Thio-click approach to the synthesis of stable glycomimetics

Abstract

Carbon-sulfur-bridged glycomimetics were prepared by free radical hydrothiolation of the exocyclic double bond of unsaturated sugars. Reaction between benzoyl-substituted pyranoid-exoglycal and a range of thiols including peptide, 1-thioglycerol and 1-thiosugar derivatives gave β-Dconfigured carbon-sulfur-linked glycoconjugates with full stereoselectivity. Addition of a panel of thiols to a 3-exomethylene-glucofuranose derivative also proceeded in a stereoselective manner and afforded a series of D-allo-configured 3-deoxy-3-C-S-bridged glycoconjugates.

Photoinitiated Thiol‐ene Reactions of Enoses: A Powerful Tool for Stereoselective Synthesis of Glycomimetics with Challenging Glycosidic Linkages

“…We have demonstrated that photoinduced addition of thiols to 2‐substituted hexoglycals led to exclusive formation of 1,2‐ cis ‐α‐S‐glycosides independently of the sugar identity and the protecting groups applied (Scheme C, a) . Further studies by our group and Somsák's group revealed that radical‐mediated hydrothiolation of exo ‐glycals or 1‐substituted endo‐ glycals enabled stereoselective formation of C‐β‐ d ‐glycosidic thiodisaccharides, including the highly challenging β‐mannosidic and 2‐deoxy β‐C‐glycosidic structures (Scheme C, b–c). These results show, that the thiyl radical‐mediated reactions of glycals represent a useful complementary strategy of the classical ionic thioglycosylation approaches.…”

“…Our group and Somsák's group investigated the thiol‐ene reactions of hexo‐ and pentopyranosyl exo ‐glycals as a stereoselective method for the synthesis of glycosylmethyl sulfide type glycomimetics (Schemes and ). Addition of thiols onto d ‐gluco ( 100 ) and galacto ( 104 ) configured exo ‐glycals furnished the β‐C‐S‐bonded glycosides ( 101 – 103 , and 105 ) with exclusive regio‐ and stereoselectivity (Scheme ) . In most cases the reaction went to completion within 15 min at room temperature (rt), demonstrating the high reactivity of exo‐ glycals in the thiol‐ene reactions.…”

“…Extension of the thiol‐ene reaction to unsaturated sugars with endo ‐ or exo ‐cyclic double bond at a non‐anomeric position allowed the synthesis of further valuable glycomimetics …”

“…The reaction was extended to furanose exomethylene derivatives including glucofuranose 131 and nucleoside exomethylenes 133 – 135 (Scheme ) . Addition of various thiols onto 3‐ exo ‐methylene‐glucofuranose derivative 131 proceeded with high yield and complete diastereoselectivity to give the d ‐allofuranosyl glycomimetics, such as 132 , as the sole products …”

Conjugation of Bioactive Molecules to a Fluorescent Dithiomaleimide by Photoin­duced and BEt3‐Initiated Thio‐Click Reactions

“…The low yield (13 %) obtained for galactose derivative 15 is presumably due to the less strongly electron‐withdrawing substituents of thiol 14 . We observed earlier that the presence of electron‐donating substituents on the thiol partner reduces its reactivity in the reversible thiol addition reaction 14,15…”