Diarylprolinol as an Effective Organocatalyst in Asymmetric Cross‐Aldol Reactions of Two Different Aldehydes

Abstract

The aldol reaction is one of the most important carbon‐carbon bond‐forming reactions in organic chemistry. Asymmetric direct cross‐aldol reaction of two different aldehydes has been regarded as a difficult reaction because of the side reactions such as self‐aldol reaction and over reaction. We found that trifluoromethyl‐substituted diarylprolinol, α,α‐bis[3,5‐bis(trifluoromethyl)phenyl]‐2‐pyrrolidinemethanol (1), is an effective organocatalyst that promotes several cross‐aldol reactions of aldehydes with excellent diastereo‐ and enantioselectivities. Acetaldehyde can be employed as a suitable nucleophilic aldehyde. Successful electrophilic aldehydes are ethyl glyoxylate, chloroacetaldehyde, dichloroacetaldehyde, chloral, α‐alkyl‐α‐oxo aldehyde, trifluoroacetaldehyde, glyoxal, alkenyl aldehyde, alkynyl aldehyde, and formaldehyde. Some of the aldehydes are commercially available as a polymer solution, an aqueous solution, or in the hydrated form. They can be used directly in the asymmetric aldol reaction as a commercially available form, which is a synthetic advantage. Given that the obtained aldol products possess several functional groups along with a formyl moiety, they are synthetically useful chiral building blocks.

Cooperative assistance of a sulfonamide in a proline-mediated direct asymmetric aldol addition

“…Proline-based catalysts have evidently been at the heart of remarkable advances in the field of asymmetric organocatalysis and have had a particularly profound influence in enamine-mediated transformations such as the direct asymmetric aldol addition. 12 Among the proline-based catalysts, the trans -4-hydroxyproline scaffold represents a major platform upon which a huge number and variety of catalysts have been constructed, particularly toward mediating asymmetric aldol additions with admirable efficiency and stereocontrol. 12 d ,13 The influential sulfonamide moiety has not been left out in this regard, and has been incorporated at the 4-position of proline derivatives that have been employed, for instance, in asymmetric Biginelli reactions and Michael additions.…”