Design and stereoselective synthesis of a C-aryl furanoside as a conformationally constrained CHIR-090 analogue

The UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine deacetylase (LpxC) is a promising target for the development of novel antibiotic substances against multidrug-resistant Gram-negative bacteria.The C-aryl glycoside 3 was designed as conformationally constrained analogue of the potent LpxC-inhibitor CHIR-090.The chiral pool synthesis of 3 started with d-mannose. The C-aryl glycoside 8 was synthesized stereoselectively by nucleophilic attack of 4-iodine-substituted phenyllithium and subsequent reduction with Et3SiH. The ester 10 was obtained in a one-pot diol cleavage, CrO3 oxidation, and esterification. A Sonogashira reaction of the aryl iodide 11 led to the alkyne 17 which was transformed with H2NOH into the hydroxamic acid 3.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We designed a conformationally constrained CHIR-090 analogue. ► A hydroxamic acid possessing a C-glycosidic scaffold was prepared in a convergent synthesis. ► A chiral pool synthesis was established giving access to a novel class of LpxC inhibitors.