Phenolic oxidative coupling morphine

Phenolic oxidative coupling the biosynthesis of tubocurarine and morphine... 

Since it is known that quaternary salts give better yields of phenolic oxidative coupling products than do tertiary bases, when oxidised with one-electron transfer agents in the laboratory, the possible role of reticuline methochloride (tembetarine chloride) in the biogenesis of more complex alkaloids has been examined. The labelled salt has been found to be very poorly incorporated into morphine, sinomenine, and protopine. 

Eventual biosynthetic postulations and revelations have led several groups over the years to approach the synthesis of morphine as does Nature, choosing to adopt a biomimetic phenolic oxidative coupling as the key step. Unfortunately, the in vitro oxidation of reticuline derivatives to salutaridines tends to proceed with poor regiocontrol and in low yield, despite employment of a variety of novel reagents. This of course... 

A study of the phenolic oxidative coupling reaction in the synthesis of morphine alkaloids. An approach to the asymmetric synthesis of codeine... 

Studies aimed at the synthesis of morphine. 3. Synthesis of (,+-.)-salutaridine via phenolic oxidative coupling of (.+-.)-reticuline... 

Although this isoquinoline at first bears little structural resemblance to morphine (108), careful rearrangement of the structure (A) shows the narcotic to possess the benzylisoquinoline fragment within its framework. Indeed, research on the biogenesis of morphine has shown that the molecule is formed by oxidative coupling of a phenol closely related to papaverine. 

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... 

Oxidative phenol coupling (4, 499-500). Schwartz and Mami have effected oxidative para-ortho coupling of the benzyltetrahydroisoquinoline alkaloid (1) to (2) with TTFA in CH2CI2 ("78 to 20°, overnight) in 23% yield. This oxidative coupling is involved in the biosynthesis of morphine alkaloids, but it has... 

Papaver somniferum.- Rapoport and Hodges have obtained from this species an enzyme which catalyzes the reduction of codeinone to codeine, in the presence of NADH as a coenz3nne. Another enzyme, partially purified by centrifugal fractionation, was obtained which catalyzed the oxidative coupling of the phenolic rings of reticuline to yield the dienone salutaridine . Hydrogen peroxide was utilized by this enzyme for the oxidation. A crude enzyme from this species converted morphine to the dimeric pseudomorphine and morphine -oxide . ... 

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). 

It has not yet been proven that the coupling of phenolate radicals takes place in the biosynthesis of phenolic alkaloids. However, there is no evidence against, and much circumstantial support for, this proposal. The brilliant work of Zenk1517 has shown that the oxidative step in morphine biosynthesis is carried out by a single P-450 type iron porphyrin enzyme, which has been isolated pure and cloned from the appropriate... 

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... 

Morphine alkaloids are a subgroup of isoquinoline alkaloids and are derived biogenetically from laudanosine bases by oxidative phenolic coupling/6,7 Alkaloids of the opposite enantiomorphic group occur in several Japanese Sinomenium and Stephania species, the most important compounds being sinomenine, hasubanonine, metaphenin, and protometaphenine. 

In a gram-scale catalytic enantioselective formal synthesis of morphine the key steps involved an ortho-para oxidative phenolic coupling and a highly diastereoselective desymmetrization of the resulting cyclohexadie-none that generated three of the four morphinan ring junction stereocenters in one step (14AGE13498). 

In 2013, Fan s group reported a formal synthesis of rac-morphine [109], for which the phenolic alkyl aryl ether 177 served as a precursor of an oxidative dearomative ortho-para phenolic coupling reaction which was promoted by DIB in HFIP to afford the car( o-spirocyclic cyclohexa-2,5-dienone 178 (Fig. 45). This... 

Fe ", Fe(CN)5 , Pb02, Ag20] and a recent chemical model (200) for morphine using thallium(III) ion has been developed to induce such an oxidative phenolic coupling reaction ... 

The key step in the biosynthesis of morphine involves the oxidative phenolic coupling of reticuline (31) to salutaridine (32). This step can be viewed mechanistically as (1) oxidation of the two aromatic rings to phenoxy radicals followed by an intramolecular radical-radical coupling or (2) oxidation of one ring to a radical cation or cation, followed by an intramolecular electrophilic aromatic reaction. This process is very important in the biosynthesis of a number of natural products, and is a process that nature has used to crosslink peptides containing aromatic residues. The biosynthesis of morphine continues with reduction of salutaridine (32) to salutaridinol (33) followed by an intramolecular Sn2 reaction to give thebaine (34). Dienol ether hydrolysis to codeinone (35), reduction of the ketone to codeine (3) and 0-demethylation completes the biosynthesis of morphine (1). 

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