Bile acids. LXXIII. Synthesis of analogs of 7α-hydroxy-4-cholesten-3-one as substrates for hepatic steroid 12α-hydroxylase
Analogs of 7α-hydroxy-4-cholesten-3-one were prepared to ascertain structural features necessary for maximal activity of hepatic microsomal 12α-steroid hydroxylase.Methyl 3α,7α-dihydroxy-5β-cholane-24-carboxylate derived from chenodeoxycholic acid was oxidized at C-3 with silver carbonate/Celite.The product was hydrolyzed and dehydrogenated with SeO2 to provide 3-oxo-7α-hydroxy-4-cholene-24-carboxylic acid. 5β-Cholestane-3α,7α,25-triol and 5β-cholestane-3α,7α,12α,25-tetrol were similarly oxidized at C-3 and dehydrogenated to provide 7α,25-dihydroxy-4-cholesten-3-one and 7α,12α,25-trihydroxy-4-cholesten-3-one, respectively.The products were characterized by thin-layer and gas chromatography, ultraviolet, infrared, proton resonance and mass spectrometry.
Joyce, Michael J.,Hiremath, S. V.,Mattammal, Michael B.,Elliott, William H.,Doisy, Edward A.
A FACILE SYNTHESIS OF 5β-CHOLESTANE-3α,7α,12α,25-TETROL
A convenient procedure for the synthesis of 5β-cholestane-3α,7α,12α,25-tetrol via a modified homologation sequence of the intermediate 3α,7α,12α-triformyloxy-24-oxo-25-diazo-25-homo-5β-cholane involving a homogeneous medium is described.This involves treating the intermediate α-diazoketone in methanol with a solution of silver benzoate in triethylamine.Grignard reaction of the resulting triformyloxy methyl homocholate yielded 5β-cholestane-3α,7α,12α,25-tetrol.Large amounts of this bile alcohol were needed to further investigate the defect of cholic acid biosynthesis in patients with cerebrotendinous xanthomatosis (CTX).
7β-Hydroxy bile alcohols: Facile synthesis and 2D 1H NMR studies of 5β-cholestane-3α,7β,12α,25-tetrol
A rapid and easily performed procedure for the synthesis of 5β- cholestane-3α,7β,12α,25-tetrol by means of an efficient homologation sequence of the intermediate, 3α,7β,12α-triformyloxy-24-oxo-25-diazo-25- homo-5β-cholane is described. The reaction sequence involved treating the intermediate, α-diazoketone in methanol with 3% AgNO3 or Ag2O, anhydrous Na2CO3, Na2S2O3/H2O resulting in the formation of homoursocholic acid in high yield. Esterification of the homoursocholic acid in methanol containing a catalytic amount of methanesulfonic acid under microwave irradiation conditions gave methyl homoursocholate. The subsequent treatment of methyl homoursocholate with methyl magnesium iodide provided 5β- cholestane-3α,7β,12α,25-tetrol in 88% yield. The products and synthetic intermediates prepared in these studies were fully characterized by the results of 1D and 2D NMR, and high-resolution mass spectral studies. These studies will help in further investigation of the defect of cholic acid biosynthesis in patients with cerebrotendinous xanthomatosis (CTX) as well as other inborn errors of bile acid metabolism.
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