The Sulfone Linker in Solid-Phase Synthesis: Preparation of 3,5-Disubstituted Cyclopent-2-enones

The preparation of functionalized 3,5-disubstituted cyclopent-2-enones via a solid-phase sulfone linker strategy is described. Polystyrene/divinylbenzene sulfinate 1 underwent S-alkylation followed by alpha,alpha-dialkylation with cis-1,4-dichloro-2-butene to form polymer-bound 3-phenylsulfonylcyclopentenes 8. Subsequent epoxidation of the cyclopentene moiety in 8 was accomplished by treatment of mCPBA, and the resulting oxirane ring in resin 9 was opened with various nucleophiles, i.e., Grignard and cuprate reagents, azide ion, and amines. To complete the sulfone-based linker strategy, Swern or TPAP oxidation of 10 gave a transient gamma-ketosulfone, which underwent sulfinate elimination, thus cleaving the sulfone linker. Eleven 3,5-disubstituted cyclopent-2-enones (11) were prepared with this five-step process in 18-40% overall yield from solid-phase benzene sulfinate 1.