An RCM-Based Total Synthesis of the Antibiotic Disciformycin B

The total synthesis of the potent new antibiotic disciformycin B (2) is described, which shows significant activity against methicillin- and vancomycin-resistantStaphylococcus aureus(MRSA/VRSA) strains. The synthetic route is based on macrocyclization of a tetraene substrate to the 12-membered macrolactone core by ring-closing olefin metathesis (RCM). Although macrocyclization was accompanied by concomitant cyclopentene formation by an alternative RCM pathway, conditions were established to give the macrocycle as the major product. Key steps in the construction of the RCM substrate include a highly efficient Evanssyn-aldol reaction, the asymmetric Brown allylation of angelic aldehyde, and the stereoselective Zn(BH4)(2)-mediated 1,2-reduction of an enone. The synthesis was completed by late-stage dehydrative glycosylation to introduce thed-arabinofuranosyl moiety and final chemoselective allylic alcohol oxidation.