Synthesis of 21-nitrogen substituted pregna-5,17(20)-dienes from pregnenolone

The facile synthesis of six [17(20) Z ]- and [17(20) E ]-isomeric 3β-hydroxy-pregna-5,17(20)-dien-21-oyl amides and three [17(20) E ]-3β-hydroxy-2-[prergna-5,17(20)-dien-20-yl]-oxazolines from pregnenolone is presented. The synthetic scheme consists of transformation of pregnenolone into the known 17α-bromo-21-iodo-3β-acetoxypregn-5-en-20-one followed by reaction with ethanolamine, 2-methyl-2-aminopropanol, and (1-aminocyclohexyl)methanol resulted in mixture of [17(20) E ]- and [17(20) Z ]-pregna-5,17(20)-dien-21-(2-hydroxy)-oyl amides; separation of [17(20) E ]- and [17(20) Z ]-isomers; their cyclization into [17(20) E ]-oxazolines under action of POCl 3 in pyridine, and removal of acetate protecting groups. Significantly different orientation of nitrogen containing substituents in [17(20) Z ]- and [17(20) E ]-isomers regarding to steroid backbone enables their configuration to be easily identified by NMR spectroscopy. All synthesized compounds did not exhibit marked toxic effects in three cell lines (MCF-7, Hep G2, and LNCaP). In androgen-sensitive LNCaP cells all testing compounds at concentrations of 50 nM potently stimulated proliferation.