4.

Alkaloids
Definition:
the term alkaloid (alkalilike) is commonly used to designate basic heterocyclic nitrogenous compounds of plant origin that are physiologically active.

Classification:
True(Typical)alkaloids thatarederivedfrom aminoacidsandhavenitrogeninaheterocyclic ring.e.gAtropine Protoalkaloids thatarederivedfromaminoacids anddonothavenitrogeninaheterocyclicring. e.gEphedrine Pseudoalkaloids thatarenotderivedfrom aminoacidsbuthavenitrogeninaheterocyclic ring. e.gCaffeine Falsealkaloids arenonalkaloidsgivefalse positivereactionwithalkaloidalreagents.

Nomenclature: Trivialnames shouldendby"ine".Thesenamesmayrefer to: Thegenus oftheplant,suchasAtropinefromAtropa belladona. Theplantspecies,suchasCocainefromErythroxylon coca. Thecommonname ofthedrug,suchasErgotamine fromergot. Thenameofthediscoverer,suchasPelletierinethat wasdiscoveredbyPelletier. Thephysiologicalaction,suchasEmetinethatactsas emetic,Morphineactsasnarcotic. Aprominentphysicalcharacter,suchasHygrinethatis hygroscopic.

Prefixes and suffixes:

Prefixes: "Nor" designates Ndemethylation or Ndemethoxylation, e.g. norpseudoephedrine and nornicotine. "Apo" designates dehydration e.g. apomorphine. "Iso, pseudo, neo, and epi" indicate different types of isomers. Suffixes: "dine" designates isomerism as quinidine and cinchonidine. "ine" indicates, in case of ergot alkaloids, a lower pharmacological activity e.g. ergotaminine is less potent than ergotamine.

Physical Properties:
I Condition:

Most alkaloidsarecrystallinesolids. Fewalkaloidsareamorphoussolidse.g.emetine. Someare liquids thatareeither: Volatile e.g.nicotineandconiine,or Nonvolatile e.g.pilocarpineandhyoscine.

II Color:
Themajority ofalkaloidsarecolorless butsomeare colored e.g.: Colchicineandberberineareyellow. Canadineisorange. Thesaltsofsanguinarinearecopperred.

III- Isomerization:
Opticallyactiveisomersmayshowdifferentphysiological activities. lephedrineis3.5timesmoreactivethandephedrine. lergotamineis34timesmoreactivethandergotamine. d Tubocurarineismoreactivethanthecorrespondingl form. Quinine(lform)isantimalarialanditsd isomerquinidineis antiarrythmic. Theracemic(opticallyinactive)dlatropineisphysiologically active.

Chemical Properties:

I Nitrogen: PrimaryaminesRNH2e.g.Norephedrine SecondaryaminesR2NHe.g.Ephedrine TertiaryaminesR3Ne.g.Atropine QuaternaryammoniumsaltsR4Ne.gd Tubocurarine II Basicity: R2NH>RNH2 >R3N Saturatedhexacyclicaminesismorebasicthan aromaticamines.

Accordingtobasicity Alkaloidsareclassified into:

Weakbasese.g.Caffeine Strongbasese.g.Atropine Amphoteric *PhenolicAlkaloidse.g.Morphine withCarboxylicgroupse.g.Narceine Neutralalkaloidse.g.Colchicine

*Alkaloids

III Oxygen: MostalkaloidscontainOxygenandaresolidin naturee.g.Atropine. SomealkaloidsarefreefromOxygenandare mostlyliquidse.g.Nicotine,Coniine.

Extraction,PurificationandIsolationof AlkaloidsfromPowderedplants
Extractionandpurification
MethodI: The powder is treated with alkalis to liberates the free bases that can then be extracted with water immiscible organic solvents. MethodII: The powdered material is extracted with water or aqueous alcohol containing dilute acid. Alkaloids are extracted as their salts together with accompanying soluble impurities. Method III: The powder is extracted with water soluble organic solvents such as MeOH or EtOH which are good solvents for both salts and free bases.

