Ketones methoximes

Spencer, T.A. and C.W. Long. 1975. Regioselectivity in a-proton abstraction from ketone methoximes. Tetrahedron Lett 16 (45) 3889-3892. 

In studies on steroid ketone methoxime formation. Homing et al (1968b)... 

Homing, M.G., Moss, A.M. and Homing, E.C. (1968b), Formation and gas-liquid chromatographic behaviour of isomeric steroid ketone methoxime derivatives. Anal Biochem., 22,284. 

The 3-methoxime (74) provides a base-stable protecting group for A " -3-ketones. It is removed in low yield by conversion to the corresponding semicarbazone. 

This derivative is useful for determining the presence and number of keto groups as well as for protecting the ketone from enolization. Some diketones that polymerize readily, such as 2,3-butanedione. should be freshly distilled and the methoxime derivatives should be prepared. 

Molecular ion The MW of aliphatic ketones can be determined from its prominent molecular ion. In general, the intensity of the molecular ions of ketones is greater for C3-C8 than for CVC u. A molecular ion is usually observed for methoxime derivatives. 

All evidence presented here indicates that the methoxime-to-ketone reaction is enzymatic, but the nature of the reaction is unclear. Hydrolysis by an uncharacterized hydrolase, as postulated by the authors, is a valid assumption. However, one should not dismiss another possibility, namely oxidative O-demethylation to the oxime, followed by spontaneous oxime-to-ketone hydrolysis, and stereospecific reduction, as explained above. 

Leenheer et al. (1983) have recently shown that ketone functional groups can be determined by one of the following techniques (1) preparation of the methoxime followed by proton or C NMR spectroscopy of the derivative (2) reduction of the ketone carbonyl group with sodium borohydride followed by methylation of the resultant alcohol and NMR analysis of the methyl ethers. 

Figure 15.43. Sequential activation of oximes in the site- and stereospecific delivery of j3-adrenergic antagonists to the eye. The original oximes or methoximes (133) and the intermediate ketones (134) are inactive they are enzymatically converted into the active S-(-)-j3-adrenergic hlocker alcohols (135) in a site- and stereospecific manner.

A few bioconversions of erythromycin have been reported (149). Certain modifications of erythromycin at both its 9-ketone and 11-hydroxyl groups inhibited hydrolysis of the lactone ring by an esterase isolated from Escherichia coli which might be involved in bacterial resistance to macrolides (150). The 9-methoxime-11-[(2-dimethylaminoethyl)oxymethyl] derivative of erythromycin, ER 42859, showed good antibacterial activity and pharmacokinetics in animals, but it gave lower blood levels than erythromycin when administered to humans (151). Other 9,11-cydic derivatives of erythromycin have been synthesized (152,153). Series of 9-A/-alkyl derivatives of both 9(5)- and 9(R)-eiythromycylamine have been prepared which improved activity in vivo over erythromycin (154,155). 

Full details of the Ciba-Geigy route which originally led to ( )-PGEi methoxime have now been publi ed [1, p. 336 61]. A noteworthy development of this work was the protection of the 9-ketone as the phenylthiomethyl oxime. This grouping was resistant to the mild oxidative and reductive stages of the synthesis and was cleaved with mercury ion catalyas to the unsubstituted oxime and thence by nitrosation to the free ketone yielding ( )-PGEi. 

Reduction of the ketone 2 and dehydration of the resulting alcohol led, after deprotection and oxidation, to the ketone 12. Protection followed by P-ehmination gave the enone 13. Direct reductive amination of 13 failed, hut reduction of the methoxime was successful, giving, after acylation, the formamide 14. Reductive N-O bond cleavage followed by deprotection and isonitrile formation then set the stage for the planned intramolecular acylation to complete the synthesis of Welwitindolinone A Isonitrile 3. 

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