R-Reticuline

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. 

Reticuline occurs in the two enantiomeric forms (S)-(+)-and (R)-(-)reticuline. Curiously this compound has the... 

In the next step (R)-reticuline is first transformed to the dienone salutaridine by regioselective para-ortho oxidative coupling, catalyzed by a stereo- and regioselective... 

The systemic transport of pathway intermediates or end-products might also occur in BA biosynthesis. Several BA biosynthetic enzymes are preferentially active in certain organs. Transcripts encoding various TYDC isoforms were most abundant in roots, or roots and stems.3 NCS was also most active in roots and stems of opium poppy,112 whereas CYP80B1 transcripts were most abundant in stems followed by roots, leaves, and floral tissues.148 STS and SOR, which convert (R)-reticuline to salutaridinol, exhibited abundant activity in roots and shoots.40,41 In contrast, COR... 

GERARDY, R., ZENK, M.H., Formation of salutaridine from (R)-reticuline by a membrane-bound cytochrome P-450 enzyme from Papaver somniferum. Phytochemistry, 1993,32, 79-86. 

Figure 2.8 Biosynthesis of morphine via the conversion of (S)-reticuline to (R)-reticuline, salutaridine and thebaine. SalS, salutaridine synthase SaIR, salutaridine reductase THS, thebaine synthase COR, codeinone reductase.

The role of reticuline as an intermediate in the biosynthesis of the mor-phinan alkaloids (Fig. 2.8) was demonstrated by the isolation both of (S)-and (f )-reticuline from the opium poppy. An excess of the (S)-reticuline over the (f )-isomer was found in opium (poppy latex) obtained from the mature plant, in contrast to the roughly equal amounts of these two isomers that occur in poppy seedlings. Both isomers were found to be incorporated into morphine, the major alkaloid isolated from opium, although incorporation of the (f )-isomer was slightly more efficient. (f )-Reticuline is firmly established in P. somniferum as the precursor of the morphinan-type alkaloids (Loefer and Zenk, 1990). (S)-Reticuline, however, is the central intermediate in isoquinoline alkaloid biosynthesis. It has been postulated that (R)-reticuline is formed from (S)-reticuline by isomerization. This inversion of configuration can be explained by the intermediate formation of the 1,2-dehydroreticulinium ion originating from (S)-reticuline, followed by stereospecific reduction to yield the (R) counterpart. The 1,2-dehydroreticulinium ion is efficiently incorporated into opium alkaloids and its role as a precursor of the morphinan-t)q)e alkaloids has been unequivocally established (De-Eknamkul and Zenk, 1990, 1992). 

De-Eknamkul, W. and Zenk, M.H. (1990) Enzymic formation of (R)-reticuline from 1,2-dehydroreticuline in the opium poppy plant. Tetrahedron Lett., 34, 4855-8. 

The later steps of morphine biosynthesis have been investigated in P. somniferum cells and tissue. Notably, in morphine biosynthesis, (S)-reticuline is converted to (R)-reticuline, thereby epimerizing the stereocenter generated by norcoclaurine synthase at the start of the pathway (Fig. Id). (S)-reticuline is converted to (R)-reticuline through a 1,2-dehydroreticuline intermediate. Dehydroreticuline synthase catalyzes the oxidation of (S)-reticuline to 1,2-dehydroreticulinium ion (44). This enzyme has not been cloned but has been purified partially and shown to be membrane-associated. This intermediate then is reduced by dehydroreticuline reductase, an NADPH-dependent enzyme that stereoselectively transfers a hydride to dehydroreti-culinium ion to yield (R)-reticuline. This enzyme has not been cloned yet but has been purified to homogeneity (45). 

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). ... 

A synthesis of (R)-reticuline included a comparison of epoxide and cyclic sulfate chemistry (Scheme 3.31) [345]. 

Following the formation of S-norcoclaurine, hydroxylation at C3 with subsequent methylation yields S-reticuline.24 Although the R form corresponds to the correct stereochemistry of morphine at C9, both R and S isomers of reticuline have been found to act as precursors for thebaine, codeine and morphine and it is therefore apparent that S-reticuline is con-verted to its R form.25 Inversion is best explained by formation of an intermediate 1,2-dehydroreticulinium ion 22, followed by stereospecific reduction to yield R-reticuline, Figure 3. An NADPH-dependent enzyme, 1,2-dehydroreticuline... 

The next step involves an intramolecular ortho-para phenolic coupling of R-reticuline to form the crucial C12-C13 bond of morphine, a process initially proposed on theoretical grounds by Barton and Cohen.27 Some eight years later, experimental proof was obtained for this regioselective oxidative coupling from in vivo studies.216 Further... 

SCHEME 14. Synthesis ofmorphinane alkaloids (45) from R-reticuline (7f) (493). 

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. 

Alkaloids of the morphinane group. If the tetrahydroisoquinoline alkaloid norlaudanosoline is written in such a way that part of the molecule is rotated around the dotted line (Fig. 280), the relationship to the morphinane-type alkaloids becomes obviously. The actual precursor of these compounds, however, is (R)-reticuline. It is probably attacked by a phenol oxidase (C 2.3.1) yielding a biradical which is stabilized by the formation of the dienone (- -)-salutaridine. After reduction of (-j-)-salutaridine closure of a new 0-heterocyclic ring results in the formation of thebaine. The alkaloids codeine and morphine are synthesized from thebaine in Papaver somniferum,... 

Enzyme 1.14.21.4 salutaridine synthase (R)-reticuline oxidase (C-C phenol-... 

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