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Biosynthesis. Part 26. Synthetic studies on structural modification of late biosynthetic precursors for colchicine

The latter part of the natural pathway to colchicine is known to involve conversion of a phenethyltetra-hydroisoquinoline (2) by phenol oxidation into a dienone (O-methylandrocymbine)(4), the dienone subsequently undergoing ring-expansion to generate the tropolone system. Synthetic routes are here described which yield the isoquinoline and dienone structures in modified forms (16), (17), and (38), all having a C-methyl group introduced adjacent to the nitrogen atom. An alternative approach for synthesis of the dienone, involving conversion of a phenanthrene into a dibenzocycloheptene, is also explored.Incorporation experiments on Colchicium autumnale plants using labelled isoquinolines (16a) and (17a) show that they are not converted enzymically into tropolone alkaloids nor is the former significantly cyclised in the plants to the C-methylated dienone (38). Clearly, at least one of the enzymes required for the late biosynthetic stages is highly sensitive to structural change close to the nitrogen atom.