Why is thiol unexpectedly less reactive but more selective than alcohol in phenanthroline-catalyzed 1,2-<i>cis O</i>- and <i>S</i>-furanosylations?

Abstract

The lack of catalytic stereoselective approaches for producing 1,2-<i>cis S</i>-furanosides emphasizes the critical need for further research in this area. Herein, we present a stereoselective <i>S</i>-furanosylation method, utilizing a 4,7-dipiperidine-substituted phenanthroline catalyst. This developed protocol fills a gap in the field, enabling the coupling of cysteine residues and thiols with furanosyl bromide electrophiles. The process allows for stereoselective access to 1,2-<i>cis S</i>-furanosides. Through computational and experimental investigations, thiol is found to be less reactive than alcohol but exhibits greater stereoselectivity. The 1,2-<i>cis</i> stereoselectivity of <i>O</i>-products depends on the nature of the electrophile, while <i>S</i>-products are obtained with excellent 1,2-<i>cis</i> stereoselectivity, irrespective of the furanose structure. The displaced bromide ion from the glycosyl electrophile influences the reaction's reactivity and stereoselectivity. Alcohol-OH forms a stronger hydrogen bond with bromide ion than thiol-SH, contributing to the difference in their reactivity. The energy difference between forming <i>S</i>-furanoside and <i>O</i>-furanoside transition states is 3.7 kcal mol^-1, supporting the increased reactivity of alcohol over thiol. The difference in transition state energies between the major and minor <i>S</i>-product is greater than that for the major and minor <i>O</i>-product. This is consistent with experimental data showing how thiol is more stereoselective than alcohol. The catalyst and reaction conditions utilized for the generation of 1,2-<i>cis O</i>-furanosides in our prior studies are found to be unsuitable for the synthesis of 1,2-<i>cis S</i>-furanosides. In the present study, a highly reactive phenanthroline catalyst and specific reaction conditions have been developed to achieve stereoselective <i>S</i>-linked product formation.