SYNTHESIS OF BIOACTIVE MOLECULES VIA VINYL SULFONES

提出了继续探索新的合成气田的五年计划。 以乙烯基砜为重点的战略 具有重要生物学意义的天然产物和天然产物的多重收敛全合成 非天然产品。 这项建议有三个主要项目领域：(1)调查 α-杂原子取代砜作为α-磺酰基的前体 阴离子和α-磺酰基。这些中间体将被利用 在开发新的中环环化反应中应用于 同型手性细胞松弛素C103的全合成；(2)全合成 抗白血病药物高手性高三尖杉酯碱104的合成 目前处于第二阶段临床试验。A的分子内转酰化 三尖杉碱衍生物将被利用来合成一种高度受阻的 (3)三个均手性吡咯稠合物的全合成 前列环素类似物151-153，通过计算机模拟预测为 特别有效的抑制血小板聚集的药物。这项研究应该 为预防中性粒细胞介导的炎症提供重要的新药物 再灌流过程中心肌的氧化损伤以及提供 具有抗肿瘤转移剂潜力的新材料。

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.