Isopavines, synthesis

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 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). 

The first synthesis of an optically active isopavine, (—)-reframoline (29), has been achieved by the acid-catalyzed double cyclization process described previously. The properly substituted diarylamine 109 was resolved using (-t-)-di-benzoyltartaric acid to afford the (-I-) enantiomer. Conversion to the acetal 110 was accomplished without racemization. Subsequent acid-catalyzed cyclization yielded the levorotatory alkaloid 29 (Scheme 21) 112). 

Kametani and co-workers used a previously demonstrated ring expansion method to construct the isopavine skeleton (144,145). The method was successfully applied to the synthesis of ( )-reframidine (27) (Scheme 23) (145). Treatment of the 3-aryl-3,4-dihydroisoquinolinium iodide 115 with diazomethane furnished aziridinium iodide 116. On standing in 6 N hydrochloric acid, crude 116 underwent a one-step ring expansion-ring closure to afford ( )-reframidine in 20% yield. The same product could be obtained via benzazepine 118 depending on the reaction conditions. It has been postulated that the aziridinium iodide 116 may have formed a transitory quinonoid intermediate 117 which is attacked... 

A recent endeavor at the total synthesis of isopavines describes a promising novel route to these bases via functionalized dibenzocyclooctadienes (Scheme 27) 148). Dibenzocyclooctadienyl ether 132, formed from homoveratraldehyde (131) by a double Friedel-Crafts alkylation, is converted to dibenzocyclooc-tatrienol 133. Treatment with hydrazoic acid, followed by thermolysis and reduction, supplies ( )-isopavine (35) in good overall yield (53%). Subsequent attempts to prepare pavine bases by this approach have proved to be unsuccessful 148). 

Other isopavines were also shown to possess the same (55,125) configuration by virtue of the similarity of their CD spectra with that of (—)-amurensine (24) (772). The simultaneous synthesis of (-)-caryachine (7) and (-)-reffamoline (29) from the same optically active precursor of known absolute configuration furnished further support for the established absolute configuration of the isopavine alkaloids (772). 

Because benzylisoquinolines have been available synthetically (in racemic form) for decades, there is quite a bit of chemistry known regarding their use as key intermediates in the synthesis of a number of more complex isoquinoline alkaloids. The asymmetric synthesis of benzylisoquinolines has been used to complete total synthesis of representative members of several of these alkaloid classes. As shown in Figure 6, the protoberberine alkaloid norcoralydine, the aporphine alkaloid ocoteine, the isopavine alkaloid reframoline and the morphinan 0-methylflavinantine have been made available in optically active form for the first time (except by isolation or resolution) using this approach. 

The Soviet workers determined the constitution of roemrefine (=reframine methohydroxide) (56a) (286,574), and Dyke and Ellis confirmed the position of the phenolic group on the aromatic ring in amurensine (56b) by a synthesis (575, 576). The alkaloids thalisopavine (417) and O-methylthalisopavine (248), isolated from Thalictrum dasy-carpum (Ranunculaceae), have the same absolute configuration as the other known isopavine alkaloids obtained from Papaveraceae plants. 

The first synthesis of the racemic isopavine compounds with methoxyl groups on both aromatic nuclei was reported by Battersby and Yeowell (577) and later used for the synthesis of thalisopavine (417). A simple and ingenious method for the synthesis of isopavine derivatives with methyl-enedioxy groups was developed by Dyke (337, 575, 578-582). The synthesis requires the formation of 4-hydroxynorlaudanosoline (9a), which is probably also a natural precursor of this group of alkaloids. This method does not, however, yield the phenolic isopavines, one of which is reframoline (56e). Therefore, another method for their synthesis has been developed (576). Instead of the amine, the urethane is prepared from the starting benzyl derivatives it is then cyclized and saponified into the corresponding alkaloid. 

For this synthesis (Scheme 24), deoxypiperoin (a) is condensed with the aminoacetaldehyde dialkyl acetal to the imine b and then, without isolation, it is reduced with sodium borohydride to the compound c. The yield was 60% from the ketone. Treatment of c with concentrated hydrochloric acid for five days at room temperature affords an isopavine base hydrochloride in 70% yield. Nine isopavine bases have been prepared in this manner. 

Scheme 25. Synthesis of isopavine alkaloids (56) via 3,4-dihydroisoquinoline and aziri-dinium salts (57a) (362).

Brown etal. reported the synthesis of many berbine derivatives, isopavine alkaloids, and amurensinine (56f) (581, 629). They describe some rearrangements of those alkaloids. 3-Hydroxy-2-methoxy-9,10-methylene-dioxyberbine (59d) and 3-hydroxy-2-methoxy-10,ll-methylenedioxy-berbine (60h) were synthesized through the N-formyl derivatives of... 

The isopavines reframine (34) and reframidine (35) have been synthesized by established routes. The details of the conventional synthesis of the pa vine bisnorargemonine and related isomers have been given, together with the appro-... 

Caryachine has been synthesized also by the action of ethanolic 6M hydrogen chloride on the (+)-(5)-isomer of the base (53), the reaction presumably proceeding via the cyclisation product, i.e. the 1,2-dihydroisoquinoline. The reaction also affords the isopavine alkaloid (-)-reframoline (52). This synthesis confirms the absolute stereochemistry deduced from the aromatic chirality rule. 

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 ... 

SCHEME 17.5. Synthesis of isopavine 18 by a [1,2]-Stevens rearrangement of ammonium ylide 17. 

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