Silver-assisted gold-catalyzed formal synthesis of the anticoagulant Fondaparinux pentasaccharide

Abstract

Clinically approved anti-coagulant Fondaparinux is safe since it has zero contamination problems often associated with animal based heparins. Fondaparinux is a synthetic pentasaccharide based on the antithrombin-binding domain of Heparin sulfate and contains glucosamine, glucuronic acid and iduronic acid in its sequence. Here, we show the formal synthesis of Fondaparinux pentasaccharide by performing all glycosidations in a catalytic fashion for the first time to the best of our knowledge. Designer monosaccharides were synthesized avoiding harsh reaction conditions or reagents. Further, those were subjected to reciprocal donor-acceptor selectivity studies to guide [Au]/[Ag]-catalytic glycosidations for assembling the pentasaccharide in a highly convergent [3 + 2] or [3 + 1 + 1] manner. Catalytic and mild activation during glycosidations that produce desired glycosides exclusively, scalable route to the synthesis of unnatural and expensive iduronic acid, minimal number of steps and facile purifications, shared use of functionalized building blocks and excellent process efficiency are the salient features.

Design and Synthesis of Neutralizable Fondaparinux

“…Unlike heterogeneous animal-sourced heparins, fondaparinux is a pure synthetic pentasaccharide exhibiting antithrombin III-mediated exclusive factor Xa (FXa) inhibition activity . Since the pentasaccharide is obtained by chemical synthesis, − the quality in terms of purity and reproducibility can be readily controlled. Additionally, fondaparinux exhibits a longer half-life and better antithrombotic efficacy and biosafety than the aforementioned two forms. , However, clinical use of fondaparinux is still restricted because the anticoagulant effect cannot be immediately neutralized in the bleeding events .…”

Glycosyl Vinylogous Carbonates as Glycosyl Donors by Metal-Free Activation

“…Glycosyl halides, esters, phosphates, imidates, thioglycosides, selenyl glycosides, glycals, hemiacetals, alkenyl and alkynyl glycosides, vinyl glycosides, and 1,2-orthoesters are well established as glycosyl donors. , In parallel, we have identified stable ethynylcyclohexyl glycosyl carbonates as glycosyl donors in the presence of a catalytic amount of a gold phosphite and silver triflate at room temperature . Subsequent investigations demonstrated their versatility by synthesizing many glycosides, oligosaccharides, and glycoconjugates. − Glycosyl vinylogous carbonates were considered in this study as the vinylene moiety was hypothesized to facilitate the extrusion of the leaving group under mild reaction conditions. The departed leaving group will be the methyl 3-oxopropanoate that will not be competing with the aglycon during the glycosylation.…”

Synthesis of L‐Hexoses: An Update

“…Recently, Hotha and co‐workers reported a new synthetic route for L‐iduronic acid (Scheme 10). [66] Nucleophilic addition on aldehyde 53 with 2‐thienylmagnesium bromide and acetylation of remaining hydroxyl group gives stereospecifically L‐ido product 54 . Thiophene moiety is preferred because it can be oxidized easily in the presence of benzyl group.…”