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: 9035402
• 负责人: Abigail Gutmann Doyle
• 金额: $ 29.69万
• 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/9035402
• 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; invention; 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（由适用提供）：在医学化学，生物学化学和糖生物学中最普遍的支架中，是α-取代的胺和醚。拟议的研究计划的目的是定义一种通用和模块化的催化策略，该策略可以使这些结构基序的对映选择性合成，包括嵌入杂环框架中的策略，与交叉耦合相同的方式与CSSP2-CSP2键组装在一起的实用方案与交叉耦合的方式几乎相同。为了实现这一目标，我们将探索低价值过渡金属催化剂对亚胺和氧化核离子进行氧化添加的能力，并表明这种未充分利用的激活模式为酒精交叉偶联反应提供了多功能。在这项贡献中，我们将使用有机碳和有条件的试剂进行催化剂设计和开发，以进行对映选择性芳基化，杂化和酗酒，并酗酒，稳定的N，O-乙酰基，O-乙酸和乙酰基（特定目标1）。我们将从这些研究中获得的取代的二氢喹啉，哌啶，染色体和pyrans构成了存在一系列药物活性的小分子的核心结构元素。在特定的目标2中，我们将开发一类新的稳定NI预催化剂，该稳定前催化剂易于激活为Ni（0），并实现更有效，方便的Suzuki-Miyaura交叉耦合反应。反应发展还将证明，伊米氨基/氧化离子激活模式的最爱构建了前所未有的键构建体，具有简单的原料化学物质，例如电子缺陷烯烃和二氧化碳，用于合成Allic Ethers，Allic氨基氨基酸，小氨基氨和α-氨基酸（特定的AIM 3）。