Synthesis of analogues of a selective modulator of the glucocorticoid receptor

DANSEY, MARÍA V.; DI CHENNA, PABLO H.; VELEIRO, ADRIANA S.; BURTON, GERARDO

Beijin, China

Simposio; XI Tetrahedron Symposium; 2010

Tetrahedron, Elsevier

The introduction of a hemisuccinate group at the 21-position of the antiglucocorticoid 21-hydroxy-6,19-epoxyprogesterone (1), leads to the analogue 2, a novel selective modulator of the glucocorticoid receptor (GR).[1,2] Molecular dynamics simulation results showed that the terminal carboxylate group of the hemisuccinate forms a strong and stable interaction with the phenolic hydroxyl group of Tyr735, a residue located within helix 11 of the GR, that does not form part of the ligand binding pocket.[1,3] Although the hemisuccinate moiety is stable in vitro, this ester is hydrolyzed in vivo. To overcome this problem, we synthesized a series of non hydrolyzable analogues, 3a-c. The strategy followed to prepare the analogues 3a-c is showed in Scheme 1. The Mukaiyama aldol reaction was used to introduce the alkyl side chain at position 21, using compound 4 as starting material. The enolate formed under kinetic control was trapped by reaction with trimethyl silyl chloride to give 5. Reaction of this intermediate with the corresponding aldehydes was carried out in the presence of different Lewis acids, the best results were obtained with BF3-Et2O. Deoxygenation of the secondary hydroxyl group in the side chain was carried out using the Barton-Mc Combie procedure. Deprotection of the methyl ester with 5% aq KOH MeOH-THF, followed by treatment with (Bu)4NF and oxidation with PCC gave compounds 3a-c. The different lengths of the side chains will allow us to establish the optimal distance to fit the expanded ligand binding pocket.