 Liberationofthefreebases:
Alkalis are used to liberate free bases. Alkalis must be strong enough to liberate free bases. However, choice of strong alkalis must be avoided in some cases: 1 EsterAlkaloidse.g.SolanaceousAlkaloids 2 AmideAlkaloidse.g.Colchicine 3 PhenolicAlkaloidse.g.Morphine 4 LactoneAlkaloidse.g.Pilocarpine 5 FattyDrugsduetosaponificationandemulsionformation.

Separation of Alkaloidal Mixtures:

FractionalCrystallization:
Ephedrine & Pseudoephedrine Oxalates
Crystallization from water

Ephedrine Oxalate Crystals

Pseudoephedrine Oxalate Solution

Atropine & Hyoscyamineine Oxalates

Crystallization from Acetone/Ether

Atropine Oxalate Crystals

Hyoscyamine Oxalate Solution

 Preparation of Derivatives:
SeparationofPrimary,SecondaryandTertiaryAlkaloids.
O
Mixture + p-toluenesulphonyl chloride
Add HCl and filter

Cl

S O

Filtrate tertiary alkaloids as salt (no reaction with reagent 1ry alk derivative
O R-HN S O acidic hydrogen OH R-N S O

Precipitate 2ry alk derivative

O keto form R-N S R O insoluble in alkalis

enol form soluble in alkalis

NaOH, filter

Filtrate 1ry alk derivative

Precipitate 2ry alk derivative

 FractionalLiberation:

Atropine & Hyoscyamine & Hyoscine the form of HCl salts

1- Alkalinize by NaHCO3 pH 7.5 2- Extract with Ether

Ether Hyoscine free base (pKa = 6.2)

Aqueous layer Atropine & Hyoscyamine HCl (pKa = 9.3)

 FractionalDistillation: e.g.SeparationofNicotineandAnabasine

ChromatographicSeparation.

 Phenylalkylamines:
e.g.Ephedrine
CH2 CH NH2 CH3

Pyridineandpiperidine
e.g.lobeline,nicotine

N H

Tropane
e.g.Atropine.
NCH3 OH

 Quinoline
e.g.quinine and quinidine

Isoquinoline
e.g. papaverine

Phenantheren
e.g. Morphine

 Indole
e.g.ergometrine
N H

Imidazole
e.g. pilocarpine

Purine
e.g. caffeine
1 N 2

6 5

7 N

8 N 4 3 Purine N 9

 Steroidal
e.g. Solanum and alkaloids Veratrum

Terpenoid
e.g. Taxol

Introduction: Asthemolecularstructureofalkaloidsisquite complex,verylittleprogresswasachievedinthe elucidationoftheirstructuresduring19th century. Butnowthenew methods fortheidentificationof unknownsubstancesareknown. Thefollowingpatternofprocedureisadoptedto establishthemolecularstructureofanalkaloid:

1)Molecular Formula determination: Afterapurespecimenhasbeenobtained,itselemental

composition,andhencetheempiricalformula,isfoundby combustionanalysis. Then,itsmolecularweightisdeterminedbytheRast procedure(depressionofthefreezingpoint)toestablishits molecularformula. Itscalculationisbaseduponthesimplefactthat introductionofadoublebondorcyclisation ofthechain decreases themolecularformulabytwohydrogenatoms relativetothecorrespondingsaturatedaliphatic hydrocarbon.

