THE AMINOGLYCOSIDE ANTIBIOTICS: IV SYNTHESIS OF AMINODEOXY ANALOGS OF NEAMINE

• Published in: Journal of antibiotics 1980, Vol.33(4), pp.383-392
• Main Authors: SITRIN, ROBERT D., PFEIFFER, FRANCIS R., ROSENBLOOM, JOANNE P., COOPER, DAVID J., SCHMIDT, STANLEY J., PETERSON, DAVID, WELLMAN, GEORGE, HOOVER, J. R. E., WEISBACH, JERRY A.
• Format: Article
• Language: English
• ISSN: 0021-8820; 1881-1469
• DOI: 10.7164/antibiotics.33.383

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-dideoxy-2, 6-bis(methoxycarbonylamino)-α-D-glucopyranosyl]-2-deoxystreptamine (5) is described. Treatment of this epoxide with sodium azide, followed by reduction and acetylation, yielded the protected 4'-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 and reaction 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 at its 4' position was also prepared by azide displacement of an appropriately 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.