Beruflich Dokumente
Kultur Dokumente
Sarah Wengryniuk
Terminology #- refers to number of carbons in the forming ring ( 3) Endo/Exo - refers to position of breaking bond relative to forming ring Endo bond is inside the newly formed ring Exo bond is outside of the newly formed ring ex. 5-exo-tet Tet/Trig/Dig- Hybridization at the ring closure point. -X Y Tet- sp3; Trig- sp2; Dig - sp For enolate reactions: Same terms as above, plus designator for position of enolate. Enol-endo: Enolate is inside of the newly forming ring. Enol-exo: Enolate is outside of the newly forming ring. C vs. O: Whether cyclization occurs via C or O centered nucleophile. Br Br O X 5-(C-enolendo)-exo-tet
-O -O
*
C-Nuc out of plane O-Nuc in plane
O 5-(O-enolexo)-exo-tet
X-
X-
107
XC
60
"Caveats" to the Rules: - Atoms involved must be in the first row - Larger atomic radii and longer bond lengths allow for more flexibility with second row elements and below - Do not apply to concerted electrocyclic processes. - Rules imply inversions at the reacting centers and therefore do not apply to processes where inversion is not required. - "I thank Professor R.B. Woodward for pointing this out to me." -JEB
Sarah Wengryniuk
TET
Y 5-exo-tet Favored Y X
-O
O Y
All 3-7 membered ring closures are favored!!! Same applies to (enolexo)-exo-trig ALDOLS. ENOLENDOEXO-TET O Y
5-endo-tet Disfavored
-O
X TRIG
3-5 membered ring closures are disfavored 6-7 membered ring closures are favored Same rules apply to (enolendo)-exo-trig ALDOLS X Y 5-exo-trig Favored Y X 5-endo-trig Disfavored Y X 6-exo-trig Favored Y X 6-endo-trig Favored Beckwith's Radical Rules: 1. Intramolecular addition under kinetic control when n5, cyclization occurs preferentially in the exo mode. A B (Y)n X A B (Y)n X exo-mode Favored A B vs. (Y)n X endo-mode Disfavored
Thermodynamic preference for secondary radical overridden by kinetic pref. based on required orbital alignment for cyclization.
2. Substituents disfavor cyclization at substituted position. X DIG Y 3-exo-dig Disfavored X Y 4-exo-dig Disfavored X Y 5-exo-dig Favored X Y 6-exo-dig Favored R R vs. Favored Disfavored R
X Y 3-endo-dig Favored
X Y 4-endo-dig Favored
X Y 5-endo-dig Favored
X Y 6-endo-dig Favored
3. Homolytic cleavage is favored when bond concerned lies close to plane of adjacent semi-occupied, filled non-bonding, or -orbital
Sarah Wengryniuk
Common Transformations that Break the Rules: Cyclic Acetal Formation: 5-endo-trig via oxonium O HO H+
Perkins, J.M.; JOC, 1981, 46, 2196.
"Tet"-Cyclizations: Overriding exo- to get endo-Since all exo-tets are favored this section with discuss how to override that selectivity to get endo-selectivity. -Examples of anionic openings (Cationic and Radical not common) -This section could also be called: "Regiochemical control in epoxide opening" -Seminal work by Nicolaou during brevotoxin synthesis Baldwin says: Nuc, Elec, Rad -trig endo exo O O XOH vs. Xexo-preferred Xendo-desired OH HO O OAc O 1. PPh 3, imid., I 2 2. PPh 3, imid., I 2 O OH O O OH O O OH O O SePh 4-exo-tet kinetic PhSe Phytuberin
Suarez, E.; JOC, 2003, 68, 4422.
HO OH
5-endotrig
3 n y
4 n y
5 n y
6 y y
7 -y HO
Common Transformations that Make you Question the Rules: -Baldwin says his rules extend to "nucleophilic, electrophilic, and homolytic" processes but is this true? Wagner Meerwein vs [1,2]-Wittig RAR
4-endo-tet: Synthesis of Phytotuberin OH HO MsOH, CH2Cl2 AcO 0 C, 1h, 53% Ac-transfer, OAc 4-endo-tet
O but cationic...
