Chemistry of Lithium Enolates

说明（由申请人提供）：烯醇化锂是有机合成中最重要的一类反应性中间体。制药行业经常使用这些试剂，并且规模非常大。在这个建议中，我们描述了努力了解最重要的反应烯醇化锂的基本化学。我们将重点确定一些烯醇化物的关键结构-反应性关系，包括衍生自简单酯和酮的烯醇化物、β-氨基酯、基于恶唑烷酮和邻苯二甲酸酯助剂的手性羧酰胺（Evans和Myers烯醇化物）、N-甲氧基羧酰胺（Weinreb酰胺）和α-氟代酯。手性邻位氨基醇盐的锂盐也将被研究。鉴于有限的进展，了解锂烯醇化物的溶液结构的报道，相当大的努力将集中在开发和完善新的方法的结构测定。结构和反应性的关系将来自于待研究的案例研究，包括（1）烷基化，（2）酰化，（3）氮杂醛缩合，和（4）亲核芳族取代。通过对机械原理的理解，我们学会了通过基于NMR光谱学，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，分析和计算化学放在一个屋檐下，我们以前所未有的清晰度揭示了溶剂化和聚合的后果。

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.