Direct, Asymmetric Synthesis of Carbocycle-Fused Uracils via [4+2] Cycloadditions: a Noncovalent Organocatalysis Approach

The peculiar versatility of remotely enolizable 6-methyluracil-5-carbaldehydes as useful vinylogous pronucleophiles in direct, asymmetric [4+2] cyclizations with suitable nitroolefins has been demonstrated. Under the strategic exploitation of noncovalent bifunctional organocatalysis, a dearomative remote enolization strategy was implemented, to generate oQDM-type dienolate intermediates that were efficiently and stereoselectively trapped by either aromatic or aliphatic nitroolefins. A series of functionalized, chiral carbocycle-fused uracils embedding three contiguous stereocenters were thus collected in one step in good yields, with generally good levels of enantioselectivity, and complete diastereocontrol. Furthermore, the ability to provide enantiopure products via simple one-cycle recrystallizations and the possibility to further functionalize these scaffolds without losing their chiral integrity were demonstrated.

Automated summary

The remote enolization strategy, strategic exploitation of noncovalent bifunctional organocatalysis, and efficient stereoselective trapping of dienolate intermediates with nitroolefins led to the successful synthesis of functionalized, chiral carbocycle-fused uracils with three contiguous stereocenters in one step, showing good levels of enantioselectivity and complete diastereocontrol. Furthermore, the enantiopure products could be obtained via simple one-cycle recrystallizations and the scaffolds could be further functionalized without losing their chiral integrity.