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。随着在第一个供资期占主导地位的解决方案结构的建立方法得到很大发展，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，包括：（1）氮杂-羟醛缩合;（2）O-甲硅烷基化;（3）烷基化;（4）酰化;（5）[2，3]-和[3，3]-σ迁移重排;和（6）亲核芳香取代（SNAr）。基于NMR光谱，溶液动力学和计算化学的组合的独特集成方法将发展对机械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。 公共卫生相关性：烯醇化锂是地球仪上其他学术和制药过程化学实验室每天使用的活性中间体。我们在此描述的机制研究旨在理解和改善其功效。该项目起源于与赛诺菲-安万特合作开发抗哮喘药。拟议的资助期包括与安进公司的合作，作为其综合治疗结直肠癌计划的一部分。

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.