Hydroxylation of quinoline

The enzymes from Comamonas testosteroni for hydroxylation of quinoline to quinol-2-one (quinoline 2-oxidoreductase) and the dioxygenase responsible for the introduction of oxygen into the benzenoid ring (2-oxo-l,2-dihydroquinoline 5,6-dioxygenase) have been described (Schach et al. 1995). 

Among the tasks remaining is the replacement of the C-16 hydroxyl group in 16 with a saturated butyl side chain. A partial hydrogenation of the alkyne in 16 with 5% Pd-BaS04 in the presence of quinoline, in methanol, followed sequentially by selective tosylation of the primary hydroxyl group and protection of the secondary hydroxyl group as an ethoxyethyl ether, affords intermediate 17 in 79% overall yield from 16. Key intermediate 6 is formed in 67 % yield upon treatment of 17 with lithium di-n-butylcuprate. 

De Beyer A, F Lingens (1993) Microbial metabolism of quinoline and related compounds XVI. Quinaldine oxidoreductase from Arthrobacter spec. Rii 61a a molybdenum-containing enzyme catalysing the hydroxylation at C-4 of the heterocycle. Biol Chem Hoppe-Seyler 374 101-120. 

Peczyfiska-Czoch W et al. (1996) Microbial transformation of azacarbazoles X re-gioselective hydroxylation of 5,ll-dimethyl-5ff-indolo[2,3-l)]quinoline, a novel DNA topoisomerase 11 inhibitor, hy Rhizopus arrhizus. Biotechnol Lett 18(2) 123-128... 

Kaiser et al. reviewed the microbial metabolism of different nitrogen compounds [320], There is agreement among the authors in suggesting an initial step in the transformation of quinoline (by whole cells) that consists of a hydroxylation at position 2 of the heterocyclic aromatic ring, leading to 2-hydroxyquinoline (see Fig. 21 [321]). 

Further transformation included additional hydroxylation steps leading to 2,6-dihydroxyquinoline and a trihydroxyquinoline (probably 2,5,6-trihydroxyquinoline). Shukla [322], working with Pseudomonas sp. identified an alternate pathway, involving additional metabolites, besides the 2-hydroxyquinoline and 8-hydroxycoumarin. These were 2,8-dihydroxyquinoline and 2,3-dihydroxyphenylpropionic acid. Quinoline-adapted cells were also able to transform 2-hydroxyquinoline and 8-hydroxycoumarin without a lag phase, providing additional support for their intermediate role as intermediates in the metabolism of quinoline. 

In summary, we may add that bacterial utilization of quinoline and its derivatives as a rule depends on the availability of traces of molybdate in the culture medium [363], In contrast, growth of the bacterial strains on the first intermediate of each catabolic pathway, namely, the lH-2-oxo or 1 II-4-oxo derivatives of the quinoline compound was not affected by the availability of molybdate. This observation indicated a possible role of the trace element molybdenum in the initial hydroxylation at C2. In enzymes, Mo occurs as part of the redox-active co-factor, and all the Mo-enzymes involved in N-heteroatomic compound metabolism, contain a pterin Mo co-factor. The catalyzed reaction involves the transfer of an oxygen atom to or from a substrate molecule in a two-electron redox reaction. The oxygen is supplied by the aqueous solvent. Certainly, the Mo-enzymes play an important role in the initial steps of N-containing heterocycles degradation. 

Modified Cinchona alkaloids catalysts have been developed in the last two decades to enhance further the bifunctional mode of the catalyst. Derivations at the C(9)-OH group, replacement of quinoline C(6 )-OCH3 with a hydroxyl group to enhance hydrogen bonding, syntheses of bis-Cinchona alkaloids, and development of thiourea-derived Cinchona alkaloids are most notable. 

Methoxy-8-hydroxylaminoquinoline, an N-hydroxylated metabolite of primaquine (Fig. 7.46), is directly toxic, causing hemolysis and methemoglobinemia in rats. However, there are several pathways of metabolism for primaquine and several potential toxic metabolites. Thus, hydroxylation of primaquine at the 5-position of the quinoline ring also forms redox-active derivatives able to cause oxidative stress within normal and G6PD-deficient human red cells as well as rat erythrocytes (Fig. 7.46). 

Electron density calculations suggest that electrophilic attack in pyridine (42) is favored at C-3, whereas nucleophilic attack occurs preferentially at C-2 and to a lesser extent at C-4. Cytochrome P-450 mediated ring hydroxylation of pyridine would, therefore, be expected to occur predominantly at C-3, the most electron-rich carbon atom. Although 3-hydroxypyridine is an in vivo metabolite in several species, the major C-oxidation product detected in the urine of most species examined was 4-pyridone (82MI10903). The enzyme system catalyzing the formation of this latter metabolite may involve the molybdenum hydroxylases and not cytochrome P-450 (see next paragraph). In the related heterocycle quinoline (43), positions of high electron density are at C-3, C-6 and C-8, while in isoquinoline (44) they are at C-5, C-7 and C-8. Nucleophilic substitution predictably occurs... 

Consequently, Dehmlow and coworkers modified the cinchona alkaloid structure to elucidate the role of each ofthe structural motifs of cinchona alkaloid-derived chiral phase-transfer catalysts in asymmetric reactions. Thus, the quinoline nucleus of cinchona alkaloid was replaced with various simple or sterically bulky substituents, and the resulting catalysts were screened in asymmetric reactions (Scheme 7.2). The initial results using catalysts 8-11 in the asymmetric borohydride reduction of pivalophenone, the hydroxylation of 2-ethyl-l-tetralone and the alkylation of SchifF s base each exhibited lower enantiomeric excesses than the corresponding cinchona alkaloid-derived chiral phase-transfer catalysts [14]. 

Figure 2 Scheme showing degradation pathways of quinoline depending on whether the initial attack occurs through a hydroxyl radical (a) or through direct electron transfer to Ti02 and subsequent reaction with superoxide (b). 

Monomeric metallochelates can also be immobilized on the polymer surface via a valent metal-carbon bonding. For example, the interaction of a copolymer of St and chloromethylstyrene with cobaloxime in a benzene-pyridine mixture gives PCMU with a Co—C bond [109]. N202-Metallochelates such as Co(II) complex with V,lV -bis(salicylaldehyde)ethylenediamine react with poly (chloromethylstyrene) (PCMSt) in THF at 193 K in a similar fashion [110], The same is true of reactions of quinoline (HQ) V(V) complexes with hydroxyl-containing polymers [111] ... 

The excited state pA-behaviour of quinoline derivatives has received considerable attention (see Tables 6.3 and 6.4). Since the heterocyclic nitrogen atom of quinoline is expected to become a stronger base in the excited state while the acidity of hydroxyl or amino-substituents increases, different ionization sequences can be obtained in the S0 and states. 3-Hydroxyquinoline is a typical example of this behaviour as shown in Scheme 2 (Haylock et al., 1963 Mason et al., 1968). 

The only example of the quantitative study of the electrophilic hydroxylation of a heteroaromatic concerns quinoline [54JBC(208)741 ]. 

Disposition in the Body. Metabolised by 2 -hydroxylation of the quinoline nucleus followed by 2-hydroxylation of the quinucli-dine ring both 2 -hydroxycinchonidine and 2,2 -dihydroxycin-chonidine have been detected in urine. 

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