Oh

= H, R2 = OH = H, R2 = NH2 H = R2 = H OH, R2 = H NH2, R2 = H

Compounds 181-185

moniae, and E. coli, but showed a marked decrease in activity against P. aeruginosa [93].

Two other analogs of kanamycin A including 3',4'-dideoxy and 4'-deoxy derivatives were synthesized by Yoneta and colleagues [94]. These compounds were synthesized from the 3',4'-epoxy intermediate 186, which was derived from treatment of its 4'-0-mesylated precursor with sodium methoxide in methanol. Treatment of 186 with sodium iodide in the presence of sodium acetate and acetic acid afforded the iodohydin 187, which after tosylation at 3'-position was converted to the 3'-ene derivative 188 under thermal conditions. Removal of the protecting groups of the olefin 188, followed by catalytic hydrogenation, gave the 3',4'-dideoxykanamycin A. Similarly catalytic hydrogenation of the iodohydrin 187 followed by treatment with methanolic sodium methoxide and trifluoroacetic acid afforded the 4'-deoxy-kanamycin A analog (compounds 186-188 ).

An attempt to make 3',4'-dideoxy analogs of kanamycin A and B by mutational biosynthesis in the presence of gentamicin-producing Micromonospora organisms

yielded combimicins (189), a mixture of aminoglycosides. These compounds are 3',4'-dideoxy derivatives of 4"-C-methyl and 3"-jV-methyl kanamycins and are structurally related to gentamicin C1a (190) (compounds 189-190). Combimicins have strong antibacterial activity against gram-negative and gram-positive bacteria, and combimicin B2 (R1 = NH2, R2 = H) has shown less ototoxicity than the gentamicin complex [95].

3',4'-Dideoxykanamycin B (dibekacin) 194 was synthesized by Matsuno and coworkers [96] and exhibited good antibacterial activity against both sensitive and resistant bacteria, including P. aeruginosa. The 4",6"-O-cyclohexylidene kanamycin B derivative 191 was employed in this synthesis. Treatment of this compound with benzylsulfonyl chloride in pyridine afforded the derivative 192, which was subjected to sodium iodide in DMF to furnish the 3',4'-unsaturated derivative 193. Cyclo-hexylidene deprotection with aqueous acetic acid (80%) followed by reductive de-sulfonylation of benzylsulfonyl groups under the Birch condition and catalytic hydrogenation of the double bond gave the 3',4'-dideoxykanamycin B (194) in high yield. A multistep synthesis of 194 also was reported by Yoshikawa et al. [97], who used d-glucosamine to construct rings I and II, as well as d-glucose to assemble the idose moiety (ring III) of the antibiotic (compounds 191-194).

Amino groups play an important role in antibacterial activity of aminoglycoside antibiotics. To probe this role, 3',4'-dideoxykanamycin B (dibekacin: 194) was used to prepare hexa- and heptadeoxy derivatives (5,2',3',4',4",6" and 5,2',3',4',2",4",6") of kanamycin A (4) and amikacin (2). The antibacterial activity data profile of these antibiotics revealed that the amino groups are essential for antibacterial activity, and that the 2"-hydroxy group and 1-jV-(S)-4-amino-2-hydroxybutanoyl (AHB) moiety markedly increase the activity of the antibiotic [98].

3',4',2"-Trideoxy- and 2"-deoxykanamycin B have also been synthesized, the former being more active than kanamycin B against resistant strains of P. aeruginosa [99]. Another report, by Albert and colleagues [100], describes the synthesis of 4"-deoxykanamycin A together with 4"-epi-chloro-, 4"-epi-bromo-, and 4"-epi-iodokan-amycin A.

(b) epi-Kanamycins. The 4'-deoxy-5'-epi derivative of kanamycin B (197) was made from its 1,4-epoxy intermediate 195 using the sequences of reactions outlined

NHR2

NHR2

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