¿QUIÉN IMPONE LA MEDIDA Y SOBRE QUIÉN RECAE LA MISMA?

The protopine alkaloids possess a ten-membered ring which contains a tertiary nitrogen atom and a C-14 ketonic group (Onda and Takahashi, 1988). Since these alkaloids are derived biosynthetically from tetrahydroprotoberberine precursors, they are classified among the isoquinoline alkaloids.

10.1 Cryptopine

The alkaloid cryptopine was first isolated from opium in 1867. Indian opium contains about 0.3% cryptopine. The isolation and purification of cryptopine were studied by Ramanathan and Chandra (Ramanathan, 1963; Ramanathan and Chandra, 1980, 1981). Cryptopine has also been isolated from poppy capsules (Hodková et al., 1972; Szabó et al., 1968).

Cryptopine has been detected in the callus tissue of the opium poppy (Furuya et al., 1972; Ikuta et al., 1974). The structure of cryptopine was elucidated by means of degradative (Emde, Hoffman and oxidative) reactions. It is of interest that cryptopine does not exhibit the properties of ketones. The carbonyl group yields no oxime, but it can be reduced to a secondary alcohol. Spectral studies indicate the presence of a transannular ground-state interaction between the carbonyl group and the basic nitrogen. Cryptopine and its reduction product (dihydrocryptopine) can be converted to the tetrahydroprotoberberine skeleton (e.g. isocryptopine chloride) by cyclization with acid chlorides (Dyke and Brown, 1968, 1969). Tetrahydroepiberberine has been converted to cryptopine in several steps. Oxidation with potassium chromate afforded a carbinolamine, which was reacted with methyl iodide to yield cryptopine hydroiodide. N-Demethylation of cryptopine was performed by means of cyanogen bromide. (Bentley and Murray, 1963b).

The structure of cryptopine was confirmed by spectral (NMR and MS) studies (Dolejs. et al., 1964; Ma and Warnhoff, 1965; Nakashima and Maciel, 1973; Pfeifer and Thomas, 1972). X-Ray analysis was also performed in order to study the structure of cryptopine (Hall and Ahmed, 1968).

10.2 Allocryptopine

Allocryptopine exists in two allotropic modifications, the a form melting at 160°C and the ß form melting at 170°C. α-allocryptopine has been isolated from the non- phenolic fraction of opium by means of preparative TLC. It was identified via the NMR, MS and IR spectra. The content of the alkaloid in opium appears to be of the order of 0.01% (Brochmann-Hanssen and Nielsen, 1966a).

ß-Allocryptopine has been isolated from dried poppy capsules (Hodková et al., 1972). Allocryptopine was detected in poppy in radioactive tracer experiments (Battersby et al., 1975).

The synthesis of α-allocryptopine was reported to occur by rearrangement of the isoindolobenzazepine skeleton (Teitel et al., 1973). Photochemical oxidation of canadine methiodide gave allocryptopine (Hanaoka et al., 1976).

Allocryptopine can be transformed into the benzophenanthridine alkaloid chelerythine (Onda et al., 1971). Treatment of allocryptopine with cyanogen bromide results in cleavage of the N-7 to N-8 bond; this reaction is in contrast with the behaviour of cryptopine (Nalliah et al., 1974b).

13-Oxycryptopine has been isolated from Indian opium. Codeine and protopine were removed from the non-phenolic fraction and the residue was subjected to preparative TLC and column chromatography (Brochmann-Hanssen et al., 1970). 13- Oxycryptopine has been characterized via its spectral (UV, IR, NMR and MS) properties (Hanus et al., 1967). It proved to be identical to the synthetic compound prepared from cryptopine (Leonard and Sauers, 1957).

10.4 Protopine

The separation of protopine from opium by the method of Hesse is exceedingly laborious and the alkaloid can be advantageously obtained from other plants. The presence of protopine in opium is rarely detected (Battersby et al., 1975; Bessonova et al., 1970; Kleinschmidt, 1959; Miram and Pfeifer, 1958; Neubauer, 1964; Neubauer and Mothes, 1961).

Protopine has been found in the callus tissue of opium poppy (Furuya et al., 1972; Ikuta et al., 1974).

The reactions of protopine are very similar to those of cryptopine. Protopine undergoes electrophilic aromatic substitution at C-12 on reaction with bromine and nitric acid in acetic acid (Castedo et al., 1986). 13-Oxoprotopine can be obtained by the reaction of protopine with mercuric acetate (Leonard and Sauers, 1957).

Protopine has been prepared by the degradation of stylopine methiodide (Kulkarni et al., 1990). The reverse process is also known, i.e. the protoberberine skeleton (coptisine, vide supra) can be prepared from protopine.

The 13-oxo-derivative of allocryptopine has been prepared from the 13- oxoprotoberberinium methosalt (Nalliah et al., 1974a).

Spectral properties (NMR and MS) of allocryptopine have been reported (Cross et al., 1965; Dolejs et al., 1964; Iwasa et al., 1982; Nakashima and Maciel, 1973) and an X-ray crystallographic study of allocryptopine has been performed (Sakai et al., 1988).

It is noteworthy that protopine can be transformed into the benzophenanthridine alkaloid sanguinarine (Onda et al., 1968, 1969). Anhydroprotopine (prepared from isoprotopine chloride) yielded an unstable substance by photochemical reaction, which was reduced to dihydrosanguinarine (Onda et al., 1971). The latter compound was oxidized to sanguinarine with DDQ. Oxidation of protopine with oxygen and a microsomal cytochrome P 450-NaDPH-dependent enzyme afforded 6- hydroxyprotopine, which underwent spontaneous cyclization to sanguinarine (Tanahashi and Zenk, 1988).

Protopine was converted to the cis-fused indenobenzazepine by the action of a strong base and sunlight (Blaskó et al., 1981). Simpler alternative methods for the preparation of dihydrocoptisine and 13-oxystylopine from protopine have also been reported (Jeffs and Scharver, 1975).

The infrared carbonyl absorptions of protopine and α-allocryptopine in dilute CCl4 solution and nuclear Overhauser experiments in the PMR spectra (Takahashi et al., 1985) reveal that these alkaloids each interconvert between two major conformations of the ten-membered ring. The spectral characteristics of protopine (NMR and MS) have been studied in detail (Dolejs et al., 1964; Nakashima and Maciel, 1973; Pfeifer and Thomas, 1972). An X-ray study of the alkaloid has also been performed (Hall and Ahmed, 1968).

10.5 Dihydroprotopine

The presence of dihydroprotopine has been reported in poppy (Stefanov et al., 1972). Dihydroprotopine was detected in poppy by radioactive tracer experiments (Battersby et al., 1975). It can be prepared by the reduction of protopine (Tani et al., 1957).

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