Bisbenzylisoquinoline alkaloids structure

This section consists primarily of total synthesis work. Most partial syntheses are to be found in Sections II and IV, and only those not previously discussed or those of particular interest are considered here. The last decade has produced relatively few new total syntheses of bisbenzylisoquinoline alkaloids, evidently because commercial applications that could not be filled with isolated or semisynthetic materials have not developed, and because instrumental methods have made structure proof by interrelation of new alkaloids with known materials increasingly easy. 

As a technique for partial synthesis, rearrangement of bisbenzylisoquinoline alkaloids has most often been used on spirodienones, as in the conversion of valdiberine to chitraline (Section n,C, 142), and is of value mainly in structure proof. 

Mass spectrometry (MS) continues to have great importance for structure determination of bisbenzylisoquinoline alkaloids, as the many cases cited in Section II demonstrate. MS has been particularly useful in cases of dimers with unusual structural features (such as the warifteines, which contain a p-xylyl moiety (21) (Section II,B,4). 

Ultraviolet (UV) spectrophotometry has been a valuable tool in bisbenzylisoquinoline alkaloid research. One example is its use in the identification of a newly isolated sample of pennsylvanine (317). In order to rule out the isomer, thalidoxine (429a), the alkaloid was oxidized (as its O-acetate) and the resulting 430 was examined by UV spectrophotometry under neutral and basic conditions. The data unequivocally confirmed structure 430, and hence 317 for the alkaloid (209). 

Phosphorescence and fluorescence of a bisbenzylisoquinoline alkaloid were observed, apparently for the first time, in tubocurarine chloride and 0,0,N-trimethyltubocurarine (311). The phenomenon has also been studied in several alkaloids of the oxyacanthine and berbamine subgroups, and it has importance as an assay method (311) and as a tool for structure determination. The emission characteristics are a function of the gross structure, the stereochemistry, and the degree of O-alkylation (310,311). 

During the last decade, as the number of bisbenzylisoquinoline alkaloids continued to increase rapidly, a systematic classification system became highly desirable, and no doubt many workers were using informal systems. In 1976, a formal line notation was developed that designates the skeleton and location of substituents (337) it is suitable for computer retrieval and has found use in review articles (see Section IX). A more extended system that allows specification of substituents and is adaptable to unusual structural types [e.g., repanduline (Section H,B,7)] has also been described (338). The chirality of asymmetric centers may also be designated (160). 

T. Kametani, The Chemistry of the Isoquinoline Alkaloids, Vol. 2, Chapt. 7. Sendai Institute of Heterocyclic Chemistry, Sendai, 1974. A listing of 95 bisbenzylisoquinoline alkaloids arranged by structural types, with structures, molecular formulas, and references to papers citing physical properties, sources, structure proof, and synthesis. A comprehensive summary with 111 references. 

Bisbenzylisoquinoline alkaloids. Comprehensive tabulation of literature for 1978-1981 (Chemical Abstracts Volumes 88-95), with 164 references. Covers structure revisions, additional (mainly spectral) data on known alkaloids, new sources of known alkaloids, structures, properties, summarized confirmatory reactions of new alkaloids, and biosynthetic evidence. Alkaloids are tabulated by botanical sources and pharmacological activity. A section on methods (CD, luminescence spectra, specific rotation, TLC) is included. 

H. Guinaudeau, A. J. Freyer, and M. Shamma, Nat. Prod. Rep. 3, 477 (1986). Spectroscopy of bisbenzylisoquinoline alkaloids. Tabulation and analysis of high resolution NMR spectra of over 100 bisbenzylisoquinoline alkaloids, arranged by structural types 27 references. 

Aromoline and thalicberine have been isolated from Thalictrum lucidum,51 and berbamine and oxyacanthine from Berberis julianeae Schneid.52 The biosynthesis of bisbenzylisoquinoline alkaloids has been reviewed.53 An X-ray structure determination of ( + )-tubocurarine dibromide methanol solvate has been reported,54 and neuromuscular sensitivity to tubocurarine55 and the cardiovascular effects of the alkaloid56 have been further studied. Highly selective biological AT-demethylation of tetrandrine to iV(2 )-nortetrandrine by Streptomyces griseus has been described.29... 

A novel type of bisbenzylisoquinoline alkaloid containing one fully aromatic isoquinoline system is sciadoline, from Sciadotenia toxifera Kruhoff and A. C. Smith (Menispermaceae), which has been shown to have the structure (54) by spectroscopic studies.65 It is related to cycleanine (43 R1 = R2 = Me) and 7-nor-cycleanine (43 R1 = H, R2 = Me). 

A number of bisbenzylisoquinoline alkaloids show antitumour activity, and a study has been made of this property in a group of 23 alkaloids, but no clear structure-activity relationship was uncovered.66... 

The active principles of curare were early recognized to be water-soluble quaternary alkaloids. Tube-curare was studied by King, who isolated (3) the crystalline quaternary bisbenzylisoquinoline alkaloid, d-tubocurarine (I), in 1935. The main plant constituent of tube-curare is the bark of menispermaceous plants, particularly of the genus Chondro-dendron, and d-tubocurarine was later isolated (4) from C. tomentosum. Further work led to the isolation and structural elucidation of many more bisbenzylisoquinoline alkaloids from these sources (5). 

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. 

A TABULAR COMPILATION OF THE STRUCTURAL TYPES OF THE BISBENZYLISOQUINOLINE ALKALOIDS 147... 

AN ANALYSIS OF THE DISTRIBUTION OF THE BISBENZYLISOQUINOLINE ALKALOIDS BY STRUCTURAL TYPE 168... 

MP Cava, KT Buck, and KL Stuart in The Alkaloids. Vol. 16. pp. 249, The Bisbenzylisoquinoline Alkaloids — Occurrence, Structure and Pharmacology, RHF Manske, Ed., Academic Press, New York (1977). 

Volume 14 of this series presents three interesting reviews of research on alkaloids. Chapter I, by Paul L. Schiff, Jr. is a monumental effort, presenting a selective, comprehensive tabular review of research on the bisbenzylisoquinoline alkaloids, with an analysis of the respective alkaloid types. The chapter should serve as a very useful tool for the bench research scientist who is involved in the isolation and elucidation of structures of bisbenzylisoquinoline alkaloids. Moreover, the data in these tables provides the botanical distribution and occurrence (family, genus, species) of the various classes of these alkaloids. The alkaloids are also categorized by their molecular weights and structural types. 

The structure of fetidine (284) has been confirmed by mass spectroscopy.257 Examination of the mass spectra of the isomeric alkaloids thalicarpine and thal-melatine, dehydrothalicarpine and dehydrothalmelatine, and thalmetine and thalcimine (thalsimine) gave conclusive structural assignments on the basis of measurements of peak intensity for fragments containing the C=N function.258 O.r.d. studies of a series of bisbenzylisoquinoline alkaloids isolated from Thalictrum species have been recorded.259... 

Quinine and quinidine block potassium channels, both calcium independent ones and calcium-activated ones in several types of membranes [498,499, 500]. Quinine also has less specific effects on other ion channels — chloride as well as cations [501]. Blocking of potassium channels has a secondary effect of stimulating synthesis of phosphatidylserine and affecting other processes that are controlled by potassium concentration [289, 502, 503]. The bisbenzylisoquinoline alkaloid dauricine seems to act similarly to quinidine [504]. Some effects of quinine and quinidine, rather than showing actions on specific ion channels may come from more general effects on membrane structure. Quinidine does decrease the fluidity of liver plasma membrane [505] and it does interact with lipid bilayers [506]. 

---