Catalytic Asymmetric Reductive Coupling Reactions to Prepare Bioactive Molecules

描述（由申请人提供）：本提案的总体目标是开发新的镍催化的对映选择性还原交叉偶联反应，用于生物活性分子的合成和研究。众所周知，药物的两种对映体可以表现出显著不同的生物学特性。因此，手性小分子的对映选择性合成已成为学术界和工业实验室的一个重要研究领域。最近，镍催化的还原性交叉偶联反应已经成为形成碳-碳键的直接方法。这些反应通常耐受一系列官能团，在温和条件下发生，并采用廉价的、地球丰富的金属作为化学计量的还原剂。最重要的是，它们不需要使用预先生成的有机金属试剂。为了实现镍催化的还原交叉偶联反应的全部合成潜力，开发这些转化的对映选择性变体是至关重要的。该提议描述了朝着这一目标的第一个重大进展：四个新的Ni催化的对映选择性交叉偶联反应的发展。每个转换获得的初步结果提供了令人信服的证据，这项研究的可行性。这项研究将由一个由PI组成的团队进行， 化学研究生和一名博士后研究员。作为该项目的一部分，研究生和博士后研究人员将接受有机化学理论，方法和策略的严格培训。这项研究的成功实施将为合成用于研究和治疗人类疾病的小分子提供新的工具。

DESCRIPTION (provided by applicant): The overarching goal of this proposal is to develop new nickel-catalyzed enantioselective reductive cross- coupling reactions for applications in the synthesis and study of bioactive molecules. It is well established that the two enantiomers of a drug can exhibit remarkably different biological properties. As a result, the enantioselective synthesis of chiral small molecules has become an important area of research in both academic and industrial laboratories. Recently, Nickel-catalyzed reductive cross-coupling reactions have emerged as direct methods for carbon-carbon bond formation. These reactions typically tolerate an array of functional groups, occur under mild conditions, and employ inexpensive, earth abundant metals as stoichiometric reductants. Most importantly, they do not require the use of pre-generated organometallic reagents. In order to realize the full synthetic potential of Ni-catalyzed reductive cross-coupling reactions, it is critical to develop enantioselective variants o these transformations. This proposal describes the first significant progress toward this objective: the development of four new Ni-catalyzed enantioselective cross- coupling reactions. Preliminary results obtained for each transformation provide compelling evidence for the feasibility of this research. This research will be carried out by a team composed of the PI, three chemistry graduate students and one postdoctoral researcher. As part of this project, the graduate students and postdoctoral researchers will receive rigorous training in the theory, methods, and strategies of organic chemistry. The successful execution of this research will provide new tools to enable the synthesis of small molecules for the study and treatment of human disease.