Chemistry of Lithium Enolates

描述(申请人提供)：有机锂试剂在学术和工业实验室中用于进行具有重要医学意义的化合物的复杂合成。与有机金属化学中的任何分支一样，依赖于溶剂的聚集体和反应机理是复杂的。我们是世界上唯一一家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，对结构、机理和选择性进行全面集成的研究。在这项提议中，我们继续研究主要用于形成C-C键的锂烯醇酸盐的化学。该计划是从一个综合的目标、观察或问题开始完全整合的。通过结构和机械相结合的研究，我们回答关键问题或提供关键问题的解决方案。在这份提案中，我们将重点介绍几类烯醇类化合物，每一类都面临着独特的挑战：(1)我们将综述各种合成上重要的、高度官能化的烯醇类化合物，这些化合物至今仍未确定其特征。(2)内酰胺和内酯烯醇酸酯是与辉瑞合作提高不对称合成选择性的核心，它们将作为评估基本结构-反应性关系的模板。(3)Evans和他的同事开发的恶唑烷酮衍生的烯醇酸盐将为这类标志性的反应中间体提供基本的机理见解，并对杂聚体的结构如何影响官能化的立体化学提供定性的探索。(4)甘氨酰亚胺衍生的烯醇酸盐提供了一系列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)[2，3]-Sigmatroic重排中心的-烯丙氧基酯烯醇酸酯存在有趣的结构挑战，将进行研究以表明重排是否发生在聚合框架内。(6)在默克公司和杜邦公司的不对称合成逆转录酶抑制剂中发挥重要作用的硫代氨基醇氧化物，将评估它们在第1-5部分所述的烯醇酸盐反应中提供高聚集控制和进而高立体控制的能力。

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.