The synthesis of colchicine analogs via palladium-mediated ring homologation reactions

Daniel John Stepuszek, Marquette University


The tricyclic alkaloid colchicine is the active principle of the toxic meadow saffron (colchicum automnale). It has been used as a gout suppressant, as a treatment for glaucoma, and in cancer research as an antimitotic agent. More recently, it is undergoing preclinical trials as an HIV inhibitor. These desirable biological properties derive from the slow, irreversible 1:1 binding of colchicine to the tubulin protein, which inhibits in vivo microtubule formation. Substantial experimental evidence has established that there are two distinct binding sites which individually recognize the A and the C rings of colchicine, while the exact nature of the B ring's contribution to the tubulin binding site is unknown. For example, the A-C linked molecule 2-methoxy-5-(2$ \sp\prime$,3$ \sp\prime$,4$ \sp\prime$-trimethoxyphenyl)tropone binds rapidly and reversibly to tubulin. Obviously, the availability of a series of rationally designed colchicine analogs bearing a modified B ring would be a value to the elucidation of the colchicine-tubulin binding mechanism. The synthesis of the colchicine analogs has followed two different methods for their generation. Both methods use palladium mediated ring homologation reactions to synthesize to highly oxidized C ring. The synthetic precursor to both palladium reactions is the same, thus simplifying the overall synthetic procedures to numerous colchicine analogs. The synthetic precursor is a substituted 1-aryl-7-methylene bicyclo (4.1.0) heptane. This molecule is synthesized from carbene addition followed by dehydrohalogenation to the corresponding 1-arylcyclohexenone. The utilization of either palladium reaction will complete the ring homologation and produce a seven membered ring. The palladium reactions can be used in a stoichiometric fashion with the methylenecyclopropanes to form a stable $\pi$-allylpalladium complex. This complex can undergo nucleophilic addition with one equivalent of malonate anion to give a substituted cycloheptadiene. Common synthetic procedures can then be employed to complete the syntheses to many colchicine derivatives. A second procedure can employ the same methylenecyclopropane precursor, but this method uses a catalytic amount of palladium to form the 4-aryl-tropone. The tropone can be converted by known procedures into the tropolone methyl ether which is a prerequisite for tubulin binding. Additional functionalization is possible, making the availability of colchicine analogs synthetically possible. The use of the palladium mediated reactions outlined above has developed new methods of synthesizing colchicine analogs. These analogs can be subjected to biological analysis in an attempt to better understand the colchicine-tubulin interactions.

Recommended Citation

Stepuszek, Daniel John, "The synthesis of colchicine analogs via palladium-mediated ring homologation reactions" (1991). Dissertations (1962 - 2010) Access via Proquest Digital Dissertations. AAI9133812.