The Silyl-Directed Borylation of Aliphatic C-H Bonds

脂肪族 C-H 键的甲硅烷基定向硼化

• 批准号: 9013486
• 负责人: Jason James Beiger
• 金额: $ 4.51万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-20 至 2016-11-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9013486
• 关键词: Alkanes; Asthma; Award; Boron; Carbon; Catalysis; Complex; Development; Electronics; Elements; Ethers; Future; Goals; Health; Hydrogen; Hydrogen Bonding; Isotopes; Ligands; Measurement; Medicine; Metals; Methodology; Methods; Molecular; Natural Products; Organic Synthesis; Pharmaceutical Preparations; Positioning Attribute; Process; Reaction; Reagent; Research; Route; Scheme; Site; Solvents; Temperature; Thermodynamics; Transition Elements; Work; catalyst; chemical synthesis; design; drug discovery; drug production; functional group; hydroxyl group; method development; screening; stoichiometry

DESCRIPTION (provided by applicant): The creation of new and efficient methods for the synthesis of complex molecules is important to drug discovery and production. The development of methods for the direct, selective and catalytic functionalization of carbon-hydrogen (C-H) bonds to produce carbon-boron bonds (i.e. borylation) is especially critical. Organoboron reagents are arguably the most versatile synthetic intermediates in organic synthesis and medicine. Direct routes to organoboronates have been developed but are often limited by their selectivity. As a result, it becomes important to develop catalysts that promote reactivity at a single site. Toward this end, ordinary hydroxyl groups may be used as directing elements for transition metal-catalyzed C-H bond functionalization. This proposal focuses on the development of an efficient method for the silyl-directed borylation of unactivated primary C-H bonds. This method will increase the efficiency by which structurally complex molecules are made. The specific aims of this research are to: (i) identify a catalyst complex that catalyzes the borylation of aliphatic C-H bonds via silyl direction, (ii) evaluate the substrate scope and functional group tolerance of the developed method, (iii) provide a detailed mechanistic picture of how this process works, and (iv) apply this method to the synthesis of structurally complex, biologically active molecules. Thoughtful screening of various transition metal and ligand combinations will be done to identify a suitably active catalyst. The reaction will then be optimized with respect to catalyst loading, reagent identity and stoichiometry, solvent and temperature. The reaction's mechanism will then be established via the measurement of rate constants, thermodynamic parameters, as well as isotope and substituent effects. The long-term objectives of this proposal are to create a new synthetic methodology for drug discovery, enhance our molecular-level understanding of catalysis, and advance the field of natural products synthesis.

描述（由申请人提供）：创建新的、有效的复杂分子合成方法对于药物发现和生产非常重要。开发直接、选择性和催化功能化碳-氢（C-H）键以产生碳-硼键（即硼化）的方法尤其重要。有机硼试剂可以说是有机合成和医药中最通用的合成中间体。有机硼酸盐的直接途径已经开发出来，但通常受到其选择性的限制。因此，开发促进单个位点反应活性的催化剂变得很重要。为此，普通羟基可用作过渡金属催化的C-H键官能化的导向元素。该提案的重点是开发一种有效的方法，用于未活化的伯碳键的甲硅烷基定向硼基化。这种方法将提高制造结构复杂分子的效率。本研究的具体目的是：（i）确定一种催化复合物 通过甲硅烷基方向对脂肪族 C-H 键进行硼基化，(ii) 评估所开发方法的底物范围和官能团耐受性，(iii) 提供该过程如何工作的详细机制图，以及 (iv) 将该方法应用于合成结构复杂、具有生物活性的分子。将仔细筛选各种过渡金属和配体组合，以确定合适的活性催化剂。然后将在催化剂负载、试剂特性和化学计量、溶剂和温度方面优化反应。然后通过测量速率常数、热力学参数以及同位素和取代基效应来确定反应机理。该提案的长期目标是为药物发现创建一种新的合成方法，增强我们对催化的分子水平理解，并推进天然产物合成领域的发展。