Synthesis and Conformational Analysis of Novel N(OCH₃)‐linked Disaccharide Analogues

Abstract

N(OMe)-linked disaccharide analogues, isosteric to the corresponding natural disaccharides, have been synthesized by chemoselective assembly of unprotected natural monosaccharides with methyl 6-deoxy-6-methoxyamino-alpha-D-glucopyranoside in an aqueous environment. The coupling reactions were found to be chemo- and stereoselective affording beta-(1-->6) disaccharide mimics when using Glc and GlcNAc; in the case of Gal, the beta-anomer was prevalent (beta:alpha=7:1). An iterative method for the synthesis of linear N(OMe) oligosaccharide analogues was demonstrated, based on the use of an unprotected monosaccharide building block in which an oxime functionality at C-6 is converted during the synthesis into the corresponding methoxyamino group. The conformational analysis of these compounds was carried out by using NMR spectroscopy, ab initio, molecular mechanics, and molecular dynamics methods. Optimized geometries and energies of fourteen conformers for each compound have been calculated at the B3LYP/6-31G* level. Predicted conformational equilibria were compared with the results based on NMR experiments and good agreement was found. It appears that N(OMe)-linked disaccharide analogues exhibit a slightly different conformational behavior to their parent natural disaccharides.

Enhancing the anticancer properties of cardiac glycosides by neoglycorandomization

“…Library member 27␤, derived from aglycon 3␤, also displayed no hydrolytic degradation under the same conditions at neutral and basic pHs, demonstrating that aglycon C3 stereochemistry does not significantly influence neoglycoside stability. In conjunction with our neoglycoside structural analyses and the previously reported NMR and molecular dynamics studies (16), these hydrolytic studies suggest the neoglycoside nitrogen to be predominately charge-neutral at physiological pH.…”

“…and J.S.T., unpublished data). Closed-ring neoglycosides were found to display conformational behavior similar to natural O-glycosides by NMR studies, molecular dynamics simulations, and ab initio calculations (16).…”

‘Sweetening’ natural products via glycorandomization

“…Although the stability of these early model neoglycosides was not examined, the distribution of pyranose (and occasionally furanose) anomers in neoglycosides was found to be dependent upon the identity of the sugar, and equilibration between the product isomers was sometimes observed. NMR studies, molecular dynamics simulations, and ab initio calculations also demonstrated the closed-ring neoglycosides to display conformational behavior similar to corresponding O-glycosides [42 ].…”

Direct, Mild, and Selective Synthesis of Unprotected Dialdo‐Glycosides

“…In this study, we report a mild, simple and efficient TEMPO-catalyzed oxidation of a range of unprotected methyl glycosides (1-6) to their corresponding oxo derivatives (7)(8)(9)(10)(11)(12). The transformation is made in one single step and products are isolated in high yield after a simple purification step.…”

“…This is a highly useful route for the preparation of reactive carbohydrate components with intact carbon skeletons. These structures have proved advantageous for a variety of reactions, including reductive amination protocols to produce N-linked glycosides and glycoconjugates, [6,7] glycoside oxime formation, [8] olefination reactions [9] and different polymerization protocols. [10,11] The synthesis of 1,5-dialdo-pyranosides has been addressed over the years, and some enzymatic, [12][13][14] as well as several synthetic, [12,15] pathways have been reported.…”