Labilization of Ester Bonds in Aminocyclitol Derivatives. II. Polyacetates of Deoxystreptamine<sup>1</sup>

Daly, J.M.; Durant, R.C.; Friess, S.L.; Holland, Gerald F.; Kny, H.; Witkop, B.

doi:10.1021/ja01507a033

J. Am. Chem. Soc.

1960

DOI: 10.1021/ja01507a033

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Labilization of Ester Bonds in Aminocyclitol Derivatives. II. Polyacetates of Deoxystreptamine¹

J.M. Daly¹,

R.C. Durant²,

S.L. Friess³

et al.

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1961

1969

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Cited by 13 publications

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“…Similar 0-desacetylation has been reported for N,N'-tetramethyl-tri-0-acetyldeoxystreptamine [6]. For this reason a modified method for the isolation and the separation of the free bases of u-and 8-methyl dihydrostreptobiosaminide (X and XI) was worked out.…”

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confidence: 64%

N‐Methyldihydrostreptomycin Synthesis, Structure, and Antibacterial Activity

Vanderhaeghe

Totté

Claes

1968

Bulletin des Soc Chimique

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Reductive methylation of dihydrostreptomycin yielded a new derivative, N-methyldihydrostreptomycin. By this reaction the N-methyl-L-glucosamine fragment of dihydrostreptomycin is converted into N-dimethyl-L-glucosamine. The structure of this derivative is confirmed by degradation and NMR spectroscopy. Methylation of the monomethylamino function of dihydrostreptomycin resulted in a complete loss of antibacterial activity.Since the isolation of streptomycin (I) numerous derivatives of this antibiotic have been reported. These derivatives can be divided into different types according to the functional groups of the streptomycin molecule which are subjected to chemical modification. These functional groups are: the guanidino groups, the free carbonyl group on the streptose fragment, and the monomethylamino function of the L-glucosamine fragment. Only three modifications of the monomethylamino function were described before 1965: the N-acetylstreptomycin (II) [I], the N-acetyldihydrostreptomycin (1IJ) [ 11, and the carbobenzyloxydihydrostreptomycin (IV) [2]. A low antibacterial activity (+ 15%) was observed for (II) and (III). The carbobenzyloxy derivative (IV) was devoid of antibiotic activity. The low biological activity of these derivatives could be related to the loss of the basic character of the monomethylamino function.In this work the synthesis of a new derivative of dihydrostreptomycin (V), N-methyldihydrostreptomycin (VI), is described. The modification consists in the introduction of a second methyl group into the monomethylamino function of the L-glucosamine fragment. Although N-methylation has no drastic effect on the basic character of the amino nitrogen, N-methyldihydrostreptomycin was devoid of biological activity when assayed on Staphylococcus aureus and Escherichia coli.The new derivative (VI) was obtained by reductive methylation of dihydrostreptomycin (V). The original Eschweiler-Clarke procedure [3] could not be used for the synthesis of V1, since one of the glycosidic linkages would not resist treatment with concentrated formic acid. For this reason an aqueous solution of dihydrostreptomycin sulfate (V) containing formaldehyde was hydrogenated in the presence of platinum. After the reaction, VI was adsorbed immediately on a weakly acidic ion-exchange column, and formaldehyde was removed by washing the column with water. N-methyldihydrostreptomycin (VI) was eluted from the column with acid and was obtained as trihydrochloride in an 82% yield.Since a complete absence of biological activity was rather surprising for a N-methylated dihydrostreptomycin (VI), one might expect that functional groups

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supporting

confidence: 64%

N‐Methyldihydrostreptomycin Synthesis, Structure, and Antibacterial Activity

Vanderhaeghe

Totté

Claes

1968

Bulletin des Soc Chimique

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Preparation of Octa‐n‐Methyl‐ and Tetra‐n‐Methylkanamycin