 Forexample,thedifferencebetweenhexene (C6H12)
fromhexane (C6H14)istwohydrogen'sandthisdifferenceis calledadoublebondequivalent. Similarly,thedifferencebetweenbenzene (C6H6)and hexane (C6H14)iseighthydrogenswhichwillcorrespondto 8/2or4doublebondequivalents(accommodatedbythe threedoublebondsandonering). Theaboveprocedureisvalidforsimplercompoundsonly. However,forcomplexformulae,whereelementsotherthan hydrogenandcarbonarepresent,thesimplermethodis thatforanyformulaCaHbNcOd thenumberofdoublebond equivalentsisgivenbythefollowingexpression: a 1/2b+1/2c+1

 Theabovemethodforthecalculationofdouble
bondequivalentsisusefultocalculatethenumberof ringsinagivencompound.Forexample,hygrine has themolecularformula,C8H15NOwhichcorrespondsto 8 15/2++1=2 doublebondequivalents.However,chemicaltests revealthathygrine containsonlyonecarbonylgroup (onedoublebondequivalent)anddoesnotshowother formofunsaturation.Thushygrine mustbemonocyclic toaccountfortheotherdoublebondequivalent. Thepresenceofunsaturation inanalkaloidmayalso beascertainedbytreatingthealkaloidwithbromine or halogen acid oralkalinepotassiumpermanganate whenaglycol isobtained

2) Functional Group Analysis: Applicationofclassicaltechniquesoforganic analysis(especiallyifthealkaloidisavailablein appreciableamounts)and/orinfraredexamination (especiallyifthealkaloidisavailableonlyinsmall amounts)canrevealthenatureofthefunctional groupspresent. Thiswillalsorevealthearomatic oraliphatic natureofthealkaloidandtheunsaturation,if present.

3)Functional Nature Of Oxygen:

Ifanalkaloidcontainsoxygen,itmaybepresentas

OH(phenolic oralcoholic),methoxy (OCH3),acetoxy ( OCOCH3 ),benzoxyl (OCOC6H5),carboxylic (COOH),carboxylate (COOK)orcarbonyl (=C=O). Occasionally,lactoneringsystemshavealsobeen encountered(e.g.,narcotine,hydrastine).Thesefunctions havebeendetectedbytheusualmethodsoforganic analysisincludinginfraredexamination. Variousoxygenfunctionalgroupscanbecharacterised accordingtothefollowingcharacteristics:

a)Hydroxylgroup: Itspresenceinanalkaloidcanbeascertainedbythe
formationofacetate,ontreatmentwithaceticanhydride oracetylchlorideorbytheformationofbenzoate on treatmentwithbenzoylchlorideinthepresenceofsodium hydroxide.

However,theabovetestforoxygenshouldbeapplied carefullybecauseprimaryaminesifpresentinanalkaloid alsoyieldacetylandbenzoylderivatives.

 Thenthenumberofhydroxylgroupsisdeterminedby
acetylation orZerewitnoffs method.Intheformermethod, thenumberofhydroxylgroupsisdeterminedbyacetylating thealkaloidandhydrolysing theacetylderivativewitha knownvolumeofINNaOH.

Theexcessofalkaliisestimatedbytitration witha standardsolutionofHCl.Thenumberofacetylgroupsor hydroxylgroupscanbecalculatedfromthevolumeofalkali usedforhydolysis.

b)Carboxylicgroup: Thesolubilityofanalkaloidinaqueoussodium

carbonateorammonia revealsthepresenceof carboxylicgroup.Theformationofester on treatmentwithanalcoholalsorevealsthepresence ofcarboxylicgroup. Thenumberofcarboxylicgroupsmaybe determinedbyvolumetricallybytitrationagainsta standardbarium hydroxide solutionusing phenolphthalein asanindicatororgravimetricallyby silversaltmethod.

c)Oxogroup: Thepresenceofthisgroupisascertainedbythereaction ofanalkaloidwithhydroxylamine,semicarbazideor phenylhydrazine whenthecorrespondingoxime, semicarbazoneorphenylhydrazoneareformed.

