Isoboldine from reticuline

Reticuline (67) is also a precursor for isoboldine (70) (in Papaver somniferum). Orientaline (62) has been isolated from P. somniferum for the first time, by adding inactive material as a carrier during isolation, after feeding ( + )-[3- C]nor-laudanosoline. However, it was shown not to be a precursor for isoboldine (70) in this plant, thus indicating a unique biosynthetic pathway for isoboldine from reticuline. 

Sz ntay et al. [36) succeeded in a biomimetic synthesis of ( )-salutari-dine (52) in 2.7% overall yield from ( )-reticuline (51) with the aid of LTA oxidation conducted in CH2CI2 in the presence of trichloroacetic acid, with ( )-isoboldine (35) also being formed (Scheme 7). Since morphinan-dienone 52 (65) is an important precursor to morphine, the above synthesis is quite interesting in spite of the low yield. 

Reticuline (25) is also the key precursor for isoboldine (33), which is a minor alkaloid of Papaver somniferum (Brochmann-Hanssen et al. 1973) (the hydrophenan-threne alkaloids of this plant, e.g. thebaine (35) also derive from reticuline). Orienta-line (36) with a methylation pattern different to that in reticuline (25) was not incorporated into (33). Coupling of the two rings in reticuline (25) is thus ortho to a hydroxy-group on one ring and para on the other. 

Both (+ )-isoboldine (81) and (+)-norboIdine (80) were specifically incorporated into boldine (79). " Isoboldine (81) and reticuline [as (82)] had previously been isolated from L. glutinosa and the presence of the latter in this plant was confirmed in a trapping experiment with [f7- C]tyrosine. ° The presence of (85) in the plant was established in the same way. A convincing picture is thus built up for the biosynthesis of boldine (85) - (86) - (82) - (81) - boldine (79). It is interesting to note that reticuline (82), used for the biosynthesis of so many benzylisoquinoline alkaloids, is again a key intermediate. 

The Pschorr reaction was described in connection with the synthesis of the papaverine (3) derivatives (350, 351). The synthesis of petaline (5b) was accomplished (352, 353). Escholamine (4a) and takatonine (4c) were synthesized by a modified Pomeranz-Fritsch reaction (354). The phenolic oxidation of (f )-(-)-N-methylcoclaurine (7c) and (S)-(+)-reticuline (7f) with peroxidase proved to be a failure (355). The oxidation of reticuline with ferricyanide yielded isoboldine (24c) and pallidine (43b) and the byproducts vanillin and thalifoline (2c) (355). A new synthesis of 3-oxo-papaverine was developed (356), and the Eschweiler-Clark method for the synthesis of codamine (7r) was modified (357). Oxidation of reticuline (7f) by enzymatic systems from homogenized P. rhoeas in the presence of hydrogen peroxide gave ( )-/3-hydroxyreticuline (10) (358). 

Aporphine-type alkaloids are formed by the intramoleculer oxidative coupling of the benzyhsoquinoline alkaloid, S-reticuline. Thus, from the ortho, ortho -, and ortho, para -intramolecular coupling of the biradicals formed from S-reticuline, bulbocapnine- and isoboldine-type aporphine alkaloids are formed, respectively. When para, ort/zo -intramolecular coupling of the biradicals formed from S-reticuline occurs, the morphine... 

The label from A -CHa labeled (+ )-(S)-reticuline is incor- reticuline is incorporated into isoboldine (39) (Kametani and... 

Brochmann-Hanssen and Blaschke have supported the thesis that direct phenolic coupling of tetrahydrobenzylisoquinolines can lead to tetrasubstituted aporphines. Along this line, it has been shown that ( )-reticuline specifically labeled with either at C-3 or on the iV-methyl group, when administered to opium poppies (Papaver somniferum L., Papaveraceae) was incorporated into isoboldine to the extent of 0.08% (see Scheme 10.7). But no incorporation of reticuline was observed in magnoflorine. It was, therefore, concluded that 1,2,9,10-tetrasubstituted aporphines such as isoboldine can be biosynthesized by direct phenolic coupling, while steric factors preclude such an avenue for 1,2,10,11 aporphines. Further support for direct oxidative coupling comes from the observation that reticuline is present in Corydalis cava Schweigg et Korte (Fumariaceae). This is of some importance since it had previously been demonstrated that labeled ( )-reticuline is converted to ( + )-bulbocapnine by the same plant (see Scheme 10.8). ... 

Norreticuline has also been synthesized by employing the Bischler-Napieralski reaction [B-HCl, mp 165°-166°J 110). The versatility of reticuline as a chemical intermediate in the production of other alkaloid structures is apparent from its controlled oxidation. When the racemic form was oxidized with manganese dioxide the dienone LIX, which is the racemic form of the alkaloid salutaridine is produced 111). The same results are obtained when the oxidation is carried out with potassium ferricyanide in aqueous solution containing sodium carbonate (— )-reticuline affords the natural ()-salutaridine (7). If the same oxidation agent is used at — 10° in ammonium acetate solution, ( + )-isoboldine (LX) is formed from racemic reticuline (112). 

The conversion of isoboldine (33) into boldine (34) involves demethylation and remethylation rather than methyl transfer since boldine (34) derived from [6-Ol CH3, l- H]reticuline [as (25)J showed a 64% loss of label. Parallel results were observed for the biosynthesis of the naturally occurring dienone, crotonosine (45), from (R)-coclaurine [as (24)] (Haynes et al. 1965). 

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