Solid-phase synthesis of hydroxysteroid derivatives using the diethylsilyloxy linker
Solid-phase synthesis of hydroxysteroid derivatives using the diethylsilyloxy linker
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DOI：
10.1021/cc0000242
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发表时间：
2000-11-01
影响因子：
--
通讯作者：
Poirier, D
中科院分区：
文献类型：
--
作者：
Maltais, R;Tremblay, MR;Poirier, D
四种不同类型的羟基类固醇（伯醇，仲醇，和苯酚），轴承环氧乙烷或叠氮化物作为前体的分子多样性，连接在良好的产量固体支持使用丁基二乙基硅烷聚苯乙烯（PS-DES）树脂。然后将这些分子用作支架以产生含有两个水平的多样性的羟基类固醇衍生物。建议的库进行了测试，通过运行甾体醇通过模型序列的反应（固相耦合，环氧乙烷的氨解或叠氮化物的还原，酰胺化，和最终裂解）。结果，两个相连的仲醇（17 β-羟基-螺-3（R）-环氧乙烷-5 α-雄甾烷和3 β-羟基-螺-17（S）-环氧乙烷-5 α-雄甾烷）和伯醇（螺环-17（S）-环氧乙烷-3-基）（羟甲基）-1，3，5（10）-雌三烯）提供了良好的总产率（>45%）和高HPLC纯度（>90%）的衍生为烷基酰胺的羟基类固醇而无需纯化。注意到第四个库的一个局限性：由二乙基甲硅烷基氧基连接体连接的酚类类固醇给出了8%的所需模型化合物的低总收率。最后，二乙基甲硅烷基氧基接头成功地用于快速固相合成20种C19-甾族衍生物（3 β-酰胺基-3 α-羟基-5 α-雄甾烷-17-酮）的模型库，平均产率为53%，平均HPLC纯度为97%，无需纯化步骤。
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 (17 beta -hydroxy-spiro-3(R)-oxirane-5 alpha -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)-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 (3 beta -amido-3 alpha -hydroxy-5 alpha -androstane-17-ones), with an average yield of 53% and average HPLC purity of 97% without purification steps.