Perfluoroalkanesulfonyl linker units for solid phase organic synthesis

Abstract

Diversity linker units exploit the cleavage step in solid phase synthesis for the incorporation of further diversity into target molecules. A solid-supported perfluorosulfonyl linker unit would allow cleavage of substrates using transition-metal- catalysed cross-coupling reactions. This thesis describes several approaches towards a perfluoroalkanesulfonyl diversity linker from diiodoperfluoroalkanes. Early work concentrated on the reaction of diiodoperfluoroalkanes with eugenol. The resulting perfluoroalkyliodides were attached to Wang resin using Mitsunobu chemistry. However, stability problems prevented the generation of resin bound perfluoroalkanesulfonic acids and the route was abandoned. A bis-perfluoroalkanesulfonyl chloride linker unit was prepared from diiodoperfluoroalkanes by generation of the bis-sodium sulfite salt and subsequent chlorination. Optimisation studies using design software allowed preparation of multigram quantities in 60 - 70% yield. Model solution phase synthesis of bis- perfluoroalkanesulfonamides and bis-perfluoroalkanesulfonate esters showed the feasibility of attaching the bis-sulfonyl chloride to amino resins and loading phenols. Diversity cleavage was demonstrated using Suzuki and Stille reactions and optimised by screening parallel arrays of reaction conditions. Loading the bis-sulfonyl chloride onto TentaGel® gave access to solid supported porfluorosulfonate osters and diversity cleavage was shown using Suzuki reactions. However, the linkage to solid supports proved to be unstable and an additional spacer unit was required if the linker was to find widespread use. To this end, a second generation perfluoroalkanesulfonyl linker unit was developed from ally I alcohol and diiodoperfluoroalkanes. Oxidation to a perfluoroalkanesulfonyl chloride was achieved using a novel reaction employing N- chlorosuccinimide. Several methods for loading this linker unit onto a solid support were investigated but none were successful and this chemistry requires further development before it offers a practical perfluoroalkanesulfonyl diversity linker.