title: Synthesis of a novel carbocyclic analog of bredinin.
abstract: The natural nucleoside antibiotic, bredinin, exhibits antiviral and other biological activities. While various nucleosides related to bredinin have been synthesized, its carbocyclic analog has remained unknown. Synthesis of this heretofore unknown analog of bredinin is described. The key precursor, (3aS,4R,6R,6aR)-6-((methoxy-methoxy)methyl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-amine (5), was prepared from the commercially available compound, (1R,4S)-2-azabicyclo[2.2.1] hept-5-en-3-one (4). Our initial approach used intermediate 6, derived in three transformations from 5, for the key photolytic step to produce the desired ring-opened precursor to the target compound. This photochemical transformation was unsuccessful. However, an appropriately protected and related precursor was synthesized from 5 through the following side-chain functional group transformations: elaboration of the amino group through malonyl ester formation, oximation at the central carbon, conversion of ester to amide and catalytic reduction of the oxime group. This precursor, on treatment with triethylorthoformate and catalytic acetic acid in ethanol, underwent cyclization to produce the desired 4-carbamoyl-imidazolium-5-olate ring. Deprotection of the latter product proceeded smoothly to give the carbocyclic analog of bredinin. This target molecule exhibits antiviral activity, albeit low, against a number of RNA viruses. Further biological evaluations are in progress.
authors.affiliation: Center for Drug Discovery and College of Pharmacy, University of Georgia, Athens, GA 30602, USA. vnair@rx.uga.edu.
authors.forename: Vasu
authors.initials: V
authors.lastname: Nair
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006477:Arenaviruses, New World / Q000187:drug effects; D003500:Cyclization; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects; D012296:Rift Valley fever virus / Q000187:drug effects; D014902:West Nile virus / Q000187:drug effects
chemical_list: C000592451:1-((1R,2S,3R,4R)-2,3-dihydroxy-4-(hydroxymethyl)cyclopentyl)-5-hydroxy-1H-imidazole-4carboxamide; D000998:Antiviral Agents; D003517:Cyclopentanes; D007093:Imidazoles
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