A five-year plan is proposed for the continued exploration of new synthetic strategies employing vinyl sulfones as the focal point of multiply-convergent total syntheses of biologically important natural and unnatural products. This proposal has three major project areas: (1) The investigation of alpha-heteroatom-substituted sulfones as progenitors for alpha-sulfonyl anions and alpha-sulfonyl radicals. These intermediates will be utilized in the development of new medium-ring annulation reactions as applied to the total synthesis of homochiral cytochalasin C 103; (2) The total synthesis of homochiral homoharringtonine 104, an antileukemia agent currently in Phase II clinical trials. Intramolecular transacylation of a cephalotaxine derivative will be exploited to synthesize a highly hindered ester; (3) The total synthesis of three homochiral, pyrrole-fused prostacyclin analogs 151-153, predicted by computer modeling to be exceptionally potent inhibitors of platelet aggregation. This study should provide important new agents for the prevention of neutrophil-mediated oxidative injury of the myocardia during reperfusion, as well as affording new materials which have potential as antimetastatic agents.
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