Distinctionbetweenanaldehydeandaketonecanbe madeonthebasisofreductionandoxidationreactions.

d)Methoxygroup:

Thedetectionofthisgroupanditsnumbermaybe
determinedbytheZeiseldetermination,analogoustothe HerzegMeyer methodforNmethylgroups. Inthismethod,aknownweightofalkaloidisheatedwith hydriodicacidatitsboilingpoint(126 C)whenthe methoxylgroupsaretherebyconvertedintomethyliodide whichisthenabsorbedbyethanolicsilvernitrateandthe precipitatedsilveriodideisfiltered,driedandweighed.From theweightofsilveriodide,thenumberofmethoxylgroups maybecalculated.

 Forexample,papavarine,C20H21O4N,whentreatedwith
hydrogeniodide,consumes4molesofhydrogeniodide, producing4molesofsilveriodideandthusconfirmingthe presenceoffourOCH3 groups.

e)Esterandamidegroups: Thesegroupscanbedetectedandestimatedbyobserving Theproductsoftheiralkali oracidhydrolysis.

4)NatureofNitrogen: Allalkaloidscontainnitrogen.Butinthemajorityof
alkaloidsitispresentasapartofaheterocyclicsystem. Therefore,itmustbeeitherasecondary(=NH)or tertiary(=NCH3 or=N). However,therearephenylalkylaminetypeofalkaloids (adrenaline,ephedrine,etc)whichdonotcontainnitrogen asapartofaheterocyclicringbutintheformofaprimary amino(NH2)group. a) Thegeneralreactionsofthealkaloidwithacetic anhydride,methyliodideandnitrousacidoftenshowthe natureofthenitrogen.

Ifthealkaloidreactswithonemoleofmethyl iodidetoformanNmethylderivative,itmeans thatasecondarynitrogenatomispresent.For example,coniine,C8H17Nreactswithonemoleof methyliodidetoformanN methylderivative, indicatingthatconiinemustcontainsecondary nitrogenatom.

Ifanalkaloidreactsadditivelywithonemoleof methyliodidetoformcrystallinequaternarysalt, thisindicatesthatnitrogenatompresentinthis alkaloidistertiary. Forexample,nicotine reacts additivelywithtwomolesofmethyliodide, indicatingthatitcontainsbothnitrogenatomsas tertiary.

 Onecandetectthetertiarynitrogenatominan
alkaloidbytreatingitwith30%hydrogenperoxide whentertiarynitrogenisoxidised toamineoxide.

b)HerzigMeyersmethodisusedtodetectby distillationofalkaloidwithsodalime whenmethyl amineisobtained.Forexample,nicotine onheating withsodalimeyieldsmethylamineindicatingthatit mustcontainaNmethylgroup.

 NMRspectroscopymayalsobeutilizedfortherapid
detectionofN methylandNethylgroupsinalkaloids.

5)EstimationofCMethylgroups:
Cmethylgroupsarequantitativelyestimatedbythe KuhnRothoxidation,theaceticacidformedbeingdistilled offanddistillatetitratedagainststandardbase.

6)DegradationOfAlkaloids: Thereactionsusedindegradationofalkaloidsareas
follows: (a)Hofmannexhaustivemethylationmethod (b)Emdesdegradation (c)Reductivedegradationandzincdustdistillation (d)Alkalifusion (e)Oxidation (f)Dehydrogenation

a)HofmannsExhaustiveMethylationMethod:

Theprincipleofthismethodisthatcompounds,which
containthestructuralunit=CH=CN R3OH ,eliminatea trialkylamine onpyrolysis at200 Corabovetoyieldan olefin.
+

 Ifthenitrogenatomsformsapartofacyclic

structure,twoorthreesuchcyclesareessentialto liberatethenitrogenandexposethecarbon skeleton. However,thismethodisapplicableonlyto reducedringsystemssuchaspiperidine andactually failswithanalogousunsaturated compoundedsuch aspyridine andthereforethelattershouldbefirstof allconvertedintotheformer

 Whenamoleculeofwateriseliminatedfrom
quaternaryammoniumhydroxide,hydrogenatomis alwayseliminatedfromtheposition,ifthishydrogenis notavailable,thereactionfails

