Bisulfite Radical (HSO<sub>3</sub><sup>•</sup>)-Mediated Modular Strategy for Synthesis of Aliphatic Sulfonate Esters
Yongxin Zhang, Hui Xu, Ligang Huang, Zhiming Zhu, Ziyang Li, Jiang Duan, Chao Shu
Abstract
Sulfonate esters are privileged scaffolds with significant applications in biochemistry and chemical biology. However, the available strategies for sulfonate esters have primarily relied on sulfonyl halides, resulting in harsh conditions, multistep processes, and difficulties in incorporating these esters into complex systems, especially scarce for alkyl sulfonates. In this work, we discovered that a bisulfite radical species was formed and presented a modular approach for the direct synthesis of aliphatic sulfonate esters using off-the-shelf olefin variants, alcohols, and NH 4 HSO 3 in a three-component cross-coupling reaction. This method efficiently enables the sulfonation of amino acids, peptides, pharmaceuticals, carbohydrates, and nucleosides, exhibiting wide functional group tolerance and facilitating the synthesis of bioactive molecules and their derivatives. Specifically, formic acid serves two critical functions in this system: (i) stabilizing carbon anion intermediates via rapid protonation and (ii) suppressing HSO 3 – ionization by maintaining acid–base equilibrium. The low oxidation potential of HSO 3 – enables its single-electron oxidation by photoexcited 4CzIPN*, generating HSO 3 • radicals─a key step in the conversion process. Furthermore, the total synthesis of DNA-methylating reagent and molecular docking prediction underscore the potential applications of the current method in drug discovery.