C-H Functionalization for the Synthesis of Amines and Nitrogen Heterocycles

 描述（由申请人提供）：通过过渡金属催化的C-H键官能化直接形成碳-碳键已成为合成用于药物发现和生产的化合物的强大新方法。这种方法与更成熟和非常重要的烯烃复分解和交叉偶联方法有两个共同的特征;（1）它能够制备生物活性天然产物和药物中存在的必需碳框架，以及（2）当使用适当的过渡金属时，它可以是高度官能团相容的。C-H键在有机化合物中的普遍存在还提供了潜在的大量不同的输入，以使得能够更快速地制备用于药物发现的类似物，以及最小化药物生产中的步骤、成本和浪费。该资助的过去资助期已经产生了许多强大的方法，这些方法构成了朝着长期目标的显着进展，即开发有效和通用的C-H键官能化方法，从而能够快速获得药物和天然产物中常见的分子复杂性结构。本申请的总体目标是开发催化C-H键活化和碳-碳键形成，用于含胺化合物的会聚组装，其代表84%的小分子药物。氮杂环的合成，这是目前在59%的药物，强调。我们的中心假设是，这些结构可以通过两种互补的过渡金属催化方法有效地制备，这两种方法定义在两个特定的目标中：1）通过过渡金属催化的C-H键与C=O/C=N键的加成，发展有效和通用的制备含胺化合物和杂环的方法;和2）开发有效的和通用的C-H键官能化/电环化级联以得到1，2-二氢吡啶，然后快速加工成药物相关的氮杂环。在第一个目标下，首先在实验室中开发的Rh（III）催化的催化C-H键加成到C=O和C=N键的方法将被推进到亚胺的不对称C-H键加成以及烯烃和C=O或C=N键的连续C-H键级联加成以形成两个新的碳-碳单键。还将开发新的地球丰富的Co（III）催化剂以补充Rh（III）催化剂。在第二个目标下，将简单和容易获得的前体转化为1，2-二氢吡啶，然后以高度区域和立体控制将其加工成哌啶、吡啶、托烷和甚至更复杂的氮杂环，包括药物制剂。这些方法是创新的，因为将探索C-H键官能化中的新型反应性，并且将开发用于阐述最初形成的C-H键加成产物的新方法。这项研究意义重大，因为这些方法的成功开发将使药物、生物活性天然产物和化学生物学工具的发现和生产更加有效。

 DESCRIPTION (provided by applicant): The direct formation of carbon-carbon bonds by transition metal-catalyzed C-H bond functionalization has emerged as a powerful new approach for the synthesis of compounds for drug discovery and production. This approach has two characteristics in common with the more established and enormously important olefin metathesis and cross-coupling methods; (1) it enables the preparation of the essential carbon frameworks present in bioactive natural products and drugs, and (2) when the appropriate transition metals are used it can be highly functional group compatible. The ubiquitous presence of C-H bonds in organic compounds also provides a potentially vast array of diverse inputs to enable the more rapid preparation of analogs for drug discovery as well as to minimize steps, cost and waste in drug production. Past funding periods of this grant have resulted in a number of powerful methods that constitute marked progress toward the long-term goal to develop efficient and general C-H bond functionalization methods that enable rapid access to structures with a level of molecular complexity commonly found in drugs and natural products. The overall objective of this application is to develop catalytic C-H bond activation and carbon-carbon bond formation for the convergent assembly of amine containing compounds, which represent 84% of small-molecule drugs. The synthesis of nitrogen heterocycles, which are present in 59% of drugs, is emphasized. Our central hypothesis is that these structures can be prepared efficiently by the two complementary transition metal-catalyzed approaches defined in the two specific aims: 1) Develop efficient and general methods to prepare amine containing compounds and heterocycles by transition metal-catalyzed C-H bond addition to C=O/C=N bonds; and 2) Develop efficient and general C-H bond functionalization/electrocyclization cascades to 1,2-dihydropyridines followed by rapid elaboration to drug relevant nitrogen heterocycles. Under the first aim, Rh(III)-catalyzed methods for catalytic C-H bond addition to C=O and C=N bonds first developed in the lab will be advanced to asymmetric C-H bond additions to imines as well as to sequential C-H bond cascade additions across alkenes and C=O or C=N bonds to form two new carbon-carbon single-bonds. New earth abundant Co(III) catalysts will also be developed to complement Rh(III) catalysts. Under the second aim simple and readily available precursors are converted to 1,2-dihydropyridines that are then elaborated with high regio- and stereocontrol to give piperidines, pyridines, tropanes, and even more complex nitrogen heterocycles, including pharmaceutical agents. The approaches are innovative because new types of reactivity in C-H bond functionalization will be explored and fundamentally new methods will be developed for elaborating the initially formed C-H bond addition products. The research is significant because successful development of these methods will enable the more efficient discovery and cost effective production of drugs, bioactive natural products and chemical biology tools.