抄録
We recently developed the stereospecific methylation of γ,δ-epoxy acrylates by trimethyl-aluminum by which both anti compounds and syn compounds can be efficiently and highly stereoselectively produced starting from (E)-γ,δ-epoxy acrylates and (Z)-epoxy acrylates, respectively (Scheme 1). We report herein a highly stereoselective construction of the eight contiguous chiral centers of ansa-chains of rifamycins and synthetic studies toward total synthesis of streptovaricin U based on the above methodology. Starting from (R)-3-benzyloxy-2-methyl-1-propanol (1), the unsaturated ester 13 having seven contiguous chiral centers of rifamycins has been highly diastereoselectively synthesized by using three times of the methylation reaction with trimethylaluminum (4→5, 9→10, 12→13) (Scheme 2). The remaining two chiral centers were introduced by the reduction of the epoxy alcohol 15 with NaBH_3CN in the presence of BF_3・Et_2O. It is noteworthy that all the stereochemistries of four secondary hydroxyl groups in the ansa-chain were stereocontrolled virtually completely by using not the asymmetric epoxidation but usual MCPBA epoxidation. The aromatic core of streptovaricin U has been regioselectively synthesized by the Diels-Alder reaction of diene 1 and dibromoquinone 2 in excellent yield (Scheme 3). On the other hand, the nine contiguous chiral centers of streptovaricin U have been constructed by using four times of the successive methylation reaction with trimethylaluminum (4→5, 7→8, 10→11, 13→14) (Scheme 4). The present work demonstrates the synthetic potential and vailidity of the methodology for the synthesis of polypropionate antibiotics.
