Enantioselective synthesis of spiro γ-butyrolactones by N-heterocyclic carbene (NHC)-catalyzed formal [3 + 2] annulation of enals with 3-hydroxy oxindoles

Abstract

The N-heterocyclic carbene (NHC)-catalyzed enantioselective formal [3 + 2] annulation of α,β-unsaturated aldehydes with 3-hydroxy oxindoles is presented. Under oxidative conditions using the bisquinone oxidant, the reaction resulted in the synthesis of spiro γ-butyrolactones in moderate to good yields, enantioselectivity and diastereoselectivity. The reaction likely proceeds via the generation of the NHC-bound α,β-unsaturated acylazolium intermediate from enals, which was intercepted by the dioxindoles in a formal [3 + 2] pathway to form the spirocyclic compounds. However, a deeper mechanistic investigation revealed that the reaction can also proceed via the homoenolate intermediate. In this case, the dioxindole was oxidized to the corresponding isatin derivative using traces of air under basic conditions, and was intercepted with the NHC-bound homoenolate intermediate in a formal [3 + 2] pathway to afford the spiro compound.

Revealing the Similarities of α,β‐Unsaturated Iminiums and Acylazoliums in Organocatalysis

“… [51] The secondary amine‐catalyzed [3+2] annulation was followed by an in situ oxidation to form the lactone product. A similar but mechanistically different [3+2] annulation reaction in NHC catalysis was uncovered almost independently by the Ye [52] and Biju groups [53] . Ye and co‐workers reported the reaction of enals with dioxindoles in the presence of the chiral NHC catalyst and nitrobenzene as the oxidant to afford the spirooxindole γ‐butyrolactones 53 in high yields, dr and ee values.…”

Recent Advances in N‐Heterocyclic Carbene Catalyzed Oxidative Cyclization for the Formation of Heterocycles

“…The synthesis of spiro γ‐ butyrolactones 185 by oxidative NHC‐catalyzed reaction of enals 184 with 3‐hydroxy oxindoles 183 as nucleophiles was reported by Biju and co‐workers (Scheme 50). [77] The reaction proceeds via the chiral α,β‐ unsaturated acyl azolium ion as the key intermediate which further reacts with enolate (generated from 3‐hydroxy oxindoles) to undergo a formal [3+2] cyclization producing chiral spiro γ‐butyrolactones in moderate to good yields and good diastereoselectivities and enantioselectivities. During mechanical investigation, it was found out that the reaction can proceed in the absence of oxidant, since presence of trace amount of air under basic condition can generate isatin.…”

Revealing the Similarities of α,β‐Unsaturated Iminiums and Acylazoliums in Organocatalysis

“…As imilar but mechanistically different [3+ +2] annulation reaction in NHC catalysis was uncovered almost independently by the Ye [52] and Biju groups. [53] Ye and co-workers reported the reaction of enals with dioxindoles in the presence of the chiral NHC catalyst and nitrobenzene as the oxidant to afford the spirooxindole g-butyrolactones 53 in high yields, dr and ee values.T he reaction was envisioned to proceed via as ingle electron transfer pathway involving the cross-coupling of homoenolates (generated from enals) and enolate (formed from dioxindoles). Thes ingle electron oxidant nitrobenzene was responsible for the formation of the radical species,a nd both aliphatic and aromatic enals worked well.…”