Isopavines

Pavines and isopavines are two relatively small subgroups of the isoquinoline alkaloids, being represented by 22 and 11 compounds, respectively. Few new examples have been reported in the last decade, which stands in contrast to the rapid increase in the number of known natural compounds in recent years as a consequence of improved isolation techniques and spectral methods of structure elucidation. 

Two numbering systems have been used for the pavines, represented by expressions la and lb (7). We adopt here the system represented in la. For the isopavines, the numbering sequence in 2 will be followed. 

The pavine and isopavine alkaloids of the Papaveraceae have been discussed in Vols. 4, 10, 12, and 17 of this treatise (2-5), and only brief references have been made to occurrences outside this botanical family. Individual chapters have been devoted to the pavine and isopavine alkaloids in the two books by Shamma (6,7), covering developments until 1977, and also in Rodd s Chemistry of Carbon Compounds (8), published in 1978. A listing of naturally known pavines and isopavines up to 1975, with references to physical and spectral data, appeared in Kametani s Chemistry of the Isoquinoline Alkaloids 9,10). A more recent compilation by Gozler and co-workers 11) has covered references to mid-1982. Relevant literature has also been summarized regularly in Vols. I-XIII of Spe-... 

The first occurrence of an isopavine alkaloid outside the Papaveraceae was demonstrated when (—)-thalisopavine (30) was found in Thalictrum dasycarpum (53). The proposed structure was verified through spectral analyses and total synthesis (53). Methylation yielded (—)-0-methylthalisopavine (26), which was later synthesized as a racemate (77). (—)-0-Methylthalisopavine was discovered in Papaver radicatum some years later (78), so this represents another case of synthesis preceding natural occurrence. 

A strongly levorotatory alkaloid isolated from Thalictrum dioicum by Shamma and co-workers (82) was named (-)-thalidine (21) and assigned an isopavine structure on the basis of mass spectral analysis. The diphenolic nature of the alkaloid was evidenced by H-NMR data and by the bathochromic shift in the UV spectrum on addition of alkali. Diazomethane 0-methylation produced (—)-thalisopavine (30) and (—)-0-methylthalisopavine (26). Of the two probable isomeric structures, 21 and 22, 21 was slightly favored on biosynthetic grounds. Final proof to structure was provided by total synthesis (82). (—)-Thalidine has also been reported from T. polygamum (83). 

The spectral analyses of another new base from Thalictrum dioicum established its structure as a diphenolic isopavine, to which the trivial name (—)-thalidicine was assigned. The nonequivalency of the aromatic protons in the NMR spectrum led to the consideration of the two possible structures, 22 and 23, where 23 was apparently favored for biosynthetic considerations and also by analogy to the NMR aromatic proton chemical shifts of other known isopavine... 

Tables V and VI include all the hitherto reported isopavine alkaloids in alphabetical order. Natural sources of the isopavines are listed in Table VII.

This method has been used by Dyke and co-workers (110) to synthesize the isopavine alkaloid reframoline (29) in the racemic form, while the corresponding... 

It has been emphasized that either pavines or isopavines can be obtained selectively depending on the choice of acid conditions used in the aforementioned cyclization process (777). It is also apparent that acid-catalyzed cycliza-tion at room temperature results almost solely in the production of isopavines, whereas application of heat at this stage, which promotes dehydration of the 4-hydroxy intermediate, affords a mixture of pavine and isopavine alkaloids in varying ratios (770,772). 

In 1955, Guthrie and co-workers (131) erroneously assigned pyrroline structure 87 to the crystalline compound obtained by treating aminoacetal 86 with sulfuric acid (Scheme 14). The structure assignment was revised by Battersby and Yeowell (69) to 35, who named it isopavine, since the structure had already been proposed but eliminated for the isomeric compound pavine (34) (95,97). The Battersby structure was conclusively confirmed through a study of the chem-... 

The isopavine bases, ( )-amurensinine (25) (81,135), ( )-0-meth-ylthalisopavine (26) (136), ( )-reframidine (27) (77), and ( )-reffamine (28) (77) were synthesized by the above-mentioned classical route, where deoxy-benzoins were utilized as starting materials. In some cases, some modification to the method has been introduced, particularly involving the formation of the requisite benzylaminoacetals (77,110). The synthesis of ( )-thalisopavine (30) was undertaken along parallel lines to confirm the structure of the naturally occurring base (53). Moreover, both ( )-reframoline (29) and its positional isomer ( )- 146 were synthesized in an attempt to establish the position of the phenolic hydroxyl (110). The synthesis of ( )-reframine (28) from the properly substituted deoxybenzoin 94 has been outlined in Scheme 16 as a typical example (77). 

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