Of -chelidonine

Hydroxysanguinarinebetaine (367) is formed on Oppenauer oxidation of Chelidonine (366) as a red compound (65MI2) (Scheme 109). Deprotonation of the benzo[c]phenanthridine alkaloid Fagaronine (93T10305), which is known to inhibit various reverse transcriptases (77MI1), resulted in the... 

Zbierska, J. and Kowalewski, Z. 1979. Anticancer and antibiotic properties of chelidonine methyliodide. Herba Polonica, 25 209-217. 

Cyclization of side chain nitriles has found extensive use in the synthesis of benzocyclobutenes (70 n = 2),104 the versatile synthons which open on mild thermolysis to give o-quinodimethanes for inter- and intra-molecular [4 + 2] trapping.108 The nitrile group in (70) can be manipulated into a variety of functionalities for appending the dienophile portion. For example, in the synthesis of chelidonine, the nitrile (71) was converted, by hydrolysis followed by Curtius degradation and reaction of the formed isocyanate with benzyl alcohol, to a urethane (72). The latter was then condensed with a benzyl bromide to get the compound (73), which was elaborated further as shown in Scheme 14.109... 

The presence of alkaloids in the family was doubled until the isolation of chelidonine from Symphoricarpos albus, and an alkaloid from Lonicera xylostemon. The phytochemistry of the family was the subject of a thesis some 20 years ago. 

The absolute stereochemistry of chelidonine has been determined by an X-ray crystallographic study of its p-bromobenzoyl ester.382 Further details of the photolysis of the unsaturated amide (151) to the two dimers reported previously (Vol. 10) have been published. Attempts have been made to trap the initial product with dieneophiles with nitrosobenzene, the adduct (152) was obtained, and this was decomposed by heat to form oxochelerythrine.383 A review of methods of synthesis of ( )-corynoline and of 12-hydroxy-, 11 -epi-, and homo-chelidonine has been published.384... 

The probability63 that (69) lies along the pathway to protoberberine and derived alkaloids, between scoulerine (65) and stylopine (70), has been supported by the observation that tritiated (69) is a precursor for protopine (73), and also for corynoline (78).64 Evidence previously obtained for the intermediacy of the metho-salt of stylopine [as (71)] in the biosynthesis of chelidonine (62)63 and protopine (73)63,65 has been affirmed, and it is apparently the a-form (71) and not the /3-form that is involved. [The authors are mistaken in assuming that ( —)-stylopine has the R-configuration at C-14 cf. ref. 63]. 

A striking novel result is that [AT-meffty/-13C]protopine [as (73)] affords appropriately labelled chelidonine (62) and sanguinarine (72).64 Previously63 the formation of chelidonine (62) had been rationalized as involving a pathway through (71)... 

Scheme 3, p. 15, in ref. 7). As discussed below, protopine (73) and (81) are precursors for rhoeadine (83) and alpinigenine (82), respectively modified proto-berberines in which further C—N bond cleavage must also occur. In this case it is the C-8—N bond [as (73)] which must be broken, whereas in the case of chelidonine (62) it is finally only the C-6—N linkage. 

The fluorescence spectra of chelerythrine, nitidine, and sanguinarine in different solvents have been shown to be dependent on the pH of the solution and to allow the determination of the equilibrium constant for the formation of the pseudobases.531 A salt of chelidonine with 5-carboxymethyl-2-thio-l,3-thiazan-4-one has been prepared.532 The intercalative binding of sanguinarine533 and the anti-tumour activities of chelidonine JV-oxide534 and of nitidine535 have been studied. 

Chelidonine, a representative benzo[c]phenanthridine alkaloid (1,2), was synthesized as the first application of this reaction in natural product synthesis (145). Initial thermal opening of the four-membered ring in 299 led to the formation of a transient -o-quinodimethane (301), which has a dienamide structure in the diene part and is then trapped by the suitably positioned multiple bond in the same molecule. They applied this intramolecular reaction to the acetylenic cyclobutene 300 for the synthesis of ( )-chelidonine (Scheme 110). 

Figure 78. Reaction of chelidonine and other snhstances present in greater celandine DE with high-energy light...

An important rule concerning the determination of the absolute configuration of benzophenanthridine alkaloids has been proposed.220 (For a brief discussion of this rule, see Section 3G.) On the basis of this rule, the absolute configuration of chelidonine (262) has been determined. 

The NMR spectroscopy of chelidonine and corynoline has been described (356a, 447) in connection with its relative configuration. The UV and IR spectroscopy of many of the known benzophenanthridine alkaloids has been recorded (221). The polarography of the alkaloids of the sanguinarine type has been described (25, 423). 

