Abstract:

Recent efforts within the Merck Research Laboratories to discover new compounds for the treatment of HIV infection have resulted in indinavir (Crixivan^®), a protease inhibitor, as well as efavirenz, a non-nucleoside reverse transcriptase inhibitor. Efavirenz has shown excellent potency against a variety of HIV-1 mutants when used in combination with Crixivan^®, or with other reverse transcriptase inhibitors, and was recently approved for use by the FDA. A practical asymmetric synthesis of efavirenz implemented for large scale manufacture will be presented. The key step in this process involves the highly enantioselective 1,2-addition of lithium cyclopropylacetylide to trifluoromethyl ketoaniline using stoichiometric amounts of lithium (1R, 2S)-N-pyrrolidinylnorephedrate as chiral mediator. A clear understanding of the reaction mechanism based upon extensive low temperature ⁶Li and ¹³C NMR spectroscopic studies is achieved. More recent research results on this project will also be presented.