Organocatalysis: Almost Everything You Wanted to Know, but Never Asked

Bryan Wakefield Frontiers in Chemistry December 17th, 2005

Bryan Wakefield @ Wipf Group 1 12/17/2005 What is an Organocatalyst?

 An organocatalyst is an organic molecule that does not contain a metal which in substoichimetric amounts accelerates a reaction.

 Examples: Proline, Cinchona alkaloids or other secondary amine derivatives

O OAc N CO H N N 2 Bn H N N H H 2 Cl-

Bryan Wakefield @ Wipf Group 2 12/17/2005 Organocatalysis: Outside “Classic” Chemistry

 Some meteors contain enantiomerically enriched L-alanine and L-isovaline amino acids with ee’s up to 15%.

 These amino acids have been shown to catalyze a simple adol reaction to give tetroses.

OH OH O H2N CO2H HO O O pH 5.4 Buffer OH OH OH OH 50 oC, 10 h D-threose L-erythrose

S. Pizzarello, A. Weber, Science Vol 303, 1151

Bryan Wakefield @ Wipf Group 3 12/17/2005 Classification of Organocatalysts

 List recently introduced a system of classification based on the mechanism of catalysis.

 The four categories are Lewis Base, Lewis Acid, Bronsted Base and Bronsted Acid catalysis.

B. List, Org. Biomol. Chem., 2005, 719

Bryan Wakefield @ Wipf Group 4 12/17/2005 Types of Lewis Basic Organocatalysis

Bryan Wakefield @ Wipf Group 5 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Iminium Ion: 1,4 Additions R

Mukaiyama-Micheal 20 mol% O N tBu O 3 Bn N H O R2 R O O 1 H DNBA O R O + R2 DCM-H O 2 R1 R1=Me, Pr, i-Pr, R2=H, Me, Et, Ph, CH2OBz, CO2Me 6:1 to 31:1 syn:anti CO Me R3=TMS, TIPS 73-87% yield 2 84-99% ee

D. MacMillan, J. Am. Chem. Soc. 2003,1192 Nitroalkane additions 20 mol% N CO2H O O2N NO2 H O + 1 2 R R R1 R2 1 R =Ph, p-ClPh, p-NO2Ph, p-HOPh, 2-thienyl, 5-100% yield 34-86% ee 2-furyl, 2-pyridyl, n-Bu, i-Pr, CO2Me R2=Me, Et, i-Pr K. A. Jorgensen, J. Am. Chem. Soc. 2002, 8831 Also see: K. A. Jorgensen, Org. Lett. 2005, 3897

Bryan Wakefield @ Wipf Group 6 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Iminium Ion: 1,4 Additions R

Malonate Additions

10 mol% N Bn N CO2H CO2Bn O BnO2C CO2Bn H O + R1 R2 Neat, RT 1 2 CO2Bn R R 1 R =Ph, p-ClPh, p-NO2Ph, o-NO2Ph, p-HOPh, 2-99% yield 59-99% ee Me2NPh, 2-thienyl, 2-furyl, 2-pyridyl, n-Bu, i-Pr, CO2Me, 2-Np R2=Me, Et, i-Pr K.A. Jorgensen, Angew. Chem. Int. Ed. 2003, 661 Dicarbonyl Additions Ph 10 mol% N OH OH R1 O O Ph N CO2H H R2 + 1 2 R R DCM, RT O O O O

1 R =Ph, p-ClPh, p-NO2Ph, p-MeOPh, 68-99% yield 2-thienyl, 2-furyl, n-Bu, i-Pr, 2-Np 75-88% ee R2=Me, Et, i-Pr K.A. Jorgensen, Angew. Chem. Int. Ed. 2003, 4955

Bryan Wakefield @ Wipf Group 7 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Iminium Ion: 1,4 Additions R

Thiol Additions

O O 1 mol% cat RSH + Toluene, RT n RS R=Ph, Bn, p-tBuPh, 55-91% yield o-MeOPh, m-MeOPh 21-99% ee p-MeOPh, p-EtOPh, 2-Np n=0-4 L. Deng, Angew. Chem. Int. Ed. 2002, 338 Azide Additions O tBu O O O O O N3 N Cat 1 or 2 N H N R N Me X N R BOCHN H X O Np N R=Me, Cy, Et, 44-97% yield R N-Boc piperidine 45-90% ee Cat 1 R=H X= CH2 or O N Cat 2 R=Me Bn

S. Miller, J. Am. Chem. Soc. 2002, 2134

Bryan Wakefield @ Wipf Group 8 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Iminium Ion: Cycloadditions R

