149
1.7 (3.5)
4100
6 / 13
9.2
gem-Me2
203
n.d. (n.d.) [g]
/ 858
9.4
oxetane
150
3.3 (4.0)
25
42 / 383
8.0
gem-Me2
204
n.d. (n.d.) [g]
20 / 423
10.4
oxetane
153
3.3 (3.6)
57
57 / 13
7.2
OH
71
n.d. (n.d.) [g]
74000
0 / 68
9.6
73
-0.5 (2.0)
6100
6 / 50
9.9
81
-0.1 (2.4)
4000
2 / 27
9.9
R = piperonyl; [a] logarithmic n-octanol/water distribution coefficient at pH 7.4; [b] intrinsic

lipophilicity of the neutral base, according to logP = logD + log10(1+10(pKa-pH)); [c] intrinsic
solubility of the neutral base, obtained from the experimental thermodynamic solubility (g/mL)
in 50 mM phosphate buffer at pH 9.9 and 22.51 C, and corrected for pKa; [d] intrinsic clearance rates in min-1 mg-1 L measured in human (hClint) and mouse (mClint) liver microsomes;
[e] amine basicity in H2O measured spectrophotometrically at 24 C; for details, see supplementary material; [f] data not determined due to insufficient stability of compound 205; [g] not
determined due to insufficient UV-absorption.
90
Table7combinesthepropertiesofallcompoundsmeasured.Adiscussionofabsolute
numbers,howeverwouldnotprovideinsightinwhetherthesubstitutionofsomefunc
tionalgroupforanoxetanemadesense.Therefore,inthefollowing,pairsofvaluesare
comparedandtheirimplicationsforagivensubstitutiondiscussed.
4.1 MeasuredProperties
Thechangesseenuponincorporationofanoxetanetotheinvestigatedscaffoldscan
largelybeattributedtothepolarityofthecyclicetheranditselectronwithdrawingna
ture as a substituent. A very important role, however also plays the threedimensional
structureofoxetanestosupportorrejectthehypothesesdrawnaboutstructuralanalo
gies.
4.1.1 StructuralConsiderations
The Cambridge Structural Database (CSD) contains xray structures of 14 oxetanes
solely substituted on the 3position. This group however is structurally very homogene
ous.
Scheme 51: Oxetanes registered in the Cambridge Structural Database (CSD).282

The disproportional occurrence of 212 as a structural motif reflects the ease with
whichthosecompoundsaresyntheticallyaccessible.283Itwasthereforenecessarytoob
tainxraystructuresthatwouldbemorerepresentativefortheenvisionedapplicationsin
drugdiscovery.
282
Searchdoneonversion5.29(November2007).AHUFEO:G.H.Lee,E.B.Choi,E.Lee,C.S.Pak,Tetrahe
dronLett.1993,34,4541.LICSUL:J.Vogelgesang,G.Huttner,E.Kaifer,P.Kircher,P.Rutsch,S.Cunskis,Eur.
J.Inorg.Chem.1999,2187.
283
Seepage67fortheirpreparation.
91
O
NO2
O
t
Bu
OH O2 N
213
O
NO2
Ph
HN
H2 C2 O4
NO2
216
126
NMe2
215
214
N
O
R
N
Ph
N
N R
25
30
166
29
SO 2Ph
NH 2
O
217
218
O
140
R=
93
Scheme 52: Compounds of which x-ray structures were prepared.284

Allthesecompounds,withtheexceptionof2,6dioxaspiro[3.3]heptane(140)andsul
fone93whichweremeasuredonlytoelucidatetheirreactivity,werebundledinadata
base that allows to perform statistical analyses in combination with the CSD.285 This
helped to define more precisely the structure of the oxetanes that are subject of this
study.
NumberofCompounds
14
12
avg. ring puckering: 7.9
10
8
H
R'
4
2
0
04
48
812 1216
RingPuckering
1620
2021
Diagram 8: Histogram showing the distribution of puckering angles.286
284
XraystructureswerepreparedbyDr.W.B.Schweizer(ETHZrich)andAndrAlker(Roche).
285
TheprogramPrequestwasusedtocombinexraystructurefilesintoadatabasethatcanthenbereadby
thedataretrievalprogramConquestwhichisusedtosearchtheCSD.
286
ThedatawasretrievedfromCSDandthedatabaseofoxetanesdescribedinRef.285usingtheprograms
ConquestandVista.
92
Theintroductionofsubstitutionatthe3positionincreaseseclipsinginteractionswith
theadjacentmethylenegroups.Therefore,theoxetaneringispuckeredinmanyofthese
structures.Theaverage(7.9)aswellasthehighest(21)puckeringangleinthissample
arestillmuchsmallerthanincyclobutane(35).Thislowpropensityforpuckeringisim
portant,asthestructuralanalogytocarbonylandgemdimethylgroupsfitsbestforpla
naroxetanes.
91
84
112
2.14
Picture 11: Averaged structural parameters of 3-substituted oxetanes.287

A more detailed analysis reveals the effect, the steric bulk of an oxetane has on the
conformationalpreferencesofitssubstituents.ShowninDiagram9isthechangeincon
formation that occurswhen a methylene group is replaced with an oxetane in the sub
structureRCH2CH2R(R,RH).
16
14
NumberofHits
12
10
8
6
4
2
0
030
3060
6090
90120
120150 150180
Diagram 9: The introduction of an oxetane leads to a preferred gauche relationship of R

and R.288
287
2oxa6azaspiro[3.3]heptanes216and126wereexcludedforthedeterminationoftheexocyclicbond
anglesasthespirocyclicringsystemlimitsthisangleto~87.
93
ForRCH2CH2RtheantiperiplanararrangementofRandRformsanenergeticmin
imum(=0).Intheoxetanecase,thisconformationisrarelyfound;insteadthesynclinal
arrangement(120)dominates.InmostofthesurveyedstructuresRconsistsatleast
ofamonosubstitutedmethylenegroupwhichhasastericdemandsimilartothemethy
lenegroupsofanoxetane.289Thereforeonecouldexpectequaldistributionbetweenthe
antiperiplanar and the synclinal conformations. In contrast, Diagram 9 shows only two
exampleswheretheantiperiplanarconformationisrealized.290Thisislikelyaresultofthe
small oxetaneCCC bond angle ( 84) that leads to a concentration of steric bulk be
tween the two methylene groups of the oxetane.291 Hence, the antiperiplanar
conformationisdisfavored.292Inthexraystructureofpiperidine30,thiseffectforcesthe
piperonylsubstituentintotheaxialposition.
xray
30
Equation 13: Axial orientation of the piperonyl substituent in piperidine 30 in the protonated state (left, NMR) and in the free base (right, x-ray).
Determinationoftheconformationofprotonatedpiperidine30inaqueoussolutionby
NMR confirms this result, showing only signals of the axial conformer.293 In the proto
288
Derivedfromthecombineddatabaseof3substitutedoxetanesforthesubstructure
,R,RH.
ItmightbeexpectedthatHCHbondangleinoxetanesiswidened,asseenforthe3positionincaseit
carriessubstituents.ThiswouldleadtohigherstericdemandoftheoxetaneinthedirectionofR.TheHC
HbondanglesfoundhoweverdonotdeviatesignificantlyfromwhatisexpectedforaHC(sp3)Hcenter.
Thisisalsothecaseforthesubsetofstructures,wherethepositionofhydrogensisdeterminedfromthe
electrondensitydistributionandnotcalculatedwithaforcefieldmethod.
290
Antiperiplanarconformationsarefoundin3,3bis(methylnitraminomethyl)oxetane(DUMPAC,C.George,
R.Gilardi,ActaCrystallogr.,Sect.C:Cryst.Struct.Commun.1986,42,1161.)andinaminooxetane215(see
Picture12toprightforapictorialrepresentation).InDUMPACthealmostplanarmethylnitraminomethyl
substituentseemstobeabletoorientitselfinawaytoavoidstericinteractionswiththeoxetanering.For
aminooxetane 215 potential doublegauche pentane interactions with the sterically demanding branched
N,NdimethylaminosubstituentRseemtobethereasonwhythemethylenegroupisforcedintotheanti
periplanarorientation.
291
SeePicture15onpage106fordetailedexplanation.
292
Based on these results one would predict that ring closures leading to spirocyclic oxetanes are faster
thanfortheirgemdimethylanalogues.
293
2DNOESYexperimentdonebyDr.JosefSchneider(Roche,Basel).SeeExperimentalfordetails.
289
94
nated state, partial cancellation of the dipole moments also helps to stabilize the axial
conformationwhichinturnhasimplicationsonpKa.
1.96
2.92
2.82
2.25
1.95
Picture 12: Examples for hydrogen bonding(top left and bottom row) and dipolar (top
row) interactions of oxetanes.294
Theabilityoftheoxetanetoactasahydrogenbondacceptorandtodonateelectron
densityisreflectedinseveralxraystructures.TheexamplesinPicture12highlighthow
accessible the oxygen is for hydrogen bonding and dipolar interactions. In the top left
example, the oxetane even accommodates two ligands. Another example for a dipolar
interaction of an oxetane with a nitro group was found in the xray structure of com
pound 215 (top right) in which the oxetane orients itself almost perpendicularly to the
planeofthenitrogroupataNOdistanceof2.82.
For3substitutedoxetanes,ringpuckeringissmallinmostcases,despitetheincreased
eclipsing interactions. The presence of an oxetane in a molecule has profound conse
294
IVAGUH:A.M.Korolev,L.T.Eremenko,L.V.Meshikhina,I.L.Eremenko,G.G.Aleksandrov,N.P.Kono
valova,V.P.Lodygina,Russ.Chem.Bull.2003,52,1859.
95
quencesforitsconformation.Alkylchainsusuallyresideinanallanticonformation,steric
repulsiondisfavoringthegaucheorientation.Uponintegrationofanoxetane,functionali
ties beta to it prefer to be gauche, the anti conformer being rarely observed in xray
structures. This gauchedirecting effect differentiates an oxetane from a gemdimethyl
groupwhichleadstoapproximatelyequalpopulationofantiandgauche.Alsofoundinx
raystructuresarehydrogenbondstooxetanes,documentingtheavailabilityoftheoxy
genlonepairstodonateelectrondensityandparticipateindipolarinteractions.
4.1.2 AcidDissociationConstantpKa
Ionizedmoleculesaremoresolubleinwaterthanneutralones.Becauseaqueoussolu
bilityiscriticalfororalbioavailability,mostdrugscontainionizablegroups.295Electrostatic
attractionofionizedfunctionalitiesisalsoanimportantcontributortotargetbinding.
acidic;
20%
non
ionizable;
5%
basic;
75%
Diagram 10: Most drugs contain ionizable functionalities.295

TheextenttowhichacompoundisionizedinsolutionismeasuredbythepKa.Itisde
finedasthenegativedecadiclogarithmoftheheterolyticdissociationconstant.
log
Equation 14: Definition of pKa

Consequently,strongacidshavealowpKaandaremoreionizedatagivenpH.Strong
baseshaveahighpKa,astheirconjugateacidsareweak.Althoughhighsolubilityisdesir
295
E.H.Kerns,L.Di,DruglikeProperties:Concepts,StructureDesignandMethods:fromADMEtoToxicity
Optimization, Elsevier, Amsterdam, Boston, Heidelberg, London, New York, Oxford, Paris, San Diego, San
Francisco,Singapore,Sydney,Tokyo,2008.
96
able and correlated with ionization, ionized compounds have difficulties permeating
through lipidbilayer membranes.296 Therefore it is often necessary to finetune pKa in
ordertobalancesolubilityandpermeability.
Theelectronwithdrawingnatureoftheoxetanecanbeusedtotemperthebasicityof
aproximalamine.ThedecreaseinpKadependsonthetopologicaldistancebetweenthe
two. Diagram 11 shows how the introduction of an oxetane changes the basicity of an
amine.
0
0.5
pKa
1
1.5
openchain
piperidines
2.5
3
pyrrolidines
azetidines
3.5
Diagram 11: Change in pKa depending on the distance to an oxetane.297

Thereareseveraldiscrepanciesbetweenthenumbersforopenchainandcycliccom
pounds. It can be argued that in the cyclic cases, the amine experiences the electron
withdrawingeffectoftheoxetaneviatwosubstituents.Onewouldexpectthattheeffect
oftheoxetaneonthepKaofthecyclicaminesshouldbestrongerthanintheopenchain
case. Moreover, ceteris paribus the effect should become more pronounced with de
creasingringsize,asforthesecondsubstituentthedistancebetweenoxetaneandamine
becomessmaller.Thiswouldaccountforthepiperidinecaseinwhichtheoxetaneisposi
tionedgammatotheamineandwherepKaisapproximatelytwiceasbigasintheopen
chaincase.
Forthecasehowever,theoppositetrendisfound.Theshiftsforthecyclicsystems
are consistently smaller than in the open chain and decrease from piperidine to azeti
296
Low membrane permeability does not only affect permeation throughcell membranes, butalso ham
persintestinaluptakeandthusreducesoralbioavailability.
297
DifferenceofpKabetweentheunsubstitutedscaffoldandtheonethatcontainsanoxetane.
97
dine.298Whereasintheopenchainandalsointhe6memberedringstaggeredconforma
tionsdominate,insmallerringseclipsinginteractionsbecomeprevalent(Picture13).
Picture 13: Staggered conformation of piperidine 27 compared with the partially eclipsed
conformation of azetidine 126.299
Inarelatedstudy,itwasfoundthatthefluorineinducedpKashiftsaremuchsmallerin
pyrrolidines than in piperidines. This was explained on the basis of the conformational
dependenceofpKashiftsandthedifferentconformationalpreferencesincyclicsystems,
The authors state that more experiments are necessary to elucidate the origin of these
results.300Itseemslikelythatintheoxetanecasethesameeffectsareresponsibleforthe
decreasedpKashifts.
Incasewheretheoxetaneislocatedalphatotheamine,amarkeddecreaseinbasicity
isfoundforpyrrolidine29andazetidine28.AsshowninEquation13,thepiperonylsubs
tituentadoptsanaxialconformationowingtothestericrequirementsofthebulkyoxe
tane unit. This steric congestion is alleviated partially in the five and fourmembered
ringsasaresultoftheincreasedspatialseparationbetweenvicinalgroups.
298
ComparedtowhatweretobeexpectedbasedonthepKashiftsintheopenchain,theextentastowhich
thiscalculateddecreaseisrealisedisinpiperidine2777%,inpyrrolidine2662%andinazetidine2439%of
thetheoreticalvalue.TheoreticalvalueswerecalculatedbyaddingtheappropriatepKashiftsoftheopen
chain,e.g.forpiperidine27:pKa()+pKa().
299
Piperidine27wasoptimizedusingChemBio3D11(GamessPlugin,AM1).Thestructureofazetidine126
wasdeterminedbyxraycrystallography(benzhydrylgroupomittedforclarity).
300
M.Morgenthaler,E.Schweizer,A.HoffmannRoder,F.Benini,R.E.Martin,G.Jaeschke,B.Wagner,H.
Fischer, S. Bendels, D. Zimmerli, J. Schneider, F. Diederich, M. Kansy, K. Mller, ChemMedChem 2007, 2,
1100.
98
H
N
O
Picture 14: Equatorial piperonyl substituent in an x-ray structure of pyrrolidine 29 (left).

Unfavorable dipole alignment leads to destabilization of the deduced structure of
protonated 29.
This is reflected in the different conformational preference of pyrrolidine 29. Upon
protonation, a conformation would result in which the dipole moments of the oxetane
andtheprotonatednitrogenarepartiallyaligned.Thisenergeticcostrendersthepyrroli
dine 29 and azetidine 28 less basic than the piperidine, in which the proton resides in
equatorial position and the dipole moments cancel each other out partially (Equation
13).301
4.1.3 Lipophilicity
Thelipophilicityofacompoundhasamajorimpactonitsaqueoussolubility,absorp
tionandmetabolicstability.302Thelipophilicityisdefinedastheaffinityofamoleculefor
alipophilicenvironment.Itwastraditionallymeasuredbydeterminingthepartitioningof
a compound between octan1ol and aqueous buffer. The resulting partition coefficient
thenisusedtodefinethenumericrepresentationsoflipophilicity,LogPandLogD.
Equation 15: Definition of LogD and LogP as logarithmic partition coefficients for a basic
compound.303
301
NMRanalysisoftheprotonatedpyrrolidine29didntgiveaclearpictureastowhatthepreferredcon
formationis.Thisisprobablyduetothehighconformationalflexibilityoffivememberedrings.
302
a)C.Hansch,A.Leo,S.B.Mekapati,A.Kurup,Bioorg.Med.Chem.2004,12,3391.b)F.Lombardo,R.S.
Obach,M.Y.Shalaeva,F.Gao,J.Med.Chem.2002,45,2867.
303
Thedefinitionforanacidisanalogous.Theconcentrationofionizedcompound[HB]+Oct.intheoctanol
layerissmallinmanycases.
99
LogDandLogParenotidentical,unlessthecompoundisnotionizedatthepHofthe
measurement.TheLogDvalueisdependentonthepKaofthecompoundandthepHof
themedium,astheconcentrationofchargedmoleculesispartofthedefinitionofLogD.
lg 1
10
Equation 16: Correlation of LogP and LogD.

Thepresenceofanoxetaneinfluencesboth,thelipophilicityofascaffoldaswellasthe
pKa of a proximal amine. Therefore, it makes sense to treat both effects independently
andlookatthechangeinLogPtoassesstheinfluenceoftheoxetaneonlipophilicity.
LogP
0.2
0.4
0.6
openchain
0.8
piperidines
pyrrolidines
azetidines
1.2
openchain
1.5
piperidines
LogD
pyrrolidines
0.5
azetidines
0
0.5
1
1.5
Diagram 12: Change in lipophilicity upon integration of an oxetane.

Theexchangeofamethylenegroupforanoxetaneresultsforallmoleculestestedina
reduction of LogP. Therefore the polarity of the oxetane oxygen overcompensates the
lipophilicityofthetwoadditionalmethylenegroups.Theextentofthiseffectdependson
100
thetopologicaldistancebetweentheoxetaneandtheamine.Additionally,anoscillation
isseenintheopenchaincase,withtheeffectoftheoxetanebeinglesspronouncedin
thebetaandthedeltacase.Whereasitisnotclearwhattheoriginoftheoscillativelipo
philicityintheopenchaincaseis,thedecreaseinlipophilicityforcompoundswithsepa
ratedpolargroupscanbeattributedtoseveralfactors.Aseachpolargroupbuildsupits
ownhydrationspherethroughhydrogenbondingorelectrostaticinteractions,thevicinity
oftwopolargroupsleadstoanoverlapofhydrationspheresandthustolesssolvation.
Throughthecloseproximityoftwopolargroups,bothactaselectronwithdrawinggroups
oneachother.Thatmeanstheoxetanesreducestheelectrondensityontheamine(as
evidencedbyitsinfluenceonthepKa),butalsotheamineactsasanelectronwithdrawing
groupontheoxetaneandmakestheoxygenlesspronetoactasanelectrondonor.304
TheoxetaneleadsoveralltoareductioninLogPoftheunderlyingscaffold,evenwhen
replacingamethylenegroup.ChangesinLogDmerelyreflectthedifferentpKavaluesof
the compounds measured. They show however that the replacement of a methylene
groupfarawayfromabasiccenterhasthehighestimpactonLogD.Theseobservations
haveconsequencesfortheaqueoussolubilityofoxetanes,asthispropertyiscloselyre
latedtolipophilicity.
4.1.4 AqueousSolubility
Aqueoussolubilityisoneofthemostimportantpropertiesinmedicinalchemistry.Low
solubilityofacompoundusuallyleadstolowabsorptionandloworalbioavailability.Dur
ing lead optimization, solubility problems can intensify, as lipophilic groups are often
addedtothescaffoldofaleadcompoundscaffoldtoimprovetargetbinding.305Forthis
study, the thermodynamic solubility of the respective compound was measured in an
aqueousbufferatpH9.9.AtthispHalmostnoprotonationofthebasiccentersoccurs,so
thesolubilitymeasuredisnotinfluencedbychangesinpKaoftherespectiveamineorthe
formationofmicelles.
304
Electrondensitythatiswithdrawnfromonegroupendsupontheotherandviceversa.Sooverallthere
isnonetlossofelectrondensity,ratherareducedgain,asproximityoftwopolargroupsmakesthemshare
thesamepoolofelectrondonating(alkyl)groups.
305
Francisco,Singapore,Sydney,Tokyo,2008.p.56.
101
openchain
IncreaseinSolubility
5000
4100
piperidines
pyrrolidines
500
azetidines
50
9.6
5
1.7
0.5
0.6
1.3
Diagram 13: Factor by which aqueous solubility at pH 9.9 increases upon replacement of
a methylene group with an oxetane.
Diagram13highlightshowstrongtheinfluenceofanoxetanecanbeonthesolubility
ofacompound,iftheunderlyingscaffoldishighlylipophilicasincaseofthelinearchain.
There, compounds with an oxetane instead of a methylene group are between 25 to
4,000timesmoresoluble.
Fortheseriesofspirocyclicoxetanes,thefactorsbywhichsolubilityincreasesareless
pronounced,probablybecausethescaffolditselfismorepolar.Butstill,someoftheoxe
tanederivativesshowimpressivegainsinsolubility.Remarkableinthisrespectistheaze
tidine24withtheoxetaneinposition.Itssolubilityof24,000g/mLalmostreachesthe
limitofwhatcanbemeasuredreliably.Thiscompoundprobablybenefitsfromthecon
currenceoftwofactors:
1. Thepartiallyeclipsedconformationoftheazetidineringinsulatesthebasicamine
from the electronwithdrawing effect of the oxtetane and vice versa. This is evi
dencedalsobytheunexpectedlylowpKashifttheoxetaneinducesinthisstruc
ture(seeDiagram11).
2. Asthetwosubstituentsoftheoxetaneringaretetheredtogethertoformthespi
rocyclic azetidine, the oxetane oxygen atom becomes sterically more accessible
forsolvation.
Thismightexplainthesignificantsolubilitydifferencetotheoxetanylcompound28,
the only compound that was found to be less soluble than its methylene counterpart.
102
Inthismolecule,theamine,beingalphatotheoxetane,experiencesthestrongelectron
withdrawing effect of the oxetane, manifested in its pKa shift of 3.3 units. Additionally,
thestericbulkoftheoxetanemightshieldtheaminelonepairfromsolvationandreduce
pyramidalityoftheamineinordertoavoideclipsinginteractionsbetweenthepiperonyl
residueandtheoxetane.
Thereplacementofamethylenegroupwithanoxetaneleadsinalmostallcasestoa
significant increase in solubility. If the underlying scaffold is apolar, this effect can be
dramatic.Therefore,compoundswithverylowsolubilityseemtobenefitmostfromthe
integrationofanoxetane.
4.1.5 MetabolicStability
Manypromisingleadscaffoldsdonotreachtheclinicalphasebecauseoftheirmeta
bolicinstability.Severalbiologicalpathwaysaresubsumedunderthetermmetabolicde
gradation.Apartfromenzymatichydrolysisreactionsthatcanhappeninthegutorinthe
bloodplasma,twodistincttypesofchemicalmodificationsthatcanoccurtoamoleculein
thebodyaretobedifferentiated.
Phase I metabolism modifies a molecule either oxidatively or reductively. Oxidations
are often conferred by the cytochrome P450 family of enzymes (CYPs). Isoforms of this
familyareubiquitousinthebodyandfoundinhighabundanceinliverhepatocytes.CYPs
containhemeboundironintheiractivesiteandtransferanoxygenatomontotheirsub
strates.306
Equation 17: NADPH- and oxygen-dependent oxidation of substrates by CYP450 enzymes.

Over 400 isozymes areknown in the CYP family, differing in their substrate specifici
ties.Ingeneral,siteandrateofmetabolismisdeterminedbytheaffinityofacompound
tothegivenenzymeandthereactivityofthepositionsbroughtincloseproximityofthe
306
Forabroaderdiscussionofbiotransformationreactions,see:J.Magdalou,S.FournelGigleux,B.Testa,
M.Ouzzine,M.Nencki,inPracticeofMedicinalChemistry(2ndEdition),2003,pp.517.
103
active site.307 Main purpose of oxidative metabolism is to make molecules more water
solubleforexcretion.Therefore,theseenzymeshaveanevolutionarypreferenceforlipo
philicmolecules.308Thiscorrelationisalsofoundfortheoxetanecontainingcompounds
measuredinthisstudy.
hClint inmin1mg1L
50
40
30
R=0.41
20
10
0
1
LogD
Diagram 14: Correlation of LogD and hClint for the oxetanes in this study.
PhaseIImetabolismcovalentlyattachesapolargroupsuchasglucuronicacidorsul
fatetoascaffold.Thegreatlyreducedlipophilicityoftheresultingconjugatesfacilitates
theireliminationfromthebody.
Allthecompoundstestedforthisstudyweresubjectedtopreparationsofhuman,rat
or mouse liver microsomes and the remaining material determined after 2 h of incuba
tion.ThistestmeasuresphaseImetabolismandyieldsadecayconstant.Itsnumberindi
cateshowmanymicrolitersofthe2M substratesolutionarecompletelyclearedfrom
thesubstrateperminuteandpermgmetabolizingenzymepresent.
Thedecayconstantsoftheoxetanecontainingcompoundscanbecomparedwiththe
unsubstitutedcaseandrevealthatplacinganoxetaneinthevicinityofanaminedecreas
esmetabolicstability.Thereasonforthismightbethereducedbasicityoftheamineand
thustheincreasedLogDatpH7.4wheretheassayiscarriedout.
307
308
F.J.Gonzalez,D.W.Nebert,TrendsGenet.1990,6,182.
104
openchain
hClint inmin1mg1L
30
piperidines
20
pyrrolidines
10
azetidines
0
10
20
30
40
mClint inmin1mg1L
300
200
100
0
100
200
300
400
500
Diagram 15: Change in intrinsic clearance upon exchange of a methylene group with an
oxetane.
Whenplacedfurtheraway,howevertheelectronwithdrawingeffectoftheoxetaneis
notfeltbytheamine,sothatanetreductionofmetabolicdegradationisseen.Forcom
pound148,wheretheoxetaneresidesdeltatotheamine,thisleadstocompletesilencing
ofmetabolicdegradationinhuman.Thesametrendisvisibleinthemouse.Duetothe
more aggressive enzymes in mice, differences between the compounds become more
pronounced.
Metabolicliabilityisdependentuponthemolecularenvironmentandthuscannotbe
quantitativelytransferredtootherstructuralcontexts.Thisisparticularlyrelevantwhen
considering incorporation into drug candidates by Nacylation or sulfonylation. There, a
proximaloxetanemightbenefitamides,asthesearenotbasicandthusthepolarnature
oftheoxetanecouldoutweighitsinductiveeffect.
105
4.1.6 ChemicalStability
Theirproclivitytoundergoacidcatalyzedringopeningreactionswasoneofthemajor
concerns for the practical use of oxetanes. It was questionable whether they would be
stableatlowpH.Therefore,theirchemicalstabilitywasmeasuredatpH1,4,6,8and10.
After2hat37C,theamountofunchangedcompoundwasdetermined.Acompoundis
classifiedaschemicallyunstableiflessthan90%canberecovered.Alloxetanesbutone
were found to be stable at every pH studied. Only the sterically less shielded 3
monosubstitutedoxetane81wasnotstableatpH1,although83%couldberecovered.
Theseresultsshowthattheconcernsregardingchemicalstabilityunderbiologicallyre
levantconditionsseemtobeunfoundedatleastfor3,3disubstitutedoxetanes.Seeming
ly, double substitution at the 3position shields the oxetane from nucleophilic attack,
eveninastronglyacidicmedia.
Thepresenceofanoxetanechangesthephysicochemicalpropertiesoftheunderlying
scaffoldinmanyways.Whencomparedwithamethylenegroup,inmostcases,theoxe
taneeffectsadecreaseinintrinsiclipophilicityandoftenadramaticincreaseinaqueous
solubility. Attention should be paid to the structural context. The strong electron
withdrawingnatureoftheoxetanenotonlytempersthepKaofvicinalamines,butalso
seemstoincreaseoxidativemetabolicdegradationwhenpositionedalphaorbetatothe
amine.Especiallyhoweverwhenappliedinapolarenvironments,theresultingoxetanes
arefoundtobemetabolicallymuchmorestablethantheoriginalmethylenecompound.
Inthesecontextsforexamplewhenreplacingotherstericallydemandingfunctionality
anoxetanecouldbeverybeneficial.
4.2 OxetanesasgemdimethylAnalogues
Consideringanoxetaneforthereplacementofagemdimethylgroup,onewouldex
pecttheconformationalchangestobesmall.Atthesametime,theimprovementsinso
lubility, lipophilicity and metabolic stability need to be documented for the different
structuralenvironments.
106
ThevanderWaalsvolumeofanoxetaneisapproximatelythesameasagemdimethyl
group.Thepartialmolarvolumesofpropaneandoxetaneinwateraresimilaraswell.309
Thexraystructureofspirocycle217allowsasidebysidecomparisonoftheoxetaneand
thegemdimethylmoiety.
Overlay:
TopViewSideView
217
Picture 15: Structure of spirocycle 217 (left), overlay of the oxetane and the gem-dimethyl
portion from different perspectives (right).
Theoverlayofoxetaneandgemdimethylsubstructureshighlightsthesimilarityofthe
two.ThissuperimpositionalsorevealsthatasaresultofthedecreasedCCCbondan
gle,themethylenegroupsoftheoxetaneareclosertogetherthanthecorrespondingme
thylresiduesofthegemdimethylgroup.Consequently,stericbulkintheoxetaneismore
concentratedandbyvirtueoftheoxygenatomexpandedfurtherout.
Thedifferentspatialdistributionofstericbulkhasimplicationsforthepreferredcon
formations of oxetanes in comparison with gemdimethyl groups. As shown in Diagram
16,asubstituentRbetatotheoxetanestronglyfavorsanarrangementsynclinaltothe
secondsubstituentRoftheoxetaneavoidingtheantiperiplanarconformation.Incaseof
agemdimethylgrouphowever, theantiperiplanarandthetwosynclinalconformations
arealmostequallypopulated.
309
Oxetanehasapartialmolarvolumeof61.4cm3/mol(J.C.Moore,R.Battino,T.R.Rettich,Y.P.Handa,E.
Wilhelm,J.Chem.Eng.Data1982,27,22.).Propanehasapartialmolarvolumeof70.7cm3/mol(J.T.Ed
ward,P.G.Farrell,F.Shahidi,J.Chem.Soc.Lond.FaradayTrans.11977,73,705.).
107
50%
DistributionofHits
40%
30%
20%
R'
CH3
H3C
10%
R'
0%
030
3060
6090
90120
120150
150180
Diagram 16: Arrangements of CH2R relative to an oxetane or a gem-dimethyl.310

Whereasantiperiplanarconformationsarefavoredinanunsubstitutedchain,achain
becomesmoreflexibleuponintegrationofagemdimethylgroupbytheequalpopulation
ofsynclinalandantiperiplanarconformations.Incaseoftheoxetane,theenergiesofthe
different arrangements seem to be different, and the preferred conformation switches
fromantiperiplanartosynclinal.Iftheoxetaneresidesinthemiddleofanalkylchainit
therebyintroducesakinkintothischain.311
4.2.2 AqueousSolubilityandLipophilicity
As a gemdimethyl group is more lipophilic than a methylene group, its introduction
usuallyleadstodecreasedaqueoussolubility.AsshowninDiagram13,aqueoussolubility
goesupwhenamethylenegroupisreplacedwithanoxetane.Thereforethedirectcom
parison of oxetanes with their gemdimethyl counterparts should show an even more
pronouncedincreaseinsolubility.
310
DerivedfromCSDversion5.29aandacombineddatabase(seeRefs.285,286)of3substitutedoxetanes
O
CH2R'
forthesubstructure R
,R,RH.
311
The respective substituents on the CH2groups alpha to the oxetane will seek to avoid double gauche
pentaneinteractionswitheachotherandtherebybothassumetherespective(+)or()synclinalarrange
mentrelativetotheoxetane.
108
4400
10000
openchain
piperidines
1000
100
pyrrolidines
51.2
10
azetidines
3.7
Diagram 17: Increase in solubility when replacing a gem-dimethyl group with an oxetane.
Thereplacementofagemdimethylgroupwithanoxetaneleadstoapronouncedim
provementinaqueoussolubilityforallthecompoundsstudied.Theincreasespansfroma
factorof3.7fortheoxetanealphatoanazetidine(28)toafactorof4100oftheoxetane
gammatoanacyclicamine(149).Themedianfactorbywhichsolubilitygoesupis51.As
expected,thisisalsoreflectedinastrongreductionoflipophilicity.
2
openchain
1.5
piperidines
LogD
pyrrolidines
0.5
azetidines
0
0.5
1
1.5
LogP
0.5
1
1.5
2
2.5
3
openchain
piperidines
pyrrolidines
azetidines
Diagram 18: Change in lipophilicity LogP upon replacement of a gem-dimethyl group with
an oxetane.312
312
TheUVabsorptionofthegemdimethylcompoundsintheopenchainwasnotsufficienttodetermine
theirlipophilicities.Insteadthelipophilicityofthecompoundwiththemethylenegroupwasusedforthis
109
As seen in Diagram 12, the decrease in lipophilicity seems to become more pro
nounced with increasing distance between the oxetane and the amine.304 Overall, the
oxetaneperformsverywellasasubstituteforagemdimethylgroupintermsofsolubility
andlipophilicity.
4.2.3 Metabolicstability
Higher aqueous solubility and the decrease in lipophilicity should make the oxetane
derivativeslesspronetometabolicoxidationthantheirgemdimethylcounterparts.Oxe
tanesinthevicinityofabasicamineareexpectedtoleadtoadecreaseinLogDandthe
polarityoftheaminebecauseoftheirelectronwithdrawingeffect.
hClint inmin1mg1L
40
openchain
30
piperidines
20
pyrrolidines
azetidines
10
0
10
20
mClint inmin1mg1L
300
200
100
0
100
200
300
400
500
Diagram 19: Change in the rate of metabolic degradation upon replacement of a gemdimethyl group with an oxetane. *(gem-dimethyl compound was completely degraded in assay)
diagram. This turns the value displayed into a lower boundary for the change in lipophilicity. As the re
placementofamethylenegroupusuallyresultsinanincreaseoflipophilicityby1Logunit,shiftscalculated
onthatbasisarealsoshowninthediagram.
110
Althoughtheexchangeofagemdimethylgroupalphatoanaminewithanoxetaneis
predictedtoimprovesolubilityandintrinsiclipophilicity,itoftenreducesmetabolicstabil
ity.Thus,thereplacementofagemdimethylgroupalphatoanaminewithanoxetanein
many cases leads to higher metabolic clearance. Almost all cases where the oxetane is
positionedfurtheraway,howevershowsignificantlyreducedmetabolicliability.313
4.2.4 hERGChannel
ThehumanEtheragogoRelatedGene(hERG)isagenethatencodesforapotassium
ion channel that is expressed mainly in heart muscle cells. Compounds that block this
channelcanleadtoaprolongationoftheQTintervalintheelectrocardiogram(ECG).314
Thiscantogetherwithotherriskfactorscauselifethreateningtorsadesdepointes(TdP)
arrhythmia:315
normalprolongedQTTdParrhythmia
Picture 16: Normal ECG (left), an ECG showing a prolonged QT-interval (middle) and an
ECG of torsades de pointes arrhythmia (right).316
DrugcandidatesthatblockthehERGchannelrequirelargeclinicaltrialswithmanypa
tientstodemonstratetheirsafety,asarrhythmiacausedbyhERGchannelblockageisa
rare event. Therefore screening for hERG blockage has become part of the discovery
phasetoavoidthehighcostsforprovingthesafetyofacompoundwhichhasapotential
hERGliability.UponelucidationoftheconnectionbetweenhERGandtorsadesdepointes
313
Inthecaseofthebetasubstitutedazetidine,thegemdimethylcompoundshowsnometabolicdegrada
tion.Theoxetaneisnotsignificantlyfasterdegradedwithaclearancerateof3min1mg1L.
314
M.C.Sanguinetti,M.TristaniFirouzi,Nature2006,440,463.
315
M.C.Sanguinetti,J.S.Mitcheson,TrendsPharmacol.Sci.2005,26,119.
316
TakenfromRef.314withpermission.
111
arrhythmia,hERGblockinghasbecomeoneoftheleadingcausesformarketwithdrawal
oruserestrictionsimposedbytheFDA.317
Figure 15: Drugs that were withdrawn or experienced major labeling restrictions due to
hERG blocking.
TdParrhythmiahasbeenreportedtooccurinabout1patientin50,000fortheantihis
tamineterfenadine.318ManycompoundsthatinteractwiththehERGchannelsharestruc
turalfeaturessuchasabasicamine(pKa>7.3),highlipophilicity(LogP>3.7),theabsence
ofnegativelyionizablegroupsortheabsenceofoxygenhydrogenbondacceptors.319
The open chain model system shares all these features and should therefore show
somehERGbinding.Asanoxetanecanreducelipophilicityoftheunderlyingscaffoldand
introduces a hydrogen bond acceptor, the introduction of an oxetane could lead to re
ducedhERGliability.
317
318
P.K.Honig,D.C.Wortham,K.Zamani,D.P.Conner,J.C.Mullin,L.R.Cantilena,JAMA,J.Am.Med.As
soc.1993,269,1513.
319
seeRef.317andRef.315
112
hERGIC50 =7.5M
hERGIC50=35M
Picture 17: Change in hERG binding upon replacement of a gem-dimethyl group with an
oxetane.320
AsshowninPicture17,theintroductionofanoxetaneleadstoamarkeddecreasein
affinitytothehERGchannel.Theintroductionofthepolaroxetaneinthelipophilicpartof
themoleculeanditsabilitytoaccepthydrogenbondsmightbethecauseforthisobser
vation.Therefore,anoxetanemightserveasatooltoreducehERGliability.321
4.2.5 AmphiphilicityandPhospholipidosis
Molecules that combine a large nonpolar residue with a highly hydrophilic, often
chargedtailaretermedamphiphilic.Cationicamphiphilicdrugscaninducetheaccumula
tionofphospholipidsinlysosomes;aneventthathasbeenconnectedtocelltoxicity.322
Different mechanisms have been proposed to account for this effect. A recent study
foundastrongcorrelationbetweentheabilityofacompoundtoinducephospholipidosis
and the strength of the compoundphospholipid interaction.323 The association of com
pound and phospholipids would then prevent their metabolic degradation and lead to
theirenrichmentwithinthemembrane.Theamphiphilicityofagivencompoundcanbe
correlatedtotheabilityofacompoundtosupportmicelleformationanditsinfluenceon
surfacetension.324
320
MeasurementwasperformedatF.HoffmannLaRoche,BaselbyDr.LiudmilaPolonchuk.
321
As the testing of compounds for hERG binding is expensive, this pair of compounds was the only one
studied.Therefore,generalconclusionsshouldnotbedrawnfromthisresult.
322
For reviews, see: a) N. Anderson, J. Borlak, FEBS Lett. 2006, 580, 5533. b) M. J. Reasor, Toxicol. Appl.
Pharmacol.1989,97,47.c)W.H.Halliwell,Toxicol.Pathol.1997,25,53.
323
P.Vitovic,J.M.Alakoskela,P.K.J.Kinnunen,J.Med.Chem.2008,51,1842.
324
Foradetaileddescription,referto:H.Fischer,M.Kansy,D.Bur,Chimia2000,54,640.
113
Equation 18: Gamph as a measure for amphiphilicity and its calculation from Gawi-w
(free energy needed to transfer the compound from the aqueous solution to the airwater interface) and Gmc-w (free energy needed to transfer the compound from the
aqueous solution to micelles).324
AcompoundcarriesaliabilitytowardsphospholipidosisifitsGamphissmallerthan6
kJ/molandhasapKagreaterthan7.Theamphiphilicpropertiesofamine34wereoneof
thereasons,whyitsscaffoldwaschoseninitiallyfortheinvestigationofoxetanes.
Picture 18: Introduction of an oxetane in the lipophilic part of the molecule reduces
Gamph below the critical threshold.325
Whereasamine185ishighlyamphiphilic,Gamph ofoxetane145isabovethecritical
threshold and thereby not amphiphilic. This compound therefore also does not carry a
liabilitytoinducephospholipidosis.Anoxetaneasinoxetane149,howeverthatislocated
awayfromthelipophiliccoredoesnotimproveGamphsignificantly.Theseresultsindi
cate again that the oxetane can be an alternative to a gemdimethyl group especially
whendealingwithverylipophilicscaffolds.
Takentogether,thedatasuggeststhattheoxetanemoietycanbeusedasanisosteric,
lesslipophilic,moresolubleandmetabolicallymorestablesurrogateforagemdimethyl
group.Moreover,intheisolatedcasestested,theoxetanewasalsoabletoaddressspe
cific problems such as hERGbinding and amphiphilicity. The oxetane is predestined to
introducestericbulkandpolaritytolipophilicenvironments,acombinationothersterical
lydemandingalkylorcycloalkylfunctionalitiesdonotoffer.
325
MeasurementwasperformedatF.HoffmannLaRoche,BaselbyDr.HolgerFischer.
114
4.3 OxetanesasCarbonylAnalogues
Thepresenceofacarbonylgrouphasfundamentalconsequencesforthestructure,the
physicochemicalproperties,andthereactivityofamolecule.Twocharacteristicsarere
sponsibleforthis;apolaroxygenthatcanaccepthydrogenbondsandtheabilityofthe
C=Odoublebondtobeconjugatedwithneighboringsystemsandabsorbelectronden
sity from them. The question is whether the oxetane, featuring a polar oxygen but not
supportingconjugation,canfillthisrole.
Theanalogyofanoxetanewithagemdimethylgroupdrawsonaveryclosestructural
resemblance,whereanoxetaneisviewedasabridgedgemdimethylgroup.Theintro
ductionoftheoxygenonlyservesthepurposeofmakingthemoleculeasawholemore
polar. For the carbonyl analogy, the roles are inverted. The structural analogy is
representedsolelybytheoxygenatom,itspolarityandlocationinspace.Themethylene
groupsonlyholdtheoxygeninplaceandsupplantthedoublebondinthatfunction.
Onehastoseparatetwoeffectswhenconsideringthestructuralchangesthereplace
mentofacarbonylwithanoxetaneconfers.Oneistheimmediatesurroundings,inwhich
theoxetaneplacestheoxygenfurtherawayfromthechainthanacarbonylandwhereit
addsstericbulkbyvirtueofitstwomethylenegroups.Theotherpertainstothedifferent
influenceanoxetaneandacarbonylhaveontheconformationandrelativearrangement
oftheirsubstituents.
Anoxetaneisstericallymoredemandingthanacarbonylbyvirtueofitsadditionalme
thylene groups. In oxetanes, beta substituents should therefore be directed away from
theoxetane.Incaseofcarbonylcompoundshowever,betasubstituentsresideinplane
withthecarbonylreflectingitssmallerstericdemand.
115
100%
DistributionofHits
80%
Oxetane
Carbonyl
60%
40%
20%
0%
030
3060
6090
90120
120150
150180
Diagram 20: Arrangements of CH2R relative to an oxetane or a carbonyl.326

