The zaragozic acids and squalestatins, a novel family of fungal metabolites isolated and characterized by researchers at Merck [1] and Glaxo, [2] respectively, in 1992, are the most potent inhibitors of squalene synthase known to date. [3] Some members of this family have also demonstrated the ability to inhibit Ras farnesyl transferase. [4] These molecules share a unique 4,6,7-trihydroxy-2,8-dioxabicyclo[3.2.1]octane-3,4,5tricarboxylic acid core with six contiguous stereogenic centers and differ only with regard to the nature of the C1 alkyl and C6 O-acyl side chains. It is therefore not surprising that the zaragozic acids (squalestatins) have elicited considerable attention from synthetic chemists. [5] Apart from an enormous number of synthetic studies, eight total syntheses, including our own total synthesis of zaragozic acid C, have now been reported. [6][7][8] A strategic point in the synthesis of zaragozic acids lies in the construction of the fully or partially functionalized 2,8-dioxabicyclo[3.2.1]octane core structure. The majority of the reported synthetic strategies rely on the acid-catalyzed internal ketalization of a polyhydroxyketone or its equivalent under kinetically or thermodynamically controlled conditions. However, this key reaction often yields, apart from the target bicyclic ketal core, variable quantities of the isomeric 6,8-dioxabicyclo[3.2.1]octane ring. Departing from the ketalization-based approach, we now report a second-generation synthesis of zaragozic acid C capitalizing on the tandem carbonyl ylide formation/1,3-dipolar cycloaddition methodology extensively studied by the Padwa group. [9][10][11] Our synthetic strategy based on the cycloaddition of a carbonyl ylide is outlined retrosynthetically in Scheme 1. [12][13][14] This approach would allow for the rapid assembly of the desired core system from a-diazo ester 3 and a suitable dipolarophile under the influence of a Rh II catalyst in a single step, wherein the problem of formation of the isomeric ketal can be avoided. We have previously demonstrated that
[*] Prof.