The synthesis of enantiomerically pure aryltetralin lignans

Abstract

The preparation of enantiomerically pure aryltetralin lignans has been accomplished using both a Diels-Alder approach and a newer oxidative free radical coupling/cyclization. Past research established that aryltetralins could be asymmetrically prepared by a Diels-Alder reaction of $\alpha$-hydroxy-$\alpha$-phenyl-ortho-quinodimethane with a chiral dienophile. In this thesis, the previous preliminary work was extended to the preparation of a cycloadduct that was further elaborated to the natural lignan ($-$)-deoxy-podophyllotoxin. In the latter steps, an unprecedented stereoselective ionic reduction was developed. In the pursuit of an even more efficient method for the synthesis of aryltetralin lignans, new stereoselective Diels-Alder reactions of ortho-quinodimethanes were investigated. Substituted chiral crotonate esters were successfully reacted with $\alpha$-hydroxy-ortho-quinodimethane and found to diastereoselectively give only one cycloadduct in high yield. A new approach to the synthesis of aryltetralin lignans involving the oxidative coupling of substituted chiral cinnamic acid esters was studied. It was discovered that the chiral methyl ($R$)-mandelyl group would induce diastereoselectivity in the oxidative coupling/cyclization of its sinapic acid ester, forming the diester of the naturally occurring lignan thomasidioic acid. This unprecedented stereoselective reaction was used to prepare (+)-rabdosiin and its ($-$)-$(1R,2S)$-isomer, the enantiomers of which are natural anti-viral lignans.