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. Silicon does it better! A comprehensive study of dienylsilane cross‐coupling establishes the most efficient route yet reported to all‐trans and 11‐cis‐retinoids. The key Hiyama reaction is superior to other couplings in terms of the overall yield, the stability and unproblematic handling of the metallic intermediates and the mild, ecologically preferable reaction conditions (see scheme).