Chemistry of Lithium Enolates

烯醇锂的化学性质

• 批准号: 8966974
• 负责人: DAVID B. COLLUM
• 金额: $ 2.51万
• 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 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8966974
• 关键词: 3-hydroxybutanal; Address; Alkylation; Amino Acids; Analytical Chemistry; Carbon; Chemistry; Collaborations; Complex; Diamines; Engineering; Esters; Ethers; Goals; Group Processes; Health; Hydroxy Acids; Investigation; Kinetics; Laboratories; Lactams; Lactones; Lithium; Methods; NMR Spectroscopy; Organic Chemistry; Organic Synthesis; Organometallic Chemistry; Oxazolidinones; Pharmacologic Substance; Physical condensation; Play; Process; Reaction; Reagent; Reporting; Research Design; Reverse Transcriptase Inhibitors; Role; Solutions; Solvents; Spectrum Analysis; Structure; Surveys; Temperature; Variant; computational chemistry; dimer; enolate; improved; insight; interest; monomer; programs; scale up; stereochemistry

DESCRIPTION (provided by applicant): Organolithium reagents are used in both academic and industrial laboratories to carry out complex syntheses of medicinally important compounds. The underlying solvent-dependent aggregates and mechanisms of reaction are as complex as in any subdiscipline in organometallic chemistry. We are the only group in the world with expertise in synthetic organic, organometallic, physical organic, analytical, and computational chemistry together in a single laboratory to produce fully integrated studies of structure, mechanism, and selectivity. In this proposal, we continue studies of the chemistry of lithium enolates used prominently to form C-C bonds. The program is fully integrated starting from a synthetic goal, observation, or question. Through a combination of structural and mechanistic studies we answer key questions or offer solutions to key problems. In this proposal we will focus on several classes of enolate that each present unique challenges: (1) We will survey a variety of synthetically important, highly functionalized enolates that remain uncharacterized to date. (2) Lactam and lactone enolates that are central to a collaboration with Pfizer to enhance selectivity in an asymmetric synthesis will serve as templates for evaluating basic structure-reactivity relationships. (3) Oxazolidinone-derived enolates developed by Evans and coworkers will provide basic mechanistic insights into this iconic class of reactive intermediate as well as offer qualitative probes into how structures of heteroaggregates can influence the stereochemistry of functionalizations. (4) Glycinimine-derived enolates offer an especially diverse array of aggregated forms, which will allow us to correlate aggregate structure with mechanism and stereocontrol of functionalizations. (5) ?-allyloxy ester enolates central to [2,3]-sigmatropic rearrangements present both interesting structural challenges and will be investigated to show whether the rearrangement occurs within an aggregate framework. (6) Lithiated amino alkoxides that played vital roles in Merck's and DuPont's asymmetric syntheses of reverse transcriptase inhibitors will be evaluated for their capacity to impart high aggregate control and, in turn, high stereocontrol in reactions of enolates described in the parts 1-5.

描述（由申请人提供）：有机锂试剂在学术和工业实验室中用于进行医学上重要的化合物的复杂合成。潜在的溶剂依赖性聚集体和反应机制与有机金属化学的任何分支学科一样复杂。我们是世界上唯一一个在单一实验室中拥有合成有机、有机金属、物理有机、分析和计算化学专业知识的团队，能够对结构、机制和选择性进行完全综合的研究。在本提案中，我们继续研究主要用于形成 C-C 键的烯醇锂的化学性质。该计划从综合目标、观察或问题开始完全集成。通过结构和机械研究的结合，我们回答关键问题或提供关键问题的解决方案。在本提案中，我们将重点关注几类烯醇化物，每种烯醇化物都面临着独特的挑战：（1）我们将调查各种迄今为止尚未表征的具有综合重要性、高度功能化的烯醇化物。 (2) 内酰胺和内酯烯醇化物是与辉瑞合作提高不对称合成选择性的核心，将作为评估基本结构-反应性关系的模板。 (3) Evans 及其同事开发的恶唑烷酮衍生烯醇化物将为这一类标志性反应中间体提供基本的机理见解，并为杂聚集体结构如何影响官能化的立体化学提供定性探讨。 (4) 甘氨酰亚胺衍生的烯醇化物提供了特别多样化的聚集形式，这将使我们能够将聚集结构与功能化的机制和立体控制相关联。 (5) β-烯丙氧基酯烯醇化物是[2,3]-σ重排的核心，它提出了有趣的结构挑战，将对其进行研究以表明重排是否发生在聚合框架内。 (6) 在默克和杜邦逆转录酶抑制剂的不对称合成中发挥重要作用的锂化氨基醇盐将评估其在第 1-5 部分中描述的烯醇化物反应中提供高聚集控制和高立体控制的能力。