Combined Proline–Surfactant Organocatalyst for the Highly Diastereo‐ and Enantioselective Aqueous Direct Cross‐Aldol Reaction of Aldehydes

Abstract

in water even in the presence of a surfactant. [5] There have been no successful asymmetric aldol reactions performed using organocatalysts in water in the absence of an organic cosolvent or other additives. Recently, we reported that a siloxyproline effectively catalyzes the highly diastereo- and enantioselective aldol reaction of ketones and aldehydes in the presence of water. [6] Barbas and co-workers reported the asymmetric aldol reaction of ketones and aldehydes in water catalyzed by a combination of a diamine and an acid. [7] Herein, we describe how combined proline–surfactant organocatalysis promotes the asymmetric direct aldol reaction of two different aldehydes in the presence of water and no other additives, with high diastereo- and enantioselectivity. The original version of this reaction reported by MacMillan and Northup was carried out in a polar organic solvent under proline catalysis, with introduction of the aldehyde donor by syringe pump. [8] The reaction of o-chlorobenzaldehyde and propanal (5 equiv) was selected as a model and performed in the presence of 18 equivalents of water and several putative organocatalysts (10 mol %, 24 h; see Scheme 1). The aldols were isolated after reduction to the corresponding diols