Erythromycins 9-oxime

One of the most famous examples of intramolecular attack of oxygen on the nitriUnm ion intermediate was observed in the Beckmann rearrangement of Erythromycin oxime derivatives and was used in the discovery and synthesis of the commercial macrolide antibiotic Azithromycin 464. In fact, the Beckmann rearrangement of Erythromycin A 9( )-oxime 460 produced only small amounts (5%) of the expected amide 463, along with two isomeric imino ethers (461 and 462) in a fair yield (38 and 43%) (equation 198). 

Lazarevski, T., Radobolja, G., and Djoklc, S. (1978). Erythromycin VI Kinetics of acid-catalyzed hydrolysis of erythromycin oxime and erythromycylamine. J. Pham. Sci. 67, 1031-1033. 

Other macrohdes have been prepared which represent hybrids of stmctures within the 14-membered family, within the 16-membered family, or between the two families. These hybrids have been made by chemical, bioconversion, or genetic manipulations. The 9-0-[(2-methoxyethoxy)methyl]oxime of tylosin (Table 7) was synthesized, using the oxime found in roxithromycin (33) (369). 3-0-Cladinosyl derivatives of 16-membered macrohdes were synthesized in which the neutral sugar of erythromycin (Table 3) was attached to tylosin derivatives at thek 3-hydroxyl group, analogous to its position in erythromycin... 

The 2-chlorobenzyl group has been used in the protection of an oxime during the modification of erythromycin K ... 

In contrast, the isomeric Erythromycin A 9(Z)-oxime 460 produced an isomeric nitril-ium ion intermediate 465 as the result of different oxime geomehy (equation 199). In comparison with the products obtained from the ii-oxime, isomeric lactam 468 and imino ethers (466 and 467) were isolated. Reaction conditions (including solvent polarity and the concentration of the reaction mixture) proved to have a strong influence on the yields of the various products of the rearrangement. 

Nachstehend als ein Beispiel aus der Naturstoff-Chemie die zweite Stufe (Reduktion) der Umwandlung von Erythromycin-B in Erythromycylamin B iiber das Oxim. 

Benzoxazoles have been prepared by intramolecular reaction of a phenolic —OH groiq) with a Beckmann intermediate (equation 30). A cyclic imidate was isolated in high yield from tosylation and in situ Beckmann reaction of the erythromycin-derived oxime (4[Pg.698]

Intramolecular participation of a neighboring hydroxy group is observed in the rearrangement of erythromycin A oxime (24) with p-toluenesulfonyl chloride and sodium hydrogencarbonate in acetone-water (equation 12). Interestingly, with the same reagent in pyridine-ether only the normal rearrangement product (25) is formed. 

The symmetrical attachment of the local anesthetic procaine to poly(ethylene glycol) increases the duration of action and probably improves water-solubility. The hypnotic etodroxizine bears a three-ethylene-oxy-unit chain but is nevertheless used as a dimaleate. In roxithromycin the oxygenated side chain is attached to the oxygen atom of the oxime of the antibiotic erythromycin. ... 

Several structural modifications of the C-9 ketone of erythromycin have been explored oximes and hydrazones are less prone to intramolecular cydization, but they often have less antibiotic activity than erythromycin (140). Synthesis of more complex oxime derivatives resulted in the development of roxithromycin, the 9-[0-(2-methoxyethoxy)methyl]oxime (33) (141). Reduction of the oximes and hydrazones produced 9(S)-erythromycylamine (34) as the principal product, with minor amounts of the 9(R)-isomer (140) however, clinical studies showed that 9(5)-erythromycyclamine and its N-benzylidene derivative were poody absorbed in humans (142). Evaluation of more complex oxazine derivatives of erythromycylamine led to dirithromycin, the 2-(2-methoxyethoxy)ethylidene oxazine derivative (35) (143). A third route to modification of the ketone utilized a Beckmann rearrangement of the 9-oxime to expand the 14-membered ring to a 15-membered intermediate, which was subsequently reduced and AT-methylated to yield azithromycin (36) (144,145). The term azalide was proposed to denote these 15-membered azalactones (10,145). 

Chantot, J. F., Case, J. C., Gouin D Ambrieres, S., and Lutz, A. (1983). New ether oxime derivatives of erythromycin A Preparation and antibacterial activities. Presented at 23rd Intersci. Conf. Antimicrob. Agents Chemother. (Las Vegas, NV). Abstr. No. 447. 

The antibacterial spectrum of these macrolides is broader. For example, the clinical modification at C6 [e.g., O-methylation (clarithromycin)] or at C9 [e.g., some 9-ether oxime derivatives (roxithromycin and dirithromycin)] stabilizes 14-membered lactone rings in acidic media, even when the modified drugs have been orally administered. Drugs with an expanded erythromycin A-lactone ring (e.g., azithromycin) are also more stable in acidic media and display better antigram-negative activity than does erythromycin A. 

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