Method for producing corytuberine and salutaridine

A method for preparing corytuberine and salutaridine via the benzylisoquinoline alkaloid reticuline as an intermediate, the process comprising the following reaction steps:

• a) amidation of 2-(4-hydroxy-3-methoxyphenyl)-N-methylethanamine (12) with 3-hydroxy-4-methoxyphenylacetic acid to yield N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl-N-methyl-3-hydroxy-4-methoxyphenylacetic acid amide (13):
• b) Bischler-Napieralski cyclization of the tertiary amide (13) to yield 1,2-dehydro-reticuline (14):
• c) biocatalytic enantioselective hydrogenation of 1,2-dehydroreticuline (14) to yield reticuline (15), either
• c1) using an imine reductase to yield (S)-reticuline (S)-(15) or
• c2) using a dehydroreticuline reductase to yield (R)-reticuline (R)-(15):
• d) biocatalytic oxidative phenol coupling between the two aromatic rings of the respective reticuline, namely either
• d1) ortho-ortho coupling of (S)-reticuline in the presence of corytuberine synthase (CorSyn) to yield corytuberine (16) or
• d2) ortho-para coupling of (R)-reticuline in the presence of salutaridine synthase (SalSyn) to yield salutaridine (17):