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: 10620171
• 负责人: Mary P Watson
• 金额: $ 38.56万
• 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/10620171
• 关键词: 3-Dimensional; Address; Alcohols; Amines; Awareness; Carbon; Chemistry; Complex; Coupling; Derivation procedure; Development; Goals; Medicine; Methods; Nickel; Nitrogen; Oxidation-Reduction; Oxygen; Pharmaceutical Preparations; Preparation; Public Health; Reaction; Reagent; Research; Salts; drug development; drug-like compound; functional group; human disease; invention; novel; 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，并提高人们的认识： 饱和原子与成功的药物开发相关，要求这些分子是三- 维度。生物活性分子中饱和碳的重要性日益增加，这令人兴奋 发明新的交叉偶联方法和新的烷基亲电子试剂的机会来自广泛 丰富的起始原料。这项研究将重点关注烷基醇和胺，因为它们独特且令人兴奋 作为交叉偶联亲电子试剂的潜力。烷基胺和醇传统上被视为合成的 目标，而不是底物。然而，它们的广泛可用性和高度准备的便利性 对映体富集形式使它们具有吸引力的烷基亲电子试剂，可解决不对称合成中的挑战 并确定以前未开发的新合成原料。 烷基胺和醇可以制备成高对映体纯度，使其成为理想的底物 立体特异性交叉偶联反应。通过碳-氧（C-O）和碳-氮（C-N）键断裂 高度对映体丰富的醇和胺衍生物，我们将解决不对称领域长期存在的挑战 合成。这些立体特异性交叉偶联将这些醇和胺中间体推进为 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四元产品 立体中心。 伯烷基胺存在于从简单原材料到药物的分子中， 生物分子。这项研究将利用普遍存在的氨基 (NH2) 基团，开发化学方法来转化 NH2 基团通过 C-N 键的断裂形成许多其他官能团。 C-N 转换的能力 与 C–C（或 C–X）键的结合为复杂烷基的后期功能化提供了强大的机会 胺、生物分子衍生化和早期合成。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，易于选择性制备 来自伯烷基胺。 这种化学的成功开发将能够有效地获取三维分子 具有来自广泛使用的前体的潜在生物活性。这项研究也将改变化学家的看法 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 亲电子试剂与长期以来已知的 C(sp2)–X 试剂一样有用，可用于发现和 新药的合成。通过为新型药物分子的合成打开一扇新的大门，这 研究将影响新分子的发现，有可能加深我们的理解和 治疗人类疾病的能力。