Chiral N‐Heterocyclic Carbene‐Catalyzed Asymmetric Michael–Intramolecular Aldol‐Lactonization Cascade for Enantioselective Construction of β‐Propiolactone‐Fused Spiro[cyclopentane‐oxindoles]

Abstract

A cascade asymmetric Michael–intramolecular aldol‐lactonization of enals with oxindolyl β,γ‐unsaturated α‐keto esters was developed. An optically pure aminoindanol‐derived triazolium‐based N‐heterocyclic carbene was used as the catalyst. The corresponding desired β‐propiolactone‐fused spiro[cyclopentane‐oxindoles] were obtained in moderate yields with excellent diastereoselectivities and enantioselectivities. Notably, the obtained enantio‐enriched highly functionalized complex molecules contain four contiguous stereocenters, including a spiro all‐carbon center and a quaternary carbon center.magnified image

Organocatalytic Synthesis of Chiral Spirooxindoles with Quaternary Stereogenic Centers

“…An enantioselective organocatalytic synthesis of β‐propiolactone‐fused spiro[cyclopentaneoxindole] 101 was carried out via an NHC‐catalyzed cascade Michael‐intramolecular aldol‐acylation reaction from oxindolyl β,γ‐unsaturated α‐keto ester 100 with cinnamaldehyde 93 . This reaction was promoted by the chiral triazolium carbene catalyst 98 (10 mol‐%).…”

“…The reaction was more favored with the presence of electron‐donating group substituents on the oxindole skeleton 100 yielding spirooxindole 101 derivatives in moderated yield and high enantioselectivity. A plausible mechanism is as follow, the resulting Breslow homoenolate intermediate I attacks the oxindolyl β,γ‐unsaturated α‐keto ester 100 to form enolate II followed of proton transfer to form the zwitterionic intermediate III in which an intramolecular aldol and cyclization reactions were carried out to give IV finally a subsequent elimination of chiral triazolium carbene catalyst moiety gave spirooxindole 101 and regeneration of catalyst 98 …”

Recent Advances in the Organocatalytic Enantioselective Synthesis of Functionalized β‐Lactones

“…Mechanistically,t his reaction proceeded through the initial generation of ah omoenolate equivalent (52) Very recently,W ang and co-workersr eported an NHC-catalyzed enantioselective cascader eaction that involved aM ichael-addition/intramolecular-aldol/lactonization sequence for the synthesis of b-propiolactone-fused spiro-cyclopentaneoxindoles 57,w hich proceeded through an NHC-homoenolate intermediate (Scheme18). [36] In this transformation,t he homoenolatest hat were generated from the enals reacted with the oxindolyl b,g-unsaturated a-keto esters (56)u nder mild conditions to form b-lactones that contained four contiguouss tereocenters, including an all-carbon spiro quaternary centera nd another quaternary carbonc enter. The initially formed homoenolate underwentaMichael addition to the isatilidenem oiety to generate NHC-enol 58,w hich,o ni ntramolecular proton transfer,f ormed NHC-enolate 59.S ubsequent intramolecular Scheme16.…”

N-Heterocyclic-Carbene-Catalyzed Domino Reactions via Two or More Activation Modes

“…Very recently, Wang and co-workers ( Zhang et al, 2017b ) have shown the application of oxindolyl β,γ-unsaturated α-keto ester 11 in an a 3 -d 3 umpolung/Michael/aldol/lactonization domino sequence ( Scheme 8 ). These substrates reacted well with α,β-unsaturated aldehydes 1 in the presence of the pre-catalyst C2, affording the corresponding products 12 in moderate to good yields with a broad scope of differently substituted aromatic substrates.…”