Bioinspired Enantioselective Catalytic alpha-Alkylation of Aldehydes

醛的仿生对映选择性催化α-烷基化

• 批准号: 8414586
• 负责人: Sean M. Kedrowski
• 金额: $ 4.92万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8414586
• 关键词: Aldehydes; Alkylating Agents; Alkylation; Binding; Biochemistry; Biological Models; Biological Process; Breathing; Carbon; Catalysis; Cations; Cell physiology; Charge; Chemicals; DNA; Degenerative polyarthritis; Development; Enzymes; Lead; Light; Mental Depression; Methionine; Methodology; Methods; Modeling; Nature; Nitrogen; Oxygen; Pharmacologic Substance; Reaction; Reagent; Regulation; S-Adenosylmethionine; Sodium Chloride; Sulfur; System; Therapeutic Uses; base; catalyst; cofactor; design; dietary supplements; insight; novel; small molecule

DESCRIPTION (provided by applicant): S-Adenosyl-L-Methionine (a.k.a., SAM, AdoMet) is a cofactor that is crucial to many biological processes. Specifically, SAM is a cationic sulfur-based alkylating agent, and enzymes use SAM to efficiently alkylate oxygen, nitrogen, and carbon atoms in a wide variety of molecules. Direct, enantioselective, catalytic ?-alkylation of carbon is one of the most fundamental ways to form new carbon-carbon bonds. SAM-dependent enzymes manage this transformation with ease, but it remains a challenge for synthetic chemists, despite considerable efforts using neutral, uncharged alkylating agents. The current proposal takes inspiration from nature and aims to develop a chiral small molecule amino-arene catalyst that accomplishes the direct, enantioselective, catalytic ?-alkylation of aldehydes using cationic sulfur-based alkylating agents like SAM. Unlike systems that use neutral alkylating agents, this system exploits the charge on the sulfur-based cation to bring it in close proximity to the activated aldehyde substrate, facilitating the reaction. This pre-binding of substrate and reagent is a hallmark of enzymatic catalysis and should lead to high levels of enantioselectivity, giving a reaction that is applicable to the syntheses of many medicinally important compounds. Finally, this proposal also aims to study this new catalytic system in detail to gain insight into the many key cellular processes involving SAM, potentially shedding light on its various therapeutic uses.

描述(申请人提供)：S-腺苷-L-蛋氨酸(又名：腺苷-L-蛋氨酸)是一种在许多生物过程中起关键作用的辅因子。具体地说，SAM是一种基于硫磺的阳离子烷化剂，酶利用SAM有效地将各种分子中的氧、氮和碳原子烷基化。碳的直接、对映选择性、催化？-烷基化反应是形成新的碳-碳键的最基本途径之一。SAM依赖的酶很容易实现这种转化，但对于合成化学家来说，这仍然是一个挑战，尽管使用中性、不带电的烷基化试剂做出了相当大的努力。目前的建议是从自然中汲取灵感，旨在开发一种手性小分子氨基芳烃催化剂，利用阳离子硫基烷基化试剂如SAM完成醛的直接、对映选择性的催化？烷基化反应。与使用中性烷基化试剂的体系不同，该体系利用硫基阳离子上的电荷使其接近活化的醛底物，从而促进反应。底物和试剂的这种预结合是酶催化的一个标志，应该会导致高水平的对映选择性，使反应适用于许多医学上重要的化合物的合成。最后，这项提案还旨在详细研究这一新的催化系统，以深入了解涉及SAM的许多关键细胞过程，潜在地揭示其各种治疗用途。