Berbamunin

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... 

Fig. 10.3 Reaction catalyzed by the cytochrome P-450-dependent oxidase berbamunine synthase (CYP80A1). This enzyme creates a branchpoint in the (5)-reticuline biosynthetic pathway to form the bisbenzylisoquinoline alkaloids.

Fig. 10.8 Selected cDNAs isolated in recent years that encode enzymes involved in the biosynthesis of various classes of isoquinoline alkaloids. 6-OMT, norcoclaurine 6-0-methyltransferase 23 CYP80A1, berbamunine synthase 19 CYP80B1, (S)-A-methylcoclaurine 3 -hydroxylase 20 CPR, cytochrome P-450 reductase 29 4 -OMT, (5)-3 -hydroxy-A-methylcoclaurine 4 -0-methyltransferase 30 BBE, berberine bridge enzyme 12 SalAT, salutaridinol 7-O-acetyltransferase 28 COR, codeinone reductase.25...

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. 

Temuconine (292), C37H42N206, [tt] 5 +68° (c 0.24, MeOH), was isolated from the Chilean species Berberis valdiviana Phil. (Berberidaceae). The structure was established principally by spectral comparison to the known alkaloid, (+)-berbamunine (182), for which the CD spectrum was apparently recorded for the first time. The 200-MHz FT NMR and 360-MHz FT NMR NOE difference spectra (see Section VI,A,2,b) of temuconine were originally interpreted as indicating structure 293 (137) a reinvestigation, which assigned all the protons, particularly the H-T (8 3.78) and H-l (3.61) multiplets, showed that temucocine actually has structure 292 (138). 

B. lycium Aromoline, baluchistanamine, berbamine, berbamunine, isotetrandrine, oxyacanthine 181... 

Oxidation has been used to convert one type of dimeric skeleton to another. Thus, a mixture (421) of racemic berbamunine and magnoline, prepared via the bis diazoketone 422, was oxidized with buffered K3Fe(CN)6 to 423, which was methylated to a mixture of pakistanamine (46) isomers (283). Electroreduction... 

Berbamunine Spasmolytic (rabbit intestine) not adrenolytic, not antiinflammatory (rats) 370... 

B. cretica Aromoline, berbamine, berbamunine, iso-tetrandrine, obaberine, obaihegine, oxyacanthine, thalrugosine 574... 

By far the most abundant alkaloid in the stem bark of the medicinally important Malmea gaumeri, and until now the only one isolated from this source, was named guattegaumerine on the basis of a misclassification of the plant material. Its structure, 7, was elucidated by the usual spectroscopic methods and supported by chromatographic comparison with the N,N -dimethyl derivative of the previously known lindoldhamine, and its absolute configuration (C-l R, C-l R) was deduced from its CD curve (28). Guattegaumerine (7) is thus a diastereoisomer of (R, S)-berbamunine and (5,/ )-magnoline. 

In this system, at least, berbamunine is the first bisbenzylisoquinoline formed [together with its diastereoisomer guattegaumerine (7)] from the monomeric precursors. The 2-norbisbenzylisoquinolines daphnoline (9) and its 12-0-methylation product daphnandrine (10) would have to be methylated at 0-7, giving 2-noroxyacanthine (141) and 2-norobaberine (169), respectively, before... 

When coclaurine and N-methylcoclaurine are combined by CYP80A1 (berbamunine synthase), dimeric bisbenzoylisoquinoline alkaloids are generated (Kraus and Kutchan, 1995), among the several with pronounced biological activities, such as berbamine and tubocurarine. 

Zenk, M.H. Gerardy, R. Stadler, R. Phenol oxidative coupling of benzylisoquinoline alkaloids is catalyzed by regio- and stero-selective cytochrome P-450 linked plant enzymes salutaridine and berbamunine. J. Chem. Soc. Chem. Com-mun. 1989, 1725-1727. 

The constitution of magnoline (XVI) was elucidated by degradation in 1940 but the stereochemistry of it remained unknown for many years thereafter and only recently was established. Magnoline was assigned the SR-configuration (9), as shown in formula XVI, for it was found to be the antipode of the new alkaloid berbamunine whose absolute con figuration was established as RS 9, 14). 

Berbamunine (XXVI) (mp 190°-191°), a new bisbenzylisoquinoline alkaloid having a single diphenyl ether linkage, was isolated by Tomita and Kugo 16) from Berberis amurensis Rupr. 

The position of the three phenolic hydroxyl groups in berbamunine was shown to be as in XXVI by subjecting the ethylated alkaloid (XXVIII) to cleavage with sodium in liquid ammonia and identifying the products as (- )-V-methyl-0,0-diethylcoclaurine (V) and (+ )-l-(4 -hydroxy-benzy 1) - 2 - methyl - 6 - methoxy - 7 - ethoxy -1,2,3.4 -tetrahydroisoquinoline iYI) l4). 

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