title: Chemical synthesis of 3beta-sulfooxy-7beta-hydroxy-24-nor-5-cholenoic acid: an internal standard for mass spectrometric analysis of the abnormal delta5-bile acids occurring in Niemann-Pick disease.
abstract: In Niemann-Pick disease, type C1, increased amounts of 3beta,7beta-dihydroxy-5-cholenoic acid are reported to be present in urinary bile acids. The compound occurs as a tri-conjugate, sulfated at C-3, N-acetylglucosamidated at C-7, and N-acylamidated with taurine or glycine at C-24. For sensitive LC-MS/MS analysis of this bile acid, a suitable internal standard is needed. We report here the synthesis of a satisfactory internal standard, 3beta-sulfooxy-7beta-hydroxy-24-nor-5-cholenoic acid (as the disodium salt). The key reactions involved were (1) the so-called "second order" Beckmann rearrangement (one-carbon degradation at C-24) of hyodeoxycholic acid (HDCA) 3,6-diformate with sodium nitrite in a mixture of trifluoroacetic anhydride and trifluoroacetic acid, (2) simultaneous inversion at C-3 and elimination at C-6 of the ditosylate derivatives of the resulting 3alpha,6alpha-dihydroxy-24-nor-5beta-cholanoic acid with potassium acetate in aqueous N,N-dimethylformamide, and (3) regioselective sulfation at C-3 of an intermediary 3beta,7beta-dihydroxy-24-nor-Delta(5) derivative using sulfur trioxide-trimethylamine complex. Overall yield of the desired compound was 1.8% in 12 steps from HDCA.
authors.affiliation: Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Kakiyama
authors.forename: Akina
authors.initials: A
authors.lastname: Muto
authors.forename: Miki
authors.initials: M
authors.lastname: Shimada
authors.forename: Nariyasu
authors.initials: N
authors.lastname: Mano
authors.forename: Junichi
authors.initials: J
authors.lastname: Goto
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 / Q000737:chemistry* / Q000652:urine*; D019826:Cholic Acid / Q000138:chemical synthesis* / Q000737:chemistry / Q000652:urine; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D006801:Humans; D013058:Mass Spectrometry / Q000592:standards*; D009542:Niemann-Pick Diseases / Q000652:urine*; D009654:Norsteroids / Q000138:chemical synthesis* / Q000737:chemistry / Q000652:urine; D012015:Reference Standards; D012680:Sensitivity and Specificity; D013463:Sulfuric Acid Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000652:urine
chemical_list: C543335:3-sulfooxy-7-hydroxy-24-nor-5-cholenoic acid; D001647:Bile Acids and Salts; D009654:Norsteroids; D013463:Sulfuric Acid Esters; D019826:Cholic Acid