CO2Me
O OH
3. N -(PSPTH) OH
H R' R C O R R
Li
R R C O R
via 3-endo-tet
R R C O R
R R C OH R
homolytic, intermol. recomb.
OH
R C O + R R
OAc
5-endo-tet thermo
Sarah Wengryniuk
5,6,7-endo-tet over 4,5,6-exo-tet General comments: -Exo- mode is always preferred (even in 6-endo case) -However, control of regiochemistry in these systems is very well understood. -Few basic strategies are employed, section catagorized by approach: - Cyclic sulfates (Sharpless) - Substituent effects (started with Nicolaou vinyl oxiranes) - Use of "-onium" ions (iodo-, bromo-, seleno-) - Use of select activating agents (LA, antibodies) Cyclic Sulfates
Enantiopure Tetrahydrofurans
Nicolaou and Brevetoxin: Endo-control via Substituent Effects Vinyl oxiranes HO vs. HO O O H R O R HO R 5-exo R 6-endo 0 CH2CH2CO2Me 100 E -CH=CHCO2Me CH=CH2 CH=CBr2 60 100 100 40 0 0
R OBn O S O O O
R2
Pachastrissamine
A,B,C Rings of Brevetoxin B enantiopure diols to enantiopure, substituted Br Br CSA 2. 4 days tetrahydrofurans R R2 O Me (0.1 equiv.) HO 5-endo 82% O 93% Sharpless, B.K.; Acta Chim Scanda, 1993, 47, 307. O H H
1. Hydrog.
HO
Br
Br H
Me
HO
N3 TrO O O S O O C13H 27
H 2N
OH
Nicolaou, K.C.; JCS Chem. Commun., 1985, 1359. Nicolaou, K.C.; JACS, 1989, 5330.
C13H 27 O Pachastrissamine
Kim, S.; OL, 2007, 9, 429.
Similar strategy used in approaches to numerous natural products 5-endo over 4-exo OH
Analogous reaction with epoxide gave only trace product under various cond.
O O O O O O HO
HO OH H O H
OH
1-Benzoxepines
OH
OH R
CO2Et OH
5-exo 100 78 18 40 8
Sarah Wengryniuk
OH MeO H Me O
O HO R
Co2(CO) 8 Co
O HO
68-96% OH
Hanaoka, M.; TL , 1994, 35, 2179. w/o Co: Hanaoka, M.; TL , 1994, 35, 2183.
Sulfones: Disfavor exo-pathway via e--withdrawing H H n-BuLi, DMPU OTBS OR OTBDPS p-TsOH, 55 O OTBDPS 80% OTf O SO2Ph O O SO Ph 2 H H 90% H H H H H O O O OTBDPS OR O H O iterative oxiranyl anion addition 6-endo-tet O H H O H H OH
CSA O or TfOH OH
TIPSOTf 5 equiv. O
OR
H HO H exo-major
up to 7:1 endo
Morimoto, Y.; ACIE, 2006, 45, 810. Se: Noto R.; Tet. , 2001, 57, 1819. S: Noto, R.; J. Het. Chem., 2001, 765.
Mori, Y.; JACS, 1996, 118 , 8158. Other ex: Mori, Y.; Chem. Eur. J.; 1997, 3, 849. Mori, Y.; TL , 1995, 40, 8019.
Epoxysilanes: 1. DIBAL; I 2 Me 3Si HO O 2. Me 3Si C C Me n-BuLi, TMEDA; CuI, DMAP Me 3Si OH BF 3 OEt2 H HO
HO HO SiMe 3
HTIB (2.0 equiv.) I 2 (0.2 equiv.) MeOH, rt 64% Initial 4-exo then RAR
I OAc O O
HOMe O
OMe
80% iterative, as O H SiMe 3 >95% ee >95% dr above SiMe 3 >95% endo H H H HO O Ladder THP Synthesis: THP triad in 18 steps Mori and Nicolaou: 10-13 steps per unit Me O O H H H Jamison, T.; OL, 2003, 5, 2339.
Mech on regio: Schumann; TL , 1995, 36, 8771.
Giannis, A.; JOC, 2011, 76 , 1499. Another ex of 5-endo with I 2: Elliott, M. C.; OL, 2007, 9, 3635.
