Chemistry of Lithium Enolates

烯醇锂的化学性质

• 批准号: 8069864
• 负责人: DAVID B. COLLUM
• 金额: $ 31.31万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8069864
• 关键词: 3-hydroxybutanal; Acylation; Alkylation; Analytical Chemistry; Anti-Asthmatic Agents; Case Study; Chemistry; Collaborations; Colorectal Cancer; DNA Sequence Rearrangement; Drug Industry; Fostering; Funding; Group Processes; Investigation; Kinetics; Laboratories; Lithium; Methods; NMR Spectroscopy; Organic Chemistry; Organic Synthesis; Pharmacologic Substance; Physical condensation; Process; Protocols documentation; Reaction; Reagent; Solutions; Staging; Structure; abstracting; base; computational chemistry; design; improved; programs; public health relevance

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.

说明(申请人提供)：项目摘要/摘要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。随着建立主导第一个资助期的解决方案结构的方法在很大程度上得到发展，结构研究将更加有针对性，以支持机械论研究。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。机理研究将集中于特定类型的反应--案例研究--包括：(1)氮杂-羟醛缩合反应；(2)O-硅烷化反应；(3)烷基化反应；(4)酰化反应；(5)[2，3]-和[3，3]-Sigma重排反应；(6)亲核芳香取代反应(SNAR)。一种基于核磁共振波谱、溶液动力学和计算化学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。 公共卫生相关性：项目叙述烯醇酸锂是全球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了解和改进它们的有效性。该项目源于与赛诺菲-安万特合作开发抗哮喘药物。拟议的资助期包括与安进合作，作为他们合成结直肠癌治疗方案的一部分。