Diels-Alder Reactions

20 mol% 20 mol% O O N 5-Me-furyl N 5-Me-furyl 1 COEt Bn N H R Bn N H O H O H R1 2 ClO - R1 2 ClO - + 4 + 4 1 2 O R R o 2 Et o 2 H2O, 0 C R R2 EtOH, -30 C R 1 R =Me, n-Pr, i-Pr 6:1 to 25:1 endo:exo R1=OMe, NHCbz, Me 100:1 to 200:1 endo:exo 2 R =Me, Et, n-Bu, i-Am 78-89% yield R2=H, Ph, Me 79-92% yield 61-92% ee 85-98% ee D. MacMillan, J. Am. Chem. Soc. 2002, 2458 D. MacMillan, J. Am. Chem. Soc. 2000, 4243 Also see: K. Ishihara, J. Am. Chem. Soc. 2005, 10504 CHO H O O n CHO 20 mol% cat R n N N R Or Bn N Bn N tBu H H H R= Ph, HC=C(Me)H, 1:20 to 20:1 endo/exo HX HX Vinyl 10-85% yield catalyst n=0 or 1 77-94% ee X= -OTf, -Cl, -ClO4 D. MacMillan, J. Am. Chem. Soc. 2005, 11616

Bryan Wakefield @ Wipf Group 9 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Iminium Ion: Cycloadditions R

[4+3] Cycloadditions O

Bn N O 20 mol% OR1 HN 2 O 2 + R R tBu O CHO R2 R2 TFA, DCM, -78 to -35 oC

R1= TMS, TES, R2=Me, Et,Pr, Ph 100% endo TBS, TIPS 18-74% yield 80-90% ee M Harmata, J. Am. Chem. Soc. 2003, 2058 [3+2] Cycloadditons R2 O O O S Ph CHO 1. 13 mol% cat. N 1 H H 1 R O DMF/H2O OH OH R O H 1 + N H Bn H N R O O N 2 2. NaBH , MeOH H H R 4 N Ph N N Ph H HX (HX)2 Major Minor R2 HX R1=Me, H or Ph 2 3:1 to 97:3 D.r. R1=H or Me R =OH, OMe, 7-70% yield X= -Cl, -ClO4, 2 piperidine or 23-93% ee -OTf R =H or OMe pyrrolidine

S. Karlsson, Tet. Asym. 2002, 923

Bryan Wakefield @ Wipf Group 10 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Iminium Ion: Friedel-Crafts Alkylation R

Pyrrole Additions O 20 mol% N Bn R1 N R O + N H TFA O N R=Me, Pr, i-Pr 1 THF/H O 1 R =Me, Bn, 2 R R Ph, p-MeOPh, Allyl, H CH2OBn, CO2Me 68-90% yield 87-97% ee D. MacMillan, J. Am. Chem. Soc. 2001, 4370 Indol Additions

O R 20 mol% N O Bn R1 N R O + N H TFA N R=Me, Pr, i-Pr R1=Me, Bn, THF/i-PrOH R1 Ph, CH OBz, o 2 Allyl, H -60 to -87 C CO2Me 70-94% yield 89-97% ee

D. MacMillan, J. Am. Chem. Soc. 2002,1172

Bryan Wakefield @ Wipf Group 11 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Iminium Ion: Friedel-Crafts Alkylation R

Aniline Additions

R1 O N R3 t R1 R R O Bn N Bu HCl R3 R2 H R=Me, Et, Ph, O R1= H, OMe, Me DCM CH2OBz, pCl-Ph, R2 -50 to 20 oC SMe, Cl CO2Me, pNO2Ph R2= Me N, Pyrrolidino 65-97% yield 2 84-97% ee D. MacMillan, J. Am. Chem. Soc. 2002, 7894

Bryan Wakefield @ Wipf Group 12 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Enamine: Aldol Reaction R

Ketone-Aldehyde Aldol

30 mol% CO H N 2 O OH O O H + H R DMSO R 20 vol%

R=Ph, p-NO2Ph, p-BrPh, 54-97% yield o-ClPh, 2-Nap, i-Pr 60-96% ee B. List, J. Am. Chem. Soc. 2002, 2395 Also see: L. Gong, J. Am. Chem. Soc. 2005, 9285 Aldehyde Cross-Aldol C. Barbas III, Org. Lett. 2005, 1383

10 mol% CO H O O N 2 O OH 1 + H R 2 H H R DMF, 4 oC H R R1= Me, n-Bu, Bn 3:1 to 24:1 anti:syn 75-88% yield R2= Et, i-Bu, Cy, Ph, 91 to 99% ee i-Pr

D. MacMillan, J. Am. Chem. Soc. 2002, 6798

Bryan Wakefield @ Wipf Group 13 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Enamine: Aldol Reaction R

Aldehyde-Ketomalonate Aldol

10 mol% CO H O O N 2 O OH H CO2Et 1 + R 2 H R2 H EtO2C R DMF, 4 oC R1 1 2 R =Me, Et, i-Pr R = CO2Et, 81-97% yield Allyl, hexyl, CF 3 67-90% ee Ph, H 2 examples had no induction

