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.

寻找新药需要发现新的分子，而且人们越来越意识到 饱和原子与成功的药物开发相关，要求这些分子是三个- 次元的。饱和碳在生物活性分子中的重要性日益增加，这一点令人兴奋 发明新的交叉偶联方法和新的烷基亲电试剂的机会 原料丰富。这项研究将重点放在烷醇和胺上，因为它们独特而令人兴奋 作为交叉偶联亲电体的潜力。烷基胺和醇传统上被认为是合成的 目标，而不是底物。然而，它们的广泛可用性和制备的简便性在很大程度上 富对映体使它们成为极具吸引力的烷基亲电化合物，以应对不对称合成中的挑战 并确定以前未开发的用于合成的新原料。 烷基胺和醇可以在高对映体纯度下制备，使它们成为 立体定向交叉偶联反应。通过碳-氧(C-O)和碳-氮(C-N)键断裂 高对映体浓缩醇和胺衍生物，我们将解决长期的不对称挑战 综合。这些立体特异性的交叉偶联将使这些醇和胺的中间体 有价值的、高度富含对映体的产品，包括那些传统上具有挑战性的全碳季铵化合物 立体中心。 伯烷基胺存在于各种分子中，从简单的原料到药物和 生物分子。利用泛氨基(NH2)，这项研究将发展化学转化 NH2通过裂解C-N键形成许多其他官能团。将C-N转换为 C-C(或C-X)键的成键为复杂烷基的后期官能化提供了强大的机会 胺、生物分子的衍生化和早期合成。这一目标将通过镍- 氧化还原活性的Katritzky吡啶盐的催化交叉偶联，容易和选择性地制备 伯烷基胺。 这种化学的成功发展将使人们能够高效地获得三维分子 从广泛可用的前体中获得潜在的生物活性。这项研究还将改变化学家们看待 并使用这些官能团。这项研究的最终目标是发明交叉耦合方法 C(Sp3)-X亲电体，与那些长期以来为人们所知的C(Sp2)-X试剂一样有用，用于发现和 新药的合成。通过为合成新的类药物分子打开了一扇新的大门，这 研究将影响新分子的发现，有可能加深我们对 治疗人类疾病的能力。