Zaragozic acids, isolated and characterized independently by Merck and Glaxo in 1992, have attracted considerable synthetic attention because of the biological activity of these compounds and their novel structural aspects. In 1997 we achieved a total synthesis of zaragozic acid C; however, this route suffered from poor selectivity (1.6:1) in the aldol fragment coupling reaction to join the C4-C5 bond. Then, we addressed a second-generation synthesis of zaragozic acids, highlighting an alternative construction of the 2,8-dioxabicyclo[3.2.1]octane core system via a tandem carbonyl ylide formation and 1,3-dipolar cycloaddition process. Toward this end, α-diazo ester 7 was prepared from di-tert-butyl D-tartrate (10) (Scheme 2). After considerable experimentation with respect to a dipolarophile, reaction of 7 and 3-butyn-2-one with catalytic Rh_2(OAc)_4 in refluxing benzene was found to give the desired cycloadduct 22 as a single diastereomer out of the four possible diastereomers in 72% yield (Scheme 3). Dihydroxylation of 22 with OsO_4 followed by sequential benzylation, DIBAL-H reduction, oxidative cleavage of diol with Pb(OAc)_4, and reduction with DIBAL-H/ZnCl_2 effected the installation of the C6, C7 trans diol moiety. Upon protecting group interchange and oxidation, alcohol 26 was uneventfully transformed to the fully functionalized core structure 4. As a means for the elaboration of C1 side chain of 2, we were attracted to the possibility of a cross-metathesis between terminal olefin 32 derived from 4 and allyl acetate 33 (Scheme 4). Gratifyingly, the cross-metathesis reaction with Grubbs' second-generation catalyst (34) in refluxing benzene was found to provide the desired cross-product 35 in good yield. As might be expected from the hindered nature of the olefinic functionality in 32, the dimer 36 from self-metathesis of 32 was not detected. Hydrogenation of 35 followed by debenzylation produced a late intermediate 37 in the synthesis of zaragozic acid C by the Carreira^<8b> and our groups.
