title: Solid-phase synthesis of hydroxysteroid derivatives using the diethylsilyloxy linker.
abstract: Four different types of hydroxysteroids (primary alcohol, secondary alcohols, and phenol), bearing either an oxirane or an azide as a precursor of molecular diversity, were linked in good yields to solid support using the butyldiethylsilane polystyrene (PS-DES) resin. These molecules were then used as scaffolds to generate hydroxysteroid derivatives containing two levels of diversity. The proposed libraries were tested by running steroidal alcohols through a model sequence of reactions (solid-phase coupling, aminolysis of oxirane or reduction of azide, amidation, and final cleavage). As a result, two linked secondary alcohols (17beta-hydroxy-spiro-3(R)-oxirane-5alpha-androstane and 3beta-hydroxy-spiro- 17(S)-oxirane-5alpha-androstane) and a primary alcohol (spiro-17(S)-oxirane-3-(hydroxymethyl)-1,3,5(10)-estratriene) afforded good overall yields (>45%) and high HPLC purities (>90%) of hydroxysteroids derivatized as alkylamides without purification. One limitation was noted for the fourth library: the phenolic steroid linked by the diethylsilyloxy linker gave a poor overall yield of 8% of the desired model compound. Finally, the diethylsilyloxy linker was used successfully for a rapid solid-phase synthesis of a model library of twenty C19-steroid derivatives (3beta-amido-3alpha-hydroxy-5alpha-androstane-17-ones), with an average yield of 53% and average HPLC purity of 97% without purification steps.
authors: Medicinal Chemistry Division, Oncology and Molecular Endocrinology Research Center, Québec, Canada.
authors: R
authors: R
authors: Maltais
authors: M R
authors: MR
authors: Tremblay
authors: D
authors: D
authors: Poirier
mesh_terms: D002851:Chromatography, High Pressure Liquid; D020650:Combinatorial Chemistry Techniques; D006914:Hydroxysteroids / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure
chemical_list: D006914:Hydroxysteroids