Pipecolic Acid-Catalyzed Direct Asymmetric Mannich Reactions

Abstract

Mannich reactions between aldehydes and N-p-methoxyphenyl-protected alpha-imino ethyl glyoxylate have been performed using (S)-pipecolic acid as catalyst. The reactions give both syn- and anti-products (dr=1.4-2:1) with high enantioselectivities (>98% ee). In contrast, (S)-proline-catalyzed reactions give mainly syn-products with high enantioselectivities. Computational studies reveal that the energetic preference between the transition structures involving the s-cis-enamine and the s-trans-enamine is smaller for the pipecolic acid as compared to proline, yielding the (2S,3R)-anti and the (2S,3S)-syn Mannich product in nearly equal amounts.

Quantum Mechanical Investigations of Organocatalysis: Mechanisms, Reactivities, and Selectivities

“…48 The diastereomeric ratio of syn - versus anti -product ranged from 2:1 to 1:1. This unusual change in diastereoselectivity upon the increase in ring size from five to six was investigated computationally by Cheong and Houk.…”

“…This unusual change in diastereoselectivity upon the increase in ring size from five to six was investigated computationally by Cheong and Houk. 48 …”

Computational prediction of small-molecule catalysts

“…In collaboration with Barbas’s research group, we modelled the transition states of these reactions and found that selectivity for the anti orientation arises when the s- cis -enamine intermediate (formed from a reaction between the catalyst and the aldehyde reactant) attacks the imine starting material, rather than the alternative possibility in which the s- trans -enamine attacks17. On this basis, several potential catalysts that would favour the s- cis transition state were proposed, and computations were carried out to predict which of these molecules would be highly selective for the product in the anti orientation.…”

Reactions of Aldehydes and Ketones and their Derivatives

“…26 (S)-Proline also gives high ee, but also predominantly syn ee product. Calculations indicate that the transition structures involving the s-cis-and s-trans-enamine intermediates are much closer in energy in the case of catalyst (10).…”