The Phthalideisoquinolines

The number of phthalideisoquinoline alkaloids was increased by the recent isolation of several new bases some of which do not incorporate a y-lactone ring. These nonlactonic compounds nevertheless may be assigned to the phthalideisoquinoline grouping on biogenetic grounds. Some of the new bases are shown below  

Fumaridine and fumaramine have now been shown to be phthalideiso-quinolines as indicated above, rather than protopines, as previously believed thus fumaridine corresponds to the known compound hydrastine imide.  

---

Cordrastinc, Ci8Hi302N(0Me)4. (Item 9 list, p. 170). Colourless needles, m.p. 196°. Its composition and reactions suggest that it belongs to the phthalideisoquinoline group and is represented by formula (I) (with R = H and the two dioxymethylene groups replaced by four methoxyl groups). ... 

Kondo et al. (182,183) reported a conversion of a fully aromatized phenolbetaine to a phthalide skeleton through photooxygenation. Reduction of norcoralyne (54) with zinc in acetic acid afforded dihydronorcoralyne (374), which was oxidized with m-chloroperbenzoic acid to the fully aromatized phenolbetaine 375 (Scheme 67). Photooxygenation of 375 in the presence of Rose Bengal, followed by reduction with sodium borohydride, gave rise directly to the phthalideisoquinoline 376 in 70% yield. The same phthalide (376) was also obtained from 2 -acetylpapaveraldine (129) (Section III,B,1). 

Preliminary accounts of the preparation and chemistry of betaines 381 (R = H, Me) have appeared. Compound 381 (R = H) is obtained in high yield by oxidation of dihydronorcoralyne (382 R = H) with w-chloroper-benzoic acid. In a similar manner, ethanolic solutions of dihydrocoralyne (382 R = Me) are oxidized to betaine 381 (R = Me) by air. The study of these compounds has so far been restricted to their oxidation products. Photooxidation of betaine 381 (R = H) followed by borohydride reduction gives a high yield of the phthalideisoquinoline 383. Photooxidation of the 8-methylbetaine 381 (R = Me) gives papaveraldine derivatives (384 R = COMe, CO2Me). The mechanisms of these transformations are open to conjecture. 

Heating of the Reissert compound 1 with sodium hydroxide in aqueous methanol gives the phthalideisoquinoline 2 in 58% yield. 

Among the phthalideisoquinoline group of alkaloids there are several pairs of diastereomers. It is shown below that CMR spectroscopy is an effective means of differentiating between such a pair of isomers. Spectra... 

The reduction of the phthalideisoquinoline alkaloids to the corresponding diols has been exhaustively studied namely, those from a- and... 

The UV and IR spectroscopy of the phthalideisoquinoline alkaloids (221) and mass spectrometry (364) have been studied. 

The structures of rhoeadine-isorhoeadine represent a new type of skeleton in alkaloids. The occurrence of rhoeadine-papaverrubine alkaloids was observed in all of the thus far examined sections of the genus Papaver. Their common occurrence leads to the assumption that a biogenetical relationship to the other alkaloids of the Papaveraceae exists. They greatly resemble the phthalideisoquinoline alkaloids. With this in... 

Alkyl ethers of narcotoline have been prepared.A new route to the phthalideisoquinoline system has been developed.It was found that acid treatment of (176) cf. Vol. 4) results in an interesting rearrangement to give the isomeric phthalideisoquinolines (177) and (178). Compound (177) was further converted into cordrastine I (179) and cordrastine II (180). 

The interesting conversion of nornarceine (181) into the rhoeadine analogues (187) and (188) has been carried out as shown in Scheme 9. Nornarceine (181), obtained from (— )-a-narcotine, was heated in base to afford the enamine (182) which readily cyclized in dilute acetic acid to the y-lactone (183). Upon standing, (183) was oxidized to the ketone (184). Lithium borohydride reduction led to the c/.s-acid (185). The derived ds-fused lactone (186) was then reduced to the hemi-acetal (187) which upon O-methylation with trimethyl orthoformate gave (188). The structure of the methiodide salt of (187) was confirmed by an X-ray analysis. The phthalideisoquinoline alkaloid (— )-bicuculline (189) was then converted into naturally occurring (+ )-rhoeadine (190) by an analogous route. Since (— )-bicuculline was obtained from (—)-)3-hydrastine, whose synthesis had been reported in 1950, this transformation represents the first total synthesis of a rhoeadine alkaloid. ... 

Although at the time of publication the structure of oxybisberberine, the crystalline ferricyanide oxidation product of berberine, is still unknown in its details, the chemistry of this dimer has proved to be rich in its diversity. Oxybisberberine played a key role in the first known in vitro conversion of berberine to the phthalideisoquinoline alkaloid jS-hydrastine. This photosensitive dimer. 

It had previously been established that reaction of the keto immonium salt 13 with diazomethane resulted in ring expansion to the benzazepine 14. Cyclization of this benzazepine with phosphorus oxychloride produced the benzindenoazepine 15 whose mild oxidation resulted in ring contraction to the phthalideisoquinoline 16. Compound 16 could readily be reduced to the erythro phthalideisoquinoline 12 ° ... 

Capnoidine, C jHigOgN. (Items 24, 25 list, p. 171.) M.p. 238°, gives a crystalline hydrochloride, m.p. 244°. It contains no methoxyl groups, is isomeric with adlumine and possibly belongs to the phthalideisoquinoline group. See also base F 38 (Item 44 list, p. 173). 

---