Thedistributionofconformationsfoundinthecrystalstructureconfirmsthis,showing
averystrongpreferenceforRtoresideinplanewiththecarbonyl.Inthecrystalstruc
turesdocumentedforoxetaneshowever,RispushedtowardsR,theothersubstituent
ontheoxetane.
DistributionofHits
100%
80%
60%
40%
20%
0%
015
1530 3045 4560 6075 7590
Diagram 21: Rotative arrangement of a phenyl ring with respect to a carbonyl and oxetane
213.327
326
DerivedfromCSDversion5.29aandacombineddatabase(seeRefs.285,286)of3substitutedoxetanes
O
CH2R'
forthesubstructure R
,R,RH.
327
DerivedfromCSDversion5.29asubstructuresearchwithRHandexcludingcompoundsinwhichthe
carbonylispartofaring.
116
Thestabilizinginteractionofacarbonylgroupwithothersystemslikephenylgroups
leadstoaplanarization(Diagram21)whichisnotobservedinthecorrespondingoxetane
213.Similarly,theconformationofamidesdifferssignificantlyfromtheonefoundinthe
oxetane analogue 215. Almost all xray structures of N,Ndimethylamides registered in
CSDfeatureplanararrangementsofcarbonylandamineportions.328
DistributionofHits
100%
80%
R3C
60%
40%
CH3
N
CH3
20%
0%
015
1530 3045 4560 6075 7590
Diagram 22: Conformational preference for rotation around an amide bond and what is
found in oxetane analogue 215.329
Inaminooxetane215however,thetorsionalangleCNCOamountsto116andthe
amineispyramidalizedwithanangleof29.Asimilarconformationwilllikelybeobserved
in other cases of 3aminooxetanes. These examples highlight that the conformational
aspectsofacarbonylwithitsattendantsubstituentsandanoxetanehavetobecautious
lyexamined.Thisisparticularlyevidentincaseswherethereplacementofthecarbonyl
group by an oxetane unit eliminates the conjugation in the former and may result in
substantiallynonplanararrangementsinthelatter.
4.3.2 InfluenceonpKa
AcarbonylgroupandanoxetanebothlowerthepKaofaproximalamine.Thechange
inpKauponreplacementofacarbonylgroupwithanoxetanefordifferentenvironments
highlightssimilaritiesanddifferencesintheirelectronwithdrawingeffects.
328
Nonplanaramideshavebeenmadeandshowntobeveryunstablewhennotprotonated(K.Tani,B.M.
Stoltz,Nature2006,441,731.).
329
DerivedfromCSDversion5.29a,substructuresearch.Whiletheamideisplanar,theamineintheoxe
taneanalogueshowspyramidalizationof29,allowingtheCNCOtorsiontoexceed90.
117
pKa
* *
piperidines
pyrrolidines
azetidines
2
**
Diagram 23: Change in pKa upon replacement of a carbonyl group with an oxetane.
*shown is the pKa of the oxetane;330 **Azetidin-3-one 205 was not sufficiently stable to be purified and measured.
Diagram23showsthatthereductionofpKabyanoxetaneissmallerinallcasesthan
bythecorrespondingcarbonylcompound.Thedifferencebetweenthetwoisbiggestfor
thecomparisonofamidesand3aminooxetanes,whereincaseoftheamidetheelectron
pairisinconjugationwiththecarbonylgroupandnotavailableforprotonation.While3
aminooxetaneslackasystemandthereforestillretainsomebasicity,theyareonlypro
tonated to a small extent with a pKa of 7 or less at physiological pH. In case of beta or
gammasubstitution,thereplacementofacarbonylgroupwithanoxetaneleadstoasimi
larpKa.
4.3.3 LipophilicityandAqueousSolubility
Oneofthe mostimportantdifferencesfromalipophilicitypointof viewbetweenan
oxetaneandacarbonylaretheadditionalmethylenegroupspresentintheoxetane.This
explainswhytheintrinsiclipophilicitylogPgoesupuponreplacementofacarbonylgroup
withanoxetane.
330
Protonationofamidestypicallyoccursontheoxygen,soadirectcomparisonisnotpossible.Protonated
aliphaticamides,howevertypicallyhaveapKabetween1and0(H.M.Grant,P.Mctigue,D.G.Ward,Aust.
J.Chem.1983,36,2211.),sothevalueshownisalowerboundaryforthepKachangetobeexpectedwhen
replacinganamidewithanaminooxetane.
118
2
piperidines
1.5
piperidines
1.5
pyrrolidines
pyrrolidines
LogD
LogP
azetidines
0.5
0
0.5
1
azetidines
0.5
0.5
Diagram 24: Change in LogP and LogD upon replacement of a carbonyl group with an
oxetane. *Azetidin-3-one 205 was not sufficiently stable to be purified and measured.
ThesametrendisseenforLogD,where3piperidone208isfoundto beslightlyless
lipophilicthanitsoxetanecounterpart.Interestingly,bothmeasuresoflipophilicityshow
thatinpositiontheincreaseinlipophilicityisstrongestasaresultoftheverylowlipo
philicitiesoftheamineketonesmeasured.331
1.6
0.8
piperidines
0.4
pyrrolidines
0.2
azetidines
0.1
Diagram 25: Change in solubility upon replacement of a carbonyl group with an oxetane.
* Azetidin-3-one 205 was not sufficiently stable to be purified and measured.
Thesamegeneraltrendisseenwhenlookingataqueoussolubilities.Thechangeinli
pophilicityhoweverisnotfullytranslatedintosolubility,probablybecauseofthediffer
331
Inthese,lipophilicitiesareonaverage1logunitlowerthanthecorrespondingamidesor3piperidone
208.Thereasonforthisdecreaseinlipophilicityisnotclear,butmaybeundertheconditionsoftheassay
partialhydrationoftheseelectronpoorketonesoccurs,leadingtoamorepolarhydrateortautomerization
givingthecorrespondingenaminols.
119
entmeltingpointsandthereforedifferentcrystallatticeenergies.332Severalpolyaromatic
compoundshavehighcrystallatticeenergies,becauseofhighlyplanarconformationsand
the resulting stabilizing stacking effects. Here the replacement of an aromatic ketone,
amideoresterwiththecorrespondingoxetanewouldleadtononplanarconformations
andthereforecould,despitehigherlipophilicity,resultinimprovedsolubilities.
4.3.4 MetabolicandChemicalStability
Oxetanesmeasuredinthisstudydisplaydramaticallyhighermetabolicstabilitiesthan
theirketonecounterparts.Thisisbecausethesebetaorgammaaminoketonesshowvery
highclearanceinbothhumanandmouselivermicrosomes.
40
hClint inmin1mg1L
20
0
20
40
piperidines
60
pyrrolidines
80
100
azetidines
120
300
mClint inmin1mg1L
200
100
0
100
200
300
400
500
600
piperidines
pyrrolidines
azetidines
Diagram 26: Change in rate of metabolic degradation upon replacement of a carbonyl

group with an oxetane. * Azetidin-3-one 205 was not sufficiently stable to be purified and measured.
332
YalkowskyandBanerjee(S.Yalkowsky,S.Banerjee,Aqueoussolubility:Methodsofestimationfororganic
compounds. 1992 New York, NY: Marcel Dekker) developed an empiric formula for the prediction of the
solubilitySofacompoundfromitsLogPandmeltingpointmp:log(S)=0.8LogP0.01(mp25)Higher
meltingpointsleadtolowersolubility,becausethecrystallatticeenergythathastobespentforsolubiliza
tionincreaseswiththemeltingpoint.
120
Oxetaneanaloguesoflactamsshowedslightlyhighermetabolicclearancerates.Inte
restingly,thestrainedlactam209displayslittlemetabolisminhuman,butisdegraded
veryquicklyinmouselivermicrosomes.Althoughnoneofthecarbonylcompoundsinthis
study shows decomposition upon exposure to buffers of different pH at 37 C for 2 h,
both amino ketones tend to decompose into insoluble products upon storage in the
refrigerator.333
Thereplacementofacarbonylgroupwithanoxetanecanleadtosignificantchangesin
theconformationalpreference,basicity,lipophilicityandmetabolicstabilityoftheunder
lying scaffold. The introduction of an oxetane in place of a carbonyl group seems to be
attractiveinsituationswherethecarbonylcompoundshowschemicalormetabolicinsta
bility,undesirablereactivityorwhenanonplanarconformationisdesired.
4.4 SpirocyclicOxetanesasMorpholineAnalogues
Agemdimethylgroupcanbereplacedbyanoxetanebecauseofitssimilarstericde
mand.Theoxygenanditspolarityarethecausefortheimprovementsseeninmanyphy
sicochemicalproperties,butdonotcontributetothestructuralanalogy.Whenacarbonyl
groupisreplacedbyanoxetane,thesimilarplacementofitspolaroxygenprovidesthe
rationalebehindthistransformation.Themethylenegroupshelptopositiontheoxygen
correctlyandreplacetheC=Odoublebond,buttheydonotcontributetothestructural
analogy themselves and are responsible for many of the differences seen between the
propertiesofoxetanesandtheircarbonylcounterparts.
Theanalogydrawnbetweenthisgroupofspirocyclicoxetanesandmorpholineaimsat
makinguseofbothofthecharacteristicsofoxetanes,polarityandstericdemand.Impor
tant for this purpose is to what extent oxetanes are able to meet the high standard of
morpholine as a solubilizing group without displaying its metabolic liability. In cases
wheremorpholinecontributestothebindingenergy,structuralaspectscomeintoplayas
well.
333
Atambienttemperature,decompositionoccursinlessthanoneday.
121
5.0
4.5
4.4
2.9
4.3
3.5
3.0
3.4
3.4
R=
piperonyl
Picture 19: Spatial distribution of polar and apolar groups in morpholine 32 and its spirocyclic oxetane analogues 24 to 31.334
The analogues in Picture 19 comprise a subset of spirooxetanes which position the
oxygenatominthemolecularsymmetryplaneatanextendeddistancefromthenitrogen
atom(24,25)withsimilarordecreasedlateralbulk(24).Others(2530)placetheoxygen
atareclinedanglefromthesymmetryplaneoftheparentmorpholine,resultinginare
ductionofsymmetrywithoutintroducingchirality.
Morpholine has one very important function in drug discovery and that is to make
compoundsmorewatersolubleandlesslipophilic.Therefore,inmanyinstancesstructur
alsimilaritybetweenmorpholineandasurrogateisnotofmajorimportance,becausethe
morpholinedoesnotcontributetotargetbinding,butmerelyservesasananchorforsol
vation.Especiallyincaseshowever,wherethemorpholineisrigidlylinkedtotherespec
tive scaffold, for example as an amide or aniline, it might interact with the target.
334
CalculationofvanderWaalssurfacesdonebyProf.KlausMllerwithMoloc(P.R.Gerber,K.Mueller,J.
CompAided.Mol.Design1995,9,251;forfurtherinformation,seewww.moloc.ch).
122
ThenthediversestructuresofthespirocyclesshowninPicture19couldserveasatool
boxforbuildingblockswithdifferentstericdemandanddipoleorientation.
4.4.2 InfluenceonpKa
Alloxetanesstudiedaremorebasicthanmorpholinewiththeexceptionofthosecom
poundswheretheamineisalphatotheoxetane.Thiscorrelateswellwiththeincreasing
numberofbondsthatseparatetheaminefromtheelectronwithdrawingoxygen.
piperidines
1.5
pyrrolidines
1.0
pKa
azetidines
0.5
0.0
0.5
0.00
31
1.0
Diagram 27: Change in pKa upon replacement of morpholine 32 with an oxetane.

Inpyrrolidine29andazetidine28,theamineisseparatedfromtheoxygenbytwocar
bonatoms,asinmorpholine.Still,thesecompoundsaresignificantlylessbasicwhilethe
correspondingpiperidineshowsthesamepKaasmorpholine.Thisdiscrepancyisrootedin
different conformations these compounds adopt in the protonated state.335 The slightly
increased pKa of tetracycle 31 seems to indicate that the small ring size of an oxetane
doesnotincreasetheinductiveeffectoftheoxygen.
4.4.3 SolubilityandLipophilicity
ThechangeinintrinsiclipophilicityLogPcorrelatesverywellwiththedifferentnumber
ofmethylenegroupsbetweenmorpholineandtherespectivespirocycle,rankingpiperi
dines before pyrrolidines and azetidines. Additionally, as seen before, accumulation of
polargroupswithinclosedistanceleadstoanincreaseinLogP.336
335
336
Seechapter4.1.2fordetailedtreatment.
Seechapter4.1.3andfootnote304fordetailedtreatment.
123
0.8
0.8
0.4
0.4
0.4
LogD
LogP
31
0.4
0.8
0.8
1.2
1.2
31
piperidines
pyrrolidines
azetidines
Diagram 28: Change in lipophilicity upon replacement of morpholine 32 with an oxetane.

ForLogD,pKabecomesathirdfactor,favoringthemorebasicaminesoftheoxetanes
positionedbetaorgammatothenitrogen.Byvirtueofitstwopolaratoms,themorpho
lineunithasabiginfluenceonthesolubilityofthescaffolditisattachedto.Consequent
ly, the piperonyl morpholine has the highest solubility (8,000 g/mL) of all compounds
measuredinthisstudythatdonotcontainanoxetane.
3.2
piperidines
1.6
pyrrolidines
0.8
azetidines
0.4
0.2
0.1
31
Diagram 29: Change in aqueous solubility at pH 9.9 upon replacement of morpholine 32

with an oxetane.
Whenmorpholine32iscomparedwithitsspirocyclicanalogues,itisfoundtobemore
than twice as soluble. There is one exception however, the substituted 2oxa6
azaspiro[3.3]heptane24.Ithasa solubilityof24,000g/mLwhichisthreetimeshigher
thanmorpholine32.337
337
Itisnotclearwhichthecloselyrelatedpyrrolidine26whichhassimilarlipophilicityandonlyonemethy
lenegroupmorepossesseslessthan3%ofthesolubilityofazetidine24.Bothcompoundsareoilsatroom
temperature,sodifferentmeltingpointsshouldnotplayarole(seeref.332).
124
Severalargumentshelpexplainwhythisspirocyclicoxetanehasthisprominentposi
tion.BothitsLogPandLogDaresubstantiallylowerthanthatofmorpholine32.Addition
ally,itslipophilicpartsareconcentratedaroundthecentralquaternarycarbonwhileboth
itsoxygenandnitrogenareexposedtothesolvent.
4.4.4 Metabolicstability
Morpholine32showsonlysmallinternalclearancebothinhumanandinmouseliver
microsomeswhichisprobablyaresultofitshighsolubilityandlowlipophilicity.Still,me
tabolicliabilityisreducedinthemostpolarspirocyclicoxetanes.
hClint inmin1mg1L
25
piperidines
20
pyrrolidines
15
azetidines
10
5
0
5
31
10
mClint inmin1mg1L
250
piperidines
200
pyrrolidines
150
azetidines
100
50
1
0
50
31
Diagram 30: Change in internal clearance upon replacement of morpholine with a spirocyclic oxetane.
Pyrrolidine 26 and 2oxa6azaspiro[3.3]heptane 24 are almost not metabolized. The
more lipophilic piperidines and oxetanes alpha to the amine show higher, but still low
internalclearance.Theseresultstogetherwithitseaseofpreparationmakecompound24
averypromisingcandidateforreplacingmorpholineasasolubilizinggroup.
125
4.5 Applications
OxetaneshavebeenappliedtoseveralprojectswithinandoutsideofRoche.Mostof
theapplicationshavenotbeenpublished,makingitdifficulttoquantifytheimpactoxe
taneshadsofaronmedicinalchemistry.338
NumberofCompounds
200
178
160
123
120
80
40
15
19
25
2003
2004
2005
projectstart
2006
1st paper
2007
2ndpaper
Diagram 31: Number of compounds that contain a 3-substituted oxetane within the global
Roche database.339
Whileitisnotpossibletodetailonindividualcompoundsorforwhichprojectsthese
weremade,thenumberofoxetanesintheglobalRochedatabaseshowninDiagram31
provides an overview. The first paper340 together with presentations in front of Roche
chemistsledtoasurgeofrequestsbymailconcerningoxetanechemistryandregistration
338
Afewpatentshaveappearedthatcoveroxetanecontainingstructuresandusechemistrystartingfrom
oxetan3one.Thesehoweverdonotpresentsignificantinformationonhowsuccessfultheintegrationof
anoxetanewascomparedwithothermeasurestaken.PatentsofRoche:a)S.Jolidon,R.Narquizian,R.D.
Norcross, E. Pinard, 2006EP761, 2006. b) G. Galley, A. Goergler, K. Groebke Zbinden, R. Norcross, H.
Stalder,2007EP60666,2008.c)J.Ackermann,K.Amrein,D.Hunziker,B.Kuhn,A.V.Mayweg,W.Neidhart,
T. Takahashi, 2007EP60667, 2008. Patent outside Roche: a) H. Meier, E. Bender, U. Brueggemeier, I.
Flamme, D. Karthaus, P. Kolkhof, D. Meibom, D. Schneider, V. Voehringer, C. Fuerstner, J. Keldenich, D.
Lang,E.Pook,C.Schmeck,2007EP4615,2007.
339
PrivatecommunicationfromDr.MarkRogersEvans.
340
G.Wuitschik,M.RogersEvans,K.Mller,H.Fischer,B.Wagner,F.Schuler,L.Polonchuk,E.M.Carreira,
Angew.Chem.,Int.Ed.2006,45,7736.
126
oftheresultingcompoundsinthedatabase.Thesecondpaper341mightfosterthistrend,
asitprovidesroutestocompoundsthatcanbedirectlyusedasbuildingblocks.
Itisdifficulttoestimatehowoftentheoxetanechemistryhasbeenappliedsofarout
side of Roche, but there is evidence for its use in several companies. Requests by out
sourcingcompaniesforexperimentaldetailsinthepreparationofoxetan3onecanserve
as an indication as well as the commercial availability of oxetan3one through several
companiesafterthepublicationofthefirstpaper.342
Picture 20: Companies that have shown interest in and/or applied the oxetane chemistry in
projects.343
OxetaneshavealsobeenappliedbyAnnaHirschfromthegroupofProf.Diederichin
the design of inhibitors of 4diphosphocytidyl2CmethylDerythritol kinase (IspE), an
enzyme of central importance to the isoprenoid biosynthesis via the nonmevalonate
pathwayinhumanpathogenssuchasPlasmodiumfalciparumorMycobacteriumtubercu
losis.344
341
G. Wuitschik, M. RogersEvans, A. Buckl, M. Bernasconi, M. Mrki, T. Godel, H. Fischer, B. Wagner, I.

Parrilla,F.Schuler,J.Schneider,A.Alker,W.B.Schweizer,K.Mller,E.M.Carreira,Angew.Chem.,Int.Ed.
2008,47,4512.
342
Oxetan3oneisnowcommerciallyavailablethroughMolBridge,ResearchSupportInternationalLtd.and
ParkwayScientific.
343
Collected from email requests of scientists of the respective companies. Bayer, Novartis, Genentech,
SyngentaandScheringPloughconfirmeduponinquirytheapplicationofoxetanes.Norepliestothesere
questswereobtainedfromGSKandDomp.ArecentpublicationbyEvotecspecificallydealswiththeprep
arationof3Aryloxetanesfortheiruseinmedicinalchemistrybycouplingofarylboronicacidswith3iodo
oxetane(M.A.J.Duncton,M.A.Estiarte,D.Tan,C.Kaub,D.J.R.O'Mahony,R.J.Johnson,M.Cox,W.T.
Edwards,M.Wan,J.Kincaid,M.G.Kelly,Org.Lett.2008,10,3259).
344
A.K.H.Hirsch,M.S.Alphey,S.Lauw,M.Seet,L.Barandun,W.Eisenreich,F.Rohdich,W.N.Hunter,A.
Bacher,F.Diederich,Org.Biomol.Chem.2008,inprint,DOI:10.1039/b804375b.
127
O
NH 2
N
H
N
O
N
O
219
CO2 Et
Picture 21: Oxetane 219 cocrystallized with Aquifex aeolicus IspE344

Theauthorsstatethattheoxetanewasusedtoimprovesolubilityanditwasfoundto
beparticularlysuccessfulinthatrespectamongthecompoundsinvestigated.345Picture
21showsacrystalstructureofoxetane219boundtoIspE.
345
Nosolubilitydataisprovided.Oxetane219wasmadebyconjugateadditionoftheaminecorresponding
to219toacrylate89.Foradetailedprocedure,seeref.344.
ConclusionandOutlook
129
In this work we established the utility of oxetanes to medicinal chemistry. We could
demonstratethatbasedonoxetan3oneasacentralbuildingblock,abroadspectrumof
oxetanescanbepreparedfromit.AcentralroleforthatplaysaclassofMichaelaccep
torstowhichavarietyofnucleophilescanbeadded.Theoxetanesobtainedareamena
bletofurtherfunctionalizationandwereusedtopreparethemembersoftwoprototypic
seriesofcompoundsonwhichthepropertychangesimpartedbytheoxetanewerestu
died.
Wecouldshowthatoxetanescanbeusedtointroducestericbulkwithoutincreasing
lipophilicityandtherebycanreplacethecommonlyfoundgemdimethylgroup.Thever
satilityofoxetanesasafunctionalgroupwasalsodemonstratedwhentheywererelated
tocarbonylcompounds.Anoxetanecanposearealalternative,ifthepresenceofacar
bonyl group inflicts chemical or metabolic instability on a given scaffold. We could also
showthatsomespirocyclicoxetanescanbeusedtosubstitutemorpholineasasolubiliz
inggroupalsoasastructuralmotif.
Contrarytowhatwassuspectedbeforeitcouldbeshownthat3,3disubstitutedoxe
tanesarechemicallyrelativelyinerttowardsringopeningundervarioussyntheticallyand
physiologicallyrelevantconditions.Theyarealsooftenresistanttometabolicdegradation
andatthesametimeincreaseaqueoussolubilitywhenreplacingamethyleneoragem
dimethylgroup.
These findings have consequences not only for the development of new drugs, but
mightalsobeappliedtocompoundsalreadyonthemarket.Oxetaneversionsofexisting
drugsmightnotonlyhaveimprovedpharmacokineticproperties,butwillalsooftennot
becoveredbytheoriginalpatent.Someofthesearecurrentlybeinginvestigatedinour
laboratories.Thisresearchwilladdexamplesfortheapplicationofestablishedmethodol
ogy,andwilladdsubstratescopeandconsolidatethechemistrydescribedinthiswork.
Butitwillcertainlyalsoprovideaccesstonewclassesofoxetanes.
130
Theconceptsdevelopedinthisworkarenotlimitedtooxetanes.Otherheterocycles
such as 3,3disubstituted 1,1dioxothietanes might prove to be even bulkier and more
hydrophilic than oxetanes, posing yet another alternative to gemdimethyl groups.
Spiro[3.3]heptanescouldalsomimicothersixmemberedringscommonlyencounteredin
medicinalchemistrysuchastetrahydropyranes,piperazines,piperidinesorcyclohexanes.
Thefeedbackreceivedforthisworkhasdemonstratedthatthereisaneedforfurther
exploration.Ademandthatcanonlybesatisfiedinclosecooperationwithapartnerlike
Roche,ableandwillingtocarryoutthemeasurementsandpropagatetheirresults.
ExperimentalSection
131
ExperimentalSection
6.1 GeneralMethods
Allnonaqueousreactionswerecarriedoutusingovendriedorflamedriedglassware
under a positive pressure of dry argon or nitrogen unless otherwise stated.
Tetrahydrofuran, acetonitrile, toluene, diethylether and methylene chloride were dried
bypassageovertwo4x36inchcolumnsofanhydrousneutralA2alumina(8x14mesh;
Macherey und Nagel; activated under a flow of nitrogen at 300C over night; solvent
dryingsystem)underanargonatmosphere(H2Ocontent<30ppmasdeterminedbyKarl
Fischertitration).346Et2OwasdistilledfromamixtureofFeSO47H2OandNa2SO4priorto
drying.Benzenewasdistilledfromsodium/benzophenoneketylunderanatmosphereof
drynitrogen.MeOHwasdistilledfrommagnesiumturningsunderanatmosphereofdry
nitrogen. NEt3, diisopropylamine and pyridine were distilled from potassium hydroxide
underanatmosphereofdrynitrogen.Ethyldiisopropylamine(Hnigsbase)wasdistilled
from sodium hydride under an atmosphere of dry nitrogen. Trimethylchlorosilane and
BF3OEt2weredistilledfromcalciumhydridepriortouse.Allchemicalswerepurchased
from Acros, Aldrich, Fluka, Merck, Lancaster, ABCR or TCI and used as such unless
otherwisestated.DeuteratedsolventswereobtainedfromArmarChemicals,Dttingen,
Switzerlandintheindicatedpuritygrade.
Reactionsweremagneticallystirredifnotindicatedotherwiseandmonitoredbythin
layer chromatography using Merck silica gel 60 F254 TLC glass plates and visualized by
fluorescence quenching under UV light. In addition, TLC plates were stained with ceric
ammoniummolybdate(CAM).
ChromatographicpurificationwasperformedasflashchromatographyonBrunschwig
silica3263,60usingaforcedflowofeluantat0.3bar.347Technicalgradesolventswere
employed,whichweredistilledpriortouse.Concentrationunderreducedpressurewas
performed by rotary evaporation at 40C at the appropriate pressure. Purified com
346
347
A.B.Pangborn,M.A.Giardello,R.H.Grubbs,R.K.Rosen,F.J.Timmers,Organometallics1996,15,1518.
W.C.Still,M.Kahn,A.Mitra,J.Org.Chem.1978,43,2923.
132
ExperimentalSection
poundswerefurtherdriedfor1248hunderhighvacuum(0.010.05Torr).Yieldsrefer
to chromatographically purified and spectroscopically pure compounds, unless stated
otherwise.
Meltingpoints:MeltingpointsweremeasuredonaBchiB540meltingpointappara
tususingopenglasscapillariesandareuncorrected.
NMRspectra:NMRspectrawererecordedonaVarianMercury300spectrometerop
eratingat300MHzand75MHzfor 1Hand 13Cacquisitions,respectively.Chemicalshifts
() are reported in ppm with the solvent resonance as the internal standard relative to
chloroform(7.26ppmfor 1Hand77.0ppmfor 13C).All 13Cspectraweremeasuredwith
complete proton decoupling. Data are reported as follows: s = singlet, d = doublet, t =
triplet,q=quartet,m=multiplet,br=broad,couplingconstantsinHz,integration.
IR spectra: IR spectra were recorded on a Perkin Elmer Spectrum RXI FTIR as thin
film.Absorptionsaregiveninwavenumbers(cm1).
Mass spectra: Mass spectra were recorded by the MS service at ETH Zrich. EIMS
(m/z):EIHIRESMicromassAutospelULTIMAspectrometerat70eV.ESIMS(m/z):IONS
PECUltimaESIFTICRspectrometerat4.7T.
Elemental analyses: Elemental analyses were performed by the Mikrolabor der
ETHZrich.
Chemical names: generated with AutoNom 2.02 (Beilstein Informationssysteme
GmbH)orChemDrawUltra11.0(CambridgeSoft)andmodifiedwhereappropriate.
Determination of solubility at thermodynamic equilibrium: For each compound, a
sample of approximately 2mg wasadded to ca 150L of a 50 mM aqueous phosphate
bufferandtransferredtoastandard96wellplateatroomtemperature(22.51C).The
pHofeachcompoundsuspensionwasadjustedtopH10byusingaconcentratedNaOH
solutionandthe96wellplatewasplacedonaplateshakerwhichagitatedthesuspen
sions over night. At the next day the samples were filtered with a micronic filter plate
(MSGVN2250) to separate the solid material from the solution. After confirming un
changedpHofthesolutionsbywayofmicropHmetermeasurements,thesolutioncon
ExperimentalSection
133
centrationsweredeterminedbycalibratedHPLC.ThecalibrationswereobtainedbyHPLC
analysisofdifferentconcentrationsofeachcompoundinDMSO.
Determination of lipophilicity (logDpH=7.4): The highthroughput assay method is de
rivedfromtheconventional'shakeflask'method:Thecompoundofinterestisdistributed
betweena50mMaqueousTAPSObufferatpH7.4and1octanol.Thedistributioncoeffi
cientisthencalculatedfromthedifferenceinconcentrationintheaqueousphasebefore
and after partitioning and the volume ratio of the two phases. To measure logD values
withintherangeof1to3.5,itisnecessarytocarryouttheprocedureatfourdifferent
octanol/waterratios.
The"onephaseanalysis"experimentstartswith2or9LofapureDMSOsolutionof
thecompound,whichisdispensedinto,respectively,38or171Loftheaqueousbuffer
solution,bringingthecompoundconcentrationtoapproximatelyc=0.5mM.Asmallpart
ofthissolutionisthenanalyzedbyUV.Theobservedopticaldensitycorrespondstothe
concentrationofthesubstancebeforepartitioning.
Toameasuredaliquotoftheaqueoussolutionamatchingaliquotof1octanolisadd
ed,andthemixtureisincubatedbyquietshakingfor2hat231C.Theemulsionisal
lowed to stand overnight at the same temperature to ensure that the partition equili
briumisreached.Then,thoroughcentrifugationat3000rpmfor10minisappliedtosep
aratethelayers,andtheconcentrationofthecompoundintheaqueousphaseisdeter
minedagainbymeasuringtheUVabsorptionunderthesameconditionsasthereference.
Highthroughputmeasurementofionizationconstants(pKa)
ProfilerSGA
Ionization constants are determined at 231 C by spectrophotometry using a Profi
lerSGASIRIUSinstrumentinbufferedwatersolutionatanionicstrengthof150mM.To
thisendtheUVspectrumofacompoundismeasuredatdifferentpHvalues.Thesolution
ofthesampleisinjectedatconstantflowrateintoaflowingpHgradient.ChangesinUV
absorbancearemonitoredasafunctionofthepHgradient.ThepKavaluesarefoundand
determinedwheretherateofchangeofabsorbanceisatamaximum.
134
ExperimentalSection
The pH gradient is established by proportionally mixing two flowing buffer solutions.

