Catalysis of 3-Pyrrolidinecarboxylic Acid and Related Pyrrolidine Derivatives in Enantioselective anti-Mannich-Type Reactions:  Importance of the 3-Acid Group on Pyrrolidine for Stereocontrol

Abstract

The development of enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives is reported in detail. Both (3R,5R)-5-methyl-3-pyrrolidinecarboxylic acid and (R)-3-pyrrolidinecarboxylic acid efficiently catalyzed the reactions of aldehydes with alpha-imino esters under mild conditions and afforded anti-Mannich products with high diastereo- and enantioselectivities (anti/syn up to 99:1, up to >99% ee). For the reactions of ketones with alpha-imino esters, (R)-3-pyrrolidinecarboxylic acid was an efficient catalyst (anti/syn up to >99:1, up to 99% ee). Evaluation of a series of pyrrolidine-based catalysts indicated that the acid group at the beta-position of the pyrrolidine ring of the catalyst played an important role in forwarding the carbon-carbon bond formation and in directing anti-selectivity and enantioselectivity.

Highly Enantioselective Construction of a Quaternary Carbon Center of Dihydroquinazoline by Asymmetric Mannich Reaction and Chiral Recognition

“…[12] To our surprise, high regioselectivities were observed in most of our cases. The dihydroquinazoline was regiospecifically attacked by the methyl side of unsymmetrical methyl ketones to give the linear b-amino ketone as the sole product.…”

Recent advances on organocatalysed asymmetric Mannich reactions

“…Similar work for the enantioselective anti-selective Mannich-type reactions of aldehydes and ketones with imines catalyzed by 3-pyrrolidinecarboxylic acid and related pyrrolidine derivatives was also reported by Tanaka at al. 39 …”

Die asymmetrische Aminokatalyse – Goldrausch in der organischen Chemie

“…Am wichtigsten war es ihnen, die Konformation des Enamins festzulegen und das Proton des Imins für die Aktivierung auszurichten (zehngliedriger cyclischer Übergangszustand I, Abbildung 5 d). [103] Ihre Erfahrung mit prolinkatalysierten Reaktionen [4d,g] und Rechnungen [25] veranlasste die Autoren, die Prolinstruktur in zweierlei Hinsicht zu modifizieren: Sie verlegten die Carbonsäureeinheit von Position 2 auf Position 3 des Pyrrolidinrings und führten an Position 5 eine zusätzliche Methylgruppe ein. Dies ergab den aktiven Katalysator XXII, der trotz seines sehr einfachen Molekülstruktur fast vollständig diastereo-und enantioselektiv wirkte.…”