A Concise, Convergent Approach to the Synthesis of (+)-Pleuromutilin

项目摘要 抗生素耐药性是对人类健康的最大威胁之一。很明显，目前 研究工作无法跟上细菌进化失活机制的速度， 求助抗生素。许多这些最后的化合物的核心结构是小的，平坦的，结构上 稀疏杂环适合于通过化学半合成快速多样化。然而，最近主要 旨在改善耐药性的运动只产生了少量FDA批准的抗菌药物 从这些分子中衍生出来。富含结构的抗生素，如万古霉素和截短侧耳素， 相对广阔的化学和结构空间，基本上尚未探索。特别是，近 自1951年发现截短侧耳素以来，已合成了1200种截短侧耳素衍生物，但由于其结构复杂， 截短侧耳素的结构复杂，大多数衍生物是乙醇酸的半合成同系物 酸性侧链。许多努力致力于截短侧耳素的全化学合成，但只有一种这样的方法， 合成存在。制备pleuromutuilin所需的34个线性步骤对于大规模制备来说都是不可行的。 生产和不允许快速合成的同系物，旨在探讨基本问题 关于这种重要抗生素的代谢降解和生物活性。我们建议第一个 截短侧耳素的高度收敛的全化学合成，其中两个快速制备的结构单元， 在合成的后期通过区域和立体特异性镍催化的还原偶联结合。一 第二个关键步骤利用我们在有机钐介导的还原环化方面的专业知识， 受阻碳-碳键并建立三个立体中心。综合起来，这些战略将使 方便地获得截短侧耳素，允许对核心碳骨架进行更广泛的多样性研究， 促进旨在开发急需的新抗生素的衍生化工作，并为 截短侧耳素的化学和生物学知识。

PROJECT SUMMARY Antibiotic resistance is one of the greatest threats to human health. It is quickly becoming evident that current research efforts are unable to keep pace with the rate at which bacteria evolve inactivation mechanisms to last- resort antibiotics. The core structures of many of these last-resort compounds are small, flat, structurally sparse heterocycles amenable to rapid diversification by chemical semi-synthesis. However, recent major campaigns aimed at improving resistance have yielded only a small number of FDA-approved antibacterials derived from these molecules. Structurally-rich antibiotics, like vancomycin and pleuromutilin, have comparatively vast chemical and structural space that remains essentially unexplored. In particular, nearly 1200 derivatives of pleuromutilin have been synthesized since its discovery in 1951, but due to the sheer structural complexity of pleuromutilin, the majority of derivatives are semi-synthetic congeners of the glycolic acid side-chain. Much effort has been devoted to a total chemical synthesis of pleuromutilin, but only one such synthesis exists. The 34 linear steps required to prepare pleuromutuilin is both infeasible for large-scale production and does not allow for the rapid synthesis of congeners designed to probe fundamental questions regarding the metabolic degradation and biological activity of this important antibiotic. We propose the first highly convergent total chemical synthesis of pleuromutilin, in which two rapidly prepared building blocks are united by a regio- and stereospecific nickel-catalyzed reductive coupling at a late stage in the synthesis. A second key step leverages our expertise in organosamarium-mediated reductive cyclizations to forge a hindered carbon-carbon bond and establish three stereocenters. Taken together, these strategies will enable expedient access to pleuromutilin, allow for a much broader diversity of studies on the core carbon skeleton, facilitate derivatization efforts aimed at the much-needed development of new antibiotics, and contribute knowledge to the chemistry and biology of pleuromutilin.