Chemistry of Lithium Enolates

说明(申请人提供)：烯醇酸锂是有机合成中最重要的活性中间体之一。制药行业经常使用这些试剂，而且规模非常大。在这项提案中，我们描述了为了解最重要的烯醇酸锂反应的基本化学所做的努力。我们将集中于确定一些烯醇酸盐的关键结构-反应性关系，包括源自单酯和酮的烯醇酸盐、β-氨基酯、基于恶唑烷酮和苯乙酸酯助剂的手性羧胺(Evans和Myers烯醇酸盐)、N-甲氧基羧胺(Weinreb酰胺)和α-氟酸酯。手性邻氨基醇盐的锂盐也将被研究。鉴于迄今为止在理解锂烯醇酸盐溶液结构方面取得的进展有限，相当大的努力将集中在开发和改进新的结构测定方法上。结构和活性的关系将从将要研究的案例研究中得到，包括(1)烷基化，(2)酰化，(3)氮杂醛缩合，和(4)亲核芳香取代。通过对机理原理的理解，我们学会了通过一种基于核磁共振光谱、溶液动力学和计算化学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结果。

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.