Synthesis and Hormonal Activity of the (25 S )‐Cholesten‐26‐oic Acids – Potent Ligands for the DAF‐12 Receptor in Caenorhabditis elegans

Using a highly stereoselective Evans aldol reaction for the introduction of the stereogenic center at C‐25, we describe an efficient synthesis of the orthogonally diprotected (25 S )‐26‐hydroxycholesterol 11 . In a few synthetic steps, this crucial intermediate 11 has been converted into the four (25 S )‐cholesten‐26‐oic acids 1 – 4 , which have been obtained in 12–15 steps and 19–53 % overall yield based on commercially available 3β‐hydroxychol‐5‐en‐24‐oic acid ( 5 ). Our biological studies of the compounds 1 – 4 reveal that (25 S )‐Δ 7 ‐dafachronic acid ( 1 ) represents the most active steroidal ligand for the hormonal receptor DAF‐12 in Caenorhabditis elegans . Moreover, the saturated (25 S )‐dafachronic acid ( 3 ) represents a new ligand for this receptor and the (25 S )‐steroidal acids are more active as compared to their corresponding (25 R )‐counterparts.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2009)