Compounds 350-353

352, and 353) incorporating a ring-expanded seven-membered ring sugar (e.g., 351). The 3'-(S) isomer of 350 gave only the corresponding epoxide 352 [181].

A synthesis of spectinomycin together with the preparation of its 5'-«-butyl analog (replacement of the methyl group with «-butyl group) has been described. The 5'-«-butyl derivative (trospectomycin or 6'-«-propylspectinomycin) showed potent antibacterial activity and is the only aminocyclitol antibiotic that is active against anaerobic bacteria [182].

F. Striptidine-Containing Aminoglycosides: Streptomycins

Tsuchiya, Umezawa, and their colleagues have described the synthesis of the 3"-deoxydihydrostreptomycin 355 by Barton deoxygenation of the 3"-O-imidazolylthio-carbonyl derivative with tributyltin hydride [183], 6-deoxydihydrostreptamin 356 by displacement of the tosyloxy group of a 6-O-tosyl derivative with chloride followed by hydrogenolysis with liquid ammonia [184], and 3"-epi-dihydrostreptamycin 357 by epimerization of the 3'-hydroxyl group via the jV,O-carbonylallopyranoside intermediate 358 (part structure) [185]. The 3"-deoxy analog 355 exhibited remarkable activity against most resistant and sensitive bacteria, except P. aerugi«osa. The 6-deoxy derivative 356 showed less activity than dihydrostreptomycin, and the 3"-epi analog 357 was as active as the 3"-deoxy derivative 355 [186] (compounds 354-

Methylation of a selectively protected derivative with diazomethane in the presence of tin(II) chloride has been used to prepare 5-O- and 6-O-methyldihydrostrep-tomycin. However, these antibiotics were only slightly active, indicating the importance of C5 and the hydroxyl groups at positions 5 and 6 for binding to the bacterial ribosome [187].

A series of dihydrostreptomycin analogs modified at the guanidino groups was synthesized. Among these, an analog with a methyl group in the guanidine at position 1 was nearly as active as dihydrostreptomycin, but all analogs having a substituted guanidino group at position 3 were devoid of activity [188].

Photosensitive derivatives of streptomycin (nitroguaiacol derivatives) have also been prepared by modification of the streptose unit, to study the mode of action of the antibiotic [189].

G. Monoaminocyclitol-Containing Aminoglycosides: Validoxylamines and Validomycins

In extensive work, Ogawa and colleagues have used glycosylation methods to prepare monoaminocyclitol-containing aminoglycoside antibiotics and their analogs. For

Compounds 354-358

instance, condensation of dl-validamine with a bromocyclenitol derivative furnished stereoisomers of validoxylamine A [190], and dl-validoxylamines A and B were prepared from condensation of the epoxycyclohexane 359 with the valienamine derivative 360 under thermal conditions [191,192]. Likewise, racemic stereo- and regio-isomers of validoxylamine A were prepared [193], and ^-glycosylation of validoxylamine A (361) with an a-d-glucopyranosyl chloride derivative led to the formal synthesis of validamycin A (365) [194] (compounds 359-366 ).

359 360

359 360

Validoxylamin A 361 R = H Validoxylamin B 362 R = OH

Validoxylamin A 361 R = H Validoxylamin B 362 R = OH

Validamycin A 365 R1 = H, R2 = OH 366 R1 = OH, R2 = H

Compounds 359-366 (Part A)

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