Fully deprotected β-(1→2)-mannotetraose forms a contorted α-helix in solution: convergent synthesis and conformational characterization by NMR and DFT

Abstract

b-(1-2)-linked oligomannosides, found in the cell wall of Candida albicans, are promising structures for the development of C. albicans vaccines. Considerable effort in recent years has been devoted to the synthesis of these carbohydrate structures. As a result, several successful synthetic methodologies based on linear approaches have emerged. Here, we demonstrate that a fully deprotected b-(1-2)-linked mannotetrasaccharide can also be conveniently constructed by the convergent direct coupling of two appropriately protected disaccharides. This improved approach offers several advantages over previously published methods. The number of steps needed to reach larger oligosaccharides is decreased, while high selectivity is retained when the crucial glycosylation step is performed with two disaccharides, herein providing b-(1-2)mannotetraose in 4.2% overall yield over 16 steps starting from D-mannose. Additionally, the complete structural characterization of the products by NMR spectroscopy is reported. In the conformational study of the final product, 2D-NOESY was used in combination with spectral simulations performed using PERCH software. The experimental results obtained confirm the contorted a-helical structure predicted earlier for these oligosaccharides in solution. As a culmination of the conformational study, a model was constructed by molecular modeling using DFT, and the minimum energy conformation was found to be in full agreement with the experimental results. This is the first study to date where the conformation of a fully deprotected mannotetraose has been reported.

Acetylated Trivalent Mannobioses: Chemical Modification, Structural Elucidation, and Biological Evaluation

“…According to the molecular dynamics simulation the glycosidicl inkages are in the expectedc onformations with the glycosidic f angle being~608 andt he aglyconic y angle being~20-308,c onsistent with the typical conformation of b-(1!2)-linked mannosides. [15,34,35] As in the other two structures, no correlations between the glycerol protons and the carbohydrate or linker protons can be seen. The most populated conformationf or 11 extracted from the molecular dynamics simulation is shown in Figure 9.…”

“…The distances acquired from the molecular dynamics simulation are 3.3, 3.2, and 4.0 , respectively.F urthermore the H2B protons showacorrelation to the H1A protons, which is characteristicf or the ab configuration of the b-(1!2)-linked mannosides present in the molecule. [34,35] The most important correlationsa re shown in Figure 4. In addition, correlationsc an be observed between protons H3A and H5A www.chemmedchem.org as well as H1B, H3B, and H5B.…”

Novel Dextran‐Supported Biological Probes Decorated with Disaccharide Entities for Investigating the Carbohydrate–Protein Interactions of Gal‐3

“…Titration of Gal‐3 with the mannans extracted from the cell wall of C. albicans , however, showed no interaction, which could be due to less than optimal availability of the β‐(1→2) epitopes caused by the complex nature of the polysaccharide or the helical structure adopted by larger β‐(1→2)‐linked mannosides.…”

Evaluation of Immunostimulatory Activities of Synthetic Mannose-Containing Structures Mimicking the β-(1→2)-Linked Cell Wall Mannans of Candida albicans

“…1A, 2A, 3A, and 4A), were prepared by applying and further modifying the recently developed methodologies for construction of ␤-(1¡2)-mannosidic linkages by Crich and others (7). The synthesis procedures have been published previously by us (9,10,28). The compounds prepared were designed as simple mimics and analogues of the hydrolyzed oligosaccharide fractions from the C. albicans cell wall, with the ␤-(1¡2) linkage serving as a basis for all structural modifications.…”