Abstract
Some symboles could not be reproduce. For the full abstract, please consult the original article C-Allyl –D-mannopyranosideswere preparedvia a variety of routesto determine an optimal route to the -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.
Highlights
Escherichia coli responsible of urinary tract infections (UTIs), intestinal bowel diseases (IBDs) such as Crohns’s disease (CD), and ulcerative colitis constitute major challenges for medicinal chemistry.[6,7]
Some were more α-stereoselective than others, we opted for the use of perbenzoylated precursors for practical reasons
Using optimized Sakurai allylation, good yields of the C-allylated glycosyl derivatives were obtained. We demonstrated that these existed in the required 4C1 conformation, in the gas phase, solutions, and in the solid-state, as requested for efficient binding interactions with one of the essential E.coli virulence factor FimH
Summary
Adherent-invasive Escherichia coli (AIEC) infections are a serious health problem for which alternative therapeutic strategies are very timely,[1,2] in light of bacterial resistance against the most recent arsenal of antibacterial agents.[3,4,5] Amongst these, Escherichia coli responsible of urinary tract infections (UTIs), intestinal bowel diseases (IBDs) such as Crohns’s disease (CD), and ulcerative colitis constitute major challenges for medicinal chemistry.[6,7] Uropathogenic E. coli infections (UPECs) affect 50% of women at least once in their life-times. X-ray crystallography, and binding studies support that C-allyl α-D-mannopyranosides exist in the required and most stable 4C1 conformation and that the corresponding 1,1’-biphenyl derivatives, obtained through palladium-catalyzed Heck cross-coupling, represent hydrolytically stable and promising leads as E. coli FimH antagonists. To simplify access to a suitable and versatile starting material, we attempted the Sakurai reaction directly from the commercially available methyl α-D-mannopyranoside 7 using previously described conditions (BTSFA, AllylTMS, TMSOTf, MeCN, 0 °C,16 h).[43,44] both the yield and the anomeric diastereoselectivity toward unprotected 8α,β in one single step from 7 was acceptable, the anomeric mixture was not readily separable.
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