Asymmetric 1,2-Additions

我们将研究在手性氨基醇盐（R*OLi）存在下乙炔锂（RLi）的对映选择性1，2-加成反应，该反应是合成非核苷类HIV逆转录酶抑制剂的关键步骤。这项工作将与杜邦制药公司和ASI应用系统公司合作进行。我们的目标将是改进和推广该过程，以包括更广泛的碳负离子和底物。在该项目的第一阶段，可观察到的RLI-R*OLi混合聚集体（R*OLi=手性/非外消旋氨基醇锂）的NMR光谱和IR光谱研究表明，在Efavirenz（Stocrin/TM）的合成中，高对映选择性乙炔锂与ArCOCF 3酮加成的机理模型。该模型将进行测试，进行额外的结构选择性研究，NMR光谱研究，和速率研究。尽管结构研究主导了当前的资助期，但了解RLI/R*OLi混合骨料如何反应的速率和机理研究将在即将到来的资助期内突出。在很大程度上，由于与杜邦公司的合作，理解和改善喹唑啉酮和相关亚胺部分的对映选择性加成也将是重要的。优化1，2-附加方案的替代策略将基于：（1）在升高的（3：1）R*OLi比例下观察到的改进的对映选择性，和（2）新的手性添加剂。我们还将继续调查的高度对映选择性乙炔除了亚胺最初用于合成逆转录酶抑制剂L-738，372，现在作为一系列的第二代逆转录酶抑制剂的一部分。虽然喹唑啉酮类化合物的高选择性加成反应与酮类化合物的加成反应有很大不同，但用于研究它们的策略和分析方法是相似的。

We will investigate enantioselective 1,2-additions of lithium acetylides (RLi) in the presence of chiral amino alkoxides (R*OLi) employed as the critical steps in syntheses of non-nucleosides HIV reverse transcriptase inhibitors. The work will be carried out in collaboration with Dupont Pharmaceuticals and ASI Applied Systems. Our goal will be to improve and generalize the process to include a wider range of carbanions and substrates. In the first phase of the project, NMR spectroscopic and IR spectroscopic studies of observable RLI-R*OLi mixed aggregates (R*OLi=chiral/non-racemic lithium amino alkoxides) l4ed to a mechanistic model for a highly enantioselective lithium acetylide addition to an ArCOCF3 ketone employed in the synthesis of Efavirenz (Stocrin/TM). The model will be tested by carrying out additional structure-selectivity studies, NMR spectroscopic investigations, and rate studies. Whereas structural studies dominated the current funding period, rate and mechanistic studies to understand how the RLI/R*OLi mixed aggregates react will e prominent in the upcoming funding period. In large part due to the collaboration with DuPont, understanding and improving the enantioselective additions to quinazolinones and related imine moieties will be important as well. Alternative strategies for optimization of the 1,2-additional protocol will be based on: (1) improved enantioselectivities noted at elevated (3:1) R*OLi proportions, and (2) new chiral additives. We will also continue investigations of the highly enantioselective acetylide addition to imines initially used in the synthesis of reverse transcriptase inhibitor L-738, 372 and now employed as part of a range of second-generation reverse transcriptase inhibitors. Although the highly selective additions to the quinazolinones behave quite differently from the additions to ketones, the strategies and analytical methods used to study them will be similar.