 Thehofmanns degradationmethodcanbe
appliedtohordenine methyl ether whichyields pmethoxy styrene.

b)Emdesdegradation: Ifthealkaloiddoesnot containahydrogen atom,theHofmannsexhaustivemethylation methodfails.Insuchcases,Emdesmethodmaybe employed. Inthismethod,thefinalstepinvolvesreductive cleavage ofquaternaryammoniumsaltseither withsodiumamalgamorsodiuminliquidammonia orbycatalytichydrogenation:

 Emdes methodcanbedemonstratedby
consideringthecaseofisoquinoline:

c)ReductiveDegradationandZincDustDistillation:

Insomecasestheringmaybeopenedbyheatingwith
hydiodicacid at300 C,e.g.,

HI 300 C

 Zincdustdistillationproducessimplefragmentsfrom
whichonecandrawtheconclusionaboutthecarbon frameworkofthealkaloidmolecule. Zincdustalsobringsaboutdehydrogenation orremoval ofoxygenifpresent.Forexample,

Asconyrine isformedbylossofsixhydrogenatoms,it meansthatconiinemustcontainapiperidinering

d)Alkalifusion:

Thisisverydrasticmethodwhichisoftenemployedto
breakdownthecomplexalkaloidmoleculeintosimpler fragments,thenatureofwhichwillgiveinformationonthe typeofnucleipresentinthealkaloidmolecule.Forexample, adrenaline whenfusedwithsolidpotassiumhydroxideyields protocateochicacid,indicatingthatadrenalineisacatechol deravative.

e)Oxidation:

Thismethodgivesusefulinformationaboutthe
structureofalkaloid.Byvaryingthestrengthofthe oxidisingagents,itispossibletoobtainavarietyof oxidationproducts.Forexample, (i) Inordertocarryoutmildoxidation,hydrogenperoxide, iodine inethanolicsolution,oralkalinepotassium ferricyanideareusuallyused. (ii)Inordertocarryoutmoderateoxidation,acidor alkalinepotassiumpermanganateorchromiumtrioxidein aceticacidaregenerallyused.

(iii)Forcarryingoutvigorousoxidation,potassium dichromatesulphuricacid,chromiumtrioxidesulphuric acid,concentratednitricacidormanganesedioxide sulphuricacidareused.Thesereagentsusuallybreakup analkaloidintosmallerfragmentswhosestructuresare eitheralreadyknownorcanbereadilyascertained.For example,

 Fromthisreaction,itcanbeconcludedthatnicotene
containsapyridineringhavingasidechaininposition. Thisclassificationofoxidisingagentsisnotrigid becausethestrengthofanoxidisingagentdependsto someextentonthenatureofthealkaloidwhichisbeing oxidised. (f)Dehydrogenation: Whenanalkaloidisdistilledwithacatalystsuchas sulphur,selenium orpalladium,dehydrogenationtakes placetoformrelativelysimpleandeasyrecognisable productswhichprovideacluetothegrossskeletonofthe alkaloid

 Duringdehydrogenation,thereoccursthe

eliminationofperipheralgroupssuchashydroxyl andCmethyl. (7)Synthesis: Thestructureofthealkaloidarrivedatbythe exclusiveanalyticalevidencebasedonthe foregoingmethodsisonlytentative.Thefinal confirmationofthestructuremustbedonebythe unambiguoussynthesis.

(8)PhysicalMethods:
Inalkaloidchemistry,themostimportantinstrumental methodsareasfollows: (a)Ultravioletspectroscopy (b)Infraredspectroscopy (c)Massspectroscopy (d)Opticallyrotatorydispersionandcirculardichroism (e)Conformationalanalysis,and (f)Xraydiffraction

(a)UltravioletSpectroscopy:

Thisismainlyusedtoestablishtheclassand/or
structuraltypetowhichthealkaloidbeinginvestigated belongs.Suchassignmentsaremadebecauseultraviolet spectrum ofacompoundisnotacharacteristicofthe wholemoleculebutonlyofthechromophoricsystem(s) present. Theusualpracticeistorecordtheultravoiletspectraof averylargenumberofdifferenttypesofalkaloids.Then, thedataareanalysedandcategorisedwithrespectto structurecorrelation.

