Chemical synthesis of 7- and 8-dehydro derivatives of pregnane-3,17alpha,20-triols, potential steroid metabolites in Smith-Lemli-Opitz syndrome.
Pregnane-3,17 alpha,20-triols bearing unsaturation at delta(7), delta(8), delta(5,7), or delta(5,8) have been tentatively identified as steroid metabolites in Smith-Lemli-Opitz syndrome (SLOS). Starting with 17 alpha-hydroxypregnenolone diacetate, we have synthesized 13 unsaturated C(21) 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 17 alpha-hydroxy-20-ketosteroids, an alternative method for reducing diethyl azodicarboxylate adducts of delta(5,7) steroids, and an efficient oxidation-isomerization of a delta(5,7) 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, 17 alpha-hydroxypregna-4,7-diene-3,20-dione and 17 alpha-hydroxy-5 beta-pregn-7-ene-3,20-dione. The unsaturated C(21) 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.
Guo
Li-Wei
LW
Department of Biochemistry and Cell Biology, Rice University, 6100 Main Street, Houston, TX 77005-1892, USA.
Wilson
William K
WK
Pang
Jihai
J
Shackleton
Cedric H L
CH
D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D011279:Pregnanetriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000378:metabolism; D012015:Reference Standards; D019082:Smith-Lemli-Opitz Syndrome / Q000378:metabolism*; D013237:Stereoisomerism
D011279:Pregnanetriol