Benzyl isoquinoline alkaloids

A new synthetic route to the phthalide-isoquinoline and spiro-benzyl-isoquinoline alkaloids has been developed. The indeno[2,l-a]benzazepine (105),... 

We move from benzo-fused pyrroles to benzo-fused pyridines and meet quinoline and isoquinolinc. Isoquinolines will feature as benzyl isoquinoline alkaloids in Chapter 51 and their synthesis will mostly be discussed there. In this section we shall concentrate on the quinolines. 

Benzyl isoquinoline alkaloids are made from tyrosine... 

We switch to a completely different kind of alkaloid made from a different kind of amino acid. The benzyl isoquinoline alkaloids have a benzyl group attached to position 2 of an isoquinoline ring. Usually the alkaloids are oxygenated on the benzene ring and many are found in opium poppies (Papaver somniferum). For all these reasons papaverine is an ideal example. 

Complex benzyl isoquinoline alkaloids are formed by radical coupling... 

A more interesting series of alkaloids arises when benzyl isoquinoline alkaloids cyclize by radical reactions. Phenols easily form radicals when treated with oxidizing agents such as Fe(III), and benzyl isoquinoline alkaloids with free phenolic hydroxyl groups undergo radical reactions in an intramolecular fashion through a similar mechanism. Here are the details of some methylations of a class of alkaloids closely related to papaverine. 

Notice that it was not necessary to protect the DH groups—the acetal on the lower ring is not for protection, and this group (methylenedloxy or dioxolan) is present in many benzyl isoquinoline alkaloids. It is formed in nature by oxidation of an MeO group ortho to an OH group on a benzene ring. 

Two other closely related benzyl isoquinoline alkaloids are papaverine (94) and escholamine iodide (95). The resonance of the fully aromatic isoquinoline of papaverine, as would be expected, was observed at 297.2 ppm. In contrast, the quaternary methyl iodide salt form of escholamine iodide shifted the resonance... 

Revision of pyridoxal mechanisms from Chapter 50 and extension to the biosynthesis of benzyl isoquinoline alkaloids. 

As with tropinone, it is possible to make benzyl isoquinoline alkaloids very simply under mild conditions in the laboratory, providing that we use an aldehyde as the carbonyl component. The reaction (sometimes known as the Pictet-Spengler reaction) gives a reduced heterocyclic ring, as does the biosynthesis, but chemical oxidation can be used to give the isoquinoline. 

Fig. 2. Alkaloid biosynthetic pathways are associated with a diverse variety of cell types. The tissue-specific localization (shaded) of enzymes and/or gene transcripts are depicted for the biosynthesis of tropane alkaloids in Atropa belladonna and Hyoscyamus niger roots (A), monoterpenoid indole alkaloids in Catharanthus roseus leaves (B), pyrrolizidine alkaloids in Senecio vernalis roots (C), pyrrolizidine alkaloids in Eupatorium cannabinum roots (D), benzyl-isoquinoline alkaloids in Papaver somniferum vascular bundles (E), and protoberberine alkaloids in Thalictrwn flamtm roots (F).

In conclusion it is now proposed that dopamine and 4-hydroxyphenylacetalde-hyde condense to form (S)-norcoclaurine as the first benzyl isoquinoline alkaloid in the pathway leading to (S)-reticuline. 

M. Rueffer and M.H. Zenk, Distant precursors of benzyl isoquinoline alkaloids and their enzymatic formation, Z.Naturforsch. 42c (1987), 319-332. 

It is because, in the event, secondary metabolites derive from but a handful of primary metabolites along pathways involving generally the simplest reactions in organic chemistry and little rearrangement, that speculation about their biosynthesis can be so accurate. Also invaluable in this regard, is the identification of metabolites of similar structure in the same, or related, species. Thus benzyl-isoquinoline alkaloids [as (2.7)] and morphine (2.2) are both found in Papaver species. It follows reasonably that morphine derives from a compound type of (2.7) (Section 6.3.4). 

Summarizing the data in this chapter one cannot conclude that generally benzyl-isoquinoline alkaloids are stored within the cells or excreted into the medium. It may be that specific types like the protopines or the benzophenanthridines are released into the medium whereas others like the protoberberines are deposited in the vacuole. 

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