Benzylisoquinoline alkaloids classes

The alkaloids range from the ubiquitous indole class to rare examples, such as benzylisoquinoline alkaloids in starfish. This is shown in Chart 8.3.A, which serves as preliminary documentation, until progress in biosynthetic studies allows us more definite conclusions. 

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

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. 

Opium contains over 50 alkaloids that fall into one of two chemical classes the phenanthrene class, including morphine and related derivatives and the benzylisoquinoline alkaloids, such as papaverine (58,Fig. 7.14 see Ref 291 for a complete listing of alkaloids present in opium). In addition to morphine, which on average accounts for 10-20%of opium, other re-... 

A large number of alkaloids have been converted to quaternary salts and examined pharmacologically. The quaternary derivatives of certain bis-benzylisoquinoline alkaloids, which are closely related structurally to one class of curare alkaloids, are potent curarizing agents. Quaternary salts of cinchona alkaloids are effective and have been used in clinical investigations. Quaternary salts of many other alkaloids have been shown to exhibit curariform activity. 

Several types of data based on feeding experiments, isolation of intermediates and in vivo NMR experiments, indicate that norcoclaurine (23) serves as a precursor to both coclaurine (24) and (S)-reticuline (20) (Stadler et al., 1987, 1989), and that (5)-coclaurine (24) serves as a specific precursor to other classes of benzylisoquinoline alkaloids, such as the protoberberines, benzophenanthridines, and morphinandie-nones, as well as for pavine and benzophenanthridine alkaloids in intact plants (Stadler et al., 1987, 1989). The five enzymes involved in the conversion of dopamine and 4-hydroxyphenylacetaldehyde (19) to (S)-reticuline (20) have been elucidated (Frenzel and Zenk, 1990b). 

To date, biosynthetic pathway for four classes of plant alkaloids has been characterized to some extent the benzylisoquinoline, monoterpenoid indole, purine, and tropane alkaloids. Benzylisoquinoline alkaloids (BIAs) are derived from tyrosine and are comprised of 2,500 defined structures found mainly in the Papaveraceae, Ranunculaceae, Berberidaceae, and Menispermaceae [11]. First step of BIA biosynthesis begins with the stereoselective Pictet-Spengler condensation of dopamine and 4-hydroxyphenylacetaldehyde to form (5)-norcoclaurine. Subsequently, through a series of methylations and hydroxylations, (5)-norcoclaurine gets converted into (5)-reticuline, which is the pivotal intermediate for many pharmaceutically important BIAs formed further down in the pathway (i.e., downstream pathways) (Fig. 8.6) [3]. 

The opium poppy (Papaver somniferum L. [Papaveraceae]) latex contains benzylisoquinoline alkaloids and is a widely known source of the analgesic drugs morphine and codeine. The biosynthesis of benzylisoquinoline alkaloids begins with a condensation reaction catalyzed by norcoclaurine synthase of DA [161]. The structural features of benzylisoquinoline alkaloids derived from DA might provide some explanation for the documented affinity of some natural alkaloids of this class, and some synthetic derivatives, for DA receptors [162]. Indeed, the chemical structure of morphine has been used as a template for the development of the PD drug, apomorphine (47). Apomorphine includes a catecholaminergic moiety in its... 

Fig. 8 (5)-Reticuline is the precursor for the various classes of benzylisoquinoline alkaloids...

Opium is the dried, powdered sap of the unripe seed pod of Papaver somniferum, a poppy plant indigenous to Asia minor. Theophrastus described its medical properties in the third century BC, but the Sumerians, ca BC 4000, probably perceived its utility. Arab physicians knew of the dmg, and Arab traders carried it to the Orient where it was used as a treatment for dysentery. Paracelsus is credited with repopularizing the dmg in western Europe in the early sixteenth century by formulating opium into "laudanum", which is still in use. More than 20 different alkaloids (qv) of two different classes comprise 25% of the weight of dry opium. The benzylisoquinolines, characterized by papaverine [58-74-2] (1.0%), a smooth muscle relaxant, and noscapine [128-62-1] (6.0%), an antitussive agent, do not have any analgesic effects. The phenanthrenes, the second group, are the more common and include 10% morphine (1, = R = H), 0.5% codeine [76-57-3], C gH2 N03, (1, R = H, R = CH3), and 0.2 thebaine [115-37-7], C 2H2 N03, (2). 

The position and the number of ether linkages in the molecule have served as a convenient criteria for the classification of these alkaloids into subgroups. Franz Faltis (69, 95) was the first to recognize that all members of this class could be considered as offsprings of the benzylisoquinoline compounds coclaurine (I) or norcoclaurine (II). According to his belief... 

Failure was met with when the formation of the dibenzoxepine ring of cula-rines was attempted by generating an electron-deficient system like that of ortho-quinones or para-quinone methides in ring C of an 8-hydroxybenzylisoquinoline 66). Finally, acid treatment of benzylisoquinoline 95 66) gives benzofuran 96, which is related to the quettamine class of alkaloids 67). 

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