The buffer solutions contain mixtures of weak acids and bases that are UV
spectroscopically transparent above 240 nm. It is necessary to calibrate the gradient in
ordertoknowexactlythepHatanygiventime.Thisisachievedbyintroducingstandard
compoundswithknownpKavalues.IncaseswherethepKacouldnotbemeasuredwith
the ProfilerSGA system due to an insufficient UV absorption of the compound the pKa
values were measured by potentiometric titration (GLpKa). Internal validation studies
(datanotshown)provedthatthedifferencebetweenthepKavaluesmeasuredwithboth
instrumentswerewithintheexperimentalerroroftheindividualexperiments.
GLpKa
pKa values with low UV absorption were determined by potentiometric titration (SI
RIUSGLpKaAnalyzer)inaqueoussolution,containing0.15 MKCltoadjustionicstrength.
To measure pKa of substances by the pH metric technique, a certain amount of sample
wasdissolvedinthebackgroundelectrolytesolutionandacidifiedtopH2byadditionof
0.5 MHCl.Thesolutionwasthentitratedwithstandardizedbase(0.5 MKOH)topH12at
constant temperature (23 C) under an atmosphere of argon to minimize absorption of
atmosphericCO2.ThepKavalueswerethencalculatedbyshapeanalysisofthetitration
curveincomparisontotheblanktitrationcurve.
Determination of metabolic stability in liver microsomes: Microsomal incubations
werecarriedoutin96wellplatesin200Loflivermicrosomeincubationmediumcon
taining potassium phosphate buffer (50 mM, pH 7.4), MgCl2 (10 mM), EDTA (1 mM),
NADP+ (2 mM), glucose6phosphate2 H2O (20 mM), glucose6phosphate dehydroge
nase(4units/ml)with0.1mgoflivermicrosomalproteinpermL.Testcompoundswere
incubatedat2Mforupto30minat37Cundervortexingat800rpm.Thereactionwas
stopped by transferring 30 L incubation aliquots to 90L of icecold MeOH. Levels of
nonmetabolized drug were determined by highperformance liquid chromatography
(HPLC)coupledwithtandemmassspectrometry(LC/MS/MS).Thesystemconsistedofa
ShimadzubinarygradientHPLCsystem,aWatersXTerraMSC18column(1mm50mm)
and a Sciex API 2000 mass spectrometer. A twocomponent mobile phase, pumped at
0.15mL/min, contained the following solvents: solvent A (1% aqueous formic acid and
ExperimentalSection
135
MeOH80:20)andsolventB(MeOH).Aninitialisocraticstepof0.5minsolventAwasfol
lowedbyagradientof0to80%solventBwithin1min.Detectionwasperformedinposi
tive mode. The intrinsic clearance (Clint) was determined in semilogarithmic plots of
compoundconcentrationsversustime.
Determinationofchemicalstabilityinaqueoussolutions:Thechemicalstabilityofa
given compound is determined in aqueous solutions at pH 1, 4, 6, 8, 10. Commercially
availablebuffersystemsfromMerckKGaA,Darmstadt(Catalognumbers109881,109884,
109886,109888,109890)areused.Anaqueousstocksolutionof10mMofeachsample
ispreparedanddilutedataratioof1:20(v/v)withbuffersolutionbeforetheyareshaken
for 10min at 37C. The solutions are then transferred to a filter plate (Millipore
MSGVN2250, pore size 0.22 m) and filtrated into Vbottom plates (from ABGene, AB
0800)thatareheatsealedpriortoanalysisbyHPLC.Samplesaretakenattimepoints0h
and2handanalyzedbyHPLC.Thepercentageofrecoveredunchangedcompoundisde
terminedbycalibratedHPLC.Acompoundisclassifiedaschemicallyunstableifafter2
hlessthan90%oftheinitialconcentrationisdetected.
Measurementofamphiphilicityviathemeasurementofsurfacetension:Anaqueous
solutionofthecompoundofknownconcentrationatthelimitofitssolubilityisdiluted
1:1(v/v)withaqueousMOPSObuffer11timesinsequence.Samplesof5Lofcompound
solution are taken at each dilution step and transferred to a 96well plate containing
45LpureaqueousMOPSObufferineachwell.ThisplateisthenplacedintoaMULTIPI
WS1instrumentofKIBRONInc.Thedeterminationofamphiphilicityinvolves(i)themea
surement of the surface tension of the compound solution at different concentrations
basedonthewellknownDuNouymaximumpullforcemethod,and(ii)thedetermina
tion of the critical micelle concentration (CMC) which is obtained at the intersection of
twoexperimentallines,thefirstbeingthecorrelationlineofdecreasingsurfacetension
withincreasingsampleconcentration,thesecondbeingtheplateaulinewherethesur
facetensionnolongerchangeswithincreasingsampleconcentration.Allmeasurements
are done at 22.51C. From the experimental data, the free energies of transfer from
136
ExperimentalSection
aqueous solution to the airwater interface and from aqueous solution to micelles are
obtained.Thedifferenceoffreeenergiesistakenasameasureofamphiphilicity.348
Automated patch clamp procedure for the hERG current measurement at Patch
Xpress 7000A: Electrophysiologcal recordings of K+ currents (IKhERG ) were conducted at
roomtemperature(2225C)usingAvivaBioscienceSealChip16(MolecularDevicesCor
poration, Cat SealChip16). CHO cells stably expressing hERG K+ channels (Roche Palo
Alto,USA)wereaddedbytheintegratedCavrorobottoeachwellofthesealchip.Cells
wereheldatarestingvoltageof80mVandtheywerestimulatedbyavoltagepatternto
activate hERG channels and conduct outward IKhERG current (Figure 1) at a stimulation
frequency of 0.1 Hz (6 bpm). Cell health and membrane parameters (access resistance
(Ra), membrane resistance (Rm) and membrane capacitance (Cm)) were monitored on
line.Afterthecellsstabilizedandthecurrentsweresteady,theamplitudeandkineticsof
IKhERGwererecordedundercontrolconditions.Thereafter,thesolutionofthetestcom
poundintheextracellularbuffer(NaCl150mM,KCl4mM,CaCl21.2mM,MgCl21mM,
HEPES 10 mM, pH 7.4 with NaOH, 300310 mOsm) was directly added by the robot to
eachwellatincreasingconcentrations.Doubleadditionofeachcompoundconcentration
wasperformedat1minintervaltoensurethefullexchangeofthesolutioninthewell.
Currentsweremonitoredcontinuouslyduringtheexposuretocompounds.
Offline analysis of the peak tail current was performed using DataXpress2 software
(MolecularDevicesCorporation,USA).TheamplitudeandkineticsofIKhERGwererecorded
in each concentration of drug and they were compared to the control values (taken as
100%)todefinefractionalblocks.ThehERGcurrentwasmeasuredastheaveragecurrent
from 10 sweeps collected at the end of vehicle or compound addition. Data were ex
pressedasmeanSEM.Concentrationresponsecurveswerefittedbynonlinearregres
sionanalysisandtheIC50valueswerereported.
348
H.Fischer,M.Kansy,D.Bur,Chimia2000,54,640.
ExperimentalSection
137
Base
Peak Cur
20mV
40mV
80mV
40mV
1000msec
80mV
100msec
500msec
NMRspectroscopicanalysisofNpiperonylpiperidine30349
1)Oxetane30
ThefreebaseisnotsufficientlysolubleinwaterforgoodNMRspectroscopicanalysis.
1
HNMRspectrainDMSOd6andCDCl3shownearlythesamechemicalshiftsandcoupl
ings.Thesignalsforthemethylenepiperidineprotonsshowtypicalaveragedsignalmul
tipletsofprotonsduetofastring/nitrogeninversionofthepiperidinering:
O
18
17
19
15
14
5
6
16
13
11
12
10
N
1
4
3
2
O
8
HNMR(400MHz,DMSOd6)ppm1.34(m,2h,H4)1.48(m,2h,H5)1.81(t,J=
6.2Hz,2h,H3)2.30(t,J=5.5Hz,2h,H6)3.65(s,2h,H10)4.23(d,J=6.3Hz,2h,H
7/9)4.59(d,J=6.3Hz,2h,H7/9)5.98(s,2HH18)6.80(dd,J=7.9,1.5Hz,1h,H
16)6.84(d,J=7.9Hz,1h,H18)6.90(d,J=1.5Hz,1h,H12)
2)DClsaltofOxetane30
The DCl salt form of 30 was produced by dissolving 30 in a mixture of D2O and DCl
(0.4mLD2Oand0.1mL1 NDCl;pH=1).Assignmentofthesignalswasachievedonthe
basisof2D1H,1HCOSYand2D1H,13CHSQCexperiments.
Bycontrasttothefreebase,the 1HNMRspectrumofthedeuteratedsaltshowssig
nals for diastereotopic methylene protons at 25 oC. Even the methylene protons of the
349
ThesespectraweretakenandanalyzedbyDr.JosefSchneideratF.HoffmannLaRoche,Basel.
138
ExperimentalSection
piperonylOCH2Ogroup(C18)at6.04ppmaresplitintoaweakABsystem.Thebenzylic
protons (CH210) at 4.39 ppm give rise to a pronounced AB system. The diastereotopic
natureofthesemethyleneprotonsarisefromthechiralquaternarynitrogencenterofthe
deuteratedpiperidine.Allsignalsofthepiperidineringmethylenegroupsarediasterotop
ic and show the typical coupling constants of a chair conformation of a sixmembered
ring.ThesignalsoftheaxialprotonsatC3,C5andC6wereidentifiedunambiguouslyon
thebasisoftheirmultiplets(largediaxialh,Hcouplingsand/ormultipletwidth).
R
CH2(10)
H-5ax
H-3ax
H-6eq
H-4eq
N+
O
18
17
19
15
14
16
13
11
12
H
10
H-3eq
H-9'
H-6ax
4
+
H-4ax
H-9''
3
2
O
8
H-7'
H-7''
O
Structureofdeuteratedoxetane30andstereochemicalassignmentsofprotonsbased
onobservedNOEs(green:NOEsidentifyingtheoxetaneprotons;red:NOEsdetermining
theaxialorientationofthepiperonylgroup;reddotted:observedNOEsthatdonotallow
adistinctionbetweenequatorialoraxialpositionofthepiperonylgroup).
1
HNMR(400MHz,D2O/DCl;d4TSP=0ppm)ppm1.62(m,1h,H4ax)1.68(m,1h,
H5equiv) 1.84 (m, 1h, H4equiv) 2.00 (m, 1h, H5ax) 2.29 (dt, J = 15.0, 4.3Hz, 1h, H
3equiv)2.36(td,J=15.0,1.3Hz,1h,H3ax)3.09(ddd,J=13.7,11.6,3.5Hz,1h,H6ax)
3.14(dt,J=13.7,3.5Hz,1h,H6equiv)4.39(AB,2h,H10)4.54(d,J=8.3Hz,1h,H7)
4.72(d,J=8.1Hz,1h,H9)4.88(d,J=8.3Hz,1h,H7)5.01(d,J=8.1Hz,1h,H9)6.04
(AB,2h,H18)6.97(m,1h,H15)7.05(m,2h,H12,H16)
ExperimentalSection
139
Assignmentsoftheoxetaneprotons:
BasedonHSQCexperiments,thesignalsat5.01,4.88,4.72,and4.54ppmcanbeas
signedtothediastereotopicmethyleneprotonsoftheoxetanemoiety.Thesignalat4.72
isassignedtooneoftheaxialmethyleneoxetaneprotons,H9,basedonthestrongNOE
toH4axandasignificantNOEtoH3equivAstrongNOEbetweenH6axandthesignalat
5.01ppmdefinesH9.TheprotonH7(4.54ppm)isdeterminedbyasignificantNOEto
H3equiv.
Assignmentsofthespatialorientationofthepiperonylgroup:
The2DNOESYspectrumshows4crosspeaks(cf.redarrows)forthebenzylicprotons
(C10).ThetwocrosspeaksbetweenCH210andH7andH6eqareambiguous(reddot
tedarrows)withrespecttothestereochemistry.Both,axialorequatorialorientationsof
the piperonyl group are compatible with the occurrence of these NOEs. The two other
cross peaks are dipolar couplings between CH210 and H3ax and H5ax respectively.
ThesetwoNOEs(cf.redsolidarrows)determineunambiguouslytheaxialorientationof
thepiperonylgroupatthepiperidinering.
2H
R
2H
NH
ring-inversion
O
NH
ring-inversion
N
O
N-protonation O
deprotonation
R
N-inversion
R
+
2H NH
ring-inversion
R
N-protonation
deprotonation
O
+ NH
2H
N
N
ring-inversion
O
Theobservationofonlyonesetof 1HsignalsintheNMRspectrumofdeuteratedoxe
tane30withwellseparatedandsharpsignalsfortheequatorialandaxialprotonsisclear
evidenceforthepredominanceofthechairconformationwithanaxialNpiperonylsubs
tituent. Furthermore, the clear differentiation into axial and equatorial piperidine ring
protonsaswellastheabsenceofNOEsbetweenthebenzylicprotonsandH6axexcludes
140
ExperimentalSection
arapidequilibriumat25CbetweenenantiomericNdeuteratedchairformswiththeN
piperonylgroupaxialviaasequenceofrapiddedeuteration,ringandNinversion,and
redeuterationprocesses.
6.2 PreparationofOxetan3one
6.2.1 PreparationofOxetan3onevia3,3Dimethoxyoxetane
O O
O
3,3dimethoxyoxetane. To a mixture of dihydroxyacetone dimer (94.2g, 0.522 mol,

1.00equivandtrimethylorthoformate(111g,1.05mol,2.00equiv,Acros)in1.5LMeOH
(bottle, Fluka puriss., p.a. ACS, >99.8% (GC)) was added pTSA (377mg, 1.98mmol,
0.00375equiv)atroomtemperature.
Picture 22: Clarification of mixture upon addition of pTSA. It is important that the solution
becomes clear. Undissolved material or turbidity indicates that the qualityof the dihydroxyacetone dimer used is not good and problems might result in the following
step.
ExperimentalSection
141
Afterstirringfor10h,thereactionwasquenchedbyadditionof20.7gAmbersep900
OH ion exchanger (not dried). After stirring for 15min, the ion exchanger resin was fil
teredoffandthefiltrateconcentratedinvacuo.Theresidualslightlyyellowoilwasdried
under high vacuum for further 16 h to give crude dihydroxyacetone dimethylketal as a
whitesolidwhichwasusedwithoutfurtherpurification.350
Picture 23 : This is how the material should look like. It takes ~2 h at high vacuum, before
crystallization starts. Shaking is important to spread the crystal mass across the inner surface of the flask. Usually the mass does not become fully crystalline, but
ends up in a semisolid state like the one shown above.
Thismaterialwasdissolvedin1.5Lofa2/1mixtureofTHF(Acros,p.a.)andEt2O(Flu
ka, puriss.) and cooled to 0C. A 2.5 M solution of nBuLi in hexanes (400mL, 1.00 mol,
1.91equiv,Acros)wasaddedslowlyover45minusingatransfercannula.
350
Followingaknownprocedure:a)F.Charmantray,L.ElBlidi,T.Gefflaut,L.Hecquet,J.Bolte,M.Lemaire,
J.Org.Chem.2004,69,9310.b)E.L.Ferroni,V.DiTella,N.Ghanayem,R.Jeske,C.Jodlowski,M.O'Connell,
J.Styrsky,R.Svoboda,A.Venkataraman,B.M.Winkler,J.Org.Chem.1999,64,4943.
142
ExperimentalSection
Picture 24: The solution of the dihydroxyacetone dimethyl ketal in THF should be clear.
Upon addition of nBuLi, the lithium alkoxide precipitates.
Afterstirringforfurther30min,asolutionofptoluenesulfonylchloride(151g,0.791
mol,1.51equiv,Acros99+%)in500mLTHFwasaddeddropwiseover1h.
Picture 25: During the addition of the solution of tosyl chloride, partial clarification will
occur together with some darkening. If the addition is too fast and/or the time after
the addition is too short, more of the undesired bistosylate will be formed
ExperimentalSection
143
Afterstirringfor40minintheicebath,themixturewastakenoutoftheicebathand
stirred for 1h, before it was concentrated in vacuo (bathtemperature <35C) to a vo
lumeofapproximately500mLanddissolvedin500mLEt2O.
BrinewasaddedandtheaqueousphaseextractedwithEt2O(400mL)twice.Thecom
binedorganicphasesweredriedoverMgSO4,filtered,concentratedinvacuountilallEt2O
wasremovedandtheresiduedissolvedinTHF togive 2.5 Lofaclearslightlyyellowish
solution.Thissolutionwascooledto0Candsodiumhydride(60%dispersioninmineral
oil,45.0g,1.13mol,2.16equiv)wasaddedinsmallportions.
Picture 26: The addition of the first portions of NaH results in vigorous H2-evolution. The
first 3 portions should be added very cautiously and not exceed 3 g.
Afterstirringfor30minat0C,themixturewasheatedto50Covernight.(Alterna
tivelyonecanalsostiratroomtemperaturefor72h.)
144
ExperimentalSection
Picture 27: The mixture adopts the consistence of mud and should be shaken with ether
remove it from the flask.
Theviscousmasswasdilutedwith500mLEt2Oandpouredonice.Theaqueousphase
was saturated with NaCl and extracted with Et2O (400mL) three times. The combined
organicphasesweredriedoverMgSO4for20min,filtered,concentratedinvacuo(bath
temperature 30C, 150 mbar) and the residue distilled (20 mbar, bp = 40C) to give
47.96gproduct(38.9%,calculatedontheamountofdihydroxyacetonedimerused)asa
clearcolorlessliquidtogetherwith1.33gTHF(2.7w%).Thismaterialcanbeusedwithout
furtherpurification.
Thefollowingprocedureworkswellforthedistillation.TheresidualTHFisremovedat
ambientpressurewithanoilbathtemperatureof83C.Vigorousstirringandtheaddi
tionofboilingchipsareimportant.WhennomoreTHFcomesover,thepressureisslowly
reducedto150mbar.Whenthispressureisreached,amiddlefractionistakeninwhich
thepressureisslowlyreducedto100mbar.Oncethispressureisreached,fractionsare
changedandthepressurefurtherreducedtoapproximately20mbarwhilethetempera
tureisraisedto93C.Neverheatthemixtureabove95C!Spontaneousandveryvigor
ousdecompositionhasbeenobservedattemperaturesabove95C.Itisadvisabletoim
mersetheflaskinwhichthefractioniscollectedinanicebath.Whennomoreproduct
comes over, the heating is removed before the vacuum. The residue of the distillation
ExperimentalSection
145
consistsmainlyofbistosylateandmineraloil.Themineraloilcanbedecantedoffandthe
bistosylatecrystallizedbystirringitwithapproximately70mLEt2Oovernight.
13
Rf=0.41(hexane/EtOAc2:1). HNMR(300MHz,CDCl3):4.55(s,4H),3.21(s,6H); C
NMR(75MHz,CDCl3):100.6,79.8,49.4;IR(thinfilm)2954,2878,2835,1473,1716,
1
1453,1352,1204,1134,1044,980cm ;Anal.calcdforC5H10O3:C,50.84;H,8.53.Found:
C,51.07;H,8.45;
O
O
Oxetan3one: 3,3dimethoxyoxetane (15.8g, 0.134 mol) was dissolved in 7 L CH2Cl2

(technical quality, distilled once via big rotovaper) and 99.1g Montmorillonite K10 clay
(Fluka)wasadded.
Picture 28: Two apparati for the refluxing step. Bumping will occur, but is usually no
problem for the reaction.
146
ExperimentalSection
The mixture was refluxed for 70h, cooled to room temperature, filtered through a
plug of celite and thoroughly washed with 3x 150mL CH2Cl2. The CH2Cl2 was removed
from the filtrate by distillation employing a 30 cm Vigreux column to prevent product
fromdistillingover.
Picture 29: Distillation of ~ 9 L CH2Cl2 should take ~7 h. If an unstirred oil bath is employed, a temperature of 100 C had to be used to get to these distillation rates.
When using an oil bath the level of the oil should be adjusted to the one inside the
flask. Also, towards the end of the distillation, the oil bath temperature should be
reduced as well as the power output of the heating mantle.
Theresiduewastransferredtoa500mLflaskanddistilledunderreducedpressure(bp
=49C,117mbar,bathtemperature=65C)togive5.96g(62%yield)productin2frac
tions. One containing 5.37g product (~90% pure) being a clear slightly yellowish liquid,
anothercontaining0.59gproduct(30w%)togetherwithCH2Cl2.Thematerialshouldbe
storedinthefreezer,wheretheneatcompoundsolidifies(mp=~5C).Safetytestsat
RocheindicatethatOxetan3oneshouldnotbeheatedover80Cduetoanexothermic
ExperimentalSection
147
autocatalytic decomposition pathway. For longer processes (> 72 h) the maximum tem
peraturewasdeterminedtobe60C.
1
13
HNMR(300MHz,CDCl3):5.40(s,4H); CNMR(75MHz,CDCl3):.199.74,92.61
TheprotonNMRofoxetan3onefoundisidenticalwiththeoneprecedentinthelite
rature.117a
Forthedistillation(carriedoutwitha14cmVigreuxcolumnshortpathcombination),
thefollowingprocedureworkswell:
Thematerialcomingfromthebulkdistillationshouldnotexceed400mL,asthesepa
ration with the Vigreuxcolumn used is not perfect. Most of the residual CH2Cl2 is re
movedatambientpressurewithvigorousstirringandboilingchipsaddedinanoilbathof
62C.OncenomoreCH2Cl2comesover,fractionsarechangedandthepressureisslowly
lowered to 100 mbar. If this pressure is reached, fractions are changed again and the
productiscollectedwhilereducingthepressurefurtherto~25mbarandheatingtheoil
bathto74C.Theflaskwithwhichthematerialiscollectedshouldbeimmersedinanice
bath.
6.2.2 PreparationofOxetan3onebyOxidationofOxetan3ol
Phosphorouspentoxide(184.5g,1.300moles,1.300equiv)wassuspendedin600mL
CH2Cl2.Glasswareneednotbepreviouslydried,thereactionisnotairsensitive.Thissus
pension was cooled in an ice/saltbath to a temperature below 0C, before DMSO
(106mL, 1.50 moles, 1.50equiv) was added followed by oxetan3ol (45, 74.1g, 1.00
moles,1.00equiv).Thewhitedispersionwasvigorouslystirredandoncethetemperature
insidereached5C,theadditionofNEt3wasstarted(307mL,2.20moles,2.20equiv).
The temperature should stay around 0C, but not exceed 5C. Usually the addition
takes3hto3.5h.Duringtheadditionthemixtureturnedorangeandbecamehomogen
ous.Aftertheadditionisfinishedthemixtureisstirredfor5min,before600mLEt2Oare
added.Aphaseseparationoccurred,thetopphasecontainingtheproduct.
148
ExperimentalSection
Thetwophasesshouldbestirredforapproximately5min.Thetopphasewasthenfil
teredusingvacuum(~700mbar)throughaplugofsilicagel(h=7cm,d=13cm)ofwhich
thetop2cmwerewettedwithEt2O.Thebottomphaseofthereactionmixturewastho
roughly washed with five times 100mL of diethyl ether, becoming very viscous. These
werethenalsofilteredthroughtheplug,resultinginatotalvolumeoffiltrateofapprox
imately1.5L.Thefiltratewasthentransferredtoaflaskequippedwithastirbarandboil
ingchips,andthesolventdistilledoffthroughacolumnfilledwithwirehelices(joint29,h
28cm).
Thetemperatureoftheoilbathshouldnotexceed60C.Oncenomoresolventwas
comingover,thecolumnwasreplacedwithashortpathdistillationapparatusandstirring
atambientpressurewascontinueduntilnomoresolventcameover.Thenfractionswere
changed with the receiving flask being cooled with ice, the temperature of the oilbath
wasraisedto75Candatthesametimethepressurewasslowlyreducedto100mbar
(~2minfromambientpressureto180mbars,~30secondsfrom180mbarto100mbar).
Once this pressure was reached, fractions were changed and pure product came over
withlessthan2w%CH2Cl2.Thepressurewasfurtherloweredslowlyto30mbarandthe
distillationstoppedwhennomoreproductcameover.Theintermediatefractionandthe
main fraction together contained 34.77g oxetan3one (48% yield). The oxetan3one
shouldbestoredinthefreezer,whereitsolidifies.
6.3 PreparationofMichaelAcceptors
Oxetan3ylideneacetic acid ethyl ester: To a solution of oxetan3one (33, 0.22g,

3.0mmol, 1.0equiv) in 6mL dry CH2Cl2 was added Carboethoxymethylene triphenyl
phosphorane (1.2g, 3.3mmol, 1.1equiv) at 0C. The solution was allowed to warm to
room temperature and after stirring for 15min filtered through silica gel (2/1 cyclohex
ane/EtOAc)togive388mg(89%yield)product(97w%byNMR)asacolorlessoil.
ExperimentalSection
149
Rf=0.0.33(SiO2,2/1cyclohexane/EtOAc); HNMR(300MHz,CDCl3):5.60(m,1H),
13
5.47 (m, 2H), 5.27 (m, 2H), 4.13 (q, 2H, J = 7.1 Hz), 1.24 (t, 3H, J = 7.1 Hz); C NMR
(75MHz,CDCl3):165.4,159.3,111.3,81.2,78.6,60.5,14.4;IR(thinfilm)2983,2927,
1
2858,1722,1698,1446,1372,1346,1298,1266,1206,1100,1038,961,870,833cm ;
Anal.calcdforC7H10O3:C,77.21;H,9.87;N,6.00.Found:C,76.99;H,9.87;N,5.98.
Oxetan3ylideneacetaldehyde: To a solution of oxetan3one (33, 441mg,

6.12mmol,1.00equiv)in8mLdryCH2Cl2wasaddedformylmethylenetriphenylphospho
rane (2.6g, 8.6mmol, 1.4equiv) at room temperature. The solution was stirred over
nightandfilteredthroughsilicagel(1/1pentane/Et2O)togive537mgproduct(~90w%
byNMR)asanorangeoil(yield81%assuming90%purity).
Rf=0.33 (SiO2, 2/1 cyclohexane/EtOAc); H NMR (300MHz, CDCl3): 9.52 (d, 1H, J =
13
5.8Hz),5.92(m,1H),5.58(m,2H),5.38(m,2H); CNMR(75MHz,CDCl3):188.6,163.4,
1
119.8, 80.0, 79.7; IR (thin film) 2918, 2856, 2747, 1693, 1650, 1149, 962, 865cm ;
+
HRMS(EI)calcdforC5H6O2[M] 98.0368.Found:98.0359
3Nitromethyleneoxetane: To a solution of oxetan3one (33, 188mg, 2.61mmol,

1.00equiv)in3mLnitromethanewasaddedacatalyticamountofNEt3(6drops)atroom
temperature. After stirring for 20min, the mixture was concentrated in vacuo and the
150
ExperimentalSection
residue dissolved in 10mL dry CH2Cl2. The mixture was cooled to 78C, NEt3 (1.6mL,
12mmol,4.4equiv)wasaddedfollowedbydropwiseadditionofmesylchloride(600L,
7.75mmol,3.00equiv)over10min(pinkcolor).Afterstirringfor20min,themixturewas
directly put on a column packed with silica gel and eluted with Et2O /pentane = 1/1 to
give243mg(81%yield)ofproductasawhitesolid(mp=4143C).
Rf=0.28(SiO2,2/1cyclohexane/EtOAc); HNMR(300MHz,CDCl3):6.92(m,1H),5.66
13
(m,2H),5.38(m,2H); CNMR(75MHz,CDCl3):155.9,130.0,79.6,75.5;IR(thinfilm)
3092, 2925, 2848, 1698, 1525, 1421, 1350, 1319, 1186, 1125, 960, 947, 904, 828, 777,
1
725cm ;HRMS(EI)calcdforC4H5NO3[MH] 114.0186.Found:114.0184.
1Oxetan3ylidenepropan2one: To a solution of oxetan3one (33, 63mg,

0.87mmol,1.0equiv)in8mLdryCH2Cl2wasaddedacetylmethylenetriphenylphospho
rane (0.33g, 1.0mmol, 1.3equiv) at room temperature. The solution was stirred over
nightandfilteredthroughsilicagel(4/1to2/1pentane/Et2O)togive75mgpureproduct
asacolorlessoilin77%yield.
13
(m,2H),5.27(m,2H),2.14(s,3H); CNMR(75MHz,CDCl3):196.4,158.3,118.0,82.0,
78.9,30.4;IR(thinfilm)2923,2855,1724,1709,1694,1672,1651,1431,1366,1198,
1
954cm ;HRMS(EI)calcdforC6H8O2[M] 112.0524.Found:112.0519
ExperimentalSection
151
1[1(4Chlorophenyl)cyclobutyl]2oxetan3ylideneethanone: To a solution of ke
tophosphonate 220 (see page 211 for its preparation; 0.95g, 3.0mmol, 1.0equiv) in
10mL dry THF was added sodium hydride (60% dispersion in mineral oil, 0.12g,
3.0mmol, 1.0equiv) at 0C. After stirring for 20min, a solution of oxetan3one (33)
(0.22g,3.0mmol,1.0equiv)in1mLdryTHFwasaddedandthesolutionstirredat0C
for30min.Thesolventwasconcentratedinvacuopartially,toluenewasaddedandthe
mixture put on a column (SiO2, 20/1 to 4/1 cyclohexane/EtOAc) to give 750mg pure
product(95%yield)asacolorlessoil.Theproductisnotstableatambienttemperature
andrearrangesto(5(1(4chlorophenyl)cyclobutyl)furan3yl)methanol.
1
8.6Hz),7.14(d,2H,J=8.6Hz),5.88(p,1H,J=2.3Hz),5.55(m,2H),5.22(m,2H),2.74(m,
13
2H), 2.38 (m, 2H), 1.90 (m, 2H); C NMR (75MHz, CDCl3): 197.7, 160.3, 141.0, 132.7,
128.8,127.6,113.5,82.4,79.0,57.6,30.3,15.9;IR(thinfilm)2926,2852,2360,1706,
1
1649, 1492, 1351, 1180, 1093, 1013, 953 cm ; HRMS (EI) calcd for C15H15ClO2 [M]
262.0756.Found:262.0752
3Benzenesulfonylmethyleneoxetane:351 To a solution methylphenylsulfone (5.0g,

32mmol, 1.0equiv) in 150mL dry THF was added nBuLi (2.5 M in hexanes, 28mL,
71mmol,2.2equiv)at0Coverthecourseof10min.Afterstirringfor30min,chlorodie
thylphosphonate(5.6mL,38mmol,1.2equiv)wasaddeddropwiseandstirringwascon
tinuedfor30min,beforethemixturewascooledto78Candoxetan3one(33,3.25g,
351
Procedureadaptedfrom:A.D.Briggs,R.F.W.Jackson,P.A.Brown,J.Chem.Soc.PerkinTrans.11998,
4097.
152
ExperimentalSection
45.1mmol,1.41equiv)wasaddedasasolutionin5mLdryEt2O.Afterstirringfor1.5h,
themixturewasfilteredthroughaplugofsilicageltogive5.08gpureproduct(76%yield)
asacolorlesssolid(mp=5153C).
13
7.8Hz),7.66(m,1H),7.57(t,2H,J=7.3Hz),6.12(m,1H),5.64(m,2H),5.28(m,2H); C
NMR(75MHz,CDCl3):156.2,140.6,133.7,129.3,127.2,119.9,79.6,77.9;IR(thinfilm)
1
3057,2923,2856,1692,1445,1324,1303,1147,1085,960,872,821,755cm ;HRMS
+
(EI)calcdforC10H10O3S[M] 210.0351.Found:210.0345
Oxetan3ylideneacetonitrile: To a solution of oxetan3one (33, 0.21g, 3.0mmol,

1.0equiv) in 10mL dry CH2Cl2 ways added cyanomethylenetriphenylphosphonium ylide
(0.90g,3.0mmol,1.0equiv)atroomtemperature.Afterstirringfor6h,thesolventwas
partiallyconcentratedinvacuoandthemixturefilteredthroughaplugofsilicagel(2/1to
1/1pentane/Et2O)togive235mgpureproduct(82%yield)asslightlyyellowcrystals(mp
=5658C).
1
13
(m,2H),5.25(td,1H,J=2.5Hz,J=5.0Hz); CNMR(75MHz,CDCl3):163.3,114.0,90.8,
1
78.6, 78.4; IR (thin film) 3065, 3015, 3940, 2220, 1696, 1445, 1328, 1219, 943 cm ;
+
HRMS(EI)calcdforC5H5NO[M] 95.0371.Found:95.0365
ExperimentalSection
153
Diethyl oxetan3ylidenemethylphosphonate:352 To a suspension of sodium hydride

(60%dispersioninmineraloil,0.80g,20mmol,1.0equiv)in30mLdryTHFwasaddeda
solutionoftetraethylmethylenediphosphonate(5.0mL,20mmol,1.0equiv)in10mLdry
THF dropwise at room temperature. After stirring for 5min, a solution of oxetan3one
(33,1.4g,20mmol,1.0equiv)in5mLdryTHFwasaddedslowly.Afterstirringfor2h,the
solventwaspartiallyconcentratedinvacuo,Et2Oandwaterwereaddedandtheaqueous
phase extracted three times with Et2O. The combined organic phases were dried over
MgSO4,filtered,concentratedinvacuoandtheresiduepurifiedbyflashchromatography
(SiO2,cyclohexanetoremovemineraloilthenelutewithEtOAc)togive2.77gpureprod
uct(67%yield)asacolorlessoil.
1
Rf=0.16 (SiO2, 2/1 cyclohexane/EtOAc); H NMR (300MHz, CDCl3): 5.49 5.35 (m,
13
3H), 5.29 5.21 (m, 2H), 4.14 3.97 (m, 4H), 1.37 1.26 (m, 6H).; C NMR (75MHz,
CDCl3): 161.1, 106.9 (d,J=189.3Hz),80.8(d,J=10.0Hz),79.5(d,J=27.6Hz),61.7(d,J
31
=5.5Hz),16.3; PNMR(121MHz,CDCl3): 15.8; IR(thinfilm)3466,2985,1699,1480,

1
1444,1393,1317,1221,1164,1026,871,770cm ;HRMS(EI)calcdforC8H15O4P[MH]+=
205.0625.Found:205.0624
352
Procedureadaptedfrom:R.D.Allan,J.R.Hanrahan,T.W.Hambley,G.A.R.Johnston,K.N.Mewett,A.
D.Mitrovic,J.Med.Chem.1990,33,2905.
154
ExperimentalSection
6.4 PreparationofOxetanesoftheOpenChainScaffold
[4(4Bromophenyl)butyl]dimethylamine: To a suspension of the hydro bromide

salt of (3(dimethylamino)propyl)triphenylphosphonium bromide353 (12.2g, 24.0mmol,
1.00equiv) in 150mL dry THF was added nBuLi (1.6 M in hexanes, 17mL, 43mmol,
1.8equiv) at 0C. After stirring for 40min at 0C, a solution of pbromobenzaldehyde
(5.3g,29mmol,1.2equiv)in15mLdryTHFwasaddedslowly.Themixturewasstirredat
60Covernight,cooledto0C;waterwasadded,followedbyconcentratedaqueousHCl.
TheclearyellowishsolutionwasfreedfromTHFbyevaporationandwashedtwicewith
50mLtoluene.Theaqueousphasewasextractedfivetimeswith40mLchloroform.The
combinedchloroformphasesweredriedoverMgSO4,concentratedinvacuoandthere
sidue dissolved in 100mL MeOH. After addition of 540mg Rh/C (5 w%), hydrogen was
bubbledthroughthesolutionfor45minandthemixturevigorouslystirredfor19h.The
mixture was filtered through a pad of celite, the filtrate concentrated in vacuo and the
residuetakenupin25mLwater.Et2O(50mL)wasadded,followedbyexcesssodiumhy
droxide(withcooling)tofreetheamine.Theaqueousphasewasextractedthreetimes
withEt2O,thecombinedorganicphasesweredriedoverMgSO4,filtered,thefiltratecon
centratedinvacuoandtheresiduedistilled(bp98Cat0.5mm)togive5.15g(84%yield)
pureproductasacolorlessoil.
HNMR(300MHz,CDCl3):7.38(d,2H,J=8.4Hz),7.05(d,2H,J=8.3Hz),2.63(m,
13
2H), 2.27 (m, 2H), 2.21 (s, 6H), 1.55 (m, 4H); C NMR (75MHz, CDCl3): 141.3, 131.2,
130.1, 119.3, 59.6, 45.6, 35.3, 29.2, 27.4; IR (thin film) 2937, 2858, 2818, 2762, 1488,
1
1462,1072,1011cm ;HRMS(EI)calcdforC12H18BrN[M] ,255.0613.Found,255.0614.
353
Preparedaccordingto:E.J.Corey,M.C.Desai,TetrahedronLett.1985,26,5747.
ExperimentalSection
155
3[4(4Dimethylaminobutyl)phenyl]oxetan3ol: To a solution of [4(4Bromo

phenyl)butyl]dimethylamine (221, 0.89g, 3.5mmol, 1.3equiv.) in 10mL dry THF was
addedasolutionof nBuLi(2.5M inhexanes,1.4mL,3.5mmol,1.3equiv)at78C.After
stirringfor10min,asolutionofoxetan3one(193mg,2.68mmol,1.0equiv.)in4mLdry
THF was added dropwise. The mixture was stirred for 10min, before it was allowed to
warm to room temperature. Water was added and the aqueous phase extracted three
timeswithEtOAc.ThecombinedorganicphasesweredriedoverMgSO4,filtered,concen
trated in vacuo and the residue purified by flash chromatography (SiO2; 10% to 40%
MeOHinCH2Cl2,0.1%NEt3)togive480mgpureproduct(71%yield)asaviscouscolor
lessoilwhichsolidifieduponcooling(mp=5758C).
Rf=0.17(SiO2,40%MeOHinCH2Cl2,0.1%NEt3); HNMR(300MHz,CDCl3):7.48(d,
2H,J=8.3Hz),7.23(d,2H,J=8.2Hz),4.92(d,2H,J=6.9Hz),4.89(d,2H,J=6.9Hz),2.65
13
(m,2H),2.26(m,2H),2.20(s,6H),1.56(m,4H); CNMR(75MHz,CDCl3):142.1,139.9,
128.5, 124.4, 85.5, 75.5, 59.6, 45.4, 35.4, 29.3, 27.3; IR (thin film) 3373, 2940, 2859,
1
2780,1467,1175,981cm ;Anal.calcdforC15H23NO2:C,72.25;H,9.30;N,5.62.Found:
+
C,72.13;H,9.30;N,5.54;HRMS(EI)calcdforC15H23NO2[M] ,249.1729.Found,249.1723
NMe2
H
O
81
Dimethyl[4(4oxetan3ylphenyl)butyl]amine: To a solution of tertiary alcohol 70

(135mg,0.54mmol,1.00equiv)in8mLdryEt2OwasaddedNaH(60%dispersioninmin
eral oil, 45mg, 1.1mmol, 2.1equiv) at 0C. After stirring for 1 h at room temperature,
pTosCl(0.14g,0.71mmol,1.3equiv.)wasaddedat0C.Afterstirringfor1hat0C,the
156
ExperimentalSection
mixture was cooled to 78C and a solution of lithium aluminum hydride (1.0mL,
4.0mmol, 7.4equiv, 4.0 M solution in Et2O) was added slowly. After stirring for 1h, the
reactionwasquenchedatthistemperaturebydropwiseadditionof2 M aqueousNaOH.
The aqueous phase was extracted three times with Et2O. The combined organic phases
werewashedoncewithbrine,driedoverMgSO4,filteredandconcentratedinvacuo.The
residuewaspurifiedbyflashchromatography(Al2O3;20/1to1/1cyclohexane/EtOAc)to
give73mg(58%yield)pureproductasacolorlessoil.
Rf=0.44(Al2O3,2/1cyclohexane/EtOAc); HNMR(300MHz,CDCl3):7.30(d,2H,J=
8.1Hz),7.18(d,2H,J=8.0Hz),5.05(dd,2H,J=5.9Hz,J=8.4Hz),4.77(dd,2H,J=6.1Hz,
J=6.7Hz),4.20(m,1H),2.63(m,2H),2.26(m,2H),2.20(s,6H),1.63(m,2H),1.50(m,
13
2H); CNMR(75MHz,CDCl3):141.2,138.7,128.7,126.6,79.1,59.8,45.7,40.1,35.5,
1
29.4,27.6;IR(thinfilm)2937,2868,2813,2763,1515,1463,983cm ;Anal.calcdfor
C15H23NO:C,77.21;H,9.87;N,6.00.Found:C,76.99;H,9.87;N,5.98;HRMS(EI)calcdfor
+
C15H23NO[M] ,233.1775.Found,233.1776.
NMe2
F
O
73
[4[4(3Fluorooxetan3yl)phenyl]butyl]dimethylamine: To a solution of tertiary

alcohol 70 (135mg, 0.54mmol, 1.00equiv) in 8mL dry CH2Cl2 was added DAST (86L,
0.65mmol,1.2equiv)at78C.Themixturewasallowedtowarmto0Cover2hand
quenchedbyadding1M aqueousNaOHat5C.Theaqueousphasewasextractedthree
timeswithEt2O.Thecombinedorganicphaseswerewashedoncewithbrine,driedover
MgSO4,filteredandconcentratedinvacuo.Theresiduewaspurifiedbyflashchromato
graphy(Al2O3;20/1to1/1cyclohexane/EtOAc)togive54mg(40%yield)pureproductas
acolorlessoil.
ExperimentalSection
157
8.0Hz),7.25(d,2H,J=8.0Hz),5.08(ddd,2H,J=1.1Hz,J=7.8Hz,J=21.2Hz),4.88(ddd,
2H,J=1.1Hz,J=7.8Hz,J=21.5Hz),2.65(t,2H,J=7.5Hz),2.26(m,2H),2.20(s,6H),
13
1.64(m,2H),1.49(m,2H); CNMR(75MHz,CDCl3):143.0,135.6(d,J=23.8Hz),128.6,
124.0(d,J=8.2Hz),83.2(d,J=25.5Hz),95.2(d,J=206.3Hz),59.72,45.64,35.6,29.30,
27.5; 19F NMR(282 MHz, CDCl3): 147.8; IR (thin film) 1940, 2858, 2814, 2764, 1518,
1
1460, 1299, 1174, 982, 820cm ; Anal. calcd for C15H22FNO: C, 71.68; H, 8.82; N, 5.57.
+
Found:C,71.44;H,8.93;N,5.77;HRMS(EI)calcdforC15H22FNO[M] ,251.1680.Found,
251.1682
2(4(4(dimethylamino)butyl)phenyl) boronic acid: To a solution of [4(4Bromo

phenyl)butyl]dimethylamine (221, 0.97g, 3.8mmol, 1.0equiv) in 30mL of a 1/1
mixture of Et2O and THF was slowly added nBuLi (1.6 M in hexanes, 3.0mL, 4.8mmol,
1.3equiv)at78C.Afterstirringfor45min,freshlydistilledtriisopropylborate(1.5mL,
6.0mmol,1.6equiv)wasaddedandthemixturewasallowedtowarmtoroomtempera
tureovernight.6mL2M aqueousHClwereaddedandthemixturevigorouslystirredfor
20min. The mixture was basified with 5 M aqueous NaOH and the aqueous phase was
washed twice with Et2O. The pH was adjusted to 910 with aqueous HCl. The aqueous
phasewassaturatedwithsodiumchlorideandextracted5timeswithEt2O.Thecombined
organic phases were dried over MgSO4, filtered, concentrated in vacuo and the residue
(whitefoam)usedwithoutfurtherpurification.
HNMR(300MHz,CDCl3):7.91(d,2H,J=7.7Hz),7.22(d,2H,J=7.9Hz),2.68(t,2H,
J=6.7Hz),2.43(m,2H),2.28(s,6H),1.62(m,4H).
158
ExperimentalSection
Ethyl 2(3(4(4(dimethylamino)butyl)phenyl)oxetan3yl)acetate: To a solution of

