The aminoglycoside antibiotics.IV. Synthesis of aminodeoxy analogs of neamine.
An efficient synthesis of the key 3',4'-galacto epoxide intermediate 4 obtained from the known 5,6-O,O'-cyclohexylidene-N,N'-bis-(methoxycarbonyl)-4-O-[2,6-bis(methoxycarbony lamino)-alpha-D-glucopyranosyl]-2-deoxystreptamine (5) is described. Treatment of this epoxide with sodium azide, followed by reduction and acetylation, yielded the protected4'-amino-4'-deoxyneamine 18 (3',4'-diequatorial), whereas treatment with ammonia followed by acetylation yielded the protected 3'-amino-3'-deoxyneamine analog 19 with a diaxial configuration of its 3' and 4' positions. Reaction of the previously described protected 3',4'-allo epoxide 3 with sodium azide yielded separable mixtures of the protected 3'-amino-3'-deoxyneamine 14 and the protected diaxial 4'-amino-4'-deoxyneamine isomer 13, the ratios of products depending on the solvent temperature. Structural assignments for 13, 14, 18 and 19 were based on their PMR spectra. An additional 4'-amino-4'-deoxyneamine analog (24) with an axial configuration as its 4' position was also prepared by azide displacement of an approximately protected 4'-methanesulfonyl neamine intermediate 10. The five protected isomers were deblocked to yield a series of aminodeoxyneamine analogs (15, 16, 20, 21 and 25), all of which were less active in vitro than neamine against a group of Gram-positive and Gram-negative bacteria.
D001419:Bacteria / Q000187:drug effects; D004352:Drug Resistance, Microbial; D008722:Methods; D008968:Molecular Conformation; D009355:Neomycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship
D009355:Neomycin