Development of Cyclopropyl Metal Carbene Based Methods for Organic Synthesis

基于环丙基金属卡宾的有机合成方法的发展

• 批准号: 7906843
• 负责人: Weiping Tang
• 金额: $ 28.77万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-03 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7906843
• 关键词: Development; Metals; Methods; Organic Synthesis; base; carbene

DESCRIPTION (provided by applicant): As part of a research program focused on the development of new catalytic chemo-, regio-, and stereoselective synthetic methods for organic chemistry and pharmaceutical sciences, chemical methods based on cyclopropyl metal carbenes will be developed for the synthesis of highly functionalized cyclobutanes, pyrans, and other complex ring systems under mild catalytic conditions. The discovery of the novel reactivity of cyclopropyl metal carbenes, mediated by various transition metal catalysts, opens a broad range of mechanistically unique pathways and improves our fundamental understanding for the chemistry of cyclopropanes and metal carbenes. In aim #1, we propose to develop: a) general methods for the preparation of aryl and alkyl substituted cyclopropyl diazo compounds and explore the chemo-, regio-, and stereoselectivity of the ring expansion of these diazo compounds in the presence of transition metal catalysts (e.g. dirhodium (II), copper (I), and silver (I)); b) an enantioselective ring expansion reaction to prepare chiral cyclobutenes from meso diazo compounds; and c) general methods for the preparation of pyran derivatives. In aim #2, we propose to develop a unified and flexible strategy for the diastereo- and enantioselective synthesis of chiral cyclobutanes based on methods we developed in preliminary study and methods proposed in aim #1. Natural products that we propose to accomplish here have broad biological activities, including antibiotics, antiviral agents, antimicrobial agents, analgesics, selective CYP inhibitors, and histamine H3 receptor antagonists. In aim #3, we propose to expand the reactivity profile of cyclopropyl metal carbenes from the formation of cyclobutenes and 4H-pyrans via rearrangement to the formation of more complex ring systems via cycloadditions. Computational results from related systems were used to guide the design of several cycloaddition reactions. Transition metal catalysts were chosen for these cycloadditions based on their properties of being able to form metal carbenes, to catalyze cycloaddition reactions, and to cleave cyclopropane C-C bonds. These studies together will greatly increase the synthetic utility of cyclopropanes and metal carbenes and enable the discovery of previously unknown reactions of cyclopropanes and metal carbenes. The cumulative result of these aims is improved fundamental understanding of the chemistry of cyclopropanes and various metal carbenes and discovery of efficient methods that will find immediate utility in the synthesis of complex organic molecules. PUBLIC HEALTH RELEVANCE: The outlined proposal provides access to important biologically active natural products and drug candidates rapidly, efficiently, and stereoselectively. Synthetic methods developed in this proposal are also flexible to make many potentially more potent analogs, which may cure human diseases more effectively.

描述（由申请人提供）：作为专注于开发有机化学和药物科学的新型催化化学、区域和立体选择性合成方法的研究计划的一部分，将开发基于环丙基金属卡宾的化学方法来合成在温和的催化条件下高度官能化的环丁烷、吡喃和其他复杂的环系统。由各种过渡金属催化剂介导的环丙基金属卡宾的新颖反应性的发现，开辟了广泛的机械独特途径，并提高了我们对环丙烷和金属卡宾化学的基本理解。在目标#1中，我们建议开发：a) 制备芳基和烷基取代的环丙基重氮化合物的一般方法，并探索这些重氮化合物在过渡金属存在下扩环的化学选择性、区域选择性和立体选择性催化剂（例如二铑（II）、铜（I）和银（I））； b)对映选择性扩环反应，由内消旋重氮化合物制备手性环丁烯； c)制备吡喃衍生物的一般方法。在目标#2中，我们建议基于我们在初步研究中开发的方法和目标#1中提出的方法，开发一种统一且灵活的策略，用于手性环丁烷的非对映和对映选择性合成。我们在这里提出的天然产物具有广泛的生物活性，包括抗生素、抗病毒剂、抗菌剂、镇痛剂、选择性 CYP 抑制剂和组胺 H3 受体拮抗剂。在目标#3中，我们建议将环丙基金属卡宾的反应性范围从通过重排形成环丁烯和4H-吡喃扩展到通过环加成形成更复杂的环系。相关系统的计算结果用于指导几种环加成反应的设计。选择过渡金属催化剂用于这些环加成反应是基于其能够形成金属卡宾、催化环加成反应以及裂解环丙烷C-C键的性质。这些研究将大大提高环丙烷和金属卡宾的合成效用，并能够发现环丙烷和金属卡宾以前未知的反应。这些目标的累积结果是提高了对环丙烷和各种金属卡宾化学的基本理解，并发现了可立即用于复杂有机分子合成的有效方法。公共卫生相关性：概述的提案提供了快速、高效和立体选择性地获取重要的生物活性天然产物和候选药物的机会。该提案中开发的合成方法也可以灵活地制造许多潜在的更有效的类似物，从而可以更有效地治疗人类疾病。