A Binary Catalytic System for Enantioselective Annulation of 3‑Amino Oxetanes with Isocyanates Leading to Antiviral Chiral 2‑Iminothiazolidines

Despite the versatility of enantioselective oxetane opening, this process has been limitedly developed and previously uniformly relied on a solo catalytic system. Herein, inspired by the careful study of the impurities in commercial reagents, we developed a binary catalytic system for this chemistry by means of Lewis-acid-assisted chiral Bro̷nsted acid (LBA) catalysis. A suitable chiral phosphoric acid catalyst and a Lewis acid (YCl3 or AlBr3) cocatalyzed the intermolecular annulation of diverse prochiral 3-amino oxetanes and isothiocyanates, leading to chiral 2-iminothiazolidines with high efficiency and good enantioselectivity under mild conditions. Control experiments combined with DFT studies suggested that the achiral Lewis acid serves to activate the chiral phosphoric acid by increasing its rigidity and acidity and that the latter activates the oxetane for ring-opening. Preliminary studies indicated that the chiral 2-iminothiazolidine products exhibited promising activity against Zika virus, thus highlighting the great potential of this chemical space in antiviral studies.