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: 9021912
• 负责人: Mary P Watson
• 金额: $ 10.6万
• 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/9021912
• 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）：三级立体中心是多种分子中的常见基序，具有针对与人类疾病相关的靶标的生物活性。二级烷基亲电子试剂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，但这些亲电子试剂用于传递对映体富集产品的偶联尚未开发。已报道的那些通常依赖于反应性偶联伙伴和/或卤化物亲电子试剂。为了解决这些限制，该研究计划将开发胺和醇衍生的亲电子试剂与空气稳定、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子试剂，因为它们以外消旋和对映体富集形式广泛存在。 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。尽管胺可以方便地制备成近乎完美的对映体纯度，但胺衍生的亲电子试剂在交叉偶联化学中实际上仍未得到探索。基于三氟甲磺酸苄基铵交叉偶联的初步结果，提出了一系列烷基铵盐与各种偶联伙伴的对映特异性交叉偶联。 第二个目标概述了醇衍生底物交叉偶联反应的发展，以提供对映体富集的产品。基于新戊酸苄酯底物的初步结果，将开发其他对映体富集的新戊酸烷基酯的对映特异性镍催化交叉偶联。还将建立外消旋醇衍生底物的对映选择性镍催化交叉偶联。迄今为止，醇衍生物的偶联很大程度上限于对映体特异性转化。这项研究将绕开对映体富集的醇起始材料的要求，并展示现成的外消旋醇衍生物的对映选择性交叉偶联以提供高度对映体富集的产品的潜力。 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、空气稳定的偶联伙伴，这项研究将极大地促进 改善一系列潜在生物活性目标分子中三级立构中心的安装。通过加速这些高度对映体富集形式的靶标的合成，这些方法将对新分子的发现和开发产生积极影响，并有可能增加我们对人类疾病的理解和治疗能力。