Modeling of synthetic phosphono and carba analogues of N-acetyl-alpha-D-mannosamine 1-phosphate, the repeating unit of the capsular polysaccharide from Neisseria meningitidis serovar A

The conformational behavior of methyl (2-acetamido-2-deoxy-a-D-mannopyranosyl)phosphate 1, and its analogues, methyl C-(2-acetamido-2-deoxy-a-D-mannopyranosyl)methanephosphonate 2 and methyl O-(2-acetamido-2-deoxy-5a-carba-a-D-mannopyranosyl)phosphate 3, where a methylene group replaces, respectively, the anomeric and the pyranose oxygen atom, was investigated at the B3LYP/6-311+G(d,p) level [6-311+G(2df,p) for the phosphorus atom]. The energy of the optimized structures was recalculated using the continuum solvent model C-PCM choosing water as the solvent. The compounds exhibited several populated conformations, but they all showed a marked preference for the 4C1 geometry of the pyranose ring; this preference was almost complete for 1, very large for the phosphono analogue 2, and large for the carba analogue 3. To give experimental support to these results, compounds 2 and 3 were synthesized and characterized by NMR spectroscopy. The comparison of the theoretical and experimental vicinal coupling constants confirmed the marked preference for the 4C1 geometry in the case of 2 and suggested that the same holds true for compound 3.