Domino Semipinacol/Iterative Aldol/Iso-Nazarov Cyclization to Triaryl-cyclopentenone: Enantioselective Synthesis of Combretastatin A-4 Analogues.

A facile domino strategy has been developed for the synthesis of a biologically active cyclopent-2-enone core containing combretastatin A-4 (CA-4) analogues from aryloxirane and aryl aldehyde. This one-pot method involves a sequence of semipinacol rearrangement, iterative aldol condensation, and iso-Nazarov cyclization reactions. The scope of this methodology is further shown in the enantioselective synthesis of 5-hydroxy-cyclopent-2-enones using the Sharpless AD catalyst. Biological studies reveal that ( S )-enantiomers exhibit better inhibitory activity against cell proliferation than ( R )-enantiomers.