Total Syntheses of Zaragozic Acids A and C by a Carbonyl Ylide Cycloaddition Strategy

Abstract

A carbonyl ylide cycloaddition approach to the squalene synthase inhibitors zaragozic acids A and C is described. The carbonyl ylide precursor 8 was synthesized starting from di-tert-butyl D-tartrate (47) via an eleven-step sequence involving the regioselective reduction of the mono-MPM (MPM = 4-methoxybenzyl) ether 48 with LiBH₄ and the diastereoselective addition of sodium tert-butyl diazoacetate to α-keto ester 10. The reaction of α-diazo ester 8 with 3-butyn-2-one (40) in the presence of a catalytic amount of [Rh₂(OAc)₄] gave the desired cycloadduct 59 as a single diastereomer. The dihydroxylation of enone 59 followed by sequential transformations permitted the construction of the fully functionalized 2,8-dioxabicyclo[3.2.1]octane core 5. Alkene 79 derived from 5 serves as a common precursor to zaragozic acids A (1) and C (2), since the elongation of the C1 alkyl side chain can be attained by olefin cross-metathesis, especially under the influence of Blechert's catalyst (85).