title: 3-Pyrrolidinecarboxylic acid for direct catalytic asymmetric anti-Mannich-type reactions of unmodified ketones.
abstract: We report the development of direct catalytic, enantioselective, anti-selective Mannich-type reactions between unmodified ketones and alpha-imino esters under mild conditions. The reactions were performed using 5-10 mol % of (R)-3-pyrrolidinecarboxylic or (R)-beta-proline as catalyst in an environmentally benign solvent, 2-PrOH, at room temperature. The anti-Mannich products were obtained in good yields with high diastereo- and enantioselectivities (up to anti/syn >99:1, 99% ee). While (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid is an excellent catalyst for the anti-Mannich-type reactions of aldehydes, it did not efficiently catalyze the corresponding Mannich-type reactions of ketones; (R)-3-pyrrolidinecarboxylic acid did efficiently catalyze the Mannich-type reactions of ketones. (S)-Proline or (S)-2-pyrrolidinecarboxylic acid has been reported to catalyze the Mannich-type reactions of ketones to afford the syn-products. Thus, the position of the carboxylic acid group on the pyrrolidine ring directs the stereoselection of the catalyzed reaction, providing either syn- or anti-Mannich products.
authors.affiliation: The Skaggs Institute for Chemical Biology, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
authors.forename: Haile
authors.initials: H
authors.lastname: Zhang
authors.forename: Maria
authors.initials: M
authors.lastname: Mifsud
authors.forename: Fujie
authors.initials: F
authors.lastname: Tanaka
authors.forename: Carlos F
authors.initials: CF
authors.lastname: Barbas