Of benzylisoquinolines

One complication of the Pictet-Spengler condensation of benzylisoquinolines 24 is regiochemical control in the closure of ring C when activating substituents are present on the D ring. Experimentally, the ring-closure reaction yields predominantly the 10,11-disubstituted product 23 rather than the 9,10-disubstituted product 25. ... 

This example demonstrates how widely chemical profiles can differ between two populations separated by only a matter of kilometers in this case, populations of halictrum minus L. in the Voj vodina area of Serbia (Popovic et al., 1992) (Fig. 2.20). Plants collected at 500 m in the Fruska Gora Mountains (Novi Sad) afforded a comparatively complex mixture of benzylisoquinoline alkaloids that consisted of... 

The above syntheses were preceded by model investigations (143), as a result of which several unnatural 1,2-secoisoquinolines, e.g., 175-177 were synthesized (Scheme 30). Finally, a reaction reported by Bentley and Murray (144) is worth mentioning since it may serve as a model for biosynthetic conversion of benzylisoquinoline alkaloids to the seco analogs (Scheme 30). Heating of ketolaudanosine (174) with methyliodide unexpectedly formed a seco derivative 175 along with to the quaternary salt. By all probability it arose from the methiodide of 174 by air oxidation followed by ring opening. 

PAULI, H.H., KUTCHAN, T.M., Molecular cloning and functional heterologous expression of two alleles encoding (5)-Y-methylcoclaurine 3 -hydroxylase (CYP80B1), a new methyl jasmonate-inducible cytochrome P-450-dependent monooxygenase of benzylisoquinoline alkaloid biosynthesis, Plant J., 1998,13, 793-801. 

Enamides 163 undergo photochemical conrotatory six-electron electrocyclic reactions to yield the dihydro intermediate 164, which in turn yields the fraws-fused cyclic product 165 (equation 105) by a (l,5)-suprafacial hydrogen shift. Several natural product syntheses like that of benzylisoquinoline and indole type alkaloids can be achieved by this type of photocyclization (equations 106163, 107164, 108165 and 109166). 

Noscapine is another opium alkaloid of benzylisoquinoline group. It is used as antitussive with no analgesic and drug abuse or drug dependence property. It is contraindicated in asthmatic patients as it releases histamine which can cause bronchoconstriction. 

Singly bridged dimers resulting from C—C coupling had been produced by in vitro oxidation of benzylisoquinoline monomers, but this is the first report of their natural occurrence. Pisopowine-type dimers may be biogenetic intermediates in the formation of alkaloids of the funiferine (71) and tiliacorine (65) groups (566). 

Yeast-based production of benzylisoquinolines represents a consistent and challenging continuation in the development of transgenic Saccharomyces for generation of complex plant-derived alkaloids [123]. In an ambitious approach, several yeast strains have been successfully designed containing for instance ... 

Other investigations of benzylisoquinoline biotransformations have been made by the groups of Kametani and Rosazza. The Japanese workers... 

This volume of The Alkaloids presents timely reviews of three groups, the Erythrina, Lythraceae, and C20-diterpenoid alkaloids. The chapters are organized in the traditional manner and cover all aspects of the recent chemistry of these groups. A useful catalogue of C20-diterpenoid alkaloids is also included. One chapter is devoted to a discussion of the 13Carbon spectra of benzylisoquinolines and the fifth chapter collects and reviews work on the microbial and in vitro transformations of the alkaloids. Both subjects have attracted increasing attention in recent years. 

Liscombe, D.K., MacLeod, B.P., Loukanina, N. et al. 2005. Evidence for the monophyletic evolution of benzylisoquinoline alkaloid biosynthesis in angiosperms. Phytochemistry 66 2501-2520. 

The isoquinolines 70 are an important subclass of the tertiary N-benzylamides, and their lithiation and benzylation is an important way of synthesising a range of benzylisoquinoline alkaloids.4849... 

RUEFFER, M., ZENK, M.H., Distant precursors of benzylisoquinoline alkaloids and their enzymatic formation. Z. Naturforsch, 1987,42C, 319-332. 

FACCHINI, P.J., BIRD, D.A., Developmental regulation of benzylisoquinoline alkaloid biosynthesis in opium poppy plants and tissue cultures. In Vitro Cell. Dev. Biol.- Plant, 1998,34, 69-79. 

The stereospecific condensation of dopamine with 4-hydroxyphenylacetaldehyde is catalyzed by NCS to yield S-norcocIaurene, the central precursor of thousands of benzylisoquinoline alkaloids, including morphine. This poorly characterized, but key enzyme in benzylisoquinoline alkaloid biosynthesis has recently been purified to homogeneity, and its kinetic properties have been elucidated.35 NCS occurs as a 28 kDa dimer composed of 15 kDa... 

