for reference, and Scheme 3E for structure of isocolchicine). MT-MTC (4), meanwhile, only had a single energetic minima at 112.9° (green, Scheme 1C). In this case, about 2 kcal/mol in energy are required to achieve a colchicinetype pose. The addition of a methyl group on either tropone (4) or benzene (5) also led to a significant increase in the rotational barrier over MTC (3, (DG ‡ = 6.8 kcal/mol vs. ~ 17 kcal/mol), although this remained below the established rotational barrier of DAAC (2, DG ‡ = 22.1 kcal/mol). DM-MTC ( ) has a ground-state profile similar to MT-MTC (4) (red vs. green, Scheme 1C), but it possesses a sharper energetic well and a ground-state closer to a coplanar orientation (c= 101.1°). It also possesses a very high rotational barrier (DG ‡ calc = 30.2 kcal/mol) which would place it at the frontier of type III atropisomer designation that has been established as a guideline for development of single atropisomer drugs. The implications to this are that if (aR)-6 is active, it would have a narrow range of accessible dihedral angles that are mostly distinct from those accessible for (-)-colchicine, and could thereby alter its selectivity and physiochemical properties. Given that the broad medicinal value of (-)-colchicine is directly tied to this AC ring, the synthesis, physical, and biochemical evaluation of 6 was warranted.