Asymmetric Synthesis of Bioactive Natural Products

生物活性天然产物的不对称合成

• 批准号: 8436596
• 负责人: Jeffrey S Johnson
• 金额: $ 27.52万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8436596
• 关键词: Address; Amination; Antimalarials; Antiviral Agents; Biological; Biological Factors; Biotechnology; Breathing; Carbamates; Chemicals; Communities; Complex; DNA Sequence Rearrangement; Development; Diamines; Exhibits; Future; Glycolates; Goals; Hydrogen Bonding; Imines; Laboratories; Masks; Methodology; Methods; Modification; Motivation; Nature; Nitrogen; Organic Chemistry; Organic Synthesis; Outcome; Pactamycin; Positioning Attribute; Preparation; Protocols documentation; Pyruvate; Reaction; Reagent; Research; Research Proposals; Schiff Bases; Series; Structure; Techniques; Therapeutic; Therapeutic Agents; Work; antimicrobial; base; catalyst; design; dimer; drug development; flexibility; functional group; interest; novel therapeutics; preconditioning; programs; public health relevance; small molecule

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.

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富有成效的研究计划。从自然界中分离出来的有机化合物为开发新的治疗剂提供了肥沃的土壤，并为开发可用于其组装的新策略、反应、催化剂和试剂提供了灵感。某些天然产物，如帕大霉素，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）的局限性阻碍了有效且实用地大量制备可用于SAR研究的高级中间体。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。复杂的生物活性天然产物，如赤霉素和棘孢菌素，提出了一系列有趣的合成挑战；它们的结构向我们暗示了目前尚不存在但对于有效合成这些目标非常有用的方法。该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他霉素的简洁不对称合成； (ii) 开发在偶氮甲碱的α位形成C-N键的新技术，从而能够快速组装不同的二胺； (iii) 通过战略性应用“密集”曼尼希加成，创造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，适用于快速构建棘孢菌素等天然产物，以及一系列其他有用的手性结构单元。这些具体目标的共同实现将推动有机化学领域的发展并可用于 通过提供对迄今为止未知的或只能通过低效和/或不切实际的方法才能访问的结构的便捷访问来实现生物医学的努力。