Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams.

Katherine M Byrd

doi:10.3762/bjoc.11.60

Abstract

The conjugate addition reaction has been a useful tool in the formation of carbon–carbon bonds. The utility of this reaction has been demonstrated in the synthesis of many natural products, materials, and pharmacological agents. In the last three decades, there has been a significant increase in the development of asymmetric variants of this reaction. Unfortunately, conjugate addition reactions using α,β-unsaturated amides and lactams remain underdeveloped due to their inherently low reactivity. This review highlights the work that has been done on both diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams.

Highlights

Conjugate additions [1,2,3,4,5] are some of the most powerful carbon–carbon bond forming reactions in the synthetic chemist’s toolbox
The utility of these reactions have been demonstrated through their use in the synthesis of numerous natural products and pharmaceutical agents
The last couple of decades have shown a significant increase in the development of asymmetric conjugate addition reactions, especially in the catalytic, enantioselective variants of these reactions

Summary

Introduction

Conjugate (or 1,4- or Michael) additions [1,2,3,4,5] are some of the most powerful carbon–carbon bond forming reactions in the synthetic chemist’s toolbox. These observations led Hayashi, Hiyama and co-workers to develop mild conditions for the rhodium-catalyzed asymmetric 1,4-arylation and alkenylation [155] They employed a series of organo[2-(hydroxymethyl)phenyl]dimethylsilanes [156,157,158] as organosilicon reagents and they used these conditions for the 1,4-addition of α,β-unsaturated amides and lactams (Scheme 17). The authors discovered that it was necessary to add a fluoride source to the reaction mixture in order to suppress side reactions, which has been reported by others to result in the isolation of the saturated carbonyl compound and phenol [163,164,165,166] They were able to apply this methodology to the asymmetric 1,4-addition of lactam 79 to afford the 4-phenyl product in moderate yield and high enantioselectivity (Scheme 19). Lowering the catalyst loading any further only led to longer reaction times and decreased yields

Asymmetric aza-Michael additions

Conclusion