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的常见基序，对人类疾病相关靶标具有生物活性。仲烷基亲电试剂的交叉偶联反应对于合成这些支架具有令人兴奋的前景，但是这些亲电试剂的偶联以提供对映体富集的产物还不发达。已经报道的那些通常依赖于反应性偶联配偶体和/或卤化物亲电体。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的官能团耐受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，因为它们以外消旋和对映体富集形式广泛可用。 在第一个目标中，提出了对映体特异性的，镍催化的烷基铵盐的交叉偶联。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仍然几乎未被探索。基于苄基三氟甲磺酸铵交叉偶联反应的初步结果，提出了一系列烷基铵盐与各种偶联伙伴的对映体特异性交叉偶联反应。 第二个目标概述了发展的交叉偶联反应的醇衍生的底物提供对映体富集的产品。基于与苄基新戊酸酯底物的初步结果，对映体特异性，镍催化的交叉偶联的其他对映体富集的烷基新戊酸酯将被开发。还将建立外消旋醇衍生底物的对映选择性、镍催化的交叉偶联。迄今为止，醇衍生物的偶联反应主要限于对映体特异性转化。这项研究将规避对映体富集的醇起始材料的要求，并证明了对映体选择性交叉偶联的潜力，容易获得的，外消旋醇衍生物，以提供高度对映体富集的产品。 通过利用胺和醇作为起始材料的广泛可用性，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 改善潜在生物活性靶分子阵列内三级立体中心的安装。通过加速这些靶标以高度对映体富集形式的合成，这些方法将对新分子的发现和开发产生积极影响，这些新分子有可能增加我们对人类疾病的理解和治疗能力。

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.