Narcotine synthesis

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. 

Utilising the formulae assigned to the two products of hydrolysis of narcotine, viz., hydrocotarnine and opianic acid, Roser constructed a formula for the alkaloid which has been confirmed by Perkin and Robinson s synthesis of narcotine from meconin and cotarnine. ... 

In 1803 the German pharmacist Seturner achieved the isolation of morphine as one of the active ingredients of opium. He named the compound after Morpheus, Ovid s god of dreams, the son of sleep. Among the other alkaloids of opium are codeine, isolated in 1832, thebaine, narceine, narcotine, and papaverine. From the isolation of pure morphine to the elucidation of its structure by first Gulland and Robinson(1,2) and later Schopf(3) took another 120 years. A total synthesis by Gates and Tschudi(4,5) confirmed the structure in the early 1950s. 

Minor alkaloids of morphine. VII. Synthesis of gnoscopine (dl-narcotine)... 

The alkaloids of the narcotine type can also be synthesized from benz[d]indeno(l,2-f ]azepine (133a) (698) (Scheme 45). Moreover, compound 133a forms a key substance for the synthesis of the tetrahydro-protoberberine (58), protopine (101), rhoeadane (154), and spiroben-zylisoquinoline (191) ring skeletons. The compounds 133a and 133b arise also by rearrangement from the spirobenzylisoquinoline, protoberberine, and 1-benzoylisoquinoline skeletons. Therefore, it is assumed that even in the plants it plays a key role in the formation and interconversion of the benzylisoquinoline alkaloids with 17 carbon atoms in the skeleton (Scheme 45). 

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. ... 

It is evident that formula II (R = Me) adequately accounts for the above reactions (5), and a subsequent synthesis (6) amply confirms it. The lactone group persists in narcotine as shown by its reactions with alkali. Only after prolonged warming in alcoholic alkali is an alkali salt formed, and this rapidly regenerates narcotine on acidification. The crux of the problem resolved itself into determining the structure of the fission products. 

The synthesis of hydrastine, being parallel to that of narcotine, was reported by Hope and Robinson in 1912 (83) and extensively described later (84). The yield of condensation product approaches 90% when hydrastinine and nitromeconin are boiled for a short time in ethanol solution. In this case, however, the product is a mixture of the two possible racemic forms, the separation of which was difficult. Separation was more readily effected after the nitro group had been reduced to the amino group, and there were thus obtained a sparingly soluble aminohy-drastine-a and a more soluble aminohydrastine-b, both still racemic. These amino compounds were convertible into dZ-hydrastine-a and dZ-hydras-tine-b, respectively. In the latter case the yield was very small, the main product being a didehydrohydrastine, m.p. 183°, which was regarded as... 

Freund and Becker suggested the correct structure for narcotine, which was confirmed by synthesis in 1911 by Perkin and Sir Robert Robinson (1886-1975). Degradation experiments performed by Eduard Vongerichten,... 

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