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.
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.
Kakiyama
Genta
G
Department of Chemistry, College of Humanities and Sciences, Nihon University, Tokyo, Japan.
Muto
Akina
A
Shimada
Miki
M
Mano
Nariyasu
N
Goto
Junichi
J
Hofmann
Alan F
AF
Iida
Takashi
T
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
C543335:3-sulfooxy-7-hydroxy-24-nor-5-cholenoic acid; D001647:Bile Acids and Salts; D009654:Norsteroids; D013463:Sulfuric Acid Esters; D019826:Cholic Acid