Reticuline

Reticuline.—Reticuline (41) is a pivotal intermediate in the biosynthesis of many alkaloids based on the benzylisoquinoline skeleton, and by association with these 

In support of earlier work where convincing evidence was obtained that (46), but most probably not (47), was an intermediate in benzylisoquinoline biosynthesis, (47) [and (48)] was incorporated into reticuline (41) to an insignificant 

Examination of the relative incorporations of (42), (43), (44), and (45) into reticuline (41) suggest that O-methylation precedes JV-methylation.  

Reticuline.—A biosynthetic study of the important benzylisoquinoline reticuline (41), published in preliminary form/ has appeared in full/ Important new information is that 4-hydroxyphenylpyruvic acid (37) and 3,4-dihydroxyphenyl-pyruvic acid (38) are incorporated, like tyrosine, into both C6-C2 units of recticuline (41), in contrast to the transamination product of (38), i.e. dopa (39), which, curiously, is only used for the elaboration of one of these units (ring A and attached ethanamine residue), being incorporated via dopamine (40). Condensation of dopamine with (38) affords (43), which has been shown to be a benzylisoquinoline precursor followed in sequence by (42). The new results confirm these findings by showing that (42) and (43) are reticuline precursors too. 

The conversion of reticuline (44) into morphinan alkaloids, which occurs with loss of tritium from C-1 in P. somniferum (see above), has been observed also for the formation of thebaine (46) in P. bracteatum, a plant which produces this alkaloid but not codeine or morphine. Radioactive 1,2-dehydroreticuline (47) labelled both reticuline (44) and thebaine (46), whilst radioactive reticuline again labelled thebaine (46). ° Codeinone (48) and codeine (50) are biosynthetic intermediates between thebaine (46) and morphine (51) in P. somniferum, and it was shown that (48) was efficiently reduced to (50) in P. bracteatumf It is apparent that alkaloid biosynthesis in the two plants is similar, with the important difference that in P. bracteatum the enzymes which effect demethylation of (46) are missing, and so biosynthesis goes no further than thebaine (46). 

Callus tissue of P. somniferum has been reported not to produce morphinan alkaloids but benzophenanthridine, protopine, and aporphine bases. Recent experiments have shown that (5)-reticuline from (R,S)-reticuline (41) administered to tissue cultures was transformed into (5)-scoulerine (52) and (5)-cheilan-thifoline (53) [(R)-reticuline was recovered unchanged]. Morphine, codeine, and thebaine were not metabolized by the culture but (—)-codeinone (48) was converted stereospecifically and in high yield into (—)-codeine (50), both by the culture and by a crude enzyme preparation from it. 

Other workers have obtained a callus tissue culture from the same plant which does produce morphinan alkaloids. The production of alkaloids was found to be stimulated by tyrosine and ascorbic acid.  

The latex of P. somniferum is known to metabolize morphine in vivo. Incubation of morphine with latex in vitro also results in its metabolism. One of the products was identified as morphine 7V-oxide, which also occurs naturally in the plant. 

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An enzyme-catalyzed appHcation has been used to prepare the enantiomers of hydroxy-substituted tetrahydroisoquinolines (160). The synthesis of ( V)-reticuline [485-19-8] (30) has been reported using similar methodology (161). The substitution of formic acid and paraformaldehyde in this method leads to lower reaction temperatures, freedom from hydrolysis of protective groups, and improved yields (162). 

A concise total synthesis of (7 )-Reticuline has been reported using the Pomeranz-... 

Banning, JW, Uretsky NJ, Patil PN, Beal JL. Reticuline a dopamine receptor blocker. Life Sci 1980 26 2083-2091. 

Fig. 10.3 Reaction catalyzed by the cytochrome P-450-dependent oxidase berbamunine synthase (CYP80A1). This enzyme creates a branchpoint in the (5)-reticuline biosynthetic pathway to form the bisbenzylisoquinoline alkaloids.

Retention time, in chromatography, 6 374-375, 409-410 ( )-Reticuline, 2 90 Retina, 7 307-308 Retinal, 25 787. See also Vitamin A carotenes and, 25 790 Retinitis pigmentosa, 17 659 Retinoic acid, 25 787-789, 790. See also Vitamin A... 

R)-Reticuline, turned over and rewritten as in the scheme, is the substrate for hydrogen abstractions via the phenol group in each ring, giving the diradical. 

This enzyme [EC 1.5.3.9], also called reticuline oxidase and tetrahydroprotoberberine synthase, catalyzes the re-... 

Animal experiments with alumina have shown that the type of reaction in lung tissue is dependent on the form of alumina and its particle size, the species of animal used, and the route of administration. For example, intratracheal administration into rats of y-alumina of 2- j, average size caused only a mild fibrous reaction of loose reticulin. ° However, intratracheal administration of y-alumina of 0.02- to... 

U size into rats produced reticulin nodules that later developed into areas of dense collagenous fibrosis." The latter alumina by the same route in mice and guinea pigs caused development of a reticulin network with occasional collagen, whereas in rabbits only a slight reticulin network was observed. Intratracheal administration of another form of alumina in rats, corundum of particle size less than Ip, caused the development of compact nodules of reticulin. 

Histologically, the silicotic nodule consists of a relatively acellular, avascular core of hyalinized reticulin fibers arranged concentrically and blending with collagen fibers toward the periphery, which has well-defined borders. ... 

Abs, Antibodies CD, celiac disease DH, dermatitis herpetiformis Dx, Diagnosis EM, endomysial antibodies GI, gastrointestinal GFD, gluten-free diet IELs, intraepithelial lymphocytes IFN, interferon Lab, laboratory tTG, tissue transglutaminase antibodies Ret, reticulin IH, immunohistochemistry. 

Reticuline (38), one of the most important intermediates in the biosynthesis of opium alkaloids, has been synthesized in racemic form (Scheme 7) (78). 6-Methoxy-7-benzyloxyisoquinoline (39), prepared from O-benzylisovanillin via a modified Pomeranz-Fritsch isoquinoline synthesis, was treated with benzoyl chloride and potassium cyanide to obtain Reissert compound 40. Alkylation of the anion generated from 40 with 3-benzyloxy-4-methoxybenzyl chloride gave the corresponding 1-substituted Reissert compound 41 which was hydrolyzed in alkaline medium to 1-benzylisoquinoline derivative 42. Quatemarization of 42 with methyl iodide followed by sodium borohydride reduction and debenzylation led to ( )-reticuline (38) in about 25% overall yield from 39. 

The biosynthesis of pavines from (-t-)-reticuline (158) through Route A has also been agreed upon by Barker and Battersby (7/5). They additionally suggested an equilibrium between the iminium ion 160 and the carbinolamine 162 (Scheme 34). 

An alternate precursor for achieving the same result may be (+)-reticuline (158), which would oxidize to quinone methide 168. Direct cyclization would result in an isopavine skeleton, whereas conversion to the enamine 167 would lead to a pavine. Similarly, a hydroxylation of the methide 168 at C-4 to furnish species 169 would either yield an isopavine by cyclization, or a pavine via the intermediacy of the 1,2-dihydro compound 167 (Scheme 37) (769). 

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