Asymmetric and Site-Selective [3 + 2]-Annulations for the Synthesis of High-Value Bicyclic Lactams

Abstract

Asymmetric and site-selective formal [3 + 2]-annulations of γ-alkyl-β,γ-unsaturated γ-lactams with α,β-unsaturated aldehydes have been developed. These organocatalysed transformations yield high value enantioenriched bicyclic γ-lactams with up to four new stereocenters (sometimes including a quarternary carbon). The overall transformation starts from simple and readily accessible furans and oversees a rapid, controlled, and dramatic enhancement in 3D complexity.

Scheme 1. Selective Formal [3 + 2]-Annulations of β,γ-Unsaturated γ-Lactams

Scheme 2. Asymmetric [3 + 2]-Annulations of β,γ-Unsaturated γ-Lactams 2 with α,β-Unsaturated Aldehydes 4

All the reactions were performed using 0.2 mmol of 2. Determined by crude ¹H NMR spectrum. Determined by chiral HPLC analysis of the major diastereoisomer. Isolated yield for major diastereoisomer.

Scheme 3. Asymmetric [3 + 2]-Annulations of β,γ-Unsuturated γ-Lactams 3 with α,β-Unsaturated Aldehydes 4

All of the reactions were performed using 0.2 mmol of 3 or 1 (in case of cond Q). Determined by the crude ¹H NMR spectrum. Determined by chiral HPLC analysis of the major diastereoisomer. Isolated yield for the major diastereoisomer.