New Class of Tetracyclines Made Tetracycloxide gives 6-demethyltetracycline by animation, methylation, and C-4 epimerization
Dr. Leon M. Stock Inter- and intramolecular selectivity
The ratio of the logarithms for para and meta partial rate factors is constant for catalytic chlorination. These results are similar to the pattern of relative reactivity found for other reactions of toluene, Dr. Stock says.
Such constancy indicates the interdependence of intermolecular and intramolecular selectivity. In reactions such as:
A new class of tetracyclines called "tetracycloxides" has been synthesized by Dr. Robert C. Esse, James A. Lowery, Dr. Richard Tamorria, and Dr. George M. Sieger of Lederle Laboratories Division of American Cyanamid [/. Am. Chem. Soc, 86, 3874 (1964)]. Treatment of 6-demethyltetracycline (6-DMTC) with various oxidizing agents, including a positive halogen source, results in the formation of 4-dedimethylamino-4-oxo-6-demethyltetr acy cline-4,6-hemiketal (4hydroxytetracycloxide). From this compound, the Lederle group has resynthesized 6-DMTC. More important, the tetracycloxides can be used as intermediates in synthesizing new tetracyclines. Thus the tetracycloxide intermediates provide a
rare opportunity for synthetic modification of the tetracycline antibiotics. A research team at Chas. Pfizer & Co. (Dr. Robert K. Blackwood and Dr. Charles R. Stephens) has also recently obtained tetracycloxide compounds [J. Am. Chem. Soc, 86, 2736 (1964)]. The Pfizer team starts with tetracycline rather than 6-DMTC, and obtains 4oxo - 4 - dedimethylaminotetracycline - 4, 6-hemiketal by treating tetracycline hydrochloride with N-chlorosuccinimide in water. The Lederle scientists encountered the first tetracycloxide compound, 4hydroxytetracycloxide, when they attempted to chlorinate 6-demethyltetracycline with a combination of concentrated hydrochloric acid and sodium chlorate in acetic acid (South
Tetracycloxides Used to Modify Tetracyclines
6-Demethyltetracycline Cone. HCI, sodium chlorate in acetic acid
his studies lead Dr. Stock to believe that intermediates other than the benzonium ion are not kinetically significant; C&EN's earlier report of the symposium implied they are. 46
C&EN
SEPT.
28,
1964
4-Dedimethylamino-4-oxo-6-demethyltetracycline4, 6-hemiketal (4-Hydroxytetracycloxide)
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Esso C & EN
47
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ALUS48
C&EN SEPT. 28, 1964
CHALMERS
African Patent Journal, April 15, 1964). The Lederle group resynthesized 6DMTC from 4-hydroxytetracycloxide in three steps: reductive amination with methylamine; reductive methylation with formaldehyde; and C-4 epimerization. Derivatives. By using ammonia or a simple aliphatic primary amine (other than methylamine) in the reductive amination step, chemists at Lederle produce several derivatives. For example, if 4-hydroxytetracycloxide is animated with ammonia, the resulting compound is 4-dedimethylamino-4-amino-6-demethyltetracycline. With n-butylamine the derivative is 4 - dedimethylamino-4-n-butylamino-6demethyltetracycline. They used 10% palladium-on-carbon as catalyst for these reactions. The reactions were carried out at room temperature at 50 p.s.i.g. or less. These derivatives have mostly the epi stereochemical configuration at C-4. This is opposite to the "natural" configuration found in biologically active compounds in fermentation broths. One piece of evidence for the 4-epi configuration is an ultraviolet absorption maximum at about 255 millimicrons. This absorption is characteristic of the A ring UV chromophore of 4-epi-tetracyclines. Another indication of the epi configuration results from a reductive methylation reaction. When one of the tetracycline derivatives, 4 - dedimethylamino-4-methylamino-6demethyltetracycline, is subjected to reductive methylation, the chief product is 4-epi-6-demethyltetracycline. Properties. Some of the synthesized tetracycline derivatives contain components which have properties similar to the "natural" C-4 epimer. For example, column chromatography of 4-dedimethylamino-4-methylami n o - 6 demethyltetracycline (prepared by the Lederle group) yields a minor component which has a UV spectrum and relative polarity similar to that of the natural epimer. The component shows increased biological activity (sevenfold) expected from the C-4 epimer found in fermentation broths. The 4-dialkylamino analogs, in contrast to the N-demethyl analogs, can be epimerized to the natural configuration. The epimers show much of the antimicrobial activity of the parent tetracycline. In general, as the C-4 substituent increases in bulkiness, the biological activity of the tetracycline compounds decreases.
