ChemInform Abstract: Synthesis and Evaluation of (S)‐Proline‐Containing α,β‐Dipeptides as Organocatalysts in Solvent‐Free Asymmetric Aldol Reactions under Ball‐Milling Conditions.

Abstract

With the aim of developing sustainable enantioselective reactions, the organocatalytic activity of three proline-based α,β-dipeptides was evaluated in the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde according to three contrasting experimental protocols: (1) solvent-free, under high-speed ball milling (HSBM) activation, (2) neat conditions with conventional stirring, and (3) in solution with conventional stirring. The HSBM technique, providing “green” solvent-free reaction conditions, proved to be the synthetic strategy of choice, proceeding in shorter reaction times and affording the aldol products with higher stereoselectivity. The organocatalytic activity of two of the α,β-dipeptides was then compared in the solvent-free asymmetric aldol reaction under ball-milling activation in order to establish the influence of a stereogenic center in the β-amino acid residue on the stereoinducing ability of the organocatalyst. The organocatalyst with one stereogenic center and the organocatalyst with two stereogenic centers exhibit similar efficiency in the asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde, affording the aldol product in excellent yield, and with high anti diastereoselectivity and good enantioselectivity. Thus, the presence of a second stereogenic center in the α,β-dipeptide organocatalysts does not result in a more stereoselective reaction relative to that induced by the α,β-dipeptide organocatalyst with one stereogenic center.