The Silyl-Directed Borylation of Aliphatic C-H Bonds

描述(由申请人提供)：创造合成复杂分子的新的有效方法对药物的发现和生产很重要。碳-氢(C-H)键的直接、选择性和催化官能化(即硼化)方法的发展尤为关键。有机硼试剂可以说是有机合成和医药中用途最广泛的合成中间体。合成有机硼化合物的直接路线已经开发出来，但往往受到选择性的限制。因此，开发能够在单一位置促进反应活性的催化剂变得非常重要。为此，可以使用普通羟基作为过渡金属催化的C-H键功能化的指导元素。这项建议侧重于开发一种有效的方法，用于未活化的初级C-H键的硅基直接硼化反应。这种方法将提高制造结构复杂分子的效率。这项研究的具体目的是：(I)确定一种催化 通过硅基方向的脂肪族C-H键的硼化反应，(Ii)评估所开发的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的机理图，以及(Iv)将该方法应用于结构复杂的生物活性分子的合成。将对各种过渡金属和配体组合进行仔细的筛选，以确定合适的活性催化剂。然后，根据催化剂的装载量、试剂的一致性和化学计量比、溶剂和温度对反应进行优化。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机理。这项建议的长期目标是创造一种新的药物发现合成方法，提高我们对催化的分子水平的理解，并推动天然产物合成领域的发展。

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.