[Rh(cod)Cl]2(25mg,50mol,0.050equiv)in3mLdrydioxanewasaddedaqueousKOH
(1.5 M, 0.9mL, 1.3mmol, 1.3equiv), followedby the ,unsaturated ester 89 (137mg,
0.96mmol, 1.00equiv) and a solution of 2(4(4(dimethylamino)butyl)phenyl) boronic
acid(147,320mg,1.45mmol,1.50equiv)in5mLdrydioxane.Afterstirringfor6h,Et2O
and brine were added. The aqueous phase was extracted three times with Et2O. The
combinedorganicphasesweredriedoverMgSO4,filteredandconcentratedinvacuo.The
residue was purified by flash chromatography (Al2O3; 8/1 to 2/1 cyclohexane/EtOAc) to
give256mg(83%yield)pureproductasacolorlessoil.
8.2Hz),7.06(d,2H,8.2Hz),4.99(d,2H,J=6.1Hz),4.84(d,2H,J=6.1Hz),3.99(q,2H,J=
7.1Hz),3.08(s,2H),2.60(m,2H),2.25(m,2H),2.19(s,6H),1.52(m,4H),1.10(t,3H,J=
13
7.1 Hz); C NMR (75MHz, CDCl3): 170.9, 141.1, 128.7, 125.8, 82.2, 60.5, 59.9, 45.7,
45.3, 45.0, 35.6, 29.4, 27.6, 14.2; IR (thin film) 2933, 2867, 2762, 1798, 1463, 1372,
1
1191, 1029, 989cm ; HRMS (MALDI) calcd for C19H29NO3 [M] 319.2142. Found:
319.2142.
N,Ndimethyl4(4(3methyloxetan3yl)phenyl)butan1amine:ToasolutionofEthyl
2(3(4(4(dimethylamino)butyl)phenyl)oxetan3yl)acetate (146, 0.23g, 0.73mmol,
1.0equiv) in 10mL Et2O was added a solution of DIBALH (20 w% in hexanes, 2.2mL,
ExperimentalSection
159
2.2mmol,3.0equiv)at78Cover45min.Afterstirringfor1hatthistemperature,the
solutionwaspouredintoicecold1NHCl.TheaqueousphasewasbasifiedwithKOH(cool
ing)andextractedthreetimeswithEt2O.Thecombinedorganicphasesweredriedover
MgSO4,filteredandconcentratedinvacuo.Theresiduewasdissolvedin30mLtoluene.
[(Ph3P)3RhCl](2.0g,2.2mmol,3.0equiv)wereaddedandthemixturestirredat105Cfor
16h.Aftercoolingtoroomtemperature,themixturewasfiltered,washedwithEt2Oand
2M aqueousNaOH.TheaqueousphasewasextractedthreetimeswithEtOAc,driedover
(Al2O3;20/1to4/1cyclohexane/EtOAc)togive66mg(33%yield)pureproductascolor
lessoil.
8.2Hz),7.10(d,2H,J=8.3Hz),4.95(d,2H,J=5.5Hz),4.61(d,2H,J=5.5Hz),2.61(m,
13
2H), 2.27 (m, 2H), 2.21 (s, 6H), 1.71 (s, 3H), 1.56 (m, 4H); C NMR (75MHz, CDCl3):
143.9, 140.7, 128.7, 125.1, 84.1, 59.9, 45.8, 43.3, 35.6, 29.5, 28.0, 27.7; IR (thin film)
1
2935,2865,2814,2763,1517,1461,1041,985,821cm ;HRMS(EI)calcdforC16H25NO
+
[M] 247.1931.Found:247.1933.
[3(4tertButylphenyl)oxetan3yl]acetaldehyde: A catalytic amount (~2mg,

~0.004mmol, 0.01equiv)of [Rh(cod)Cl]2 was dissolved in 1.6mL dry dioxane within
10min.1.5 M aqueousKOH(0.17mL,0.25mmol,0.5equiv)wasaddedandthemixture
was stirred for 5min before ptBuphenylboronic acid (198mg, 1.11mmol, 2.00equiv)
was added. A solution of ,unsaturated aldehyde 90 (49mg, 0.5mmol, 1.0equiv) in
0.6mLdrydioxanewasaddedandthemixturestirredfor20minatroomtemperature.
160
ExperimentalSection
Another170mgofptBuphenylboronicacid(0.96mmol,1.9equiv)wereaddedtodrive
thereactiontocompletion.Afterfurtherstirringfor1h,Et2O(20mL)andwaterwasadd
ed.TheaqueousphasewasextractedthreetimeswithEt2O.Thecombinedorganicphas
esweredriedoverMgSO4,filteredandconcentratedinvacuo.Theresiduewaspurified
byflashchromatography(SiO2;8/1to2/1cyclohexane/EtOAc)togive90mg(78%yield)
pureproductasawhitesolid(mp=6667C).
Rf=0.35(SiO2,2/1cyclohexane/EtOAc); HNMR(300MHz,CDCl3):9.71(t,1H,J=1.7
Hz),7.38(d,2H,J=8.6Hz),7.10(d,2H,J=8.5Hz),5.06(d,2H,J=6.2Hz),4.77(m,2H),
13
3.25 (d, 2H, J = 1.7 Hz), 1.32 (s, 9H); C NMR (75MHz, CDCl3): 200.1, 149.7, 140.2,
125.5, 125.4, 82.0, 53.3, 44.6, 34.6, 31.4; IR (thin film) 3092, 2925, 2848, 1698, 1525,
1
1421,1350,1319,1186,1125,960,947,904,828,777,725cm ;Anal.calcdforC15H20O2:
C,77.55;H,8.68.Found:C,77.60;H,8.72.
3(4tertButylphenyl)3(3nitroallyl)oxetane: To a solution of [3(4tertButyl

phenyl)oxetan3yl]acetaldehyde (114, 90mg, 0.4mmol), 1.0equiv) in 4mL nitrome
thanewasaddedNEt3(8.0L,58mol,0.2equiv).Afterstirringfor3h,thesolventwas
concentrated in vacuo, the residue dissolved in 10mL dry CH2Cl2 and cooled to 78C.
NEt3 (162L, 1.16mmol, 3.00equiv) was added, followed by mesyl chloride (90L,
1.2mmol, 3.0equiv). After stirring for 30min at 78C, NEt3 (162L, 1.16mmol,
3.00equiv)wasaddedandthemixtureslowlyallowedtowarmto0C.Thissolutionwas
added to cold brine and the aqueous phase was extracted three times with Et2O. The
combinedorganicphasesweredriedoverMgSO4,filteredandconcentratedinvacuo.The
residue was purified by flash chromatography (SiO2; 8/1 to 4/1 cyclohexane/EtOAc) to
give62mgalmostpureproduct(58%yield)asayellowishoilthatsolidifiedinthefreezer
(mp=6972C).
ExperimentalSection
161
8.4Hz),7.06(m,2H),6.93(d,2H,J=8.5Hz),5.01(d,2H,J=6.1Hz),4.63(d,2H,J=6.2
13
Hz),3.00(d,2H,J=7.5Hz),1.32(s,9H); CNMR(75MHz,CDCl3):150.0,141.3,139.4,
137.4,125.7,125.1,80.8,46.6,39.4,34.6,31.4;IR(thinfilm)3098,2963,2906,2872,
1
1912,1650,1526,1464,1396,1352,1270,1202,1116,982,835,736cm ;Anal.calcdfor
C16H21NO3:C,69.79;H,7.69;N,5.09.Found:C,70.00;H,7.68;N,4.91.
[3[3(4tertButylphenyl)oxetan3yl]propyl]dimethylamine:Toasolutionofnitro
3(4tertButylphenyl)3(3nitroallyl)oxetane (222, 250mg, 0.91mmol, 1.00equiv) in
15mLMeOHwasaddedPd(OH)2/C(20w%,600mg).Hydrogenwasbubbledthroughthis
mixturefor45minundervigorousstirring,beforeformaldehyde(37w%inwater,1.7mL,
21mmol, 23equiv) and AcOH (0.2mL) were added. After stirring for 72h, the mixture
was filtered through a pad of celite, the filtrate concentrated in vacuo, treated with
aqueousNaOHandextractedthreetimeswithEt2O.Thecombinedorganicphaseswere
dried over MgSO4, filtered, concentrated in vacuo and the residue dissolved in 10mL
MeOH. Formaldehyde (37 w% in water, 2.0mL, 25mmol, 27equiv) and AcOH (34L)
wereadded.Themixturewasstirredovernight,concentratedinvacuo,takenupinEt2O
andbasifiedwithaqueousNaOH(cooling).Theaqueousphasewasextractedthreetimes
withEtOAc.ThecombinedorganicphasesweredriedoverMgSO4,filteredandconcen
trated in vacuo. The residue was purified by flash chromatography (Al2O3; 20/1 to 2/1
cyclohexane/EtOAc) to give 84mg (34% yield) pure product as a white solid (mp = 36
37C).
1
8.5Hz),6.95(d,2H,J=8.4Hz),4.96(d,2H,J=5.6Hz),4.64(m,2H),2.18(m,2H),2.14(s,
13
6H), 2.06 (m, 2H), 1.31 (s, 9H); C NMR (75MHz, CDCl3): 148.9, 141.7, 125.3, 125.2,
162
ExperimentalSection
82.0,59.8,47.0,45.5,38.9,34.5,31.5,23.0;IR(thinfilm)2961,2867,2814,2763,1511,
1
1462, 11364, 1269, 1114, 986, 828cm ; HRMS (EI) calcd for C18H29NO [M] , 275.2249.
Found,275.2247.
[3(4tertButylbenzyl)oxetan3yl]acetic acid ethyl ester: To a suspension of CuI

(38mg,0.20mmol,0.10equiv)andOxetan3ylideneaceticacidethylester89(309mg,
2.17mmol, 1.00mmol) in 4mL dry THF was added freshly distilled TMSCl (0.3mL,
2.4mmol, 1.1equiv) at room temperature. After stirring for 5min, the mixture was
cooledto15CinaMeOH/icebath.Asolutionof4tBuBnMgBr(4mL,1M inEt2O)was
dropwiseaddedover1h.Afterstirringfor2h,saturatedaqueousKHSO4wasadded.The
aqueousphasewasextractedthreetimeswithEt2O.Thecombinedorganicphaseswere
driedoverMgSO4,filteredandconcentratedinvacuo.Theresiduewaspurifiedbyflash
chromatography (SiO2; 8/1 to 2/1 cyclohexane/EtOAc) to give 439mg (70% yield) pure
productasacolorlessoil.
8.3Hz),7.06(d,2H,J=8.3Hz),4.65(d,1H,J=6.2Hz),4.52(d,2H,J=6.2Hz),4.16(q,1H,
13
J=7.1Hz),3.10(s,2H),2.65(s,2H),1.31(s,9H),1.29(t,3H,J=7.1Hz); CNMR(75MHz,
CDCl3):171.2,149.4,134.2,129.3,125.380.9,60.5,41.8,41.3,40.1,34.5,31.5,14.4,;IR
1
(thinfilm)2967,2871,1733,1509,1371,1177,1028,981,668cm ;HRMS(EI)calcdfor
+
C18H26O3[M] 290.1882.Found:290.1880.
ExperimentalSection
163
[2[3(4tertButylbenzyl)oxetan3yl]ethyl]dimethylamine: To a solution of ester

89 (359mg, 1.23mmol, 1.00equiv) in 10mL Et2O was added a solution of DIBALH (20
w%inhexanes,2.0mL,5.2mmol,1.7equiv)at78Cover45min.Afterstirringfor1hat
thistemperature,thesolutionwaspouredintoicecold4N HCl.Theaqueousphasewas
extracted three times with Et2O. The combined organic phases were dried over MgSO4,
filtered and concentrated in vacuo. The residue was dissolved in 50mL MeOH, before
NEt3 (0.3mL, 1.8mmol, 1.5equiv) and dimethylammonium chloride (1.04g, 12.8mmol,
10.4equiv)wereadded.AcOHwasaddeduntilthepHwasbetween4and5.Themixture
was stirred for 1.5h, before NaCNBH3 (785mg, 12.3mmol, 10.0equiv) was added. The
mixturewasstirredovernightatroomtemperature,concentratedinvacuoandtakenup
with Et2O. Water was added, followed by NaOH with cooling. The aqueous phase was
extracted three times with Et2O. The combined organic phases were dried over MgSO4,
filtered and concentrated in vacuo. The residue was purified by flash chromatography
(Al2O3;20/1to4/1cyclohexane/EtOAc)togive95mg(28%yield)pureproductasyello
wishoil.
8.2Hz),7.06(d,2H,J=8.2Hz),4.59(d,2H,J=5.9Hz),4.43(d,2H,J=5.9Hz),2.94(s,2H),
13
2.37(m,2H),2.24(s,6H),1.80(m,2H),1.30(s,9H); CNMR(75MHz,CDCl3):149.1,
134.5, 129.0, 125.2, 81.0, 55.1, 45.8, 42.5, 41.5, 34.4, 33.3, 31.4; IR (thin film) 2961,
1
2866, 1463, 1365, 1267, 981, 835cm ; Anal. calcd for C18H29NO: C, 78.49; H, 10.61; N,
+
5.09. Found: C, 78.38; H, 10.83; N, 4.96; HRMS (EI) calcd for C18H29NO [M] , 275.2249.
Found,275.2241.
164
ExperimentalSection
3[2(4tertButylphenyl)vinyl]3nitromethyloxetane: To a solution of [Rh(cod)Cl]2

(10mg, 20 mol, 0.030equiv)in 4mL dry dioxane was added aqueous KOH (1.5 M,
0.60mL,0.90mmol,1.3equiv)atroomtemperature.Afterstirringfor2min,nitromethy
leneoxetane96(0.10g,0.90mmol,1.0equiv)wasadded,followedbyasolutionof(E)4
tertbutylstyrylboronic acid (0.20g, 1.1mmol, 1.2equiv) in 3mL dry dioxane. After stir
ring for 30min, additional (E)4tertbutylstyrylboronic acid354 (75mg, 0.40mmol,
0.40equiv)wasadded.Afterstirringforfurther20min,Et2Oandbrinewereadded.The
aqueousphasewasextractedthreetimeswithEt2O.Thecombinedorganicphaseswere
driedoverMgSO4,filteredandconcentratedinvacuo.Theresiduewaspurifiedbyflash
chromatography(SiO2;8/1to4/1cyclohexane/EtOAc)togive137mgpureproduct(55%
yield)asawhitesolid(mp=108110C).
Rf=0.40 (SiO2, 2/1 cyclohexane/EtOAc); H NMR (300MHz, CDCl3): 7.34 (q, 4H, J =
8.4Hz),6.55(d,1H,J=16.3Hz),6.30(d,1H,J=16.3Hz),4.89(s,2H),4.85(d,2H,J=6.5
13
Hz),4.74(d,2H,J=6.5Hz),1.32(s,9H); CNMR(75MHz,CDCl3):151.4,132.9,131.7,
126.1,126.0,125.5,80.2,78.7,44.6,34.7,31.3;IR(thinfilm)2953,2919,2868,1547,
1
1377, 1270, 1108, 976, 814cm ; Anal. calcd for C16H21NO3: C, 69.79; H, 7.69; N, 5.09.
+
Found:C,69.50;H,7.96;N,5.00;HRMS(EI)calcdforC16H21NO3[M] ,275.1521.Found,
275.1515.
354
Preparedaccordingto:A.Torrado,S.Lopez,R.Alvarez,A.R.Delera,SynthesisStuttgart1995,285.
ExperimentalSection
165
[3[2(4tertButylphenyl)ethyl]oxetan3ylmethyl]dimethylamine:Throughamix
ture of 3[2(4tertbutylphenyl)vinyl]3nitromethyloxetane (152, 0.16g, 0.60mmol,
1.0equiv)andPd(OH)2/C(20w%,70mg)wasbubbledhydrogenfor50min.Themixture
was then vigorously stirred over night. After filtration through a pad of celite, aqueous
formaldehyde(37w%,1.6mL,2.0mmol,3.3equiv)andthesolutionadjustedtoapHbe
tween 4 and 5 with AcOH. After stirring for 30min, NaCNBH3 (120mg, 1.90mmol,
3.20equiv) was added. The mixture was stirred for 5.5h, concentrated in vacuo to ap
proximately 1mL and Et2O and aqueous NaOH were added with cooling. The aqueous
phasewassaturatedwithNaClandextractedthreetimeswithEt2O.Thecombinedorgan
ic phases were dried over MgSO4, filtered and concentrated in vacuo. The residue was
purified by flash chromatography (Al2O3; 20/1 cyclohexane/EtOAc) to give 109mg pure
product(67%yield)asayellowishoilthatsolidifiedinthefreezer(mp=4042C).
8.3Hz),7.18(d,2H,J=8.2Hz),4.46(d,2H,J=5.9Hz),4.40(d,2H,J=5.9Hz),2.58(m,
13
4H), 2.17 (s, 6H), 2.12 (m, 2H), 1.31 (s, 9H); C NMR (75MHz, CDCl3): 148.5, 139.1,
127.9,125.1,81.0,64.3,46.3,46.3,42.7,36.6,34.4,31.5,29.8;IR(thinfilm)2961,2859,
1
2817,2765,1517,1458,1364,1266,1036,989,823,772cm ;Anal.calcdforC18H29NO:
C,78.49;H10.61,N,5.09.Found:C,78.41,h,10.60,N,5.16;HRMS(EI)calcdforC18H29NO
+
[M] ,275.2249.Found,275.2245.
166
ExperimentalSection
[3[3(4tertButylphenyl)propyl]oxetan3yl]dimethylamine: To a solution of a
catalytic amount of DBU in 1.5mL dry THF was added dimethyl amine (0.5 M in Et2O,
2.4mL, 1.2mmol, 1.0equiv) followed by a solution of ,unsaturated aldehyde 90
(117mg, 1.20mmol, 1.00equiv) in 1mL dry THF at 15 C. The solution was stirred for
50min, before it was added to a solution of ptBuphenylmethylene triphenylphospho
rane (154) in 20mL dry THF (This solution was made by adding nBuLi (1.6 M solution in
hexanes, 3.0mL, 4.8mmol, 4.0equiv) at 0C to a dispersion of (4tertButylbenzyl)
triphenylphosphoniumbromide(2.8g,4.8mmol,4.0equiv)in20mLdryTHFat0Cand
stirringthismixturefor30minat0C.).Thereactionmixturewasstirredfor30minat
0C, and then warmed for 30min to 60C. After cooling to 0C, 1 M aqueous HCl was
addedandtheTHFconcentratedinvacuo.Theresiduewaswashedthreetimeswithto
luene,andthenextractedfourtimeswithchloroform.Thecombinedchloroformphases
were washed once with brine (acidified with HCl), dried over MgSO4, filtered, concen
tratedinvacuoandtheresiduedissolvedin20mLMeOH.TothissolutionPd/C(10w%,
100mg)wasaddedandtheatmosphereexchangedwithhydrogen.Hydrogenwasbub
bledthroughthemixturefor30minandthemixturewasvigorouslystirredovernightand
filteredthroughaplugofcelite.Thefiltratewasconcentratedinvacuoandtheresidue
mixedwithwaterandEt2O.AqueousNaOH(2M,2.5mL)wasaddedwithcoolingandthe
aqueousphaseextractedfourtimeswithEt2O.Thecombinedorganicphasesweredried
overMgSO4,filteredandconcentratedinvacuo.Theresiduewaspurifiedbyflashchro
matography(Al2O3;8/1cyclohexane/EtOAc)togive120mgpureproduct(36%yield)asa
colorlessoil.
8.3Hz),7.15(d,2H,J=8.1Hz),4.64(d,2H,J=6.2Hz),4.32(d,2H,J=6.3Hz),2.66(t,2H,
13
J = 7.0 Hz), 2.24 (s, 6H), 1.81 (m, 4H), 1.32 (s, 9H); C NMR (75MHz, CDCl3): 148.5,
ExperimentalSection
167
138.9, 127.9, 125.1, 77.9, 63.4, 38.2, 35.8, 34.3, 31.3, 30.7, 25.8; IR (thin film) 2952,
1
2870,2782,1902,1511,1476,1462,1364,1269,1109,1046,1019,984,830,573cm ;
+
HRMS(EI)calcdforC18H29NO[MCH3] ,260.2009.Found,260.2007.
6.5 PreparationofOxetanesoftheCyclicScaffolds
24
6(benzo[d][1,3]dioxol5ylmethyl)2oxa6azaspiro[3.3]heptane: Piperonal (1.0g,
6.9mmol,1.3equiv)wasdissolvedin20mLCH2Cl2andtothesolutionwasadded2oxa
6azaspiro[3.3]heptane (130, 0.53g, 5.3mmol, 1.0equiv) and NaBH(OAc)3 (2.8g,
13mmol,2.5equiv).Theresultingwhitesuspensionwasstirredovernightatroomtem
perature. Saturated aqueous K2CO3 was added until complete dissolution of the borate
byproducts. The aqueous phase was extracted with EtOAc three times. The combined
organicphasesweredriedoverNa2SO4,filteredandconcentratedinvacuo.Theresidue
wasdissolvedin250mLEt2Oandasolutionofanhydrousoxalicacid(0.48g,5.3mmol,
1.0equiv)inlittleEtOHwasadded.Thewhiteprecipitationformedwasfiltered,washed
withEt2Oandthendissolvedin1M KOH.TheaqueousphasewasextractedwithEtOAc,
thecombinedorganicphasesweredriedoverNa2SO4,filteredconcentratedinvacuoto
give0.91gofclearwhiteliquidaspureproduct(74%yield).
Rf=0.24(Al2O3,2/1cyclohexane/EtOAc); HNMR(300MHz,CDCl3)6.766.71(m,
13
2H), 6.71 6.64 (m, 1H), 5.93 (s, 2H), 4.74 (s, 4H), 3.43 (s, 2H), 3.34 (s, 4H); C NMR
(75MHz,CDCl3)147.6,146.5,131.5,121.4,108.8,107.9,100.8,81.3,63.4,63.1,38.9;IR
(thinfilm)2931,2863,2815,1608,1503,1410,1442,1377,1247,1110,1039,973,927,
1
869, 811,774,746cm ;Anal.calcdforC13H15NO3:C:70.92,H:6.45,N:6.89, O:15.74.
168
ExperimentalSection
FoundC:70.80,H:6.53,N:6.88,O:15.79;HRMS(EI)calcdforC13H15NO3[M]+233.1047.
Found233.1052.
25
7(benzo[d][1,3]dioxol5ylmethyl)2oxa7azaspiro[3.5]nonane 3: To a solution of
dimethyl malonate (1.1mL, 9.6mmol, 3.2equiv) in 25mL dry THF was added Sodium
hydride(60w%suspensioninmineraloil,0.32g,8.0mmol,2.5equiv)atroomtempera
ture. After stirring for 20min, tetrabutylammonium bromide (0.32g, 1.0mmol,
0.30equiv) was added, followed by a solution of the ,unsaturated ester 89 (0.43g,
3.0mmol,1.0equiv)in1mLdryEt2O.Themixturewasstirredovernightatroomtemper
ature and quenched by adding 0.47mL glacial AcOH. The solvent was concentrated in
vacuo and the residue treated with Et2O. The aqueous phase was washed with brine,
driedoverMgSO4andconcentratedinvacuo.Theresiduewasdissolvedin30mLDMSO,
water(150L)andsodiumchloridewasaddedandthemixturestirredat160Cfor2h.
Brine and Et2O (200mL) were added and the aqueous phase washed twice with brine.
TheaqueousphasewasdriedoverMgSO4,filtered,concentratedinvacuoandtheresi
duebeingproduct(Rf=0.31(SiO2,2/1cyclohexane/EtOAc); 1HNMR(300MHz,CDCl3)
4.54(m,4H),4.12(q,2H,J=7.1Hz),3.67(s,3H),2.93(s,2H),2.90(s,2H),1.25(t,3H,J=
7.1Hz);13CNMR(75MHz,CDCl3)171.3,170.8,81.0,60.5,51.6,40.0,39.8,38.8,14.2;IR
(thin film) 2934, 1736, 1440, 1375, 1176, 1070, 1028, 978 cm1) of good purity used
withoutfurtherpurification.Thiscrudematerialwasdissolvedin30mLdryEt2O,theso
lutioncooledto0CandLiAlH4(3mL,4.0MinEt2O,12mmol,3.8equiv)addeddropwise
leadingtowhiteprecipitation.Afterstirringfor3hat0C,Na2SO410H2Owascautiously
added.Themixturewasfilteredafterstirringfor20min.Thefiltercakewasboiledwith
two portions of 20mL EtOAc. The combined filtrates were dried over Na2SO4, filtered,
concentratedinvacuoandtheresidualdiol(1HNMR(300MHz,CDCl3)4.47(s,4H),3.78
(t,4H,J=6.4Hz),2.06(t,4H,J=6.4Hz),1.94(s,2H))dissolvedin30mLdryCH2Cl2.The
ExperimentalSection
169
solutionwascooledto0C,MsCl(0.74mL,9.6mmol,3.0equiv)wasadded,followedby
dropwiseadditionofNEt3(1.8mL,13mmol,4.0equiv).Afterstirringfor1h,asamplein
theNMRindicatedfullconversion.AqueoussaturatedNH4Clwasaddedandtheaqueous
phase extracted three times with EtOAc. The combined organic phases were dried over
MgSO4,filtered,concentratedinvacuoandtheresidualbismesylate(1HNMR(300MHz,
CDCl3)4.49(s,4H),4.35(t,4H,J=6.4Hz),3.03(s,6H),2.26(t,4H,J=6.4Hz))dissolved
in4.0mLpiperonylamine(32mmol,10equiv).Afterstirringfor40minat90C,asample
intheNMRshowedfullconversionofstartingmaterial.SaturatedaqueousSodiumbicar
bonate was added and the aqueous phase extracted three times with EtOAc. The com
binedorganicphaseswerewashedoncewithbrine,driedoverMgSO4,filteredandcon
centratedinvacuo.Theresiduewaspurifiedoncolumn(Al2O3,cyclohexaneto8/1cyclo
hexane/EtOAc)togive0.26gpureproductasawhitesolid(mp=7880C).
Rf=0.54(Al2O3,2/1cyclohexane/EtOAc); 1HNMR(300MHz,CDCl3)6.82(d,1H,J=
0.9Hz),6.72(m,2H),5.93(s,2H),4.39(s,4H),3.34(s,2H),2.28(s,4H),1.85(t,4H,J=5.4
Hz);13CNMR(75MHz,CDCl3)147.4,146.3,132.1,121.9,109.2,107.7,100.7,81.8,62.9,
50.3, 38.6, 35.0; IR (thin film) 2924, 2858, 2361, 1480, 1441, 1370, 1241, 1099, 1039,
977,929,810,688cm1;Anal.calcdforC15H19NO3:C,68.94;H,7.33;N,5.36.Found:C,
69.00;H,7.47;N,5.27.;HRMS(EI)calcdforC15H19NO3[M]+=261.1360.Found:261.1361.
103
(3Nitromethyloxetan3yl)acetic acid ethyl ester: To a solution of ,unsaturated

ester 89 (1.62g, 11.4mmol, 1.00equiv) in 10mL dry MeCN was added nitro methane
(3.08mL, 56.9mmol, 5.00equiv), followed by a catalytic amount of DBU (340 L,
2.28mmol,0.200equiv)at0C.Afterstirringfor4hatroomtemperature,themixture
170
ExperimentalSection
wasfilteredthroughaplugofSiO2with4/1cyclohexane/EtOActogive2.13galmost(>98
w%byNMR)purematerialasacolorlessliquid(92%yield).
Rf=0.26(SiO2,2/1cyclohexane/EtOAc); 1HNMR(300MHz,CDCl3)4.95(s,2H),4.63
(d,2H,J=7.0Hz),4.56(d,2H,J=7.0Hz),4.16(q,2H,J=7.1Hz),2.95(s,2H),1.27(t,1H,J
=7.1Hz);13CNMR(75MHz,CDCl3)170.1,78.6,78.6,61.2,40.3,38.1,14.3;IR(thinfilm)
2918,2872,1723,1549,1378,1188,1075,1024977cm1;Anal.calcdforC8H13NO5:C,
47.29;H,6.45.Found: C,47.11;H,6.39;HRMS(EI)calcdforC8H13NO5:[M]+= 203.0794.
Found:203.0747.
26
6(benzo[d][1,3]dioxol5ylmethyl)2oxa6azaspiro[3.4]octane: To a solution of (3
Nitromethyloxetan3yl)aceticacidethylester(103,0.64in15mLdrytoluenewasadd
ed DibalH (1.4 M in toluene, 4.3mL, 6.3mmol, 2.0equiv) at 78 C over 15min. After
30min, TLC indicated full conversion. After further 10min, 5mL 1 M aqueous HCl were
addedandthemixtureallowedtowarmtoroomtemperature.Et2Oandanother15mLof
1M HClwereaddedandtheaqueousphaseextractedthreetimeswithEtOAc.Thecom
binedorganicphaseswerewashedoncewith1 M HCl,brineandsaturatedaqueousso
dium bicarbonate, dried over Na2SO4, filtered, concentrated in vacuo and the residue
(0.41g)foundtobe~90%purebyNMRwiththeresidualmaterialbeingtheprimaryal
cohol resulting from overreduction. (Rf= 0.15 (SiO2, 2/1 cyclohexane/EtOAc); 1H NMR
(300MHz,CDCl3)9.74(s,1H),4.92(s,2H),4.63(d,2H,J=7.1Hz),4.50(d,2H,J=7.1
Hz),3.18(s,2H); 13CNMR(75MHz,CDCl3)198.7,78.8,78.6,47.3,39.5;IR(thinfilm)
2934,2819,2734,1715,1545,1428,1382,1258,1097,990,901cm1;HRMS(EI)calcdfor
C6H9NO4[MCH2NO2]+=99.0442;Found:99.0446.)Thismaterialwasusedwithoutfurther
purification,dissolvedin25mLMeOHand48mgPd(OH)2/C(20w%),wereadded.After
ExperimentalSection
171
exchangingtheatmospherewithhydrogen,hydrogenwasbubbledthroughthemixture
for 45min and stirred under hydrogen overnight (balloon), when a sample in the NMR
indicated clean conversion to product. The mixture was filtered through celite, concen
tratedinvacuoandtheresidue(1HNMR(300MHz,CDCl3)4.64(d,2H,J=5.9Hz),4.60
(d,2H,J=5.9Hz),3.15(s,2H),2.91(t,2H,J=7.0Hz),2.05(t,2H,J=7.1Hz))dissolvedin
30mL CH2Cl2. Piperonal (0.41g, 2.7mmol, 1.2equiv), followed by NaHB(OAc)3 (1.2g,
5.7mmol, 2.5equiv). The mixture was stirred for 7h. Aqueous saturated K2CO3 (80mL)
was added and the mixture stirred vigorously for 15min. The aqueous phase was ex
tracted three times with CH2Cl2. The combined organic phases were dried over Na2SO4,
filtered, concentrated in vacuo and the residue purified by flash chromatography (SiO2,
1/2 cyclohexane/EtOAc to 5% MeOH in EtOAc) to give 0.29g pure product as a slightly
yellowishoil(53%yield).
Rf=0.2(SiO2,EtOAc);1HNMR(300MHz,CDCl3)6.82(d,1H,J=0.5Hz),6.73(m,2H),
5.94(s,2H),4.60(q,4H,J=5.9Hz),3.48(s,2H),2.78(s,2H),2.51(t,2H,J=7.0Hz),2.11
(t, 2H, J = 7.0 Hz); 13C NMR (75MHz, CDCl3) 147.5, 146.4, 132.6, 121.6, 109.0, 107.8,
100.7, 83.8, 64.6, 59.8, 53.4, 44.9, 36.3; IR (thin film) 2921, 2861, 2788, 1489, 1442,
1382,1345,1240,1097,1039,976,928,809cm1;Anal.calcdforC14H17NO3:C,68.00;H,
6.93; N, 5.66. Found: C, 67.71; H, 7.06; N, 5.72; HRMS (EI) calcd for C14H17NO3:
[M]+=247.1203.Found:247.1201.
144
3(3Hydroxymethyloxetan3yl)propionicacidtertbutylester:ToasolutionofN,N
diisopropylamine(0.48mL,3.6mmol,6.0equiv)in3mLdryTHFwasaddednBuLi(2.5Min
hexanes,1.3mL,3.3mmol,5.5equiv)at78C.Afterstirringfor20min,3mLdryhexane
was added and stirring was continued for another 20min, before tertbutyl acetate
(0.40mL,3.0mmol,5.0equiv)wasaddedasasolutionindryTHF(2mL).Afterstirringfor
172
ExperimentalSection
25min, the mixture was cooled to 95C (Et2O/liquid nitrogen cooling bath) and 2,6
dioxaspiro[3.3]heptane (140, 60mg, 0.60mmol, 1.0equiv)355 was added, followed by
dropwiseadditionofBF3OEt2(0.37mL,3.0mmol,5.0equiv).Themixturewasallowedto
warm to 78 C. After stirring for 2.5h, another 0.3mL BF3OEt2 (2.4mmol, 4.1equiv)
wereadded.Afterstirringforfurther5h,themixturewasquenchedbyaddingsaturated
aqueousNH4Cl.TheaqueousphasewasextractedfourtimeswithEtOAc.Thecombined
organic phases were dried over MgSO4, filtered, concentrated in vacuo and the residue
purifiedbyflashchromatography(SiO2,2/1cyclohexane/EtOActoEtOAc)togive109mg
(89w%byNMR,restEtOAc)productasacolorlessliquid(75%yield).
Rf=0.31(SiO2,2/1cyclohexane/EtOAc);1HNMR(300MHz,CDCl3)4.39(q,4H,J=6.1
Hz),3.74(d,2H,J=5.4Hz),2.66(s,1H),2.24(dd,2H,J=6.8Hz,7.4Hz),2.04(t,2H,J=7.0
Hz), 1.44 (d, 9 H); 13C NMR (75MHz, CDCl3) 173.4, 81.1, 78.6, 65.4, 43.8, 30.3, 28.1,
27.9; IR (thin film) 3424, 2977, 2873, 1728, 1452, 1368, 1306, 1256, 1157, 1047, 977,
844cm1;HRMS(EI)calcdforC11H20O4:[MC4H8]+=159.0652.Found:159.0652.
27
6(benzo[d][1,3]dioxol5ylmethyl)2oxa6azaspiro[3.5]nonane: To a solution of 3
(3Hydroxymethyloxetan3yl)propionic acid tertbutyl ester (144) (0.16g, 0.76mmol,
1.0equiv)in25mLdryEt2OwasslowlyaddedLiAlH4(4.0 M inEt2O,0.57mL,2.3mmol,
3.0equiv) at 0C. After stirring for 45min, Na2SO410 H2O was added and the mixture
stirredfor15min.Afterfiltration,thefiltercakewasboiledwithtwoportionsof20mL
EtOAc. The combined filtrates were dried over Na2SO4, filtered, concentrated in vacuo
and the residual diol dissolved in 20mL dry CH2Cl2, cooled to 0C and MsCl (0.18mL,
2.3mmol, 3.0equiv) was added, followed by slow addition of NEt3 (0.42mL, 3.0mmol,
4.0equiv). After 1h, a sample in the NMR indicated full conversion. Saturated aqueous
NH4Cl was added, the aqueous phase extracted three times with EtOAc. The combined
355
Preparedaccordingto:A.R.AbdunNur,C.S.Issidorides,J.Org.Chem.1962,27,67.
ExperimentalSection
173
organicphaseswerewashedwithbrine,driedoverNa2SO4,filteredandtheresidue(Rf=
0.19(SiO2,2/1cyclohexane/EtOAc);1HNMR(300MHz,CDCl3)4.46(m,4H),4.42(d,2H,
J=1.4Hz),4.28(t,2H,J=6.0Hz),3.08(s,3H),3.04(s,3H),1.92(m,2H),1.81(m,2H))
mixed with piperonylamine (0.95mL, 7.6mmol, 10equiv). The mixture was heated to
90Cfor1h,whenasampleintheNMRshowedfullconversion.EtOAcwasaddedand1
MaqueousKOH.TheaqueousphasewasextractedthreetimeswithEtOAc,thecombined
organicphaseswashedoncewithbrine,driedoverMgSO4,filtered,concentratedinvacuo
and purified by flash chromatography (Al2O3, 20/1 to 8/1 cyclohexane/EtOAc) to give a
mixtureofproductandpiperonal.Thismaterialwasdissolvedin40mLEt2O,andasolu
tionofoxalicacid(54mg,0.76mmol,1.0equiv)inEtOHwasadded.Thewhiteprecipitate
wascollectedanddissolvedin1M aqueousKOH.Themixturewasextractedthreetimes
with Et2O, the combined organic phases were dried over MgSO4, filtered and concen
tratedinvacuotogive97mgpureproduct(49%yield)asslightlyyellowishoil.
(m,2H),5.95(s,2H),4.35(q,4H,J=5.9Hz),3.40(s,2H),2.51(s,2H),2.30(s,2H),1.68(s,
2H), 1.51 (m, 2H); 13C NMR (75MHz, CDCl3) 147.4, 146.3, 132.4, 121.7, 109.0, 107.7,
100.7, 81.0, 62.8, 61.1, 53.3, 39.7, 33.5, 22.6; IR (thin film) 2931, 2860, 2765, 1857,
1732, 1607, 1489, 1441, 1369, 1243, 1100, 1040, 976, 931, 810 cm1; Anal. calcd for
C15H19NO3:C,68.94;H,7.33;N,5.36.Found:C,68.69;H,7.40;N,5.29.;HRMS(EI)calcd
forC15H19NO3:[M]+=261.1360.Found:261.1362.
106
2(3(benzo[d][1,3]dioxol5ylmethylamino)oxetan3yl)ethanol : To 2(oxetan3
ylidene)acetate(89,305mg,2.15mmol;1.00equiv)wasaddedpiperonylamine(0.28mL;
2.4mmol;1.1equiv).Thismixturewasheatedat60Cunderargonatmospherefor2h,
174
ExperimentalSection
before 30mL dry Et2O were added and the reaction mixture was cooled to 0C, LiAlH4
(4.0M inEt2O;2.4mL,9.4mmol,4.0equiv)wasdropwiseadded,andthewhitesuspen
sion stirred for 2h. Na2SO410 H2O was added slowly and the mixture stirred at room
temperaturefor25min,beforeitwasfiltered.Thefiltercakewascookedwith4portions
of EtOAc and the combined filtrates dried over Na2SO4, filtered, concentrated in vacuo
and the residue purified by flash chromatography (SiO2; CHCl3 to CHCl3/MeOH 92:8) to
give399mg(95w%byNMR)product(70%yield)asayellowishoil.
Rf = 0.78 (SiO2, CHCl3/MeOH 4:1); 1H NMR (300MHz, CDCl3) 6.77 (m, 3H), 5.94 (s,
2H),4.56(d,2H,J=6.7Hz),4.50(d,2H,J=6.8Hz),3.82(t,2H),3.72(s,2H),2.14(m,2H);
13
C NMR (75MHz, CDCl3) 147.6, 146.5, 132.7, 121.5, 108.7, 108.3, 101.0, 81.4, 61.0,
59.5, 47.0, 35.1; IR (thin film) 3386, 2873, 1503, 1490, 1443, 1250, 1099, 1039, 975,
928.0,810cm1;HRMS(EI)calcdforC13H17NO4[MCH2O]+=221.1052.Found:221.1052
28
1(benzo[d][1,3]dioxol5ylmethyl)6oxa1azaspiro[3.3]heptanes:
Tetrabromocar
bon(750mg,2.26mmol,1.50equiv)isaddedtoasolutionof2(3(benzo[d][1,3]dioxol5
ylmethylamino)oxetan3yl)ethanol (106, 379mg, 1.51mmol, 1.00equiv) and PPh3
(593mg,2.26mmol,1.50equiv)in25mLdryMeCN(immediateorangecolor),followed
by distilled NEt3 (475 L, 3.41mmol, 2.00equiv). The flask is wrapped in aluminum foil
and stirred for 40 h at room temperature. Brine and Et2O is added and the aqueous
phase extracted three times with Et2O. The combined organic phases are dried over
Na2SO4,filtered,concentratedinvacuoandtheresiduepurifiedbyflashchromatography
(Al2O3,cyclohexaneto8/1cyclohexane/EtOAc)togive253mgpureproduct(72%yield)
asayellowoilthatsolidifieduponstorageinthefridge(mp=62.5C,measuredbyDSC).
ExperimentalSection
175
Rf=0.15(SiO2,2/1cyclohexane/EtOAc); 1HNMR(300MHz,CDCl3);6.85(s,1H),6.76
(m,2H),5.93(s,2H),4.97(d,2H,J=7.9Hz),4.63(d,2H,J=7.9Hz),3.72(s,2H),3.03(t,
2H, J = 6.8 Hz), 2.36 (t, 2H, J = 6.8 Hz); 13C NMR (75MHz, CDCl3) 173.5, 146.5, 131.7,
121.4,109.0,108.1,100.9,81.4,69.1,56.2,49.8,29.5;IR(thinfilm)3403,2939,2864,
1608,1502,1490,1442,1377,1347,1247,1185,1117,1094,1038,973,927,866,810,
776cm1;Anal.calcdforC13H15NO3:C,66.94;H,6.48;N,6.00;O,20.58;Found:C,66.65;
H,6.53;N,6.04;O,20.78;HRMS(EI)calcdforC13H15NO3[M]+233.1052.Found:233.1048.
115
3allylN(benzo[d][1,3]dioxol5ylmethyl)oxetan3amine: To a solution of piperony

