A class III atropisomeric colchicine analog, (aR)-6, has been described with an experimental energy barrier to inversion of 31.2 ± 0.3 kcal/mol, nearly 10 kcal/mol higher than that of B-ring containing desacetomidocolchicine (2). Access to this molecule, as well as several congeners that were also studied, was enabled by a newly established 3-hydroxy-4-pyrone-based oxidopyrylium cycloaddition/reductive ring-opening sequence for methoxytropolone synthesis. Experimental and computational studies demonstrate that (aR)-6 exists with a torsional angle of its pharmacoactive AC ring of approximately 100°, which is nearly 50° away from how it exists in colchicine in both solution phase and when bound to tubulin. Despite this difference, (aR)-6 still possesses cytotoxicity against many cell-lines at low micromolar concentrations, and is capable of binding to tubulin and inhibiting microtubule polymerization. Molecular dynamics studies suggest that (aR)-6 may prefer to bind to tubulin with a dihedral angle at or around 80°, which differentiates it from the 60° dihedral angle preferred 3, 4 and 5 in similar modelling experiments. Thus, (aR)-6 represents a new and novel tubulin binding analogue that could complement existing microtubule destabilizing agents that bind to the colchicine-binding site.