Chemistry of Lithium Enolates

项目概述/摘要烯醇化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。随着建立解决方案结构的方法在第一个资助期的主导地位得到很大发展，结构研究将更有针对性地支持机制研究。在最一般的意义上，我们将研究溶剂化和聚集如何影响反应性。机理研究将集中在特定类别的反应案例研究上，包括：(1)脲醛缩合；(2) O-silylations;(3)烷基化;(4)酰化;(5)[2,3]-和[3,3]-符号矩阵重排；(6)亲核芳香取代（SNAr）。基于核磁共振波谱学、溶液动力学和计算化学相结合的独特集成方法，将发展对机理原理以及如何控制反应性和选择性的理解。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): Project Summary/Abstract Lithium enolates constitute one of he 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. With methods to establish solution structures that dominated the first funding period largely developed, structural studies will be more targeted in support of mechanistic studies. In the most general sense, we will examine how solvation and aggregation influence reactivity. The mechanistic investigations will focus on specific classes of reaction-case studies-that include: (1) aza-aldol condensations; (2) O-silylations; (3) alkylations; (4) acylations; (5) [2,3]- and [3,3]-sigmatropic rearrangements; and (6) nucleophilic aromatic substitutions (SNAr). A uniquely integrated approach based on a combination of NMR spectroscopy, solution kinetics, and computational chemistry will develop an understanding of the mechanistic principles and how to control reactivity and selectivity. 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. PUBLIC HEALTH RELEVANCE: Project Narrative Lithium enolates are reactive intermediates used by other academic and pharmaceutical process chemistry laboratories on a daily basis around the globe. Our mechanistic studies described herein are designed to understand and improve their efficacy. The project originated from collaboration with Sanofi-Aventis to develop anti-asthmatics. The proposed funding period includes a collaboration with Amgen as part of their program to synthesize treatments for colorectal cancer.