Hydroxy lation

Figure 2.11 y-Carboxylation of glutamate residues (Glu) yields y-carboxyglutamate (Gla), whereas (3-hydroxy lation of aspartate (Asp) yields (3-hydroxyaspartate (Hya) and (3-hydroxylation of asparagine (Asn) yields 3-hydroxyasparagine (Hyn)... 

In vitro studies have suggested that the oxidation of quinidine to 3-hydroxyquinidine is a specific marker reaction for CYP3A4 activity. In six healthy young men the pharmacokinetics of a single oral dose of quinidine 200 mg were studied before and during daily administration of itraconazole 100 mg (106). Itraconazole reduced quinidine total clearance, partial clearance by 3-hydroxy-lation, and partial clearance by A-oxidation by 61, 84, and 73% respectively. 

Ap-90, Tori, K., and Kondo, E., Steroids 4, 713 (1964). NMR method for determination of position of hydrojqrl groiq> introduced microbiological transformation. 15a-Hydrojqrlation from Helmlnthosporium signnoideum on Compound S. 15/3-Hydroxy-lation from Cercospora melonis on Compound S. la, 14a-Dihydroxylatlon from Curvularia lunata on Compound S. 6/S, Ha -Dihydroxylatlon by Cunninghamella echinulata on progesterone. 

FIGURE 27 5 Tyrosine is the biosynthetic precursor to a number of neurotransmit ters Each transformation IS enzyme catalyzed Hydroxy lation of the aromatic ring of tyrosine converts it to 3 4 dihyd roxyphenylalanine (l dopa) decarboxylation of which gives dopamine Hy droxylation of the benzylic carbon of dopamine con verts It to norepinephrine (noradrenaline) and methy lation of the ammo group of norepinephrine yields epi nephrine (adrenaline)... 

Dichloro-s-triazine and its 6-alkyl analogs are as easily hydrolyzed by water as trichloro-s-triazine and, on suspension in aqueous ammonia (25°, 16 hr), the first is diaminated in good yield. 2,4-Bistrichloromethyl-6-methyl- and -6-phenyl-s-triazines (321) require a special procedure for mono-alkoxylation (0-20°, 16 hr, alcoholic triethylamine) disubstitution occurs at reflux temperature (8 hr). Aqueous triethylamine (100°, 3 hr) causes complete hydroxy-lation of 2,4,6-tris-trichloromethyl-s-triazine which can be mono-substituted with ammonia, methylamine, or phenoxide ion at 20°. 

RI1.531 at 31° (Ref 3) prepd by the hydroxy lation of PE monoallyl ether followed by nitration of the pentahydroxy compd (Ref 3). Other phys and expl props are given in Ref 2 Refs 1) Beil 1, <2816) 2) Anon, SPIA M3a... 

Some insect pheromones are internal ketals. We have already mentioned multistriatin (pp T 2 and 99) and frontalin p 193). Brevicomin (22) is another example. Disconnection of the ketal gives (23) containing a 1,2-diol. Among other syntheses, hydroxy-lation of protected enone (24) by epoxidation and acid catalysed rearrangement gives brevicomin stereo-specifically,... 

RH above can represent a very wide variety of xenobi-otics, including drugs, carcinogens, pesticides, petroleum products, and pollutants (such as a mixture of PCBs). In addition, endogenous compounds, such as certain steroids, eicosanoids, fatty acids, and retinoids, are also substrates. The substrates are generally lipophilic and are rendered more hydrophilic by hydroxy-lation. 

In this particular instance, u) and m-l hydroxylation, which is then followed by further oxidation and chain degradation, are the principal reactions ( ) In the case of di-n-pro-pylnitrosamine both a- and 3-oxidation occur, with the latter being about 15% of the former (44) The a-hydroxy lation leads to the formation of the n-propyldiazonium ion (22), while the 3-hydroxylation results, at least in part, in oxidation to N-propyl-N-(2-oxopropyl)nitrosamine. Krdger and Bertrum (45) suggested that this product can be cleaved to methyl-... 

NPYR Rat Liver and lung microsomes and postmitochondrial supernatant a-hydroxylation but not p-hydroxy-lation in both tissues 13... 

