Nickel Cross-Coupling Cascades with α-Heteroatom Radicals to Prepare Sterically Hindered Alcohols and Amines

镍与α-杂原子自由基交叉偶联级联制备位阻醇和胺

• 批准号: 10604535
• 负责人: Omar Beleh
• 金额: $ 6.91万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2026-02-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604535
• 关键词: Academia; Acids; Acylation; Adopted; Alcohols; Amines; Amino Acids; Amino Alcohols; Area; Bypass; Carbon; Chemicals; Complex; Coupling; Development; Dissociation; Free Radicals; Future; Generations; Goals; Hydrogen; In Situ; Industry; Intercept; Ketones; Ligands; Mediator; Methodology; Methods; Molecular Conformation; Natural Products; Nickel; Outcome Study; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Process; Production; Reaction; Reagent; bioactive natural products; driving force; drug candidate; drug development; drug discovery; drug synthesis; forging; functional group; improved; interest; ketal; novel; scaffold; unnatural amino acids

Project Summary The overarching theme of this proposal is to apply robust and reliable reaction mechanisms to improve the efficiency of forming C–C bonds adjacent to alcohol or amine functionality. Among the most common strategies to these products is the addition of a Grignard reagent (or other carbon nucleophile) to a ketone or ketimine electrophile, but the broad applicability of these methods is limited by (1) the poor compatibility of organometallic nucleophiles with many functional groups common to drug scaffolds and (2) significant limitations inherent to migratory insertion mechanisms, such as sluggish or undesired reactivity. The central hypothesis of this proposal is that α-heteroatom radical generating processes can be implemented in tandem with nickel cross-coupling for C–H functionalization to install hindered stereocenters. The emergence of nickel catalyzed cross-electrophile coupling strategies has provided novel and complementary reactivity to traditional cross-couplings and the controlled generation of organic free radicals is central to the development of new methods in this area. Intramolecular hydrogen atom transfer (HAT) mechanisms proceed at a higher rate than nickel capture of alkyl radicals, and should be an appropriate approach to generate the radical. The Specific Aims of this proposal are: (1) development of a 1,5-HAT and nickel C–C bond forming cascade to synthesize tertiary alcohols from readily available secondary alcohols and a traceless auxiliary group; (2) a strategy in which α-heteroatom radicals formed through 1,5-HAT are intercepted for nickel facilitated C–C bond formation to prepare functionalized amino alcohols and amino acids; and (3) an approach for Csp3–Csp3 coupling of α-heteroatom radicals to primary radicals is presented, in which cross-selectivity should be driven by radical stability differences. All three of these Aims can be adopted into enantioconvergent reactions by employing chiral ligands to generate stereocenters, which is highly desirable in the context of pharmaceutical and natural product synthesis. The development and synthesis of drug candidates is limited by the reactions available to make them, and the strategies described in this proposal will facilitate Csp2–Csp3 and Csp3–Csp3 bond formation at α-heteroatom carbon centers, an important motif found in pharmaceuticals and bioactive natural products. The continued improvement of catalytic conditions that employ a large pool of coupling partners to prepare sterically congested alcohols and amines will be of significant interest to both academia and industry, and will enable broader chemical space accessible in future drug discovery endeavors.

项目摘要 该提案的首要主题是应用强大而可靠的反应机制，以改善 与醇或胺官能团相邻形成C-C键的效率。在最常见的策略中， 这些产物的另一种方法是将格氏试剂（或其它碳亲核试剂）加成到酮或酮亚胺上 这些方法的广泛适用性受到以下限制：（1）有机金属化合物的相容性差， 具有许多药物支架共有的官能团的亲核试剂和（2）药物支架固有的显著限制， 迁移插入机制，如缓慢或不希望的反应性。这项提议的核心假设是 α-杂原子自由基产生过程可以与镍交叉偶联串联实施， C-H官能化以安装受阻立体中心。镍催化交叉亲电试剂的出现 偶联策略为传统的交叉偶联提供了新的和互补的反应性， 有机自由基的受控产生是该领域新方法开发的核心。 分子内氢原子转移（HAT）机制比镍捕获烷基的速率更高 自由基，并且应该是产生自由基的适当方法。该提案的具体目标是： (1)开发了1，5-HAT和镍C-C键形成级联反应， 可用的仲醇和无痕迹的辅助基团;（2）α-杂原子基团 通过1，5-HAT形成的产物被拦截，用于镍促进的C-C键形成， 醇和氨基酸;和（3）α-杂原子基团与伯氨基酸的Csp 3-Csp 3偶联的方法 自由基，其中交叉选择性应驱动自由基的稳定性差异。所有这三 通过使用手性配体产生立体中心， 这在药物和天然产物合成中是非常需要的。发展和 候选药物的合成受到制备它们的可用反应的限制， 这一提议将促进Csp 2-Csp 3和Csp 3-Csp 3键在α-杂原子碳中心的形成， 在药物和生物活性天然产物中发现的重要基序。催化剂的不断改进 使用大量偶联配偶体制备空间拥挤的醇和胺的条件将 对学术界和工业界都有重大意义，并将使更广泛的化学空间在 未来的药物研发