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.

项目摘要 该研究计划的目的是开发立体选择性和区域选择性烯烃 功能化方法可实现有效且可持续的有机合成。专业 药物合成中的挑战是手性分子的催化构造。烯烃 是多功能官能团。烯烃的1,2-二核功能化和氢烷基化具有 出现是快速提高分子复杂性的引人注目的策略，但分子间 对于简单的烯烃，尚未开发出不对称方法。研究项目 在本提案中描述的是通过开发一系列的一系列综合挑战 对映选择性还原1,2-二核功能化和分支选择性水烷基化 广泛的烷烃反应。这些新方法将使有效的路线能够 访问目标分子具有复杂的替代模式，同时引入立体中心。 催化剂的发展是基于以下假设 导致新的立体定义步骤，例如自由基捕获或还原性消除。 将进行系统的机械研究以构建立体化学模型和洞察力 获得的将有助于克服扩大扩大范围和实用性遇到的局限性 新方法。初步结果显示了新的反应性和验证机理建议 为这项研究的可行性提供了令人信服的证据。预期的结果 研究如下：（1）立体选择性和区域选择性还原的发展 烷烃的功能化反应将有效地进入阴道脱卜属性 模式和第三碳中心，因此是新颖的反折叠式断开 药物分子； （2）从模型反应的机械研究中获得的见解 催化剂不仅会促进催化剂的合理设计 该建议，但也提供了一个指导方针，可以更多地理解NI催化的耦合反应 广泛。