NHC-Catalyzed Aldimine Umpolung/6π-Electrocyclization Cascade to Access Tetracyclic Dihydrochromeno Indoles

The umpolung of aldimines using N-heterocyclic carbenes (NHCs) is less explored compared to the established polarity reversal of aldehydes. Described herein is an NHC-catalyzed imine umpolung /6π-electrocyclization cascade, which leads to the atom- and pot-economic synthesis of biologically important dihydrochromeno indoles. For the first time, the nucleophilic aza-Breslow intermediates have been intercepted with unactivated alkynes. Preliminary mechanistic and DFT studies shed light on the role of the phenolic -OH moiety in promoting the addition of the aza-Breslow intermediate to the unactivated alkyne via an intramolecular proton transfer in a stepwise manner. DFT studies also support the regioselectivity preference for the 5-exo-dig cyclization pathway, leading to the exclusive formation of the indole products. Moreover, a comparison of Gibbs free energies provides insight into a thermodynamically preferred 6π-electrocyclization over a competing oxa-Michael pathway. Further, this strategy is applied to the formal synthesis of a Hepatitis C Virus (HCV) NS5A inhibitor in a step-economical method.