Development of Asymmetric Cooperative Gold Catalysis and Beyond

不对称协同金催化及其他领域的发展

• 批准号: 10322384
• 负责人: Liming Zhang
• 金额: $ 37.46万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10322384
• 关键词: Aldehydes; Alkynes; Biological; Carboxylic Acids; Catalysis; Development; Disease Management; Future; Gold; Ligands; Medical; Metals; Methods; Molecular Probes; Nature; Pathway interactions; Pharmacologic Substance; Preparation; Reaction; Reagent; Research; Structure; System; base; carbonyl compound; chemical synthesis; design; drug candidate; enolate; improved; novel; programs; propadiene; protonation; pyrroline; research and development

Cooperative catalysis or catalysis involving metal-ligand cooperation is a highly versatile approach in catalysis that have resulted in a myriad of highly efficient synthetic methods and conferred exceptional value to chemical synthesis of bioactive and/or pharmaceutical compounds. Despite extraordinary advances on this research topic, there are still much need to develop new cooperative systems based on unique ligand designs to enable the development of new and/or much improved synthetic methods for chemical synthesis. In 2014, the PI initiated a program on the development of bifunctional biaryl-2-ylphosphine ligands that are designed to enable cooperative gold(I) catalysis. These ligands feature remote basic groups that can engage bonding interactions with substrates or reagents during catalysis and thereby achieve ligand-metal cooperation. Several preliminary studies, including a ppm-level gold-catalyzed addition of carboxylic acid to alkyne, an asymmetric isomerization of alkyne into allene, and trapping of catalytically generated σ-allenylgold intermediate with aldehyde, have validated the ligand design and the cooperative nature of the catalysis. As the major focus of the PI’s future effort, this proposal seeks to apply this cooperative gold(I) catalysis strategy to the development of asymmetric transformations of exceptional synthetic values. These include expedient construction of chiral butenolids and 2,5-disubstituted pyrrolines and asymmetric propargylation reactions/propargylic C-H functionalizations. The extension of this strategy to much cheaper cooperative Cu(I) and Ag(I) catalysis offers new and distinct opportunities in asymmetric enolate protonation, which would open valuable access to various carbonyl products. The transition to functionalized N,N-bidentate ligands would enable the application of the cooperative ligand design concept to a much broader range of metal catalysis and offer unprecedented opportunities to manipulate carbonyl compounds in asymmetric manners. This proposal, if implemented, would introduce a range of new and versatile chiral bifunctional ligands to metal catalysis and inspire increasing research effort in cooperative catalysis. Moreover, the methods developed would provide efficient access to a variety of chiral structures of high value to chemical synthesis in general and pharmaceutical R&D in particular.

协同催化或涉及金属-配体合作的催化是一种高度通用的方法 催化产生了无数高效的合成方法，并赋予了特殊的价值 生物活性和/或药物化合物的化学合成。尽管在这方面取得了非凡的进展 研究课题，仍然非常需要开发基于独特配体设计的新合作系统 能够开发新的和/或大大改进的化学合成合成方法。 2014年，PI启动了双功能联芳基-2-基膦配体的开发计划，该配体是 旨在实现协同金（I）催化。这些配体具有远程碱性基团，可以接合 在催化过程中与底物或试剂发生键合相互作用，从而实现配体-金属合作。 几项初步研究，包括 ppm 级金催化羧酸与炔烃的加成， 炔烃不对称异构化为丙二烯，并捕获催化生成的 σ-丙二烯基金 与醛的中间体，验证了配体设计和催化的协同性质。 作为 PI 未来工作的主要重点，该提案旨在应用这种合作性金（I）催化 开发特殊合成值的不对称变换的策略。这些包括 手性丁烯醇和2,5-二取代吡咯啉的便捷构建和不对称炔丙基化 反应/炔丙基C-H官能化。将此策略扩展到更便宜的合作 Cu(I) Ag(I) 催化为不对称烯醇化物质子化提供了新的、独特的机会，这将打开 获得各种羰基产品的宝贵机会。向功能化 N,N-二齿配体的转变将 使协同配体设计概念能够应用于更广泛的金属催化和 提供了前所未有的机会以不对称方式操纵羰基化合物。 该提案如果实施，将引入一系列新型多功能手性双功能配体 金属催化并激发了合作催化方面不断增加的研究工作。此外，开发的方法 将提供对一般化学合成具有高价值的各种手性结构的有效获取 尤其是医药研发。