K.A. Jorgensen, Chem. Comm. 2002, 6205 Enolexo Aldolization

OH OHC CHO 10 mol% N CO2H OHC R1 H R1 R DCM, RT R 4:1 to 20:1 d.r. R and R1= H or Me 74-95% yield 75-99% ee

B. List, Angew. Chem. Int. Ed. 2003, 2785

Bryan Wakefield @ Wipf Group 14 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Enamine: Aldol Reaction R

Self-Condensation Reactions

CO H N 2 OH O O H

H Various H Solvents 2-13% yield 0 oC or RT 56-90% ee C. Barbas III, J. Org. Chem. 2002, 301

O 10 mol% O O R1 O N CO2H + H R1 H H DMF, 4 oC 1 OH R =Et, i-Pr 2. MnO2, EtOAc i-Bu 24-53% yield 11-47% ee

C. Barbas III, Tet. Lett. 2002, 9591

Bryan Wakefield @ Wipf Group 15 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Enamine: Mannich Reaction R

Aldehyde-Imine Mannich Reactions

PMP CO H PMP O N N 2 O HN H 1 + R H CO Et H EtO2C H 2 5 mol% 1 Dioxane, RT R R1=Me, Et, i-Pr n-Bu, n-Pent, 45-89% yield TBS-propanol, 1.1 to 19:1 d.r. 2-octene, 3 butene 91-99% ee C. Barbas III, J. Org. Chem. 2003, 9624

PMP PMP CO H PMP O PMP O HN O N N 2 O HN 0.2-5 mol% cat. H N 1 + + 1 R CO2R H EtO C H H CO2Et 1 NHSO2CF3 2 30 mol% CO2R 1 2 1 R R R DMSO, RT R2 R 1 11:1 to 20:1 d.r. R=Me, n-Bu, R =Et, allyl, t-Bu R1=Ph, Thienyl, p-tol, i-Pr, t-Bu NH 42-99% yield 60:40 to 96:4 syn:anti 97-99% ee p-i-PrPh, p-t-BuPh, 66-99% yield R2=Me 55-99% ee 1 2 R =R = (CH2)2 K. Maruoka, J. Am. Chem. Soc. 2005, 16408 C. Barbas III, Org. Lett. 2004, 2507

Bryan Wakefield @ Wipf Group 16 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Enamine: Mannich Reaction R

Three Component Coupling Mannich Reactions

O MeO PMP O N CO2H O HN + + O MeO PMP H O N CO2H OH HN R2 H H R2 + + R1 H H NH2 35 mol% 1 2 2 R 1 R H R DMSO, RT R 10 mol% R1=H, Me, OMe, OH NH2 R1 2 1 NMP, -20 to RT R =p-NO2Ph, n-Pentyl, i-Bu, Bn-ethanol, 3:1 to 20:1 d.r. R =Me, Et, n-Pr then 2 95:5 syn:anti 3-butene, phenethyl,2-nap, i-Pr, 35-92% yield R =p-NO2Ph,2-nap, Ph, p-ClPh NaBH4, MeOH 61-99% ee 10-95% yield p-CNPh, p-BrPh, p-Biphenyl, p-tol p-BrPh, p-tol, furyl, pyridine 71-99% ee B. List, J. Am. Chem. Soc. 2002, 827 Y. Hayashi, Angew. Chem. Int. Ed. 2003, 3677

Ketimine Mannich Reactions O O N O N O O NH N CO Et 1 + H R1 2 R H CO2Et CHO 4 4 R 5 mol% R R2 R2 R4=i-Pr, Me, Allyl Et O, DCM R3 2 R3 0 oC 1 2 R =R =C4H4 4:1 to 20:1 d.r. R1=H 72-99% yield R2=OMe or H 83-98% ee R3=H, Me, OMe, F K. A. Jorgensen, Angew. Chem. Int. Ed. 2004, 4476

Bryan Wakefield @ Wipf Group 17 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Enamine: Micheal Addition R

Additions to Nitroalkenes

N H N R N N O H O 10 mol% O Ar O Ar Ar R=H, NMe2, pyrrolidine NO2 NO + NO2 + Ar 2 NO2 OH 15 mol% 5 mol% DNBA OH CHCl , 0 oC CHCl3, RT Ar= 4-MeOPh, 2-MeOPh 3 Ar=Ph, 4-MePh, 4-MeOPh 1-nap, 2 nap, thienyl 93:7 to 99:1 d.r. 65-85% yield 4-Cl-Ph, 2-CF3-Ph 92-100% yield 96-98% ee 2,6-Cl2Ph, 3,4-Cl2Ph, 88-98% ee 2,4-Cl2Ph, 1-nap, thienyl A. Alexakis, Org. Lett. 2003, 2559 H. Kotsuki, J. Am. Chem. Soc. 2004, 9558