Me HO R
CO2Me N Ns
O Ph Br
CO2Me N Ns
Sarah Wengryniuk
Fischer Carbene: Example of a carbon nucleophile: Tetrahydronapthols H 3CO OH O R O R Ph Li R2 W(CO)5 OCH3 3-endo-trig: As you might imagine, Li 52-83% yield no examples in the literature dr >98:2 R1 OCH3 R W(CO)5 6-endo only [CoIII(salen)] Complex: Regio- and Kinetic Res. O 1 mol% cat. O OH ( )n TBME ( )n OH tBu 95% ee, 46% W(CO)5
Gasparrini, F.; OL, 2005, 7 , 4895.
"Trig" Cyclizations -Many examples of overcoming Baldwin's rules here -Primarily rely on heteroatoms (O, N, S...) -Nucleophilic, electrophilic and radical methods -Primary focus will be on 5-endo-trig -Will be broken down by method of activation
107
H N
H N
tBu
Ph Br
Y O
O HO
No Ab
HO
Rousseau, G.; TL , 2001, 42, 2477. Rousseau, G.l JOC, 1999, 64, 81.
R Racemic
-O
5-endo-trig Alabugin suggests aromatic character to 5-endo t.s.: lone pair, -bond, -bond "Anionic 5-endo closures are "aborted" sigmatropic shifts" Think of 5-endo closures are competition between pericyclic and ring closure: [2,3] X X X Nu X Nu 5-endo Wittig Nu Nu Y Y Y Y Y= EWG Stabilize (-) at X EWGs at the Y-position promote 5endo cyclizations by further lowering energy of "intermediate".
Alabugin, I.; JACS, 2012, 134 , 10584.
N+ R
Sarah Wengryniuk
Nucleophilic Cyclizations: EWGs at 4-position SO2R RO 2S O R R EtO 2C EtO 2C SO2R KH CO2Et 65% R CO2Et R SO2R
Activating Alkene: "-Onium Cyclizations -Put them here because these the authors called 5-endo-trig, but similar approach to -onium ions in 5-endo-tet section
More iodoniums: Total synthesis of ()-Muscarine
HO R R OH CO2Me R
OH R R
I 2, NaHCO 3 63%
HO R O R
HO O NMe 3+
Knight, D.; Eur. JOC; 2004, 1973.
SO2Ph
RNH 2
NHBn O OH
OBn
SO2Ph
NBn H OBn
O
OBn
HO
N OH OH
H HO
PhO 2S SESHN R
R + N H O
R N
MgI 2, THF 75 C
R N
5-(enolexo)endo-trig
Nitro-group
NO 2 Ar O2N
NHR Ar
O2N Ar N H Ar
TIPS R N HN O
N H O
TIPS
N N O H
()-Spirotryptostatin B
Carreira, E.; JACS, 2005, 127 , 11505.
CF 3 R HY R Base 57-96%
F 2C Y
R or R
F 3C Y
R R
F 2C or
R R
N H
TIPS
Sarah Wengryniuk
5-endo Heck Reactions IHR typically proceed via exo-pathway - For 5-endo requires harsh reaction conditions and/or specially designed substrates and yields are typically low.
Diastereoselective C-2 Alkenylation of Indoles via 5-endo "Fujiwara-Moritani"
R R N O R
Oestreich, M.; ACIE, 2012, 51, 1265.
H N
CHO
CO2H H N OMe O
TfO
N H
CO2Et
N H
CO2Et
5-(enolendo)-exo/endo-trig
Onto an oxonium: THFs from 1,3-Dioxolan-4-ones
Tanner, D.; Synlett, 2006, 18 , 3140.
O R O
R1 R2
Bu 3AlO R O R2 R1
HO R1 R O R2
Radicals: Focus on 4-exo vs 5-endo - Despite being a favored process, not many examples of 4-exo in literature - Examples of 5-endo radicals are scare, often involve heteroatoms. 4-exo-trig-rad: Employing the gem-dialkoxy effect EtO OEt Br 1. Bu 3SnH, AIBN 2. HCl 67% overall CO2Et O Without subtituents or with gem-dimethyl, no cyclization was observed. CO2Et
Jung, M.E.; TL , 1992, 33, 6719.
