Steric vs hydrogen-bonding control of atropisomerization: preparation of either diastereomer of configurationally stable allocolchicinoids.

Steric vs hydrogen-bonding atropisomerization control of configurationally stable analogues of the biaryl natural product allocolchicine is described. Intramolecular hydrogen bonding between the C8 hydroxy group and the C7 oxygen functionality in (aR,7R)-diastereomer II of 2 and 4 leads to its thermodynamic stabilization relative to the opposite diastereomer (aR,7S)-I, which is manifested by the strong preference toward II under thermal equilibration conditions (>94% de). Protection of C8-OH removes the H-bonding and results in repulsive interaction between C7 and C8 functionalities, which destabilizes II. Steric tuning of the C8 protecting group in 7-12 allows for almost complete inversion of the axial configuration in 2 under thermal equilibration conditions (>96% de toward I). Previously unavailable phenolic allocolchicinoids (aR,7S)-2,I are subsequently released by deprotection.