TY - JOUR
T1 - Chemical synthesis of 7- and 8-dehydro derivatives of pregnane-3,17α,20-triols, potential steroid metabolites in Smith-Lemli-Opitz syndrome
AU - Guo, Li Wei
AU - Wilson, William K.
AU - Pang, Jihai
AU - Shackleton, Cedric H.L.
N1 - Funding Information:
This work was supported by the National Institutes of Health (Grants HL-49122 and R03HD-39707).
PY - 2003/1/1
Y1 - 2003/1/1
N2 - Pregnane-3,17α,20-triols bearing unsaturation at Δ7, Δ8, Δ5,7, or Δ5,8 have been tentatively identified as steroid metabolites in Smith-Lemli-Opitz syndrome (SLOS). Starting with 17α-hydroxypregnenolone diacetate, we have synthesized 13 unsaturated C21 triols by four different routes in one to four steps. These multifunctional steroids were prepared by a series of regio- and stereoselective transformations chosen to minimize facile olefin isomerization and 17-deoxygenation. The results include a study of stereoselectivity in the reduction of 17α-hydroxy-20-ketosteroids, an alternative method for reducing diethyl azodicarboxylate adducts of Δ5,7 steroids, and an efficient oxidation-isomerization of a Δ5,7 steroid using cholesterol oxidase. The 13 triols and their synthetic precursors were fully characterized by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. The NMR data, together with molecular modeling, indicated unanticipated conformational heterogeneity for two synthetic intermediates, 17α-hydroxypregna-4,7-diene-3,20-dione and 17α-hydroxy-5β-pregn-7-ene-3,20-dione. The unsaturated C21 triols are useful as reference standards to study adrenal steroid production in SLOS and to develop methods for pre- and postnatal diagnosis of this congenital disorder.
AB - Pregnane-3,17α,20-triols bearing unsaturation at Δ7, Δ8, Δ5,7, or Δ5,8 have been tentatively identified as steroid metabolites in Smith-Lemli-Opitz syndrome (SLOS). Starting with 17α-hydroxypregnenolone diacetate, we have synthesized 13 unsaturated C21 triols by four different routes in one to four steps. These multifunctional steroids were prepared by a series of regio- and stereoselective transformations chosen to minimize facile olefin isomerization and 17-deoxygenation. The results include a study of stereoselectivity in the reduction of 17α-hydroxy-20-ketosteroids, an alternative method for reducing diethyl azodicarboxylate adducts of Δ5,7 steroids, and an efficient oxidation-isomerization of a Δ5,7 steroid using cholesterol oxidase. The 13 triols and their synthetic precursors were fully characterized by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. The NMR data, together with molecular modeling, indicated unanticipated conformational heterogeneity for two synthetic intermediates, 17α-hydroxypregna-4,7-diene-3,20-dione and 17α-hydroxy-5β-pregn-7-ene-3,20-dione. The unsaturated C21 triols are useful as reference standards to study adrenal steroid production in SLOS and to develop methods for pre- and postnatal diagnosis of this congenital disorder.
KW - Conformational analysis
KW - Mass spectrometry
KW - NMR
KW - Smith-Lemli-Opitz syndrome
KW - Steroid metabolites
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U2 - 10.1016/S0039-128X(02)00113-7
DO - 10.1016/S0039-128X(02)00113-7
M3 - Article
C2 - 12475721
AN - SCOPUS:0037211577
SN - 0039-128X
VL - 68
SP - 31
EP - 42
JO - Steroids
JF - Steroids
IS - 1
ER -