Generating Multimillion Chemical Space Based on the Ugi Four-Сenter Three-Component Reaction with Oxocarboxylic Acids

The scope of the Ugi four-center three-component reaction involving oxocarboxylic acids, primary amines, and isonitriles under parallel synthesis conditions was studied thoroughly. Special attention was paid to the limitations of each starting material; in particular, the relative reactivity of various oxocarboxylic acid types was established. For a model validation library of 1,000 members, an experimental synthesis success rate of 88% was achieved. The obtained results and established trends were used to generate a 363-million synthetically tractable virtual chemical space of gamma- and delta-lactams. The distribution of physicochemical properties within this chemical space revealed that 43% of its members complied with the Lipinski rule-of-five, and a significant fraction of members (21.5 million) were lead-like. Furthermore, the chemical space showed low similarity to already existing compound collections and was enriched with disk-like molecules. Comparison with the ChEMBL database revealed that over 100 representatives generated had biological activity, with some exhibiting potency in the low nanomolar range.