Asymmetric macrocyclization enabled by Rh(III)-catalyzed C-H activation: Enantioenriched macrocyclic inhibitor of Zika virus infection

The development of enantioselective C-H macrocyclizations to efficiently access structurally diversified macrocycles is highly desirable, but remain a big challenge. Herein, we reported the first rhodium(III)-catalyzed asymmetric intramolecular C-H macrocyclization, enabling the efficient synthesis of structurally diverse enantioenriched macrocycles. This robust enantioselective C-H macrocyclization has a broad functional group tolerance, excellent enantioselectivities (up to 98.5:1.5 e.r.) and a mild reaction condition, releasing CO2 as the single by-product. More significantly, the resulting unique enantioenriched 19-membered macrocycle 2f was found to demonstrate a potent in vitro anti-Zika virus (ZIKV) activity without obvious cytotoxicity. Further investigation revealed that the anti-ZIKV activity is presumably attributed to an autophagy inhibition in the early stage of viral infection by down-regulating the expression of autophagy related gene Atg12.