ASYMMETRIC 1,2-ADDITIONS

描述：(首席调查员)我们将调查 乙酰锂(RLI)的不对称1，2-加成反应 作为关键步骤的手性氨基醇氧化物(RstarOLi) 艾滋病病毒逆转录酶抑制剂L-743,726和 L-738,372。这项工作将与默克公司合作进行， 杜邦-默克和ASI应用系统。我们的目标将是改进和 将该过程概括为包括更广泛的碳负离子和酮 底物。在合作的第一阶段，核磁共振波谱， 可观测到的RLi-RstarOLi混合物的红外光谱和计算研究 聚集体(RstarOLi=合成的麻黄酸锂)导致了机械性的 ArCOCF3的高对映选择性乙炔锂加成反应模型 用于L-743,726合成的酮。该模型将通过以下方式进行测试 进行额外的结构选择性研究，核磁共振波谱 调查、理论-实验相关性和比率研究。使用 由机械模型提供指导，计算将发挥作用 在新型手性助剂的设计中表现突出。另类战略 对于1，2-加法方案的优化将基于：(1) 提高(3：1)RstarOLi/RLI的对映体选择性 比例，以及(2)新的锂化二胺助剂 与锂化氨醇衍生物同构。我们还将 发起并开展高对映体选择性的研究 用于反式合成的亚胺的乙酰基加成反应 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有很大的不同(需要 锂基奎宁或奎尼丁)、所用策略和分析方法 对它们的研究将是相似的。

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.