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: 9896861
• 负责人: Tianning Diao
• 金额: $ 46.38万
• 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/9896861
• 关键词: Address; Alkenes; Biological; 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; Structure; Study models; Styrenes; Variant; base; biological preparation; catalyst; chiral molecule; design; diene; drug discovery; drug production; functional group; insight; method development; novel; predictive modeling; programs

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.

项目摘要 本研究计划的目标是开发立体选择性和区域选择性的烯烃 碳官能化方法，以实现高效和可持续的有机合成。一个主要 药物合成中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具有 作为迅速增加分子复杂性的引人注目的策略出现，但分子间 对于简单烯烃，还没有开发出不对称方法。的研究项目 本提案中所述的解决这些综合挑战的方法是， 对映选择还原1，2-二碳官能化和支链选择加氢烷基化 广泛的烯烃反应。这些新方法将使有效的路线， 在引入立体中心的同时获得具有复杂取代模式的靶分子。 催化剂的开发建立在Ni介导的烯烃自由基加成可以 导致新的立体决定步骤，如自由基捕获或还原消除。 将进行系统的机理研究，以建立立体化学模型， 所取得的进展将有助于克服在扩大 新方法初步结果显示新的反应性和验证机制的建议 为这项研究的可行性提供令人信服的证据。预期的结果 研究内容如下：（1）立体选择性和区域选择性还原剂的开发 烯烃的碳官能化反应将允许有效地获得邻位双取代 模式和叔碳中心，因此新的逆合成断开， 药物分子;（2）从模型反应的机理研究中获得的见解 并且催化剂将不仅促进用于在专利申请中描述的反应的催化剂的合理设计， 这一建议，也为理解镍催化偶联反应提供了指导， 大致上