Proaporphine dienones

Chitraline is obtained from B. baluchistanica under neutral conditions, so it is an actual alkaloid and not an artifact from acid-catalyzed dienone-phenol rearrangement of a proaporphine-benzylisoquinoline dimer (61). Chitraline has also been isolated from B. zebiliana Schneider (62), and B. calliobotrys (62). A possible biosynthetic scheme relating chitraline with co-occurring alkaloids has been proposed (62, see Section VII,C). 

Morphinandienones have also been synthesized by the oxidation of mono-phenolic benzylisoquinolines with vanadium oxyfluoride in trifluoroacetic acid, other products of the reaction being proaporphines, and similar oxidations have been accomplished with phenethylisoquinolines.183 The same reagent will oxidize the lactam (150) to the dienone (151), which is an analogue of dehydrometatheb-ainone, and the same cyclization may be effected by electrochemical oxidation.184... 

A careful study of the dienone-phenol rearrangement in vitro of pakistanamine (60), which is the sole proaporphine-benzylisoquinoline alkaloid presently known,... 

Analogous rearrangements were reported for similar systems such as proaporphines , the alkaloids of Croton sparsiflorusMorong and cannabinoids . The dienone-phenol and dienol-benzene rearrangements were studied in the eupodienone-1 series (a constituent of Eupomatia laurina R. Br.). These compounds 311 were transformed under a variety of acidic conditions into dibenzocyclooctene derivatives (equation 149). 

In an eady attempt to understand the genesis of alkaloids from amino acids it was postulated (56) that intramolecular phenolic coupling should lead from benzylisoquinoline bases such as laudanosine (77, R = CH3), before it was completely methylated, to aporphine bases such as isothebaine (81). For example, between a benzylisoquinoline derived from laudanosoline (77, R = H), such as orientaline (82), and an aporphine alkaloid such as isothebaine (81), there should be a proaporphine alkaloid such as orientalinone (83) (56). The isolation of 83 lent credence to the hypothesis. Indeed, the fragile nature of 83 (it readily undeigoes the dienone—phenol rearrangement on acid treatment) required unusual skill in obtaining it from total plant extract. 

Before kreysiginone was isolated from a natural source diphenolic isoquinoline 76 had been oxidized with ferric chloride to yield homo-proaporphines 19 and 20 (40), one of which, dienone 19, was isolated from Kreysigia multiflora by Battersby (2a). Battersby also synthesized both dienones 19 and 20 by the same reaction of 76 with potassium ferricyanide. In this reaction he examined the phenol oxidation of the diphenolic isoquinoline 86 and obtained product 87 containing... 

On reductive cleavage (JOO) with sodium in liquid ammonia the proaporphine alkaloids with dienone structure are converted into benzyl-isoquinoline bases (IV I XIV XIII). By treatment with W-hydro-chloric acid the dienone alkaloids are transformed (69, 349) into the aporphine alkaloids (Schemes 1 and 2) by dienone-phenol rearrangement (IV -> II XIV -5- XV, XVI, and XVII). Substitution of the proaporphine base at C-9 by a methoxyl function involves rearrangement which gives rise to two isomers, i.e., XV and XVI. On the other hand, by reduction of dienone with sodium borohydride (formation of two dienols) and following treatment with hydrochloric acid these dienols are converted (65,66, 68, 69, 349) into the aporphine alkaloids with formation of a new aromatic ring (VI and VII III XVIII XIX and XX). 

The reduction with borohydride and the acid-catalyzed dienone-phenol/dienol-benzene rearrangements leave the center of chirality at C-6a intact. Consequently, the absolute configuration of this center can be intercorrelated with that of the benzylisoquinoline, proaporphine, and aporphine alkaloids (Schemes 1, 2, and 20). 

