Some Surprising Transformations of Colchicone and Other Colchicine-Derived Tropolones

The alkaloid colchicine represents a prominent lead structure for the development of tubulin-binding chemotherapeutics. In the course of explorative research into semi-synthetic colchicinoids we stumbled upon a number of unexpected and mechanistically surprising transformations which reflect the very particular reactivity of the tropolone ether unit and its interplay with adjacent functional groups. Examples are the selective C-8-methylation of colchicone upon reaction with the Wittig reagent triphenylphosphonium methylide, the AlMe3-mediated isomerization of colchicone to a tetracyclic lactone, and the cyanide-induced reaction of the colchicol-derived mesylate to a rearranged and ring B-defunctionalized cyano-allo-colchicinoid. Finally, the fragmenting rearrangement of a tetracyclic colchicinoid with (BF3OEt2)-O-. in the presence of vinyl-MgBr afforded a tropolonyl difluoroborate under concomitant transfer of an O-methyl group from ring C to ring A.

Automated summary

Unexpected transformations of colchicine derivatives were discovered in this study, highlighting the unique reactivity of the tropolone ether unit. These insights into the reactivity of these compounds can be crucial for understanding their synthesis and activity.