Solid-phase synthesis of hydroxysteroid derivatives using the diethylsilyloxy linker

Four different types of hydroxysteroids (primary alcohol, secondary alcohol s, and phenol), bearing either an oxirane or an azide as a precursor of mol ecular diversity, were linked in good yields to solid support using the but yldiethylsilane polystyrene (PS-DES) resin. These molecules were then used as scaffolds to generate hydroxysteroid derivatives containing two levels o f diversity. The proposed libraries were tested by running steroidal alcoho ls through a model sequence of reactions (solid-phase coupling, aminolysis of oxirane or reduction of azide, amidation, and final cleavage). As a resu lt, two linked secondary alcohols (17 beta -hydroxy-spiro-3(R)-oxirane-5 al pha -androstane and 3 beta -hydroxy-spiro-17(S)-oxirane-5 alpha -androstane ) and a primary alcohol (spiro-17(S)-oxirane-3-(hydroxymethyl)-1,3,5(10)-es tratriene) afforded good overall yields (>45%) and high HPLC purities (>90% ) of hydroxysteroids derivatized as alkylamides without purification. One l imitation was noted for the fourth library: the phenolic steroid linked by the diethylsilyloxy linker gave a poor overall yield of 8% of the desired m odel compound. Finally, the diethylsilyloxy linker was used successfully fo r a rapid solid-phase synthesis of a model library of twenty C19-steroid de rivatives (3 beta -amido-3 alpha -hydroxy-5 alpha -androstane-17-ones), wit h an average yield of 53% and average HPLC purity of 97% without purificati on steps.