Cross Couplings of Amine and Alcohol Derivatives to Give Enantioenriched Products

胺和醇衍生物的交叉偶联产生对映体富集的产品

• 批准号: 8766156
• 负责人: Mary P Watson
• 金额: $ 28.79万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8766156
• 关键词: Air; Alanine; Alcohols; Alkanes; Alkylation; Amines; Amino Acids; Ammonium; Biological; Chemistry; Cods; Coupled; Coupling; Development; Dioxanes; Esters; Felis catus; Generations; Goals; Ligands; Methods; Nickel; Pharmacologic Substance; Preparation; Public Health; Reaction; Reagent; Reporting; Research; Salts; Scheme; Sodium Chloride; Staging; adduct; alcohol availability; base; catalyst; functional group; human disease; improved; programs; propadiene; public health relevance; scaffold

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.

描述(由申请人提供)：三级立体发生中心是各种分子中的一个常见基序，具有针对与人类疾病相关的靶点的生物活性。仲烷基亲电体的交叉偶联反应为这些支架的合成带来了令人兴奋的前景，但这些亲电体之间的偶联反应还不够发达。已报道的那些通常依赖于反应性偶联伙伴和/或卤化物亲电试剂。为了解决这些限制，该研究计划将开发胺和醇类亲电体与空气稳定、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体，因为它们以外消旋和富含对映体的形式广泛存在。在第一个目标中，我们提出了烷基铵盐的对映选择性镍催化交叉偶联反应。尽管胺可以方便地制备成近乎完美的对映体纯度，但胺衍生的亲电体在交叉偶联化学中仍然几乎没有被探索过。根据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对的对映选择性交叉偶联。第二个目标概述了乙醇衍生底物的交叉偶联反应的发展，以提供富对映体产品。在初步研究结果的基础上，将开发其他富含对映体的烷基丙戊酸酯的对映选择性镍催化的交叉偶联反应。对映体选择性，镍催化的外消旋醇衍生底物的交叉偶联也将被建立。到目前为止，醇衍生物的偶联在很大程度上仅限于对映异构体的转化。这项研究将绕过对映体浓缩醇起始材料的要求，并展示容易获得的外消旋醇衍生物的对映选择性交叉偶联来提供高度对映体富集物的潜力。通过利用胺和醇的广泛可用性作为起始材料，并优先使用温和的、空气稳定的偶联伙伴，这项研究将极大地 改进潜在生物活性目标分子阵列中的第三立体中心的安装。通过加快这些目标的合成，这些方法将对新分子的发现和开发产生积极影响，有可能增加我们对人类疾病的理解和治疗能力。