Protoberberine alkaloids of poppy contain quaternary protoberberine salts e.g. berberine and coptisine, or tetrahydroprotoberberine derivatives, for example canadine. These alkaloids bear substituents at C-2, C-3, C-9 and C-10 positions without exception. Protoberberine alkaloids were reviewed earlier in the monograph The Alkaloids (Bhakuni and Jain, 1986; Jeffs, 1967).
9.1 Berberine
In a patented process for chromatographic separation, the isolation of appreciable quantities of berberine was described from opium poppies (Ose et al., 1960). Later, negative tests were reported for berberine in several varieties of opium poppy by means of paper chromatography and paper electrophoresis (Hakim et al., 1961).
The detection of berberine in opium poppy was unsuccessful even by a carrier dilution method (Brochmann-Hanssen et al., 1971c). Battersby et al., detected berberine by using radioactively labelled precursors (Battersby et al., 1975).
The evidence indicative of the existence and structures of the ammonium form and the pseudobase form have been elucidated for berberine or coptisine (Beke, 1958). Berberine chloride may be reduced to canadine with a variety of reducing agents. This reduction may be stopped at the dihydroberberine stage. Berberine is unstable in the presence of concentrated alkali yielding oxyberberine. The Cannizzaro reaction of berberine leads to dihydroberberine and oxyberberine, whereas reduction with sodium borohydride gives tetrahydroberberine (Bentley and Murray, 1963b).
Oxidation of berberine with potassium ferricyanide affords a dimer (oxybisberberine), which can be converted to 8-methoxyberberine phenolbetaine. The latter compound rearranges into a mixture of α- and ß-hiydrastines (Moniot and Shamma, 1976). Photooxidation of oxyberberine gives an intermediate ?-lactol, which can be reduced to (±)-ß-norhydrastine (Shamma et al., 1977a). Hydrolysis with concomitant air oxidation of polyberbine, derived from berberine chloride, yields a papaveraldine-like compound (Murugesan and Shamma, 1980). Oxidation of berberine with nitric acid results in berberidic acid as main product (Chinnasamy and Shamma, 1979).
Photo-oxygenation of berberine chloride gives 8-methoxyberberinephenolbetaine, which can be converted to α- and ß-hydrastines (Hanaoka et al., 1977). 8- Methoxyberberine phenolbetaine proved to be a starting material for the synthesis of non-naturally occurring protoberberines (Hanaoka et al., 1982a).
Berberine reacts with nucleophilic anions, e.g. cyanide ion or the anion of acetone, to undergo a C-8 substitution. C-8-Substituted products were formed in the reaction of berberine with dichlorocarbene (Manikumar and Shamma, 1981) and diazoacetic ethyl ester (Göber, 1972).
Degradation of berberine to naphthalene derivatives has been reported on the action of acetic anhydride and sodium acetate (Shamma et al., 1975, 1977b).
Kametani et al. (1969c) reported the total synthesis of (±)-canadine, whose dehydrogenation with iodine afforded berberine iodide. Berberine can be prepared by the photochemical reaction of allocryptopine (Dominguez et al., 1967).
The PMR and UV spectra of berberine have been studied (Blaskó et al., 1988; Hruban et al., 1970; Jewers et al., 1972).
9.2 Canadine
Canadine has been detected in Kirghiz opium (Bessonova et al., 1970). It has also been detected in poppy in tracer experiments (Battersby et al., 1975). Canadine is readily oxidized by atmospheric oxygen to berberine and it is doubtless that berberine is a constituent of all plants which contain canadine. The synthesis of canadine was reported in the Mannich reaction of 2'-bromobenzyltetrahydroisoquinoline followed by O-methylation (Kametani et al., 1969c, 1971a). Canadine can be prepared from hydrastine with the appropriately substituted homophthalic anhydride (Cushman and Dekow, 1979).
The synthesis of canadine has been reported from the corresponding isochromanone (Narasimhan et al., 1981, 1983). The asymmetric synthesis of canadine has also been described (Pyne, 1987).
Hydrogenation of ophicarpine acetate yields canadine (Ohta et al., 1963a) which clarifies the absolute configuration of the latter substance.
Canadine undergoes C-8-N cleavage on the action of cyanogen bromide (Albright and Goldman, 1969; Rönsch, 1974; Sallay and Ayres, 1963).
