Semisynthetic aminoglycoside antibiotics. II. Synthesis of analogues of paromomycin modified in the glucosamine moiety.

Sir: The accomplishment of an efficient method for obtaining the previously unknown 1,3,2"',6"'tetra-N-acetylparomomycin (1) and the subsequent preparation of the pseudotrisaccharide 5-0[3-0(2,6-diami no-2,6-dideoxy-f-L-idopyranosyl)-/3-L-ribo-furanosyl]-2-deoxystreptamine(5), as described in the preceding papery, by nitrous acid deamination, suggested a route for providing a useful intermediate for the synthesis of novel aminoglycoside antibiotics related to paromomycin and neomycin and modified in the glucosamine moiety. In order to investigate the structure-activity requirements for the glycoside unit linked to the C-4 hydroxy group of 2-deoxvstreptamine and to obtain new analogues, we have undertaken the preparation of a selectively protected derivative of the pseudotrisaccharide 5 derived from paromomycin and lacking the glucosamine moiety. Reaction of 1,3,2"',6"'-tetra-N-acetylparomomycin (1)1) with benzyloxycarbonyl chloride gave the corresponding 2'-N-benzyloxycarbonyl derivative (2) (m.p. 198"200'C; [a]D +57°, MeOH), that was O-acetylated to give the fully acylated compound 3 (m.p. 269-271°C; [Lx],, + 56°, MeOH). Hydrogenolysis of the benzyloxycarbonyl group in acidic methanol on 10% palladium-carbon afforded 1,3,2"',6"'-tetra-N-acetyl-octa-O-acetylparomomycin (4) as the hydrochloride (nz.p. 200205°C; [a]D +62°, MeOH). Nitrous acid deamination of 4 gave a mixture containing two main products which were separated by column chromatography on silica gel. The less polar component was identified as 5-(acetoxymethyl)-2-furaldehyde after comparison with an authentic sample prepared by deamination of 1,3,4,6-tetraO-acetyl-2-amino-2deoxy-a-n-glucopyranose hydrochloride> . The major product (m.p. 157-160°C; [a]D +17', CHC13), obtained in an overall yield of 50%, was identified as 6-O-acetyl-1,3-di-N-acetyl-5-O[2, 5-di-O-acetyl-3-O-(2, 6d iacetamido 3, 4di -0acetyl-2, 6-dideoxy-/3-L-idopyranosyl)-/-D-ribofuranosyl]-2-deoxystreptamine. Since no analogues of paromomycin have been found to contain the 6-amino-6-deoxy-a-D-glycopyranosyl unit linked to the 4-position of the 2-deoxystreptamine ring, it seemed worthwhile to prepare such analogues from compound 6. For the glycosidation of compound 6, we applied the LEMIEUx-NAGABHUSHAN reaction which has been reported to give a-glycosides3> and which had been successfully used for the synthesis of kanamycin analogues". As an example of the general procedure, the synthesis of 9 is reported.