Total Synthesis of Anticoagulant Pentasaccharide Fondaparinux

Abstract

The anticoagulant pentasaccharide fondaparinux was synthesized using an improved and optimized synthetic strategy including a convergent [3+2] coupling approach, orthogonal protecting groups and various glycosyl donors. The new methods of glycosylation were also used for controlling the stereochemical configuration and improving the yield of the glycosylation. In addition, HPLC and NMR methods to monitor the process of total synthesis of fondaparinux were employed. This work provides a comprehensive elaboration for the synthesis and analysis of fondaparinux based on related literature, as well as abundant information for the synthesis of heparin-like oligosaccharides.

Chemical Synthesis of the Pentasaccharide Related to the Repeating Unit of theO-Antigen fromSalmonella entericaO4

“…1), 4, [9] 7, [10] 12 (Sch. 2), and 15 [11] were prepared from commercially available sugars following literature procedures or as described in the following schemes (Fig. 2).…”

Advances in Chemical Synthesis of Fondaparinux

“…It is also possible to make the methyl ester (Scheme 21) donor for fragment B monosaccharide 68 as reported by several research groups [19,20,23,25,29]. Few additional steps are needed for protections and deprotections to make the methyl ester, but it is worth the effort as it avoids latestage modifications of the pentasaccharide.…”

“…However, in Sinay's report [17], the coupling reaction (Scheme 5) between the trisaccharide donor 22 and the disaccharide acceptor 23 in the presence of TMSOTf described the formation of only the α-linked pentasaccharide 12 in good yield (70%). Recently, several research groups such as Lin et al [18], Dai et al [19], and Li et al [20] used the similar EDC + BA strategy to report the synthesis of protected fondaparinuxrelated pentasaccharide. Furthermore, 3 + 2 (EDC + BA) strategy was also utilized in the programmable one-pot method which was employed by Wong to synthesize one fondaparinux-related pentasaccharide [21].…”

Total Synthesis of a Partial Structure from Arabinogalactan and Its Application for Allergy Prevention

“…In addition, the separation of natural polysaccharides from other immune‐modulating contaminants, such as endotoxins, is, at least, highly challenging, especially under the good manufacturing practice conditions required for pharmaceutical applications. Gratifyingly, the prime example of fondaparinux, a synthetic pentasaccharide used as an anticoagulant, showcases that the total synthesis of carbohydrate pharmaceuticals can be cost‐effective, despite their intrinsic high complexity and polyfunctionality [12–15] . In terms of AG, there are a few examples for the synthesis of related oligosaccharides but structure–activity relationships are unfortunately missing [16–21] …”