 Eachgroupofalkaloidshavingaparticular
chromophoricsystembenzene,pyridine,indole,quinoline, etc.yieldscharacteristicabsorptionmaximaand extinctioncoefficients. Therefore,thecomparisonofthesedatawiththose observedforanewalkaloidmayallowtheidentificationof theexactnatureofthearomaticorheterocyclicsystemin thenewcompound. (b)Infraredspectroscopy: Inalkaloidchemistry,itismainlyusedtoascertainthe presenceandsometimestheabsenceofparticular functionalgroup.

 Thepresenceofaldehyde,ketone,alcohols,phenols,
ester,amide,lactone,carboxylic acid,carbonylgrroups andprimaryandsecondaryaminescanrapidlybe identifiedanddistinguishedbycomparisonofthe observedfrequencieswiththosereportedforstructural relatedcompounds. OnecanalsoascertainthepresenceofOmethyl,N methylandaromaticgroupsfromtheinfraredspectrum ofanalkaloidbutthequantitativeanalysisofsuchgroups isbestaccomplishedbyNMRspectroscopy.

(c)Massspectroscopy: Thistechniqueisquiteusefulbecauseitgivesquiteuseful informationaboutthealkaloidlike. (i)Themolecularweight. (ii)Theempiricalformulabyaccuratemassmeasurementof themolecularion,and (iii)Knowledgeofthemolecularstructurebycomparisonof thefragmentationpatternwiththoseofanalogoussystem. Mostofthesuccesshasbeenachievedinthecaseof polycyclicindolealkaloidsbecausetheindolenucleusof thesesubstancesgivesrisetoanabundant,stablemolecular ionwhichsubsquentlyundergoesdecompositionbyhighly specificbondfusioninvolvingtheacyclicportionofthe moleculecontainingtheothernitrogenatom(s).

d)Opticallyrotatorydispersionandcirculardichroism: Theseareonlyinstrumentalmethodswhicharemainly usedforelucidationofthestereochemistryofalkaloidsbut theirapplicationisrestrictedtothosecompoundswhich areopticallyactive,i.e.,tothoseinwhicharotation reflectionsymmetryaxisisabsent. Duetothisreason,fewalkaloidsoftheyohimbine, aprophine,morphine andbenzlisoquinoline serieshave beenexaminedsofarbythesetechniques.

e)ConformationalAnalysis:

Theprinciplesofconformationalanalysishavebeen
widelyusedtoestablishthestereochemistry aswellas physical propertiesandchemical reactivity ofalkaloids. Theapproachismainlyexperimentalwhichinvolves determination,correlation andinterpretation ofthe kineticsandproductratiosobtainedfromsimplechemical transformationssuchasreductionofdoublebondsand carbonylgroups,hydrolysisandesterfication,oxidationof alcoholsandquaternization ofamines,epimerization,etc

f)XrayDiffraction: Thistechniqueiswidelyusedtostudyalkaloids becauseitgivestheexactstructureofhemolecule, includingbondanglesandbondlengths;italso givestheinformationabouttherelative stereochemistry,includinginformationon overcrowdingtwistedbonds,etc. Xraydiffractionmethodisalsousefultoreveal theabsoluteconfigurationofthemolecule.

 Structural elucidation of RESERPINE

Content:

Introduction ConstitutionofReserpine StructureofYobyrine&reserpicacid confirmation Structureofreserpineconfirmationby synthesis

Introduction:

ReserpineisthemainconstituentofRauwolfia species,perticularlyR.serpentina& R.vomitoria. Itismainlyusedforthetreatmentof hypertension,headache,tension,asthma& dermatologicaldisorders.

