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: 8517139
• 负责人: Weiping Tang
• 金额: $ 33.24万
• 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 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8517139
• 关键词: Acids; Analgesics; Antibiotics; Antiviral Agents; Biological; Biological Factors; Chemicals; Chemistry; Cleaved cell; Complex; Copper; Cyclobutanes; Cyclopropanes; DNA Sequence Rearrangement; Development; Health; Histamine H3 Receptors; Ligands; Mediating; Metals; Methods; Natural Product Drug; Organic Chemistry; Organic Synthesis; Pathway interactions; Pharmacologic Substance; Preparation; Property; Pyrans; Reaction; Research; Science; Silver; System; Transition Elements; analog; antimicrobial drug; base; carbene; catalyst; cycloaddition; cyclopropane; design; diazo compound; drug candidate; flexibility; human disease; improved; incarvillateine; inhibitor/antagonist; novel; programs; public health relevance

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）：作为一个研究项目的一部分，重点是开发新的催化化学、区域和立体选择合成方法，用于有机化学和制药科学，将开发基于环丙基金属碳的化学方法，在温和的催化条件下合成高功能化的环丁烷、吡喃和其他复杂的环体系。各种过渡金属催化剂介导的环丙基金属碳烯的新反应活性的发现，开辟了一系列独特的机制途径，提高了我们对环丙烷和金属碳烯化学的基本认识。在目标#1中，我们建议发展：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催化剂(例如镝（II），铜（I)和银(I)）存在下的化学，区域和立体选择性；B)对映选择性扩环反应，从中介重氮化合物制备手性环丁烯；c)吡喃衍生物的一般制备方法。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，开发一种统一的、灵活的手性环丁烷的非映对和对映选择性合成策略。我们打算在这里完成的天然产物具有广泛的生物活性，包括抗生素、抗病毒药物、抗菌药物、镇痛药、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碳烯的反应性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体系。利用相关体系的计算结果指导了几个环加成反应的设计。选择过渡金属催化剂用于这些环加成反应是基于它们能够形成金属羰基、催化环加成反应和裂解环丙烷C-C键的性质。这些研究将极大地增加环丙烷和金属碳烯的合成用途，并使环丙烷和金属碳烯以前未知的反应得以发现。这些目标的累积结果是提高了对环丙烷和各种金属羰基化学的基本理解，并发现了在复杂有机分子合成中立即实用的有效方法。公共卫生相关性：概述的提案提供了快速、有效和立体选择性地获得重要的生物活性天然产物和候选药物的途径。在这个提议中开发的合成方法也很灵活，可以制造许多潜在的更有效的类似物，这可能更有效地治疗人类疾病。

项目成果

Effect of ester on rhodium-catalyzed intermolecular [5+2] cycloaddition of 3-acyloxy-1,4-enynes and alkynes.

• DOI: 10.1039/c3cc40634b
• 发表时间: 2013-04-04
• 期刊: Chemical communications (Cambridge, England)
• 作者: Schienebeck CM;Robichaux PJ;Li X;Chen L;Tang W
• 通讯作者: Tang W

Rhodium-catalyzed chemo- and regioselective cross-dimerization of two terminal alkynes.

• DOI: 10.1021/ol303531m
• 发表时间: 2013-02-15
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Xu, Hua-Dong;Zhang, Ren-Wei;Li, Xiaoxun;Huang, Suyu;Tang, Weiping;Hu, Wen-Hao
• 通讯作者: Hu, Wen-Hao

Rhodium-catalyzed acyloxy migration of propargylic esters in cycloadditions, inspiration from the recent "gold rush".

• DOI: 10.1039/c2cs35235d
• 发表时间: 2012-12-07
• 期刊: Chemical Society reviews
• 影响因子: 46.2
• 作者: Shu XZ;Shu D;Schienebeck CM;Tang W
• 通讯作者: Tang W

Rhodium-Catalyzed Intermolecular [5+1] and [5+2] Cycloadditions Using 1,4-Enynes with an Electron-Donating Ester on the 3-Position.

• DOI: 10.1055/s-0034-1380160
• 发表时间: 2015-05
• 期刊: Synthesis
• 作者: Schienebeck CM;Song W;Smits AM;Tang W
• 通讯作者: Tang W

Synthesis of Naturally Occurring Tropones and Tropolones.

自然发生的肌管和轨道的合成。

• DOI: 10.1016/j.tet.2014.07.065
• 发表时间: 2014-12-09
• 期刊: TETRAHEDRON
• 影响因子: 2.1
• 作者: Liu, Na;Song, Wangze;Schienebeck, Casi M.;Zhang, Min;Tang, Weiping
• 通讯作者: Tang, Weiping