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; 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）：第三纪立体中心是各种具有与人类疾病相关靶标的生物活性的分子中的常见基序。次级烷基电力的交叉耦合反应对这些脚手架的合成具有令人兴奋的希望，但是这些电力液的耦合以提供映射的产物的耦合欠发达。报告的人通常依赖于反应性耦合伙伴和/或卤化物电力。为了解决这些局限性，该研究计划将发展胺和酒精衍生的电力与空气稳定的，功能性的耐受耦合伙伴的交叉耦合反应。胺和酒精衍生物是理想的电物质，因为它们的外星体和对映基形式的广泛可用性。 在第一个目的中，提出了烷基铵盐盐的对映体，镍催化的交叉耦合。尽管可以方便地以几乎完美的对映射进行方便地制备胺，但在交叉耦合化学中，胺衍生的电力物几乎没有探索。基于苯并铵三叶酸盐的交叉耦合的初步结果，提出了一系列烷基铵盐与各种耦合伴侣的对照型交叉耦合。 第二个目的概述了酒精衍生的底物的交叉耦合反应的发展，以提供对映体含量的产品。将开发基于苯并二动底物的初步结果，将开发其他元素烯基烯基烷基矛盾的元素，镍催化的交叉耦合。还将建立对映射的，镍催化的镍催化的外星酒精衍生底物的交叉耦合。迄今为止，酒精衍生物的耦合在很大程度上仅限于对映体转化。这项研究将规定对映体醇的起始材料的要求，并证明了随时可用的外星酒精衍生物的对映选择性交叉耦合的潜力，以提供高度映射的产品。 通过利用胺和酒精的广泛可用性作为起始材料，并优先使用温和的，空气稳定的耦合伙伴，这项研究将大大 改善在潜在的生物活性靶标分子阵列中的高等立体中心的安装。通过以高度映射的形式加快这些靶标的合成，这些方法将对新分子的发现和开发产生积极影响，从而有可能提高我们对治疗人类疾病的理解和能力。