OPh Co(CO) 3 R O
O Ph
Co2(CO) 6 R
(OC) 3Co
Other approaches: Substituent effects still important O O Titan. (10mol%) SmI2 OH Mn (2 equiv.) H CO2Et
OH CO2NMe
R
Harrity, J.; JOC, 2005, 70 , 10046.
CO2Et
CONMe2
Ganauser, A.; JACS, 2008, 130 , 1788.
Sarah Wengryniuk
H SPh R N O N no rxn CO2Me
OTMS
SPh SPh N O
Ph N
Ph N Ph
Me Br O
Ph HN
Ph N Ph
Me O
Krause, J.; TL, 1993, 34, 797.
CN CO2Et 30%
CN CO2Et
same cond. No dp
Br O N Bn O O
O Br
O
Reddy, K.M.; TL , 1993, 34, 2665.
I N Ms OMe OMe
H 30% 5-endotrig N H Ms
HO Me R R Si H O
SPh SPh N O
General Notes -Must have carbonyl incorporated into 5-mem ring -Initiators: Bu 3SnH/AIBN; Ni/AcOH, CuCl/bipyridine -X: Cl, Br, I, SPh, Se -Alkene: Isolated, benzylic, , -unsaturated carbonyl
SePh
R R Si O
OBn
5-endotrig 75% H
R O Si
R OBn
CO2Me
CO2Me
H CO2 Me
Sarah Wengryniuk
This section will cover: 3-exo vs. 4-endo (rad, anionic, cationic) 4-exo vs. 5-endo (rad, anionic, cationic) Not covered: 5-exo vs 6-endo. Both favored. See review for details.
"Favored" Trajectory for Digonal Closure XBaldwin Acute angle of attack 60 60 XObtuse angle of attack 120
X
120
based on X-ray studies and preference for endo- closure theoretical calculations, avoidance of *-nodal plane, analogous to Burgi-Dunitz angle
Revised
120
X
120
The obtuse trajectory should translate into stereoelectronic preference for exo-cyclization as opposed to endo! Stereoelectronic Differences in Nucleophilic vs Electrophilic Cylization Nucleophilic LUMO NuNuLUMO Electrophilic HOMO E+ + Nuc: Secondary orbital interaction is destabilizing Elec: Secondary orbital interaction is stabilzing
O CO2Me I X
n
CO2Me
H H
R X= C, O
R= i-Pr, H,
Endo
Exo
Endo/Exo
Nu
Electrophilic Closure
N N N N H H Nu E+ Berg, C.; Eur. J. Org. Chem. 2005, 4988. E+-Promoted Nu-Promoted Electrophilic Closure (NPEC) Nucleophilic Closure (EPNC)
Sarah Wengryniuk
R2
Me Me NHAc
-Clear thermodynamic preference for 5-endo (much more exothermic) -Kinetic preference can often favor 4-exo closure so selectivity is balance of two factors. Radical 4-exo-dig: Only two examples in literature 1. Bu 3SnH, AIBN O Si Br Bu 3SnH HO H Si Bicyclo[3.1.1]Heptanes MeLi H O Si 4-exodig 5-exo-dig 2. 1,6-H transfer O Si 6-endotrig O Si
4-endo-dig??? Despite being "Favorable" by Baldwins rules, these types of nucleophilic cyclizations remain unknown. This is not surprising based on activation barrier: vs. Ea E r Cationic 7.8 -4.5 27.0 -13.0 ~20 kcal/mol higher barrier to activation for 4-endo, which overrides the fact that it is ~7kcal/mol more exothermic than 3-exo
Alabugin, I. et. al.; JACS, 2011, 133 , 12608. Hanack, M.; JACS, 1974, 96, 6686. Hanack, M.; JOC, 1983, 48, 5260. Wilson, J.W.; JACS, 1969, 91, 3238.
3-exo-dig vs. 4-endo-dig 1 carbocation: Controlled by substitution on alkyne: Example of NPEC R Nf R ROH, H 2O R 3-exo : 4-endo H Me Ph An 0:100 1:99 31:17 57:43 R -OR ROH, H 2O Br
Carbamoyl Radicals via photolysis of carbamotelluroates O Bu N TeAr h PhCH 3 110 C R R Bu N O 4-exodig ArTe R O N Bu exclusive 4exo. only trace 5endo when R=Et
O N
Sarah Wengryniuk
5-endo-dig: Examples employing O, S, Si, C radicals Is a favored process by Baldwin's Rules , but examples are scarce! Went 40 years without example of carbon radical 5-endo-dig cyclization!
