Chemistry of Lithium Enolates

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重要药用化合物的复杂合成。潜在的依赖溶剂的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将合成有机、有机金属、物理有机、分析化学和计算化学的专业知识集中在一个实验室进行结构、机制和选择性的全面综合研究的团队。在这个提议中，我们继续研究锂烯醇酸酯的化学作用，主要用于形成C-C键。程序是完全集成的，从一个合成的目标、观察或问题开始。通过结构和机械研究的结合，我们回答关键问题或为关键问题提供解决方案。在本提案中，我们将重点介绍几类具有独特挑战的烯醇化物：(1)我们将调查各种合成上重要的，高度功能化的，迄今为止尚未表征的烯醇化物。(2)内酰胺和内酯烯醇化物是与辉瑞公司合作提高不对称合成选择性的核心，可作为评估基本结构-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类标志性的反应中间体提供基本的机理见解，并为异质聚集体的结构如何影响官能化的立体化学提供定性探索。(4)甘氨酸亚胺衍生的烯醇酸酯提供了一种特别多样化的聚集形式，这将使我们能够将聚集结构与官能化的机制和立体控制联系起来。(5) ?烯丙氧基酯烯醇化物[2,3]的中心-异位重排提出了有趣的结构挑战，并将进行研究，以显示重排是否发生在聚集体框架内。(6)在默克和杜邦的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氧化物将被评估其在第1-5部分中描述的烯醇酸反应中具有高聚集控制和高立体控制的能力。

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.