Organocatalytic Asymmetric Synthesis Using Proline and Related Molecules. Part 2.

Organocatalytic asymmetric synthesis has been extensively studied and several important procedures for preparing optically active organic compounds have been developed.Research activities in this area have progressed rapidly in the last ten years.This review addresses the most significant advances in asymmetric synthesis using proline and related chiral organocatalysts, mainly from the viewpoint of synthetic applications.This includes (1) Mannich reactions,(2) Michael addition reactions, (3) α-oxidation, (4) α-amination, (5) α-sulfenylation / selenenylation, (6) α-halogenation, (7) cycloaddition reactions, and (8) miscellaneous reactions such as C-C bond formation, epoxidation / oxidation, and reduction. MANNICH REACTIONSThe Mannich reaction is one of the most important multi-component condensation reactions using aldehyde, ketone and amine for the preparation of β-amino carbonyl compounds.This type of reaction is considered to be analogous to aldol condensation, and hence several approaches using organocatalytic systems have been reported to date. 1 In 2000, List and coworkers reported the first example of the asymmetric Mannich reaction using L-proline as an organocatalyst. 2For example, the reaction of acetone (excess), p-nitrobenzaldehyde, and p-anisidine in the presence of L-proline (35 mol%) gave the desired adduct in 50% yield with 94% ee (Scheme 1).The proposed mechanism involves the hydrogen-bonding activation mode between the enamine intermediate obtained from acetone and L-proline and the imine substrate in situ generated from p-nitrobenzaldehyde and p-anisidine.It is plausible that the stereochemistry of the product might be governed by steric repulsion between the anisidine and pyrrolidine moieties in the transition state. 3O 4 (5 mol%) CH 2 Cl 2 16 h, rt O HN CO 2 Et 70% yield dr > 19 : 1 ee > 99% H CO 2 Et N MeO OMe Scheme 5. Asymmetric Mannich reactions catalyzed by 4 18a + Scheme 6.