Constitution of reserpine: 1.Molecularformula: C33H40N2O9 2.Presenceoffivemethoxygroups:

Byzeiselmethodi.e.whentreatedwithHIyieldsfivemoleculesof methyliodideindicatingthepresenceoffivemethoxygroups.

3.NatureofNatom:
a)SecondaryN Formationofmonoacetylderivativewithacetic anhydrideindicatessecondaryN. b)TertiaryN ReserpineformsquaternaryammoniumsaltswithCH3I thatindicatingoneofNistertiary.

4. Hydrolysis: Hydrolysisofreserpineyieldsmixtureof
i)Methylalcohol ii)3,4,5trimethoxybenzoicacid iii)Acid(A)ofcomposition
C22H28N2O5

C33H40N2O9

2 H2 O

NaOH Hydrolysis

CH3OH

+ C22H28N2O5 +
MeO

COOH

OMe OMe

AsreserpinedoesnotcontainCOOH&OHgroups,henceits hydrolysisproductrevealthatreserpineisadiester. Theesterlinkageinreserpinehasbeenfurtherconfirmedbyits reductionwith

LiAlH4

5. Reduction:
CH2OH C33H40N2O9 LiAlH4 Reserpic Alcohol + C22H30N2O4 MeO OMe

OMe

#Structure of Reserpic acid:

a)Molecularformula: C 22 H 28 N 2 O 5 b)Presenceofonecarboxylgroup:
Byusualtestse.g.silversaltmethod

c) PresenceoneOHgroup:
Reserpicacidonoxidationyieldsa secondaryalcoholicgroup. Byzeiselsmethod. ketonethatmeansithas

d)Natureoftwomethoxygroups:

e)NatureoftwoNatom:
ItshownthatitcontainstwoNatomsinheterocyclic ringinthe formof i)SecondaryN ii)Tertiaryaminogroup

f)

Reductionofreserpicacid:
Onreductionwithyieldsreserpicalcohol.
4

LiAlH g) Oxidationofreserpic acid:

Onoxidationwithitgives4methoxyNoxalylanthranilicacid.

KmnO4
C OOH MeO NHC O C OOH oxidation Reserpic acid ThusoneofthemethoxylgroupispresentinmetapositiontoNHgroup 4-methoxy N-oxalyl Anthranilic acid C 22 H 28 N 2 O 5 K mnO 4

h) FusionwithKOH:
Whenreserpicacidisfusedwithpotashityields5hydroxyisophthalic acid. Oneoftheacidicgroupsofisophthalicacidmustbe
COOH C22H28N2O5 KOH Fusion HOOC OH

presentinm positiontoeachother thisconfirm bythefactthat 5-hydroxy isophthalic acid reserpicacidwhenheatedwithaceticanhydrideyieldsagamma lactone.

C 22H28N2O 5

A C 2O O OC v-lactone

i)

Dehydrogenation:
Whenmethylreserpateisdehydrogenatedwithseleniumityieldsa hydrocarbonof molecularformula C H N
19 16 2

ThishydrocarbonisalsoobtainedbydehydrogenationofYohimbine withselenium&wasthereforenamedasYobyrine.
M ethyl r e s e r p at e Se D e hy d r o g e n ati o n C 19H16N2 Yobyrine Se D e hy d r o g e n ati o n

Yohimbine

Structure of Yobyrine:_

1. Molecularformula: 2. ZincDistillation: 3. Oxidation:

C19H16N2 Zn dust Distillation Isoquinoline N

C 19H 16N 2
H N

C2H5

3-ehtyl indole Whenyobyrineisoxidizedwithpermangnate ityieldsphthalicacid

C 19H 16N 2 cr2 o 3

K mnO4

COOH COOH Pthalic acid

C H3 COOH

o-Toulic acid

4. Condensationwithaldehydes:
Yobyrinegivescondensationproductssuggestingthepresenceof pyridineringwithamethylenesubstitution adjacenttothenitrogen. Onthebasisofabovefactsfollowingstructurehas been postulatedforyobyrine.
N