The shikimate pathway is the major route in the biosynthesis of ubiquinone, menaquinone, phyloquinone, plastoquinone, and various colored naphthoquinones. The early steps of this process are common with the steps involved in the biosynthesis of phenols, flavonoids, and aromatic amino acids. Shikimic acid is formed in several steps from precursors of carbohydrate metabolism. The key intermediate in quinone biosynthesis via the shikimate pathway is the chorismate. In the case of ubiquinones, the chorismate is converted to para-hydoxybenzoate and then, depending on the organism, the process continues with prenylation, decarboxylation, three hydroxy-lations, and three methylation steps. - ... 

For polychlorinated biphenyls (PCBs), rate constants were highly dependent on the number of chlorine atoms, and calculated atmospheric lifetimes varied from 2 d for 3-chlorobiphenyl to 34 d for 236-25 pentachlorobiphenyl (Anderson and Hites 1996). It was estimated that loss by hydroxy-lation in the atmosphere was a primary process for the removal of PCBs from the environment. It was later shown that the products were chlorinated benzoic acids produced by initial reaction with a hydroxyl radical at the 1-position followed by transannular dioxygenation at the 2- and 5-positions followed by ring fission (Brubaker and Hites 1998). Reactions of hydroxyl radicals with polychlorinated dibenzo[l,4]dioxins and dibenzofurans also play an important role for their removal from the atmosphere (Brubaker and Hites 1997). The gas phase and the particulate phase are in equilibrium, and the results show that gas-phase reactions with hydroxyl radicals are important for the... 

Upon heating anthraquinone with fuming sulphuric acid at 160° for about 1 hour, the main product Is anthraquinone-p-sulphonic acid, which is isolated as the sparingly soluble sodium salt. The latter when heated imder pressure with sodium hydroxide solution and an oxidising agent (sodium or potassium chlorate) yields first the corresponding hydroxy compound further hydroxy-lation occurs in the a-position through oxidation by the chlorate and 1 2-di-hydroxyanthraquinone (alizarin) is formed. 

Grootveld, M. and Halliwell, B. (1986a). An aromatic hydroxy-lation assay for hydroxyl radicals utilising high performance liquid chromatography (HPLC). Use to investigate the effect... 

Roh, H. K., Dahl, M. L., Johansson, I. etal. (1996). Debrisoquine and S-mephenytoin hydroxy-lation phenotypes and genotypes in a Korean population. Pharmacogenetics, 6, 441-7. 

Catalysts of the Co(salen) family incorporating chiral centers on the ligand backbone are useful in asymmetric synthesis and the field has been reviewed.1377,1378 In two examples, the hydroxy-lation reaction (Equation (14)) involving (269) proceeds with 38% ee,1379 whereas the cyclo-propanation reaction with (271) (Equation (15)) proceeds with 75% ee and with 95 5 trans cis.1380 A Co(V) salen carbenoid intermediate has been suggested in these reactions. 

Inoue K, Yamazaki H, Imiya K, Akasaka S, Guengerich FP, Shimada T. Relationship between CYP2C9 and 2C19 genotypes and tolbutamide methyl hydroxy-lation and S-mephenytoin 4 -hydroxyla-tion activities in livers of Japanese and Caucasian populations. Pharmacogenetics 1997 7[2] 103—113. 

Implementation of the C5, C5 -hydroxy lation protocol as described in Scheme 7.19 above (71/72 to 73/74) provided further efficiencies. The C5,C5 -chlorination proceeded uneventfully, but the chloro to alkoxy interchange was difficult and required optimization of the reaction conditions. The catalyst system derived from Pd2dba3 and the X-phos(t-Bu) ligand proved to be effective in the coupling with KOH to provide the desired bisphenol. The resulting product was highly unstable and decomposed under a one-pot alkylation protocol. Isolation of the bisphenol under carefully controlled conditions followed by immediate benzylation (BnBr, NaH, DMF) furnished key intermediate 79 in 70 % yield. 

D. Dolphin Groves and his co-workers 9 have shown that ferrous perchlorate and hydrogen peroxide can carry out hydroxy-lations which bear close parallels to the P-450 mediated systems. 