Though the chemical evidence had been satisfactory but not quite unambiguous for the structure of chelidonine, it was still desirable to obtain confirmation and to reaffirm its stereochemistry. An exhaustive NMR spectral study has confirmed not only the general structure but has indicated that the most likely stereo structure which accounts for the strong hydrogen bonding is that shown (XXXVI) 53). 

The structure of this alkaloid had already been announced but the stereochemistry remained uncertain. An independent study has confirmed the earlier work and the stereostructure XXXIX is now given on the basis of exhaustive spectral data and a comparison of these with those of chelidonine Alkaloid-V, also isolated from Corydalis incisa Pers. and obtainable from eorynoline, is given structure XL (55). 

The absolute configurations of chelidonine, chelidonine acetate, and norchelidonine have been independently studied by application of a kinetic method of partial resolution during esterification with a-phenylbutyric anhydride, by CD analysis (662), and by H NMR analysis (785). The mass spectra and the NMR spectra of chelirubine, chelilutine, sanguinarine, and sanguilutine have been reported (770, 786). 

An interesting first synthesis of ( )-chelidonine (160) has appeared. Bromina-tion and dehydrobromination of the urethane olefin (157) provided the acetylenic urethane (158). Pyrolysis and Brown hydroboration furnished two diastereo-isomeric alcohols which were separated The cis b/c fused isomer (159) upon oxidation and reduction, removal of the urethane group, and N-methylation gave ( )-chelidonine, itself a natural product (Scheme 7). ... 

The chelidonine group of alkaloids cannot conveniently be looked upon as derived from benzylisoquinolines. In view, however, of the copresence of chelidonine with those already mentioned, it is to be expected that the ultimate precursors are the same. It can be assumed that the dihydroxy-phenylalanine is converted to a substituted phenylacetaldehyde, and two molecules of this can give rise to the aldol XX, which could conceivably ring-close to XXI, in strict analogy with the mechanism which must be involved in the well-known formation of /3-phenylnaphthalene from phenyl-... 

When dealing with unpurified isolates it is not practical to attempt the direct crystallization of chelidonine from the ether mother hquor. It is best to convert the bases into their hydrochlorides and let the sparingly soluble chelidonine salt crystallize from an aqueous solution and recrystallize until it is colorless. Traces of protopine do not interfere in the next step. The regenerated free base is again taken up in ether, and the dried solution (potassium carbonate) is evaporated to a thin sirup. Hot methanol—about five milliliters per gram of residue—is added, the remaining ether is expelled, and the solution inoculated while hot. Chelidonine in large monoclinic tablets separates very rapidly, and since protopine is more soluble in methanol than in ether it is not a contaminant. 

The oxychelidonine of Gadamer and Theissen (37) which was obtained from some residues left from the preparation of chelidonine is also one of the products when the latter is oxidized with mercuric acetate. It was assumed that the methylene vicinal to the carbinol was oxidized in this reaction to a carbonyl, but such a formulation could not account for the non-basic nature of the compound. Such properties are consistent only with an amide structure (XVII), and its formation then is quite analogous... 

Chelidonine.—Chelidonine (66) has been proved to be a modified benzyl-isoquinoline arising along a pathway from (5)-reticuline, through (5)-scou-lerine, (S)-stylopine (64), and protopine (65) (detailed pathways are given in ref. 7, p. 12, and ref. 8, p. 14). The steps which lie beyond stylopine (64) manifestly involve fracture of the C-14—N and C-6—N bonds in (64). It has been shown that the pro-S proton at C-13, as well as the one at C-14, is lost on formation of chelidonine (those at C-5 and C-8 are retained). The most recent results are that in the scission of the C-6—N bond it is again the pro-S proton which is lost. It is interesting to note that all three protons are lost from the 5i-face of the molecule. 

Cholestatic hepatitis indicative of drug toxicity was reported in a 69-year-old man that had taken celandine capsules (about 2 daily, each containing 4 mg of chelidonin) (Stickel et al. 2003). A 58-year-old man experienced severe acute cholestatic hepatitis in association with use of a celandine and turmeric product (dose and duration of use not specified) (Rifai et al. 2006). A 42-year-old woman developed jaundice due to acute hepatitis after several weeks of... 

In the brine shrimp lethality assay, the LC50 of chelidonine was 319 ppm, and for prototropine was 49 ppm. LC50 values for ethanol and aqueous extracts of celandine could not be determined at concentrations up to 1000 ppm (Saglam and Arar 2003). 

In a series of papers, Battersby and co-workers have described the origins of chelidonine and sanguinarine in Chelidonium majus L. (Papaveraceae). Scheme 21.8 can be written for the biogenesis of these two benzophenanthri-dine alkaloids. The conclusions were supported by careful and thorough studies with labeled precursors. 

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