lamine (0.82mL, 6.6mmol, 1.1equiv) and DBU (9.0 L, 60 mol, 1.0mol%) in 6mL dry
THF was added the ,unsaturated aldehyde90 (0.60g, 6.0mmol, 1.0equiv) at 18C
(MeOH/icebath).Afterstirringfor4hatthistemperature,thesolutionwastransferred
to a solution H2C=PPh3 in THF (prepared by addition of nBuLi (2.5 M in hexanes, 6.7mL,
17mmol,2.8equiv)toasuspensionofPh3PMeBr(6.4g,18mmol,3.0equiv)in50mLdry
THF at 0C). The mixture was allowed to warm to room temperature and stirred over
night,beforewaterandbrinewereadded.Theaqueousphasewasextractedthreetimes
withEtOAc.ThecombinedorganicphasesweredriedoverNa2SO4,filtered,concentrated
in vacuo and the residue purified by flash chromatography (Al2O3, 8/1 to 2/ cyclohex
ane/EtOAc)togive435mgpureproductasayellowishoil(29%yield).
Rf=0.68(SiO2,2/1cyclohexane/EtOAc);1HNMR(300MHz,CDCl3)6.85(m,1H),6.76
(m,2H),5.94(s,2H),5.85(m,1H),5.20(m,2H),4.57(d,2H,J=6.6Hz),4.43(d,2H,J=6.7
Hz),3.71(s,2H),2.65(d,2H,J=7.1Hz),1.58(s,1H); 13CNMR(75MHz,CDCl3)147.6,
146.5,134.0,132.6,120.9,118.6,108.5,108.0,100.8,80.7,59.3,46.9,40.3;IR(thinfilm)
176
ExperimentalSection
3312,3072,2398,2870,1640,1607,1503,1490,1442,1250,1099,1037,980,926,811
cm1;HRMS(EI)calcdforC14H17NO3:[MCH2O]+=217.1103.Found:217.1100.
29
5(benzo[d][1,3]dioxol5ylmethyl)2oxa5azaspiro[3.4]octane:
3allylN
(benzo[d][1,3]dioxol5ylmethyl)oxetan3amine(115,0.20g,0.81mmol,1.00equiv)was
dissolved in 5mL dry THF. Hg(O2CCF3)2 (659mg, 1.42mmol, 1.76equiv) was added at
roomtemperature.Themixturewasheatedto60C(turningdarkbrown,formationofa
grey precipitate), before it was cooled to 0C and a solution of sodium borohydride
(70mg, 1.8mmol, 2.3equiv; 0.5 M in 2 N aqueous NaOH) was added. The mixture was
allowedtowarmtoroomtemperatureandstirredfor2.5h.TothismixtureEt2O(30mL)
was added and the aqueous phase decanted off. The aqueous phase was dried over
K2CO3,filtered,concentratedinvacuoandtheresiduepurifiedbyflashchromatography
(SiO2,2/1to1/2cyclohexane/EtOAc).ThematerialisolatedwithRf=0.31(SiO2,2/1cyc
lohexane/EtOAc) was repurified (Al2O3, cyclohexane to 8/1 cyclohexane/EtOAc) to give
75mgpureproduct(38%yield)asaslightlyyellowishoilthatsolidifieduponstoragein
thefridgemp=39.2C(measuredbyDSC).
Rf=0.31(SiO2,2/1cyclohexane/EtOAc); 1HNMR(300MHz,CDCl3)6.87(dd,1H,J=
0.5Hz,1.5Hz),6.77(m,2H),5.94(s,2H),4.89(d,2H,J=6.8Hz),4.55(d,2H,J=6.7Hz),
3.92(s,2H),2.58(m,2H),2.19(dd,2H,J=6.7Hz,8.8Hz),1.69(tt,2H,J=6.9Hz,7.6Hz);
13
C NMR (75MHz, CDCl3) 147.5, 146.3, 133.7, 121.0, 108.6, 107.9, 100.8, 80.1, 66.4,
53.2, 51.4, 37.2, 20.9; IR (thin film) 2940, 2867, 2802, 1857, 1607, 1503, 1489, 1443,
1378,1363,1241,1171,1115,1093,1039,978,929,865,809,774cm1;Anal.calcdfor
C14H17NO3:C,68.00;H,6.93;N,5.66.Found:C,67.97;H,7.11;N,5.75;HRMS(EI)calcdfor
C14H17NO3:[M]+=247.1203.Found:247.1204;.
ExperimentalSection
177
165
N,3diallylN(benzo[d][1,3]dioxol5ylmethyl)oxetan3amine: To a solution of N
allylNpiperonylamine(0.95g,5.0mmol,1.0equiv)andDBU(7.6L,50mol,1.0mol%)
in4mLdryTHFwasaddedthe,unsaturatedaldehyde90(0.61g,5.0mmol,1.0equiv)
asasolutionin1mLdryTHFat18C(MeOH/icebath).Thesolutionwasstoredfor5d
in the freezer (18C), when a sample in the NMR showed 73% conversion to the 1,4
addition product. The solution was then transferred to a solution of H2C=PPh3 in THF
(preparedbyadditionofnBuLi(2.5Minhexanes,5.0mL,13mmol,2.6equiv)toasuspen
sionofPh3PMeBr(4.73g,13.0mmol,2.60equiv)in50mLdryTHFat0C).After2h,the
reaction was quenched by adding 1 M aqueous HCl. Most of the solvents were concen
trated in vacuo and the aqueous phase washed three times with toluene. The aqueous
phasewasthenthreetimesextractedwithchloroform.Thecombinedchloroformphases
wereconcentratedinvacuoandtheresiduetreatedwithaqueousNa2CO3andextracted
fourtimeswithEt2O.ThecombinedEt2OphasesweredriedoverMgSO4,filtered,concen
tratedinvacuoandtheresiduepurifiedbyflashchromatography(SiO2,20/1to2/1cyclo
hexane/EtOAc)togive0.77g(53%yield)pureproductascolorlessoil.
(m,2H),6.09(m,1H),5.94(m,2H),5.72(m,1H),5.24(m,2H),5.04(dddd,2H,J=1.0Hz,
2.5Hz,3.0Hz,10.1Hz),4.59(d,2H,J=6.2Hz),4.26(d,2H,J=6.3Hz),3.48(s,2H),3.07
(d,2H,J=6.6Hz),2.63(d,2H,J=7.3Hz); 13CNMR(75MHz,CDCl3)147.6,146.4,136,
134.0,133.9,121.1,118.2,116.7,108.7,107.7,100.8,79.8,63.2,53.0,53.6,36.2;IR(thin
film)3073,2943,2873,1364,1488,1441,1380,1238,1182,1093,1039,981,918,867,
808,779cm1;HRMS(EI)calcdforC17H21NO3[M]+=287.1516.Found:287.1518.
178
ExperimentalSection
166
5(benzo[d][1,3]dioxol5ylmethyl)2oxa5azaspiro[3.5]non7ene: To a solution of
N,3diallylN(benzo[d][1,3]dioxol5ylmethyl)oxetan3amine (165, 760mg, 2.64mmol,
1.00equiv)in100mLdryCH2Cl2wasaddedpTosOHH2O(503mg,6.64mmol,1.00equiv)
at room temperature. The mixture was stirred until complete solvation (30 min) was
reached and then degassed twice (freezing with liquid nitrogen, then applying high va
cuum,meltingunderArgonatmosphere).GrubbsIIcatalyst(56mg,66mol,2.5mol%)
was added and the mixture stirred for 15 h at room temperature, before 1 M aqueous
NaOHwas addedandthemixturestirredfor15min. The aqueousphasewasextracted
threetimeswithCH2Cl2.ThecombinedorganicphasesweredriedoverMgSO4,filtered,
concentrated in vacuo and the residue purified by flash chromatography (SiO2, 20/1 to
2/1cyclohexanetoEtOAc)togive604mgpureproduct(88%yield)asawhitesolid(mp=
7677C).
(m,2H),5.93(s,2H),5.77(m,1H),5.55(m,1H),4.66(d,2H,J=6.0Hz),4.30(d,2H,J=6.1
Hz), 3.42 (s, 2H), 3.07 (m, 2H), 2.51 (m, 2H); 13C NMR (75MHz, CDCl3) 147.5, 146.4,
133.1,125.0,123.3,121.5,109.0,107.7,100.8,81.1,59.1,52.2,45.0,29.8;IR(thinfilm)
3026,2868,1608,1502,1490,1441,1384,1342,1251,1184,1118,1093,1039,980,918,
810,654cm1;Anal.calcdforC15H17NO3;HRMS(EI)calcdforC15H17NO3:[M]+=259.1203.
Found:259.1202.
ExperimentalSection
179
30
5(benzo[d][1,3]dioxol5ylmethyl)2oxa5azaspiro[3.5]nonane: Through a mixture

of 5(benzo[d][1,3]dioxol5ylmethyl)2oxa5azaspiro[3.5]non7ene (166, 552mg,
2.13mmol, 1.00equiv) and 5 w% Rh/C (39 mg) in 100mL MeOH under hydrogen was
bubbledhydrogenfor45min,whenasampleintheNMRindicatedfullconsumptionof
starting material. The mixture was filtered through a plug of Celite, the filtrate concen
tratedinvacuoandtheresiduepurifiedbyflashchromatography(SiO2,8/1to2/1cyclo
hexane/EtOAc)togive438mgpureproduct(79%yield)asawhitesolid(mp=4444.5C).
Rf=0.37(SiO2,2/1cyclohexane/EtOAc);1HNMR(300MHz,CDCl3)6.92(d,1H,J=1.1
Hz),6.80(d,1H,J=7.9Hz),6.74(d,1H,J=7.9Hz),5.94(s,2H),4.75(d,2H,J=6.4Hz),
4.36 (d, 2H, J = 6.4 Hz), 3.74 (s, 2H), 2.41 (m, 2H), 1.93 (m, 2H), 1.50 (m, 4H); 13C NMR
(75MHz,CDCl3)147.5,146.2,133.9,121.0,108.5,107.7,100.7,79.0,61.7,52.7,47.5,
33.8, 22.9, 21.3; IR (thin film) 2934, 2867, 1608, 1502, 1489, 1441, 1375, 1357, 1249,
1133, 1103, 1039, 979, 928, 864, 810, 775 cm1; Anal. calcd for C15H19NO3: C, 68.94; H,
7.33; N, 5.36. Found: C, 68.94; H, 7.37; N, 5.36; HRMS (EI) calcd for C15H19NO3: [M
CH3O]+=230.1176.Found:230.1175.
31
3(benzo[d][1,3]dioxol5ylmethyl)6oxa3azabicyclo[3.1.1]heptane:356 Cis/trans(4
Benzyloxymethyloxetan2yl)methanol357 (216mg, 1.04mmol, 1.00equiv) was hydro
genatedat1.2barfor2hover73mg(0.10equiv)20%Pd(OH)2/Cin5mLMeOHatroom
356
ThisreactionwasperformedinthelaboratoriesofF.HoffmannLaRoche,BaselbyDr.ThierryGodel.
357
Preparedaccordingto:S.K.Chung,S.H.Ban,S.H.Kim,S.H.Woo,KoreanJournalofMedicinalChemi
stry1996,6,294.
180
ExperimentalSection
temperature. The suspension was filtered and concentrated to give crude cis/trans(4
hydroxymethyloxetan2yl)methanol as a yellow liquid. This first intermediate was dis
solvedin5mLdrypyridineat0Cunderargon.MsCl(0.32mL,4.2mmol,4.0equiv)was
addeddropwiseandthemixturewasstirredovernight,allowingtheicebathtoexpire.
Themixturewaspouredontocoldwater,acidifiedwith4 Maq.HClandextractedwith
CH2Cl2.Theaqueousphasewaswashedwithbrine,driedoverMgSO4,filteredandcon
centratedtogiveacrudeoilymixturecontainingcis/trans4methanesulfonyloxymethyl
oxetan2ylmethylmethanesulfonate.Thissecondintermediatewasdissolvedin5mLdry
dioxaneandpiperonylamine(0.62mL,5.0mmol,4.8equiv)wasaddeddropwiseatreflux.
Themixturewasfurtherstirredfor16hatreflux,concentratedinvacuo,themixturesus
pended in EtOAc and filtered(Sartorius). Afterconcentration (625 mg) the product was
chromatographed (MPLC, 80g SiO2, EtOAc (200mL), EtOAc/iPrOH 99:1, 49:1, 19:1, 9:1,
4:1, 1:1 (100mL each)) to give 48mg 3benzo[1,3]dioxol5ylmethyl6oxa3aza
bicyclo[3.1.1]heptaneasayellowliquid.AnalysisbyHPLCshowedapurityof97.5%.Prior
tothemeasurements,anadditionalpurificationviapreparativeHPLConaChiralpakAD
columnwasconducted.
Rf=0.30(SiO2,EtOAc);1HNMR(300MHz,CDCl3)6.89(s,1H),6.80(d,J=8.0Hz,1H),
6.75 (d, J = 7.9Hz, 1H), 5.94 (s, 2H), 4.49 (d, J = 6.3Hz, 2H ), 3.66 (s, 2H), 3.04 (d, J =
11.4Hz,2H),3.05(q,J=7.2Hz,1H),2.77(d,J=11.4,2H),2.41(d,J=7.8Hz,1H);13CNMR
(75MHz,CDCl3)160.8,147.7,146.5,132.6,121.7109.1,108.4,100.9,80.2,60.7,55.4,
30.5;IR(thinfilm)2960,2877,2808,1685,1609,1502,1487,1439,1389,1361,1239,
1179,1148,1116,1094,1034,958,926,877,836,806,772,714cm1;HRMS(ESI)calcd
forC13H15NO3:[M+H]+=234.1247.Found:234.1242.
ExperimentalSection
181
6.6 PreparationofNonpublishedOxetanes
6.6.1 3Aryloxetan3ols
3Phenyloxetan3ol: To a solution of bromobenzene (1.1mL, 10mmol, 2.5equiv) in

25mLdryTHFwasadded nBuLi(1.6M inhexanes,6.3mL,10mmol,2.5equiv)at78C.
Aftertheadditionwasfinished,themixturewasstirredfor5h,before15mLofthismix
turewereaddedtoasolution of oxetan3one(33,0.14g,2.0mmol, 1.0equiv)in5mL
dryTHFat78C.Themixturewasstirredovernight,allowingittowarmtoroomtem
perature.Saturatedaqueousammoniumchloridewasaddedandtheaqueousphaseex
tracted twice withEt2O. The combined organic phases were dried over MgSO4, concen
trated in vacuo and the residue purified by flash chromatography (SiO2, 1/1 hex
ane/EtOAc)togive260mgpureproduct(87%yield)ascolorlesscrystals(mp=48C).
Rf=0.17(SiO2,2/1cyclohexane/EtOAc); 1HNMR(300MHz,CDCl3)7.60(m,2H),7.42
(m,2H),7.34(m,1H),4.93(m,4H),2.65(s,1H); 13CNMR(75MHz,CDCl3)142.4,128.9,
128.2,124.6,85.8,76.0;IR(thinfilm)3387,2953,2877,1603,1495,1449,1176,971,
876,759cm1;Anal.calcdforC9H10O2:C,71.98;H,6.71.Found:C,72.02;H,6.81.
Thespectracollectedforthiscompoundareinaccordancewiththeliterature.358
3Pyridin3yloxetan3ol:Adryandargonflushed10mLflaskequippedwithamag
netic stirrer and a septum was charged with freshly prepared iPrMgClLiCl177 (2.0 mL,
1.0 M in THF, 2.0 mmol, 2.0 equiv). The reaction mixture was cooled to 0 C, and 3
358
L.E.Friedrich,P.Y.S.Lam,J.Org.Chem.1981,46,306.
182
ExperimentalSection
bromopyridine(0.31g,2.0mmol,2.0equiv)wasaddedinoneportion.Themixturewas
allowedtowarmtoroomtemperaturefor10min.(orangecolor,turbid),cooledto0C
againandstirredfor40min.Asolutionofoxetan3one(72mg,1.0mmol,1.0equiv)in1
mLdryTHFwasaddedandthemixturestirredfor1hat0C,beforeitwasallowedto
warmtoroomtemperatureandstirredforfurther72h.Et2Owasadded,followedbysa
turated aqueous ammonium chloride solution. The aqueous phase was extracted three
timeswithEt2O;thecombinedorganicphasesweredriedovermagnesiumsulfate,con
centratedinvacuoandtheresiduepurifiedbyflashchromatography(SiO2;EtOAc)togive
0.14gpureproduct(yield83%)asslightlyyellowsolid(mp=9394C).
(d,1H,J=4.0Hz),8.03(m,1H),7.37(dd,1H,J=4.8Hz,J=7.9Hz),4.97(d,2H,J=7.4Hz),
4.85(d,2H,J=7.4Hz),4.70(s,1H);13CNMR(75MHz,CDCl3)148.3,145.7,138.7,132.8,
123.6,85.8,74.0;IR(thinfilm)3108,2954,2876,2712,1576,1479,1418,1338,1227,
1179, 1039, 978, 876, 773, 710, 636 cm1; HRMS (EI) calcd for C8H9NO2: [MCH2O]+ =
121.0528.Found,121.0540
3(4methoxyphenyl)oxetan3ol: To a solution of 4methoxyphenylmagnesium bro

mide in THF (2.0mL, 2.0mmol, 2.0equiv) was added a solution of oxetan3one (33,
72mg,1.0mmol,1.0equiv)in1mLTHFat0C.Themixturewasallowedtoslowlywarm
toroomtemperatureandstirredovernight.Saturatedaqueousammoniumchloridesolu
tionwasadded.TheaqueousphasewasextractedthreetimeswithEt2O,thecombined
organicphasesweredriedoverMgSO4,concentratedinvacuoandtheresiduepurifiedby
flashchromatography(SiO2;hexane/EtOAc=4/1to2/1)togive0.14gpureproduct(77%
yield)aswhitesolid(mp=6061C).
Hz) 6.93 (d, 2H, J = 8.7 Hz), 4.88 (m, 4H), 3.82 (s, 3H), 2.99 (s, 1H); 13C NMR (75 MHz,
ExperimentalSection
183
CDCl3) 159.03, 134.4, 125.8, 113.9, 85.6, 75.5, 55.4; IR (thin film) 3319, 2993, 2954,
2882,2837,1611,1581,1514,1464,1441,1301,1245,1179,1027,970,876,772cm1;
HRMS(EI)calcdforC10H12O3:[M]+=180.0781.Found:180.0776.
Thespectracollectedforthiscompoundareinaccordancewiththeliterature.359
3(4Bromophenyl)oxetan3ol:Toasolutionofoxetan3one(33,0.20g,2.8mmol,
1.0equiv)in5mLdryEt2Owasaddedasolutionof4bromophenylmagnesiumbromide
(~0.63M inEt2O,6.3mmol,2.3equiv)in10mLdryEt2Oat0C.Themixturewasstirred
for5h,allowingittowarmtoroomtemperature,beforewaterwasadded.Theaqueous
phase was extracted three times with EtOAc, the combined organic phases dried over
(SiO2,4/1to2/1hexane/EtOAc)togive0.54gpureproduct(85%yield)aswhitecrystals
(mp=9394C).
Hz),7.49(d,2H,J=8.7Hz),4.90(d,2H,J=7.2Hz),4.85(d,2H,J=7.2Hz),2.74(s,1H);13C
NMR(75MHz,CDCl3)141.5,132.0,126.4,122.1,85.9,75.6;IR(thinfilm)3364,2948,
2878,1416,984,668cm1;HRMS(EI)calcdforC9H9BrO2:[MCH2O]+ =197.9680.Found:
197.9674.Anal.calcdforC9H9BrO2:C,47.19;H,3.96.Found:C,47.24;H,3.84.
359
F.D.Lewis,N.J.Turro,J.Am.Chem.Soc.1970,92,311.
184
ExperimentalSection
3(2,4dimethylphenyl)oxetan3ol: A few drops of 1bromo2,4dimethylbenzene

(0.93g, 5.0mmol, 5.0equiv) were added to magnesium turnings (0.14g, 6.0mmol,
6.0equiv)suspendedin5mLdryEt2O,followedbyagrainofiodinetoactivatethemag
nesiumandpromotemetalation.Afteraddingtheresidualarylbromide(turbidsolution,
slightboilingofEt2O),themixturewasstirredovernightatroomtemperatureandasolu
tionofoxetan3one(33,72mg,1.0mmol,1.0equiv)in1mLdryTHFwasaddedat0C
(whiteprecipitation).Aftertheadditionwasfinishedthemixturewasallowedtowarmto
room temperature and stirred for further 6h. Saturated aqueous ammonium chloride
solution was added. The aqueous phase was extracted three times with Et2O, the com
binedorganicphasesweredriedoverMgSO4,concentratedinvacuoandtheresiduepuri
fiedbyflashchromatography(SiO2;hexane/EtOAc=4/1to2/1)togive0.15gpureprod
uctasacolorlessoil(87%yield)thatsolidifieduponstanding(mp=4850C).
(s,1H),5.07(d,1H,J=7.7Hz),4.73(d,1H,J=7.8Hz),3.65(s,1H)139.4,135.5,133.3,
131.7,129.3,126.7,83.8,77.0,21.218.9;IR(thinfilm)3368,2946,1501,1217,1132,
976,850,813,772cm1;HRMS(EI)calcdforC11H14O2:[M]+=178.0989.Found:178.0983.
3(4tertButylphenyl)oxetan3ol: To a solution of 4tBuphenyl bromide (0.21mL,

1.5mmol, 1.5equiv) in 25mL dry THF was added nBuLi (1.6 M in hexanes, 0.81mL,
1.2mmol,1.2equiv)at78C.Aftertheadditionwasfinished,themixturewasstirredfor
30min, before a solution of oxetan3one (72mg, 1.0mmol, 1.0equiv) in 1mL dry THF
wasaddedat78C.Themixturewasallowedtowarmtoroomtemperatureovernight
andquenchedwithwater.Theaqueousphase wasextractedtwicewithEt2O,thecom
binedorganicphasesweredried,concentratedinvacuoandtheresiduepurifiedbyflash
ExperimentalSection
185
chromatography (SiO2, 8/1 to 2/1 cyclohexane/EtOAc) to give 0.17g pure product (80%
yield)aswhitecrystals(mp=126C).
Hz),7.45(d,2H,J=8.7Hz),4.94(d,2H,J=7.0Hz),4.90(d,2H,J=7.0Hz),2.55(s,1H),
1.34(s,9H); 13CNMR(75MHz,CDCl3)151.2,139.8,125.8,124.5,85.7,76.0,34.8,31.5;
IR(thinfilm)3373,2960,2873,1514,1424,1237,1193,1178,971,872,834cm1;HRMS
(EI)calcdforC13H18O2:[MCH2O]+ =176.1201.Found:176.1205.Anal.calcdforC13H18O2:
C,75.69;H,8.79.Found:C,75.85;H,8.87.
3Biphenyl4yloxetan3ol: To a solution of 4bromobiphenyl (1.0g, 4.3mmol,

1.4equiv) in 10mL dry THF was added nBuLi (1.6 M in hexanes, 2.5mL, 4.0mmol,
1.3equiv)at78C.Aftertheadditionwasfinished,themixturewasstirredfor45min,
beforeasolutionofoxetan3one(33,216mg,3.0mmol,1.0equiv)in3mLdryTHFwas
addedat78C.Themixturewasallowedtowarmtoroomtemperatureovernightand
quenchedwithwater.TheaqueousphasewasextractedtwicewithEt2O,thecombined
organicphasesweredried,concentratedinvacuoandtheresiduepurifiedbyflashchro
matography(SiO2,8/1to2/1cyclohexane/EtOAc)togive0.46gpureproduct(68%yield)
aswhitecrystals(mp=139142C(toluene)).
(d,2H,J=6.8Hz),4.94(d,2H,J=6.9Hz),2.79(s,1H); 13CNMR(75MHz,CDCl3)141.4,
141.1, 140.6, 129.0, 127.7, 127.6, 127.3, 125.2, 85.9, 75.9; IR (thin film) 3686, 1557,
1220,963,875,773,697cm1;Anal.calcdforC15H14O2:C,79.62;H,6.24.Found:C,79.78;
H,6.39
186
ExperimentalSection
3(2,4Dimethoxyphenyl)oxetan3ol:
To
solution
of
1bromo2,4
dimethoxybenzene(0.58mL,4.0mmol,1.3equiv)in10mLdryTHFwasadded nBuLi(1.6
M inhexanes,2.5mL,4.0mmol,1.3equiv)at78C.Aftertheadditionwasfinished,the
mixturewasstirredfor2.5h,beforeasolutionofoxetan3one(33,216mg,3.00mmol,
1.00equiv) in 3mL dry THF was added at 78 C. The mixture was allowed to warm to
room temperature over night and quenched with water. The aqueous phase was ex
tractedtwicewithEt2O,thecombinedorganicphasesweredried,concentratedinvacuo
andtheresiduepurifiedbyflashchromatography(SiO2,4/1to1/2cyclohexane/EtOAc)to
give0.50gpureproduct(80%yield)aswhitecrystals(mp=7275C).
Hz),6.49(m,2H),5.01(d,2H,J=7.0Hz),4.84(d,2H,J=6.9Hz),3.83(s,1H),3.82(s,1H),
3.21(s,1H);13CNMR(75MHz,CDCl3)160.6,126.7,126.5,122.3,103.9,99.1,83.1,75.3,
55.6,55.4;IR(thinfilm)2946,1613,1510,1462,1219,1030,973,773cm1;Anal.calcd
forC11H14O4:C,62.85;H,6.71.Found:C,62.84;H,6.82
Preparationandanalyticaldataofcompound70canbefoundonpage155.
3(4(1(1(dimethylamino)3methylbutyl)cyclobutyl)phenyl)oxetan3ol: To a solu
tionofarylbromide223(seepage215foritspreparation,0.71g,2.4mmol,1.2equiv)in
10mLdryTHFwasadded nBuLi(1.6M inhexanes,1.4mL,2.2mmol,1.1equiv)at78C.
Aftertheadditionwasfinished,themixturewasstirredfor10min,beforeasolutionof
oxetan3one(33,144mg,2.0mmol,1.0equiv)in3mLdryTHFwasaddedat78C.The
mixturewasallowedtowarmto0Candquenchedwithwater.Theaqueousphasewas
ExperimentalSection
187
extractedthreetimeswithEtOAc,thecombinedorganicphasesweredried,concentrated
invacuoandtheresiduepurifiedbyflashchromatography(nAl2O3,4/1to1/2cyclohex
ane/EtOAc)togive0.46gpureproduct(73%yield)asslightlyyellowishcrystals(mp=64
66C).
Rf=0.40(Al2O3,2/1cyclohexane/EtOAc); 1HNMR(300MHz,CDCl3)7.44(d,2H,J=
8.4Hz),7.27(d,2H,J=8.4Hz),4.94(d,2H,J=6.9Hz),4.89(d,2H,J=6.6Hz),3.03(s,1H),
2.91(dd,1H,J=2.9Hz,J=10.5Hz),2.39(m,3H),2.16(s,6H),2.10(m,1H),1.94(m,1H),
1.76(m,1H),1.54(m,1H),1.22(m,1H),1.09(m,1H),0.96(d,3H,J=6.5Hz),0.88(d,3H,
J=6.6Hz); 13CNMR(75MHz,CDCl3)147.4,139.0,128.0,123.2,85.6,67.6,51.8,44.0,
36.2, 33.4, 33.1, 26.2 (cyclohexane), 24.2, 21.6, 15.8; IR (thin film) 3389, 2951, 2866,
C20H31NO2:[MH]+=316.2271.Found:316.2272.
6.6.2 3Aryl3fluorooxetanes
3(4tertbutylphenyl)3fluorooxetane: To a solution of alcohol 67 (41mg,

0.20mmol,1.0equiv)in1mLdryCH2Cl2wasaddedDAST(26L,0.20mmol,1.0equiv)at
78 C. After stirring for 1min, saturated aqueous NaHCO3 was added and the mixture
allowed to warm to room temperature. The aqueous phase was extracted twice with
CH2Cl2,driedoverMgSO4,filtered,concentratedinvacuoandtheresiduepurifiedbyflash
chromatography(SiO2,pentane/Et2O=10/1)togive19mgpureproduct(47%yield)asa
colorlessoil.
(ddd,2H,J=0.9Hz,J=7.8Hz,J=21.2Hz),4.90(ddd,2H,J=1.0Hz,J=7.8Hz,J=21.6
Hz),1.35(s,9H);13CNMR(75MHz,CDCl3)151.9,135.5(d,1H,J=23.7Hz),125.8,124.0
188
ExperimentalSection
(d,1H,J=8.4Hz),95.4 (d,1H,J=206.8Hz),83.3(d,1H,J=25.6Hz),34.8,31.5, 24.2,

21.6, 15.8; 19F NMR(282 MHz, CDCl3): 149.1; IR (thin film) 2963, 2872, 1466, 1364,
1300, 1142, 983, 833, 668, 575 cm1; HRMS (EI) calcd for C13H17FO: [M]+ = 208.1258.
Found:208.1260.
Theanalyticaldataofcompound73canbefoundonpage156.
1(1(4(3fluorooxetan3yl)phenyl)cyclobutyl)N,N,3trimethylbutan1amine: To a
solution of alcohol 71 (see page 187, 0.11g, 0.35mmol, 1.0equiv) in 10mL dry CH2Cl2
was added DAST (75 L, 0.63mmol, 1.8equiv) at 78 C. The mixture was allowed to
warmto10C,stirredfor15minatthistemperatureandquenchedbydropwiseaddi
tionof2MaqueousNaOH.TheaqueousphasewasextractedthreetimeswithEtOAc,the
combinedorganicphasesweredried,concentratedinvacuoandtheresiduepurifiedby
flashchromatography(nAl2O3,cyclohexaneto2/1cyclohexane/EtOAc)togive47mgpure
product(43%yield)asayellowishoil.
Hz),7.29(d,2H,J=8.2Hz),5.10(dd,2H,J=7.9Hz,J=21.2Hz),4.92(dddd,2H,J=1.1Hz,
J=3.3Hz,J=7.5Hz,J=21.7Hz),2.93(dd,1H,J=2.8Hz,J=10.5Hz),2.41(m,3H),2.17
(s,6H),2.14(m,1H),1.95(m,1H),1.78(m,1H),1.54(m,1H),1.23(ddd,1H,J=3.4Hz,J=
10.6Hz,J=14.0Hz),1.10(m,1H),0.97(d,3H,J=6.5Hz),0.89(d,3H,J=6.6Hz);13CNMR
(75MHz,CDCl3)148.3,134.9(d, J=24.1Hz),128.0,122.8(d,J=8.1Hz),95.4 (d,J=
205.7Hz),83.2(dd,J= 2.3Hz,J=25.6Hz),67.6,52.0,44.1,36.3,33.2(d,J= 22.2Hz),
27.0,24.2,21.6,15.9;19FNMR(282MHz,CDCl3):147.2;IR(thinfilm)2951,2866,2773,
C20H30FNO:[MC3H7]+=262.1607.Found:262.1601.
ExperimentalSection
189
6.6.3 3Aryloxetanes
3(4Methoxyphenyl)oxetane: To a solution of alcohol 64 (18mg, 0.10mmol,

1.0equiv)andtriethylsilane(17L,0.11mmol,1.1equiv)in2mLdryCH2Cl2wasadded
trifluoroacetic acid (84L, 1.1mmol, 11equiv) at 0C. After stirring for 1 h at 0C, the
mixturewasallowedtowarmtoroomtemperatureandstirredforfurther24h,before
thereactionwasquenchedbyadditionofsaturatedaqueousNaHCO3.Theaqueousphase
wasextractedtwicewithEt2O,thecombinedorganicphasesweredried,concentratedin
vacuo and the residue purified by flash chromatography (SiO2, 8/1 to 2/1 cyclohex
ane/EtOAc)togive12mgpureproduct(76%yield)asacolorlessoil.
Hz),6.91(d,2H,J=8.6Hz),5.05(dd,2H,J=5.9Hz,J=8.3Hz),4.75(t,2H,J=6.4Hz),4.19
(m,1H),3.81(s,3H); 13CNMR(75 MHz,CDCl3)158.4,133.5, 127.7, 114.0, 79.3,55.3,
39.7; IR (thin film) 2957, 2870, 1161, 1582, 1514, 1464, 1292, 1249, 1179, 1036, 980,
912,828,743cm1;HRMS(EI)calcdforC10H12O2:[M]+=164.0832.Found:163.0830.
3Phenyloxetane: To a solution of 3phenyloxetan3ol (62, 60mg, 0.40mmol,

1.0equiv) in 2mL dry THF was added sodium hydride (60% dispersion in mineral oil,
19mg,0.48mmol,1.2equiv)at0C.Afterstirringfor30min,asolutionofpTsCl(92mg,
0.48mmol,1,2equiv)in0.8mLdryTHFwasaddeddropwise.Themixturewasstirredfor
2 h at 0C, before saturated aqueous KHSO4 was added. The aqueous phase was ex
tractedtwicewithEt2O,thecombinedorganicphasesweredried,concentratedinvacuo
190
ExperimentalSection
andtheresiduetreatedwith1mLcoldEt2O/pentane=3/1togive112mg95w%tosylate
78(Rf=0.42(SiO2,2/1cyclohexane/EtOAc); 1HNMR(300MHz,CDCl3)7.377.19(m,
7H),7.116.99(m,2H),5.30(d,J=8.6,2H),5.02(d,J=8.6,2H),2.35(s,3H); 13CNMR
(75MHz,CDCl3)144.3,136.7,135.3,129.5,129.2,128.6,127.4,127.0,86.0,81.4,21.7.).
Ofthismaterial38mgweredissolvedin5mLdryEt2O,beforeLiAlH4(0.10g,2.6mmol,
20equiv)wasaddedat0C.Afterstirringfor40minat0C,themixturewasaddedslow
ly to a saturated aqueous solution of K2CO3. The aqueous phase was extracted three
timeswithEt2O,thecombinedorganicphasesweredried,concentratedinvacuoandthe
residuefilteredthroughashortplugofsilicagel(10/1pentane/Et2O)togive12mgprod
uct(~60%yieldcalculatedfromtosylate78)asacolorlessoil.
(dd,1H,J=6.0Hz,J=8.4Hz),4.79(dd,2H,J=6.0Hz,J=6.7Hz),4.24(tt,1H,J=7.0Hz,J
=8.2Hz)
Thespectrumisidenticalwiththeonereportedintheliterature.360
Theanalyticaldataofoxetane81canbefoundonpage155.
6.6.4 3Phenyl3aminooxetanes
3Dibenzylaminooxetane3carbonitrile:361To a mixture of dibenzylamine (1.0mL,

5.0mmol, 4.5equiv) and 6mL AcOH was added oxetan3one (33, 79mg, 1.1mmol,
1.0equiv), followed by TMSCN (0.33mL, 2.5mmol, 2.3equiv). The mixture was stirred
overnightatroomtemperature,beforemostoftheAcOHwasevaporatedinvacuoand
Et2Oandwaterwereadded.TheaqueousphasewasextractedthreetimeswithEt2O.The
360
a)P.Picard,D.Leclercq,J.P.Bats,J.Moulines,SynthesisStuttgart1981,550.b)B.Delmond,J.C.Pom
mier,J.Valade,J.Organomet.Chem.1973,47,337.
361
Proceduredaptedfrom:E.Bacque,J.M.Paris,S.LeBitoux,Synth.Commun.1995,25,803.
ExperimentalSection
191
combined organic phases were washed with aqueous Na2CO3 until evolution of CO2
ceased, dried over MgSO4, filtered, concentrated in vacuo and the residue purified by
flash chromatography (SiO2, 8/1 to 4/1 cyclohexane/EtOAc) to give pure product (88%
yield)asslightlyyellowcrystals(mp=6466C).
Rf= 0.46 (SiO2, 2/1 cyclohexane/EtOAc); 1H NMR (300MHz, CDCl3) 7.34 (m, 10H),
4.34(d,2H,J=6.8Hz),4.29(d,2H,J=6.8Hz),3.51(s,4H); 13CNMR(75MHz,CDCl3)
136.9,129.4,128.8,128.3,118.0,78.6,60.9,55.7;IR(thinfilm)3029,2923,2849,1494,
1454,1369,750,700cm1;Anal.calcdforC18H18N2O:C,77.67;H,6.52;N,10.06.Found:
C,77.61;H,6.41;N,10.06.
Dibenzyl(3phenyloxetan3yl)amine:361 To a solution of PhMgBr (c ~3.0 M, 8mL

THF,2.8mLbromobenzene,584mgmagnesiumturnings,15equiv)wasaddedasolution
ofaminonitrile82(0.45g,1.6mmol,1.0equiv)in2.3mLdryTHFat50C.Afterstirring
for2.5h,asampleintheNMRindicatedfullconversionandcleanreaction.Themixture
(greengreysolution)wascooledto0C,Et2Owasadded,followedbybrine(slowly).Sa
turated aqueous KHSO4 and water were added to dissolve salts (pH~10). The aqueous
phasewasextractedfourtimeswithEt2O,thecombinedorganicphasesweredriedover
(SiO2, cyclohexane to 20/1 cyclohexane/EtOAc; 0.1% NEt3) to give 0.43g pure product
(71%yield)asacolorlesssolid(mp=8890C).
Rf= 0.46 (SiO2, 2/1 cyclohexane/EtOAc); 1H NMR (300MHz, CDCl3) 7.40 (m, 15H),
4.85(d,2H,J=6.3Hz),4.72(d,2H,J=6.3Hz),3.43(s,4H); 13CNMR(75MHz,CDCl3)
139.6,139.0,128.6,128.0,127.5,126.9,80.7,67.7,54.0;IR(thinfilm)3251,3057,3025,
2936,2879,1681,19616,1576,1493,1455,1358,1165,1116,1027,990,959,696cm1;
HRMS(EI)calcdforC23H23NO:[MCH2O]+=299.1674.Found299.1650.
192
ExperimentalSection
3Phenyloxetan3ylamine:361 To a solution of N,Ndibenzylamine 83 (0.42g,

1.3mmol,1.0equiv)in40mLMeOHwasaddedPd(OH)2/C(20w%).Afterexchangingthe
atmospherewithhydrogen,hydrogenwasbubbledthroughthemixturefor45min.The
mixturewasthenvigorouslystirredfor72h,filteredthroughaplugofCeliteandconcen
tratedinvacuo.TheresiduewasthendissolvedinEtOAc,MgSO4wasadded,filteredand
concentratedinvacuotogive183mgalmostpureproduct.Afterdistillation,168mgpure
compound(88%yield)wereobtainedasacolorlessoilthatsolidifiedinthefreezer(mp=
5254C).
(d, 2H, J=6.3Hz), 4.74 (d, 2H, J=6.3Hz), 2.13 (s, 2H); 13C NMR (75 MHz, CDCl3) 128.9,
127.6,125.1,86.7,59.3;IR(thinfilm)3360,2951,2870,2360,1604,1495,1445,1326,
1220,1057,1030,978,861,761,709cm1;Anal.calcdforC9H11NO:C72.46;H,7.43;N,
9.39.Found:C,72.20;H,7.64;N,9.17.
6.6.5 ConjugateAdditionProducts
6.6.5.1 AdditionstoAcrylate89
EtO2C
104
CN
O
(3Cyanooxetan3yl)acetic acid ethyl ester:362 To a solution of acrylate 89 (30mg,

