Stereoselective Synthesis of Annular 9-<i>cis</i>-Retinoids and Binding Characterization to the Retinoid X Receptor

Abstract

Analogues of 9-cis-retinoic acid incorporating an alicyclic ring between the C19 and C10 positions have been synthesized and evaluated as ligands for the RXRalpha nuclear receptor. The stereocontrolled synthesis of these configurationally constrained retinoids combines a Stille cross-coupling and the Wittig reaction as key bond-forming steps. The palladium-catalyzed cross-coupling reaction of the beta-bromo-alpha,beta-unsaturated aldehydes 5 to dienylstannane 6 is very fast at room temperature, and takes place with preservation of the dienylstannane geometry. A highly stereoselective Wittig reaction afforded the C7-C8 bond connecting the hydrophobic ring to the retinoid side chain. The binding affinities of these compounds for the receptor were determined, and the structural and energetic rationale behind the affinity profile of the cyclic 9-cis-retinoic acid derivatives for the RXRalpha nuclear receptor was characterized by using Molecular Mechanics protocols.