O N N R2 + Ph 30 mol% H O Ph H NO 2 30 mol% TFA NO R1 H 2 2 1 1 R R R =Me 2-PrOH, 4 oC 1 2 R =R = (CH2)4 or (CH2)5 55:45 to 89:11 d.r. R2=Me, Et, Pr, nonyl, Ph, 64-95% yield 18-91% ee 4-i-PrPh, 4-t-BuPh C. Barbas III, Org. Lett. 2004, 2527

Bryan Wakefield @ Wipf Group 18 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Enamine: Micheal Addition R

Additions to Enones

O N O R Bn O O N O H HCl R H H 10 mol% THF, RT

R= Ph, 2-nap, 8:1 to 49:1 anti:syn Me, H 85-99% yield X=CH2 or NTs 80-97% ee

B. List, Angew. Chem. Int. Ed. 2004, 3958

Bryan Wakefield @ Wipf Group 19 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Enamine: Oxidations R

α-Aminations

O Cbz Cbz CO2H N N N Cbz H + H HO N N R Cbz 10 mol% R o R= i-Pr, n-Pr, n-Bu CH3CN, 0 C to RT 93-99% yield Me, Bn 95-97% yield then NaBH4

B. List, J. Am. Chem. Soc. 2002, 5656

α-Chlorinations O N O Cl Bn N O O Cl Cl H TFA R R + H H Cl Cl 5 mol% Cl Cl Acetone, -30 oC R= n-Hexyl, 5-hexenyl 71-94% yield Cy, Am, Bn, MOM-propanol, 80-95% ee 4-pentanone D. MacMillan, J. Am. Chem. Soc. 2004, 4108 Also see: K. A. Jorgensen, J. Am. Chem. Soc. 2004, 4790 For α-Fluorination see: D. MacMillian, J. Am. Chem. Soc. 2005, 8826

Bryan Wakefield @ Wipf Group 20 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Enamine: Oxidations R

α-Aminoxylations

O O O O N CO2H O N CO2H O H NHPh H NHPh

10 mol% X 10 mol% o o R R DMF, 0 C R R X=O, NMe DMF, 0 C R R R=H, (OCH ) , Me 77-96% yield 53 and 84% yield 2 2 99% ee 96 and 99% ee

O N CO2H O O H Ph O N NHPn OH 10 mol% o DMF, 0 C 40% yield 33% yield 99% ee 4% ee

Y. Hayashi, Angew. Chem. Int. Ed 2004, 1112 Also see: G. Zhong, Angew. Chem. Int. Ed. 2003, 4247 A. Cordova, Angew. Chem. Int. Ed. 2004, 1109 D. MacMillan, J. Am. Chem. Soc. 2003, 10808

Bryan Wakefield @ Wipf Group 21 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Iminium/Enamine Tandem Reactions R

Cyclopropanation

R CO2H N R1 S R1 H R O + OHC 20 mol% 1 R=Pr, CH2OAllyl, R = COPh, 6:1 to 72:1 d.r. Me, 5-hexenyl, CO4-BrPh 63-85% yield 89-96% ee Ph, i-Bu CO4-MeOPh

D. MacMillan, J. Am. Chem. Soc. 2005, 3240

O 1,4 Addition/ α-Chlorination N Bn N N O H Cl Cl Cl Cl 20 mol% Nu O Nu + + R O Cl Cl R Nu= 2-Mefuran, 2-MeOthiophene 2Me-5-OTMS furan, N-Bn indole Cl 9:1 to 25:1 d.r. R=Me, Pr, CO2Et, 67-97% yield CH2OAc, Ph, iPr 99% ee D. MacMillan, J. Am. Chem. Soc. 2005, 15051

Bryan Wakefield @ Wipf Group 22 12/17/2005 O R R R2NH N 1 R -H O 1 Lewis Basic Organocatalysis: 2 2 R R 2 Iminium/Enamine Tandem Reactions R

1,4 Reduction/Micheal Addition

O N

Bn N tBu COR COR H 20 mol% CHO EtO C CO Et CHO 2 2

R=Ph, 2-nap, Me N 15:1 to 50:1 d.r. 2-Br-thiophenyl, H 86-98% yield 86-96% ee

B. List, J. Am. Chem. Soc. 2005, 15036

Bryan Wakefield @ Wipf Group 23 12/17/2005 O NR3 C R3N Lewis Basic Organocatalysis: O 1 H R 1 1-Ammonium Enolate R

Ketene Dimerization

OMe O 1 eq. iPr2NEt O O 5 mol% cat OTMS R MeO R Cl DCM, RT N N then Me R R= Et, iPr, tBu, HN(OMe)Me H N CH OTIPS, 58-88% yield 2 91-96% ee CH2CO2Me Catalyst

