(Dimethylamino)methylene hydantoins as building blocks in the synthesis of oxoaplysinopsins and parabanic acids with antifungal activity

Abstract

A short, efficient, and stereoselective methodology is described for the synthesis of 5-((dimethylamino)methylene)hydantoins and their conversion into oxoaplysinopsins and parabanic acids. A highly convergent one-pot, two-step reaction between methyl N-arylglycinates, isocyanates, and DMFDMA under microwave irradiation provided the corresponding (dimethylamino)methylene hydantoins as a single E-stereoisomer in high overall yields. The synthesis of (S)-1-(1-phenylethyl) chiral hydantoins, which undergo a stereoselective addition of acetic anhydride, aza-heterocycles, and amines, received special attention. The reaction with indole delivered a series of novel oxoaplysinopsins. Meanwhile, parabanic acids were prepared by a new approach, treating (dimethylamino)methylene hydantoins with mCPBA to generate the oxidative fragmentation of the exocyclic methylene. The antifungal evaluation of the prepared products was carried out on a series of Candida spp., finding potent growth inhibition. According to previous docking studies, this activity is probably due to the inhibitory interaction of the derivatives with the active site of the fungal HMGR enzyme.