Vicinal Halothiolcarbonates as Pseudo-Ambident Electrophiles: Carbamate Synthesis, Unified Thiol Reactivity, and Architecture-Dependent Antibacterial Activity of Ciprofloxacin Glycoconjugates

Abstract Vicinal bis-electrophilic halothiolcarbonates (vic-HTCs) are introduced as a platform for the chemoselective synthesis of carbohydrate carbamates under mild conditions. Their aminolysis accommodates a broad range of nucleophiles, including complex bioactive amines, providing access to glycoconjugates that remain difficult to obtain by conventional methods. Beyond their synthetic utility, vic-HTCs display an unusual thiol reactivity in which exchange at a C(sp2) center and substitution at a remote C(sp3) site arise from a common tetrahedral intermediate. Combined experimental and DFT (Density Functional Theory) analyses show that chemoselectivity is governed by substituent-dependent kinetic partitioning rather than intrinsic hard-soft site differentiation, providing a mechanistic basis for describing vic-HTCs as pseudo-ambident electrophiles. Application of this platform to ciprofloxacin (Cip) afforded glycoconjugates without prior biological design. Two closely related conjugates differing only in the carbohydrate anomeric state exhibited sharply contrasting antibacterial profiles. The most active conjugate showed up to a 46-fold molar potency improvement over Cip against Staphylococcus aureus, while activity was retained or partially improved against Gram-negative strains, including Pseudomonas aeruginosa. These findings contrast with the commonly reported loss of activity upon fluoroquinolone glycoconjugation and demonstrate that carbohydrate architecture can enhance antibacterial potency.