M. Calter, Org. Lett. 2003, 4745

β-Lactam Synthesis

O Cl Ts Cat. OBz N + Ts O N N 2 eq NaH BnO H H CO2Et 15-crown-5 N H EtO2C OBn Toluene, 0 oC Catalyst 25:1 d.r. 60% yield 99% ee T. Lectka, Acc. Chem. Res. 2004, 592

Bryan Wakefield @ Wipf Group 24 12/17/2005 O O R N Lewis Basic Organocatalysis: R1 3 R1 X - HX NR3 2-Ammonium Enolate

Cyclopropanations

O O 3 1.3 eq. Cs2CO3 O R + 1 2 2 R R 1 R MeCN, 80 oC R Br R3 10-20 mol% cat O

2 R1= OtBu, NEt , R = Ph, 4-Et2NPh 53-96% yield 2 80-97% ee NMe(OMe) 4-BrPh, 3-BrPh OBn, OMe, n-pentyl, 3-indole 3 R = H, Me, Boc2N

OMe OMe N H N

M. Gaunt, Angew. Chem. Int. Ed. 2003, 4641

Bryan Wakefield @ Wipf Group 25 12/17/2005 O R3N O R1 Lewis Basic Organocatalysis: -H2O R1 3-Ammonium Enolate NR3

Baylis-Hillman Reaction

N CO2H OH O O O 10 mol% + H R R H 10 mol% co-cat CHCl3 R= 2-NO2Ph, 4-NO2Ph, 52-95% yield Co-catalyst 2, 4-NO2Ph, furyl, 63-81% ee 2-CF3Ph, S. Miller, Org. Lett. 2003, 3741 1-NO2-3-OMePh 1-NO2-2-nap

N CO2H OH O O 10 mol% H HO O O + R 10 mol% co-cat R H N CHCl3 N H 24-88% yield R=4-NO2Ph, 4-ClPh 4-BrPh 7-49% ee co-Catalyst

M. Shi, Tet. Asym. 2002, 1941

Bryan Wakefield @ Wipf Group 26 12/17/2005 O O

1 R3N 1 Lewis Basic Organocatalysis: R X R NR3 - X Acyl-Ammonium Ion

Kinetic Resolution

OH OAc O O NHAc 0.1 eq Ac2O NHAc N N H 0.005 mol% cat N Me BOCHN H O rac 90-100% yield Ph (based on Ac2O) N 0-84% ee depending NH on solvent

S. Miller, J. Am. Chem. Soc. 1998, 1629 Also see S. Miller, Acc. Chem. Res. 2004, 601

Bryan Wakefield @ Wipf Group 27 12/17/2005 R R X R2S S Lewis Basic Organocatalysis: R1 -HX R1 Sulfur Ylide

Epoxidation of Aldehydes 10 mol%

O R S R O Br R=Me or Et + Ar H NaOH, Ar Ph t-BuOH/H2O 9/1 Bu4NI Ar= Ph, 4-ClPh, 4-CF3Ph, 4-MeOPh, 3,4-MeOPh, 75-86% d.e. 2-nap, furyl, thienyl, 33-97% yield phenethenyl 64-93% ee P. Metzner, J. Org. Chem. 2001, 5620

10 mol% Ph Ph O O

O O O Br O S + Ar H NaOH, Ar Ph MeCN/H2O 9/1 Ar= Ph, 4-NO2Ph 12:1 to 5:1 d.r. 4-ClPh, 4-CF3Ph 14-41% yield 94-98% ee J. Goodman, Tet. Lett. 2002, 5427

Bryan Wakefield @ Wipf Group 28 12/17/2005 R R O + N N OH R1 H Lewis Basic Organocatalysis: X X R Carbene Catalysis

Benzoin Condensation Ph N N N O 10 mol% O O tBu Ar Ar Ar H KOtBu, THF OH Ar= Ph, 4-FPh, 4-ClPh, 4-BrPh, 8-100% yield 3-Cl, 4-Me-Ph, 3-MePh, 62-91% ee 4-MeOPh, 2-furyl, 2-nap D. Enders, Angew. Chem. Int. Ed. 2002, 1743

BF Stetter Reaction O 4 N N F N F O F O 2 F R CO2R 20 mol% F R1 2 X R1 o X CO2R 2 eq. Et3N, Toluene, 25 C R=H or Br 92-96% yield 89-99% ee X=O, S, CH2 R1=Et, Me R2=Me, Et T. Rovis, J. Am. Chem. Soc. 2004, 8876

Bryan Wakefield @ Wipf Group 29 12/17/2005 L.B. L.B. Lewis Basic Organocatalysis: L.A. R L.A. R Lewis Acid Activation

Allylations N O H O N H P (CH2)5 P 1 H N N H R SiCl3 O N N + OH 2 5 mol% R R H R 1 o R =H or Me R= Ph, 2-nap, 4-MeOPh, DCM, iPr2NEt, -78 C 1 2 2 R R R =H or Me 4-CF Ph, 2-furyl 3 95:5 to 99:1 syn:anti 57-92% yield 81-96% ee S. Denmark, J. Am. Chem. Soc. 2001, 9488

