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

Abstract

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.

N-Heterocyclic Carbene-Catalyzed Enantioselective Synthesis of Carbocycle-Fused Uracils via Formal [4 + 2] Annulation/Lactone Formation/Decarboxylation Cascade

“…Later on, Albrecht reported the similar aminocatalytic double cycladditive reaction cascade. In 2021, Zanardi disclosed an asymmetric [4 + 2] cyclization of aldehydes 1 with nitroolefins enabled by noncovalent bifunctional organocatalysis (Scheme b). Therefore, it is still desirable to develop more asymmetric synthetic methods for the rapid and effective elaboration of easily available uracil-based compounds to access structurally novel fused uracils.…”

Mechanistic Insights into the Stepwise (4+2) Cycloaddition toward Chiral Fused Uracil Derivatives

“…To fulfil the objectives of the work, we needed a model reaction featuring substrates with “computing‐friendly” low‐complexity structure with high probative output. We thus performed the reaction between N , N ‐dimethyl‐protected 6‐methyl‐uracil‐5‐carbaldehyde 1 a (which had already proven to be a viable pronucleophile in our previous work) [10] and trans ‐ β ‐nitrostyrene ( 2 a ) under the guidance of C1 catalyst, affording the corresponding (5 S ,6 R ,7 R )‐configured fused uracil 3 aa in 50% yield and 68:32 enantiomeric ratio ( er , Scheme 3).…”

“… Formerly Proposed Catalytic Cycle for the One Pot‐Four Step (4+2) Cycloaddition between Uracil Derivatives 1 and Nitroalkenes 2 [10] …”

Regiodivergent Organocatalytic Reactions

“…Moreover, these derivatives are also widely used as bifunctional catalysts in combinations such as amine-thiourea and phosphine-thiourea. Along with their catalytic activity, they are also involved as a component in various reactions including guanylation, thioarylation, and C-S cross-coupling reactions [159][160][161][162][163][164][165][166].…”