Polyketides via C-C Coupling of Alcohols: Green Chemistry

描述(由申请人提供)：我们的实验室发现了一类广泛的、新的催化过程，通过直接的醇C-H官能化来促进C-C键的形成。在之前的资助期，这项技术实现了对 6-脱氧赤霉素B、Bryostatin 7、三线菌素A和F、氰内酯A、罗沙菌素，以及利福霉素S和镰刀菌素C的正式合成，为这些各自的天然产物家族中的任何成员提供了最简洁的路线。在拟议的资助期内，这些路线将被调整以制备功能类似物苔藓抑素和三苯氧霉素。我们的Bryostatin类似物将在与NCI癌症生物学和遗传学实验室肿瘤促进分子机制科主任Peter M.Blumberg博士的持续合作中进行评估。Bryostatin类似物还将与葛兰素史克的同事合作，在艾滋病毒重新激活试验中进行评估。曲尼霉素类似物将在德克萨斯州药物和诊断开发研究所(TI-3D)进行评估。在利用醇C-C偶联来简化几种I型聚酮的合成后，我们现在将开始进化一套方法来组装具有治疗相关的II型聚酮天然产物，例如(+)-乳糖霉素，它对MRSA显示出强大的抗菌活性。

DESCRIPTION (provided by applicant): Our laboratory has discovered a broad, new class of catalytic processes that promote C-C bond formation via direct alcohol C-H functionalization. In the prior funding period, this technology enabled total syntheses of 6-deoxyerythronolide B, bryostatin 7, trienomycins A and F, cyanolide A, roxaticin, and formal syntheses of rifamycin S and scytophycin C, availing the most concise routes to any member of these respective natural products families. In the proposed funding period, these routes will be adapted to prepare functional analogues of bryostatin and trienomycin. Our bryostatin analogues will be evaluated in an ongoing collaboration with Dr. Peter M. Blumberg, who is Chief, Molecular Mechanisms of Tumor Promotion Section in the Laboratory of Cancer Biology and Genetics at the NCI. The bryostatin analogues also will be evaluated in HIV viral reactivation assays in collaboration with colleagues at GlaxoSmithKline. Trienomycin analogues will be evaluated at the Texas Institute for Drug and Diagnostics Development (TI-3D). Having utilized alcohol C-C coupling to streamline the synthesis of several type I polyketides, we will now begin to evolve a suite of methods to assemble therapeutically relevant type II polyketide natural products, such as (+)-lactonamycin, which displays potent antibacterial activity against MRSA.