Mono O-demethylation

Hwu and co-workers reported selective cleavage of a benzyl (Bn) ether with lithium di-isopropylamide (LDA) in the presence of a methoxy group however, by using sodium bis(trimethylsilyl)amide [NaN(SiMe3)2], the dimethoxybenzene undergoes selectively mono-O-demethylation (Scheme 1.21). 

The first atropo-enantioselective total synthesis of a phenylanthraquinone natural product (Af)-knipholone was reported by G. Bringmann et al. In the late stages of the synthesis, an acetyl group had to be introduced under mild conditions. The advanced substituted anthraquinone intermediate was first deprotected with TiCU and then acylated with AC2O in the presence of TiCU. A spontaneous Fries-rearrangement took place to afford the ortho-acylated product in high yield. The natural product was obtained by a mono O-demethylation at C6 with AIBrs. 

Stresser, D.M. and D. Kupfer (1997). Catalytic characteristics of CYP3A4 Requirement for a phenolic function in ortAo-hydroxylation of estradiol and mono-O-demethylated methoxy-chlor. Biochemistry 36, 2203-2210. 

The metabolic pathways including stereochemistry of methoxychlor metabolism by liver slices obtained in this study are proposed in Figure 6. When the metabolic pathways are expressed in 2-dimentional molecular structures, mouse and quail show quite similar patterns, since the oxidative mono-O-demethylation and subsequent glucuronidation are the main metabolic pathways for both species. However, once the stereological structures are taken into account, the metabolic pathways in these two species turn out to be different, because of the enantioselectivity of the mono-demethylation reactions. Indeed, when the stereological structures are taken into consideration, it is shown that the metabolic pathways of methoxychlor from the four test animal species are all... 

Furthermore, boron trichloride can selectively O-demethylate a methoxyl group adjacent to a phenolic function to afford the corresponding catechol. In this fashion, the mono-(5-methyl derivative of boldine, i.e. (31), was converted into the unstable catechol (32), whose methylenation using methylene chloride in DMSO containing sodium hydroxide provided dicentrine (33). ... 

The metabolism of maduramycin ammonium alpha following oral dosing of chickens, turkeys and rats showed that maduramycin-a was the main compound excreted (26%) and the other major metabolites were madmamydn-alpha, maduramycin glucmonide, di-O-desmethyl-maduramycin and mono-O-desmethyl-maduramycin. In the rat, the metabolites identified in the liver were maduramycin-alpha and an O-demethylated metabolite. After eessation of treatment, levels of residues rapidly decreased in all tissues investigated. 

Over the last decades, large amounts of different man-made chemicals which can act as weak estrogens have been released into the terrestrial and aquatic environment and are distributed world-wide. Classical environmental estrogens are pesticides, such as o,p -DDT, and its metabohtes o,p -DDE and o,p -DDD, methoxychlor and its metabolites, chlordecone (Kepone ), dieldrin, Toxaphene, and endosulfan [126, 135, 136]. It is also known that many chemicals with very weak or no measurable estrogenic activity can be metabolized in organisms especially to hydroxylated compounds which may have much more estrogenic potency than the parent compound. Examples are methoxychlor and its mono- and di-demethylated derivatives [126,127] as well as the alkylphenol... 

After consumption of p-methoxyamphetamine (PMA), more than 80% of the amount of substance taken is excreted within a day via the urine, up to 15% unchanged, >25% in the form of the free 4-hydroxyamphetamine, and ca. 50% as conjugated 4-hydroxyamphetamine. The remainder, in analogy to amphetamine, is further metabolized [44]. In analogy to PMA, TMA undergoes a demethylation to form mono- and di-O-desmethyl derivatives. In methoxyamphetamines, two methoxy groups are located in the para position (DOB, DOM), so that demethylation to hydroquinone is also possible [51]. 

Using methyl ethers of di- and tri-hydric phenols, selective mono-demethylation occurs, e.g. resorcinol monomethyl ether is obtained from resorcinol dimethyl ether and sodium ethanethiolate in DMF. An exception is pyrogallol trimethyl ether which afforded pyrogaUol 1-monomethyl ether in high yield. Methylene ethers, such as methylenedioxybenzene, can be quantitatively converted to catechol, via the intermediate formation of ethyl o-hydroxyphenoxymethyl sulphide . 

Figure 3 shows the ratio of (mono-OH-MXQ/(mono- -I- bis-OH-MXC), where the values of mono- and bis- demethylated metabolites also include the amounts of their corresponding conjugates. After reaction in each animal preparation, more than 80% of demethylated metabolites were detected as a mono-demethylated form for mouse and quail, about 50% for trout, and less than 5 % for rat. The results indicate that O-demethylase enzyme(s) in rat can easily remove both methyl groups from the parent molecule, but only one methyl group can be preferably demethylated by the enzyme(s) in mouse and quail. Rainbow trout produces almost equal amounts of mono- and bis- demethylated metabolites. These facts suggest that there are species differences in the manner of phase I oxidative demethylation, and such differences are probably due to the... 

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