Reticuline oxidation

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). 

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... 

Oxidative phenolic coupling.1 A new hiomimetic approach to morphine alkaloids involves oxidative intramolecular coupling of the reticuline derivative 1 to a salutaridine derivative 2 with VOCl3 in ether.1 If the reaction is conducted in CH2C12 2 is obtained in markedly lower yield and the undesired aporphine 3 is formed as a major product. The dienone 2 has been converted into 2-hydroxycodeine (4). 

R)-Reticuline, rewritten as in Figure 6.50, is the substrate for one-electron oxidations via the phenol group in each ring, giving the diradical. Coupling ortho to the phenol group in the tetrahydroisoquinoline, and para to the phenol in the benzyl substituent, then yields the dienone... 

Methylarmepavine has been found in Annona squamosa.23 Reticuline and its N-oxide (a new natural product) have been isolated from Pachygone ovata24 and another new base, the quaternary hydroxide zanoxyline, has been isolated from the stem bark of Zanthoxylum oxyphyllum, its structure being... 

AT-Formylnor-reticuline, on treatment with 2,3-dichloro-5,6-dicyano-l,4-benzoquinone in methanol, is oxidized to the 4-methoxy-compound (35), which can be cyclized to N-norbisnorargemonine (36) (converted by N- and O-methylation into argemonine) by mineral acid or to the isopavine N-formyl-northalidine (37) by treatment with methanesulphonic acid in acetonitrile. The N-formyl compounds can be reduced to AT-methyl by borane or converted into the secondary bases by hydrazinolysis.69... 

The bases (142 R = H) and (142 R = Me) have been synthesized by Pschorr cyclizations of the appropriate benzylisoquinolines.173 Oxidative cyclization of 7V-(carbethoxy)nor-reticuline with titanium trifluoroacetate gives N-(carbethoxy)norsalutaridine, and the same process with the seco-reticuline... 

The conversion of reticuline N- oxide into the aporphine corydine under the influence of cuprous chloride has been described in full.28... 

The benzylisoquinoline alkaloids are widely distributed in nature and are intermediates in the biosynthesis of alkaloids of this family (2, 3). It is not surprising therefore that several groups (6, 7, 15, 23) have examined their spectra. Among the alkaloids that have been studied are reticuline (26) (7), norlaudanosine (27) (7), laudanosine (28) (6, 15), and the cis- and trans-N-oxides of laudanosine, 29 and 30, respectively (7). The chemical shifts of laudanosine are recorded in Table IV and the structures of the alkaloids may be found in Fig. 4. 

In the absence of hydrogen peroxide, the final oxidizing agent in the peroxidase enzyme system, homoorientaline (138), is transformed to the one-hydroxy derivative 139 by potato peel homogenate (100). The related benzylisoquinoline reticuline (88) is also hydroxylated at saturated carbon... 

Papaverine.—The biosynthesis of the simple benzylisoquinoline papaverine (89) is known to proceed via nor-reticuline (48) and tetrahydropapaverine (88).71 Dehydrogenation of the latter affords papaverine, and examination of the stereochemistry of the processes involved has led to the conclusion72 that loss of the proton at C-3 [in nor-reticuline (48)] is stereospecific (loss of the pro-S hydrogen atom) but removal of the C-4 proton is essentially non-stereospecific. These observations are perhaps best explained if enzyme-catalysed oxidation of (88) occurs to give (90), subsequent non-stereospecific imine-enamine isomerization occurring without enzyme participation to give (91). A further amine to imine oxidation then occurs to give papaverine (89).72... 

Oxidation of (+ )-reticuline perchlorate with cuprous chloride and oxygen in pyridine produced (+ )-corytuberine (36) in 28% yield, and (+)-isoboldine (37) in 8% yield. Oxidation with cuprous chloride, therefore, favours ortho-ortho over ortho-para coupling.28... 

Chlorination and bromination of iV-formyl- and N-ethoxycarbonyl-nor-reticuline have been shown to give 8,6 -dihalogenated compounds32 and anodic oxidation of the bridged hexamethylene diether of reticuline has been found to give the proerythradienone (17) and the morphinandienone (18).33... 

Bischler-Napieralsky synthesis of the benzylisoquinoline (39), iV-formylation, cyclization, and oxidation has given the pentamethoxy-compound (40), identical with glabrine dimethyl ether and glabrinine methyl ether.114 Reticuline N-oxide has... 

The reaction of reticuline A-oxide (14) with cuprous chloride in methanol, followed by treatment with sodium hydrosulphite, furnished corytuberine (15) in... 

The oxidation of the nor-reticuline derivatives (40a) and (40b), using a variety of tetraethylammonium diacyloxyiodates as oxidizing agents, supplied good yields of the norisoboldines (41a) and (41b).46a This marks the first recorded use of diacyliodates for the synthesis of aporphines. 

Conversion of (S)-reticuline to its ( )-epimer is the first committed step in morphinan alkaloid biosynthesis in certain species. 1,2-Dehydroreticuline reductase catalyzes the stereospecific reduction of 1,2-dehydroreticuline to (7 )-reticuline.39 Intramolecular carbon-carbon phenol coupling of (if)-reticuline by the P450-dependent enzyme salutaridine synthase (STS) results in the formation of salutaridine.40 The cytosolic enzyme, salutaridine NADPH 7-oxidoreductase (SOR), found in Papaver bracteatum and P. somniferum, reduces salutaridine to (7S)-salutaridinol.41 Conversion of (7S)-salutaridinol into thebaine requires closure of an oxide bridge between C-4 and C-5 by acetyl coenzyme A salutaridinol-7-0-acetyltransferase (SAT). The enzyme was purified from opium poppy cultures and the corresponding gene recently isolated (Fig.7.2).42,43 In the last steps of morphine... 

Methylating only one phenol on each ring of norreticuline leaves the other one free for radical coupling. Reticuline is oxidized in the plant to isoboldine by a radical cyclization with the formation of a new C-C bond. 

A more recent attempt<34) to improve yields at the phenolic oxidation stage of the Barton synthesis rested on the argument that species such as hypervalent iodine(35) offered milder reaction conditions because the iodine (III <= I) redox is closer to the potential required for the reticuline-salutaridine transformation. A range of aryliodosobistrifluoracetates was used, with the... 

Is (/ )-reticuline, which is required for the synthesis of morphine in plants (272,273) and formed from the (5 )-enantiomer in benzyliso-quinoline-producing plants (274) by an oxidation-reduction sequence (257), also the crucial intermediate in the biosynthesis of mammalian morphine Confirmation that it is must await its detection. Conversion of... 

S)-reticuline to ( )-reticuline in Papver somniferum is achieved by enantiospecific oxidation of the (5 )-enantiomer (273), and it is followed by an NADPH-dependent enzymatic reduction of the dehydroreticulinium ion, which also is highly substrate specific since no reduction of 1,2-dehydronorreticuline was observed (275). 

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