Asymmetric Synthesis of Bioactive Natural Products

描述（由申请人提供）：这是一份更新申请，旨在继续进行生物活性物质实验室制备的生产性研究计划。从自然界中分离出来的有机化合物为开发新的治疗药物提供了肥沃的土壤，并为开发新的策略、反应、催化剂和试剂提供了灵感，这些新策略、反应、催化剂和试剂可用于有机化合物的组装。某些天然产物如帕霉素表现出良好的生物活性，需要进行更深入的探索；然而，现有合成方法（或生物技术）的局限性妨碍了高效和实际地制备大量高级中间体，而这些中间体将对SAR研究有用。本研究计划的总体目标是利用天然产物作为新反应和新试剂开发的灵感。复杂的生物活性天然产物，如帕霉素和棘孢菌素提出了一系列有趣的合成挑战；它们的结构向我们提出了目前尚不存在的方法，但在有效地合成这些目标方面将特别有用。本研究计划的具体目标是：(i)通过独特的非对异选择去对称策略实现复杂天然产物帕霉素的简洁不对称合成；（ii）开发在亚胺a位形成C-N键的新技术，从而能够快速组装各种二胺；（iii）通过战略性地应用“拥挤”的曼尼奇添加物，为功能密集的二胺和三胺的组装创造新的方法；（iv）开发新的多功能试剂，适用于快速构建天然产物，如棘球孢素，以及一系列其他有用的手性构建块。这些具体目标的共同实现将推动有机化学领域的发展，并将在化学领域中发挥作用

DESCRIPTION (provided by applicant): This is a renewal proposal that seeks to continue a productive research program directed toward the laboratory preparation of biologically active substances. Organic compounds isolated from Nature serve as fertile ground for the development of new therapeutic agents and as inspiration for the development of new strategies, reactions, catalysts, and reagents that can be used in their assembly. Certain natural products such as pactamycin exhibit favorable biological activities for which more in-depth exploration would be desirable; however, limitations in extant synthetic methods (or biotechnologies) preclude the efficient and practical preparation of advanced intermediates in quantities that would be useful for SAR studies. The general goal of this research program is to use natural products as an inspiration for new reaction and new reagent development. Complex bioactive natural products like pactamycin and echinosporin present a series of interesting synthetic challenges; their structures suggest to us methodologies that do not currently exist but would be exceptionally useful in efficient syntheses of these targets. The specific goals of this research proposal are to (i) achieve a concise asymmetric synthesis of the complex natural product pactamycin via a unique diastereoselective desymmetrization strategy; (ii) develop new techniques for C-N bond formation at the a-position of azomethines, thereby enabling rapid assembly of diverse diamines; (iii) create new methods for the assembly of functionally dense di- and triamines through the strategic application of a "congested" Mannich addition; (iv) develop new polyfunctional reagents that will be applicable to the rapid construction of natural products like echinosporin, as well as a range of other useful chiral building blocks. Collectively the realization of these specific aims will advance the field of organic chemistry and be of use in biomedical endeavors by providing facile access to structures that were heretofore unknown or accessible only by virtue of methods that were inefficient and/or impractical.