Stereoselective Alkene Carbofunctionalization: Method Development and Mechanism

立体选择性烯烃碳官能化：方法开发和机制

• 批准号: 10374039
• 负责人: Tianning Diao
• 金额: $ 34.13万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374039
• 关键词: Address; Alkenes; Carbon; Complex; Coupling; Cyclization; Development; Dimerization; Ethylenes; Goals; Guidelines; Hydrogenation; Ligands; Mediating; Metals; Methods; Modeling; Molecular; Organic Synthesis; Outcomes Research; Pathway interactions; Pattern; Periodicity; Pharmacologic Substance; Production; Public Health; Pyrrolidines; Reaction; Reporting; Research; Research Project Grants; Rest; Route; Series; Study models; Styrenes; Variant; base; biological preparation; catalyst; chiral molecule; design; diene; drug discovery; drug production; feasibility research; functional group; insight; method development; novel; predictive modeling; programs; rational design

Project Summary The goal of this research program is to develop stereoselective and regioselective alkene carbofunctionalization methods to enable efficient and sustainable organic syntheses. A major challenge in pharmaceutical synthesis is the catalytic construction of chiral molecules. Alkenes are versatile functional groups. 1,2-Dicarbofunctionalization and hydroalkylation of alkenes have emerged as compelling strategies to rapidly increase molecular complexity, but intermolecular asymmetric methods have not yet been developed for simple alkenes. The research projects described in this proposal address these synthetic challenges by developing a series of enantioselective reductive 1,2-dicarbofunctionalization and branch-selective hydroalkylation reactions of a broad scope of alkenes. These new methods would enable efficient routes to access target molecules with complex substitution patterns while introducing stereocenters. Catalyst development is built on the hypothesis that Ni-mediated radical addition to alkenes could result in new stereo-determining steps, such as radical capture or reductive elimination. Systematic mechanistic studies will be carried out to build stereochemical models, and insight gained will help overcome the limitations encountered in expanding the scope and utility of the new methods. Preliminary results showing new reactivity and verifying mechanistic proposals provide compelling evidence for the feasibility of this research. The expected outcomes of this research are as follows: (1) The development of stereoselective and regioselective reductive carbofunctionalization reactions of alkenes will allow for efficient access to vicinal disubstitution patterns and tertiary carbon centers, and thus novel retrosynthetic disconnections of pharmaceutical molecules; (2) The insight gained from mechanistic studies of model reactions and catalysts will not only facilitate the rational design of catalysts for the reactions described in this proposal, but also provide a guideline for understanding Ni-catalyzed coupling reactions more broadly.

项目概要 该研究计划的目标是开发立体选择性和区域选择性烯烃 碳功能化方法可实现高效且可持续的有机合成。一个专业 药物合成的挑战是手性分子的催化构建。烯烃 是多功能的官能团。烯烃的 1,2-二碳官能化和加氢烷基化 成为快速增加分子复杂性的引人注目的策略，但分子间 尚未开发出用于简单烯烃的不对称方法。研究项目 本提案中描述的通过开发一系列解决这些综合挑战 对映选择性还原1,2-二碳官能化和支链选择性加氢烷基化 广泛的烯烃反应。这些新方法将为 在引入立体中心的同时访问具有复杂取代模式的目标分子。 催化剂的开发建立在这样的假设之上：镍介导的烯烃自由基加成可以 导致新的立体决定步骤，例如自由基捕获或还原消除。 将进行系统的机理研究，建立立体化学模型，并深入了解 所获得的成果将有助于克服在扩大其范围和效用时遇到的限制 新方法。初步结果显示新的反应性并验证机制建议 为本研究的可行性提供令人信服的证据。本次活动的预期成果 研究进展如下：（1）立体选择性和区域选择性还原的发展 烯烃的碳官能化反应将允许有效地进行邻位取代 模式和三级碳中心，因此新颖的逆合成断开 药物分子； (2) 从模型反应机理研究中获得的见解 和催化剂不仅有助于合理设计用于描述的反应的催化剂 该提案，还为更多地理解镍催化偶联反应提供了指导 广泛地说。