Laudanosoline, oxidation

Fig. 3. Oxidative coupling products of methylated derivatives of laudanosoline (77, R = H). See Table 8.

Initially Robinson and Sugasawa (8) proposed that laudanosoline (5), prepared from laudanosine (4) by O-demethylation with aluminium chloride in refluxing xylene, could be oxidized to an aporphine or morphine prototype. To demonstrate that no rearrangement had occurred, 4 was regenerated from 5 by O-methylation. Oxidation of 5 was accomplished with chloranil in buffered alcohol solution, and 6 was isolated in 60% yield as the chloride (Scheme 1). Di-benzopyrrocoline 6 was also obtained in 30-50% yield when aqueous solutions... 

Extension of oxidative coupling of laudanosoline by Harley-Mason (20), who investigated the oxidation of tetrahydropapaveroline (27) with potassium ferri-cyanide, afforded 2,3,9,10-tetrahydroxy-5,6-dihydrodibenzopyrrocoline (28) in... 

Oxidative coupling of (5)-(-)-laudanosoline (5) with horseradish peroxidase in the presence of hydrogen peroxide, studied by Brossi et al. (27), afforded dibenzopyrrocoline (—)-6 in 81% yield, and conversion to (5)-(—)-0-meth-ylcryptaustoline (14) by methylation provided additional proof for the absolute configuration of this and related alkaloids. Enzyme specificity in the C— coupling reaction was demonstrated with similar oxidation of (/ )-(—)-laudanosoline methiodide, which afforded an aporphine converted by O-meth-ylation to (R)-(-)-glaucine. 

Additional oxidative coupling processes among the various methylated derivatives of laudanosoline yield many other families of bases, including the pavine argemonine (88) from Argemone mexicana E berberine (89) from Hydrastis canadensis E which, despite its toxicity, has been used as an antimalarial protopine (90) and chelidonine (91) from Chelidonium majus E rhoeadine (92) and the cephalotaxus ester harringtonine (93) from Japanese plum yews ( Cephalotaxus spp.), which is a compound of some significance because it possesses potent antileukemic activity (see Fig. 3). 

Laudanosoline (XCV), labeled with at both the C-3 position (64% of the total activity) and in its iV -methyl group, when administered to Berberis japonica gave rise to radioactive alkaloids 125). Conversion of the berberine to phenyldihydroberberine (XCVI), followed by oxidation, gave benzoic acid containing 34% of the total activity of the alkaloid. 

Taken together these experiments establish a) the formation of the berberine bridge by oxidative cyclization of the iV-methyl group, (6) the derivation of the methylenedioxy group by oxidative cyclization of the 0-methoxyphenol grouping, and (c) the validity of laudanosoline and reticuline as intermediates in the biosynthetic pathway. 

Attempts have been made to realize experimentally the conversion of laudanosine-type bases to bases of the aporphine and morphine series, so far without success. In an attempt to convert laudanosoline [xtx] to norglaucine [x ] it was discovered that the former is very readily oxidized to intractable materials, but that oxidation with chloranil [5-6] or tetrabromo-o-benzoquinone [7] affords, not the expected norglaucine, but 2 3 11 12-tetrahydro-8-methyldibenzotetrahydropyrrocolinium ohloride [xxi]. Protosinomenine [i] has been synthesized in two ways [3, 8], but the conditions required for the conversion of this base to sinomenine [iv] have not yet been realized and their discovery must be largely fortuitous [6],... 

More recently, the preparative value of VOCl3 and VOF3-TFA in chemical oxidation has been demonstrated (see Section III, on the pro-aporphine and promorphinane alkaloids) (415,462). Some other authors used the purified enzyme horseradish peroxidase (463). By this method the aporphine base (besides the quaternary dibenzopyrrocoline) is readily obtained from (S)-( + )-laudanosoline hydrobromide or from (/ )-(—)-laudanosoline methiodide with retention of the absolute configuration. The synthesis of 6a,7-dehydroaporphine bases was also carried out by making use of the benzyne reaction (439). Reduction of these substances affords the corresponding aporphine bases (439). The synthesis of isoquinoline alkaloids by lead tetraacetate oxidation was reviewed by Umezawa and Hoshino (343). 

Early attempts to simulate the synthesis of the aporphine and morphine alkaloids often met with failure. Efforts to oxidize laudanosoline (30), for example, did not give the desired type of coupling, but resulted in the formation of dibenzopyrrocoline structures (Fig. 32.30) (Elliott, 1987 Geissman and Crout, 1969). Alkaloids of this general structure were discovered in the Australian plant Cryptocarya bowiei (Lauraceae). Among these were cryptaustoline (91) and cryptowolline (92). 

In an interesting synthesis of 0-methylcryptaustoline iodide, Brossi s group has shown that enzymic oxidation of alkaloids can be a useful preparative method. Optically active laudanosoline was oxidized with horseradish peroxidase and hydrogen peroxide to furnish the tetraphenol 12 in 81% yield, with complete retention of configuration. Subsequent O-methylation afforded 0-methylcryptaustoline. For a parallel enzymic conversion to an aporphine see Sec. 10.2.8. 

Laudanosoline and norlaudanosoline have been converted in good yields into the corresponding aporphines by oxidation with an excess of ferric chloride cyclic iron complexes are believed to be intermediates in this reaction. 

It is well known that the attempts to transform laudanosoline (199, 200) or iV-norlaudanosoline (201) into aporphine bases by oxidation have failed instead compounds with a dibenzopyrrocoline structure (CXXXIX) were obtained. Franck and Schlingloff (202) found that if the reactivity of the nitrogen atom is eliminated by quaternization, then the mild oxidation of laudanosoline methiodide (CXL) with ferric chloride in aqueous solution affords in 60% yield the aporphine base... 

Oxidative coupling of phenols. (IR)-(-)-Laudanosolin methiodide mixed with horseradish peroxidase in water, treated during 1 hr. with 0.02%-HgOg while maintaining neutral pH by addition of 0.1 M triethylamine, and acidified with dil. HCl quaternary aporphine deriv. Y 60-90%. 

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