New synthesis of idraparinux, the non-glycosaminoglycan analogue of the antithrombin-binding domain of heparin

Replacement of the L-iduronic acid unit of the anticoagulant pentasaccharide idraparinux by a 6-deoxy-L-talopyranose – Synthesis and conformational analysis

“…Over the last years, we have developed several new methods for the synthesis of idraparinux 20 , 40 , 41 . The most efficient strategy involves a 3 + 2 coupling of a FGH trisaccharide acceptor and a DE disaccharide donor, and application of acetyl groups to mask the hydroxyls to be methylated and benzyl ethers to protect the hydroxyls to be sulfated in the final product 20 . We applied the same strategy for the synthesis of compounds 2 – 4 .…”

“…This disaccharide was isolated together with a small amount of the 2′,4′-di- O -acetyl byproduct due to the undesired acetyl-migration occurred during the column chromatographic purification. Condensation of acceptor 12 with donor 13 20 in the presence of NIS and trimethylsilyl trifluoromethanesulfonate (TMSOTf) resulted in an inseparable 1:1 mixture of the α- and β -linked trisaccharides 14 in a moderate yield (Fig. 3 ).…”

“…In the field of heparinoid anticoagulants, current research focuses on unmet issues such as low oral bioavailability of heparin 10 , lack of specific antidote for low molecular weight heparins 11 , and chemoenzymatic production of heparin oligosaccharides 12 – 15 . Furthermore, many research efforts have been devoted to the development of highly efficient synthetic routes to the outstanding anticoagulant pentasaccharides fondaparinux 16 – 18 and idraparinux 19 , 20 as well as the preparation of various analogues of the antithrombin-binding pentasaccharide unit of heparin as novel anticoagulant candidates 21 – 25 .…”

“…A range of synthetic approaches have been described to generate heparinoids including solid-supported synthesis 28 , modular approach 29 , 30 and nonglycosylating strategy 19 . To avoid the inherent low reactivity and base-sensitivity of uronic acid donors, typically the corresponding glycopyranosides are used as glycosyl donors and the formation of the uronic acid can be performed at the disaccharide level 31 or by TEMPO-mediated late-stage oxidation at the higher oligosaccharide level 20 , 32 .…”

Synthesis of C‐2‐ and C‐3‐Sulfonatomethyl O‐ and S‐Glycosides by Horner–Wadsworth–Emmons Olefination

“…[12][13][14][15] Some years ago we initiated a research project to prepare isosteric sulfonic acid analogues of the antithrombin binding pentasaccharide domain of heparin to access new anticoagulants. [6,[16][17][18][19][20][21][22] Recently, we demonstrated that the blood clotting inhibitory activity of the parent highly sulfated pentasaccharide could be improved by the replacement of the primary sulfate esters with a sodium sulfonatomethyl group. [19] Continuing on from this, we targeted the synthesis of further pentasaccharide analogues bearing the sulfonic acid moiety at secondary positions by using thioglycoside building blocks bearing a dynamics and DFT calculations.…”