Organocatalytic Asymmetric 1,6-Addition/1,4-Addition Sequence to 2,4-Dienals for the Synthesis of Chiral Chromans

Abstract

A novel asymmetric organocatalytic 1,6-addition/1,4-addition sequence to 2,4-dienals is described. Based on a 1,6-Friedel-Crafts/1,4-oxa-Michael cascade, the organocatalyst directs the reaction of hydroxyarenes with a vinylogous iminium-ion intermediate to give only one out of four possible regioisomers, thus providing optically active chromans in high yields and 94-99 % ee. Furthermore, several transformations are presented, including the formation of an optically active macrocyclic lactam. Finally, the mechanism for the novel reaction is discussed based on computational studies.

Keywords: Michael addition; asymmetric synthesis; heterocycles; organocatalysis; synthetic methods.