Synthesis and Chemical Biology of Oxazolidinone and Pyrrolidine Natural Products

 描述(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发展，以及这些反应在生物活性天然产物中的应用。具体地说，一锅亚胺酰化/烯醇环化级联反应已被开发出来，它可以以立体选择性的方式选择性地提供4-恶唑烷酮或吡咯烷酮，这些反应已被应用于齐诺唑烷酮和倍他西汀的全合成。赛诺唑烷酮类化合物是新近发现的抗菌天然产物，结构新颖，对多种临床相关菌株具有良好的抗菌活性。 倍他西汀是一种生物碱，具有高度功能化的吡咯烷核心和细胞毒活性，可抗多种类型的肿瘤。拟议研究的目的是为这两类生物活性天然产物开发一种可扩展和便捷的方法，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方法来合成合诺唑烷酮类化合物，并制备了活性高于天然产物的类似物。我们的目标是进一步改进我们的合成方法，并将其应用于赛诺唑烷酮家族的其他成员，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，我们扩大了反应的范围，提供了在药物化学和天然产物合成中广泛有用的吡咯烷酮衍生物。利用这种方法，我们提出了一种非常快速地制备倍他西汀的方法，这是一种受到人工合成的生物碱的极大关注 社区。我们希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，并导致获得能够将其用作化学探针的天然产品的方法。这些合成研究与化学生物学研究相辅相成，旨在探索天然产品和类似物对临床相关细菌和肿瘤细胞株的活性。综上所述，这些努力将为开发新的合成化学和治疗细菌感染和癌症的潜在先导化合物提供一个框架。

 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.