PPRROOLLIINNEE CCAATTAALLYYZZEEDD AALLDDOOLL,, MMAANNNNIICCHH,, AANNDD MMIICCHHAAEELL RREEAACCTTIIOONNSS:: AAPPPPLLIICCAATTIIOONN OOFF AASSYYMMMMEETTRRIICC OORRGGAANNOOCCAATTAALLYYSSIISS JANUARY 19, 2005 SANJIT SANYAL DEPARTMENT OF CHEMISTRY MICHIGAN STATE UNIVERSITY WWhhaatt iiss Organocatalysis?  “ A field of chemistry that pays my mortgage and has gotten me many free dinners.” - David W. C. Macmillan WWhhaatt iiss Organocatalysis?  “A catalysis field wherein small organic molecules efficiently and selectively catalyze organic transformations.” - David W. C. Macmillan  “Organocatalysis is the catalysis of a reaction with an organic small molecule. By accepted convention, organic small molecule means a molecule without a metal, and not a macromolecule like protein, nucleic acid, or polymer.” - K. N. Houk  “Catalytic reactions mediated by small organic molecule in absence of metals or metal ions.” - Carlos F. Barbas, III Organocatalysts Me N Ph t-BuO Me N H O i-Pr H O H O H O R12N N N N N BOCHN N N N OMe H H H N O O O i-Pr O Me Ot-Bu Me R Fe R N Trt N Me R R R Peptide-Based Catalyst (Scott J. Miller) Chiral DMAP (Gregory C. Fu) Br H N O O O H N N AcO O O O OMe CO H O N 2 H N chiral quaternary fructose-derived acetylquinine L-proline ammonium salt chiral-ketone H N HO S OMe N O N H H N 5,5-dimethyl thiazoli- H N OH 2 (S)-2-methoxy-methyl dinium-4-carboxylate (-)-cinchonidine -pyrrolidin (SMP) (S)-phenylalanine (DTMC) a cinchona alkaloid CCllaassssiiffiiccaattiioonn ooff Organocatalysts  Type-I : Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst. O O O 3 mol % L-proline O DMF, 20 ºC, 20 h O 100% OH 1 2 93% ee Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621.  Type-II : Organic molecules that form reactive intermediates. The chiral catalyst is consumed in the reaction and requires regeneration in parallel catalytic cycle. O O O O O O O R R 2 30 mol % 2 R1 R3 30% H2O2 (3 equiv.) R1 R3 CH CN-K CO 3 2 3 3 4 Shu, L.; Shi, Y. J. Org. Chem. 2000, 65, 8807–8810. CCllaassssiiffiiccaattiioonn ooff Organocatalysts  Type-III : Phase-transfer reactions. The chiral catalyst forms a host-guest complex with the substrate and shuttles between the standard organic solvent and a second phase. Catalytic Enantioselective Enolate Alkylation : Br Catalyst (10 mol %) Ph O Ph O H N CsOH•H O 2 N EtI N N OtBu OtBu Ph CH2Cl2, -60 ºC, 30 h Ph H Et O 5 6 Chiral quaternary Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414–12415. ammonium salt  Type-IV : Molecular-cavity-accelerated asymmetric transformations in which the catalyst may select between competing substrates, depending on size and structure criteria. O O O O OH O H Nu OH N BOCHN NO2 1. Polymer BOCHN HN HO 2. Nu O H NO2 O 7 8 Polymer Sellergren, B.; Karmalkar, R. N.; Shea, K. J. J. Org. Chem. 2000, 65, 4009–4027. TTyyppee--II  Activation of the reaction based on the nucleophilic/electrophilic properties of the catalyst.  Background Information  Direct Catalytic Asymmetric Aldol Reaction  Direct Catalytic Asymmetric Mannich Reaction  Direct Catalytic Asymmetric Michael Reaction BBaacckkggrroouunndd IInnffoorrmmaattiioonn OH 1. HCN, Catalyst, H N CHO CHCl , rt, 24 h 3 COOH HO 2. 4N H SO , 8.7% 2 4 9 (-)-10 8.9% ee N (-)-Cinchonidine A cinchona alkaloid Bredig, G.; Fiske, P. S. Biochem. Z. 1912, 46, 7–23. Catalyst O Ph 1 mol % Catalyst, toluene Me C O MeOH MeO H N Me 110 ºC, 90% Ph AcO 11 12 OMe 74% ee (R) N Acetylquinine Pracejus, H. Justus Liebigs Ann. Chem. 1960, 634, 9-29. BBaacckkggrroouunndd IInnffoorrmmaattiioonn Hajos-Parrish-Eder-Sauer-Wiechert Reaction Catalyst O O Me 47 mol % catalyst, 1N HClO CO H 4 N 2 O O CH3CN, 80 ºC, 25 h O H 83% 13 14 15 L-proline 71% ee Eder, U.; Sauer, G.; Wiechert, R. Angew. Chem. Int. Ed. 1971, 10, 496–497. Catalyst O O O O 3 mol % catalyst p -TsOH CO H N 2 O DMF, 20 ºC, 20 h PhH, 15 min O O 100% OH 99% H 1 2 16 L-proline 93% ee 95% ee Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615–1621. WWhhyy PPrroolliinnee??  Proline is an optically active pyrrolidine derivative. O O N O H O DMF, rt O OH 1 (±)-2  Asymmetric carbon is in the same molecule next to the functional groups. O H N N 2 O S O 3 O H H pyrrolidinium camphorsulphonic acid L–proline Hajos, Z. G.; Parrish, D. R. J. Org. Chem. 1974, 39, 1615-1621.