Benzylisoquinolines structures

In this chapter alkaloids with the typical 1-benzylisoquinoline structure will be considered. It is a continuation and a complement to that written by Alfred Burger in Volume IV, p. 29, of this series. 

This base, isolated from Berberis nepalensis Sprang, by Chatterjee 217) and to which a benzylisoquinoline structure was assigned, has been shown to be identical with jatrorrhizine 218). 

On the other hand, evidence was accumulating showing that the two aromatic units derived from tyrosine were not identical in the step of condensation leading to the benzylisoquinoline structure. This had already been pointed out by Rapoport et al. (223) in a study on the distribution of the radioactivity in the morphine isolated from P. somni-ferum grown in an atmosphere of labeled carbon dioxide. Similar conclusions were reached in an investigation of the biogenesis of hydrastine in Hydrastis canadensis L. fed with labeled tyrosine, where the ratio of the radioactivity of the two carbon atoms representative of the original tyrosine molecules indicated unequal incorporation (224). 

It is not surprising that variations in the ratio of incorporation of the two units of tyrosine were found when the experiments were carried out under different conditions (222). It is evident that several factors in the plant must affect the concentrations of labeled dopamine (CLIII) and 3,4-dihydroxyphenylpyruvic acid (CLIV) derived from the original tyrosine, and whose condensation leads to the benzylisoquinoline structure. 

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]... 

Whereas the Annonaceae are characterized primarily by benzylisoquinoline alkaloids, two pyrrolidine alkaloids have recently been found in species belonging to this family. Squamolone (29) was isolated from Annona squamosa L. by Chinese workers in 1962 (68). Despite careful spectroscopic investigation and a total synthesis (Eq. 1), squamolone was assigned the incorrect diazepine formula 30. The correct structural formula (29) was later established by an unambiguous synthesis of 30 (Eq. 2). Compounds 29 and 30 proved to have very similar spectroscopic properties, which could justify the early confusion (69). 

The parent dibenzopyrrocoline 3 was prepared by von Braun and Nelles (37) from 1-benzylisoquinoline when heated with copper powder at elevated temperatures. The product obtained was a yellow, weakly basic solid, melting at 238°C and reduced to a tetrahydro derivative by tin and hydrochloric acid. However, no structure was assigned to this product. 

Papaverine (Figure 6.45) is a benzylisoquinoline alkaloid, and is structurally very different from the morphine, codeine, thebaine group of alkaloids (morphinans). It has little or no analgesic or hypnotic properties put possesses spasmolytic and vasodilator activity. It has been used in some expectorant preparations, and in the treatment of gastrointestinal spasms, but its efficacy was not substantiated. It is sometimes used as an effective treatment for male impotence, being administered by direct injection to achieve erection of the penis. 

Berberis actinacantha Mart, ex Schult. (Berberidaceae) furnished (+)-epiberbivaldine (475), C36H3gN206, amorphous, [ot] 5 +45.7° (c 0.12, CHC13). Epiberbivaldine is di-astereomeric to the known berbivaldine (89). Structure proof was by NOEDS and di-enone-phenol rearrangement to an aporphine-benzylisoquinoline dimer (556). 

Epivaldivianine (476), C37H40N2O6, amorphous, from Berberis valdiviana Phil., has [a] 5 +69.4° (c 0.1, MeOH). Structure proof consisted of NMR correlations and rearrangement of the alkaloid in acid to the known (—)-kalashine (177). Epivaldivianine is the third epi proaporphine-benzylisoquinoline dimer (the first two being 108 and 475) (557). 

Natalinine (491), C25H23N05, amorphous, is a minor alkaloid of Berberis empetrifolia Lam. MS and high-resolution NMR established the skeletal structure, and CD indicated the (R) configuration (561). Natalinine may be derived biogenetically from catabolism of an aporphine-benzylisoquinoline dimer [such as pakistanine (92), a major co-occurring alkaloid] (561), or by rearrangement of a coyhaiquine (107)-type dimer (562). 

Carbon-13 n.m.r. spectroscopy has been used to study benzylisoquinoline and tetrahydroisoquinoline alkaloids and their JV-methyl quaternary salts.30 N-Benzylpapaverinium bromide has been shown to undergo aerial oxidation in alkaline solution to 2-benzyl-6,7-dimethoxyisoquinolone and to give bases of general structure (10) with methylamine, benzylamine, and pyrrolidine.31 Chlorosulphonation of papaverinol affords the sulphonic acid ester (11), mild hydrolysis of which yields the acid (12), which with diazomethane is esterified and dehydrated to (13).32 N-Methyl-l,2-dihydropapaverine has been shown by kinetic studies and orbital-symmetry requirements to rearrange to the salt (14) by the route previously postulated.33... 

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 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... 

Batrachotoxins, 187-194 biological activity. 189, 191 occurrence, 192-194 structures, 187-190 Benzylisoquinolines, 142-144 biosynthesis, 153 Berbines, acetaldehyde, 153, 155 Betaine, fluorescent, 135 Bicyclic alkaloids, 199 decahydroquinolines, 206-212 histrionicotoxins, 200-206... 

Benzylisoquinolines, of which more than 2500 structures are known, are found as defence chemicals within the families of the superorder Mag-noliids (comprising Piperales, Laurales and Magnoliales with the families Annonaceae, Eupomatiaceae, Aristolochiaceae, Magnoliaceae, Lau-raceae, Monimiaceae), Nelumbonaceae and Ranunculales (i.e. Berberidaceae,... 

Speculations on the biosynthesis of berberine date back to the beginning of the century (121). Most of the early proposals recognized the structural relationship of the protoberberine alkaloids with the simpler benzylisoquinoline bases, from which it was supposed that they are derived. The additional carbon atom necessary for the formal conversion... 

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