Catalytic activity in benzene hydroxy lation (Table LIV), on the other hand, followed the total concentration of the various superoxo species, which increased in the order TS-1 (with anatase) < TS-1 (without anatase) < TS-1 (fluoride). The total concentration of the superoxo species was obtained from the integrated intensity of all the EPR signals representing superoxo species. This intensity in various solvents increases in the order acetone < methanol [Pg.156]

There are a few data in the literature to suggest that the hydrolysis of aliphatic nitriles occurs in mammals, but only as a minor or even undetectable pathway in competition with oxidative denitrilation. For example, benzyl cyanide (11.80, Fig. 11.12) undergoes cytochrome P450 catalyzed hydroxy-lation to mandelonitrile (11.81), from which cyanide and benzaldehyde are produced, the latter being oxidized to benzoic acid (11.83) [118]. However, a careful metabolic study of mandelonitrile has shown that, in the rat, this pathway accounts for ca. 90% and not 100% of the dose [122], Only ca. 10% of orally administered benzyl cyanide was converted to mandelic acid (11.82, Fig. 11.12) by hydrolysis of the CN group. 

To favor the coupling reaction, the competing side reaction of the radical cation with nucleophiles must be suppressed by the use of a medium of low nucleophilicity. The solvent of choice is dichloromethane. Especially in elec-troanalytic studies, neutral alumina is frequently added to suppress hydroxy-lation of the radical cation [162]. The reversible cyclic voltammetric behavior of radical cations is also enhanced in mixtures of methylene dichloride, triflu-oroacetic acid, and trifluoroacetic anhydride (TFAn) with TBABF4 as supporting electrolyte. With acetonitrile as solvent... 

One reaction characteristic of phase 1 metabolism is monooxygenase-catalysed hydroxy-lation at specific C—H bonds without chemical activation. Different enzymes show varying degrees of regio-, chemo-, and enantio-specificity, so the reaction is usually challenging for the synthetic chemist to reproduce once preparation of such a metabolite is required. It should be evident that biocatalysts with such capabilities would also be highly desirable as tools for chemical synthesis in general. 

Coriolin (689), a metabolite of the Basidiomycete Coriolus consors, has attracted widespread interest because of its unusual anti-tumor activity and highly functionalized triquinane structure. Accordingly, a number of syntheses of689 have appeared on the scene. One of the earliest, due to Tatsuta, et al., begins with epoxide 690, whose preparation had been earlier realized in connection with their work on hirsutine (see Scheme LXIII). Deoxygenation of 690, hydrolysis, and cis-hydroxy-lation provided keto triol 691 (Scheme LXXII) The derived acetonide was transformed via 692 into tetraol 693 which could be selectively acetylated and dehydrated on both flanks of the carbonyl group. Deacetylation of 694 followed by epoxidation completed the synthesis. 

Investigation of the in vitro metabolism of delavirdine is accomplished using mouse, rat, dog, monkey, rabbit, and human liver microsomes. The primary metabolite observed is the A-dealkylated delavirdine 26. Another primary metabohte observed is the hydroxy-lation of the pyridine ring at C-6 (compound 27). The primary metabolism is by CYP3A4 and also CYP2D6. Delavirdine reduces the activity of CYP3A4, thereby inhibiting its own metabolism. 

Snbsequent detailed kinetic stndies revealed that the reaction mechanism for the hydroxy-lation of arenes is mnch more complicated than that indicated above Furthermore, the active intermediate is likely an anion radical species formed upon interaction of two molecules of the vanadium peroxo complex. The sequence of the various steps is indicated in equations 17-24. The steps indicated in equations 17-21 refer to a radical chain which accounts for decomposition of the peroxo complex to form dioxygen, whereas the subsequent steps are those required for the functionalization of the substrate. 

These systems are also described as normal copper proteins due to their conventional ESR features. In the oxidized state, their color is light blue (almost undetectable) due to weak d-d transitions of the single Cu ion. The coordination sphere around Cu, which has either square planar or distorted tetrahedral geometry, contains four ligands with N and/or 0 donor atoms [ 12, 22]. Representative examples of proteins with this active site structure (see Fig. 1) and their respective catalytic function include galactose oxidase (1) (oxidation of primary alcohols) [23,24], phenylalanine hydroxylase (hydroxy-lation of aromatic substrates) [25,26], dopamine- 6-hydroxylase (C-Hbond activation of benzylic substrates) [27] and CuZn superoxide dismutase (disproportionation of 02 superoxide anion) [28,29]. 

TABLE 5 5. Elimination half-life of benzodiazepines undergoing hydroxy lation... 

---