Chemical synthesis of 7- and 8-dehydro derivatives of pregnane-3,17α, 20-triols, potential steroid metabolites in Smith-Lemli-Opitz syndrome

Abstract Pregnane-3,17α,20-triols bearing unsaturation at Δ 7 , Δ 8 , Δ 5,7 , or Δ 5,8 have been tentatively identified as steroid metabolites in Smith–Lemli–Opitz syndrome (SLOS). Starting with 17α-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 17α-hydroxy-20-ketosteroids, an alternative method for reducing diethyl azodicarboxylate adducts of Δ 5,7 steroids, and an efficient oxidation–isomerization of a Δ 5,7 steroid using cholesterol oxidase. The 13 triols and their synthetic precursors were fully characterized by 1 H and 13 C 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 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.