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: 8526104
• 负责人: Jason James Beiger
• 金额: $ 4.71万
• 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 2017-02-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8526104
• 关键词: Antifungal Agents; Antioxidants; Asthma; Award; Biological Factors; Boron; Carbon; Catalysis; Complex; Development; Electronics; Elements; Ethers; Future; Goals; HIV; Hydrogen; Hydrogen Bonding; Hypersensitivity; Iridium; Isotopes; Ligands; Malignant Neoplasms; Measurement; Medicine; Metals; Methodology; Methods; Molecular; Organic Synthesis; Pharmaceutical Preparations; Positioning Attribute; Process; Reaction; Reagent; Research; Research Training; Route; Scheme; Site; Solvents; Temperature; Thermodynamics; Transition Elements; Work; antimicrobial; catalyst; chemical synthesis; design; direct application; drug discovery; drug production; functional group; hydroxyl group; method development; montelukast; public health relevance; 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）：创建用于合成复杂分子的新的有效方法对药物发现和生产至关重要。开发碳 - 氢（C-H）键直接，选择性和催化功能化的方法，以产生碳 - 波纹键（即borylation）尤其重要。有机体试剂可以说是有机合成和医学中用途最广泛的合成中间体。已经开发了有机碳酸盐的直接路线，但通常受其选择性的限制。结果，开发在单个位点促进反应性的催化剂变得重要。为此，普通的羟基可以用作指导金属催化的C-H键官能化的元素。该提案的重点是开发一种有效的方法，用于未激活的原代C-H键的均匀定向。该方法将提高制造结构复杂的分子的效率。这项研究的具体目的是：（i）确定一种催化催化剂的催化剂络合物 （ii）评估已开发方法的底物范围和功能组耐受性，（iii）提供了有关此过程如何工作的详细机械图，（iv）将此方法应用于合成结构复杂的生物活性分子。将对各种过渡金属和配体组合进行周到的筛选，以识别适当的活性催化剂。然后，将相对于催化剂载荷，试剂身份和化学计量，溶剂和温度来优化反应。然后，将通过测量速率常数，热力学参数以及同位素和取代基效应来确定反应的机制。该提案的长期目标是创建一种新的合成方法来进行药物发现，增强我们对催化的分子水平的理解，并推进天然产物合成的领域。