0.21mmol, 1.0equiv) in 2mL dry MeCN was added acetone cyanohydrine (16 L,
0.42mmol, 2.0equiv), KCN (14mg, 0.42mmol, 2.0equiv) and 18crown6 (0.11g,
0.42mmol, 2.0equiv) at ambient temperature. After stirring for 20h, the mixture was
concentratedinvacuoandtheresiduepurifiedbyflashchromatography(SiO2,4/1cyclo
hexane/EtOAc)togive29mgpureproductasacolorlessoil.
362
Procedureadaptedfrom:S.Proemmel,R.Wartchow,H.M.R.Hoffmann,Tetrahedron2002,58,6199.
ExperimentalSection
193
Hz),4.55(d,2H,J=6.6Hz),4.22(q,2H,J=7.1Hz),3.08(s,2H),1.29(t,3H,J=7.2Hz);13C
NMR (75 MHz, CDCl3) 168.6, 120.3, 78.1, 61.9, 40.2, 34.0, 14.3; IR (thin film) 2981,
2895, 2242, 1732, 1374, 1347, 1203, 989 cm1; HRMS (EI) calcd for C8H11NO3:
[M]+=169.0739.Found:169.0739.
Ethyl 2(3(dimethylamino)oxetan3yl)acetate: To a solution of acrylate 89 (1 M in

Et2O, 0.2mL, 0.2mmol, 1equiv) in EtOH was added N,Ndimethylammmonium chloride
(0.15g,1.9mmol,9.3equiv),followedbyNEt3(0.4mL,2.8mmol,14equiv).Afterstirring
for9hatroomtemperature,thesolventwasconcentratedinvacuoandtheresiduepar
titioned between EtOAc and water. The aqueous phase was extracted three times with
EtOAc, the combined organic phases dried over MgSO4, filtered, concentrated in vacuo
andtheresiduepurifiedbyflashchromatography(SiO2,7%MeOHinCH2Cl2,0.1%NEt3)to
give53mgpureproduct(135%yield)asacolorlessoil.363
Rf=0.66(SiO2,10%MeOHinCH2Cl2,0.1%NEt3); 1HNMR(300MHz,CDCl3)4.57(d,
2H,J=6.2Hz),4.53(d,2H,J=6.3Hz),4.13(q,2H,J=7.1Hz),2.67(s,2H),2.17(s,6H),
1.24(t,3H,J=7.2Hz);13CNMR(75MHz,CDCl3)171.9,78.9,62.9,60.9,38.2,34.4,14.3;
IR(thinfilm)3502,2875,2787,1730,1457,1369,1306,1180,1102,1067,1030,983,
836 cm1; HRMS (EI) calcd for C9H17NO3: [M]+= 187.1208. Found: 187.1196; [MCH2O]+=
157.1098.Found:157.1098;Anal.calcdforC9H17NO3:C,57.73;H,9.15;N,7.48.Found:C,
57.46;H,9.23;N,7.59
363
SupraquantitativeyieldprobablyresultsfromevaporationofEt2Ofromthesolutionofacrylate89.
194
ExperimentalSection
Cl
CO2Et
O
224
Ethyl 2(3(4chlorophenyl)oxetan3yl)acetate: To a solution of [Rh(cod)Cl]2 (45mg,

90mol,0.04equiv)in7mLdioxanewasadded1.5 M aqueousKOH(1.6mL,2.4mmol,
1.0equiv) and the yellow solution was stirred for 15min. Then, a mixture of 4
Chlorobenzeneboronic acid (0.59g, 3.7mmol, 1.6equiv) and acrylate 89 (0.33g,
2.3mmol, 1.0equiv) in 7mL dioxane was slowly added and the color of the solution
turned to orange. After stirring 30min at room temperature additional 4
Chlorobenzeneboronicacid(0.17g,1.1mmol,0.48equiv)aswellas1.5 M aqueousKOH
(0.50mL,0.75mmol,0.33equiv)wereadded.Thereactionwasquenchedafterfurther2
h by the addition of Et2O (60mL) and brine (40mL). The aqueous phase was extracted
two times with Et2O (25mL). The combined organic phases were dried over MgSO4, fil
teredandconcentratedinvacuo.Theresiduewaspurifiedbyflashchromatography(SiO2;
8/1to2/1cyclohexane/EtOAc)togive0.33gofpureproduct(56%yield)asslightlyyello
wishoil.
(m,2H),4.96(d,2H,J=6.2Hz),4.84(d,2H,J=6.2Hz),4.01(q,2H,J=7.1Hz),3.11(s,
2H),1.13(t,3H,J=7.1Hz); 13CNMR(75MHz,CDCl3)170.3142.0132.6,128.6,127.2,
81.7, 60.6, 45.1, 44.7, 14.2; IR (thin film) 2979, 2875, 2360, 1732, 1494, 1402, 1370,
1344, 1253, 1227, 1189, 1094, 1061, 1014, 984, 829, 720 cm1; HRMS (EI) calcd for
C13H15ClO3:[MCH2O]+224.0595.Found:224.0604.
2(3Naphthalen2ylmethyloxetan3yl)ethanol: A suspension of CuI (0.11g,

0.56mmol, 0.1equiv), acrylate 89 (0.80g, 5.6mmol, 1.0equiv) and TMSCl (0.86mL,
6.7mmol,1.2equiv)in20mLdryTHFwasstirredfor5minatambienttemperature,be
ExperimentalSection
195
foreitwascooledto18C.Then,asolutionof(naphthalen2ylmethyl)magnesiumbro
mide in 20mL dry Et2O (~0.7 M, prepared by addition of 2(bromomethyl)naphthalene
(3.1g,14mmol,2.5equiv)tomagnesiumturnings(0.37g,14.5mmol,2.6equiv)inEt2O)
wasaddeddropwise.Aftertheadditionwasfinished,theflaskbroke,becauseofwhich
thereactionstoppedatlowconversion.Thecrudeproductisolatedfromthecoolingbath
wasdissolvedindryTHF,thesolutioncooledto0C,beforeLiAlH4(0.15g,4.0mmol)was
cautiouslyadded.Afterstirringfor3h,Na2SO410H2Owasaddedandthemixturestirred
for20min. Afterfiltration,thefiltrationresiduewasboiledthreetimeswithEtOAcand
the combined filtrates then dried over MgSO4, filtered, concentrated in vacuo and the
residuepurifiedbyflashchromatography(SiO2,8/1cyclohexane/EtOActoEtOAc)togive
0.18gpureproduct(13%yield)asacolorlessoilthatcrystallizeduponstanding(mp=60
62C).
Rf= 0.38 (SiO2, EtOAc); 1H NMR (300MHz, CDCl3) 7.86 7.70 (m, 3H), 7.59(s, 1H),
7.517.40(m,2H),7.327.18(m,1H),4.71(d,J=6.0,2H),4.55(d,J=6.0Hz,2H),3.84
(t, J = 6.8 Hz, 2H), 3.19 (s, 2H), 1.93 (t, J = 6.8 Hz, 2H), 1.74 (s, 1H); 13C NMR (75 MHz,
CDCl3)135.5,133.5,132.2,128.1,128.0,127.8,127.6,127.6,126.2,125.6,81.3,59.4,
42.5, 42.3, 37.8; IR (thin film) 3400, 3051, 2932, 2869, 1633, 1600, 1508, 1444, 1051,
1018,976,820,753cm1;HRMS(EI)calcdforC16H18O2:[M]+=242.1301.Found242.1301.
6.6.5.2 AdditionstoNitroolefin96
3(4Chlorophenyl)3nitromethyloxetane: To 1bromo4chlorobenzene (13.1g,

68.3mmol, 5.00equiv) in 180mL dry THF was added nBuLi (2.5 M in hexanes, 24mL,
60mmol,4.5equiv)at78C.Thesolutionwasstirredfor35min,beforeasolutionof3
nitromethyleneoxetane (96, 1.57g, 13.7mmol, 1.00equiv) in 10mL dry THF was slowly
196
ExperimentalSection
added over 80min. The mixture was then stirred for 40min before it was poured on
150mLicecold5%aqueousHCl.Afterstirringfor15minat0C,theaqueousphasewas
extracted with CH2Cl2 three times (100mL). The combined organic phases were dried
overMgSO4,filteredandconcentratedinvacuo.Theresiduewaspurifiedbyflashchro
matography (SiO2; 8/1 to 2/1 cyclohexane/EtOAc) giving 1.20g of >90% pure product
(35%yield)asacolorlesssolid(mp=115117C).
Hz),7.03(d,2H,J=8.6Hz),5.03(d,2H,J=6.7Hz),5.00(s,2H),4.90(d,2H,J=6.8Hz);13C
NMR(75MHz,CDCl3)138.0,133.8,129.1,127.1,82.0,78.9,46.8;IR(thinfilm)2936,
2884, 2360, 1553, 1495, 1424, 1379, 1339, 1100, 1015, 989, 903, 834, 820 cm1; HRMS
(EI)calcdforC10H10ClNO3:[M]+227.0349.Found:227.0343;Anal.calcdforC10H10ClNO3:C,
52.76;H,4.43;N,6.15.Found:C,52.54;H,4.55;N,6.34.
3(4tertbutylphenyl)3(nitromethyl)oxetane: To a solution of [Rh(cod)Cl]2 (5mg, 9

mol, 0.04equiv) in 2mL dry dioxane was added 1.5
aqueous KOH (0.17mL,
0.25mmol, 1.0equiv) and the yellow solution was stirred for 3min. Then, 4tert
butylbenzeneboronic acid (0.10g, 0.50mmol, 2.0equiv) and nitroolefin 96 (29mg,
0.25mmol,1.0equiv)wereconsecutivelyadded.After2h,thereactionmixturewaspar
titionedbetween120mLEt2Oandbrine.Theaqueousphasewasextractedthreetimes
with Et2O. The combined organic phases were dried over MgSO4 , filtered and concen
trated in vacuo. The residue was purified by flash chromatography (SiO2; 8/1 cyclohex
ExperimentalSection
197
ane/EtOAc) to give 65mg (105% yield)364 of pure product as a colorless solid (mp = 86
87C).
Rf=0.39(SiO2,2/1cyclohexane/EtOAc);1HNMR(300MHz,CDCl3)7.39(d,J=8.6Hz,
2H),7.04(d,J=8.6Hz,2H),5.09(d,J=6.6Hz,2H),5.01(s,2H),4.92(d,J=6.7Hz,2H),
1.31(s,9H); 13CNMR(75MHz,CDCl3)151.0,136.7,126.1,125.6,82.4,79.4,47.0,34.7,
31.4;IR(thinfilm)2960,2878,1548,1380,1220,980,773,569cm1;HRMS(EI)calcdfor
C14H19NO3:[M]+249.1360.Found:249.1360.
2(3(nitromethyl)oxetan3yl)acetaldehyde: To a solution of nitroolefin 96 (0.45g,

3.9mmol,1.0equiv)andacetaldehyde(2.5mL,44mmol,11equiv)in15mLdryTHFwas
addedpyrrolidine(80L,1.0mmol,0.26equiv)slowlyatroomtemperature.Themixture
wasstirredatroomtemperatureovernight.CH2Cl2(50mL)wasadded,followedby1 M
aqueous HCl. The aqueous phase was extracted three times with CH2Cl2, the combined
organicphasesdriedoverMgSO4,filtered,concentratedinvacuoandtheresiduepurified
byflashchromatography(SiO2,2/1to1/1cyclohexane/EtOAc)togive0.29gpureproduct
(46%yield)asayellowoilthatsolidifiedinthefreezer.
Theanalyticaldataofaldehyde112canbefoundonpage170.
364
Thedeviationfrom100%probablyresultsfromaweighingerrorthatiswithintheerrormarginof5%(2
significantdigits).
198
ExperimentalSection
6.6.5.3 AdditionstoAldehyde90
2(3azidooxetan3yl)ethanol: To a solution of sodium azide (0.98g, 15mmol,

3.0equiv) in 10mL 80v% AcOH was slowly added a solution of acrolein 90 (0.49g,
5.0mmol, 1.0equiv) in 1mL Et2O at room temperature. After 20min, the mixture was
cooledto0CandNaBH4(0.55g,15mmol,3.0equiv)wascautiouslyaddedintwopor
tions.After20min,thereactionmixturewaspartitionedbetweenwaterandEt2Oandthe
aqueous phase extracted four times with Et2O. The combined organic phases were
washedtwicewith2M aqueousNaOH,driedoverMgSO4,filtered,concentratedinvacuo
andtheresidueanalyzedbyNMR,showingproduct(0.44g)withgreaterthan90%purity.
Duetopotentialexplosionhazards,thismaterialwasnotfurtherpurified,butusedcrude.
Hz),4.66(d,2H,J=7.1Hz),3.79(t,2H,J=5.8Hz),2.11(t,2H,J=6.0Hz),1.94(s,1H);13C
NMR (75 MHz, CDCl3) 80.5, 63.5, 58.7, 38.1; IR (thin film) 3402, 2956, 2882, 2106,
1667, 1431, 1261, 1052, 978, 837 cm1; HRMS (EI): A massspectrum could not be ob
tainedforthiscompound.
6.6.5.4 AdditionstoPhenylsulfone93
3phenyl3(phenylsulfonylmethyl)oxetane: To a solution of [Rh(cod)Cl]2 (2mg, 4

mol, 0.05equiv) in 1.6mL dry dioxane was added 1.5
aqueous KOH (0.16mL,
0.24mmol,1.0equiv)andtheyellowsolutionwasstirredfor1min.Then,phenylboronic
ExperimentalSection
199
acid (58mg, 0.48mmol, 2.0equiv) and phenylsulfone 93 (50mg, 0.24mmol, 1.0equiv)

were consecutively added. After 6h, a sample showed 60% conversion, so more
[Rh(cod)Cl]2 (2mg,4mol,0.05equiv),KOH(0.16mL,0.24mmol,1.0equiv)andphenyl
boronicacid(58mg,0.48mmol,2.0equiv)wereaddedtothemixture.Afterstirringfor
1h, the reaction mixture was partitioned between Et2O and brine. The aqueous phase
was extracted four times with Et2O. The combined organic phases were dried over
MgSO4,filteredandconcentratedinvacuo.Theresiduewaspurifiedbyflashchromato
graphy(SiO2;20/1to2/1cyclohexane/EtOAc)togive60mgofpureproduct(87%yield)
asacolorlesssolid(mp=162C).
Rf= 0.21 (SiO2, 2/1 cyclohexane/EtOAc); 1H NMR (300MHz, CDCl3) 7.57 7.41 (m,
3H),7.387.28(m,2H),7.257.14(m,3H),7.06(m,,2H),5.07(d,J=6.5Hz,2H),4.95
(d, J = 6.6 Hz, 2H), 4.04 (s, 2H); 13C NMR (75 MHz, CDCl3) 140.4, 140.3, 133.1, 128.8,
128.5,127.3,127.2,126.3,80.9,65.1,45.8;IR(thinfilm)3063,2959,2906,0870,1583,
1498,1446,1319,1308,1268,1132,1084,982,858,751,687,550,525cm1;HRMS(EI)
calcdforC16H16O3S:[MCH2O]+=258.0709.Found:258.0710.
3methyl3phenyloxetane:Toasolutionofsulfone172(0.25g,0.86mmol,1.0equiv)
in 20mL MeOH was addedmg granulate (1.0g, 42mmol, 48equiv) and the mixture
stirredfor2mininanultrasoundbath.Stirringwascontinuedfor12h,whenasamplein
the NMR showed full conversion to product. Et2O (40mL) was added followed by
Na2SO410H2O.Afterstirringfor15min,themixturewasfiltered,thefiltratedriedover
MgSO4,filtered,evaporatedandtheresiduefilteredthroughaplugofsilicagel.Thecom
binedfiltratewasevaporatedandtheresiduedistilledbulbtobulbat200mbartogive
76mgpureproduct(59%yield)asacolorlessoil.
200
ExperimentalSection
Rf=0.0.21(SiO2,2/1cyclohexane/EtOAc); 1HNMR(300MHz,CDCl3)7.397.29(m,
3H),7.237.12(m,2H),4.96(d,J=5.7Hz,2H),4.61(d,J=5.2Hz,2H),1.71(s,3H).; 13C
NMR(75MHz,CDCl3)146.2,128.4,126.1,124.9,83.7,43.5,28.1;IR(thinfilm)2924,
2852,1220,772cm1;HRMS(EI)calcdforC10H12O:[MC6H5]+=71.0497.Found:71.0854.
1benzyl4(3methyloxetan3yl)piperazine: A solution of Nbenzypiperazine

(0.19mL,1.1mmol,1.1equiv)andsulfone93(0.21g,1.0mmol,1.0equiv)in5mLMeOH
was stirred for 20 h at 50C. Then, magnesium turnings (0.13g, 5.0mmol, 5.0equiv)
were added to the solution and the mixture stirred for 30 sec in an ultrasound bath to
start the reaction (slight bubbling). After stirring over night, more magnesium (0.13g,
5.0mmol,5.0equiv)wasaddedandstirringwascontinuedfor16h.Et2Owasadded,fol
lowed by Na2SO410 H2O and the mixture was stirred for 20min, filtered, dried over
Na2SO4,filtered,concentratedinvacuoandtheresiduepurifiedbyflashchromatography
(nAl2O3, 20/1 to 4/1 cyclohexane/EtOAc) to give 141mg pure product (57% yield) as a
yellowishoil.
Rf=0.39(Al2O3,2/1cyclohexane/EtOAc); 1HNMR(300MHz,CDCl3)7.357.23(m,
5H),4.57(d,J=5.3Hz,2H),4.20(dJ=5.3Hz,2H),3.51(s,2H),2.51(s,4H),2.452.33
(m,4H),1.37(s,3H).; 13CNMR(75MHz,CDCl3)137.8,129.0,128.0,126.9,81.4,63.0,
60.0, 53.1, 45.1, 15.3; IR (thin film) 2937, 2866, 2814, 1493, 1451, 1384, 1367, 1352,
1317,1294,1269,1239,1215,1134,1016,972,906,836,743,701cm1;HRMS(EI)calcd
forC15H22N2O:[MCH2O]+=216.1621.Found:216.1621.
ExperimentalSection
201
Nbenzyl3methyloxetan3amine: A solution of benzylamine (0.12mL, 1.1mmol,

1.1equiv)andsulfone93(0.21g,1.0mmol,1.0equiv)in5mLMeOHwasstirredfor3h
at50C.Then,magnesiumturnings(0.13g,5.0mmol,5.0equiv)wereaddedtothesolu
tionandthemixturestirredfor30secinanultrasoundbathtostartthereaction(slight
bubbling). After stirring over night, more magnesium (0.13g, 5.0mmol, 5.0equiv) was
addedandstirringwascontinuedfor16h.Et2Owasadded,followedbyNa2SO410H2O
andthemixturewasstirredfor20min,filtered,driedoverNa2SO4,filtered,concentrated
invacuoandtheresiduepurifiedbyflashchromatography(nAl2O3,20/1to4/1cyclohex
ane/EtOAc)togive140mgpureproduct(79%yield)asayellowishoil.
Rf=0.50(Al2O3,2/1cyclohexane/EtOAc); 1HNMR(300MHz,CDCl3)7.397.22(m,
5H),4.57(d,J=6.6,2H),4.41(d,J=6.6,2H),3.79(s,2H),1.65(s,1H),1.55(s,3H); 13C
NMR(75MHz,CDCl3)140.0,128.4,127.9,127.0,83.1,57.5,47.9,23.6;IR(thinfilm)
3302,3028,2935,2867,1604,1495,1453,1378,1227,1151,1070,1029,978,914,740,
701cm1;HRMS(EI)calcdforC11H15NO:[MCH3O]+=146.0965.Found:146.0966.
6.6.6 2Oxa6azaspiro[3.3]heptanes
129
6tosyl2oxa6azaspiro[3.3]heptane: To a solution of KOH (33.23g, 0.5923 mol,
3.200equiv) and ptosylamide (37.96g, 0.2217 mol, 1.200equiv) in 600mL EtOH 3
Bromo2,2bis(bromomethyl)propan1ol(60.12g,0.1851mol,1.000equiv)wasaddedat
room temperature and the reaction mixture was heated to reflux for 90h. The solvent
wasremovedbyevaporation,500mL1M KOHwasaddedandthewhitesuspensionwas
lefttostirforanother2hatroomtemperature.Themixturewasfilteredandthewhite
filtercakewasrinsedwithwateruntilthewashingwaterwasneutral.Thefiltercakewas
driedunderhighvacuumtogive30.55gofproductcontaining10mole%oftosylamide
202
ExperimentalSection
asawhitesolid.TheoverallyieldofpureNtosyl2oxa6azaspiro[3.3]heptanewascalcu
latedtobe27.38g(58%yield).
Rf=0.14(SiO2,2/1cyclohexane/EtOAc); HNMR(300MHz,CDCl3)7.71(d,2H,J=8.3
13
Hz), 7.37 (d, 2H, J = 8.0 Hz), 4.59 (s, 4H), 3.91 (s, 4H), 2.46 (s, 3H); C NMR (75MHz,
CDCl3) 144.6, 131.6, 130.0, 128.5, 80.5, 59.7, 37.7, 21.8; IR (thin film) 2930, 2865,
1958,1846,1687,1595,1459,1442,1335,1312,1292,1209,1165,1143,1039,973,943,
1
890,829,683,542cm ;Anal.calcdforC12H15NO3S;C,56.90;H,5.97;N,5.53.Found:C,
56.79; H, 5.98; N, 5.48. HRMS (EI) calcd for C12H15NO3S: [M]+ = 253.0768. Found:
253.0769.
130
2oxa6azoniaspiro[3.3]heptane oxalate salt: Ntosyl2oxa6azaspiro[3.3]heptane

(129, 7.30g, 28.8 mol, 1.00equiv) and magnesium granulate (4.90g, 0.202 mol,
7.00equiv) were sonicated for 1 h in MeOH (500 ml). Almost all solvent was removed
fromthegreyreactionmixtureonarotaryevaporatortogiveaviscousgreyresidue.Et2O
(500mL)andNa2SO410H2O(15g)wereaddedandtheresultinglightgreymixturewas
stirredvigorouslyfor30minbeforefiltration.ThefiltratewasdriedoverNa2SO4andan
hydrousoxalicacid(1.30g,14.4mol,0.500equiv)dissolvedinEtOH(~1mL)wasaddedto
theorganicphase.Athickwhiteprecipitateformedinstantly.Itwasfilteredoffanddried
undervacuumtogive3.37g(81%yield)ofanamorphouswhitesolid.Theobtainedprod
uctshowedtheanticipatedsignalsin13CNMRand1HNMRwithnoimpuritiesbutdidnot
passelementalanalysis.Thismaybeduetothepresenceofacertainfractionofthehy
drooxalatesaltintheproduct.
ExperimentalSection
203
13
H NMR (300MHz, D2O) 4.87 (s, 4H), 4.34 (s, 4H), 2.22 (m, 2H); C NMR (75MHz,
D2O) 168.6, 79.9, 54.5, 40.0; IR (thin film of 2Oxa6azaspiro[3.3]heptane) 3400,

1
2953,2875,1653,1556,1431,1352,1315,1250,963,829,774cm ;HRMS(EI)donewith
2Oxa6azaspiro[3.3]heptane,calcdforC5H9NO[MH]+=98.0601.Found98.0603.
N,4biphenyl2oxa6azaspiro[3.3]heptane5: In a dry 50mL twoneck flask 4

bromobiphenyl (0.517g, 2.22mmol, 1.00equiv) was dissolved in 10mL of dry and de
gassed toluene. To the clear solution were added palladium(II)acetate (0.026g,
0.12mmol,0.050equiv),BINAP(0.078g,0.18mmol,0.050equiv),dryCesiumcarbonate
(0.666g, 11.1mmol, 5.00equiv), bis(2oxa6azoniaspiro[3.3]heptane) oxalate (130,
0.384g,1.33mmol,0.600equiv)and4dropsofNEt3.Themixturewasheatedtoreflux
over night and then filtered through a plug of celite. The filter cake was washed with
CH2Cl2andthesolventwasremovedfromthefiltrate.Theorangeoilyresiduewaspuri
fied by flash chromatography (nAl2O3, cyclohexane to 4/1 cyclohexane/EtOAc) yielding
0.327g(59%yield)yellowcrystalsasthepureproduct.
Rf = 0.5 (Al2O3, cyclohexane/EtOAc 2:1); mp 164165C; 1H NMR 7.50 (dd, 4H, J =

7.9Hz,16.2Hz),7.40(t,2H,J=7.7Hz),7.28(d,1H,J=9.0Hz),6.53(d,2H,J=8.6Hz),
4.86(s,4H),4.07(s,4H); 13CNMR150.3,141.0,130.9,128.6,127.6,126.3,126.2,111.9,
81.2, 61.7, 39.2; IR (thin film) /cm1: 3061, 2940, 2871, 1626, 1572, 1494, 1450, 1420,
1352,1317,1219,1121,1067,1028,973,935,866,788,758,711;HRMS(EI)calculated
for C17H17NO [M]+ 251.1305. Found 251.1308; EA calculated for C17H17NO C: 81.24, H:
6.82,N:5.57,O:6.37.FoundC:81.23,H:7.07,N:5.50,O:6.20.
204
ExperimentalSection
Nbenzoyl2oxa6azaspiro[3.3]heptane:
Benzoylchloride
(0.7mL,
6.0mmol,
1.5equiv), NEt3 (3.0mL, 22mmol, 5.0equiv) and bis(2oxa6azoniaspiro[3.3]heptane)

oxalate(130,0.577g,2.00mmol,0.5equiv)weresuspendedin25mLDCM.Thereaction
mixturewasstirredvigorouslyfor30minandsonicatedforanother30min.Thentheyel
low reaction mixture was poured into a separation funnel, 30mL water was added and
the aqueous phase was extracted four times with 30mL CH2Cl2. The combined organic
phasesweredriedoverMgSO4andthesolventwasremoved.Theresultingyellowliquid
was purified by flash chromatography (Al2O3, cyclohexane/EtOAc 2:1 to pure EtOAc) to
give0.623gwhitesolidasthepureproduct(77%yield).
Rf=0.065(Al2O3,cyclohexane/EtOAc2:1);mp9596C;1HNMR(300MHz,CDCl3)7.61
(m,2H),7.44(m,3H),4.81(d,4H,J=10.7Hz),4.44(s,2H),4.36(s,2H); 13CNMR170.2,
132.7,131.1,128.3 , 127.7, 80.7, 62.7, 58.1, 38.2; IR (thin film) /cm1: 3061, 2940,
2872,1625,1572,1494,1450,1420,1352,1317,1219,1121,1067,1028,973,935,866,
788, 758, 711; MS (EI) calculated for C12H13NO2 [MH]+ 202.0863. Found 202.0862; EA
calculated for C12H13NO2: 70.92, H: 6.45, N: 6.89, O: 15.74. Found C: 70.80, H: 6.53, N:
6.88,O:15.79.
ExperimentalSection
205
N((anthracen10yl)methyl)2oxa6azaspiro[3.3]heptan4:
Bis(2oxa6azoniaspiro
[3.3]heptane) oxalate (130, >90% pure, 0.23g, 0.78mmol, 0.50equiv) was stirred
together with K2CO3 (1.17g, 8.47mmol, 6.00equiv) in 8mL DMF for 10min at room
temperature.10(chloromethyl)anthracene(0.322g,1.42mmol,1.00equiv)wasaddedto
themixtureandthereactionwaslefttostirovernight.After24hTLCindicatedremaining
starting material. To complete conversion the reaction was refluxed for 10min. To the
reaction mixture was added Et2O (200mL) and the aqueous phase was washed three
times with brine in order to remove residual DMF. The aqueous phase was dried over
Na2SO4 and anhydrous oxalic acid (0.0639g, 0.710mmol, 0.500equiv) dissolved in little
EtOH was added. The resulting yellow precipitate was filtered, washed with ether and
dissolvedinchloroform.Inaseparationfunnel150mLNaOH(2 M)wereaddedandthe
aqueous phase was extracted three times with 100mL EtOAc. The combined organic
phasesweredriedoverNa2SO4andthesolventwasconcentratedinvacuotogive0.217g
pureproduct(52%yield)asyellowcrystals(mp=177178C).
Rf = 0.41 (Al2O3, cyclohexane/EtOAc 2:1); mp 177178C; 1H NMR (300 MHz,CDCl3)

8.42(m,3H),8.01(m,2H),7.50(m,4H),4.69(s,4H),4.54(s,2H),3.46(s,4H); 13CNMR
(75MHz,CDCl3)131.3,130.8,129.0,127.4,125.7,124.6,81.3,63.5,53.4,39.0,twoaro
matic signals overlap and cannot be distinguished; IR (golden gate) /cm1: 3053, 2916,
2890, 2858, 2825, 2809, 1733, 1622, 1521, 1490, 1444, 1338,1308, 1243, 1223, 1184,
1161,1136,1113,1068,1025,989,970,940,906,893,880,865,839,784,753,721,703,
647,631;MS(EI)calculatedforC20H19NO[M]+289.15.Found289.15.
206
ExperimentalSection
(1R,2S)1phenyl2(2oxa6azaspiro[3.3]heptan6yl)propan1ol:365 To a solution of
3,3bis(bromomethyl)oxetane (119, 5.0g, 22mmol, 1.0equiv) and (1R,2S)norephedrine
(3.2g, 22mmol, 1.0equiv) in 50mL toluene was added NaHCO3 (3.8g, 45mmol,
2.1equiv).Themixturewasrefluxedfor60husingaDeanStarktrap,allowedtocoolto
room temperature, before water was added. The aqueous phase was extracted three
tratedinvacuoandtheresiduepurifiedbyflashchromatography(nAl2O3,2/1cyclohex
ane/EtOActoEtOAc)togive0.67gpureproduct(13%yield)asawhitesolid(mp=144
146C)
1
Rf=0.12(SiO2:hexane/EtOAc2:1); HNMR(300MHz,CDCl3):7.29(m,5H),4.76(s,
4H),4.68(d,1H,J=3.0Hz),3.43(q,4H,J=7.0Hz),2.96(s,1H),2.35(dq,1H,J=3.0Hz,J
13
=6.5Hz),0.64(d,3H,J=6.5Hz); CNMR(75MHz,CDCl3):128.0,126.9,125.7,81.2,
71.2, 68.2, 62.1, 38.3, 9.2 (aromatic quat. carbon not observed); IR (thin film) 3404,
1
2936, 2866, 1450, 1383, 1333, 1245, 1199, 1170, 1068, 1043, 972 cm ; Anal. calcd. for
C14H19NO2:C,72.07;H,8.21;N,6.00;Found:C,71.96;H,8.21;N,6.03;MS(EI)calcd.for
+
C14H19NO2[MH] 232.1333;Found,232.1330.
N
126
6Benzhydryl2oxa6azaspiro[3.3]heptane:366 A solution of bis(bromomethyl)

oxetane (119, 5.0g, 22mmol, 1.0equiv), benzhydrylamine (4.1g, 22mmol, 1.0equiv)
and N,Ndiisoproylethylamine in 140mL MeCN was refluxed for 20h. The mixture was
cooledtoroomtemperatureandconcentratedinvacuo.Et2Owasaddedandthemixture
filtered.Thefiltratewasconcentratedinvacuoandtheresiduepurifiedbyflashchroma
365
Procedure adapted from: D. Zhao, C.Y. Chen, F. Xu, L. Tan, R. Tillyer, M. E. Pierce, J. R. Moore, Org.
Synth.2000,77,12.
366
Procedureadaptedfrom:F.H.Tsai,C.G.Overberger,R.Zand,Biopolymers1990,30,1039.
ExperimentalSection
207
tography(nAl2O3,20/1to2/1cyclohexane/EtOAc)togive0.59gpureproduct(10%yield)
ascolorlesscrystals(mp=139141C).
1
Rf=(SiO2:hexane/EtOAc2:1); HNMR(300MHz,CDCl3):7.26(m,10H),4.75(s,4H),
13
4.23 (s, 1H), 3.29 (s, 4H); C NMR (75MHz, CDCl3): 141.7, 128.3, 127.3, 127.0, 81.6,
78.0, 63.0, 38.1; IR (thin film) 3024, 2934, 2864, 2822, 1597, 1492, 1451, 1342, 1240,
1
1074,973,744,707cm ;MS(EI)calcd.forC18H19NO[MH] 232.1333;Found,232.1330.
6.6.7 SibutramineAnalogues
3(4Chlorophenyl)oxetane3carbonitrile:367
To
3(4Chlorophenyl)3
nitromethyloxetane (110368, 83mg, 0.40mmol, 1.0equiv) in 3.5mL dry THF was added
tetrabutylammonium iodide (6.9mg, 19mol, 0.050equiv), benzylbromide (47L,
0.40mmol,1.1equiv)andpotassiumhydroxide(22mg,0.39mmol,1.1equiv).Thewhite
mixturewasstirredfor24hatroomtemperature.Itwasthencooledto20CandNEt3
(0.45mL, 3.20mmol, 9.0equiv) and thionyl chloride (0.11mL, 1.6mmol, 4.5equiv) was
added.Theslightlyyellowmixturewasstoredfor8hat20Cbeforeitwasquenched
with10mLwater.TheaqueousphasewasextractedwithEt2Othreetimes(20mL).The
combinedorganicphasesweredriedoverMgSO4andconcentratedinvacuo.Theresidue
waspurifiedbyflashchromatography(SiO2;cyclohexane/EtOAc20/1to2/1)giving47mg
of 90% pure product (61% yield) as yellow oil. Upon upscaling (899.6mg of 3(4
chlorophenyl)3nitromethyloxetane), the yield decreased to 40% but pure product as
colorlesssolid(mp=4244C)wasobtainedbydistillation(0.27mbar,bp=140C).
367
368
Adaptedfrom:C.Czekelius,E.M.Carreira,Angew.Chem.,Int.Ed.Engl.2005,44,612
Forthepreparationofthiscompound,refertopage195.
208
ExperimentalSection
Rf=0.51(SiO2:hexane/EtOAc2:1); HNMR(300MHz,CDCl3):7.59(m,4H),5.32(d,
13
2H,J=6.3Hz),4.82(d,2H,J=6.3Hz); CNMR(75MHz,CDCl3):135.0,134.5,129.5,
126.7,119.6,81.0,40.6;IR(thinfilm)3046,2965,2889,2360,2243,1905,1597,1493,
1
1406,1329,1281,1097,1013,985,942,861,824,714cm ;Anal.calcd.forC10H8ClNO:C,
+
62.03;H,4.16;N,7.23.Found:C,61.79;H,4.28;N,7.11;MS(EI)calcd.forC10H8ClNO[M]
193.0294.Found:193.0286.
[1[3(4Chlorophenyl)oxetane3yl]3methylbutyl]dimethylamine 3: To magne
sium(137.1mg,5.6mmol,4.0equiv)in3mLdryEt2Owasslowlyaddedisobutylbromide
(0.8mL, 7.0mmol, 5.0equiv). The mixture was refluxed for 20min. 3(4Chlorophenyl)
oxetane3carbonitrile (158, 274.5mg, 1.4mmol, 1.0equiv) in 4.5mL dry toluene was
then added at the rate the Et2O was removed by distillation. Distillation was stopped
whentheinternaltemperaturereached90Candthemixturewasstirredfor2hatthis
temperature.AslurryofNaBH4(0.22g,5.7mmol,4.0equiv)in10mL iPrOHwasadded.
Themixturewasrefluxedfor5handthenstirredfor19hatroomtemperaturebefore
the iPrOH was evaporated in vacuo. Water (20mL) was added and the mixture was al
lowed to stand for 30min before the aqueous phase was extracted with EtOAc three
times(50mL).ThecombinedorganicphasesweredriedoverMgSO4andconcentratedin
vacuo. For purification, the residue was dissolved in 30mL EtOAc and the solution was
acidified with 3 M HCl to pH 1. The mixture was extracted with 1 M HCl three times
(30mL) and the combined aqueous phases were extracted with EtOAc three times
(40mL). The Aqueous phase was basified with KOH to pH 14 and extracted with EtOAc
threetimes(40mL).ThecombinedorganicphasesweredriedoverMgSO4andconcen
trated in vacuo giving 244mg (69% yield) of 85% pure 1[3(4Chlorophenyl)oxetane3
1
yl]3methylbutylamine (159, Rf=0.50 (Al2O3: hexane/EtOAc 2:1); H NMR (300MHz,

CDCl3):7.32(m,2H),6.95(m,2H),4.89(m,3H),4.66(d,1H,J=5.9Hz),3.41(dd,1H,J=
2.0Hz,J=10.8Hz),1.70(m,1H),1.63(m,2H),1.15(m,1H),0.90(m,6H),0.76(m,1H);
ExperimentalSection
209
MS (EI) calcd. for C5H12N [M C9H8ClO] 86.0969. Found: 86.0972.). To 1[3(4

Chlorophenyl)oxetane3yl]3methylbutylamine (159, 40mg, 0.20mmol, 1.0equiv) in
1mLMeCNwasadded37w%formaldehyde(58L,0.80mmol,5.0equiv)andthesolu
tionwasstirredfor15min.NaCNBH3(22mg,0.40mmol,2.3equiv)wasadded,followed
15min later by AcOH (50 L, 0.90mmol, 5.8equiv). The mixture was stirred for 2.25 h
before 10mL 2% MeOHCH2Cl2 was added. The aqueous phase was extracted with 1 M
NaOHthreetimes(10mL),driedoverMgSO4andconcentratedinvacuo.Theresiduewas
purifiedbyflashchromatography(SiO2;cyclohexane/EtOAc8/1to4/1)giving21.1mgof
awhitesolidaspureproduct(50%yield).
Rf=0.47(SiO2:hexane/EtOAc2:1); HNMR(300MHz,CDCl3):7.27(m,2H),6.99(m,
2H),4.89(m,2H),4.75(d,1H,J=5.8Hz),4.56(d,1H,J=5.8Hz),3.42(dd,1H,J=2.9Hz,J
=10.8Hz),2.18(s,6H),1.56(m,1H),1.31(ddd,1H,J=3.4Hz,J=10.8Hz,J=14.2Hz),
13
1.01(d,3H,J=6.5Hz),0.97(m,1H),0.90(d,3H,J=6.6Hz); CNMR(75MHz,CDCl3):
141.5,132.1,128.9,127.7,82.0,81.2,66.6,52.0,43.8,36.4,26.0,23.9,21.4;IR(thinfilm)
2955,2868,2826,2780,2359,1897,1772,1494,1466,1398,1368,1276,1095,1045,
1
1014,985,822cm ;Anal.calcd.forC7H10O3:C,68.19;H,8.58;N,4.97.Found:C,68.22;
+
H,8.37;N,4.92;MS(EI)calcd.forC7H16N[MC9H8ClO] 114.1277.Found:144.1308.
6(4Chlorophenyl)2oxaspiro[3.3]heptane6carbonitrile:369 A solution of 4
chlorophenylacetonitrile (13.1g, 86.4mmol, 1.00equiv) and bis(bromomethyl)oxetane
(119,21.0g,86.4mmol,1.00equiv)in22mLEt2Owasaddeddropwiseover30mintoa
vigorously stirred suspension of KOH (11.3g, 201mmol, 2.34equiv) in 60mL DMSO at
roomtemperature.Aftertheadditionwascomplete,themixturewasstirredfor3h,be
369
Procedureadaptedfrom:J.E.Jeffery,F.Kerrigan,T.K.Miller,G.J.Smith,G.B.Tometzki,J.Chem.Soc.,
PerkinTrans.11996,2583.
210
ExperimentalSection
forethereactionwasquenchedbyadditionoficewater(40mL).Et2O(40mL)wasadded,
themixturefilteredthroughCeliteandthefiltercakewashedwithEtOAc.Theaqueous
layer of the combined filtrate was extracted twice with EtOAc. The combined organic
phaseswerewashedthreetimeswithbrine,driedoverMgSO4,filtered,concentratedin
vacuoandtheresiduerecrystallizedfrom25mLtoluenetogive1.97gpureproduct(10%
yield)ascolorlesscrystals(mp=148150C(toluene)).
1
Rf=0.38 (SiO2: cyclohexane/EtOAc 2:1); H NMR (300MHz, CDCl3): 7.44 7.32 (m,
2H),7.297.24(m,2H),4.96(s,2H),4.63(s,2H),3.163.06(m,2H),2.832.72(m,2H);
13
C NMR (75MHz, CDCl3): 136.9, 129.2, 126.9, 123.1, 83.4, 81.6, 44.6, 39.1, 35.0; IR
(thin film) 3498, 2939, 2863, 2614, 2353, 2230, 1961, 1898, 1808, 1601, 1494, 1449,
1
1425,1274,975,772,698cm ;Anal.calcd.forC13H12ClNO:C,66.81;H,5.18;N,5.99;Cl,
15.17.Found:C,66.77;H,5.19;N,5.96;Cl,14.98;HRMS(EI)calcd.forC13H12ClNO:[M]+=
233.0602.Found:233.0598.
2,6Diphenylspiro[3.3]heptane2,6dicarbonitrile:369 A solution of phenylacetonitrile

