Why colchicine does not show mutarotation. With M05‐2X density functional in the realm of tricky natural products

It is shown here that density functional theory (DFT) calculations with the recent M05‐2X hybrid functional correctly reproduced the conformation of, and energy difference between, (Ra,7S)‐ and (Sa,7S)‐type atropisomers of isocolchicine. Interconversion of these 1H NMR‐observable atropisomers accounts for mutarotation with this compound. In contrast, the classical B3LYP hybrid functional failed to simulate satisfactorily both the geometries and the energies involved. This extends the use of M05‐2X to natural products that embody aromatic and flexible pseudoaromatic and saturated rings, as well as cis/trans amide chains, which bring on subtle conformational problems. DFT calculations with M05‐2X also shed new light on a long‐date conundrum in organic chemistry and pharmacology, i.e., why mutarotation was never observed with colchicine. This is now best attributed to a larger energy gap between the (Ra,7S) atropisomer and the elusive (Sa,7S) atropisomer with this compound. These results solicit a rethinking of the interactions between colchicinoids and proteins.