N O OMe O SiCl3 OH + R H R 5 mol% R= Ph, Cinnamyl, methylcinnamyl 60-85% yield 1 eq. iPr NEt 4-MeOPh, 2-furyl, 2-thiophenyl 2 5-96% ee 4-NO2Ph, 4-ClPh, 4-FPh, 4-CF3Ph P. Kocovsky, Angew. Chem. Int. Ed. 2003, 3674

Bryan Wakefield @ Wipf Group 30 12/17/2005 L.B. L.B. Lewis Basic Organocatalysis: L.A. R L.A. R Lewis Acid Activation

Aldol Reactions Me Me

N N t-Bu O O tBu On-Bu n-BuO OH O OSiCl3 O + 1 1 2 R 2 OMe OMe R R 10% mol R R1=Ph, 4-CF Ph, 4-MeOPh, 84-97% yield 3 60:40 to 93:7 e.r. Cinnamyl, Et, Phenethyl cyclopropyl, Cy, t-Bu, 1-nap, 2-furyl S. Denmark, J. Am. Chem. Soc. 2002, 4233 R2= Et, alkynyl, Me

N H O O N H P (CH2)5 P H N N N N H OSiCl O 3 O OH + + SiCl 5 mol% 1 4 n-Bu R H 1 o n-Bu R 10 mol% iPr2NEt, DCM -78 C R1=Cinnamyl, methylcinnamyl then 79-98% yield 1-nap, 2-nap, 4-MeOPh, NaHCO3, KF 78:22 to 99:1 e.r. 4-CF3Ph, 2-furyl, 2-thiophenyl

S. Denmark, Org. Lett. 2003, 2303

Bryan Wakefield @ Wipf Group 31 12/17/2005 L.A. L.A. S Lewis Acidic Organocatalysis: S

HF Micheal Additions Ar 2

R2 CHO Ar R2 R1 OTMS 2 mol% 3 Ar=3,5-t-BuPh OTMS N R 3 O + NO2 R 1 R2=Ph, n-Pr R Toluene, -78 oC 81:19 to 97:3 anti:syn R3=H, Me 87-99% yield R1=Me, Et 2 3 R =R = (CH2)4 90-98% ee K. Maruoka, J. Am. Chem. Soc. 2003, 9022 Epoxidation O CO2Et N F O N SO Me O 2 H 10 mol% O O O O R1 O O R2 R1 10 mol% R2 Ph Ph 1 Oxone, RT R = Ph, Me, CH2OH, R R 51-100% yield CH OAc, n-Bu Oxone 2 14-83% ee R=H, Ph 61-72% conv. H, CO2Et, C(O)Ph 80-90% ee R2= Ph, n-Pr, A. Armstrong, J. Org. Chem. 2002, 8610 Y. Shi, Org. Lett. 2003, 293

Bryan Wakefield @ Wipf Group 32 12/17/2005 B B Bronsted Basic Organocatalysis: S H S H

Desymmetrization

O H CO H 5-30 mol% Cat 2 O RO OR MeOH, Et2O CO2Me H O O O 70-99% yield 8 other various 90-98% ee cyclic anhydrides OMe catalyst OR R= OR or N N N H H N

L. Deng, J. Am. Chem. Soc. 2000, 9542

Bryan Wakefield @ Wipf Group 33 12/17/2005 H-A X A-H X Bronsted Acidic Organocatalysis: R1 R2 R1 R2

Strecker Reaction 1. 2 mol% cat O 1 1 R toluene, -70 oC R t-Bu O N + HCN N CF3 H Ph N N N H R 2. TFFA R H H H O N R= Ph, tBu, 4-MeOPh, 3-MeOPh, 65-99% yield 2-MeOPh, 4-MePh, 3-MePh, 77-97% ee Catalyst HO 2-MePh, 4-BrPh, 3-BrPh, 2-BrPh, 4-tBuPh, Cy, I-Amyl t-Bu OCOt-Bu pentyl, iPr, cyclopropyl cyclooctyl R1=Allyl, benzyl E. Jacobsen, Angew. Chem. 2002, 1336

Acyl-Pictet-Spengler

1. 3A MS or NaSO4 R NH2 O 2. AcCl, 2,6 lutidine R NAc t-Bu S + 2 5-10 mol% cat R N 1 N R H 2 N N R R2 H R1 N H H H O N Ph R=H, OMe R2= iPr, n-penty, R=iBu 1 R =H, OMe CH(CH2CH3)2 Catalyst CH2CH2OTBDPSl iBu E. Jacobsen, J. Am. Chem. Soc. 2004, 10558

