Aminosulfine‐Based Donor Platform for Controlled Release of Sulfenic Acid (HSOH)

Abstract

ABSTRACT Reactive sulfur species derived from hydrogen sulfide are central regulators of redox signaling; however, sulfenic acid (HSOH) has remained largely inaccessible owing to the absence of chemically defined donor systems. Here we report a mechanistically delineated strategy for controlled HSOH generation based on an intramolecular cyclization–release platform incorporating an aminosulfine (thioamide S‐oxide) motif. Aminosulfine derivatives containing an ester group can undergo a unique acyl transfer process via the nucleophilicity of the α‐amide ion, followed by intramolecular cyclization to release HSOH, providing a chemically tractable route for transient HSOH release. Systematic structure–activity relationship and kinetic studies further indicate that achieving efficient HSOH release requires precise kinetic matching between the acyl transfer rate and the intramolecular cyclization rate. Using complementary chemical trapping approaches and a persulfide‐selective fluorescent probe, we demonstrate that transiently generated HSOH exhibits exceptionally high reactivity, rapidly undergoing disproportionation and efficiently promoting thiol persulfidation even at low concentrations. Importantly, HSOH signaling confers protection against oxidative injury in a cellular oxygen–glucose deprivation model. This work establishes a chemically defined framework for probing HSOH‐initiated sulfur signaling and provides fundamental insights into the reactivity and biological implications of this elusive reactive sulfur species.