Synthesis of antiviral carbocycle-fused-uracils via organocatalytic asymmetric [4+2] cycloaddition reactions

Reported herein is an unprecedented example of enantioselective formal [4+2] cycloaddition between vinylogous1 uracil-based diene precursors of type 1 and dienophile nitroolefins 2. The transformation proceeds through the challenging in-situ generation of a dienolate o-quinodimethane (oQDM) intermediate 1' and exploits the strategic bifunctional action of a thiourea-amine organocatalyst.2 A series of carbocycle-fused uracils of type 3 embedding three contiguous stereocenters were efficiently obtained with excellent diastereocontrol and good enantioselectivities. DFT calculations supported an intriguing stepwise vinylogous Michael/Henry cascade, highlighting the crucial role of the organocatalyst in triggering the dearomative formation of the oQDM species and orchestrating the stereochemistry of the process.3 Preliminary screening in cellular assays toward a large set of viral strains showed that some compounds of type 3 possess low-micromolar antiviral activity with low cytotoxicity. The evolution of the work is highlighted, starting from a methodology-centered basic research, going through in-depth mechanistic investigation, and landing on possible applications in the medicinal chemistry domain.