Bryan Wakefield @ Wipf Group 34 12/17/2005 H-A X A-H X

Bronsted Acidic Organocatalysis: R1 R2 R1 R2

Hydrophosphonylation

NO 2 O NO2 Bn O N P P R t-Bu S + O H 10 mol% Cat H O O N R H O N N HN H H R= Ph, 3-pentyl, iPr, Cy, Bn O N tBu, 4-FPh, 4-MeOPh NO2 NO2 HO 4-MeO2CPh, 2-MePh, Catalyst 2-ClPh, 3-ClPh, 4-ClPh, 2-nap, 3-pyridyl, 2-furyl 52-98% yield t-Bu OCOt-Bu 2-thienyl, 2-pyrrolyl 81-98% ee E. Jacobsen, J. Am. Chem. Soc. 2004, 4102

Bryan Wakefield @ Wipf Group 35 12/17/2005 H-A X A-H X

Bronsted Acidic Organocatalysis: R1 R2 R1 R2 Mannich Reactions

Boc 1. 5 mol% cat O NBoc t-Bu S N OTBS + N 2. TFA PrO R Bn N N H R OiPr H H O N R= Ph, 2-MePh, 3-MePh, 84-99% yield 4-MePh, 4-MeOPh, 86-98% ee HO 4-FPh, 3-BrPh, 4-BrPh Catalyst 1-nap, 2-nap, 2-furyl, 2-thienyl, 3-pyridyl, t-Bu OCOt-Bu 3-quinolinyl E. Jacobsen, J. Am. Chem. Soc. 2002, 12964

R Boc Boc N O O 2 mol% cat HN O O + Ac P R H DCM R O OH Ac R= 4-MeOPh, 4-MePh, R 4-BrPh, 4-FPh, 93-99% yield 2-MePh, 1-nap 90-98% ee R= 4-(!-Naph)-C6H4

M. Terada, J. Am. Chem. Soc. 2004, 5356 For a similar catalyst for Mannich rxn with Silyl ketene acetals see T. Akiyama, Angew. Chem. 2004, 1592

Bryan Wakefield @ Wipf Group 36 12/17/2005 H-A X A-H X

Bronsted Acidic Organocatalysis: R1 R2 R1 R2 Reductive Amination

OMe EtO2C CO2Et R NH 2 O O N O HN R=SiPh3 R H P Me + 10 mol% Cat R O OH 5A MS, Benzene Me OMe R Catalyst R= H, 4-Me, 4-MeO, 4-NO2 60-87% yield 4-Cl, 4-F, 3-F, 2-F 83-97% ee

Also works well with non-aromatic ketones D. MacMillan, J. Am. Chem. Soc. ASAP Other examples of reductive amination M. Reuping, Org. Lett. 2005, 378 B. List, Angew. Chem. Int. Ed. 2005, 7424

Bryan Wakefield @ Wipf Group 37 12/17/2005 H-A X A-H X

Bronsted Acidic Organocatalysis: R1 R2 R1 R2 Aza-Henry Reaction

N H H F3C N N

P(O)Ph S N 2 P(O)Ph 10 mol% HN 2 + MeNO2 CF3 Ar NO Ar 2 Ar= Ph, 4-MePh, 4ClPh, 2-nap, 2-furyl, 2-pyridyl, 68-91% yield 2-thienyl, cinnamyl 63-76% ee

Y. Takemoto, Org. Lett. 2004, 625

OTf

Boc Boc H H N NO2 10 mol% cat N + HN N Ar R NO2 H Ar N N R H Ar= Ph, 4-NO2Ph, 3-NO2Ph H 4-CF3Ph, 4-ClPh, 2-NO2Ph 7:1 to 19:1 d.r. R=H or Me 51-69% yield catalyst 60-95% ee

J. Johnson, J. Am. Chem. Soc. 2004, 3418

Bryan Wakefield @ Wipf Group 38 12/17/2005 H-A X A-H X

Bronsted Acidic Organocatalysis: R1 R2 R1 R2 Micheal Addition

N H H F3C N N S 10 mol% EtO2C CO2Et NO CF 1 2 + EtO C CO Et 3 R 2 2 NO R1 2 R1= Ph, 2,6-MeOPh, 4-FPh, 74-95% yield 1-nap, 2-nap, pentyl, iBu 81-93% ee

Y. Takemoto, J. Am. Chem. Soc. 2003, 12672

O N O 2 O R 10 mol% cat 5b R 1 + MeNO2 R R1

R=H, 4-Cl, 4-F, 2-Me 80-94% yield R1=H or 4-MeO 89-96% ee

T. Soos, Org. Lett. 2005, 1967 Also see A. Lattanzi, Org. Lett. 2005, 2579

Bryan Wakefield @ Wipf Group 39 12/17/2005 H-A X A-H X

Bronsted Acidic Organocatalysis: R1 R2 R1 R2 Morita-Baylis-Hillman

O OH O O 10 mol% cat + OH Et P, THF R R H 3 OH

R= Phenethyl, Bn ethanol, 39-88% yield 3-hexene, Cy, iPr, Ph, 67-96% ee cinnamyl Catalyst

