A general synthesis of 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octane lignans applicable to unsymmetrically substituted compounds

Abstract

A new synthesis is described of 2,6-diaryl-3,7-dioxabicyclo[3.3.0]octanes which has been used to prepare unsymmetrically substituted lignans such as methyl piperitol, and affords the first stereoselective synthesis of equatorial–axial isomers such as methyl pluviatilol and methyl xanthoxylol. The method utilises a new four carbon synthon (6) which allows regiospecific and stepwise anion production. Two alternative routes are given from the 2,6-diaryl-4,8-dimethoxy-1-methylthio-3,7-dioxabicyclo[3.3.0]octanes (14b) and (14c) to the parent lignans. One of these procedures shows that the methylthio group is capable of acting as a highly effective stereocontrol element. The stereochemical consequences of both procedures have been analysed and can be rationalised in terms of equilibration during a Lewis acid catalysed reduction step. Thus, while one route affords selectively methyl pluviatilol (19) in high yield, the other route gives a 2:1:1 mixture of methyl piperitol, methyl pluviatilol, and methyl xanthoxylol.