Herein, we describe the synthesis and evaluaNon of a novel acyclic AC analog of colchicine that is highly stable to epimerizaNon based not on thermodynamic stabilizaNon, but rather a high rotaNonal barrier energy (DG ‡ = 31.2 kcal/mol, t1/2, 298K ~ 300 y). Access to this molecule, as well as several structural homologs, was enabled through the development of a convenient intermolecular oxidopyrylium (5 + 2) cycloaddiNon/reducNve ring-opening approach from 3-hydroxy-4-pyrones. Profiling and characterizaNon of the dihedral angles were carried out computaNonally and experimentally using vibraNonal circular dichroism (VCD), demonstraNng that the ground state dihedral angles of the new molecules differ significantly from colchicine and MTC. However, despite this difference, the molecule retained anN-cancer, tubulin-binding, and tubulin polymerizaNon inhibitory acNvity.