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.

Lewis Base Catalysis in Organic Synthesis

“…(2) in Scheme 124]. [420] High levels of anti diastereoselectivity can be obtained in the reactions of aldehydes and ketones with imino glyoxylates when 107 is employed as a catalyst.…”

Lewis‐Base‐Katalyse in der organischen Synthese

“…(2) in Schema 124]. [420] So verläuft die Umsetzung von Aldehyden und Ketonen mit Iminoglyoxylaten in Gegenwart des Katalysators 107 mit hoher anti-Diastereoselektivität.…”

2.16 The Bimolecular and Intramolecular Mannich and Related Reactions

“…123 Anti-selective Mannich reaction of ketone with a-imino glyoxylate was also reported by means of 57. 124 The same research group developed a novel method for the anti-selective Mannich reaction by means of primary amine catalyst. 125 Screening of amino acids elucidated that L-tryptophan (58) is the catalyst of choice for the three-component Mannich reaction of a-hydroxyacetone derivatives to give the corresponding Mannich adducts with high anti-selectivity and with excellent enantioselectivities (Scheme 101).…”