O phenol coupling

KRAUS, P.F.X., KUTCHAN, T.M., Molecular cloning and heterologous expression of a cDNA encoding berbamunine synthase, a C - O phenol coupling cytochrome P450 from the higher plant Berberis stolonifera, Proc. Natl. Acad. Sci. USA, 1995, 92,2071-2075. 

Bisbenzylisoquinoline alkaloids are dimeric benzyltetrahydroisoquinoline alkaloids that are known for their pharmacological activities. A well-described example is the muscle relaxant (+)-tubocurarine, which in crude form serves as an arrow poison for South American Indian tribes. In the biosynthesis of this broad class of dimeric alkaloids, it has been postulated that the mechanism of phenol coupling proceeds by generation of phenolate radicals followed by radical pairing to form either an inter- or intramolecular C - O or C - C bond. Enzyme studies on the formation of bisbenzylisoquinoline alkaloids indicated that a cytochrome P-450-dependent oxidase catalyzes C - O bound formation in the biosynthesis of berbamunine in Berberis cell suspension culture.15 This enzyme, berbamunine synthase (CYP80A1), is one of the few cytochromes P-450 that can be purified to... 

The one-electron reduction potentials, (E°) for the phenoxyl-phenolate and phenoxyl-phenol couples in water (pH 2-13.5) have been measured by kinetic [pulse radiolysis (41)] and electrochemical methods (cyclic voltammetry). Table I summarizes some important results (41-50). The effect of substituents in the para position relative to the OH group has been studied in some detail. Methyl, methoxy, and hydroxy substituents decrease the redox potentials making the phe-noxyls more easily accessible while acetyls and carboxyls increase these values (42). Merenyi and co-workers (49) found a linear Hammett plot of log K = E°l0.059 versus Op values of substituents (the inductive Hammett parameter) in the 4 position, where E° in volts is the one-electron reduction potential of 4-substituted phenoxyls. They also reported the bond dissociation energies, D(O-H) (and electron affinities), of these phenols that span the range 75.5 kcal mol 1 for 4-amino-... 

If the five resonance forms of the phenoxy radical (Figure 3.6) can couple to any other phenoxy radical, the theoretical number of dimeric structures possible is 25. The relative frequency of involvement of individual sites in the phenolic coupling reaction depends on their relative electron densities. Quantum mechanical calculations predict that the high electron densities at the phenolic oxygen atom and the carbon atom would give rise to a high proportion of fi-O-4 linkages, which is indeed observed to be the case (Table 3.1). 

Alkoxide or aryloxide anions are also reputed to be inactive in Sr I reactions. There is, however, one example of such a reaction at an sp carbon the nitro-derivative of 4-nitrocumyl reacts with phenoxide and 1-methyl-2-naphthoxide ions yielding the corresponding ethers (Kornblum et al., 1967). A similar reaction has been reported for halobenzenes in t-butyl alcohol upon stimulation by sodium amalgam (Rajan and Sridaran, 1977). This reaction could not, however, be reproduced (Rossi and Pierini, 1980) and other attempts to make phenoxide ions react at sp carbons have been equally unsuccessful (Ciminale et al, 1978 Rossi and Bunnett, 1973 Semmelhack and Bargar, 1980). It has been found, more recently, that phenoxide ions react with a series of aryl halides under electrochemical induction, but that the coupling occurs at the p- or o-phenolic carbon rather than at the phenolic oxygen (Alam et al, 1988 Amatore et al, 1988). This is... 

Thus the 2,4-dinitrophenyldiazonium cation will couple with PhOMe and the 2,4,6-compound with even the hydrocarbon 2,4,6-trimethylbenzene (mesitylene). Diazonium cations exist in acid and slightly alkaline solution (in more strongly alkaline solution they are converted first into diazotic acids, PhN=N—OH, and then into diazotate anions, PhN=N—O ) and coupling reactions are therefore carried out under these conditions, the optimum pH depending on the species being attacked. With phenols this is at a slightly alkaline pH as it is PhO , and not PhOH, that undergoes attack by... 

