The Benzylisoquinolines

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). 

Although this isoquinoline at first bears little structural resemblance to morphine (108), careful rearrangement of the structure (A) shows the narcotic to possess the benzylisoquinoline fragment within its framework. Indeed, research on the biogenesis of morphine has shown that the molecule is formed by oxidative coupling of a phenol closely related to papaverine. 

Scheme 2 Structures of the benzylisoquinoline alkaloid laudanosine and its transformed products (2, 3, and 4) by utilizing Pseudomonas putida incubated at 30 °C for 96 h [47]... 

Figure 3.10. An example of a common feature of some types of alkaloid biosynthesis, the linking of a substance with an amino group (such as the amino acid shown here) and a substance with an aldehyde group (in this case, comprising the first stages of the route to the benzylisoquinoline alkaloids).

Benzylisoquinolines,2 A short synthesis of the benzylisoquinoline (4) involves reaction of lithiomethyl isocyanide with 2 equivalents of piperonal (1) to give, after acetylation, the oxazoline 2, formed via a 2-lithiooxazoline. The remaining steps are outlined in equation (I). 

A survey of the H NMR spectra of the benzylisoquinoline-aporphine alkaloids [60]—[65] enables assignment of some of the methoxyl proton resonances. The lowest frequency methoxyl proton signals at ca. 8 3-58 are characteristic of a 7 -methoxyl function, and the 10-methoxyl protons are found to absorb to higher frequency of 8 3-90. (52) This latter shift is also shown in the spectrum of fetedine [66] the aromatic proton signals of which are completely resolved at 220 MHz. (53) In the... 

Northalicarpine (498), C40H46N2Og, from Hernandia peltata Meissner, was identified by MS and FT NMR. It is the first nor aporphine-benzylisoquinoline dimer demethylated on the aporphine (rather than the benzylisoquinoline) nitrogen (549). 

Protoberberine and Related Alkaloids.—The benzylisoquinoline skeleton [as (64)], which appears in diversely modified form in various alkaloids [see, e.g., (66)—(71)], is formed from two molecules of tyrosine label from this amino-acid often appears equally divided over the two halves of the alkaloid examined,1,219 but dopa (60), like dopamine (59), is incorporated only into the isoquinoline moiety cf. Vol. 6, pp. 17, 26 Vol. 7, p. 10 Vol. 9, p. 8). 

Partial reduction of the benzylisoquinolines (33 R1 = Me, R2 = CH2Ph) and (33 R1 = CH2Ph, R2 = Me) with sodium borohydride gives the corresponding 1,2-dihydro-compounds, which are cyclized by phosphoric and formic acids (with removal of the benzyl group) to the pavines caryachine (34 R1 = Me, R2 = H) and isocaryachine (34 R1 = H, R2 = Me),66 but attempts to repeat... 

Details of the Diels-Alder addition of aromatic nitroso-compounds to thebaine to give adducts (117), the ring-opening of these to 14-hydroxylamino-compounds (118 R = OH), the reduction of these to 14-arylamino-compounds (118 R = H), and cyclization to (119) have been published.162 Dihydro-thebaine-< 4-phenyl ether (120 R = OPh) has been transformed into the benzylisoquinoline (121) by potassamide in liquid ammonia, but the same transformation could not be effected with the free phenol (120 R = H) or with the deoxy-compound (120 R = H).163... 

The readily available reagent diphenyl selenoxide has been used as a mild and selective oxidant in the synthesis of aporphines (and homoaporphines). When the benzylisoquinoline (13) was treated with one equivalent of the reagent at room temperature in methanol, and the product was O- methylated with diazomethane, the aporphine (14) was obtained in 80% yield. The alternative use of chloranil, which is a commonly used oxidant for catechols, yielded less than 10% of (14).20... 

Using a combination of transgenic E. coli and S. cerevisiae engineered with the appropriate expression vectors, the benzylisoquinoline alkaloid reticuline, the... 

The benzylisoquinoline alkaloids are widely distributed in nature and are intermediates in the biosynthesis of alkaloids of this family (2, 3). It is not surprising therefore that several groups (6, 7, 15, 23) have examined their spectra. Among the alkaloids that have been studied are reticuline (26) (7), norlaudanosine (27) (7), laudanosine (28) (6, 15), and the cis- and trans-N-oxides of laudanosine, 29 and 30, respectively (7). The chemical shifts of laudanosine are recorded in Table IV and the structures of the alkaloids may be found in Fig. 4. 

The bisbenzylisoquinoline alkaloid, isochondodendrine (33), (Fig. 5 and Table V) and its (9-methyl and O-acetyl derivatives have been studied by 13C NMR (23). The aliphatic carbon atoms of this symmetrical molecule were assigned by comparison to the benzylisoquinoline alkaloids and by the off-resonance spectrum. The oxygen substituent at C-8 caused a shielding of C-l. In the aromatic region of the spectrum C-9 and C-l2 had chemical shifts which remained essentially constant in all derivatives examined. Methylation and acetylation of the phenolic group produced characteristic shift changes which allowed the assignment of C-4a, C-6, C-7, C-8,... 

Formamidines also activate secondary centres towards lithiation, and have been used extensively in the synthesis of the benzylisoquinolines, where the lithiation takes place at a benzylic position. Formamidines bearing chiral substituents (for example the serine-derived 85) allow the introduction of asymmetry at such centres.58... 

In the reaction of the benzylisoquinoline 72 with dimsyl sodium, it has been suggested that a proerythrinadienone intermediate results from nucleophilic attack on a benzyne formed in the lower ring. This postulated intermediate was thought then to rearrange to an iminium salt which is trapped by the dimsyl sodium to give 73a, which on reduction and desulfuration would finally lead to dibenzazonine 74 (60) (Scheme 19). Later work, however, proved that the product of the dimsyl sodium treatment is instead the dibenz[6,/]azonine (73b), which is formed by N-attack on the intermediate benzyne followed by cleavage of the C-N+ bond (67). 

Also examined as precursors in these experiments were four possible bisphenethylamines derived from (32) as well as the acids (38) used to synthesize the benzylisoquinoline precursors. Consistent with biosynthesis of (36) and (37) along the pathway deduced above (Scheme 6) they were not incorporated.48... 

An improved method for the removal of methylenedioxy-groups in alkaloids of the benzylisoquinoline and tetrahydroberberine series has been derived. Alkaloids such as remneine (26) can be converted into the dihydroxy-bases (27) by treatment with boron trifluoride followed by 5-chloro-5-phenyl-l//-tetrazole and subsequent hydrogenolysis of the resulting bis-tetrazolyl ethers. The yields in the process are good.39... 

An examination of Corydalis ochotensis has been followed by the isolation of the benzylisoquinoline aobamine (28) and the oxidized base aobamidine (29).40... 

Bischler-Napieralsky synthesis of the benzylisoquinoline (39), iV-formylation, cyclization, and oxidation has given the pentamethoxy-compound (40), identical with glabrine dimethyl ether and glabrinine methyl ether.114 Reticuline N-oxide has... 

RUEFFER, M., EL-SHAGI, H., NAGAHURA, N ZENK, M.H., (S)-Norlaudanosoline synthase The first enzyme in the benzylisoquinoline biosynthetic pathway. FEBSLett., 1981,129, 5-9. 

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