Chemistry of Lithium Enolates

描述（由申请人提供）：烯醇酸锂是有机合成中最重要的反应中间体之一。制药工业经常大规模地使用这些试剂。在本提案中，我们描述了理解锂烯醇化最重要反应的潜在化学的努力。我们将重点确定一些烯醇化物的关键结构-反应性关系，包括由简单酯和酮衍生的烯醇化物、β -氨基酯、基于恶唑烷酮和麻黄酸辅剂的手性羧化物（Evans和Myers烯醇化物）、n -甲氧基羧化物（Weinreb酰胺）和α氟酯。手性邻胺酸盐的锂盐也将被研究。鉴于迄今为止对烯醇酸锂溶液结构的理解进展有限，将会有相当大的努力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从案例研究中得到，包括：(1)烷基化，(2)酰化，(3)氮杂酚缩合，(4)亲核芳香取代。通过对机械原理的理解，我们学会了通过一种独特的综合方法来控制反应性和选择性，该方法基于核磁共振光谱，溶液动力学和计算化学的结合。通过将合成有机、物理有机、分析化学和计算化学结合在一起，我们以前所未有的清晰度揭示了溶剂化和聚集的后果。

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.