ASYMMETRIC 1,2-ADDITIONS

描述：（主要研究者）我们将进行调查 乙炔锂（RLi）的对映选择性1，2-加成反应 的手性氨基醇盐（RstarOLi）作为关键步骤， Merck合成HIV逆转录酶抑制剂L-743，726和 L-738372 这项工作将与默克公司合作进行， 杜邦-默克公司和ASI应用系统公司。 我们的目标是改善和 将该过程概括为包括更广泛的碳负离子和酮 印刷受体. 在合作的第一阶段，NMR光谱， 可观测到的RLi-RstarOLi混合物的IR光谱和计算研究 聚集体（RstarOLi =合成锂锂）导致了 高对映选择性乙炔锂与ArCOCF 3加成反应的模型 L-743，726合成中使用的酮。 该模型将由 进行额外的结构选择性研究，NMR光谱 调查，理论-实验相关性，和率的研究。 与 在机械模型提供的指导下，计算将发挥 在新型手性助剂的设计中具有突出的应用价值。 替代战略 用于优化1，2-加成方案将基于：（1） 在升高的（3：1）RstarOLi/RLi下观察到改进的对映选择性 比例，和（2）新的锂化二胺助剂， 与锂化氨基醇衍生物同构。 我们还将 启动和开展对高对映选择性 乙炔基加成到亚胺上用于合成反式 转录酶抑制剂L-738，372。 虽然高度选择性的添加到 亚胺的行为与酮的加成完全不同（需要 锂化奎宁或奎尼丁），所用的策略和分析方法 研究它们的方法是相似的。

DESCRIPTION: (Principal Investigator's) We will investigate enantioselective 1,2-additions of lithium acetylides (RLi) in the presence of chiral amino alkoxides (RstarOLi) employed as the critical steps in the Merck syntheses of HIV reverse transcriptase inhibitors L-743,726 and L-738,372. The work will be carried out in collaboration with Merck, Dupont-Merck, and ASI Applied Systems. Our goal will be to improve and generalize the process to include a wider range of carbanions and ketone substrates. During the first phase of the collaboration, NMR spectroscopic, IR spectroscopic, and computational studies of observable RLi-RstarOLi mixed aggregates (RstarOLi = synthetic lithium ephedrate) led to a mechanistic model for a highly enantioselective lithium acetylide addition to an ArCOCF3 ketone employed in the L-743,726 synthesis. The model will be tested by carrying out additional structure-selectivity studies, NMR spectroscopic investigations, theory-experiment correlations, and rate studies. With guidance provided by the mechanistic model, computations will play prominently in the design of new chiral auxiliaries. Alternative strategies for optimization of the 1,2-addition protocol will be based upon: (1) improved enantioselectivities noted at elevated (3:1) RstarOLi/RLi proportions, and (2) new lithiated diamine auxiliaries that are isostructural to the lithiated amino alcohol derivatives. We will also initiate and carry out investigations of the highly enantioselective acetylide addition to imines employed in the synthesis of reverse transcriptase inhibitor L-738,372. While the highly selective additions to imines behave quite differently from the additions to ketones (requiring lithiated quinine or quinidine), the strategies and analytical methods used to study them will be similar.