Carbon-Carbon Bond Forming Reactions in Via C-H Activation

描述（由申请人提供）：碳-碳键几乎存在于所有药物、生物活性天然产物和用于生物系统研究的化学工具中。因此，碳-碳键的形成方法对于生物活性小分子的合成至关重要，过渡金属催化的过程，如烯烃复分解（2005年诺贝尔奖）和交叉偶联（2010年诺贝尔奖）由于其高官能团相容性而产生深远的影响。通过C-H键的直接功能化，过渡金属催化碳-碳键的形成具有巨大的潜力，通过消除需要用卤化物/假卤化物或有机金属官能团预先激活起始材料，加速药物的发现和生产。这大大增加了可用投入物的数量和种类，从而能够更有效地制备药物发现和优化所需的药物类似物，并减少了药物生产中的步骤数量、成本和浪费。由美国国立卫生研究院资助的研究在当前的资助周期中取得了许多非常重要的进展，对药物的发现和生产产生了相当大的影响，包括(1)高度官能基相容的铑催化方法，用于直接芳化药学上重要的杂环，包括唑和嗪，直接邻芳化以前没有报道过，(2)开创性的对映选择性催化C-H键功能化，(3)应用于复杂生物活性天然产物的高效合成。本应用的总体目标是通过催化C-H键活化和C-C键形成来制备含胺化合物的一般方法的发展。尽管事实上绝大多数药物都含有胺功能，但迄今为止只有非常有限的通过C-H键功能化合成胺的例子被报道。中心假设是，两种互补的过渡金属催化方法可以有效地制备出广泛的胺，这些方法由具体目标定义：(1)通过过渡金属催化非反应性C-H键的活化，然后在C-N ？(2)开发高效和通用的方法，通过过渡金属催化在炔上加成C-H键来制备具有重要药学意义的6元氮杂环，以提供通过电环化原位形成C-N键的氮杂环。预期的结果将是通过减少对预官能化起始材料的需求，更快速和有效地合成药物，如含胺化合物。由于胺存在于绝大多数药物和候选药物中，预计会对药物发现和生产的速度和成本产生相当大的积极影响。本应用中提出的研究是创新的，因为它为通过C-H键功能化聚合制备胺提供了两种新的方法，这与先前报道的策略有明显的不同。

DESCRIPTION (provided by applicant): Carbon-carbon bonds are present in virtually all drugs, bioactive natural products, and chemical tools for the study of biological systems. Consequently, methods for the formation of carbon-carbon bonds are of central importance to the synthesis of bioactive small molecules, with transition metal catalyzed processes such as olefin metathesis (2005 Nobel Prize) and cross coupling (2010 Nobel Prize) having a profound impact due to their high functional group compatibility. Transition metal catalyzed carbon-carbon bond formation via the direct functionalization of C-H bonds has enormous potential to accelerate drug discovery and production by eliminating the need to preactivate starting materials with halide/pseudohalide or organometallic functionality. This dramatically increases the number and variety of available inputs to enable the more efficient preparation of drug analogues necessary for drug discovery and optimization and also reduces the number of steps, cost and waste in drug production. The research funded by the NIH in the current grant cycle resulted in a number of highly significant advances with considerable impact on drug discovery and production, including (1) highly functional group compatible Rh-catalyzed methods for the direct arylation of pharmaceutically important heterocycles, including azoles and azines, for which direct ortho-arylation had not previously been reported, (2) pioneering enantioselective catalytic C-H bond functionalization, and (3) application to the efficient synthesis of complex bioactive natural products. The overall objective of this application is the development of general methods to prepare amine containing compounds through catalytic C-H bond activation and C-C bond formation. Despite the fact that a large majority of drugs contain amine functionality, only very limited examples of amine synthesis through C-H bond functionalization have been reported to date. The central hypothesis is that a broad range of amines can efficiently be prepared by the two complementary transition metal catalyzed approaches defined by the specific aims: (1) Develop efficient and general methods to prepare amine containing compounds by transition metal catalyzed activation of unreactive C-H bonds followed by addition across C-N ? bonds, and (2) Develop efficient and general methods to prepare pharmaceutically important 6-membered nitrogen heterocycles by transition metal catalyzed addition of C-H bonds across alkynes to provide azatrienes that undergo in situ C-N bond formation via electrocyclization. The expected outcomes will be the more rapid and efficient syntheses of drug like amine containing compounds by reducing the need for prefunctionalized starting materials. Because amines are present in a large majority of drugs and drug candidates, considerable positive impacts upon the pace and cost of drug discovery and production are anticipated. The research proposed in this application is innovative because it provides two new approaches for the convergent preparation of amines by C-H bond functionalization that are marked departures from previously reported strategies.