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.
