Laudanosoline

Phenohc intermolecular coupling (46) of two laudanosoline (77, R = H) fragments, which may be preceded or followed by partial O- or N-methylation, gives rise to the dimeric or bisben2yhsoquinoline alkaloids such as oxyacanthine (79), obtained along with related materials from the roots... 

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

Laudanosoline and Dehydrolaudanosaline. When laudanosine is de-methylated it yields laudanosoline, first prepared by Oberlin, ... 

Reference may also be made to the synthesis of various alkylated laudanosolines by Schopf, Jackh and Perrey, e.g., laudanosoline 6 7 3 -tribenzyl-4 -methyl ether and laudanosoline 4 -methyl ether, to the preparation of the 3 7-dimethyl ether by Schopf and Thierfelder (1939), and to Robinson and Sugasawa s synthesis of proiosinomenine (4 7-dimethyl ether of laudanosoline). 

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. 

As part of their program of study of neuroamine metabolism in mammals, Davis and co-workers investigated the biotransformations of nor-laudanosoline (87) by rat liver and by brain preparations. They were successful in isolating a catechol O-methyltransferase enzyme system from rat liver which performed methylations of 87 to give two unidentified products (94) and later they obtained soluble enzyme preparations from rat brain and liver which, in the presence of [14C]methyl-5 -adenosylmethio-nine, gave three radioactive metabolites identified by mass spectral analysis as 90, 93, and a ring A monomethyl derivative of 93 (95, 96). 

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],... 

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. 

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). 

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