title: Mechanistic aspects of rearrangement of 16alpha-hydroxy-17-keto steroids to the 17beta-hydroxy-16-keto isomers.
abstract: The mechanistic aspects of the alkali-catalyzed rearrangement of 16alpha-hydroxy-17-keto steroid 1 to 17beta-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 17beta-ketol 2 toward the C-17 position (k(16,17)) was about 8-10 times higher than those of 16alpha-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.
authors.affiliation: Tohoku Pharmaceutical University, Sendai, Japan. numazawa@tohoku-pharm.ac.jp
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Numazawa
authors.forename: Masao
authors.initials: M
authors.lastname: Nagaoka
authors.forename: Hisao
authors.initials: H
authors.lastname: Matsuzaki
authors.forename: Kouwa
authors.initials: K
authors.lastname: Yamashita
authors.forename: Sachiko
authors.initials: S
authors.lastname: Komatsu
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Osawa
mesh_terms: D000107:Acetylation; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013256:Steroids / Q000737:chemistry*
chemical_list: D013256:Steroids