Mass spectrometry (22, 96,181, 530, 531) and NMR spectroscopy (65, 69,181,209,431) have been recorded. The UV spectra of the dienone alkaloids differ in the extinction maxima (proaporphine alkaloids at 220 nm (e 24800) and 285 nm (c 3000) promorphinane alkaloids 230 nm (e 24,000) and 285 nm (e 7500)). IR Spectroscopy reveals characteristic frequencies of the cross-conjugated dienone at 1655, 1630, and 1613 cm"i. On polarography the proaporphine and the promorphinane dienone compoimds are reduced (335) at a half-wave potential similar to that of aromatic aldehydes. 

The biosynthesis of aporphine alkaloids takes the course—laudanoso-line, norlaudanosoline, reticuline, or orientaline—by means of phenolic oxidation via the cyclohexadienone proaporphine (27, 28, 39, 40, 47, 49, 65, 66, 68, 69,147,148,150, 229, 231, 240, 250, 275, 349, 445, 451, 512) after dienone-phenol or dienol-benzene rearrangement, as described in more detail in the preceding section. The foregoing results, considered as a whole (39,49), provide good evidence that isothebaine is biosynthesized in P. orientale along the following pathway ... 

N-Methylcrotsparine (5) is a hypotensive agent and proaporphines incorporating a dienone system may possess both analgesic and hypotensive activity (no data). There is a claim that glaziovine (4) may be used as a tranquillizer " the alkaloid does possess anxiolytic properties similar to diazepam. ... 

Scheme 13) this may not be the case for aporphines with substituents in positions 1,2,10, and 11 [corytuberine type (25e)]. Because of steric factors these aporphines are more likely to be produced via a dienone proaporphine intermediate followed by a dienone-phenol rearrangement. In the second work, the same authors report that orientaline was detected in the opium poppy by an isotope-dilution method based on its biosynthesis from norlaudanosoline (7p) (258). Administration of labeled orientaline (7s) revealed that in P. somniferum this alkaloid was not a precursor of isoboldine (24c), and the experimental results provided no evidence for a pathway involving norprotosinomenine (7t) this route is, however, very likely for P. orientate and P. bracteatum (Scheme 13). 

Proaporphine-BeHzylisoquinoline Dimers.—The first known proaporphine-benzylisoquinoline dimer, pakistanamine (112), has been isolated from Berber is baluchistanica Ahrendt (Berberidaceae). Dienone-phenol rearrangement of pakistanamine (112) using dilute hydrochloric acid gave rise to the phenolic aporphine-benzylisoquinoline dimer (113), and O-methylation of this product with diazomethane provided 00-dimethylpakistanine (114) of known structure and stereochemistry. ... 

Biosynthesis A. a. are formed from phenolic tetrahy-drobenzylisoquinolines either by direct oxidative coupling or via dienones (proaporphines). The direct oxidative coupling can be either ortho-para (to isoboldine type) or ortho-ortho (to bulbocapnine type) . Lit, Eur. J. Pharmacol. 219,67-74(1992). PlantaMed. 57, 406ff. (1991). Biochem. Pharmacol. 43, 323-329 (1992). 

Proaporphine alcaloido. P. a. are precursors of some aporphines and possess a characteristic, spiro-anne-lated five-membered ring. They can be converted to aporphine alkaloids by a dienone-phenol rearrangement of, after reduction to a dienol, by a dienol-ben-zene rearrangement. P. a. occur primarily in the plant families Euphorbiaceae, Lauraceae, Menispermaceae, Monimiaceae, Nymphaeaceae, and Papaveraceae. 

Beside the potential use of glaziovine as a tranquilizer referred to above, a claim has been made (no data) that proaporphines with a dienone system possess analgesic and hypotensive activity. A-Methylcrotsparine does show some hypotensive activity.The two proaporphine alcohols obtained by sodium borohydride reduction of the ketonic functions of ( )-8,9-dihydroglaziovine and of ( )-l 1,12-dihydroglaziovine had sedative activity when tested on rabbits. 

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