Some Surprising Transformations of Colchicone and Other Colchicine‐Derived Tropolones

Abstract

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 AlMe 3mediated isomerization of colchicone to a tetracyclic lactone, and the cyanide-induced reaction of the colchicol-derived mesylate to a rearranged and ring B-defunctionalized cyanoallo-colchicinoid. Finally, the fragmenting rearrangement of a tetracyclic colchicinoid with BF 3 . OEt 2 in the presence of vinyl-MgBr afforded a tropolonyl difluoroborate under concomitant transfer of an O-methyl group from ring C to ring A.