(2.4g,21mmol,2.0equiv)inEt2Owasaddedtoamixtureoftetrabromoerithrytol(4.0g,
10mmol,1.0equiv)andKOH(2.4g,43mmol,4.1equiv)in15mLDMSOoverthecourse
of30minatroomtemperature.Themixturewasstirredfor1h,beforethereactionwas
stoppedbytheadditionoficewater.Et2Owasaddedandthemixturefilteredthrougha
plugofsand.TheaqueousphaseofthefiltratewasextractedthreetimeswithEt2O,the
combined organic phases were washed three times with water, dried over MgSO4, fil
tered, concentrated in vacuo and the residue purified by flash chromatography (SiO2,
20/1to4/1cyclohexane/EtOAc)togive0.45gpureproduct(15%yield)ascolorlesscrys
tals(mp=114116C).
ExperimentalSection
211
Rf=0.59 (SiO2: cyclohexane/EtOAc 2:1); H NMR (300MHz, CDCl3): 7.38 (m, 10H),
3.35(dd,2H,J=4.3Hz,J=12.2Hz),3.01(d,2H,J=12.3Hz),2.88(dd,2H,J=4.3Hz,J=
13
12.3Hz),2.70(d,2H,J=12.3Hz); CNMR(75MHz,CDCl3):168.0,139.0,129.3,128.4,
125.8,124.2,47.2,46.2,35.9,35.2;IR(thinfilm)3065,3028,2981,2938,2230,1961,
1
1884,1812,1601,1495,1448,1426,1272,1081,755,699cm ;Anal.calcd.forC21H18N2:
C,84.53;H,6.08;N,9.39;Found:C,84.31;H,6.19;N,9.32;HRMS(EI)calcd.forC21H18N2:
[M]+=298.1465.Found:298.1463.
[2[1(4Chlorophenyl)cyclobutyl]2oxoethyl]phosphonicaciddimethylester:Toa
solution of dimethyl methylphosphonate (5.62mL, 64.0mmol, 4.00equiv) in 50mL dry
THF was added nBuLi (2.5 M in hexanes, 22.3mL, 55.9mmol, 3.5equiv) at 78 C. After
stirring for 15min, a solution of 1(4chlorophenyl)cyclobutanecarbonitrile (3.05g,
15.9mmol,1.00equiv)in10mLdryTHFwasaddedover30min.Thebrightredmixture
was then allowed to warm to room temperature and stirred for further 2h. Saturated
aqueous KHSO4 was added (resulting in pH 5) and the aqueous phase extracted three
trated in vacuo and the residue purified by flash chromatography (SiO2, 2/1 cyclohex
ane/EtOActoEtOAc)togiveamixtureofproductandprobablythecorrespondingimine.
ThismixturewasdissolvedinTHFandstirredwithsaturatedaqueousKHSO4for30min.
The mixture was extracted three times with EtOAc, dried over MgSO4, filtered, concen
tratedinvacuo,giving3.45gpureproduct(68%yield)asacolorlessoil.
1
Rf=0.12 (SiO2: cyclohexane/EtOAc 2:1); H NMR (300MHz, CDCl3): 7.35 7.29 (m,
2H),7.197.09(m,2H),3.70(dd,J=0.8,11.2,6H),2.922.74(m,4H),2.35(ddd,J=7.5,
13
9.4,12.2,2H),2.031.71(m,2H); CNMR(75MHz,CDCl3):201.3(d,J=6.9Hz),140.4,
133.3,129.2,127.3,59.8(d,J=4.3Hz),53.1(d,J=6.5Hz),35.3(d,J=137.2Hz),30.3,
31
15.8; P NMR (121MHz, CDCl3): 24.2; IR (thin film) 3468, 2954, 2854, 1708, 1492,
212
ExperimentalSection
1399,1255,1184,1034,998,872,816cm ;HRMS(ESI)calcdforC14H18ClO4P:[M+Na]+=
339.0523.Found:339.0529
Theanalyticaldatafor,unsaturatedketone94canbefoundonpage151.
1[1(4Chlorophenyl)cyclobutyl]2oxetan3ylethanol: To a solution of ketophos

phonate 220 (see page 211 for its preparation; 1.22g, 3.84mmol, 1.05equiv) in 10mL
dry THF was added sodium hydride (60% dispersion in mineral oil, 146mg, 3.65mmol,
1.00equiv) at 0C. After stirring for 20min, a solution of oxetan3one (33, 263mg,
3.65mmol, 1.00equiv) in 1mL dry THF was added and the solution stirred at 0C for
30min.Thesolventwaspartiallyconcentratedinvacuo,toluenewasaddedandthemix
ture put on a column (SiO2, 20/1 to 4/1 cyclohexane/EtOAc) to give 1[1(4Chloro
phenyl)cyclobutyl]2oxetan3ylideneethanone(94)asacolorlessoil.Thismaterialwas
dissolvedin10mLMeOHandaddedover20mintoasuspensionofRh/C(5w%,70mg)in
60mL MeOH under hydrogen. Stirring was continued for 20min, when a sample in the
NMRindicatedfullconversion.ThemixturewasfilteredthroughaplugofCelite,thefil
trateconcentratedinvacuoandtheresiduepurifiedbyflashchromatography(SiO2,8/1
to2/1cyclohexane/EtOAc)togive0.56gofthepureketone(58%yield)asacolorlessoil
1
(Rf=0.35(SiO2:cyclohexane/EtOAc2:1); HNMR(300MHz,CDCl3):7.33(d,2H,J=8.5
Hz),7.15(d,2H,J=8.5Hz),4.76(dd,2H,J=6.2Hz,J=7.8Hz),4.13(t,2H,J=6.3Hz),3.21
(m,1H),2.72(m,2H),2.64(d,2H,J=7.6Hz),2.38(ddd,2H,J=5.5Hz,J=9.7Hz,J=9.0
13
Hz), 1.88 (m, 2H); C NMR (75MHz, CDCl3): 208.4, 141.1, 132.7, 129.0, 128.8, 127.6,
127.5,77.1,58.2,40.3,30.9,30.6,16.0;HRMS(EI)calcd.forC13H117ClO2:[M]+=264.0912.
Found:264.0914.).Partsofthismaterial(365mg,1.38mmol,1.00equiv)weredissolved
in10mL iPrOHandNaBH4(52mg,1.4mmol,1.0equiv)wasaddedat0C.Afterstirring
ExperimentalSection
213
for20min,themixturewasallowedtowarmtoroomtemperatureandstirredovernight.
The mixture was partitioned between brine and Et2O and the aqueous phase extracted
threetimeswithEt2O.Thecombinedorganicphaseswerewashedoncewithbrine,dried
overMgSO4,filtered,concentratedinvacuoandtheresiduepurifiedbyflashchromato
graphy(SiO2,4/1to1/1cyclohexane/EtOAc)togive300mgpureproductasacolorlessoil
(82%yield).
1
Rf=0.11 (SiO2: cyclohexane/EtOAc 2:1); H NMR (300MHz, CDCl3): 7.29 (d, 2H, J =
8.5Hz),7.09(d,2H,J=8.5Hz),4.75(ddd,2H,J=6.0Hz,J=7.9Hz,J=10.2Hz),4.33(dt,
2H,J=3.6Hz,J=6.2Hz),3.66(dd,1H,J=5.3Hz,J=10.0Hz),3.15(m,1H),2.31(m,4H),
13
1.92 (m, 3H), 1.32 (d, 1H, J = 6.7 Hz), 1.21 (m, 1H); C NMR (75MHz, CDCl3): 143.8,
131.8, 128.3, 127.9, 77.9, 75.7, 50.5, 35.6, 33.1, 30.6, 30.4, 15.6; IR (thin film) 3414,
1
2937,2058,1492,1395,1294,1092,1012,970,826cm ;Anal.calcd.forC13H12ClNO:C,
66.81;H,5.18;N,5.99;Cl,15.17.Found:C,66.77;H,5.19;N,5.96;Cl,14.98;HRMS(EI)
calcd.forC15H19ClO2:[M]+=266.1074.Found:266.1035.
3[2Azido2[1(4chlorophenyl)cyclobutyl]ethyl]oxetane:370Toasolutionofalcohol
160 (490mg, 1.84mmol, 1.00equiv), PPh3 (600mg, 2.28mmol, 1.24equiv) and DEAD
(367 L, 2.33mmol, 1.26equiv) in 30mL dry THF was added DPPA (500 L, 2.33mmol,
1.26equiv)at0Cover15min.Themixturewasallowedtowarmtoroomtemperature
and stirred over night, before PPh3 (600mg, 2.28mmol, 1.24equiv), DEAD (367 L,
2.33mmol, 1.26equiv) and DPPA (500 L, 2.33mmol, 1.26equiv) were added consecu
tivelytodrivethereactiontocompletion.Afterstirringforfurther20h,thesolventwas
2/1cyclohexane/EtOAc)togive306mgpureproduct(57%yield)asayellowishoil.
370
Procedureadaptedfrom:A.Miyadera,K.Satoh,A.Imura,Chem.Pharm.Bull.2000,48,563.
214
ExperimentalSection
8.5Hz),7.14(d,2H,J=8.5Hz),4.78(m,2H),4.33(dt,2H,J=1.1Hz,J=6.2Hz),3.44(dd,
1H,J=2.3Hz,J=11.1Hz),3.09(m,1H),2.43(m,3H),2.28(m,1H),2.04(m,1H),1.85(m,
13
2H),1.37(m,1H); CNMR(75MHz,CDCl3):142.9,132.1,128.5,127.9,77.2,76.7,69.0,
50.5, 33.5, 33.1, 31.7, 31.2, 15.7; IR (thin film) 2961, 2867, 2182, 1492, 1255, 1093,
1
1012,978,829cm .
1(4Bromophenyl)cyclobutanecarbonitrile:369 To a mixture of powdered KOH

(13.3g, 237mmol, 4.31equiv) and DMSO (42mL) was added a solution of 4
bromophenylacetonitrile (10.8g, 55.0mmol, 1.00equiv) and 1,3dibromopropane
(5.78mL,57mmol,1.04equiv)in15mLEt2Oinawaysothattheinnertemperatureof
theflaskdidnotexceed10C(icecooling).Aftertheadditionwasfinished,themixture
was allowed to warm to room temperature and stirred for 1.5h. The reaction was
quenched by addition of ice water (30mL) to the precooled mixture, followed by Et2O
(35mL).ThemixturewasthenfilteredthroughCeliteandtheaqueousphaseofthefil
trateextractedtwicewithEt2O.Thecombinedorganicphaseswerewashedthreetimes
withwater,driedoverMgSO4,filtered,concentratedinvacuoandtheresiduedistilledto
give5.94gpureproduct(46%yield)asaslightlyyellowishoil.
1
13
8.7Hz),7.29(d,1H,J=8.6Hz),2.82(m,1H),2.59(m,1H),2.43(m,1H),2.07(m,1H); C
NMR(75MHz,CDCl3):138.7,131.9,127.3,123.8,121.8,39.8,34.7,17.1;IR(thinfilm)
1
2951,2234,1590,1488,1398,1074,1009,820cm ;Anal.calcd.forC11H10BrN:C,55.96;
H,4.27,N,5.93.Found:C,56.18;H,4.25,N,5.76.;HRMS(EI)calcd.forC11H10BrN:[M]+=
234.9991.Found:234.9993.
ExperimentalSection
215
[1[1(4Bromophenyl)cyclobutyl]3methylbutyl]dimethylamine:369To a mixture
of dry Et2O (7mL) and Grignard turnings (0.49g, 20mmol, 2.0equiv) was added slowly
isobutyl bromide (2.2mL, 20mmol, 2.0equiv) maintaining slight reflux of the solution.
Themixturewasstirredat40Cfor1h,beforeasolutionofnitrile227(2.3g,10mmol,
1.0equiv)in7mLdrytoluenewasaddeddropwise.Et2Owasdistilledoutofthereaction
mixtureatthesamerateasthesolutionwasadded(bathtemperatureadjustedto102C
duringtheaddition).Whenthetemperatureofthemixturereached90C,thedistillation
was stopped and stirring at 90C continued for 8h. Then, a slurry of NaBH4 (1.5g,
40mmol,4.0equiv)in12mL iPrOHwasaddedcautiously.Themixturewasrefluxedfor
20h,beforeitwasallowedtocooltoroomtemperature.Waterwasaddedandafterstir
ringfor30min,theaqueousphasewasextractedthreetimeswithEtOAc.Thecombined
organicphaseswereconcentratedinvacuoanddissolvedin60mLMeCN,beforeformal
dehyde (37w%, aqueous solution, 4.1mL, 50mmol, 5.0equiv) was added. The mixture
wasstirredfor15min,NaCNBH3(1.3g,20mmol,2.0equiv)wasadded,stirringwascon
tinuedforanother15min.AcOH(3.0mL)wasaddedandthemixturewasstirredfor2h.
200mLCH2Cl2wereaddedandthemixturewashedtwicewith1 M aqueousNaOH.The
organic phase was dried over MgSO4, filtered, concentrated in vacuo and the residue
treatedwith3M aqueousHCl.TheaqueousphasewaswashedtwicewithEt2O,basified
and extracted three times with Et2O. The combined organic phases were dried over
MgSO4,filtered,concentratedinvacuoandtheresiduepurifiedbyvacuumdistillationto
give2.43gpureproduct(82%yield)asacolorlessoilthatsolidifiedinthefreezer(mp=
6364C).
1
8.6Hz),7.10(d,1H,J=8.5Hz),2.90(dd,1H,J=2.8Hz,J=10.7Hz),2.45(m,1H),2.28(m,
1H),2.17(s,1H),2.09(m,1H),1.94(m,1H),1.76(ttd,1H,J=5.6Hz,J=9.3Hz,J=11.3
Hz),1.54(dtdd,1H,J=3.3Hz,J=6.6Hz,J=9.9Hz,J=13.1Hz),1.21(ddd,1H,J=3.3Hz,J
13
=10.7Hz,J=14.1Hz),1.06(m,1H),0.97(d,1H,J=6.5Hz),0.88(d,1H,J=6.6Hz); C
216
ExperimentalSection
NMR(75MHz,CDCl3):146.6,130.0,129.5,119.0,67.4,51.7,44.1,36.2,33.2,33.0,26.2,
24.2, 21.5, 15.7; IR (thin film) 2955, 2866, 2822, 1898, 1589, 1487, 14671392, 1367,
1
1278,1110,1074,1010,820,741cm ;Anal.calcd.forC17H26BrN:C,62.96;H,8.08;N,
4.32.Found:C,63.17;H,8.12;N,4.44;HRMS(EI)calcd.forC17H26BrN:[M]+=322.1165.
Found:3223.1163.
Fortheanalyticaldataof3hydroxyoxetane71,seepage187.
Fortheanalyticaldataof3fluorooxetane74,seepage188.
6.7 PreparationofAnalogues
6.7.1 MethyleneAnalogues
1(1(4(3fluorooxetan3yl)phenyl)cyclobutyl)N,N,3trimethylbutan1amine: To a
suspensionofthehydrobromidesaltof(3(dimethylamino)propyl)triphenylphosphonium
bromide353(3.8g,7.5mmol,1.0equiv)in100mLdryTHFwasadded nBuLi(1.6 Minhex
anes,9.9mL,15mmol,2.0equiv)at0C.Afterstirringfor40minat0C,asolutionofp
t
Bubenzaldehyde(1.2g,7.5mmol,1.0equiv)in5mLdryTHFwasaddedslowly.Themix
turewasstirredat60Covernight,cooledto0C;waterwasadded,followedbyconcen
tratedaqueousHCl.TheclearyellowishsolutionwasfreedfromTHFbyevaporationand
washed twice with 50mL toluene. The aqueous phase was extracted five times with
40mLchloroform.Thecombinedchloroformphasesweredriedovermagnesiumsulfate,
evaporatedandtheresiduedissolvedin100mLmethanol.Afteradditionof60mgPd/C
(10w%),hydrogenwasbubbledthroughthesolutionfor45minandthemixturevigorous
lystirredfor24h.Themixturewasfilteredthroughapadofcelite,thefiltrateevaporated
andtheresiduetakenupin~25mLwater.Diethylether(50mL)wasadded,followedby
excesssodiumhydroxide(cooling)tofreetheamine.Theaqueousphasewasextracted3
timeswithdiethylether,thecombinedorganicphasesweredriedovermagnesiumsul
fate,filtered,thefiltrateevaporatedandtheresiduedistilledtogive1.044g(60%)pure
productasacolorlessoil.
ExperimentalSection
217
HNMR(300MHz,CDCl3)=7.30(d,2H,J=8.3Hz),7.13(d,2H,J=8.2Hz),2.61(m,2H),
2.27(m,2H),2.22(s,6H),1.56(m,4H),1.32(s,9H); 13CNMR(75MHz,CDCl3)=148.3,
139.3, 127.9, 125.0, 59.7, 45.5, 35.2, 34.2, 31.3, 29.2, 27.5; IR (thin film) 2939, 2858,
1
2813,2762,1515,1461,1392,1363,1268,1042,828,570cm ;Anal.calcdforC16H27N:C,
82.34;H,11.66;N,6.00.Found:C,82.27;H,11.63.;N,5.95;HRMS(EI)calcdforC16H27N:
[M]+=233.2139.Found233.2139.
197
1(benzo[d][1,3]dioxol5ylmethyl)piperidine:371
Piperidine
(0.99mL,
10mmol,
1.0equiv)andpiperonylchloride(1.7g,10mmol,1.0equiv)weredissolvedin20mLDMF
and stirred overnight at room temperature. Brine was added and Et2O. The aqueous
phase was extracted two times with Et2O. The combined organic phases were washed
withbrine5times,driedoverMgSO4,filtered,concentratedinvacuoandtheresiduedis
tilled(Kugelrohr)togive1.64gpureproductasacolorlessoil(75%yield).
Rf=0.84(Al2O3,2/1cyclohexane/EtOAc);1HNMR(300MHz,CDCl3)=6.886.82(m,
1H),6.73(d,J=1.0Hz,2H),5.93(s,2H),3.37(s,2H),2.35(s,4H),1.631.49(m,4H),1.49
1.37 (m, 2H); 13C NMR (75 MHz, CDCl3) = 147.4, 146.2, 132.5, 122.1, 109.5, 107.7,
100.8, 63.6, 54.4, 26.1, 24.5; IR (thin film) 2934, 2853, 2800, 2760, 1700, 1609, 1503,
1
1489,1442,1394,1370,1240,1104,1039,995,933,868,808,780cm ;Anal.calcdfor
C13H17NO2:[M]+=219.1254.Found:219.1254.
371
K.Hejno,Z.Arnold,Chem.Listy1953,47,601.
218
ExperimentalSection
198
1(benzo[d][1,3]dioxol5ylmethyl)pyrrolidine: To a solution of pyrrolidine (0.80mL,

10mmol, 1.0equiv) and piperonal (1.5g, 10mmol, 1.0equiv) in 20mL dry CH2Cl2 was
added NaBH(OAc)3 (5.3g, 25mmol, 2.5equiv) at room temperature and stirred over
night.SaturatedaqueousK2CO3wasaddeduntilcompletesolvationofboratebyproducts
occurred. The aqueous phase was extracted three times with EtOAc. The combined or
ganicphasesweredriedoverMgSO4,filtered,concentratedinvacuoandtheresiduedis
tilled(Kugelrohr)togive1.50gpureproduct(73%yield)asacolorlessoil.
Rf=0.63(Al2O3,2/1cyclohexane/EtOAc); 1HNMR(300MHz,CDCl3)=6.85(dd,J=
0.5Hz,1.4Hz,1H),6.806.69(m,2H),5.93(s,2H),3.51(s,2H),2.552.38(m,4H),1.78
(dd,J=3.4Hz,7.0,4H); 13CNMR(75MHz,CDCl3)=147.4,146.2,133.3,121.8,109.3,
107.8,100.8,60.5,54.1,23.5;IR(thinfilm)2964,2784,1502,1489,1441,1247,1040,
1
937, 810cm ;Anal.calcdforC12H15NO2:C,70.22;H,7.37;N,6.82.Found:C,69.99;H,

7.45;N,6.82;HRMS(EI)calcdforC12H15NO2:[MH]+=204.1019.Found:204.1018.
199
1(benzo[d][1,3]dioxol5ylmethyl)azetidine: To a solution of azetidine (0.52mL,

7.7mmol,1.1equiv)andpiperonal(1.1g,7.0mmol,1.0equiv)in30mLCH2Cl2wasadded
NaBH(OAc)3(3.7g,18mmol,2.5equiv)atroomtemperatureandstirredovernight.Satu
rated aqueous K2CO3 was added until complete solvation of borate byproducts. The
ExperimentalSection
219
aqueousphasewasextractedthreetimeswithEtOAc.Thecombinedorganicphaseswere
driedoverMgSO4,filtered,concentratedinvacuoandtheresiduepurifiedbyflashchro
matography(SiO2,EtOActo10%MeOHinCH2Cl2)togive1.06gpureproduct(79%yield)
asacolorlessoil.
HNMR(300MHz,CDCl3)=6.76(dd,J=0.4Hz,1.0Hz,1H),6.746.65(m,2H),5.89
(d,J=0.4Hz,2H),3.44(s,2H),3.16(t,J=7.0Hz,4H),2.05(p,J=7.0Hz,2H);13CNMR(75
MHz,CDCl3)=147.4,146.3,132.1,121.4,108.9,107.9,100.7,63.6,54.9,17.7;IR(thin
film)2958,2820,1503,1499,1375,1301,1249,1176,1114,1040,938,864,811,773
1
cm ; Anal. calcd for C11H13NO2: C, 69.09; H, 6.85; N, 7.32. Found: C, 68.80; H, 6.76; N,
7.25;HRMS(EI)calcdforC11H13NO2:[M]+=191.0946.Found:191.0941.
6.7.2 GemdimethylAnalogues
6.7.2.1 OpenChainScaffold
[4(4tertButylphenyl)4methylpentyl]dimethylamine:
To
tertbutylbenzene
(5.8mL,38mmol,5.0equiv)wasaddedsulfuricacid(80L,1.5mmol,0.2equiv)followed
by 5bromo2methylpent2ene (1.0mL, 7.5mmol, 1.0equiv) at 0C. The mixture was
then allowed to warm to room temperature, stirred overnight and poured on ice. The
aqueousphasewasextractedthreetimeswithEt2O,thecombinedorganicphaseswere
washed once with brine, dried over MgSO4, filtered and concentrated in vacuo. The re
sulting mixture was dissolved in EtOH, Me2NH2Cl (5.0g, 61mmol, 8.2equiv) and K2CO3
(8.3g,60mmol,8.0equiv)wereaddedandthemixtureheatedat50Cfor2d.Thesol
ventwasconcentratedinvacuoandtheresiduepartitionedbetween1M aqueousNaOH
andEt2O.TheaqueousphasewasextractedthreetimeswithEt2O.Thecombinedorganic
220
ExperimentalSection
phasesweredriedoverMgSO4,filtered,concentratedinvacuoandtheresiduepurified
byflashchromatography(SiO2,10%MeOHinCH2Cl2,0.1%NEt3)togivepureproductto
getherwithSiO2.Thismaterialwasthendistilledtogive0.29gpureproduct(13%yield)
asacolorlessoil.
Rf=0.37(SiO2,10%MeOHinCH2Cl2,0.1%NEt3); 1HNMR(300MHz,CDCl3)=7.27(m,
4H),2.21(m,8H),1.60(m,2H),1.27(m,17H);13CNMR(75MHz,CDCl3)=148.0,146.4,
125.5, 125.0, 60.5, 45.6, 42.3, 37.2, 34.3, 31.5, 29.0, 23.2; IR (thin film) 2963, 2762,
1513,1464,1362,1272,1122,1042,831cm1;Anal.calcdforC18H31N:C,82.69;H,11.95;
N,5.36.Found:C,82.64;H,11.97;N,5.43.;HRMS(EI)calcdforC18H31N:[M]+=261.2452.
Found:261.2453.
[4(4tertButylphenyl)3,3dimethylbutyl]dimethylamine: To a suspension of
Grignard turnings (0.63g, 26mmol, 1.3equiv) in 30mL dry Et2O was added 4(tert
butyl)benzyl bromide (5.5mL, 21mmol, 1.0equiv) in 24mL dry Et2O over 30min. After
stirringfor30min,asolutionofdiethyl2(propan2ylidene)malonate(4.0mL,20mmol,
1.0equiv) in 20mL dry Et2O was added over 2h. The mixture was poured on ice, the
aqueousphaseextractedthreetimeswithEt2O,thecombinedorganicphasesdriedover
(SiO2, cyclohexane to 20/1 cyclohexane/EtOAc) to give 5.41g pure diethyl 2(1(4tert
butylphenyl)2methylpropan2yl)malonate. Parts of this material (2.95g, 8.47mmol,
1.00equiv) were dissolved in 20mL DMSO, water (228 L, 12.7mmol, 1.50equiv) and
NaBr(958mg,9.32equiv,1.10equiv)wereaddedandthemixtureheatedto190Cfor
20h. The mixture was cooled to room temperature and five times extracted with Et2O.
The combined organic phases were washed three times with brine, dried over MgSO4,
filtered, concentrated in vacuo and the residue purified by flash chromatography (SiO2,
20/1to4/1cyclohexane/EtOAc).Theproductcontainingfractionswereconcentratedin
vacuo and the residue distilled to give 0.93g ethyl 4(4tertbutylphenyl)3,3
ExperimentalSection
221
dimethylbutanoateina3/1togetherwithstartingmaterial.Thismixturewasusedwith
outfurtherpurificationanddissolvedin20mLdryEt2O.TothismixturewasaddedLiAlH4
(4.0 M solution in Et2O, 2.5mL, 10mmol, 2.9equiv) at 0C. After the addition was fi
nished, the mixture was allowed to warm to room temperature and stirred for 1.5h.
Na2SO410H2Owasslowlyaddedandafterstirringfor30min,themixturewasfiltered.
ThefiltercakewasboiledthreetimeswithEtOAcandthecombinedfiltratesdriedover
(SiO2, 4/1 to 1/1 cyclohexane/EtOAc) to give 0.48g pure 4(4tertbutylphenyl)3,3
dimethylbutan1ol as a colorless oil (20% yield, 3 steps). Parts of this material (0.47g,
2.0mmol,1.0equiv)weredissolvedin20mLCH2Cl2,NEt3(0.36mL,2.6mmol,1.3equiv)
wasaddedandthesolutioncooledto0C.MsCl(0.17mL,2.2mmol,1.1equiv)wasadd
edandthemixturestirredfor1h,beforeitwasconcentratedinvacuoandtakenupin
Et2O.Thesolutionwaswashedoncewithwaterandoncewithbrine.Theorganicphase
was dried over MgSO4, filtered, concentrated in vacuo and the residue dissolved in
Me2NH (2.0 M in THF, 5.0mL, 10mmol, 5.0equiv). The mixture was stirred for 20 h at
50C, before the solvent was concentrated in vacuo. The residue was partitioned be
tweenEtOAcand1M aqueousNaOH.Theaqueousphasewasextractedthreetimeswith
EtOAc, the combined organic phases dried over MgSO4, filtered, concentrated in vacuo
andtheresiduepurifiedbyflashchromatography(nAl2O3,cyclohexaneto8/1cyclohex
ane/EtOAc)togive0.18gpureproduct(34%yield)asacolorlessoil.
Rf=0.88(Al2O3,2/1cyclohexane/EtOAc);1HNMR(300MHz,CDCl3)=7.27(d,2H,J=
8.2Hz),7.05(d,2H,J=8.2Hz),2.48(s,2H),2.31(m,2H),2.23(s,6H),1.42(m,2H),1.31
(s,9H),0.88(s,6H); 13CNMR(75MHz,CDCl3)=148.3,135.7,130.1,124.4,55.4,48.3,
45.8, 39.6, 34.3, 33.6, 31.4, 26.9; IR (thin film) 2962, 2867, 2814, 2762, 1512, 1463,
1364, 1269, 1203, 1110, 1023, 837 cm1; Anal. calcd for C18H31N: C, 82.69; H, 11.95; N,
5.36. Found: C, 82.47; H, 11.99 N, 5.34; HRMS (EI) calcd for C18H31N: [M]+ = 261.2452.
Found:261.2448.
222
ExperimentalSection
[4(4tertButylphenyl)2,2dimethylbutyl]dimethylamine: To a suspension of 4
(tertbutylbenzyl)triphenylphosphoniumbromide(2.2g,3.9mmol,1.0equiv)in20mLdry
THFwasadded nBuLi(2.5M inhexanes,2.4mL,3.9mmol,1.0equiv)at0Cover15min.
The red solution was stirred for 20min, before a solution of 3(dimethylamino)2,2
dimethylpropanal372(0.5g,3.9mmol,1.0equiv)in5mLdryTHFwasadded.Themixture
was stirred for 10 h at room temperature, before 1 M aqueous HCl was added and the
organicsolventconcentratedinvacuo.Theaqueousresiduewaswashedthreetimeswith
toluene,basifiedandthenextractedthreetimeswithEt2O.Thecombinedetherealphas
es were dried over MgSO4, filtered, concentrated in vacuo and the residue dissolved in
20mLMeOH.Pd/C(10w%,0.13g)wereaddedandtheatmosphereexchangedwithhy
drogen.Themixturewasstirredfor16h,filteredthroughCelite,thefiltrateconcentrated
invacuoandtheresiduepurifiedbyflashchromatography(nAl2O3,cyclohexaneto20/1
cyclohexanetoEtOAc)togive0.32gpureproduct(32%yield)asayellowishoil.
Rf=0.88(Al2O3,2/1cyclohexane/EtOAc);1HNMR(300MHz,CDCl3)=7.31(d,2H,J=
8.3Hz),7.14(d,2H,J=8.2Hz),2.54(m,2H),2.32(s,2H),2.14(s,6H),1.55(m,2H),1.32
(s,9H),0.95(s,6H); 13CNMR(75MHz,CDCl3)=148.4,140.6,128.1,125.3,71.0,49.1,
42.8, 35.7, 34.5, 31.6, 30.2, 25.7; IR (thin film) 2962, 2866, 2817, 2765, 1896, 1788,
1516,1455,1363,1268,1150,1109,1045,832,814cm1;Anal.calcdforC18H31N:C,82.69
;H,11.95;N,5.36.Found:C,82.43;H,11.84N,5.41;HRMS(EI)calcdforC18H31N:[M]+=
261.2452.Found:261.2453.
4(4tertbutylphenyl)N,Ndimethylbutanamide: To a suspension of AlCl3 (29.3g,

220mmol,2.20equiv)in300mLdryCH2Cl2at0Cwasaddedsuccinicanhydride(11.0g,
110mmol, 1.10equiv) and the mixture was allowed to warm to room temperature. A
solution of tertbutylbenzene (15.4mL, 100mmol, 1.00equiv) in 50mL dry CH2Cl2 was
added dropwise and the mixture stirred for 9 h at room temperature. The mixture was
372
Preparedaccordingto:M.S.Newman,A.Tye,W.J.J.Broger,J.B.Lapidus,J.Med.Chem.1972,15,1003.
ExperimentalSection
223
slowlypouredonamixtureoficeandconcentratedaqueousHCl.Theaqueousphasewas
extractedtwicewithCH2Cl2,thecombinedorganicphaseswashedtwicewithbrine,dried
overMgSO4,filtered,concentratedinvacuoandtheresiduerecrystallizedfromtoluene.
The crude material was washed with cold toluene, dried under highvacuum and dis
solvedin200mLAcOH.Pd/C(10w%,250mg)wasaddedandtheatmosphereexchanged
withhydrogen.Themixturewasstirredfor10h,beforeitwasfilteredthroughaplugof
Celite.Thefiltratewasconcentratedinvacuoandwaterwasaddedtotheresidue,caus
ing precipitation of pure 4(4tertbutylphenyl)butanoic acid (16.4g, 75% yield over 2
steps). Parts of this material (15g, 68mmol, 1.0equiv) were dissolved in 200mL Et2O,
beforeoxalylchloride(7.1mL,81mmol,1.2equiv)wasadded,followedbythreedropsof
DMF.Afterstirringfor2hatroomtemperature,themixturewasconcentratedinvacuo,
Et2Owasaddedandthesolutioncooledto0C.AqueousMe2NH(7.8M,35mL,0.27mol,
4.0equiv)wasaddedandthemixturestirredatroomtemperaturefor1h.Et2Owasadd
edandtheaqueousphaseextractedthreetimeswithEt2O.Thecombinedorganicphases
were dried over MgSO4, filtered, concentrated in vacuo and the residue distilled
(bp~230Cat0.3mbar)togive14.964gpureproduct(88%yield)asayellowishoil(Rf=
0.13(SiO2,2/1cyclohexane/EtOAc);1HNMR(300MHz,CDCl3)=7.30(d,2H,J=8.3Hz),
7.13(d,2H,J=8.2Hz),2.95(s,3H),2.94(s,3H),2.65(t,2H,J=7.6Hz),2.33(m,2H),1.98
(m,2H),1.31(s,9H); 13CNMR(75MHz,CDCl3)=148.4,138.6,128.0,125.1,37.3,35.4,
34.9,34.4,32.7,31.5,26.6;IR(thinfilm)2953,1651,1462,1397,1268,1135,834cm1;
HRMS(EI)calcdforC16H25NO:[M]+=247.1931.Found:247.1930)
[4(4tertButylphenyl)1,1dimethylbutyl]dimethylamine:373 To a solution of
amide228(4.9g,20mmol,1.0equiv)in40mLdryTHFwasaddedZrCl4(4.7g,20mmol,
1.0equiv)intwoportionsat10C.Afterstirringfor30min,asolutionofMeMgBr(3.0M
inEt2O,40mL,0.12mol,6.0equiv)wasaddedinawaythattheinnertemperaturedid
373
Preparedadoptingaprocedure:S.M.Denton,A.Wood,Synlett1999,55.
224
ExperimentalSection
not rise above 0C. The mixture was allowed to warm to room temperature over the
course of 4 h and was quenched by cautious addition of 30w% aqueous NaOH. The
aqueousphasewasextractedthreetimeswithEt2O,thecombinedorganicphasescon
centratedinvacuoandtheresiduetreatedwith1MaqueousHCl.Theaqueousphasewas
washedthreetimeswithEtOAc,basifiedandextractedthreetimeswithEt2O.Thecom
bined ethereal phases were dried over MgSO4, filtered, concentrated in vacuo and the
residuedistilledtogive1.01gpureproduct(19%yield)asacolorlessoil.
1
HNMR(300MHz,CDCl3)=7.30(d,2H,J=8.2Hz),7.13(d,2H,J=8.2Hz),2.57(t,
2H,J=7.7Hz),2.20(s,6H),1.64(ddd,2H,J=6.1Hz,J=10.0Hz,J=11.3Hz),1.43(m,2H),
1.31(s,9H),1.22(t,2H,J=7.1Hz),0.99(s,6H);13CNMR(75MHz,CDCl3)=148.5,139.7,
128.1, 125.2, 55.7, 39.4, 38.6, 36.2, 34.5, 31.6, 26.0, 22.6; IR (thin film) 2963, 2818,
2777,1899,1789,1721,1661,1513,1462,1362,1268,1046,974,831cm1;Anal.calcd
forC18H31N:C,82.69;H,11.95;N,5.36.Found:C,82.53;H,12.01N,5.20;HRMS(EI)calcd
forC18H31N:[MCH3]+=246.2217.Found:246.2217.
6.7.2.2 CyclicScaffolds
190
1(benzo[d][1,3]dioxol5ylmethyl)3,3dimethylazetidine: To a solution of 3chloro

2,2dimethylpropanal374 (3.5g, 29mmol, 1.0equiv) in 30mL dry Et2O was added
MgSO40.5 H2O (3.0 g), followed by piperonylamine (3.7mL, 30mmol, 1.0equiv). After
stirringfor4h,asampleintheNMRindicatedfullconversion.Themixturewasfiltered,
thefiltrateslowlyaddedtoasolutionofLiAlH4(6.0mLof4.0MsolutioninEt2O,30mmol,
1.0equiv) at room temperature. The mixture was then refluxed over night, cooled to
roomtemperature,beforeNa2SO410H2Owasslowlyadded.Afterstirringfor20min,the
solventwasdecantedoffandtheresiduerefluxedwithfivetimes20mLEtOAc.Thecom
binedorganicphasesweredriedoverMgSO4,filtered,concentratedinvacuoandthere
374
Preparedaccordingto:F.Effenberger,J.Eichhorn,J.Roos,Tetrahedron:Asymmetry1995,6,271.
ExperimentalSection
225
siduefilteredthroughacolumn(nAl2O3,4/1cyclohexane/EtOAc)togive3.8gpureprod
uct(58%yield)asacolorlessoil.
Rf = 0.74 (Al2O3, 2/1 cyclohexane/EtOAc); 1H NMR (300 MHz, CDCl3) = 6.80 (d, J =
0.5Hz, 1H), 6.77 6.67 (m, 2H), 5.92 (s, 2H), 3.50 (s, 2H), 2.95 (s, 4H), 1.21 (s, 6H). 13C
NMR(75MHz,CDCl3)=147.4,146.2,132.6,121.2,108.7,107.8,100.7,66.5,63.4,31.4,
27.4; IR (thin film) 2958, 2820, 1608, 1503, 1489, 1442, 1376, 1252, 1193, 1041, 937,
1
810, 776cm ;Anal.calcdforC13H17NO2:C,71.24;H,7.81;N,6.39.Found:C,71.07;H,

