Ortho-para Oxidative phenolic coupling

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). 

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... 

Parallel oxidations either electrochemically [117] or with iron([Il) salts [119] in water have also been made using l-alkyl-7-hydroxy-6-methoxytetrahydroisoquinO line salts as substrates. 4-Methy phenol is oxidised at a carbon anode in alkaline solution to give Pummerer s ketone 25 by the ortho-para coupling of two phenoxy radicals [120],... 

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... 

In a recent paper, the same authors showed that iron(III) chloride can mediate the oxidative coupling of substituted aryl ethers with an observed regioselectivity that depends on the substitution pattern [66] meta-substituted phenol ethers 77 led to polymers (Scheme 18a) whereas para-substituted phenol ether 79 gave predominantly biphenyl structures (Scheme 18b). ortho-Substituted phenol ether 81 provided a dimer with the Ar-Ar bond at a position para to one of the methoxy substituents (Scheme 18c). 

The new C-C bond is marked in black and the free phenolic OHs in green. Notice the relationship between them. The new bond is between a carbon atom ortho to one OH group and a carbon atom para to the other. We shall see in all these phenolic couplings that the ortho and para positions are the only activated ones (ortho/ortho, ortho/para> and para/para couplings are all possible). Oxidation occurs at the phenolic hydroxyl groups, and the resulting oxygen radicals couple. 

Lunarine (26), one of the typical neolignans, is biosynthesized by the ortho-para radical coupling between two molecules of p-hydroxycinnamic acid. In this connection, oxidative coupling reactions of 4-substituted phenols have been extensively stndied using thallium trifluoroacetate (TTFA), potassium ferricyanide (K3[Fe(CN)g]) and other reagents. p-Cresol (27) was also electrolyzed at a controlled potential (+0.25 V vi. SCE) in a basic medium to afford Pummerer s ketone 28 in 74% yield. The snggested mechanism is given in Scheme 4. 

Organic peroxides such as di-terf-butyl peroxide are effective for radical coupling of phenols. 3,5-Dimethylphenol (557) having free ortho- and para-positions was oxidized by heating with di-ferf-butyl peroxide at 140 °C to afford mainly an ortho-ortho coupled product 558 (77%) together with an ortho-para coupled product 559 (16%). In contrast, on oxidation of 557 by di-ferf-butyl peroxyoxalate at 25 °C, the yield (40%) of the ortho-para coupled product 559 increased, while the yield (17%) of 558 decreased. In addition, the para-para coupled product 560 was produced, although the yield (8%) was low (Scheme 103). In the case of phenol, a similar result was also obtained. These results and MINDO-3 calculations with standard parametrization show that stereoelec-tronic factors can explain the preferred formation of the ortho-ortho or ortho-para coupled products. ... 

Tetra- and pentavalent vanadium compounds such as VCI4 and VOCI3 are generally used for phenolic oxidation. Phenol was oxidized with VCI4 in CCI4 to afford two ortho-para and para-para coupled biphenyls 622 and 19 in 18 and 34% yields. 

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... 

The pyrrolo[de]phenanthridine alkaloids (lycorine type) and the 2-benzopirano-[3,4-g]indole alkaloids (homolycorine type) both originate from an ortho-para phenol-oxidative coupling (Fig. 5). 

Vanadium-mediated oxidative coupling of the polymer-supported diarylamine (167) gave, after de-anchoring from the support, a modest yield of the nine-membered ring (168) (Equation (11)). The orientation of the phenol coupling ortho, ortho) is different to that obtained with similar substrates in solution ortho, para) <82CJC368>. 

Biosynthesis A. a. are formed from phenolic tetrahy-drobenzylisoquinolines either by direct oxidative coupling or via dienones (proaporphines). The direct oxidative coupling can be either ortho-para (to isoboldine type) or ortho-ortho (to bulbocapnine type) . Lit, Eur. J. Pharmacol. 219,67-74(1992). PlantaMed. 57, 406ff. (1991). Biochem. Pharmacol. 43, 323-329 (1992). 

A minor constituent of P. somniferum is the aporphine alkaloid isoboldine. Other species of poppy, e.g., Papaver orientate and P. pseudoorientale, are known to synthesize aporphine alkaloids as principal constituents rather than morphinan structures. (5)-lsoboldine is readily appreciated to be the product of oxidative coupling of (5)-reticuline, coupling ortho to the phenol group in the tetrahydroisoquinoline and para to the phenol of the benzyl substituent. Some... 

In the biosynthesis of lycorine 1, alkaloid norpluviine 261 and its congener fortucine 30 were demonstrated as the first intermediate formed via ortho-para phenol oxidative coupling of 4 -methylnorbelladine 10 based on the labeling... 

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... 

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