Catalytic stereodivergent and simultaneous construction of axial and point chirality

Abstract

Atropisomers possessing additional stereogenic centres have found wide applications in various fields; however, the development of catalytic asymmetric reactions for their preparation through a single transformation has been much less studied. In particular, no example of catalytic diastereodivergent and enantioselective simultaneous construction of axial and point chirality has been disclosed, which stands for an unmet synthetic challenge. Herein, we report the realization of such a goal for the first time. An unprecedented silver-catalyzed desymmetric [3 + 2] cycloaddition reaction of N-quinazolinone maleimides with isocyanoacetates was developed, producing a series of bicyclic N-heterocycles bearing a remote chiral N–N axis and three contiguous stereogenic carbon centres with high efficiencies and high-to-excellent stereoselectivities. Most strikingly, an interesting diastereodivergent synthesis was also achieved allowing facile access to both endo- and exo-cycloadducts. DFT calculations revealed that the stereoselectivity is mainly controlled by the coordination type of the ligand, ligand–substrate non-bonding interaction, and distortion of the annulation transition state.