Asymmetric Synthesis of the HIV Protease Inhibitor TMC-126, a PMX Antimalarial Protease Inhibitor, and a Putative COVID-19 Inhibitor Using a Highly Stereoselective Glycolate Aldol Addition Reaction Pathway.

An asymmetric glycolate aldol addition pathway was developed for the synthetic preparation of a series of protease inhibitors based on the hydroxyethylamine structural motif. A single glycolate aldol adduct derived from a highly diastereoselective (≥95:5 d.r.) asymmetric aldol reaction served as the starting point for the synthesis of the inhibitors. The starting material is easily prepared and purified via recrystallization on multigram scales. This work describes the synthesis of the HIV protease inhibitor TMC-126, the Plasmepsin X (PMX) inhibitor 49c for the treatment of malaria, and a computationally derived inhibitor for the 3CLpro of the SARS-CoV-2 from a single common synthetic intermediate.