Developing Nickel-Catalyzed Sonogashira Couplings for Affordable HIV Drug Synthesis

Abstract

Lenacapavir, a novel drug for HIV, is administered as only a twice-yearly injectable, and it has shown to be 100% effective in clinical trials. However, its reliance on palladium catalysts to synthesize key fragments of lenacapavir contribute to its immense cost, thus presenting a significant barrier to accessing advanced HIV treatments. Expanding global access to lenacapavir has motivated replacement of palladium conditions with more sustainable and affordable earth-abundant transition metal catalysts such as nickel to substantially decrease the cost of synthesis. In particular, this thesis targets the Sonogashira C(sp)–C(sp2) coupling to synthesize Fragment A. Previous studies have shown bidentate N-donor ligands such as bipyridine to be effective in nickel-catalyzed Sonogashira cross-couplings; interest has thus been drawn to α-diimine (DI) ligands, due to their affordable synthesis and high modularity. This work explores the use of substituted DI ligands and well-defined nickel complexes for catalyzing a regioselective Sonogashira coupling on model bromopyridine substrates relevant to Fragment A. Well-defined nickel complexes — including bis ligand complexes, (MesDI)NiMe2, and (MesDI)Ni(η2-alkyne) complexes — were all synthesized and demonstrated catalytic competence, suggesting the presence of several potential pathways for entering the catalytic cycle. DI ligands therefore proved to be effective alternatives for nickel-catalyzed, regioselective Sonogashira couplings of model substrates applicable to improving the synthesis of lenacapavir.