Pavines

Some recently isolated pavines and isopavines are shown below  

Reduction of papaverine methiodide with tin and hydrochloric acid produces, in addition to laudanosine, A -methylpavine formed through cyclization of the transitory 1,4-dihydroisoquinolinium intermediate. Recent syntheses in 

Stermitz and his collaborators constructed the benzylisoquinoline methiodides necessary for conversion to the unsymmetrically substituted pavines platycerine and munitagine by way of a Reissert compound. Alkylation of the Reissert compound derived from the isoquinoline 2 with the appropriately 

Turning now to the synthesis of isopavines, a required intermediate for this purpose is again an appropriately substituted 1,2-dihydro-A -methylbenzyl-isoquinoline. Hydroboration of the enamine system and oxidative work-up induce formation of a 4-hydroxybenzylisoquinoline which can be cyclized in acid to the isopavine skeleton. A recent example of such a synthesis leads to the new isopavine thalidine  

The methylenedioxy substituted isopavine amurensine was prepared by a parallel method, as were the related bases reframine and reframoline. In the latter study, undertaken to confirm the structure of reframoline, the two positional isomers with respect to the hydroxyl and methoxyl groups, namely, 5 and 6, were prepared synthetically, but could not be distinguished by spectral means. They were, however, easily characterized by way of the UV spectra of their respective methine bases, 7 and 8. The 3-hydroxy methine base exhibited a large bathochromic shift upon the addition of base, while little alteration of the spectrum of the 2-hydroxy isomer occurred in base  

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The cyclization reaction of some substituted 1,2-dihydroisoquinolines is of interest (255). The reduction of papaverine with tin and hydrochloric acid affords the 1,2-dihydro compound in the form of immonium salt 172, which then undergoes a cyclization reaction in the acidic medium to give compound 173, called pavine (257). 

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-... 

Since the previous reviews on the pavine group in Vol. 4, 10, 12, and 17 of this treatise, which cover references prior to 1976, five new alkaloids of the pavine series have been discovered. These alkaloids are (—)-2,3-methylene-dioxy-4,8,9-trimethoxypavinane (3), thalipoline, (—)-caryachine Af-metho salt (16), (-)-eschscholtzidine Af-metho salt (17), and (-)-eschscholtzine A -oxide (20a). 

A tertiary base isolated from Thalictrum strictum was assigned a pavine structure based on the spectral data (27). Three methoxyl and one methylenedioxy functions were detected with the aid of mass spectroscopy. Structure 3 was proposed as the most probable representation for this new pavine alkaloid, which indeed is the first example of a pentasubstituted pavine base. However, when the reported aromatic proton chemical shifts (8 6.23, 6.36, and 6.54) were evaluated in the light of empirical rules about the H-NMR absorptions of pavine bases (Section V,B), and it seemed possible that the two upfield absorptions belong to H-4 and H-10 rather than to H-1 and H-10. Therefore, alternative structure 4 cannot presently be completely excluded from consideration. 

A recent addition to the pavine series may be thalipoline, C has been isolated from Thalictrum minus 28). The pavine framework was deduced from spectral data which, however, were not described. 

The new quaternary pavine base (-)-caryachine A-metho salt was isolated from Cryptocarya chinensis (29), previously shown to yield both the levorotato-ry and racemic forms of caryachine (7) (30,31). The structure 16 was derived... 

It is a general feature of alkaloid chemistry that less is known about the quaternary alkaloidal components than the tertiary bases due to the difficulties encountered in handling the isolation and analyses of these highly polar compounds. It is interesting to note, however, that in the pavine series, 5 naturally occurring A -metho salts as against a total of 15 tertiary pavine alkaloids have been recognized. 

The synthetic process leading to pavine formation can now be illustrated as in Scheme 1. It includes quatemization and selective reduction of the iminium bond to afford a 1,2-dihydroisoquinoline (36), which is the key intermediate in the synthesis of pavine bases. Acid-catalyzed cyclization of this enamine furnishes the pavinane framework 38 via the 1,4-dihydroisoquinolinium ion 37. Langhals... 

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 a novel synthetic route involving the transformation of a tetrahydroproto-berberine nucleus to a pavine skeleton (Scheme 10) 119), canadine methiodide (67), was subjected to Hofmann degradation to yield styrene 68. This compound was successively oxidized with osmium tetraoxide-sodium periodate and the... 

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