Alkaloids Containing Three Diphenyl Ether Linkages

Further knowledge regarding the constitution of the two alkaloids was obtained by subjecting their methines to ozonolysis. By this means Kondo and Tomita (92) split the molecule of trilobine (or isotrilobine) 

XC produced the o-vinylaldehyde (XCI) which on hydrogenation yielded the synthetic XCII. 

Trilobine and its derivatives are toxic to frogs and mice when injected subcutaneously (89, 93), the minimum lethal dose being 500 mg. per kilogram. These compounds cause motor paralysis with occasional convulsions, and death is usually due to respiratory failure. 

In order to elucidate the structure of micranthine Bick and Todd (113) subjected 0,0,Ar-trimethylmicranthine methine to ozonolysis and obtained two products. One proved to be 4, 5-diformyl-2-methoxydiphenyl ether (XXXIV). The other was an amino aldehyde which on further degradation (Hofmann) yielded a crystalline substance which from its analysis and properties appeared to be a diformyldimethoxydivinyldi-phenylene dioxide. Bick and Todd deduced the structure of micranthine by recourse to the Faltis theory of the biogenesis of bisbenzylisoquinoline alkaloids. 

the assumption was made that micranthine is unsubstituted at the 5-positions of the isoquinoline nuclei on the basis that no substituents are present in the 5-positions of all known bisbenzylisoquinoline alkaloids. Then, all the possible structures containing a diphenylene dioxide ring, one 

Alkaloids Containing Three Diphenyl Ether Linkages 

Isotrilobine, an alkaloid of menispcrmaeccus plants, had been assigned constitution CXL. Recent degradative studies have completed 

The conversion of epistephanine (LXXXI) to the antipode of isotrilobine (105) and of 0-methylrepandine (LXXIII) to isotrilobine (106) were recently reported. 0-Methylrepandine (LXXIII) w as demethylated with hydrobromic acid to the tetrahydroxy compound CLI ivhich, because of the proximity of the two phenolic groups, dehydrated readily to form compound CXLI. Methylation of the latter yielded isotrilobine (CXL). Epistephanine (LXXXI) was converted similarly to the antipode of isotrilobine. 

Trilobine, another alkaloid occurring in menispermaceous plants, was previously given the ambiguous formula CXLII. It can now be assigned the SS-configuration by virtue of its methylation to isotrilobine (CXL). 

In order to locate the secondary amino group, the alkaloid was N-acetylated, and the X-acetyltrilobine was subjected to cleavage with sodium-sodium hydride and liquid ammonia (102, 107). The phenolic base CXLVII, obtained by partial cleavage, was methylated and the resulting compound (CXLVIII) was submitted to a second-stage cleavage with sodium in liquid ammonia. There was obtained l-(4 -methoxy-benzyl)-2-methyl-6-methoxy-l,2,3,4-tetrahydroisoquinoline (XXXIII) and l-(4 -methoxybenzyl)-2-acetyl-6-methoxy-8-hydroxy-l,2,3,4-tetra-hydroisoquinoline (CL). These results show that trilobine is represented by CXLII (Ri=H). 

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IV. Alkaloids Containing Three Diphenyl Ether Linkages. 163... 

The only bisbenzylisoquinoline alkaloids whose structures preclude the simple oxidative pairing mode of synthesis are those containing three diphenyl ether linkages (trilobine, isotrilobine, menisarine, normenis-arine, and micranthine). However, Barton and Cohen (10) have proposed a mechanism for the formation of the dibenzo-p-dioxin system of these alkaloids which comprises phenoxy free-radical coupling with a subsequent migration reaction. 

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