Short Synthesis of Idraparinux by Applying a 2‐O‐Methyl‐4,6‐O‐arylmethylene Thioidoside as a 1,2‐trans‐α‐Selective Glycosyl Donor

Abstract

The fully O‐sulfated, O‐methylated, heparin‐related anticoagulant pentasaccharide idraparinux was prepared by a new synthetic pathway in 38 steps using d‐glucose and methyl α‐d‐glucopyranoside as starting materials, with 23 steps for the longest linear route. The l‐idose‐containing GH fragment was obtained by a short and straightforward synthesis whereby a 4,6‐cyclic‐acetal‐protected l‐idosyl thioglycoside bearing a C2‐nonparticipating group was used as the α‐selective glycosyl donor. The novel l‐idose donor was prepared with high chemo‐ and stereoselectivity by hydroboration–oxidation‐based C5 epimerization starting from an orthogonally protected α‐thioglucoside. The assembly of the pentasaccharide backbone was achieved by an F+GH and DE+FGH coupling sequence with full stereoselectivity in each glycosylation step.

Synthesis of L‐Hexoses: An Update

“…On the other hand, α ‐thioglucoside 43 furnished the L‐ido analogue 44 as a major product (Scheme 7). Around the same time, Hercezg, Borbás and co‐workers diligently used the strategy to synthesize L‐idose thioglycoside building block in less steps and appreciable yield for the synthesis of Idraparinux, a simplified derivative of well renowned antithrombiotic drug Fondaparinux (See Figure 1 for structures) [52] …”

“…Around the same time, Hercezg, Borbás and co-workers diligently used the strategy to synthesize L-idose thioglycoside building block in less steps and appreciable yield for the synthesis of Idraparinux, a simplified derivative of well renowned antithrombiotic drug Fondaparinux (See Figure 1 for structures). [52] Epimerization at C5 center of readily available D-sugars leading to corresponding L-sugar analogues can also be carried out using photoredox catalysts. Photocatalysis is classified under non-hazardous methods of CÀ H bond functionalization in accessing biologically relevant complex organic molecules.…”

“…Fondaparinux is a synthetic antithrombotic and anticoagulant belonging to the domain of heparan sulphate [11] . Idraparinux is a simplified analogue of fondaparinux which also contains L‐iduronic acid [12] . L‐Hexoses have also been explored in the field of biomimetics [13] .…”

“…[11] Idraparinux is a simplified analogue of fondaparinux which also contains L-iduronic acid. [12] L-Hexoses have also been explored in the field of biomimetics. [13] In order to monitor the activity of enzymes like fucosyltransferase, fluorescent moiety of 6-amino 6-deoxy L-galactose is used.…”

Synthesis and Cell Growth Inhibitory Activity of Six Non‐glycosaminoglycan‐Type Heparin‐Analogue Trisaccharides

“…Our research group has long been working on the synthesis of heparin-analogue oligosaccharides. Several pathways have been developed to prepare the non-glycosaminoglycan, fully sulfated and fully methylated heparinoid anticoagulant pentasaccharide idraparinux 2 a, [17][18][19][20] and its sulfonic acid derivatives 2 b and 2 c (Figure 1) in which several sulfate esters were substituted by sulfonatomethyl moieties to improve the binding affinities. [20,21,22] We envisaged that trisaccharides fragments of these highly sulfated/sulfonylated pentasaccharides (3-8, Figure 2) might bind to the protein ligands, for example, heparanase, with charge-charge interactions and might display cell growth inhibitory activity.…”