N H

C H3

Yobyrine

Synthesis of Yobyrine:
CH3

N H 2-(3-indolyl)ethyl amine

NH2

ClOC

CH2

O-tolyl acetyl chloride

1) -HCl 2)Reduction N H N CH2 CH3

POCl3 N H

NH CO CH2

CH3

- 2H dehydrogenation

N H

C H3

Yobyrine

j)

AsYobyrineisformedfromreserpicaciditmeansthat possessesthefollowingtypesof skeletonstructures.

reserpicacidmay

N H

k)

SKELETON STRUCTURE

Fromthefact5(g)itfollowsthatoneofthemethoxylgroupispresentinm positiontotheNHgroupofindolei.e.onC11i.e.OmeisatC11.

Reserpicacidwhendehydrogenatedyields11hydroxy16methylyobyrine,this maybeonlyformedifCOOHgroupispresentonC16

C22H28N2O5

Se dehydrogenation

HO

N H

N CH2

H3C

CH3

Fromthestep(h)itfollowsthatCOOH &OHgroupare inmpositiontoeach 11-hydroxy-16-methyl yobyrin otherbutCOOHgroupispresentatC16 thereforeOHgroupmustbeatC18.

Frompurelybiogenicreasons,the2nd methoxylgrouphasbeenassigned positionC17. Onthebasisabovementionedfactsthestructureofreserpicacidmaybe

MeO

N H

HOOC OMe Reserpic acid

OH

Structure of Reserpine:
Asreserpineisdiesterofreserpicacid,itmeansthat,

COOH MeO N H N

+
OH OMe

CH3OH

+
MeO OMe OMe

-2 H2O

HOOC Reserpic acid

MeO

N H

N OMe O OMe CO OMe OMe

H3COOC

Reserpine

Synthesis of Reserpine:
Thestructureofreserpinehasbeenconfirmedbyitssynthesisgivenby Woodwardet.al.
O H2C O C C O
p-Benzoquinone

+
CH

Diels Alder reaction O

CH2 CH CH COOH CH

COOH

Adduct Reduction NaBH4 of less hindered ( =CO) OH

OH O Ac2O O COOH C6H5COOH

phenoxy benzoic acid O COOH

Synthesis continue..
O O O CO O Aluminium isopropoxide OH O O Br NBS- H2SO4 HO O CO OMe O CO OMe CO O O CO CH3ONa CH3OH -H2O O

Cro3

Synthesiscontinue..
O Br O O CO OMe OH Zn / CH COOH 3 O OMe COOH
i) CH2N2 ii) Ac2O Pyridine iii) OSO4-H2O

COOCH3 COOCH3 MeO

N H

COOCH3 MeO OAc OH O OH

CH2 CHO

ii) CH2N2 i) HIO4

MeO

H2N

6-methoxy tryptamine

OAc

Synthesiscontinue..
MeO N H H3COOC CH2 OAc OMe H3COOC N H C i) NaBH4 ii) CH3OH N MeO N H O

H3COOC OMe i) POCl3 ii) NaBH4

OAc

Synthesiscontinue..

OMe

N H

i)Resolve

ii)NaOH MeO
iii)Hcl iv)DCC

N H

OMe OC O

H3COOC OMe

OAc

Synthesiscontinue..

Isomerisation

(CH3)3CCOOH

MeO

N H

OMe
CH3OH
OCO OMe
MeO

H3COOC

OMe OMe
HOOC

N H

OMe OMe

OMe OC O

Reserpine

OMe

Reserpic acid Lactone

References :

1)OrganicOrganicChemistryofNaturalProducts by GurudeepChatwal,VolI. 2)OrganicChemistrybyI.L.Finar,VolII. 3)PharmacognosybyC.K.Kokate, A.P.Purohit,S.B.Gokhale

O.D