Synthesis and Chemical Biology of Oxazolidinone and Pyrrolidine Natural Products

 描述（由申请人提供）：本提案描述了用于杂环合成的新型化学反应的开发以及这些反应在生物活性天然产物中的应用。具体而言，一锅亚胺酰化/烯醇环化级联已被开发，可以选择性地提供4-恶唑烷酮或吡咯烷酮的立体选择性的方式，这些反应已被应用于synoxazolidinones和pretazettine的全合成。synoxazolidinones是最近发现的具有新颖结构和对几种临床相关细菌菌株有前景的抗菌活性的天然产物。 普他西汀是一种以吡咯烷为核心的生物碱，具有抗肿瘤活性。拟议研究的目标是为这两个生物活性天然产物家族开发一种可扩展的权宜方法，并利用合成工作开发新的化学探针和先导化合物，用于抗菌和抗癌开发。我们已经开发了一种非对映选择性的synoxazolidinones和制备类似物的活性优于天然产物的上级。我们的目标是进一步完善我们的合成方法，并将其应用于synoxazolidinone家族的其他成员，同时继续优化4-恶唑烷酮支架对细菌的效力和选择性。在这些努力的同时，我们扩大了我们的反应范围，以提供吡咯烷酮衍生物，这是广泛有用的药物化学和天然产物合成的基石。利用这种方法，我们提出了一个非常快速的制备pretazettine，生物碱，已收到显着的关注，从合成 社区 我们期望我们的合成工作将提供新的反应来构建具有广泛用途的杂环，并导致天然产物的方法，使其能够用作化学探针。这些合成研究与化学生物学研究相辅相成，以探索天然产物和类似物对临床相关细菌和肿瘤细胞系的活性。总之，这些努力将为开发用于治疗细菌感染和癌症的新合成化学和潜在先导化合物提供框架。

 DESCRIPTION (provided by applicant): This proposal describes the development of novel chemical reactions for heterocycle synthesis and the application of these reactions to bioactive natural products. Specifically, a one-pot imine acylation/enol cyclization cascade has been developed that can selectively provide 4-oxazolidinones or pyrrolidones in a stereoselective fashion and these reactions have been applied to the total synthesis of the synoxazolidinones and pretazettine. The synoxazolidinones are recently discovered antimicrobial natural products with novel structures and promising activity against several clinically relevant bacterial strains. Pretazettine is an alkaloid bearing a densely functionalized pyrrolidine core and cytotoxic activit against several types of tumors. The objective of the proposed research is to develop a scalable and expedient approach to these two families of bioactive natural products and leverage the synthetic work to develop new chemical probes and lead compounds for antimicrobial and anticancer development. We have already developed a diastereoselective approach to the synoxazolidinones and prepared analogs with activity superior to that of the natural products. We aim to further refine our synthetic approach and apply it to other members of the synoxazolidinone family while continuing to optimize the 4-oxazolidinone scaffolds for potency and selectivity towards bacteria. In parallel to these efforts we have expanded the scope of our reaction to provide pyrrolidone derivatives, which are broadly useful building blocks in medicinal chemistry and natural product synthesis. Utilizing this approach we propose an extremely rapid preparation of pretazettine, an alkaloid that has received significant attention from the synthetic community. We expect that our synthetic work will provide new reactions to construct heterocycles of broad utility and lead to approaches to natural products that enable their use as chemical probes. These synthetic studies are complimented by chemical biology studies to explore the activity of both natural products and analogs against clinically relevant bacteria and tumor cell lines. Taken together, these efforts will provide a framework for the development of new synthetic chemistry and potential lead compounds for the treatment of bacterial infections and cancer.