Chemistry of Lithium Enolates

烯醇锂的化学性质

• 批准号: 7414400
• 负责人: DAVID B. COLLUM
• 金额: $ 29.08万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7414400
• 关键词: Acylation; Alkylation; Amides; Antithrombin III; Case Study; Chemistry; Class; Collaborations; Drug Industry; Esters; Funding; Investigation; Ketones; Kinetics; Learning; Lithium; Methods; Modeling; NMR Spectroscopy; Numbers; Occupations; Organic Synthesis; Oxazolidinones; Physical condensation; Preparation; Reaction; Reagent; Reporting; Salts; Solutions; Structure; Variant; base; computational chemistry

DESCRIPTION (provided by applicant): Lithium enolates constitute one of the most important classes of reactive intermediate in organic synthesis. The pharmaceutical industry uses these reagents frequently and on very large scales. In this proposal we describe efforts to understand the underlying chemistry of the most important reactions of lithium enolates. We will focus on ascertaining key structure-reactivity relationships for a number of enolates including enolates derived from simple esters and ketones, beta-amino-esters, chiral carboxamides based on oxazolidinone and ephedrate auxiliaries (Evans and Myers enolates), N-methoxycarboxamides (Weinreb amides), and alpha fluoro esters. The lithium salts of chiral vicinal amino alkoxides will also be investigated. Given the limited progress toward understanding solution structures of lithium enolates reported to date, considerable effort will focus on developing and refining new methods of structure determination. The relationships of structure and reactivity will derive from case studies to be investigated including (1) alkylation, (2) acylation, (3) azaaldol condensation, and (4) nucleophilic aromatic substitution. Through an understanding of the mechanistic principles we learn to control reactivity and selectivity via a uniquely integrated approach based on a combination of NMR spectroscopy, solution kinetics, and computational chemistry. By bringing synthetic organic, physical organic, analytical, and computational chemistry together under one roof, we reveal the consequences of solvation and aggregation with an unprecedented clarity.

描述（由申请人提供）： 烯醇锂构成有机合成中最重要的一类反应性中间体。制药工业经常大规模地使用这些试剂。在本提案中，我们描述了理解烯醇锂最重要反应的基础化学的努力。我们将重点确定许多烯醇化物的关键结构-反应性关系，包括衍生自简单酯和酮的烯醇化物、β-氨基酯、基于恶唑烷酮和麻黄酸助剂的手性羧酰胺（Evans 和 Myers 烯醇化物）、N-甲氧基羧酰胺（Weinreb）酰胺）和α氟酯。手性邻位氨基醇盐的锂盐也将被研究。鉴于迄今为止报道的了解烯醇锂溶液结构的进展有限，相当大的努力将集中在开发和完善新的结构测定方法上。结构和反应性的关系将来自于要研究的案例研究，包括（1）烷基化、（2）酰化、（3）阿扎醛缩合和（4）亲核芳香取代。通过了解机械原理，我们学习通过基于核磁共振波谱、溶液动力学和计算化学相结合的独特集成方法来控制反应性和选择性。通过将合成有机、物理有机、分析和计算化学集中在一个屋檐下，我们以前所未有的清晰度揭示了溶剂化和聚集的后果。