S. Schaus, J. Am. Chem. Soc. 2003, 12094

iPr Ts O O NHTs N N 10 mol% cat + R1 1 2 R2 H R R OH N OH 1 R2=Ph, 4-ClPh, R =Me, Et, H 88-100% yield catalyst 3-ClPh,4-BrPh 87-95% ee 4-MeOPh, 2-nap 2-furyl, 4-NO Ph 2 H. Sasai, J. Am. Chem. Soc. 2005, 3680 Also See W. Wang, Org. Lett. 2005, 4293

Bryan Wakefield @ Wipf Group 40 12/17/2005 H-A X A-H X

Bronsted Acidic Organocatalysis: R1 R2 R1 R2 Formal [4+2] Cycloaddition

Ar Ar O OH O OH O R TBSO H R TBSO R CH COCl + Ar Ar 3 O O 10 mol%, 52-97% yield N Ar= 1-nap N 96:4 to 99:1 e.r.

V. Rawal, Nature 2003, 146

Bryan Wakefield @ Wipf Group 41 12/17/2005 OH

O H Organocatalysis in Total Synthesis: O H O OH (-)-Littoralisone OH O O O OH O

O O H O O H OH O OH OH OH O O HO O OH O O OH O O (-)-littoralisone (-)-brasoside

-Extracted from Verbena littoralis, a plant widely used in folk medicine -Found to increase nerve growth factor induced neurite outgrowth in PC12D cells

D. MacMillan, J. Am. Chem. Soc. 2005, 3696

Bryan Wakefield @ Wipf Group 42 12/17/2005 OH

O H Organocatalysis in Total Synthesis: O H O OH (-)-Littoralisone OH O O O OH O

Retrosynthesis OH OP

O H O O H O O OH O OP OH OP O OH O O O O O OP O O

O O O + OP OP PO O O O TMSO OP OAc

O OP OP + 2 O PO O TMSO OP O

Bryan Wakefield @ Wipf Group 43 12/17/2005 OH

O H Organocatalysis in Total Synthesis: O H O OH (-)-Littoralisone OH O O O OH O

Synthesis of brasoside core

1. TBDSPCl 1. MesCl 1. 40 mol% D-Proline HO TBDPSO O 2. DIBAL O 2. O3 2. (EtO)2P(O)CH2CO2Me CO2Me 3. DMP OH 95% over OMes 56% over 2 steps OMes O 2 steps 92% over 3 steps

(-)-citronellol O 30 mol% L-Proline OH 1. POCl , DMF O o 3 DMSO, 40 C 2. NaClO2 then AcO2 3. HF•pyridine 91% yield O 56% over 3 steps O 10: cis/trans OAc OAc Synthesis of Sugar fragment OR O O O OH OH D-Proline TMSO OBn OBn RO O H H H HO OBn 98% ee MgBr2•OEt2 OBn OBn 78% OBn 65%, 10: 1 d.r. R= p-benzyloxy cinnamoyl 1. Ag O, BnBr 2 O 2. Pd/Al2O3, HCO2NH4 3. TMSCl OBn OBn BnO O O 62% over 3 steps TMSO OBn D. MacMillan, Angew. Chem. Int. Ed. 2004, 2152

Bryan Wakefield @ Wipf Group 44 12/17/2005 OH

O H Organocatalysis in Total Synthesis: O H O OH (-)-Littoralisone OH O O O OH O

Fragment Coupling OBn O O O O OBn TMSOTf O + OBn O BnO O O TMSO OBn 74% O OBn OBn OAc O O O OBn OH O h! = 350 nm; H2, Pd/C O H 84% O H O OH OH O O O OH O -First total synthesis of (-)-Littoralisone was completed in 13 steps in 13% overall yield - Proline was used to in 3 steps to set 4 stereocenters.

Bryan Wakefield @ Wipf Group 45 12/17/2005 Conclusions

 Organocatalysts can be used for a wide arrary of synthetically useful transformations.

 The current state of the art involves the use of chiral secondary amines to form iminium ions or enamines.

 The use of chiral H-bond donors is an immerging area has been shown to be an effective alternative to secondary amines in some reactions.

Bryan Wakefield @ Wipf Group 46 12/17/2005 Future Directions

 Innovation- The world doesn’t need a new Diels-Alder catalyst.

 Replacement- Removing the Pd from cross-coupling reactions. There are some examples, but no synthetically viable protocols.

 Discovery- Development of a “privileged” catalyst structure that does multiple reactions extremely well.

 Use- Show practical applications of the catalysts and the reactions they promote.

Bryan Wakefield @ Wipf Group 47 12/17/2005