Construction of Chiral Isotetronic Acid-Fused Thiochromane via Doubly Annulative Strategy

Abstract

A sulfa-Michael/aldol/lactonization cascade reaction has been established to construct isotetronic acid-fused thiochromanes in a highly stereoselective fashion (≥11:1 dr, 35–98% ee). The tricyclic products were obtained in 35–99% isolated yields in the presence of a bifunctional squaramide. Three reactive sites of β,γ-unsaturated α-ketoester, including the less-explored ester carbonyl group, were sequentially utilized to construct two fused heterocycles in a one-pot operation.

Further developments of β,γ-unsaturated α-ketoesters as versatile synthons in asymmetric catalysis

“…The desired products were obtained in high yields with excellent stereoselectivities under the catalysis of a chiral bifunctional thiourea-tertiary amine. Similarly, the Li group demonstrated that isotetronic acid-fused thiochromanes 167 could be prepared via the sulfa-Michael/aldol/lactonization cascade in a highly stereoselective fashion ( Scheme 21 F) ( Mo et al., 2021 ). The authors highlighted the lactonization of a less-explored ester carbonyl group of β,γ -unsaturated α -ketoesters.…”

Advances in Bifunctional Squaramide-Catalyzed Asymmetric Sulfa-Michael Addition: A Decade Update

“…60 Very recently, Li and co-workers explored 1-Sq-catalyzed new synthetic approach employing 2-mercaptobenzaldehyde (23) and β,γ-unsaturated α-ketoester (24) in 1,4-dioxane to afford chiral isotetronic acid-fused thiochromane scaffold (25) (Scheme 15). 61 In this strategy, three reactive sites on 24 were utilized in a cascade reaction sequence of sulfa-Michael addition of 23, followed by intramolecular aldol reaction and cyclization to fused tricyclic heteroarene. The 23 served as nucleophilic/electrophilic ambident regent through mercapto and aldehyde carbonyl groups, respectively.…”

Asymmetric Sequential Michael Addition and Cyclization Reactions of 2-(2-Nitrovinyl)phenols Catalyzed by Bifunctional Amino-Squaramides

“…29 Recently, amino-squaramides were applied in a variety of cascade or sequential reactions utilizing Michael addition as a key step for building complex heterocyclic scaffolds. [30][31][32][33][34][35][36] Part of our research program focuses on the applications of squaramide organocatalysts in the syntheses of chiral heterocyclic compounds. Within this area, we have recently described amino-squaramides as efficient catalysts for Michael additions/hemiketalization of hydroxycoumarins with unsaturated ketones and keto esters.…”