Benzyltetrahydroisoquinoline alkaloids

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... 

In the first place, the structure of the target molecule is submitted to a rational analysis in order to perceive the most significant structural features, and it may be useful to use different types of molecular models at this point. It should be remembered that a molecular structure has "thousand faces" and finding the most convenient perspective may greatly simplifly the synthetic problem. The synthesis of opium alkaloids, for instance, is much simplified if one realises that they are, in fact, derivatives of benzyltetrahydroisoquinoline (18) (see Scheme 3.8). This was indeed the inspired intuition of Sir Robert Robinson which led to the structural elucidation of morphine (19) and to a first sketch of the biogenetic pathway [22], and later on to the biomimetic synthesis of thebaine 20 [23] [24]. 

The intermolecular coupling of phenols is used extensively in what are believed to be biomimetic alkaloid syntheses. Aqueous solutions of iron(lll) salts are most frequently used as the oxidising agent and the dimerization process must involve phenoxy radicals. Examples are the dimerization of orcinol 21 [114] and the formation of bis-benzyltetrahydroisoquinolines 22 [115],... 

Many starfish cause an escape response in usually sessile marine invertebrates [7]. The starfish Dermasterias imbricata causes the sea anemone Stomphia coccinea to release its basal disc from the substratum and swim away on contact. Bioassay-directed fractionation of the starfish extract led to the isolation of the compound found to elicit this response, the benzyltetrahydroisoquinoline alkaloid imbricatine (646). The structure of compound 646 was elucidated by spectral data interpretation. The amino acid residue in imbricatine is related to the thiol containing amino acids ovothiols A-C. Imbricatine (646) is active in both LI210 and P388... 

The alkaloid content of curare is from 4% to 7%. The most important constituent in menispermaceous curare is the bis-benzyltetrahydroisoquinoline alkaloid (+)-tubocurarine (Figure 6.48). This is a monoquaternary ammonium salt, and is water soluble. Other main alkaloids include non-quaternary dimeric structures, e.g. isochondrodendrine and curine (bebeerine) (Figure 6.48), which appear to be derived from two molecules of (R)-N-methylcoclaurine, with the former also displaying a different coupling mode. The constituents in loganiaceous curare (from calabash curare, i.e. Strychnos toxifera) are even more complex, and a series of 12 quaternary dimeric strychnine-like alkaloids has been identified, e.g. C-toxiferine (toxiferine-1) (see page 359). 

The family of the Papaveraceae includes 31 genera and approximately 700 species (2). The alkaloids contained therein are derivatives of the 1-benzyltetrahydroisoquinoline alkaloid reticuline (1). For the classification and chemical data of the described alkaloids (3-5) as well as for the pharmacodynamic properties of morphine and codeine (6, 7) see reviews. Some pharmacological aspects have been dealt with by Shamma (5) and Krueger et al. (8). 

Pathirana, C. and Andersen, R. J., Imbricatine, an unusual benzyltetrahydroisoquinoline alkaloid isolated from the starfish Dermasterias imbricata, J. Am. Chem. Soc., 108, 8288, 1986. 

Another heterocyclic nucleus investigated as a basis for analgesics is isoquinoline with a fully reduced heterocycle moiety and carrying a 1-phenethyl substituent. The series was reported by Hoffman-La Roche in 1960(1S) but no further information has appeared since 1965, when a full account of the work appeared in deStevens book Analgetics.(16) 1-Benzyltetrahydroisoquinoline alkaloids such as papaverine occur in opium but lack analgesic properties, while others, for example, a-narcotine (noscapine), have antitussive activity. Some of the novel 1-phenethyl analogs 9 behaved as analgesics in mice after sc administration when tested by the tail-flick assay, but potency levels were mostly low and close to that of codeine. Details of the most active compounds are shown in Table 11.2. All have 6,7-methoxyls and 4 -substituents with... 

Of all the alkaloid-producing families, one of the most prolific is the Rutaceae (Waterman, 1975). The alkaloids obtained included 1-benzyltetrahydroisoquinoline, simple tryptophan derivatives, imidazoles and, most commonly, quinoline alkaloids originating from anthranilic acid. The Rutaceae was the only family in which the direct use of anthranilic acid in alkaloid production occurs to any extent. 

The ( )-benzyltetrahydroisoquinoline (149), with 3, 7- rather than 4, 7-dihydroxylation as in (142), was coupled - using potassium ferricyanide to the spiroketone (ISO), as a pair of diastereoisomers (up to 50% yield). One stereoisomer, on reduction of carbonyl and aqueous acid treatment, was converted to the new spirodienone (151), the alkaloid orientalone. 

Reviews have appeared on the distribution and systematic significance of alkaloids of the Rutaceae and of the Papaveraceae and on the taxonomic significance of benzyltetrahydroisoquinoline-derived alkaloids in particular. The isolation of alkaloids from plants in the Soviet Union has been discussed. In addition to continued alkaloid screening studies, surveys encompassing detection of alkaloids have been carried out on plants from Argentina, India, and Morelos State, Mexico. ... 

Five aporphines and an unknown base (HBr, m.p. 215—218 "C) also isolated Main alakloids were aporphines, but two minor phenolic alkaloids thought to be 1-benzyltetrahydroisoquinolines were also isolated Four aporphine alkaloids also isolated. 

Aporphine-Benzyltetrahydroisoquinoline Dimeric Thalictrum Alkaloid Subgroups... 

Approximately ten years ago, it was observed that the Thalictrum aporphine-benzyltetrahydroisoquinoline dimeric alkaloids could be conveniently grouped into three subgroups, and that certain empirical observations could be drawn from these subgroups [1]. The alkaloids were drawn in a uniform fashion, with the benzyltetrahydroisoquinoline half on the left side (numbered 1 to 14 in a standard fashion) and the aporphine half on the right side (numbered 1 to 11 in a standard fashion). The following observations were made at that time ... 

Waters, who has been thinking on identical lines in Oxford, has pointed out to the author that an extension of this free-radical mechanism can account for the production of ourare alkaloids from those of the benzyltetrahydroisoquinoline series. 

Thalfine (102), a benzyltetrahydroisoquinoline-benzylisoquinolinc alkaloid, is the ring B oxidized derivative of thalfinine (103). Thalfine (102) has also only been isolated from Thalictrum foetidum and Thalictrum minus. 

There are two subgroups of these type of alkaloids. The alkaloids of the first subgroup, thalictrinine (220) and dibydrothalictrinine (198), are characterized by being benzyltetrahydroisoquinoline-benzylisoquinoline dimers. Thalictrinine (220) is characterized by having a carbonyl group at the a -carbon, while dibydrothalictrinine (198) is the reduced form and bears a Q-hydroxy group at the a -carbon. 

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