Harnessing Alkyl Amines and Alkyl Alcohols in Cross-Coupling Reactions

在交叉偶联反应中利用烷基胺和烷基醇

• 批准号: 10617925
• 负责人: Mary P Watson
• 金额: $ 5.97万
• 依托单位: UNIVERSITY OF DELAWARE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10617925
• 关键词: 3-Dimensional; Address; Alcohols; Amines; Awareness; Carbon; Chemistry; Complex; Coupling; Development; Goals; Medicine; Methods; Nickel; Nitrogen; Oxidation-Reduction; Oxygen; Pharmaceutical Preparations; Preparation; Public Health; Reaction; Reagent; Research; Salts; drug development; functional group; human disease; invention; novel therapeutics; programs

The search for new medicines requires the discovery of new molecules, and the increasing awareness that saturated atoms correlate to successful drug development mandates that these molecules be three- dimensional. This increasing importance of saturated carbons in bioactive molecules provides exciting opportunities for the invention of new cross-coupling methods and new alkyl electrophiles from widely abundant starting materials. This research will focus on alkyl alcohols and amines for their unique and exciting potential as cross-coupling electrophiles. Alkyl amines and alcohols have traditionally been seen as synthetic targets, not substrates. However, their wide availability and the ease of their preparation in highly enantioenriched form makes them attractive alkyl electrophiles to address challenges in asymmetric synthesis and to identify new, previously untapped feedstocks for synthesis. Alkyl amines and alcohols can be prepared in high enantiopurity, making them ideal substrates for stereospecific cross-coupling reactions. Via carbon–oxygen (C–O) and carbon–nitrogen (C–N) bond cleavage of highly enantioenriched alcohol and amine derivatives, we will solve longstanding challenges in asymmetric synthesis. These stereospecific cross-couplings will advance these alcohol and amine intermediates into valuable, highly enantioenriched products, including those with traditionally challenging all-carbon quaternary stereocenters. Primary alkyl amines are found in molecules ranging from simple starting materials to drugs and biomolecules. Harnessing the ubiquitous amino (NH2) group, this research will develop chemistry to transform NH2 groups into a host of other functional groups via cleavage of the C–N bond. The ability to transform a C–N bond to a C–C (or C–X) bond offers powerful opportunities in late-stage functionalization of complex alkyl amines, derivatization of biomolecules, and early-stage synthesis. This goal will be accomplished via nickel- catalyzed cross couplings of redox-active Katritzky pyridinium salts, which are readily and selectively prepared from primary alkyl amines. The successful development of this chemistry will enable efficient access to three-dimensional molecules with potential bioactivity from widely available precursors. This research will also change the way chemists see and use these functional groups. The ultimate goal of this research is to invent cross-coupling methods for C(sp3)–X electrophiles that are as useful as those long-known for C(sp2)–X reagents for the discovery and synthesis of new medicines. By opening a new door for the synthesis of novel, drug-like molecules, this research will impact the discovery of new molecules with the potential to deepen our understanding of and ability to treat human disease.

寻找新药物需要发现新分子，以及越来越多的意识到 饱和原子与成功的药物开发相关，要求这些分子是三个 尺寸。饱和碳在生物活性分子中的越来越重要，可提供令人兴奋的 从广泛的 财富起始材料。这项研究将重点介绍其独特而令人兴奋的酒精和胺 电位作为交叉偶联电力。传统上，烷基胺和醇被视为合成 目标，而不是基板。但是，它们的广泛可用性和高度的准备 映射形式使它们具有吸引力的烷基电力，以应对不对称合成的挑战 并确定以前未开发的原料以进行合成。 烷基胺和醇可以在高映体中制备，使其成为理想的底物 立体特定的交叉偶联反应。通过碳 - 氧（C – O）和碳 - 亚硝（C – N）键裂解 在高度映体的酒精和胺衍生物中，我们将解决不对称的长期挑战 合成。这些立体特定的跨耦合将使这些酒精和胺中间体推进 有价值的，高度映射的产品，包括传统上挑战全碳四元的产品 立体中心。 在从简单的起始材料到药物和 生物分子。该研究利用无处不在的氨基（NH2）组，将发展化学以转化 NH2组通过C – N键的切割进入许多其他官能团。转换C – N的能力 与C – C（或C – X）债券的键在复杂烷基的后期功能中提供了强大的机会 胺，生物分子的衍生化和早期合成。这个目标将通过镍来实现 - 氧化还原活跃的katritzky吡啶盐盐的催化交叉耦合，这些盐很容易准备好 来自原代烷基胺。 该化学的成功开发将有效访问三维分子 具有广泛可用前体的潜在生物活性。这项研究还将改变化学家看到的方式 并使用这些功能组。这项研究的最终目的是发明交叉耦合方法 C（sp3）–x电器与C（SP2）–X试剂的常见的c（SP2）–X型电池有用。 新药物的合成。通过为合成新颖的类似药物的分子打开新的门，这是 研究将影响新分子的发现，以加深我们对和 治疗人类疾病的能力。