Asymmetric Lignan Synthesis: Isolariciresinol Dimethyl Ether

An asymmetric synthesis of the lignan (+)-isolariciresinol dimethyl ether 1 in nine steps and 13% yield (83% optical purity) from veratraldehyde is described. Veratraldehyde was converted to 6-(3,4-dimethoxybenzyl)-veratraldehyde 3 by bromination, acetal formation, metalation, and coupling to 3,4-dimethoxybenzyl bromide. 3 was irradiated in the presence of SO₂to give the 3-hydroxy-l-aryl-1,3-dihydrobenzo[c]thiophene 2,2-dioxide 4, which was converted to the (R)-1-phenylethoxy derivative 5b. 5b on heating with dimethyl fumarate gave a mixture of primarily two diastereomeric cycloadducts 7b and 7b’, both of which had the 1,2-trans, 2,3-trans, 3,4-cis stereochemistry. The major adduct 7b was subsequently assigned the stereochemistry 1S,2R,3S,4S. Separation and hydrogenolysis of the major adduct gave the diester 8,1S,2R,3R, which was reduced with LiAlH₄to give (+)-isolariciresinol dimethyl ether 1. A racemic synthesis was also carried out via the methoxy sulfone 5a and its trans isomer 5a’ in 33% yield.