The syntheses of 3-substituted perfluoroalkyl steroids

The syntheses of three classes of C-3 perfluoroalkyl substituted steroids are described. They are the 3 beta-hydroxy-3 alpha-perfluoroalkylandrost-4-en-17-ones (5a-c), 3-perfluoroalkylandrosta-3,5-dien-3-ones (8a-c) and 3 beta-hydroxy-3 alpha-perfluoroalkylandrost-5-en-17-ones (12a-c). Addition of a series of perfluoroalkylorganometallic reagents (RFLi; RF = C2F5, C3F7, or C4F9) to the 3 position of silylated testosterone 2b afforded delta 4 perfluoroalkyl carbinols 3. In Scheme 1, deprotection with HF and oxidation at the C-17 carbon with PCC produced delta 4 ketones 5. In Scheme 2 dehydration of 3 with 1,2-phenylenephosphorochloridite and iodine afforded delta 3,5 dienes 6 which were deprotected and oxidized as above to the C-17 ketones 8. In Scheme 3 isomerization of the double bond of 3 from the C-4 to the C-5 position using the allylic halogenation followed by treatment with lithium aluminum hydride led to the synthesis of the double bond isomer series 12. A new method for dehydration was developed. On average and within experimental error, 3 beta-hydroxy-3 alpha-perfluoroalkylandrost-5-en-17 ones (12a-c) were better than the 3-perfluoroalkylandrosta-3,5-dien-17-ones (8a-c) and 3 beta-hydroxy-3 alpha-perfluoroalkylandrost-4-en-17-ones (5a-c) at inhibiting glucose-6-phosphate dehydrogenase.