Deciphering the conformation of C-linked α-D-mannopyranosides and their application toward the synthesis of low nanomolar E. coli FimH ligands

Abstract : C-Allyl α–D-mannopyranosideswere preparedvia a variety of routesto determine an optimal route to the α-anomers. The relative conformational energies of the key intermediate was evaluated by molecular modelingwhich showed the conventional 4C1chair conformation to be the lowest energy conformer. This finding was also confirmed by NMR and X-ray crystallography. The perbenzoylated C-allyl mannoside was also converted into 1,1’-biphenyl analogues using a palladium-catalyzed Heck reaction. Two of the resulting minor reaction products were co-crystallized with the uropathogenic E. coliFimH. Alternatively, the KDof the major and expected Heck product was in the low nM range as measured by SPR. Crystal data showed that the C-linked derivatives efficiently bind in the FimH binding cavity near the so-called hydrophobic tyrosine gate.