Catalytic Enantioselective Synthesis of (−)-Prostaglandin E₁ Methyl Ester Based on a Tandem 1,4-Addition−Aldol Reaction

Abstract

Catalytic enantioselective 1,4-additions and tandem 1,4-addition-aldol reactions of dialkylzinc reagents to cyclopentene-3,5-dione monoacetals in the presence of an in situ generated Cu(OTf)(2)/chiral phosphoramidite catalyst result in highly functionalized cyclopentane building blocks with ee's up to 97%. A new synthesis of cyclopentene-3,5-dione monoacetals is presented as well as its use in a tandem 1,4-addition-aldol protocol for the catalytic asymmetric total synthesis of (-)-PGE(1) methyl ester. This synthesis represents a new approach to this class of natural products. By using only 3 mol % of an enantiomerically pure catalyst in the key step, the absolute configurations at three stereocenters of the basic structure of the PGE(1) are established at once.