Solid-Phase Synthesis of a Combinatorial Cross-Conjugated Dienone Library

Significance

The solid-phase synthesis of a combinatorial library of cross-conjugated dienones and the biological activity of the library members are described. Reaction of cyclopentenone 1 with 3-trimethylsilyl-2-propynyl lithium in THF at -78 °C gave diol 2 in 85% yield as a single isomer. Removal of the TMS group under basic conditions and selective oxidation of the secondary alcohol gave cyclopentenone 3 in 65% yield. Cyclopentenone 3 was anchored onto the 3,4-dihydro-2H-pyran polystyrene to give solid-supported 4-propynyl-4-hydroxylcyclopentenone 4 as a key intermediate. A 96-member combinatorial synthesis using the Sonogashira coupling reaction of 4 with 12 halides (5a-l) and aldol condensation of 6a-l with eight aldehydes 7A-H led to 74 cross-conjugate dienones 9 (yield: 55-137%, purity: 11-97%).