Synthesis of Antiviral Carbocycle-Fused-Uracils via Organocatalytic Asymmetric [4+2] Cycloaddition Reactions

Reported herein is an unprecedented example of enantioselective [4+2] cycloaddition between vinylogous uracil-based diene precursors of type 1 and dienophile nitroolefins 2. The transformation proceeds through the challenging in-situ generation of a dienolate ortho-quinodimethane (oQDM) intermediate 1’ and exploits the strategic bifunctional action of a thiourea-amine organocatalyst. 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. Preliminary screening in cellular assays toward SARS-CoV-2 viral strains in U87.ACE2+ cells showed that some compounds of type 3 possess low-micromolar antiviral activity with low cytotoxicity.