Metal-Catalyzed Cross Coupling with N,O-Acetals and Acetals

N,O-缩醛和缩醛的金属催化交叉偶联

• 批准号: 8822307
• 负责人: Abigail Gutmann Doyle
• 金额: $ 29.57万
• 依托单位: PRINCETON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8822307
• 关键词: Acetals; Address; Alkenes; Alkylation; Amines; Amino Acids; Architecture; Benzopyrans; Biochemistry; Carbon; Carbon Dioxide; Catalysis; Chemicals; Coupling; Development; Disease; Electrons; Elements; Ethers; Evaluation; Exhibits; Glycobiology; Goals; Health; Human; Investigation; Ions; Lead; Libraries; Ligands; Medicine; Metals; Methodology; Methods; Mission; Molecular Medicine; Nitrogen; Organic Synthesis; Organometallic Chemistry; Oxygen; Pharmaceutical Chemistry; Preparation; Process; Protocols documentation; Pyrans; Reaction; Reagent; Research; Synthesis Chemistry; Therapeutic Agents; Transition Elements; United States National Institutes of Health; Variant; aryl halide; carboxylation; catalyst; chemical synthesis; design; enantiomer; functional group; novel; nucleophilic addition; operation; piperidine; programs; scaffold; small molecule; stoichiometry

DESCRIPTION (provided by applicant): Among the most ubiquitous scaffolds in medicinal chemistry, biological chemistry, and glycobiology are α-substituted amines and ethers. The goal of the proposed research program is to define a general and modular catalytic strategy that enables the enantioselective synthesis of these structural motifs, including those imbedded within heterocyclic frameworks, in much the same way that cross coupling serves as an all-purpose and powerful protocol for the assembly of Csp2-Csp2 bonds. To achieve this goal, we will exploit the ability of low-valent transition metal catalysts to undergo oxidative addition to iminium and oxocarbenium ions and show that this underutilized activation mode offers a versatile entry to alkyl cross-coupling reactions. In this contribution, we will pursue catalyst design and development for enantioselective arylation, heteroarylation, and alkylation of readily available and stable N,O-acetals and acetals using organoboronate and organozinc reagents (Specific Aim 1). The substituted dihydroquinolines, piperidines, chromenes, and pyrans that we will obtain from these studies constitute the core structural elements of small molecules that exhibit an array of pharmacological activities. In Specific Aim 2, we will develop a new class of stable Ni precatalyst that is easily activated to Ni(0) and enables more efficient and convenient Suzuki-Miyaura cross-coupling reactions. Reaction development will also demonstrate that the iminium/oxocarbenium ion activation mode facilitates unprecedented bond constructions with simple feedstock chemicals such as electron-deficient olefins and carbon dioxide for the synthesis of allylic ethers, allylic amines, and α-amino acids (Specific Aim 3).

描述（由申请人提供）：药物化学、生物化学和糖生物学中最普遍的支架是α-取代胺和醚。拟议研究项目的目标是定义一种通用的模块化催化策略，以实现对映选择性合成。这些结构基序，包括嵌入杂环框架内的结构基序，其方式与交叉偶联作为组装的通用且强大的协议非常相似为了实现这一目标，我们将利用低价过渡金属催化剂对亚胺和氧碳鎓离子进行氧化加成的能力，并证明这种未充分利用的活化模式为烷基交叉偶联反应提供了多种途径。在此贡献中，我们将使用催化剂设计和开发易于获得且稳定的 N,O-缩醛和缩醛的对映选择性芳基化、杂芳基化和烷基化我们将从这些研究中获得的取代的二氢喹啉、哌啶、色烯和吡喃构成了具有一系列药理活性的小分子的核心结构元素。开发一类新型稳定的 Ni 预催化剂，易于活化为 Ni(0)，使 Suzuki-Miyaura 交叉偶联反应更加高效、便捷。开发还将证明，亚胺/氧碳鎓离子活化模式有助于利用简单的原料化学品（例如缺电子烯烃和二氧化碳）进行前所未有的键构建，用于合成烯丙醚、烯丙胺和α-氨基酸（具体目标3）。