Numerous papers have appeared that deal with the NMR and MS spectra of canadine (Chen and MacLean, 1968; Hughes et al., 1976; Janssen et al., 1990; Richter and Brochmann-Hanssen, 1975).
9.3 Coptisine
Coptisine has been detected in opium by means of paper chromatography (Hakim et al., 1961).
The structure of coptisine was elucidated via its reduction to (±)-stylopine. The reverse reaction was also performed, i.e. the oxidation of stylopine yields coptisine. (±)-Stylopine has been prepared by several cyclization methods (Bradsher and Dutta, 1961; Dai-Ho and Mariano, 1987). Racemic stylopine was obtained through an isochromanone derivative (Narasimhan et al., 1983). Stylopine and canadine were prepared by Bischler—Napieralsky cyclization of the appropriate isoquinolin-3-ones (Yasuda et al., 1987).
Rhoeadine can be converted to coptisine via rhoeageninediol in several steps (Klasek et al., 1968). The photochemical formation of coptisine has been described from protopine (Dominguez et al., 1967).
Coptisine can be converted to a spirobenzylisoquinoline derivative (Hanaoka et al., 1982b). The UV and NMR spectra of coptisine have been measured (Hruban et al., 1970; Jewers et al., 1972). The pseudobase formation of coptisine was studied by means of UV and NMR spectroscopy (Simanek et al., 1976).
9.4 Scoulerine
The isolation of this alkaloid from opium has been reported. Scoulerine is a weak base and can be extracted at pH 1.5 It has been purified by preparative TLC and its structure elucidated via its NMR and MS spectra (Brochmann-Hanssen and Nielsen, 1966b).
Three routes have been elaborated for the synthesis of scoulerine. Two of these employ the Bischler—Napieralsky reaction. In the third, N-norreticuline is resolved, and the (+) and (-) enantiomers are used for synthesis of the enantiomers. (-)- Norreticuline can be converted into a separable mixture of (-)-scoulerine and (-)- coreximine by employing formaldehyde in the Mannich reaction. Since the absolute configuration of (-)-norreticuline is known, the latter reaction confirms the configuration of scoulerine (Battersby et al., 1966). Scoulerine has been prepared from the bromo-substituted tetrahydro-isoquinoline via the Mannich reaction with formaldehyde, followed by the debromination of 12-bromoscoulerine (Bhakuni and Kumar, 1983; Kametani and Ihara, 1967). Dibenzylscoulerine has been prepared by
Bischler—Napieralsky cyclization of the corresponding lactam (Pandey and Tiwari, 1979).
Treatment of (±)-reticuline N-oxide with ferrous sulphate in methanol afforded a mixture of (±)-scoulerine and (±)-coreximine (Kametani and Ihara, 1979).
The NMR and MS spectra of scoulerine have been studied (Cashaw et al., 1976; Chen and MacLean, 1968; Ohiri et al., 1983). ORD and CD studies have also been performed to establish the absolute configuration (Kametani and Ihara, 1968; Ringdahl et al., 1981b).
9.5 Stepholidine
Preparative TLC of the opium fraction containing minor phenolic alkaloids revealed a new alkaloid, which was purified by column chromatography. The NMR and MS spectra indicated a 2,3,9,10-substituted protoberberine skeleton. Methylation of the alkaloid with diazomethane yielded tetrahydropalmatine. The new substance proved to be identical with Stepholidine, as revealed by comparison of the respective IR and mass spectra (Brochmann-Hanssen and Richter, 1975). Several syntheses of Stepholidine have been reported (Chiang and Brochmann-Hanssen, 1977; Rajeswari et al., 1977).
The stereochemistry of Stepholidine has been studied by X-ray crystallography (Wu et al., 1987). Detailed PMR and MS studies have been carried out on Stepholidine (Ohiri et al., 1983; Richter and Brochmann-Hanssen, 1975).
9.6 Isocorypalmine
This alkaloid has been isolated from opium (Pfeifer, 1966b) and from poppy at the stage of opium ripeness (Proksa and Cerny, 1981; Proksa et al., 1979).
It has also been detected with the aid of labelled reticuline (Battersby et al., 1975). Isocorypalmine can be methylated to tetrahydropalmatine with diazomethane. The NMR and MS spectra of isocorypalmine have been studied (Cashaw et al., 1976; Ohiri et al., 1983; Richter and Brochmann-Hanssen, 1975). The crystal structure of isocorypalmine has also been determined (Ribar et al., 1992).