Synthesis of (1→3) Thiodisaccharides of GlcNAc and the Serendipitous Formation of 2,3-Dideoxy-(1→2)-thiodisaccharides through a Vinyl Azide Intermediate

Abstract

The syntheses of β-S-GlcA(13)GlcNAc and β-S-Gal(13)GlcNAc thiodisaccharides were achieved by SN2 displacement of a triflate group allocated at 3-position of a convenient 2-azido-4,6-O-benzylidene-2-deoxy-β-D-allopyranose precursor, by the corresponding nucleophilic suitable protected thioaldoses derived from GlcA and Gal.The study of the reaction led to the finding that the vinylazide formed by the competitive E2 reaction of the mentioned triflate, was an interesting precursor of a new kind of 2,3dideoxy-2-azido-(12) thiodisaccharides, through an addition reaction. The determination of the stereochemistry of the new stereocenter at C-2 was achieved by NOESY experiments. Final protecting group manipulation of the (13) thiodisaccharides led to a family of derivatives that could be used as building blocks for the synthesis of more complex glycomimetics.

Synthesis of Thiodisaccharides Bearing N‐Acetylhexosamine Residues: Challenges, Achievements and Perspectives

“…Further S N 2 displacement of the triflate group using suitable protected thioaldoses derived from either glucuronic acid (βGlcASH) and galactose (βGalSH), led to thiodisaccharides 142 and 143, respectively. [84] This S N 2 step was also challenging, and the reaction conditions should be carefully optimised. Taking into account the complexity of these molecules, the yields were acceptable (40-45 %).…”

“…Thus, β-S-GlcA (1!3)GlcNAc, β-S-Gal(1!3)GlcNAc and β-S-GlcA(1!3) AllNAc thiodisaccharides can be considered mimetics of the repeating units of hyaluronan and keratan GAG structures. [72,84] Indeed, we used the synthesised hyaluronan mimetic thiodisaccharides to construct resorcinarene-based amphiphilic multivalent ligands to assess binding studies towards the C-type lectin Langerin, which is involved in a wide number of critical biological processes (unpublished results).…”

“…Thus, the reaction required microwave irradiation to progress. Further S N 2 displacement of the triflate group using suitable protected thioaldoses derived from either glucuronic acid (βGlcASH) and galactose (βGalSH), led to thiodisaccharides 142 and 143 , respectively [84] . This S N 2 step was also challenging, and the reaction conditions should be carefully optimised.…”

“…All these results are related to our project concerning the synthesis of defined GAG‐derived glycomimetics for both, the study of biological processes involving these biopolymers and the exploration of multivalent architectures. Thus, β‐ S ‐GlcA(1→3)GlcNAc, β‐ S ‐Gal(1→3)GlcNAc and β‐ S ‐GlcA(1→3)AllNAc thiodisaccharides can be considered mimetics of the repeating units of hyaluronan and keratan GAG structures [72,84] . Indeed, we used the synthesised hyaluronan mimetic thiodisaccharides to construct resorcinarene‐based amphiphilic multivalent ligands to assess binding studies towards the C‐type lectin Langerin, which is involved in a wide number of critical biological processes (unpublished results).…”

“…Considering the chemistry and reactivity of vinyl azides, we also were able to propose a mechanism for this addition reaction, involving an iminodiazonium cation intermediate (Scheme 47). [84] Remarkably, the rigidity of the sugar ring, must in some way preclude the classic 1,2‐substituent migration observed in iminodiazonium ions with the concomitant loss of N 2 , (known as the Schmidt reaction, Scheme 45, path b). Similar results on the addition of nucleophiles to this unsaturated bond were obtained by Wang and co‐workers by treating some aliphatic vinyl azides with alcohols in the presence of SelectFluor, as source of electrophilic F + [122] …”