Asymmetric Synthesis of the Squalene Synthase Inhibitor Zaragozic Acid C

Abstract

The recently discovered fungal metabolites known both as the squalestatins' and zaragozic acids2 have become attractive targets for synthesis3 as a consequence of their picomolar inhibition of the enzyme squalene synthase (EC 2.5.1.21), the first committed step in the biosynthesis of sterols. Members of this family of natural products have also been found to be potent inhibitors of famesyl-protein tran~ferase.~ In independent studies from Merck2 and Glaxo,' a number of closely related structures sharing the common 2,8-dioxabicyclo[3.2. lloctane core have been isolated and characterized to date. The purpose of this communication is to disclose a route to the synthesis of zaragozic acid C (1)5 which is amenable to the synthesis of the other members of this family of natural products.6