Biosynthesis. Part 30. Colchicine: studies on the ring expansion step focusing on the fate of the hydrogens at C-4 of autumnaline

Autumnaline 1 is a key biosynthetic precursor of colchicine 4. Syntheses are described of autumnalines that are labelled stereospecifically with tritium at C-4 of their isoquinoline ring. This corresponds to C-12 of the later intermediate dienone 2, Incorporation experiments with the labelled autumnalines using Colchicum autumnale plants show that (a) both H-R and H-S at C-4 of 1 are fully retained as the dienone is generated, (b) there is stereospecific loss of H-S from C-12 of the dienone during the ring expansion process by which the tropolone ring of colchicine is formed and (c) also, there is partial loss (ca. 20%) of the H-3 label from the H-R position at C-12, These results are rationalised by a proposal for the biosynthesis of colchicine that involves a cyclopropane intermediate in the ring expansion step plausibly formed by a radical process.