Asymmetric Synthesis of Bioactive Natural Products

描述(由申请人提供)：这是一项更新提案，旨在继续一项针对生物活性物质的实验室制备的生产性研究计划。从大自然中分离出来的有机化合物为开发新的治疗剂提供了肥沃的土壤，并启发了可用于组装的新策略、反应、催化剂和试剂的开发。某些天然产物，如紫霉素，显示出良好的生物活性，因此需要进行更深入的探索；然而，现有合成方法(或生物技术)的局限性使得无法有效和实用地大量制备高级中间体，这对SAR研究是有用的。这项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，如紫霉素和棘球菌素，提出了一系列有趣的合成挑战；它们的结构向我们建议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。这项研究计划的具体目标是：(I)通过独特的非对映选择性不对称反应策略实现复杂天然产物紫霉素的简洁不对称合成；(Ii)开发在甲亚胺a位形成C-N键的新技术，从而使不同的二胺能够快速组装；(Iii)通过战略应用“拥挤的”Mannich加成反应，创造组装功能密集的双胺和三胺的新方法；(Iv)开发适用于快速构建棘球菌素等天然产物以及一系列其他有用的手性构建块的新型多功能试剂。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 通过提供对迄今为止未知或只能通过低效和/或不切实际的方法才能访问的结构的便捷访问，生物医学努力。

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.