title: Design and stereoselective synthesis of a C-aryl furanoside as a conformationally constrained CHIR-090 analogue.
abstract: 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 Et(3)SiH. The ester 10 was obtained in a one-pot diol cleavage, CrO(3) oxidation, and esterification. A Sonogashira reaction of the aryl iodide 11 led to the alkyne 17 which was transformed with H(2)NOH into the hydroxamic acid 3.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Münster, Germany.
authors.forename: Alberto
authors.initials: A
authors.lastname: Oddo
authors.forename: Ralph
authors.initials: R
authors.lastname: Holl
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D002236:Carbohydrate Conformation; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D006027:Glycosides / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D006877:Hydroxamic Acids / Q000737:chemistry*; D013237:Stereoisomerism; D013379:Substrate Specificity; D013912:Threonine / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: C525369:CHIR 090; D004791:Enzyme Inhibitors; D006027:Glycosides; D006877:Hydroxamic Acids; D013912:Threonine; D000581:Amidohydrolases; C097307:UDP-3-O-acyl-N-acetylglucosamine deacetylase