8.00; N, 6.392951, 2902, 2814, 1609, 1503, 1489, 1442, 1374, 1337, 1247, 1187,1159,
1115, 1094, 1041, 939, 886, 863, 811, 759; HRMS (EI) calcd for C13H17NO2: [M]+=
219.1254.Found:219.1252.
191
1(benzo[d][1,3]dioxol5ylmethyl)4,4dimethylpiperidine: To a solution of 4,4

dimethylpiperidine2,6dione (5.7g, 40mmol, 1.0equiv) in 45mL DMF was added KOH
(2.5g,44mmol,1.1equiv)at0C.Afterstirringfor30min,piperonylbromide377(9.1g,
42mmol,1.1equiv)wasaddedasasolutionin8mLDMF.Themixturewasthenstirredat
roomtemperaturefor5handthenpouredonwater.Theaqueousphasewasextracted
threetimeswithEt2Oandthecombinedorganicphaseswerewashedwith2M aqueous
NaOHtwice,oncewithwaterandoncewithsaturatedaqueousNH4Cl.Afterdryingover
MgSO4, filtration and evaporation, the residue was purified by flash chromatography
(SiO2,8/1to2/1cyclohexane/EtOAc)to3.9gpure1(benzo[d][1,3]dioxol5ylmethyl)4,4
dimethylpiperidine2,6dione(Rf=0.33(SiO2,2/1cyclohexane/EtOAc);1HNMR(300MHz,
CDCl3)=6.88(d,J=7.4Hz,2H),6.71(d,J=8.6Hz,1H),5.91(s,2H),4.85(s,2H),2.51(s,
13
4H), 1.04 (s, 6H). C NMR (75MHz, CDCl3) 171.7, 147.3, 146.7, 131.0, 122.6, 109.6,
108.0,100.9,46.5,42.5,29.3,27.8;IR(thinfilm)2959,2896,2779,1724, 1674, 1609,
226
ExperimentalSection
1504,1491,1446,1365,1344,1330,1249,1137,1101, 1038, 926, 891cm ;HRMS(EI)

+
calcdforC15H23NO2[M] ,275.1157.Found,275.1157)asawhitesolid(mp=7072C).Of
this material, 2.8g (10mmol, 1.0equiv) were dissolved in 100mL dry Et2O and slowly
addedtoasolutionofLiAlH4(1.2g,30mmol,3.0equiv)in100mLdryEt2Oat0C.The
mixturewasthenallowedtowarmtoroomtemperaturerefluxedfor12handcooledto
0C.Na2SO410H2Owasslowlyadded,themixturestirredfor20minatroomtempera
ture and filtered. The filter cake was boiled with 2 portions EtOAc for 30 seconds. The
combinedfiltratesweredriedoverNa2SO4,filtered,concentratedinvacuoandtheresi
duepurifiedbyKugelrohrdistillationtogive1.8gpureproductaswhitecrystals(mp=53
54C).
HNMR(300MHz,CDCl3)=6.85(s,1H),6.74(s,2H),5.92(s,2H),3.41(s,2H),2.44
13
2.23(m,4H),1.441.29(m,4H),0.91(s,6H); CNMR(75MHz,CDCl3)147.4,146.3,
132.6,122.1,109.5,107.7,100.7,63.3,50.0,38.8,28.6;IR(thinfilm)2948,2910,2838,
2805, 2765, 1609, 1502, 1489, 1442, 1369, 1331, 1295, 1241, 1207, 1182, 1128, 1105,
1
1042,989,940,865,810,799,776,715cm ;Anal.calcdforC15H21NO2:C,72.84;H,8.56;
+
N,5.66.Found:C,72.68;H,8.46;N,5.55;HRMS(EI)calcdforC15H21NO2[M] ,247.1567.
Found,247.1565
192
1(benzo[d][1,3]dioxol5ylmethyl)3,3dimethylpyrrolidine: A solution of 3,3

dimethyldihydrofuran2,5dione(1.0g,7.8mmol,1.0equiv)andpiperonylamine(1.0mL,
7.8mmol, 1.0equiv) in 30mL dry toluene were refluxed overnight using a DeanStark
trap.Aftercoolingtoroomtemperature,aqueousHCl(1 M)wasaddedandtheaqueous
phase extracted three times with EtOAc. The organic phases were washed with brine,
ExperimentalSection
227
filtered, concentrated in vacuo and the crude 1(benzo[d][1,3]dioxol5ylmethyl)3,3

dimethylpyrrolidine2,5dione(Rf=0.33(SiO2,2/1cyclohexane/EtOAc)usedwithoutfur
therpurification.Thismaterialwasdissolvedin90mLdryEt2Oandslowlyaddedat0C
to a solution of LiAlH4 (0.89g, 2.3mmol, 3.0equiv) in 45mL dry Et2O. The mixture was
then allowed to warm to room temperature refluxed for 12 h and cooled to 0C.
Na2SO410 H2O was slowly added, the mixture stirred for 20min at room temperature
and filtered. The filter cake was boiled with two portions of EtOAc for 30 seconds. The
duepurifiedbyKugelrohrdistillationtogive1.3gpureproductaswaxysolid(mp=33
35C).
HNMR(300MHz,CDCl3)=6.87(s,1H),6.806.67(m,2H),5.93(s,2H),3.49(s,2H),
13
2.59(t,J=7.0Hz,2H),2.27(s,2H),1.58(t,J=7.0Hz,2H),1.07(s,6H); CNMR(75MHz,
CDCl3)147.4,146.1,133.7,121.4,109.1,107.7,100.7,68.2,60.4,54.3,39.9,37.7,29.7;
IR(thinfilm)2952,2868,2783,1609,1503,1489,1442,1378,1346,1316,1245,1185,
1
1106,1041,940,864,810,776cm ;Anal.calcdforC14H19NO2:C,72.07;H,8.21;N,6.00.
+
Found:C,71.78;H,8.05;N,6.11;HRMS(EI)calcdforC14H19NO2[M] ,233.1411.Found,
233.1408
193
1(benzo[d][1,3]dioxol5ylmethyl)3,3dimethylpiperidine: To a solution of 3,3

dimethyldihydro2Hpyran2,6(3H)dione (2.8g, 20mmol, 1.0equiv) in 40mL THF was
addedpiperonylamine(3.3g,22mmol,1.1equiv)atroomtemperature.Themixturewas
stirred for 30min, before the solvent was concentrated in vacuo. The residue was dis
solvedinEtOAcand1M aqueousHClwasaddedandtheaqueousphaseextractedthree
times with EtOAc. The aqueous phase was washed once with brine, dried over MgSO4,
228
ExperimentalSection
filteredandconcentratedinvacuo.Theresiduewasdissolvedin20mLaceticanhydride
and3.5mLNEt3wasadded.Themixturewasheatedto80Candstirredfor1h.Thenthe
solventwasconcentratedinvacuo.TheresiduewasdissolvedinEtOAcand1M aqueous
HCl was added and the aqueous phase extracted three times with EtOAc. The aqueous
phasewaswashedoncewith1 M aqueousHCl,brineandsaturatedaqueoussodiumbi
carbonate,driedoverMgSO4,filtered,concentratedinvacuoandtheresiduepurifiedvia
chromatography (SiO2, 1/1 cyclohexane/EtOAc) to give 2.7g 90w% (NMR) pure 1
(benzo[d][1,3]dioxol5ylmethyl)3,3dimethylpiperidine2,6dione (49% yield) (1H NMR
(300MHz,CDCl3)=6.82(dd,J=1.7Hz,6.0,2H),6.69(d,J=8.4Hz,1H),5.90(s,2H),
4.82 (s, 2H), 2.71 (t, J = 6.8Hz, 2H), 1.78 (t, J = 6.8Hz, 2H), 1.25 (s, 6H); IR (thin film)
2969, 1805, 1765, 1722, 1674, 1504, 1491, 1446, 1690, 1355, 1325, 1282, 1247, 1164,
1038, 1017, 927, 885, 808, 778 cm1; HRMS (EI) calcd for C15H15NO4 [M]+, 275.1153.
Found,275.1155).Toasolutionof0.29gLiAlH4(7.7mmol,3.0equiv)in15mLdryEt2O
was added a solution 1(benzo[d][1,3]dioxol5ylmethyl)3,3dimethylpiperidine2,6
dionein30mLdryEt2Oslowlyat0C.Themixturewasthenallowedtowarmtoroom
temperature and refluxed for 2.5h. After cooling to room temperature, Na2SO410 H2O
wasslowlyadded,stirredfor20minandfiltered.Thefiltercakewasrefluxedoncewith
EtOAc, the combined filtrates concentrated in vacuo and the residue purified by flash
chromatography(SiO2,20/1to4/1cyclohexane/EtOAc)togive0.26gpureproductasa
slightlyyellowishoil(42%yield).
Rf = 0.50 (SiO2, 2/1 cyclohexane/EtOAc); 1H NMR (300 MHz, CDCl3) = 6.88 (s, 1H),
6.74 (d, J =0.8Hz, 2H), 5.94 (s, 2H), 3.33 (s, 2H), 2.29 (s, 2H), 1.98 (s, 2H), 1.58 (dt, J =
5.6Hz,11.1Hz,2H),1.261.14(m,2H),0.92(s,6H); 13CNMR(75MHz,CDCl3)147.4,
146.1, 133.4, 121.4, 108.9, 107.5, 100.6, 65.7, 62.9, 54.4, 37.5, 30.8, 27.2, 22.6; IR (thin
film)2974,2771,1608,1488,1441,1365,1240,1181,1107,1042,991,936,865,804,
774cm1;Anal.calcdforC15H21NO2:C,72.84;H,8.56;N,5.66.Found:C,72.97;H,8.46;N,
5.79;HRMS(EI)calcdforC15H21NO2[M]+,247.1567.Found,247.1567
ExperimentalSection
229
194
1(benzo[d][1,3]dioxol5ylmethyl)2,2dimethylazetidine: A mixture of ethyl 3

methylbut2enoate (4.1mL, 30mmol, 1.0equiv) and piperonylamine was stirred at
120Cfor6dinasealedvessel.Themixturewasthenseparatedbyflashchromatogra
phy(SiO2,CH2Cl2to6%MeOHinCH2Cl2)togive1.9gpureethyl3(benzo[d][1,3]dioxol5
ylmethylamino)3methylbutanoate in 23% yield (Rf = 0.19 (SiO2, EtOAc); 1H NMR (300
MHz,CDCl3)=6.916.84(m,1H),6.846.69(m,2H),5.955.87(m,2H),4.14(q,J=
7.1Hz,2H),3.62(s,2H),2.49(s,2H),1.71(s,1H),1.26(t,J=7.1Hz,3H),1.22(s,6H); 13C
NMR (75 MHz, CDCl3) = 171.8, 147.5, 146.2, 134.9, 121.1, 108.9, 108.0, 100.7, 60.0,
52.4, 46.6, 44.1, 27.5, 14.2; IR (thin film) 3410, 2972, 2901, 1726, 1490, 1442, 1368,
1
1327,1249,1098,1039,931,809cm ;HRMS(EI)calcdforC15H21NO4:[MH]+=278.1387.
Found:278.1388.).Thismaterial(1.9g,6.7mmol,1.0equiv)wasaddedslowlyasasolu
tionin10mLdryEt2OtoasolutionofLiAlH4(5.0mLofa4.0M solutioninEt2O,20mmol,
3.0equiv)in40mLdryEt2Oatroomtemperature.Afterstirringovernightatroomtem
perature, Na2SO410 H2O was slowly added. After stirring for 20min, the mixture was
filtered, the filter cake cooked with five times 20mL EtOAc for 30 seconds each. The
due (2.5g pure amino alcohol, Rf = 0.27 (Al2O3, 2/1 cyclohexane/EtOAc); 1H NMR (300
MHz,CDCl3)=6.78(s,1H),6.74(d,J=0.6Hz,2H),5.955.88(m,2H),3.923.81(m,
2H), 3.66 (s, 2H), 1.68 1.57 (m, 2H), 1.24 (s, 6H); 13C NMR (75 MHz,CDCl3) = 147.6,
146.6,133.7,121.2,108.8,108.1,100.8,60.5,54.2,46.3,40.1,26.8;IR(thinfilm)3298,
1
2965,1609,1490,1442,1367,1249,1039,928,809cm ;HRMS(EI)calcdforC13H19NO3:
[MCH3]+= 222.1125. Found: 222.1124.) dissolved without further purification in 100mL
dryMeCN.PPh3(4.1g,16mmol,2.3equiv)wasadded,followedundercooling(icebath)
by carbon tetrabromide (5.2g, 16mmol, 2.3mmol) and NEt3 (2.9mL, 21mmol,
3.1equiv). After stirring overnight, the NMR showed full conversion. The mixture was
230
ExperimentalSection
concentratedinvacuoandtheresiduedispersedinEt2O.Aqueous1M NaOH(60mL)was
added and the aqueous layer extracted three times with Et2O. The combined organic
phasesweredriedoverMgSO4,filtered,concentratedinvacuoandtheresiduepurified
by flash chromatography (SiO2, CH2Cl2 to 10% MeOH in CH2Cl2) to give 656mg pure
product(44%yield)asaslightlyyellowishoil.
Rf=0.11(SiO2,EtOAc); 1HNMR(300MHz,CDCl3)=6.886.80(m,1H),6.776.63
(m,2H),5.91(s,2H),3.44(s,2H),3.153.01(m,2H),1.941.77(m,2H),1.19(s,6H).13C
NMR(75MHz,CDCl3)=147.3,146.6,133.1,121.4,109.2,107.8,100.7,63.4,55.0,49.3,
31.9,25.0;IR(thinfilm)2958,2820,1608,1503,1489,1442,1376,1252,1193,1041,
1
937,810,776cm ;Anal.calcdforC13H17NO2:C,71.24;H,7.81;N,6.39.Found:C,71.04;
H,7.80;N,6.58;HRMS(EI)calcdforC13H17NO2:[M]+=219.1254.Found:219.1253.
195
1(benzo[d][1,3]dioxol5ylmethyl)2,2dimethylpyrrolidine: To a solution of 1
(benzo[d][1,3]dioxol5ylmethyl)pyrrolidin2one (210) (2.2g, 10mmol, 1.0equiv) in 20
dryTHFwasaddedZrCl4(2.3g,10mmol,1.0equiv)in2portionsat10C.Afterstirring
for30min,asolutionofMeMgBr(3.0 M inEt2O,20mL,60mmol,6.0equiv)wasadded
slowlyenoughnottoexceedatemperatureofthereactionmixtureof0C.Themixture
was stirred for 4 h and allowed to warm to room temperature. Aqueous NaOH (30w%)
was added slowly and the aqueous phase extracted three times with CH2Cl2. The com
sidue purified by flashchromatography (nAl2O3, 20/1 cyclohexane/EtOAc) to give 0.84g
pureproduct(36%yield)asayellowishsolid(mp=3334C).
ExperimentalSection
231
0.5Hz,1.4,1H),6.786.68(m,2H),5.92(s,2H),3.42(s,2H),2.60(ddd,J=2.7Hz,5.4,
13
6.0, 2H), 1.68 (d, J = 2.9Hz, 4H), 1.07 (s, 6H); C NMR (75MHz, CDCl3) 135.0, 121.2,
109.0,107.7,100.7,60.0,53.0,50.9,40.0,23.1,20.5;IR(thinfilm)2960,2795,1609,1489,
1
1441, 1381, 1360, 1242, 1180, 1094, 1041, 940, 865, 809, 776 cm ; Anal. calcd for
+
C14H19NO2[M] ,233.1410.Found,233.1411
196
1(benzo[d][1,3]dioxol5ylmethyl)2,2dimethylpiperidine: To a solution of 1
(benzo[d][1,3]dioxol5ylmethyl)piperidin2one (211) (2.3g, 10mmol, 1.0equiv) in 20
dryTHFwasaddedZrCl4(2.3g,10mmol,1.0equiv)in2portionsat10C.Afterstirring
for30min,asolutionofMeMgBr(3.0 M inEt2O,20mL,60mmol,6.0equiv)wasadded
slowlyenoughnottoexceedatemperatureofthereactionmixtureof0C.Themixture
wasstirredfor4handallowedtowarmtoroomtemperature.AqueousNaOH(30w%)
was added slowly and the aqueous phase extracted three times with CH2Cl2. The com
siduepurifiedbyflashchromatography(nAl2O3,cyclohexaneto4/1cyclohexane/EtOAc)
togive0.23gpureproduct(10%yield)asayellowishliquid.
0.5Hz,1.5Hz,1H),6.75(dd,J=4.3Hz,5.1Hz,1H),6.72(dd,J=0.5Hz,7.9Hz,1H),5.92
13
(s,2H),3.39(s,2H),2.382.22(m,2H),1.47(s,6H),1.10(s,6H); CNMR(75MHz,CDCl3)
147.4,145.9,135.6,121.1,108.8,107.6,100.7,53.8,53.3,47.0,40.7,26.8,21.4;IR(thin
232
ExperimentalSection
film) 2966, 2929, 2794, 1609, 1502, 1489, 1440, 1396, 1284, 1244, 1201, 1184, 1144,
1
1127,1093,1041,940,861,810,774cm ;Anal.calcdforC15H21NO2:C,72.84;H,8.56;N,
+
5.66. Found: C, 72.89; H, 8.61; N, 5.76; HRMS (EI) calcd for C15H21NO2 [M] , 247.1568.
Found,247.1567
6.7.3 CarbonylAnalogues
206
1(benzo[d][1,3]dioxol5ylmethyl)piperidin4one:375 4hydroxypiperidine (1.0g,

10mmol,1.0equiv)andpiperonylchloride(1.7g,10mmol,1.0equiv)weredissolvedin
20mLDMF andstirredovernightatroomtemperature.BrinewasaddedandEt2O.The
aqueous phase was extracted two times with Et2O. The combined organic phases were
washed with brine 5 times, dried over MgSO4, filtered, concentrated in vacuo and the
residue(~95%purebyNMR)usedwithoutfurtherpurification(Rf=0.61(Al2O3,2/1cyc
lohexane/EtOAc);1HNMR(300MHz,CDCl3)=6.85(s,1H),6.74(t,J=3.9Hz,2H),6.00
5.86(m,2H),3.773.57(m,1H),3.40(s,2H),2.73(d,J=11.7,2H),2.11(t,J=10.8,2H),
1.88 (dd, J = 4.0Hz, 12.8, 2H), 1.65 1.50 (m, 2H), 1.50 1.42 (m, 1H); IR (thin film)
1
3341,2939,2360,1490,1442,1367,1245,1096,1064,4040,933,810,778cm ;HRMS
(EI) calcd for C13H17NO3: [MH]+= 234.1125. Found: 234.1125). From this material 0.70g
(3.0mmol,1.0equiv)weredissolvedinmixture7mLdrybenzeneand3.5mLDMSO,fol
lowed by the addition of DCC (1.9g, 9.0mmol, 3.0equiv) and dry pyridine (0.24mL,
3.0mmol,1.0equiv).Aftercoolingto0C,TFA(0.11mL,3.0mmol,1.0equiv)wasadded
dropwiseandthemixturethenstirredovernight,allowingittowarmtoroomtempera
ture. EtOAc (50mL) was added and the mixture filtered. The filtrate was washed with
375
J.K.Lynch,C.A.Collins,J.C.Freeman,J.Gao,R.R.Iyengar,A.S.Judd,P.R.Kym,M.M.Mulhern,H.L.
Sham,A.J.Souers,G.Zhao,2005.
ExperimentalSection
233
brinethreetimes,driedoverMgSO4,filtered,concentratedinvacuoandtheresiduepuri
fiedbyflashchromatography(SiO2,2/1cyclohexane/EtOActoEtOAc)togive0.39gpure
productaswhitecrystallinesolid(mp=6569C).
6.77(d,J=0.9Hz,2H),5.96(s,2H),3.53(s,2H),2.73(t,J=6.1Hz,4H),2.45(t,J=6.2Hz,
13
4H); CNMR(75MHz,CDCl3)209.0,147.6,132.0,121.9,109.1,107.8,100.9,61.7,52.8,
41.4;IR(thinfilm)3323,2911,2808,1716,1623,1502,1489,1442,1368,1342,1244,
1
1195,1113,1085,1038,933,866,799,776cm ;Anal.calcdforC13H15NO3:C,66.94;H,
+
6.84; N, 6.00. Found: C, 66.94; H, 6.48; N, 6.00; HRMS (EI) calcd for C13H15NO3 [M] ,
233.1047.Found,233.1046
207
1(benzo[d][1,3]dioxol5ylmethyl)pyrrolidin3one:376 3hydroxypyrrolidine (0.30g,

3.5mmol, 1.0equiv), piperonyl chloride (0.59g, 3.5mmol, 1.0equiv) and K2CO3 (2.9g,
21mmol,6.0equiv)weredispergedin20mLDMFandstirredovernightatroomtemper
ature.BrinewasaddedandEt2O.TheaqueousphasewasextractedtwotimeswithEt2O.
The combined organic phases were washed with brine 5 times, dried over MgSO4, fil
tered, concentrated in vacuo and the residue purified by flash chromatography (Al2O3,
8/1to1/1cyclohexane/EtOAc)togivepure1(benzo[d][1,3]dioxol5ylmethyl)pyrrolidin
3ol(0.67g,88%yield).Thismaterial(0.67g,3.1mmol,1.0equiv)wasaddedat78Cto
asolutioncontainingDMSO(0.43mL,6.1mmol,2.0equiv)andoxalylchloride(0.39mL,
4.6mmol, 1.5equiv) in a way that the temperature of the mixture stays below 60C.
376
D.J.McCaustland,W.H.Burton,C.C.Cheng,J.Heterocycl.Chem.1971,8,89.
234
ExperimentalSection
Then,NEt3(1.3mL,9.2mmol,3.0equiv)wasaddeddropwiseandafterstirringfor2hat
78C,themixturewasallowedtowarmtoroomtemperature.Aqueous1M NaOHwas
addedandtheaqueousphaseextractedthreetimeswithCH2Cl2.Thecombinedorganic
phases were washed with brine, dried over K2CO3, filtered, and concentrated in vacuo.
Theresiduewaspurifiedbyflashchromatography(SiO2,4/1to2/1cyclohexane/EtOAc)
togive0.32gpureproduct(48%yield)asacolorlessoilthatdecomposesquicklywhen
storedatroomtemperature.
6.75(d,J=1.0Hz,2H),5.94(s,2H),3.61(s,2H),2.962.84(m,5H),2.40(t,J=6.9Hz,
13
2H); C NMR (75MHz, CDCl3) 206.9, 147.6, 146.7, 131.0, 121.7, 109.0, 107.9, 100.9,
61.5, 60.5, 51.2, 38.1; IR (thin film) 2909, 2800, 1756, 1608, 1502, 1490, 1443, 1383,
1
1330, 1246, 1187, 1132, 1106, 1038, 928, 874, 810cm ; Anal. calcd for C12H13NO3: C,
65.74;H,5.98;N,6.39.Found:C,65.60;H,6.13;N,6.36;HRMS(EI)calcdforC12H13NO3
+
[M] ,218.0890.Found,219.0888
208
1(benzo[d][1,3]dioxol5ylmethyl)piperidin3one:
3hydroxypiperidine
(3.0g,
30mmol, 1.0equiv), piperonyl chloride (5.1g, 30mmol, 1.0equiv) and K2CO3 (25g,
180mmol, 6.0equiv) were disperged in 20mL DMF and stirred overnight at room tem
perature. Brine was added and Et2O. The aqueous phase was extracted two times with
Et2O.Thecombinedorganicphaseswerewashedwithbrinefivetimes,driedoverMgSO4,
filtered,concentratedinvacuoandtheresiduepurifiedbyflashchromatography(nAl2O3,
8/1 to 1/1 cyclohexane/EtOAc) to give pure 1(benzo[d][1,3]dioxol5ylmethyl)piperidin
ExperimentalSection
235
3ol (4.4g, 91w% by NMR, rest DMF and EtOAc, yield 56%) as a white solid (mp = 57
58C; Rf = 0.14 (SiO2, 2/1 cyclohexane/EtOAc); IR (thin film) 3362, 2937, 2800, 1666,
1608, 1502, 1489, 1442, 1392, 1369, 1242, 1155, 1097, 1039, 973, 930, 885, 867, 810,
1
775cm ; HRMS (EI) calcd for C13H16NO3 [M] , 234.1125. Found, 234.1124). Of this ma
terial (0.50g, 2.1mmol, 1.0equiv) was added at 78 C to a solution containing DMSO
(0.30mL,4.2mmol,2.0equiv)andOxalylchloride(0.27mL,3.2mmol,1.5equiv)inaway
thatthetemperatureofthemixturestaysbelow60C.Then,NEt3(0.88mL,6.4mmol,
3.0equiv)wasaddeddropwise,andafterstirringfor2hat78C,themixturewasal
lowed to warm to room temperature. Aqueous 1 M NaOH was added and the aqueous
phaseextractedthreetimeswithCH2Cl2.Thecombinedorganicphaseswerewashedwith
brine,driedoverK2CO3,filtered,andconcentratedinvacuo.Theresiduewaspurifiedby
flash chromatography (SiO2, 8/1 to 2/1 cyclohexane/EtOAc) to give 0.21g pure product
(77%yield)asacolorlesscrystals(mp=5455C)thatdecomposequicklywhenstoredat
roomtemperature.
Rf=0.23(SiO2,2/1cyclohexane/EtOAc); 1HNMR(300MHz,CDCl3)=6.856.78(m,
1H),6.786.67(m,2H),5.92(s,2H),3.49(s,2H),2.98(s,2H),2.64(dd,J=4.1Hz,6.9,
13
2H),2.36(t,J=6.9Hz,2H),1.94(dt,J=6.9Hz,12.4Hz,2H); CNMR(75MHz,CDCl3)
206.9,147.6,146.7,130.9,122.1,109.2,107.8,100.8,64.3,62.1,51.3,38.6,23.8;IR(thin
1
film) 2928, 2803, 1714, 1605, 1483, 1441, 1245, 1124, 1038, 987, 933, 870, 808cm ;
Anal. calcd for C13H15NO3: C, 66.94; H, 6.48; N, 6.00. Found: C, 66.80; H, 6.47; N, 5.93;
+
HRMS(EI)calcdforC13H15NO3[M] ,233.1047.Found,233.1048
236
ExperimentalSection
209
1(benzo[d][1,3]dioxol5ylmethyl)azetidin2one: To a solution of piperonylamine

(1.6mL, 13mmol, 1.1equiv) and NEt3 (2.5mL, 18mmol, 1.5equiv) was added 3
bromopropanoylchloride(1.2mL,12mmol,1.0equiv).Themixturewasallowedtowarm
toroomtemperatureandstirredfor3h.Thereactionwasquenchedbyadditionofsatu
ratedaqueousNH4ClandtheaqueousphaseextractedthreetimeswithEtOAc.Thecom
bined organic phases were washed three times with brine, dried over MgSO4, filtered,
1/2 cyclohexane/EtOAc) to give 2.4g pure N(benzo[d][1,3]dioxol5ylmethyl)3
bromopropanamide(Rf=0.31(SiO2,2/1cyclohexane/EtOAc);1HNMR(300MHz,CDCl3)
=6.826.76(m,1H),6.74(t,J=1.0Hz,2H),5.94(s,2H),4.39(dd,J=5.7Hz,13.7Hz,2H),
3.66(t,J=6.6Hz,2H),2.77(t,J=6.6Hz,2H); 13CNMR(75MHz,CDCl3)=169.4,147.8,
147.0,131.5,121.1,108.3,108.2,101.0,43.5,39.7,27.4;IR(thinfilm)3267,3075,2899,
1
1634,1556,1503,1445,1420,1366,1261,1223,1190,1100,1037,926,872,812cm ;
+
HRMS(EI)calcdforC10H9NO3Br[M] =284.9995.Found,284.9998).Ofthismaterial,1.0g
(3.5mmol,1.0equiv)weredissolvedin45mLdryCH2Cl2.Thissolutionwasaddedover6
htoasuspensionoffinelypowderedKOH(0.23g,4.2mmol,1.2equiv)in45mLCH2Cl2.
Afterfiltrationandevaporationofthefiltrate,theresiduewaspurifiedbyflashchroma
tography(SiO2,4/1cyclohexane/EtOActoEtOAc)togive0.22gpureproduct(31%yield)
asacolorlessoil.
13
3H), 5.94 (s, 2H), 4.26 (s, 2H), 3.12 (t, J = 4.1Hz, 2H), 2.92 (t, J = 4.1Hz, 2H); C NMR
(75MHz,CDCl3)167.3,147.9,147.0,129.4,121.5,108.5,108.3,101.1,46.0,38.5,36.9;
IR(thinfilm)3477,2962,2904,1744,1608,1503,1491,1446,1404,1371,1296,1247,
ExperimentalSection
237
1190,1124,1098,1037,926,865,811,770,739,713cm ;Anal.calcdforC11H11NO3:C,
64.38;H,5.40;N,6.83.Found:C,64.09;H,5.41;N,6.79;HRMS(EI)calcdforC11H11NO3
+
[M] ,205.0733.Found,205.0733
210
1(benzo[d][1,3]dioxol5ylmethyl)pyrrolidin2one: To a solution of butyro lactam

(3.5mL,45mmol,1.0equiv)in50mLdryTHFwascautiouslyaddedsodiumhydride(60%
in mineral oil, 2.0g, 50mmol, 1.1equiv) at 0C. After stirring for 30min, a solution of
piperonylbromide377(9.7g,45mmol,1.0equiv)in10mLdryTHFwasslowlyaddedover
10min,themixtureallowedtowarmtoroomtemperatureandstirredovernight.Brine
andwaterwereaddedandthemixturewasextractedthreetimeswithEtOAc.Thecom
binedorganicphaseswerewashedoncewithbrine,driedoverMgSO4,filtered,concen
ane/EtOActoEtOAc)togive5.67gpureproduct(58%yield)aswhitecrystals(mp=63
65C).
3H), 5.93 (s, 2H), 4.34 (s, 2H), 3.30 3.17 (m, 2H), 2.42 (t, J = 8.1Hz, 2H), 1.97 (dq, J =
7.5Hz,11.3Hz,2H);13CNMR(75MHz,CDCl3)=174.6,147.8,146.9,130.4,121.4,108.5,
108.1,101.0,46.5,46.4,31.1,17.8;IR(thinfilm)2895,1682,1491,1443,1245,1037,
1
925,810,772cm ;Anal.calcdforC12H13NO3:C,65.74;H,5.98;N,6.39.Found:C,65.62;
H,5.97;N,6.27;HRMS(EI)calcdforC12H13NO3:[M]+=219.0890.Found:219.0891.
377
A.R.Beard,S.J.Hazell,J.Mann,C.Palmer,J.Chem.Soc.,PerkinTrans.11993,1235.
238
ExperimentalSection
211
1(benzo[d][1,3]dioxol5ylmethyl)piperidin2one: To a solution of valero lactam

(4.5g,45mmol,1.0equiv)in50mLdryTHFwascautiouslyaddedsodiumhydride(60w%
in mineral oil, 2.0g, 50mmol, 1.1equiv) at 0C. After stirring for 30min, a solution of
piperonylbromide377(9.7g,45mmol,1.0equiv)in10mLdryTHFwasslowlyaddedover
10min,themixtureallowedtowarmtoroomtemperatureandstirredovernight.Brine
andwaterwereaddedandthemixturewasextractedthreetimeswithEtOAc.Thecom
binedorganicphaseswerewashedoncewithbrine,driedoverMgSO4,filtered,concen
ane/EtOActoEtOAc)togive7.78gpureproduct(58%yield)aswhitecrystals(mp=68
69C).
3H),5.94(s,2H),4.49(s,2H),3.19(d,J=6.0Hz,2H),2.44(d,J=6.3Hz,2H),2.17(s,3H),
1.851.65(m,4H).13CNMR(75MHz,CDCl3)=169.6,147.8,146.7,131.1,121.4,108.5,
108.0, 100.9, 49.9, 47.1, 32.5, 23.3, 21.5; IR (thin film) 2945, 1638, 1491, 1443, 1352,
1
1241,1177,1038,927,808,772,664cm ;Anal.calcdforC13H15NO3:C,66.94;H,6.48;N,
6.00. Found: C, 67.03; H, 6.49; N, 5.95; HRMS (EI) calcd for C13H15NO: [M]+= 233.1046.
Found:233.1045.
CurriculumVitae
239
CurriculumVitae
BornJanuary05,1980inBadTlz,GermanyassonofRosaandJosefjun.Wuitschik.
19861990
Primaryschool,Sachsenkam,Germany
19901999
Gymnasium,BadTlz,Germany
10/199909/2004 Undergraduatestudies,TechnicalUniversityMunich,Germany
08/200109/2001 MaxPlanckInstitut fr Biochemie, Martinsried, Germany; Intern
shipdealingwithpeptidesynthesis
03/200210/2003 BayerischeEliteakademie,Munich,Germany
07/200311/2003 WackerSiltronic,Singapore;Internship;planning,programmingand
implementationofadatabaseminingtoolinMSExcel.
03/200409/2004 Diploma thesis in the group of Prof. Barry M. Trost, Stanford Uni
versity,USA
Title:TowardsaSynthesisofBryostatin7
01/2005present Ph.D.studiesinthegroupofProf.ErickM.Carreira,ETHZrich
Title:OxetanesinDrugDiscovery
Fellowships:
ScholarshipoftheFritzterMeerFoundation(01/200209/2004)
ScholarshipoftheStudienstiftungdesdeutschenVolkes(03/200204/2004)
ForeignexchangescholarshipoftheStudienstiftungdesdeutschenVolkes(0309/2004)
ScholarshipfromeFellows.net(sinceJuly2002)
ScholarshipfromF.HoffmannLaRocheAG,Basel(since01/2005)
DuringmyPh.D.studies,Iwasthreetimesteachingassistantfororganicchemistryexer
cises and lectures and responsible for the training of a chemistry technician apprentice
for 3 years as well as for four undergraduate students in the context of their research
projects.
Zrich,July2008
GeorgWuitschik
Appendix
O O
O
241
242
Appendix
Appendix
243
244
Appendix
Appendix
245
246
Appendix
Appendix
247
248
Appendix
Appendix
249
250
Appendix
Appendix
251
252
Appendix
NMe2
HO
O
Appendix
253
254
Appendix
Appendix
255
256
Appendix
Appendix
257
258
Appendix
Appendix
259
260
Appendix
Appendix
261
262
Appendix
Appendix
Bu
NO2
O
263
264
Appendix
Appendix
265
266
Appendix
Appendix
267
268
Appendix
Appendix
269
270
Appendix
Appendix
271
272
Appendix
Appendix
273
274
Appendix
Appendix
275
276
Appendix
Appendix
277
278
Appendix
Appendix
279
These NMR-spectra were recorded by the NMR-service of F. Hoffmann-La Roche, Basel.
280
Appendix
Appendix
281
282
Appendix
Appendix
283
284
Appendix
Appendix
285
286
Appendix
Appendix
287
288
Appendix
Bu
F
O
Appendix
289
290
Appendix
Appendix
291
292
Appendix
Appendix
293
294
Appendix
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295
296
Appendix
Appendix
297
298
Appendix
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301
302
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303
304
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305
306
Appendix
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307
308
Appendix
Appendix
309
310
Appendix
O
N
O
Appendix
311
O
N
312
Appendix
Appendix
313
314
Appendix
O
CN
Cl
Appendix
Cl
315
316
Appendix
Appendix
317
318
Appendix
Appendix
319
320
Appendix
Appendix
N
Br
321
322
Appendix
Appendix
N
t
Bu
323
324
Appendix
Appendix
325
326
Appendix
Appendix
Me
Me
NMe2
Bu
327
328
Appendix
Appendix
329
330
Appendix
Appendix
331
332
Appendix
Appendix
333
334
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335
336
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Appendix

Oxetanes in Drug Discovery

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OxetanesasCarbonylAnalogues ________________________________________ 114

PreparationofOxetan3one ___________________________________________ 140

PreparationofMichaelAcceptors _______________________________________ 148

PreparationofOxetanesoftheCyclicScaffolds ____________________________ 167

PreparationofAnalogues ______________________________________________ 216

Picture 1: Drug candidate facing resistance on the way to the market.1

wavespectroscopy.9 The replacement of a methylene unit by an oxygen atom reduces

Figure 1: Comparison of the puckering angles between cyclobutane13 and oxetane.

Scheme 1: Ring-opening reaction of oxetanes:24 a) LiO(tBuO)C=CH2, BF3OEt2; b)

Scheme 2: Hydrazination of oxetane under thermal conditions.32

Diagram 2: Relative reaction rates of a variety of substrates standardized for oxetane.33

Scheme 3: Common ways to prepare oxetanes.

Scheme 4: Grob fragmentation as side reaction competing with ring closure. 44

The onepot conversion of aldehydes or ketones with sulfoxonium ylides to give 2

Scheme 6: Oxetanes as transition-state analogues for Renin, an aspartate protease51

Scheme 7: Marketed drugs containing oxetanes53

Figure 2: Natural products containing oxetanes

Figure 3: Oxetane-containing pesticides

Equation 1: An oxetane is the sum of its bulky and polar nature.

Diagram 3: Launched drugs containing different forms of gem-dimethyl groups.77

Figure 4: Effect of geminal substitution on the distribution between antiperiplanar ( ap)

However, for a typical small molecule in medicinal chemistry the replacement of hy

Diagram 4: Hydroxylation of gem-dimethyl containing compounds.89

Figure 5: Oxetanes as a replacement for gem-dimethyl groups.

In terms of lipophilicity, substitution of a methylene unitwith a gemdimethyl group

Diagram 5: Prevalence of carbonyl groups in marketed drugs.

Picture 4: Vant Hoff representation of a carbonyl group.97

Picture 5: Structural comparison of a carbonyl group with an oxetane. 100

Figure 6: Possible applications for oxetanes as a carbonyl surrogate.

= Oxidation and/or ring cleavage

Scheme 8: Marketed drugs containing a morpholine liable to metabolic oxidation.106

Scheme 9: Spirocyclic oxetanes (R = piperonyl) as a substitute for morpholine.108

Picture 6: Commercially available oxetanes by december 2006.112

Figure 7: Reactions of oxetane-3-one in the literature.113

Equation 2: Preparation of oxetan-3-one from chloroacetyl chloride.114

Scheme 11: DuPont route to oxetan-3-one.115

Scheme 12: Oxidation of oxetan-3-ol (45).117

Scheme 13: Preparation of oxetan-3-ol (45) on industrial scale.121

Figure 8: Proposed buildup of oxetanes starting from oxetan-3-one

Scheme 14: Preparation of oxetan-3-one by DuPont.115

Scheme 15: Preparation of oxetan-3-ol from epichlorohydrine.120

Equation 3: Proposed cleavage of dioxolane 57 to give oxetan-3-one 58.128

Figure 9: Slow ring closure of -tosylatolithioxide 60.

Aqueous workup should be avoided as well as expensive, toxic or explosive rea

Table 3: 3-Aryloxetan-3-ols made by addition of organometal reagents to oxetan-3-one.

Scheme 19: Significance of 3-fluorooxetanes and their preparation of oxetan-3-ols by

Table 4: Conversion of 3-aryloxetan-3-ols into the corresponding fluorinated compounds.

Equation 5: Preparation of 3-chloro-3-phenyloxetane (75) and formation of 2phenylpropenal181 as byproduct.

Equation 6: Dehydroxylation of 3-(p-methoxyphenyl)oxetan-3-ol (64).

Table 5: Screening of conditions for the hydro-dehydroxylation of 3-phenyloxetan-3-ol.

Equation 8: One-pot preparation of 3-aryloxetane 81 from its corresponding alcohol 70.

Equation 9: Preparation of 3-amino-3-aryloxetanes from aminonitriles.

Equation 10: Bruylants reaction of aminonitrile 82 and hydrogenolytic deprotection to

Figure 10: Preparation of quaternary centers by substitution or conjugate addition.

Picture 7: Comparison of the transition state of a nucleophilic substitution with conjugate

Equation 11: Preparation of the ,unsaturatedester39byHWEreaction.211

Figure 11: Michael-acceptors prepared from oxetan-3-one.

MeNO2, 0.2 equiv DBU

MeCN, rt, < 4 h

MeNO2, 1.0 equiv DBU

Scheme 21: Addition products derived from ester 89.

Scheme 22: Addition products derived from nitro compound 96.

Scheme 23: Addition products derived from aldehyde 90.217