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

This content will become publicly available on January 2, 2026

Title: Why is thiol unexpectedly less reactive but more selective than alcohol in phenanthroline-catalyzed 1,2- cis O - and S -furanosylations?
The lack of catalytic stereoselective approaches for producing 1,2-cis S-furanosides emphasizes the critical need for further research in this area. Herein, we present a stereoselective S-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-cis S-furanosides. Through computational and experimental investigations, thiol is found to be less reactive than alcohol but exhibits greater stereoselectivity. The 1,2-cis stereoselectivity of O-products depends on the nature of the electrophile, while S-products are obtained with excellent 1,2-cis 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 S-furanoside and O-furanoside transition states is 3.7 kcal/mol, supporting the increased reactivity of alcohol over thiol. The difference in transition state energies between the major and minor S-product is greater than that for the major and minor O-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-cis O-furanosides in our prior studies are found to be unsuitable for the synthesis of 1,2-cis S-furanosides. In the present study, a highly reactive phenanthroline catalyst and specific reaction conditions have been developed to achieve stereoselective S-linked product formation.  more » « less
Award ID(s):
1856437
PAR ID:
10612971
Author(s) / Creator(s):
; ; ; ; ;
Publisher / Repository:
Royal Society of Chemistry
Date Published:
Journal Name:
Organic & Biomolecular Chemistry
Volume:
23
Issue:
2
ISSN:
1477-0520
Page Range / eLocation ID:
328 to 342
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
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