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.