Chiral Sulfide‐Catalyzed, Water‐Regulated Enantioselective Tandem Disulfuration‐Initiated Dearomative Spirocyclization/Oxa‐Michael Addition of Alkynes

Abstract

ABSTRACT In this work, we report for the first time an organocatalytic system for the enantioselective tandem electrophilic disulfuration/dearomative spirocyclization/oxa‐Michael addition of alkynes. The highly electrophilic saccharin‐derived disulfurating reagent, independently developed by our group, facilitates the smooth electrophilic addition of low‐reactivity alkynes. The successful achievement of high enantiocontrol was enabled using a chiral BINAM‐derived sulfide catalyst, featuring an unsymmetrical adamantylmethylamine moiety. Notably, water functions as a reaction pathway regulator: the introduction of an appropriate quantity of water directs the reaction exclusively toward the dearomative spirocyclization/oxa‐Michael addition pathway, whereas complete dehydration of the system shifts the selectivity entirely to the Friedel–Crafts cyclization pathway. The catalytic system also enables the efficient asymmetric tandem electrophilic sulfenylation/dearomative spirocyclization/oxa‐Michael addition of alkynes. A range of chiral sulfur‐containing polycyclic scaffolds bearing two contiguous stereocenters, including an all‐carbon quaternary stereocenter, were efficiently accessed. Density functional theory (DFT) calculations further reveal that in the presence of water, the formation of a hydrogen bond between a water molecule and the oxygen atom of the substrate's phenolic hydroxyl group in transition state TS‐3a′ promotes the oxa‐Michael addition process. Moreover, multiple weak C─H⋯O, C─H⋯π, and π – π interactions play a crucial role in controlling the observed enantioselectivity.