Mechanistic aspects of rearrangement of 16α-hydroxy-17-keto steroids to the 17β-hydroxy-16-keto isomers

Abstract The mechanistic aspects of the alkali-catalyzed rearrangement of 16α-hydroxy-17-keto steroid 1 to 17β-hydroxy-16-keto steroid 2 are elucidated by use of 18 O- and deuterium-labeling experiments. The 18 O-labeling experiments refute the gem-hydration-quasi-diaxial dehydration mechanism for the rearrangement previously proposed and support the conventional enolization mechanism. Moreover, equilibrium by gem-hydration–dehydration occurs at the C-17 carbonyl more efficiently than at the C-16 carbonyl. Enolization rate of a carbonyl group at C-16 of 17β-ketol 2 toward the C-17 position ( k 16,17 ) was about 8–10 times higher than those of 16α-ketol 1 toward the C-16 position ( k 17,16 ) and ketol 2 toward the C-15 position ( k 16,15 ). The marked deuterium-isotope effect on each enolization was observed with k H / k D ranging between 5.4 and 8.8. The present findings reveal that the initial hydration–dehydration equilibration at the C-17 carbonyl of ketol 1 followed by enolization of the carbonyl gives the ene–diol intermediate that isomerizes quantitatively to the 16-keto isomer of which the 16-carbonyl moiety enolizes preferentially toward the C-17 position rather than the C-15 position, yielding the ene–diol. Computational calculations of ground state energies of ketols 1-M and 2-M , trans -cyclohexane/cyclopentane structures, and their activation energies in the rearrangement support the dynamic aspects of the rearrangement as well as the kinetics data of the enolization.