O and S require flash vaccum pyrolysis
Other Examples of Proposed 5-endo-dig radicals: O Ar 4 equiv. LiNaph 52% Ar O Ar OH Ar O Li Computational studies support this proposed mechanism. If only one ketone present, dimerization rather than radical cyclization occurs.
Yamaguchi, S.; OL, 2009, 11, 3076.
Li
O Ar
Y 5-endo-dig
6-endo-trig aromat.
Y= O, 36% Y= S, 28% Ar OH
Aitken, R. A.; Synlett, 1995, 53. Aitken, R. A.; JCS PT1, 1994, 2455.
1. MeO Si O OMe
N N
OtBu
BuOt
Si O
Si
PhLi OH
SiR 3
Anionic: -4-exo-dig is disfavored by Baldwin's Rules but is possible! -5-endo is not easy to facilitate either; diff. btw 4-exo/5-endo is very small -Can facilitate 5-endo: - Stab/Destab of resulting negative charge - 4-exo product disfavored by ring strain - Aromatic Stability of products - Use of an external electrophile 4-exo-dig
Achieving 4-exo is still not easy: Use of Propargylic leaving group
C-Centered Radical: Igor contributes a reaction! -40 years since Baldwin's Rules and no 5-endo-dig radical from carbon -DFT calculations predicted that while plausible, 5-endo-dig is a slow process -Bias system with strain effects and prediction that vinyl radical should cyclize fastest -Use of AIBN/Bu3SnH led to complex product mixtures
R OMe tBuLi
R R OMe
R 88% R
RO RO
Me h TsBr Me
RO RO
Me
5-endodig Br Ts
RO RO
Me Br
Me
R= H, 5 or 6-mem ring
Alabugin, I.; JACS, 2008, 130 , 10984.
Me
X Y
Bailey, W.F.; TL , 1990, 31, 627. Cooke, M.; JOC, 1994, 59, 2930. Bailey, W.F.; JACS, 1993, 115, 3080. Cooke, M.; JOC, 1993, 58, 6833.
Sarah Wengryniuk
EWG
H O
PhO 2S
OEt
1. n-BuLi 2. MeI
H R O
Ph
CO2Ph
CO2Ph
Ph
O HN O N
ZnCl2/DCM or
CO2Me
CO2Me
CO2Me
HN MeO 2C
Cu: Robins, M.J.; J.M.C., 2006, 49, 391. Zn: Dembinski, R.; JOC, 2008, 73 , 5881. For I 2: Knight, D.W.; TL , 2001, 42, 5945.
X CF 3
X R
X Ph
HO
Me CO2Et NHTs
HO Me CO2Et N Ts
Johnson, F.; JOC, 1986, 51, 5040. For related N-nuc: Knochel, P.; ACIE, 2000, 39, 2488.
MeCN 54-80%
Sarah Wengryniuk
TET
Y 5-exo-tet Favored Y X
X = No examples in literature still = Possible, sparse examples = Many methods available F = Favored by Baldwin's Rules
TETRAHEDRAL : Cationic and Radical are as per Baldwin Anionic endo exo TRIGONAL Anionic endo exo Radical endo exo Cationic endo exo DIGONAL 3 X F 3 X F 3 X F 4 F 4 X F 4 X F 5 F 5 F 5 F 6 F F 6 F F 6 F F 3 X --4 --5 F 6 F
5-endo-tet Disfavored
X TRIG
Y 5-exo-trig Favored Y X
5-endo-trig Disfavored
X Y 4-exo-dig Disfavored
X Y 5-exo-dig Favored
X Y 6-exo-dig Favored
3 X (F ) 3 X (F ) 3 X (F )
4 X (F ) 4 X (F ) 4 (F )
5 (F ) F 5 (F ) F 5 (F ) F
6 (F ) F 6 F F 6 F F
X Y 3-endo-dig Favored
X Y 4-endo-dig Favored
X Y 5-endo-dig Favored
X Y 6-endo-dig Favored