Isoquinoline, enzymic oxidation

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... 

R)-Reticuline (294), one of the most fundamental isoquinoline alkaloids, has been known to be converted into morphine alkaloids by intramolecular oxidative phenolcoupling. Thus, 294 was treated with cytochrome P-450 hnked microsomal Papaver enzyme in a buffer solution (pH 7.5) containing NADPH under aerobic conditions (25 °C, 1 h) to afford in high efficiency and high selectivity salutaridine (295), which was chemically converted to thebaine (296), morphine (297) and related alkaloids. In contrast, the enzyme was not effective in reaction with (5 )-reticuline (Scheme 63). ... 

More recently, the preparative value of VOCl3 and VOF3-TFA in chemical oxidation has been demonstrated (see Section III, on the pro-aporphine and promorphinane alkaloids) (415,462). Some other authors used the purified enzyme horseradish peroxidase (463). By this method the aporphine base (besides the quaternary dibenzopyrrocoline) is readily obtained from (S)-( + )-laudanosoline hydrobromide or from (/ )-(—)-laudanosoline methiodide with retention of the absolute configuration. The synthesis of 6a,7-dehydroaporphine bases was also carried out by making use of the benzyne reaction (439). Reduction of these substances affords the corresponding aporphine bases (439). The synthesis of isoquinoline alkaloids by lead tetraacetate oxidation was reviewed by Umezawa and Hoshino (343). 

On the other hand, the pyridine ring portion of quinolines and isoquinolines can be oxidized to various hydroxyl-derivatives by enzymes. 1,2,3,4-Tetrahydroquinoline and 1,2,3,4-tetrahydroisoquinoline derivatives are easily aromatized to quinolines and isoquinolines, respectively, by using hypervalent iodine reagents or DDQ. ... 

The experiments by Canonica et al. (1981) suggest a third plausible formation of simple isoquinoHnes with no carbon-1 substituent in plants mainly producing alkaloids of the benzylisoquinoline type. Treatment of the benzylisoquinoline N-methylcoclaurine with ascorbic acid oxidase, an enzyme widespread in plants, resulted in benzyhc fission giving about 40% yield of corypalline, its quaternary 1,2-dehydroderivative and benzyl alcohol. Thus, both isoquinolones and simple isoquinolines may be formed directly by the action of oxidative enzymes in benzyl-isoquinoline-producing plants. 

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