1-tetrahydrobenzylisoquinoline alkaloids

Figure 12.13. The biosynthetic pathway for L-tyrosine derived tetrahydrobenzylisoquinoline alkaloids. The core production of (5)-reticuline and the branch points for berberine, macarpine, and morphine production. Reprinted with permission from Chou and Kutchan (I998)" .

Baxendale, I.R., Davidson, T.D., Ley, S.V. and Pemi, R.H. (2003) Enantioselective synthesis of the tetrahydrobenzylisoquinoline alkaloid (—)-norarmepavine using polymer supported reagents. Heterocycles, 60, 2707-2715. 

The simplest alkaloids of this series are those in which the nitrogen-containing ring of the isoquinoline system is completely saturated (Fig. 32.7). Quaternary bases also are found. Tetrahydrobenzylisoquinoline alkaloids are widespread and are found in almost all the families that possess benzylisoquinoline alkaloids. About 100 alkaloids of this type are known (Guinaudeau and Bruneton, 1993). 

From the biogenetic point of view, the most important tetrahydrobenzylisoquinoline alkaloids is undoubtedly (+ )-reticuline (20). This alkaloid is the precursor of a number of more elaborate compounds (Fig. 32.6) and is widely distributed. (+ )-Reticuline is first synthesized and then converted to (- )-reticuline (21) in the plant (Fig. 32.8) (Bat-tersby and Foulkes, 1965 Beecher and Kellelior, 1988). Reticuline occurs in the ( + )-form in Annona reticulata (An-nonaceae), Cinnamomum camphora (Lauraceae), and in... 

The simplest derivatives of the tetrahydrobenzylisoquinoline alkaloids are the aporphine alkaloids (Fig. 32.12). Aporphine alkaloids (about 650) are widespread and occur in almost the same families as benzylisoquinoline alkaloids (Guinaudeau and Bruneton, 1993 Kametani and Honda, 1985). Several subgroups of aporphine alkaloids are known [noraporphines, dehydroaporphines (34), oxoaporphines (35), dimeric apor-phines, and phenanthrenes (36)] (Fig. 32.13) (Cave et al., 1987). The aporphine alkaloids present in members of the Annonaceae and in the genus Thalictrum (Ranunculaceae) have been reviewed (Cave et al., 1987 Schiff, 1987). 

In an important series of experiments involving and doubly labeled precursors, Wilson and Coscia have shown that in Papaver orientate L., dopa may be metabolized in at least two ways to yield dopamine and 3,4-dihydroxy-phenylpyruvic acid. Decarboxylation of dopa to yield dopamine is actually favored over transamination to the substituted pyruvic acid. Norlaudanosoline carboxylic acid is the first tetrahydrobenzylisoquinoline alkaloid to be formed, and it is readily converted to norlaudanosoline through the presumed intermediacy of an imine (see Scheme 2.10). ... 

Chattopadhyay S, Shamma M (1982) A convergent synthetic route to the quettamines and the 7,8-dioxygenated tetrahydrobenzylisoquinoline alkaloids. Heterocycles 19 697-701 Cheng CC, Zee-Cheng RKY (1981) The N-0-0 triangulation hypothesis - an assessment after one decade. Heterocycles 15 1275-1283... 

Enzymatic Formation of Tetrahydrobenzylisoquinoline Alkaloids 2.1 (S)-Norlaudanosoline Synthase... 

The year under review has witnessed the isolation and structural elucidation of no less than nine new aporphines, as well as of five aporphine-benzylisoquinoline dimers. Two of these five aporphine-benzylisoquinolines, namely kalashine and khyberine, are the first such dimers known to be substituted at C-l 1 of the aporphine moiety. Thallium(m) trifluoroacetate is an oxidizing agent which effects the cyclization of tetrahydrobenzylisoquinolines to aporphines in satisfactory yields.1 A listing of aporphinoid alkaloids has appeared.2... 

A second major structural type, commonly known as benzylisoquinoline (BIQ) or tetrahydrobenzylisoquinoline (TBIQ), alkaloids constitute one of the two most numerous types of alkaloids. As is true for the simple isoquinoline alkaloids mentioned above, all are derived from a 3,4-dihy-droxytyramine (dopamine) precursor condensed with a carbonyl compound. In this case, the precursor of most, if not all, benzylisoquinoline alkaloids is 4-hydroxyphenylacetal-dehyde. Benzylisoquinoline alkaloids are found in a limited group of plant families some have great medical impor-... 

Benzylisoquinoline (BIQ) or tetrahydrobenzylisoquinoline (THBIQ) alkaloids are formed by condensation of dopa-... 

Tetrahydrobenzylisoquinoline and derived alkaloids have physiological effects in most animals (Schiff, 1987). 

Kupchan and his colleagues were the first to use vanadium oxytrifluoride in trifluoroacetic acid (VOF3-TFA) for the oxidation of tetrahydrobenzylisoquinolines in the synthesis of aporphines and related alkaloids. This significant development has allowed the ready preparation of a variety of aporphines in high yield, and has also provided an insight into possible modes of aporphine biogenesis in plants. 

Five isoquinoline alkaloid dimers with pavine and tetrahydrobenzylisoquinoline moieties, known as hervelines A-D (VIII.1-VIII.4) and HB (VIII.5), have been isolated from the stem bark of Hernandia voyronii Jum. (8,9,48), used as an adjuvant to chloroquine in Malagasy herbal practice and against chronic malaria (8,9). Two of them, harvelines B (VIII.2) and C (VIII.3) reversed in vitro chloroquine resistance to the resistant strain of P. falciparum (9) and exhibited moderate antimalarial activity (8,9,48). Harveline HB (VIII.5), an alkaloid whose structure has not been determined, also potentiated the effect of chloroquine and showed weak in vitro cytotoxicity against HeLa cells (48). 

Thalicarpine was isolated from Cocculus laurifolius (73) in 1982. It is one of the rare examples of a tetrahydrobenzylisoquinoline-aporphine dimer. Thalicarpine seems to originate biogenetically from the oxidative coupling of two molecules of reticuline forming initially a Bis-BIQ. A second oxidative coupling, this one intramolecular, leads to the final product (Scheme 22). This alkaloid was also isolated from Thalictrum spp. (Ranunculaceae) and Hernandia ovigera (Hemandiaceae). 

---