Asymmetric Synthesis of Bioactive Natural Products

描述（由申请人提供）：这是一项更新提案，旨在继续开展针对生物活性物质实验室制备的生产性研究计划。从自然界分离的有机化合物是开发新治疗剂的肥沃土壤，也是开发可用于其组装的新策略、反应、催化剂和试剂的灵感来源。某些天然产物，如帕塔霉素表现出良好的生物活性，更深入的探索将是可取的;然而，在现存的合成方法（或生物技术）的限制排除了有效和实用的先进的中间体的制备量，将是有用的SAR研究。该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。复杂的生物活性的天然产物，如pactamycin和棘孢菌素提出了一系列有趣的合成挑战，他们的结构向我们建议的方法，目前不存在，但将是非常有用的，在这些目标的有效合成。本研究计划的具体目标是：（i）通过独特的非对映选择性去对称化策略实现复杂天然产物帕塔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，从而能够快速组装不同的二胺;（iii）通过“拥挤”曼尼希加成的策略性应用，创造用于组装功能密集的二胺和三胺的新方法;（iv）开发新的多功能试剂，其将适用于诸如棘孢菌素的天然产物以及一系列其他有用的手性构件的快速构建。总的来说，这些具体目标的实现将推动有机化学领域的发展， 通过提供对迄今为止未知的或仅通过低效和/或不切实际的方法可访问的结构的容易访问，来促进生物医学努力。

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.