Claes

Vanderhaeghe

1969

Bulletin des Soc Chimique

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Two N-methylated derivatives of kanamycin A were synthesized. The first compound, octa-N-methylkanamycin, was prepared by reductive methylation of kanamycin A . The second, tetra-N-methylkanamycin, was obtained by catalytic debenzylation of tetra-N-benzyl-tetra-N-methylkananiycin. Both derivatives were devoid of antibacterial activity.Samuel et NI. [I, 21 reported that the oral administration of kanamycin and nconiycin reduces the serum cholesterol level. Studies in this laboratory have shown that this activity is not due to the antibacterial propertics of these antibiotics but is related to the basic character of these compounds. It could be shown that neomycin had a cholesterol-lowering activity in germfree chicks [3] and that N-methylated neomycin, which was devoid of antibiotic activity, reduced the serum cholesterol level in animals and humans [4-61. In this study various N-alkyl derivatives of basic antibiotics were prepared [7]. The present publication deals with the synthesis of octa-N-methylkanamycin (I) and tetra-N-methylkanamycin (11) from kanainycin (1 I I).It has been shown that during the fermentation of Streptonzyces karzo/iiycetici,s a mixture of kanamyciii A , B and C is produced [8]. In this publication kanamycin rcfcrs always to kanamycin A , because the commercial product contains only this component.The reductive methylation by the method of Eschweiler and Clark [9] has been used for the conversion of 2-deoxystreptamine (IV), one of the degradation products of kanamyciii. into its tetra-N-methyl derivative (V) [lo, 1 I]; however. this procedure was not applied to kanamycin since the glucosidic linkages would probably not resist treatment with a concentrated aqueous solution of formic acid. For this reason an aqueous solution of kananiycin sulfate, containing formaldehyde, was hydrogenated in the presence of platinum. The N-inethylated sulfate was converted into its free base by passage through a column of Dowex 2-X8 ion-exchange resin (OHform) and crystallized from ethanol. Octa-N-niethylkanamycin (I) free base was obtained in a 45.5 Yo yield. The structure of this compound is based upon the elenental analysis and the assay by the method of Wagner et nl. [12], which showed the absence of primary and secondary amino functions. Further evidence for the structure of I was obtained by NMR spectroscopy (a 6 H N-methyl singlet at 2.45 p.p.m. and an 18 H N-methyl singlet at 2.27 p.p.m.). by determination of the molecular rotation [MI,, which was almost identical with the value of the parent molecule, and by transformation into the tetra-methiodide (VI) by reaction of I with methyliodide.Octa-N-methylkanamycin (I) could also be obtained in a 52% yield, by carrying out the Eschweiler-Clarke procedure in practically anhydrous conditions. For this

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Konfiguration der bei Cyclisierung von 6‐Nitro‐D‐glucose und ‐L‐idose gebildeten Desoxynitroinosite und ihre Isomerisierungen mit Alkali

Lichtenthaler

1961

Chem. Ber.

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Die Cyclisierung der 6‐Desoxy‐6‐nitro‐Derivate von D‐Glucose und L‐Idose mit Bariumhydroxyd ergibt ein Gemisch von drei Desoxynitroinositen im ungefähren Verhältnis 3:1:2, die scyllo‐ („Nitrodesoxyinositol III”︁1), muco‐3‐(„Nitrodesoxyinositol II”︁1) und myo‐1‐Konfiguration besitzen. „Nitrodesoxyinositol I”︁1) ist ein Gemisch des scyllo‐ und myo‐1‐Isomeren. Die Zuordnung der Konfigurationen ergab sich Vergleich der durch Hydrierung erhaltenen Inosamine mit solchen bekannter Struktur und Verhältnis von axialen und äquatorialen Substituenten im Cyclohexanring, ermittelt aus Kernresonanzspektren. Penta‐O‐mesyl‐N‐acetyl‐scyllo‐inosamin ließ sich durch Behandeln mit Natriumacetat in 2‐Methoxy‐äthanol, wobei zwei Mesylgruppen unter Waldenscher Umkehr abgespalten werden, in epi‐Inosamin‐(3)‐Derivate überführen.

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Labilization of Ester Bonds in Aminocyclitol Derivatives. II. Polyacetates of Deoxystreptamine¹

Cited by 13 publications

References 0 publications

N‐Methyldihydrostreptomycin Synthesis, Structure, and Antibacterial Activity

N‐Methyldihydrostreptomycin Synthesis, Structure, and Antibacterial Activity

Preparation of Octa‐n‐Methyl‐ and Tetra‐n‐Methylkanamycin

Konfiguration der bei Cyclisierung von 6‐Nitro‐D‐glucose und ‐L‐idose gebildeten Desoxynitroinosite und ihre Isomerisierungen mit Alkali

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Labilization of Ester Bonds in Aminocyclitol Derivatives. II. Polyacetates of Deoxystreptamine1

Cited by 13 publications

References 0 publications

N‐Methyldihydrostreptomycin Synthesis, Structure, and Antibacterial Activity

N‐Methyldihydrostreptomycin Synthesis, Structure, and Antibacterial Activity

Preparation of Octa‐n‐Methyl‐ and Tetra‐n‐Methylkanamycin

Konfiguration der bei Cyclisierung von 6‐Nitro‐D‐glucose und ‐L‐idose gebildeten Desoxynitroinosite und ihre Isomerisierungen mit Alkali

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Labilization of Ester Bonds in Aminocyclitol Derivatives. II. Polyacetates of Deoxystreptamine¹