1-a-Narcotine

The new /-hydrastine is considered to be /-a-hydrastine and natural hydrastine to be /- -hydrastine, which implies (1) that the latter differs from natural narcotine (/-a-narcotine) in stereochemical configuration (2) that since a-gnoscopine, but not -gnoscopine, can be resolved, the synthesis of natural hydrastine will involve the deracemisation of hydra-stine-b, to /-a-hydrastine, which can be epimerised to natural hydrastine (/- -hydrastine) by boiling with methyl-alcoholic potassium hydroxide. 

It is considered that in these new forms racemisation or reversible inversion has occurred at the centre of asymmetry in the phthalide group, and that the centre of asymmetry in the isoquinoline nucleus is unaffected. The melting-point, 176°, of each new isomeride is depressed by addition of the corresponding a-narcotine and the specific rotation of l-j3-narcotine, W548 is 101° (CHCI3) or — 59-2° (N. HCl), that of i-a-narcotine, under the same conditions being — 246° and -f 50-4° respectively. 

The enol lactones were synthesized by Hofmann degradation of metho salts of classic phthalideisoquinoline alkaloids. The biogenetically relevant transformations were highly stereospecific. In this way aobamidine (96) was obtained from the methiodide of (erythro) bicuculline (88) (2), and ad-lumidiceine enol lactone (97) was produced from both (threo) isomeric adlumidiceine (89) and capnoidine (90) methiodides (14,15,91-93). (Z)- (98) and ( )-N-methylhydrastine (99) were obtained from / - (91, erythro) and a-N-methylhydrastinium (92, threo) iodides (5,87,91,96-98), respectively, as were (Z)- (101) and (JE)-narceine enol lactones (102) synthesized from a- (94, erythro) and /J-narcotine (95, threo) quaternary N-metho salts (87,90), respectively. In a similar process /J-hydrastine (91) JV-oxide heated in chloroform yielded enol lactone 124 of Z configuration (99) however, a-narcotine (94) N-oxide was transformed to benzoxazocine 125 (99). ... 

Narcotine was isolated by Derosne (592) and Robiquet (593) from opium. It has a mild antitussic and a relaxant effect on smooth muscles (similar to those of papaverine). The relaxant effect is about ten times smaller than that of papaverine (594-597). LaBarre and Plisnier (598, 599) found that narcotine is a better antitussic than codeine. j8-Narcotine proved to be much more effective than a-narcotine (600) the effect of the N-oxides of the two isomers was more marked than that of the base. /3-Narcotine N-oxide was much more effective than dihydrocodeine. Those substances did not increase the analgesic effect of morphine. Contrary to codeine they did not cause obstipation (601). The therapeutic dose of the hydrochloride is 25-50 mg three times daily for adults and 25 mg three times daily per os for children. For the effect of narcotine upon the cough reflex and upon the bronchial muscle, see (602-613). 

The preparation of a- and /3-hydrastines from berberine has been described above.100 Photoracemization and epimerization of (—)-a-narcotine and of (—)-/3-hydrastine to mixtures of ( )-a- and ( )-/3-narcotines and of the corresponding hydrastines has been observed.114... 

Phthalideisoquinolines a-narcotine and narcotoline (MD-IQ-C4L[Phe) (opium-derived spasmolytics) (+)-bicucculine (MD-IQ-C4L Phe-MD) (Corydalis species (Papaveraceae) GABA receptor antagonist). 

Another heterocyclic nucleus investigated as a basis for analgesics is isoquinoline with a fully reduced heterocycle moiety and carrying a 1-phenethyl substituent. The series was reported by Hoffman-La Roche in 1960(1S) but no further information has appeared since 1965, when a full account of the work appeared in deStevens book Analgetics.(16) 1-Benzyltetrahydroisoquinoline alkaloids such as papaverine occur in opium but lack analgesic properties, while others, for example, a-narcotine (noscapine), have antitussive activity. Some of the novel 1-phenethyl analogs 9 behaved as analgesics in mice after sc administration when tested by the tail-flick assay, but potency levels were mostly low and close to that of codeine. Details of the most active compounds are shown in Table 11.2. All have 6,7-methoxyls and 4 -substituents with... 

Since the structures of the known phthalideisoquinoline alkaloids are known, recent papers deal with problems of their absolute configurations. Narcotine (II) contains two asymmetric centers at C-1 and at C-9 it is known 6-8) that natural (— )-a-narcotine may be converted into (— )-j8-narcotine by the action of hot methanolic potassium hydroxide and that it is the carbon atom bearing the hydroxyl group which takes part in this epimerization. Similarly, natural /3-hydrastine may be converted into unnatural a-hydrastine 6, 9). The application of ORD-curves was not entirely successful 10) but a combination of this method with NMR-spectra and chemical proofs solved this problem 7, 11-17). 

In summary, the absolute configurations of a-narcotine and /3-narcotine are given by the structural formulas III and IV, respectively, together with absolute configurations of some other alkaloids. 

Novoseven eptacogalfa factor VII. noscapine [ban, inn] (narcotine i-a-narcotine) is an alkaloid from Corydalis cava (Corydalis tuberosa), Papaver somniferum and other Papaver spp. It is a by-product in extraction of morphine from opium, and one of the first alkaloids to be isolated. It can be used as a centrally acting ANTITUSSIVE, similar in pharmacology to codeine, novobiocin [ban, inn] (Albamycin ) is an antibiotic with ANTIBACTERIAL activity against Gram-positive bacteria. It is also a LEUKOTRIENE RECEPTOR ANTAGONIST. 

P. somniferum In this plant the present (-)-scoulerine must suffer oxidation of the N-7 and C-8 bond while the integrity of the C-14 asymmetric center is essentially maintained, (-)-a-Narcotine and (-)-jS-hydrastine underwent photochemical racemization and epimerization to give a mixture of the racemic epimers (696). 

Scheme 48. Reaction of a-narcotine (123h) with Grignard reagents or trimethoxyaluminum hydride (706-708).

The interesting conversion of nornarceine (181) into the rhoeadine analogues (187) and (188) has been carried out as shown in Scheme 9. Nornarceine (181), obtained from (— )-a-narcotine, was heated in base to afford the enamine (182) which readily cyclized in dilute acetic acid to the y-lactone (183). Upon standing, (183) was oxidized to the ketone (184). Lithium borohydride reduction led to the c/.s-acid (185). The derived ds-fused lactone (186) was then reduced to the hemi-acetal (187) which upon O-methylation with trimethyl orthoformate gave (188). The structure of the methiodide salt of (187) was confirmed by an X-ray analysis. The phthalideisoquinoline alkaloid (— )-bicuculline (189) was then converted into naturally occurring (+ )-rhoeadine (190) by an analogous route. Since (— )-bicuculline was obtained from (—)-)3-hydrastine, whose synthesis had been reported in 1950, this transformation represents the first total synthesis of a rhoeadine alkaloid. ... 

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