Reticuline stereochemistry

Figure 5 Two different formulas showing the stereochemistry of (S)-reticuline...

Papaverine.—The biosynthesis of the simple benzylisoquinoline papaverine (89) is known to proceed via nor-reticuline (48) and tetrahydropapaverine (88).71 Dehydrogenation of the latter affords papaverine, and examination of the stereochemistry of the processes involved has led to the conclusion72 that loss of the proton at C-3 [in nor-reticuline (48)] is stereospecific (loss of the pro-S hydrogen atom) but removal of the C-4 proton is essentially non-stereospecific. These observations are perhaps best explained if enzyme-catalysed oxidation of (88) occurs to give (90), subsequent non-stereospecific imine-enamine isomerization occurring without enzyme participation to give (91). A further amine to imine oxidation then occurs to give papaverine (89).72... 

Following the formation of S-norcoclaurine, hydroxylation at C3 with subsequent methylation yields S-reticuline.24 Although the R form corresponds to the correct stereochemistry of morphine at C9, both R and S isomers of reticuline have been found to act as precursors for thebaine, codeine and morphine and it is therefore apparent that S-reticuline is con-verted to its R form.25 Inversion is best explained by formation of an intermediate 1,2-dehydroreticulinium ion 22, followed by stereospecific reduction to yield R-reticuline, Figure 3. An NADPH-dependent enzyme, 1,2-dehydroreticuline... 

ScouIerine (83), which is derived from (+)-reticuline (80), is found in P. somniferumP Coreximine (84), with the alternative oxygenation pattern to scoulerine, has not been previously isolated from this plant. Dilution of P. somniferum with inactive (+ )-coreximine after administration of [S- C]- or [N-Me- C]-( )-reticuline gave radioactive coreximine, which after the former feed was degraded and shown to be specifically labelled. Thus coreximine (of necessarily uncertain stereochemistry) is shown to be present in this plant and derivable from reticuline. 

Morphinan alkaloids are the pharmaceutically most important class of isoquinoline alkaloids. Codeine and morphine are found only in Papaver somniferwn and closely related species. Both alkaloids are derived from (R)-reticuline, the absolute stereochemistry of which corresponds with the configuration of morphinan alkaloids. Re-ticuline is therefore an important branch point in isoquinoline bio nthesis. However, either enantiomer of reticulme, when fed separately, is incorporated into morphinan alkaloids essentially to the same extent. The question therefore arises by which mechanism (R)-reticuline is formed within the plant. 

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