Enantioselective catalytic Urech hydantoin synthesis

Abstract

5,5-Dicarbon-substituted hydantoins are the key skeletons of numerous drugs, but a general method for the enantioselective de novo synthesis of such scaffolds is elusive. On the other hand, Urech hydantoin synthesis (UHS) represents an efficient approach for hydantoin preparation, but its enantioselective variant remains unknown. Based on desymmetrization and kinetic resolution strategies, we disclose herein the first example of asymmetric catalytic UHS, providing synthetically challenging thiohydantoins with high stereoselectivities. Readily accessible 2-amino malonic esters and racemic amino esters were employed to react with isothiocyanates in the presence of chiral acids, respectively. The resulting products can be facilely functionalized and serve as pivotal scaffolds in various drugs. Experimental studies and DFT calculations suggest that an unexpected dynamic kinetic resolution in the ester ammonolysis step is responsible for the enantiocontrol.