Synthesis of Islatravir Enabled by a Catalytic, Enantioselective Alkynylation of a Ketone
Niki R. Patel, Christopher C. Nawrat, Mark McLaughlin, Yingju Xu, Mark A. Huffman, Hao Yang, Hongming Li, Aaron M. Whittaker, Teresa Andreani, François Lévesque, Anna Fryszkowska, Andrew P. J. Brunskill, David M. Tschaen, Kevin M. Maloney
Abstract
The synthesis of the potent anti-HIV investigational treatment islatravir is described. The key step in this synthesis is a highly enantioselective catalytic asymmetric alkynylation of a ketone. This reaction is a rare example of the asymmetric addition of an alkyne nucleophile to a ketone through ligand-accelerated catalysis that was performed on a greater than 100 g scale. By leveraging a multienzyme cascade, a highly diastereoselective aldol-glycosylation was used to complete the target in eight steps.
Topics & Concepts
Enantioselective synthesisKetoneChemistryAlkynylationAldol reactionNucleophileAlkyneCatalysisCombinatorial chemistryGlycosylationLigand (biochemistry)StereochemistryOrganic chemistryReceptorBiochemistryCarbohydrate Chemistry and SynthesisHIV/AIDS drug development and treatmentChemical Synthesis and Analysis