Asymmetric 1,2-Additions

我们将研究手性氨基氧基（R*OLi）存在下乙酰化锂（RLi）的1,2-选择性加成，作为合成非核苷类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。我们的目标是改进和推广这一过程，以包括更广泛的碳和底物。在项目的第一阶段，通过对可观察到的RLI-R*OLi混合聚集体（R*OLi=手性/非外消旋锂氨基醇）的核磁共振光谱和红外光谱研究，建立了用于合成Efavirenz （Stocrin/TM）的高对映选择性乙酰化锂加入ArCOCF3酮的机理模型。该模型将通过进行额外的结构选择性研究、核磁共振光谱研究和速率研究来进行测试。虽然结构研究在当前资助期内占主导地位，但在即将到来的资助期内，了解RLI/R*OLi混合聚集体如何反应的速率和机制研究将成为重点。在很大程度上，由于与杜邦的合作，了解和改进对喹啉酮和相关亚胺部分的对映选择性添加也将是重要的。优化1,2-附加方案的备选策略将基于：(1)提高（3:1）R*OLi比例时提高的对映体选择性，以及(2)新的手性添加剂。我们还将继续研究高对乙酰基选择性亚胺添加剂，最初用于合成逆转录酶抑制剂l - 738,372，现在用作一系列第二代逆转录酶抑制剂的一部分。虽然对喹唑啉酮的高选择性加成与对酮的高选择性加成的行为完全不同，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.