The Pavines and Isopavines

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-... 

An interesting variation on the above theme for the biosynthesis of the pavines and isopavines has been proposed by Dyke (169). This proceeds via a quinone methine intermediate. The precursor, a l-benzyltetrahydroisoquinoline-3-car-boxylic acid 165 oxidizes to a quinone methide 166, which then decarboxylates to afford a reactive enamine 167. Cyclization then readily furnishes a pavine. Alternatively, hydration of the enamine 167 at C-4 would ultimately result in formation of an isopavine (Scheme 36). 

Undoubtedly, work with labeled precursors is in order at this point to establish with certainty the exact biosynthesis of the pavine and isopavine bases. 

The H-NMR and mass spectral data of homopavines and homoisopavines are in conformity with those of the pavine and isopavine bases, respectively. A brief note should be made, however, on a divergent mode of fragmentation in the mass... 

The fact that the pavine and isopavine alkaloids have the same absolute configuration points to the possibility of a common biogenetic precursor such as the 4-hydroxyreticuIine (9b) (or the already mentioned 4-hydroxy-norlaudanosoline (9a)] which, depending upon the plant family or genus, can cyclize directly to an isopavine species or alternatively can undergo dehydration, double-bond isomerization, and intramolecular cyclization to a pavine analog (584) (Scheme 26). 

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. 

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). 

References relevant to the spectral analyses of naturally occurring pavine and isopavine bases are presented in Tables XIII and XIV. An exhaustive numerical compilation of spectral data of these alkaloids may also be consulted (77). 

The absorption maximum of isopavine alkaloids appear at 290-294 nm. The shoulder at 250 nm, which is missing in the spectra of pavines, provides complementary information in distinguishing between pavine and isopavine alkaloids (7,67,69). Additionally, the Hofmann degradation products of the two nuclei have been shown to differ greatly in their UV spectral behavior (67,69,75). 

The fact that pavine and isopavine alkaloids have the same absolute configuration also suggests an alternative biosynthetic sequence where both nuclei are derived from a common 4-hydroxybenzyltetrahydroisoquinoline precursor (Scheme 35) (77,135). A dehydration reaction to afford a 1,2-dihydrobenzyliso-quinoline, followed by cyclization, would yield a pavine. Alternatively, dis-... 

The presence of pavines and isopavines has been used to provide assistance for taxonomic classifications, and to determine intergeneric and phylogenic relationships in the genera Papaver and Argemone. The results of extensive chemical research on Papaver species demonstrated that morphologically distinct sections are also chemically distinguishable by virtue of their alkaloidal profile (170). Out of nine well-defined sections of Papaver, the Section Scapiflora, which displays... 

In addition a range of oxidised cularines matching that of the oxidised aporphines is also known. The bases limousamine (92) and 4-hydroxysarcocapnine (93) represent hydroxy substitution unknown in the benzylisoquinoline and.bisbenzylisoquinoline series (probably because of the ease with which such compounds can be converted into pavines and isopavines) but... 

Suzuki coupling with bromopolystyrene provided the linker 76. Syntheses of a-branched amines required condensation of 76 with different aldehydes and addition of ethylmagnesium bromide. Detachment of alkylated amines 77 from the resin was accomplished by treatment with HCI in dichloromethane and yielded 90-95% product. Diastereomeric ratios varied between 88 12 and 97 3. This method was also used in the asymmetric formation of pavine and isopavine. These alkaloids were obtained with complete stereoselectivity. 

Rates of methiodide formation provide a facile means for differentiation between pavine and isopavine bases, because the latter quaternize at a faster rate (585). I. 

Scheme 26. The possible common pathway of the biosynthesis (and. the absolute configuration) of pavine and isopavine alkaloids (3, 584).

Pavines and Isopavines.—(—)-Norargemonine and (—)-bisnorargemonine have been isolated from the roots of Eschscholtzia californica, E. douglassi, and E. glauca (Papaveraceae). ... 

Pavine and Isopavine. A chiral tert-butanesulhnamide resin 107 (Scheme 12.26) has been developed from tertiary alcohol 106 by Ellman and coworkers. Condensation of resin 107 with 3,4-dimethoxyphenyl acetaldehyde with excess Ti(OEt)4 followed by addition of 3-methoxyphenylmagnesium bromide afforded the desired amine 108. The sulhnyl... 

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. 

A base peak corresponding to a 6,7 (or 7,8)-disubstituted isoquinolinium ion is the prime criterion in considering a pavine or an isopavine structure. In the case of a pavine, the presence of the expected peaks may only confirm the structure deduced by other spectral and chemical means. In isopavines, however, mass spectroscopy is an exceptionally powerful tool in differentiating this group from the pavine alkaloids, as well as from other related isoquinoline bases. 

S)-(+)-reticuline (20) and orientaline (25). The alkaloids of the Papaveraceae and Fumariaceae can be subdivided into several constitutional types (Fig. 3), viz., simple isoquinolines, benzylisoquinolines, pavines, isopavines, cularines, proaporphines, aporphines, promorphinanes, morphinanes, protoberberines, retroprotoberberines, secoberbines, benzophenanthridines, protopines, phthali-deisoquinolines, secophthalideisoquinolines, indenobenzazepines, spirobenzyl-isoquinolines, and rhoeadines. 

Various species of Argemone and Eschscholtzia (Papavera-ceae) and Thalictrum (Ranunculaceae) contain pavine alkaloids (about 20) and isopavine alkaloids (about 10) with a tetracyclic nucleus derived from benzylisoquinoline alkaloids (Gozler, 1987 Guinaudeau and Bruneton, 1993 Schiff, 1987). The formation of argemonine (93) and related alkaloids is rationalized as follows (Fig. 32.31) (Geissman and Crout, 1969). An alternate mode of cyclization also has been observed in the formation of (— )-eschscholtzine (94) and (- )-munitagine (95). 

A close relationship exists between the alkaloids of the two families Papaveraceae and Fumariaceae. Their relationship, as well as their independence, is particularly well demonstrated by the external structure of the flowers and various anatomical characteristics of different organs (Novak and Preininger 1983). Characteristically, the Fumariaceae contain spirobenzylisoquinoline (7), indenobenzazepine (8), se-cophthalideisoquinoline (10) and phthalideisoquinoline (9) alkaloids, whereas rhoeadine (11), pavine (12) and isopavine (13) type alkaloids, which are characteristic of Papaveraceae, are absent. The secoberbines have been found in C. incisa (Thunb.) Pers. and in C. ochotensis Turcz. (37—39). The cularine alkaloids (40) which are characteristic of the genus Corydalis are also found in species of Dicentra which is a member of the Papaveraceae. 

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-... 

It has already been mentioned that a novel synthetic process furnished race-mates and optically active forms of pavine bases via unstable quinone methide intermediates (Section III,A) 117). In this process, isopavine formation has also been achieved by the proper choice of reaction sequence. Racemates of thalidine (21) and 0-methylthalisopavine (26) were efficiently obtained by the above-mentioned route 117). Moreover, the sequence provides a convenient route to... 

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