An exploratory study on the synthesis of heparin-like oligosaccharides by polycondensation

Niels-Christian Reichardt,Manuel Martín-Lomas,Anthony Waring

doi:10.3998/ark.5550190.0006.914

Niels-Christian Reichardt, Manuel Martín-Lomas + Show 1 more

Open Access

https://doi.org/10.3998/ark.5550190.0006.914

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Abstract

The synthesis of heparin oligosaccharide fragments by autocondensation of suitably protected D- glucosamine α1→4 L-iduronic acid disaccharide constructs containing both glycosyl- donor and glycosyl- acceptor functionalities has been explored. Trichloroacetimidate and n-pentenyl groups have been investigated for anomeric activation. The generation of building blocks equipped with a trichloroacetimidate function is seriously hampered by the presence of the free- OH glycosyl- acceptor group on the same molecule, which favors an intramolecular transesterification reaction. Using an n-pentenyl leaving group, the glycosylation promoter competes as a nucleophile with the OH glycosyl acceptor in the autocondensation process, giving rise to fast termination of the chain reaction, a low yield, and low degree of polymerization. It is concluded that, in this area, polycondensation can hardly compete with elaborate stepwise approaches as a result of the intrinsic low reactivity—both as a glycosyl donor and as glycosyl acceptor—of the D-glucosamine α1→4 L-iduronic acid building blocks.

Highlights

As part of a program on the molecular basis of the activation of fibroblast growth factors (FGFs) by glycosaminoglycans (GAGs) we have developed a modular approach for a completely stereoselective block synthesis of oligosaccharides containing the repeating unit (D-glucosamine α1→4 L-iduronate) of the major sequence of heparin.[1]
We thought that a polycondensation reaction of a properly selected disaccharide building block as the repeating unit would represent an attractive alternative to the stepwise synthesis for the preparation of regular sequences
Higher oligomers from subsequent glycosylation cycles could never be observed. From this exploratory study it can be concluded that the glucosamine α1→4 L-iduronate building block is not a suitable candidate for self-condensation, because it has low reactivity both as a glycosyl donor and as a glycosyl acceptor

Summary

Introduction

As part of a program on the molecular basis of the activation of fibroblast growth factors (FGFs) by glycosaminoglycans (GAGs) we have developed a modular approach for a completely stereoselective block synthesis of oligosaccharides containing the repeating unit (D-glucosamine α1→4 L-iduronate) of the major sequence of heparin.[1]. When no further evolution was observed the reaction mixture was acetylated by treatment with acetic anhydride and pyridine in the presence of DMAP.[20] It was submitted to extensive TLC fractionation and compounds 10–13 could be isolated and characterized (Scheme 5).

Results

Conclusion