Cross-coupling reactions of organosilicon compounds in the stereocontrolled synthesis of retinoids

This paper presents a full account of the use of Hiyama cross-coupling reactions in a highly convergent approach to retinoids in which the key step is construction of the central C10-C11 bond. Representatives of two families of oxygen-activated dienyl silanes (ethoxysilanes and silanols) and of all reported families of "safety-catch" silanols (siletanes, silyl hydrides, allyl-, benzyl-, aryl-, 2-pyridyl- and 2-thienylsilanes) were regio- and stereoselectively prepared and stereospecifically coupled to an appropriate electrophile by treatment with a palladium catalyst and a nucleophilic activator. Both all-trans and 11-cis-retinoids, and their chain-demethylated analogues, were obtained in good yields regardless of the geometry (E/Z) and of the steric congestion in each fragment. This comprehensive study conclusively establishes the Hiyama cross-coupling reaction, with its mild reaction conditions and stable, easily prepared, ecologically advantageous silicon-based coupling partners, as the most effective route to retinoids reported to date.