Exploring the reactivity of 5,5-dimethyl-1,2-oxathiolan-4-one 2,2-dioxide and their spirocyclopropyl counterpart

Abstract

1,2-Oxathiolan-4-one 2,2-dioxides (put simply, β-keto γ-sultones) is the underexplored class of compounds. Within the framework of the present work, 5,5-dimethyl-1,2-oxathiolan-4-one 2,2-dioxide (1a) and 4-oxa-5-thiaspiro[2.4]heptan-7-one 5,5-dioxide (1b) were used as the model compounds whose reactivity was studied and compared in terms of strain cycle effects. Keto sultones are considered the sulfur-containing bioisosteres of naturally occurring compounds and their spirocyclic derivatives are of interest for medicinal chemistry. The reactivity of keto sultones is associated with three reaction centers: the activated methylene group, the carbonyl functionality, and the tertiary γ-carbon atom. The highly strained spirocyclopropyl substituent altered the reactivity of the keto sultone core: the reactivity of the carbonyl group was suppressed whereas the reactivity of the methylene group was greatly enhanced. The density functional theory (DFT) calculations confirmed and supplemented the experimental data. Aminomethylidene derivatives of keto sultones exhibited moderate cytotoxicity against MD Anderson-metastatic breast-231 (MDA-MB-231) breast cancer cell line. The molecular docking study rationalized the experimental in vitro data and predicted potential activity as anti-Parkinson's and anti-Alzheimer's disease compounds.