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: 8690110
• 负责人: Abigail Gutmann Doyle
• 金额: $ 29.47万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690110
• 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; 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; public health relevance; scaffold; small molecule; stoichiometry

DESCRIPTION (provided by applicant): Among the most ubiquitous scaffolds in medicinal chemistry, biological chemistry, and glycobiology are ?-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 ?-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？-取代的胺和醚。拟议的研究计划的目标是定义一个通用的和模块化的催化策略，使这些结构基序的对映选择性合成，包括那些嵌入在杂环框架内，在很大程度上相同的方式，交叉偶联作为一个通用的和强大的协议Csp 2-Csp 2键的组装。为了实现这一目标，我们将利用低价过渡金属催化剂的能力进行氧化加成亚胺和oxocarbenium离子，并表明这种未充分利用的活化模式提供了一个通用的进入烷基交叉偶联反应。在这方面的贡献，我们将追求催化剂的设计和开发的对映选择性芳基化，杂芳基化，烷基化容易获得和稳定的N，O-缩醛和缩醛使用有机硼酸盐和有机锌试剂（具体目标1）。我们将从这些研究中获得的取代的二氢喹啉、哌啶、色烯和吡喃构成了表现出一系列药理活性的小分子的核心结构元素。在具体目标2中，我们将开发一类新的稳定的Ni预催化剂，其易于活化为Ni（0），并能够实现更有效和方便的Suzuki-Miyaura交叉偶联反应。反应的发展也将表明，亚胺/氧碳正离子活化模式有利于前所未有的键结构与简单的原料化学品，如缺电子烯烃和二氧化碳的合成烯丙基醚，烯丙基胺，和？氨基酸（具体目标3）。