For the first time, an efficient one-pot method for the construction of an angularly fused 5–6–5 aza-tricyclic framework has been developed in a highly stereoselective manner. This domino reaction is a novel combination of aza-Piancatelli rearrangement and intramolecular Diels–Alder reaction, which readily furnishes hexahydro-2a,5-epoxy-cyclopenta­[cd]­isoindole adducts, bearing six contiguous stereogenic centers in very good yields. The BBr3-mediated cleavage of the oxa-bridged adduct results in the formation of octahydro-1H-cyclopenta­[cd]­isoindole, an aza-tricyclic BCE core of a gracilamine alkaloid.

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.