Fluorous Mixture Synthesis of Two Libraries with Hydantoin-, and Benzodiazepinedione-Fused Heterocyclic Scaffolds

Abstract

Diversity-oriented synthesis (DOS) and fluorous mixture synthesis (FMS) are two aspects of combinatorial chemistry. DOS generates library scaffolds with skeletal, substitution, and stereochemistry variations, whereas FMS is a highly efficient tool for library production. The combination of these two aspects in solution-phase synthesis of two novel heterocyclic compound libraries is presented in this paper. Mixtures of different fluorous amino acids undergo [3 + 2] cycloadditions followed by postcondensation reactions. The mixtures are then demixed by fluorous HPLC. Fluorous tags are removed by cyclization to afford hydantoin- and benzodiazepinedione-fused heterocyclic compounds as individual, pure, and structurally defined molecules. The application of MS-directed HPLC purification and parallel four-channel LC/MS analysis further increases the efficiency of FMS.