TY - JOUR
T1 - Chemical synthesis of 3β-sulfooxy-7β-hydroxy-24-nor-5-cholenoic acid
T2 - An internal standard for mass spectrometric analysis of the abnormal Δ5-bile acids occurring in Niemann-Pick disease
AU - Kakiyama, Genta
AU - Muto, Akina
AU - Shimada, Miki
AU - Mano, Nariyasu
AU - Goto, Junichi
AU - Hofmann, Alan F.
AU - Iida, Takashi
N1 - Funding Information:
This work was supported by a Grant-in-Aid for Young Scientists (B) (to G.K., Grant 20,750,141) for 2008–2009, a Grant-in-Aid for Scientific Research (C) (to T.I., Grant 19,510,223) for 2007–2008, JST Research for Promoting Technological Seeds (to T.I.) for 2007, and a Nihon University Multidisciplinary Research Grant (to T.I.) for 2007–2008.
PY - 2009/9/15
Y1 - 2009/9/15
N2 - In Niemann-Pick disease, type C1, increased amounts of 3β,7β-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, 3β-sulfooxy-7β-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 3α,6α-dihydroxy-24-nor-5β-cholanoic acid with potassium acetate in aqueous N,N-dimethylformamide, and (3) regioselective sulfation at C-3 of an intermediary 3β,7β-dihydroxy-24-nor-Δ5 derivative using sulfur trioxide-trimethylamine complex. Overall yield of the desired compound was 1.8% in 12 steps from HDCA.
AB - In Niemann-Pick disease, type C1, increased amounts of 3β,7β-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, 3β-sulfooxy-7β-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 3α,6α-dihydroxy-24-nor-5β-cholanoic acid with potassium acetate in aqueous N,N-dimethylformamide, and (3) regioselective sulfation at C-3 of an intermediary 3β,7β-dihydroxy-24-nor-Δ5 derivative using sulfur trioxide-trimethylamine complex. Overall yield of the desired compound was 1.8% in 12 steps from HDCA.
KW - 24-Nor-hyodeoxycholic acid
KW - Bile acid multi-conjugates
KW - Internal standard
KW - LC-MS/MS
KW - Niemann-Pick disease type C1
KW - Nor-bile acid
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U2 - 10.1016/j.steroids.2009.04.007
DO - 10.1016/j.steroids.2009.04.007
M3 - Article
C2 - 19394355
AN - SCOPUS:67349164318
VL - 74
SP - 766
EP - 772
JO - Steroids
JF - Steroids
SN - 0039-128X
IS - 9
ER -