Consistent with the results of this study is the outcome of the oxidation of 4-X-substituted phenols by use of PINO, generated from HPI with Pb(OAc)4 at 25 °C in MeCN containing 1% AcOH . The reactivity (fcn) of PINO towards phenolic O—H bonds (BDE 85-90 kcal moC ) was about one order of magnitude higher than that measured towards the C—H bond of benzyl alcohols (cf. Table 4). A p value of —3.1 was obtained from plotting log kn vs. for this reaction, where removal of H-atom from the phenolic O—H bond (which is weaker than the O—H bond of aliphatic or benzyl alcohols) induces an oxidative phenolic coupling with the PINO moiety. In view of the low redox potential of the substituted phenols (in the 0.8-1.1 V/NHE range), and of the substantial value of the kinetic isotope effect = 3.1-3.7 measured, ... 

The formation of o-quinones by the above oxidative methods is less reliable since the ortho quinonoid system is more susceptible to attack by electrophilic and nucleophilic species mild conditions are therefore essential. The use of the silver carbonate/Celite reagent noted above for phenol coupling reactions is particularly suitable the conditions are those described in Expt 6.129, and they have been applied to the oxidation of catechol, 4-methylcatechol, 4-t-butylcatechol, and 3,5-di-t-butylcatechol to yield the corresponding o-quinones in almost quantitative yield. 

Lycorine and haemanthamine, which more frequently accompany narciclasine (376), are biologically derived from O-methylnorbelladine (343) by phenol coupling along path a or path b, and it seemed possible that 376 might arise by a variant of the same biosynthetic process involving late degradation of the C1S skeleton formed by either way (Scheme I). 

Oxidative phenolic coupling.1 The vancomycin antibiotics are polypeptides with bridging diphenyl ether groups. Evans et al. have shown in model systems such as 1 that cyclization to o-halophenolic peptides (2) can be accomplished by oxidation with thallium(III) nitrate in THF-methanol or CH2Cl2-methanol followed by CrCl2 reduction of a para-quinol intermediate (a). In three cases the yield of cyclic products was 40-48%. 

Figure 10 Reactions of phenolates with /u.-ri ri -peto o complex (7) yields an ort/ro-hydroxylation reaction reminiscent of Tyr, while reactions of phenols by both (7) and his-/r-oxo complex (8) results in ort/ro-phenol coupled dimers through an apparent PCET pathway...

Activation ofquinones. Quinones under ordinary conditions react with phenol ethers to give products of C—C and O—C coupling. Acid catalysis favors C—C coupling (equation I). ... 

These results, summarized in Scheme 2, indicate that the methylation pattern can be important in deciding the metabolic fate of precursors at this particular stage of biosynthesis (c/. ref. 75) as well as during oxidative phenol coupling. In addition in vivo O- and 7V-methylation in P. somniferum was found to be dependent, and variably so, on the configuration of the substrate. Further, dehydrogenation of (59) depends on the stereochemistry at C-1 since only the (-)-isomer affords papaverine (62). Moreover it is (-)-norreticuline [as (55)] rather than the ( + )-isomer which is implicated. Finally it is to be noted that norlaudanidine (66) is as efficient a precursor for papaverine as is (59). ... 

It is not yet clear whether the next stage of the biosynthesis involves an N-methylation or phenol coupling. However, given the pattern of O-methylation in (55), phenol coupling can take place in two senses leading to the dienones (57) and (58) respectively. Rearrangement of dienone (58) as indicated would lead via boldine (59) to glaucine (60) and dicentrine (61). Boldine was tested as a precursor and was efficiently incorporated into both alkaloids. 

Amaryllidaceae Alkaloids.—Narciclasine (73) occurs in Narcissus plants along with the Amaryllidaceae alkaloids haemanthamine (70), lycorine (71), and nor-pluviine (72). The three alkaloids (70), (71), and (72) are derived41,42 from O-methylnorbelladine (68) following pathways outlined in Scheme 10. In path a phenol coupling of (68) in the para-para direction leads ultimately to haemanthamine (70) ortho-para coupling as in path b leads to lycorine (71) and nor-pluviine (72). 

Phenols. In the benzene series the azo group enters almost wholly at the /rara-position. The small amount of ortho-product can sometimes be removed by distillation in steam.356 When the /wra-position is already occupied, coupling occurs at the arf/w-position, e.g., in /7-chlorophenol357 or/ -cresol 358 when the orf/w-positions are also occupied, coupling either does not occur or, as with also /7-hydroxybenzoic acid,359 occurs with removal of the blocking substituent in addition, O-azo coupling may then result, as with 2,4,6-tri-... 

---