Cross Couplings of Amine and Alcohol Derivatives to Give Enantioenriched Products

描述（由申请人提供）：三级立体中心是多种分子中常见的基序，具有针对人类疾病相关靶点的生物活性。仲烷基亲电试剂的交叉偶联反应为这些支架的合成提供了令人兴奋的前景，但这些亲电试剂的偶联传递富集对映体的产物尚不发达。那些已报道的通常依赖于反应偶联伙伴和/或卤化物亲电试剂。为了解决这些限制，本研究计划将开发胺和醇衍生的亲电试剂与空气稳定、官能团耐受的偶联伙伴的交叉偶联反应。胺和醇衍生物是理想的亲电试剂，因为它们在外消旋和对映体富集形式中广泛存在。在第一个目标中，提出了烷基铵盐的对映特异性，镍催化的交叉偶联。尽管胺可以方便地以接近完美的对映体纯度制备，但胺衍生的亲电试剂在交叉偶联化学中几乎尚未被探索。基于三氟化苄铵交叉偶联的初步结果，提出了一系列烷基铵盐与不同偶联体的对映特异性交叉偶联。第二个目标概述了醇衍生底物的交叉偶联反应的发展，以提供富集对映体的产物。基于对苯基戊酸酯底物的初步研究结果，将开发其他对映体富集的烷基戊酸酯的镍催化交叉偶联反应。对映选择性，镍催化的外消旋醇衍生底物的交叉偶联也将建立。迄今为止，醇衍生物的偶联在很大程度上仅限于对映体特异性转化。本研究将绕过对富集对映体的醇起始材料的要求，并证明了对映选择性交叉偶联的潜力，现成的外消旋醇衍生物提供高度富集对映体的产品。通过利用广泛可用的胺和醇作为起始材料，并优先使用温和的、空气稳定的偶联伙伴，这项研究将大大提高

DESCRIPTION (provided by applicant): Tertiary stereogenic centers are a common motif in a variety of molecules with biological activities against targets associated with human disease. Cross coupling reactions of secondary alkyl electrophiles hold exciting promise for the synthesis of these scaffolds, but the couplings of these electrophiles to deliver enantioenriched products are underdeveloped. Those that have been reported often rely on reactive coupling partners and/or halide electrophiles. To solve these limitations, this research program will develop cross coupling reactions of amine- and alcohol-derived electrophiles with air-stable, functional group tolerant coupling partners. Amine and alcohol derivatives are ideal electrophiles due to their wide availability in both racemic and enantioenriched form. In the first aim, enantiospecific, nickel-catalyzed cross couplings of alkyl ammonium salts are proposed. Despite the fact that amines can be conveniently prepared in near perfect enantipurity, amine-derived electrophiles remain virtually unexplored in cross coupling chemistry. Based on preliminary results in the cross couplings of benzylic ammonium triflates, enantiospecific cross couplings of a range of alkyl ammonium salts with various coupling partners are proposed. The second aim outlines the development of cross coupling reactions of alcohol-derived substrates to deliver enantioenriched products. Based on preliminary results with benzylic pivalate substrates, enantiospecific, nickel-catalyzed cross couplings of other enantioenriched alkyl pivalates will be developed. Enantioselective, nickel-catalyzed cross couplings of racemic alcohol-derived substrates will also be established. To date, couplings of alcohol derivatives have been largely limited to enantiospecific transformations. This research will circumvent the requirement for enantioenriched alcohol starting materials and demonstrate the potential of enantioselective cross couplings of readily available, racemic alcohol derivatives to deliver highly enantioenriched products. By exploiting the broad availability of amines and alcohols as starting materials and prioritizing the use of mild, air-stable coupling partners, this research will vastly improve the installation of tertiary stereocenters within an array of potentially bioactive target molecules. By expediting the synthesis of these targets in highly enantioenriched form, these methods will positively impact the discovery and development of new molecules with the potential to increase our understanding of and ability to treat human disease.