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，人们越来越认识到， 与成功的药物开发相关的饱和原子要求这些分子是三个- 立体的饱和碳在生物活性分子中的重要性日益增加， 新的交叉偶联方法和新的烷基亲电试剂的发明机会， 丰富的起始原料。本研究将集中在烷基醇和胺的独特和令人兴奋的 作为交叉耦合亲电体的电势。烷基胺和醇传统上被认为是合成的。 目标，而不是基质。然而，它们的广泛可用性和制备的容易性在很大程度上限制了它们的应用。 对映体富集的形式使它们成为有吸引力的烷基亲电试剂，以解决不对称合成中的挑战 并鉴定新的、以前未开发的合成原料。 烷基胺和醇可以以高对映体纯度制备，使它们成为制备手性化合物的理想底物。 立体定向交叉偶联反应。通过碳-氧（C-O）和碳-氮（C-N）键断裂 高度对映体富集的醇和胺衍生物，我们将解决长期存在的挑战，不对称 合成.这些立体特异性交叉偶联将使这些醇和胺中间体进一步转化为 有价值的，高度对映体富集的产品，包括那些传统上具有挑战性的全碳季铵盐 立体中心 伯烷基胺存在于从简单的起始材料到药物的分子中， 生物分子利用无处不在的氨基（NH 2）基团，这项研究将发展化学， NH 2基团通过C-N键的裂解转化为许多其他官能团。将一个C-N 键与C-C（或C-X）键的键合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。这一目标将通过镍来实现- 氧化还原活性Katritzky吡啶鎓盐的催化交叉偶联，其容易且选择性地制备 由伯烷基胺制得。 这种化学方法的成功开发将使人们能够有效地获得三维分子 具有来自广泛可获得的前体的潜在生物活性。这项研究也将改变化学家看待 并使用这些官能团。本研究的最终目标是发明交叉耦合方法， C（sp3）-X亲电试剂，其与长期已知的C（sp2）-X试剂一样可用于发现和 合成新药。通过为新型药物样分子的合成打开一扇新的大门， 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。