The mammalian alkaloids are formed from aromatic amino acids and their metabolically derived amines by reaction with carbonyl substrates at physiological pH. The reaction is catalyzed by acid and is commonly referred to as the Pictet-Spengler cyclization (I0a,b,II). Winterstein and Trier in 1910 proposed that the Pictet-Spengler reaction might be of significance in the biosynthesis of benzylisoquinoline alkaloids in plants (5a). The carbonyl compounds participating in the Pictet-Spengler synthesis of mammalian alkaloids are aldehydes and a-keto acids, which are produced... 

The biosynthesis of benzylisoquinolines has recently been investigated by Zenk and colleagues in great detail, and the results of their work have been reviewed 209a,b). Two major metabolites detected by incubation of THP with soluble rat liver and brain supernatants, which were found in the urine of rats given the alkaloid and in the urine of parkinsonian patients, were the berbines 124 and 125, shown in Fig. 30 (2/0). They were found to be identical with the compounds obtained in the condensation of THP with formaldehyde under slightly acidic conditions 211). 

Investigations of a number of enzymes involved in tyrosine conversion have suggested that the first committed step in the biosynthesis of benzylisoquinolines involves a Picfef-Spengler-type condensation of dopamine with 4-hydroxyphenylacetaldehyde (which derived from tyrosine) to give (S)-norcoclaurine, a compound that has proved to be pivotal in the formation of all benzylisoquinoline alkaloids (Fig. 2.5). The condensafion sfep is cafalysed... 

Metalation of benzylisoquinoline with LDA was chosen and gave better results than other tested bases on condensation with 38 to give 39 as a tautomeric mixture. Construction of the... 

The cytochrome P450 responsible for the oxidation of (S)-N-methylcoclaurine to (S)-3 -hydroxy-N-methylcocluarine has been overexpressed in opium poppy plants, and morphinan alkaloid production in the latex is increased subsequently to 4.5 times the level in wild-type plants (58). Additionally, suppression of this enzyme resulted in a decrease in morphinan alkaloids to 16% of the wild-type level. Notably, analysis of a variety of biosynthetic gene transcript levels in these experiments supports the hypothesis that this P450 enzyme plays a regulatory role in the biosynthesis of benzylisoquinoline alkaloids. Collectively, these studies highlight that the complex metabolic networks found in plants are not redirected easily or predictably in all cases. 

Fig. 27 Biosynthetic zinterrelationships of the major classes of benzylisoquinoline alkaloids.

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. 

Because benzylisoquinolines have been available synthetically (in racemic form) for decades, there is quite a bit of chemistry known regarding their use as key intermediates in the synthesis of a number of more complex isoquinoline alkaloids. The asymmetric synthesis of benzylisoquinolines has been used to complete total synthesis of representative members of several of these alkaloid classes. As shown in Figure 6, the protoberberine alkaloid norcoralydine, the aporphine alkaloid ocoteine, the isopavine alkaloid reframoline and the morphinan 0-methylflavinantine have been made available in optically active form for the first time (except by isolation or resolution) using this approach. 

The scavenging and iron-reducing properties of a series of benzylisoquinoline alkaloids and synthetic benzylisoquinoline compounds was studied. Glaucine was found to act as a scavenger of the hydroxyl radical in the deoxyribose degradation by Fe+3-EDTA + H202 [265],... 

From the viewpoints of biological activities and structural architectures, a variety of benzylisoquinoline alkaloids have been chosen as synthetic target molecules. These alkaloids are well known to be biosynthesized by oxidative phenol coupling via a radical mechanism. However, White and coworkers demonstrated that hypervalent iodobenzenes are effective oxidants for syntheses of morphinane-type alkaloids such as (—)-codeine °. 

Of phenolic oxidations using vanadium compounds, intramolecular oxidative phenolcoupling reactions are quite attractive from the viewpoint of natural products synthesis. A number of benzylisoquinoline alkaloids, lignans and neolignans are well known to be produced, in a key step, by oxidative radical coupling of open phenolic precursors. 

In particular, extensive studies on biomimetic syntheses of benzylisoquinoline alkaloids using vanadium compounds were made independently by Kupchan and Schwartz. ... 

SCHEME 120. Oxidative coupling of benzylisoquinoline 626 with metal compounds... 

Of a variety of metal compounds described in this section, iron compounds represented by ferric chloride (FeCF) and potassium ferricyanide [K3Fe(CN)6] have long been used for phenolic oxidation, particularly for biomimetic syntheses of benzylisoquinoline alkaloids and neolignans ° . ... 

As already shown in Scheme 101, an oxidative cross-coupling of two different phenols takes place, but the yield is relatively low. In order for satisfactory cross-coupling to occur it is essential that the phenoxy radicals will be generated to a comparable extent from each of the substrates. Based on biogenetic consideration of benzylisoquinoline alkaloids, extensive studies on oxidative cross-coupling of two different phenols have been undertaken... 

Biomimetic syntheses of benzylisoquinoline alkaloids have been performed by intramolecular oxidative phenol-coupling reactions using a variety of oxidants. Of them, K3Fe(CN)e has long been used for alkaloid syntheses The amine 732 bearing... 

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