Alkaloids Containing One Diphenyl Ether Linkage

6-methoxy-7-ethoxy-V-methyltetrahydroisoquinoline (IX, R = CaHs). These results showed that of the three phenolic groups in magnoline one is in the 4-position of the diphenyl ether and the other two in the 7-positions of the isoquinoline rings. Thus formula VI is assigned to magnoline. 

Closely related to magnoline is the alkaloid dauricine which has been found in Menispermum dauricum DC. by Kondo and Narita (3), and later by Manske (4) in the subterranean stems and roots of a woody liana, Menispermum canadense L., widely distributed throughout North America. It is a phenolic yellow resinous base soluble in most organic solvents. On the basis of the Rast molecular weight determination the Japanese workers 

Five years later Kondo and Narita (8) redetermined the methoxyl values of a number of 0-methyldauricine derivatives and found that these new values agreed better with the C38 formula. Finally they proved the structure of dauricine to be of the bisbenzylisoquinoline type by the synthesis of well-defined dauricine derivatives and by comparison with the natural products. 

Dauricine has been shown to have some pharmacological action in animals (9). When administered as the hydrochloride to frogs, mice, and rabbits it provokes a mixed picture of paralysis and convulsions. Dauricine dimethiodide is curare-like in action but is only about one-seventh as potent as d-tubocurarine and is more toxic (114). It causes ataxis, respiratory depression, poor relaxation, and anoxic death at doses of 6 mg. per kilogram when administred to mice intraperitoneally. 

Magnolamic acid was next examined in order to determine the structure 

The constitution of magnoline (XVI) was elucidated by degradation in 1940 but the stereochemistry of it remained unknown for many years thereafter and only recently was established. Magnoline was assigned the SR-configuration (9), as shown in formula XVI, for it was found to be the antipode of the new alkaloid berbamunine whose absolute con figuration was established as RS 9, 14). 

A synthesis of magnoline has not yet been achieved but an attempt toward this end led to the related compound XXV (15). Reaction of the acid chloride of 2-methoxy-4, 5-bis(carboxymethyl)diphenyl ether (XVII) with 3-methoxy-4-benzyloxyphenethylamine afforded the 

Xumbers in parentheses refer to pages in Chapter 33, Volume IV, and in Chapter 21, Volume V II, respectively a dash indicates no reference. 

Berbamunine (XXVI) (mp 190°-191°), a new bisbenzylisoquinoline alkaloid having a single diphenyl ether linkage, was isolated by Tomita and Kugo 16) from Berberis amurensis Rupr. 

The position of the three phenolic hydroxyl groups in berbamunine was shown to be as in XXVI by subjecting the ethylated alkaloid (XXVIII) to cleavage with sodium in liquid ammonia and identifying the products as (- )-V-methyl-0,0-diethylcoclaurine (V) and (+ )-l-(4 -hydroxy-benzy 1) - 2 - methyl - 6 - methoxy - 7 - ethoxy -1,2,3.4 -tetrahydroisoquinoline iYI) l4). 

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The alkaloids of Types I, la, lb, II, Ila, Ilb, and III contain one diphenyl ether linkage and are linked tail-to-tail. There are no alkaloids in this group that are imines, with only a few secondary amines being found. 

The alkaloid was found to contain two methylimino groups, seven methoxyl groups, and one diphenyl ether linkage. Oxidation of fetidine with permanganate gave l-oxo-2-methyl-6,7-dimethoxy-l,2,3,4-tetra-hydroisoquinoline. Reduction with sodium in liquid ammonia furnished (+ )-laudanosine (XLI) and (-I- )-laudanidine (XXXII). Thus it was concluded that the alkaloid is represented by formula LII, or a variation of this formula having the ether linkage attached to C-10 or C-14. 

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