title: An efficient synthesis of 7α,12α-dihydroxy-4-cholesten-3-one and its biological precursor 7α-hydroxy-4-cholesten-3-one: Key intermediates in bile acid biosynthesis.
abstract: This paper describes a method for the chemical synthesis of 7α,12α-dihydroxy-4-cholesten-3-one (1a) and its biological precursor, 7α-hydroxy-4-cholesten-3-one (1b), both of which are key intermediates in the major pathway of bile acid biosynthesis from cholesterol. The principal reactions involved were (1) building of the cholesterol (iso-octane) side chain by 3-carbon elongation of the cholane (iso-pentane) one, (2) oxidation sequence to transform the 3α-hydroxy group of the steroidal A/B-ring to the desired 4-en-3-one system, and (3) appropriate protection strategy for hydroxy groups in the positions at C-7 and C-12 in the steroid nucleus. The absolute structure of 1a and 1b were confirmed by NMR and X-ray crystallography. The targeted compounds 1a and 1b, prepared in 11 steps from 2a and 2b respectively, should be useful for biochemical studies of bile acid biosynthesis or clinical studies of bile acid metabolism, as plasma levels of 1b (also termed C4) have been shown to correlate highly with the rate of bile acid biosynthesis in man.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
authors.forename: Shoujiro
authors.initials: S
authors.lastname: Ogawa
authors.forename: Biao
authors.initials: B
authors.lastname: Zhou
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kimoto
authors.forename: Kaoru
authors.initials: K
authors.lastname: Omura
authors.forename: Akiko
authors.initials: A
authors.lastname: Kobayashi
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Higashi
authors.forename: Kuniko
authors.initials: K
authors.lastname: Mitamura
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ikegawa
authors.forename: Lee R
authors.initials: LR
authors.lastname: Hagey
authors.forename: Alan F
authors.initials: AF
authors.lastname: Hofmann
authors.forename: Takashi
authors.initials: T
authors.lastname: Iida
mesh_terms: D001647:Bile Acids and Salts / Q000138:chemical synthesis* / Q000737:chemistry; D002783:Cholestenones / Q000138:chemical synthesis* / Q000737:chemistry; D018360:Crystallography, X-Ray; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction
chemical_list: D001647:Bile Acids and Salts; D002783:Cholestenones; C030140:7 alpha,12 alpha-dihydroxy-5-cholesten-3-one; C002656:7 alpha-hydroxy-4-cholesten-3-one
keywords: 2,2,6,6-tetramethylpiperidine 1-oxyl free radical; 2-iodoxybenzoic acid; 3β-hydroxy-Δ(5)-C(27)-steroid oxidoreductase; 7α,12α-Dihydroxy-4-cholesten-3-one; 7α-Hydroxy-4-cholesten-3-one; Bile acid biosynthesis; CYP7A1; Cholesterol oxidase; HSD3B7; Hydroxy-Δ(5) steroid dehydrogenase; IBX; TEMPO; X-ray analysis; cholesterol 7α-hydroxylase