Total Synthesis of (±)-Rocaglamide via Oxidation-Initiated Nazarov Cyclization

This article describes the evolution of a Nazarov cyclization-based
synthetic strategy targeting the anticancer, antiinflammatory, and
insecticidal natural product (±)-rocaglamide. Initial pursuit
of a polarized heteroaromatic Nazarov cyclization to construct the
congested cyclopentane core revealed an unanticipated electronic bias
in the pentadienyl cation. This reactivity was harnessed in a successful
second-generation approach using an oxidation-initiated Nazarov cyclization
of a heteroaryl alkoxyallene. Full details of these two approaches
are given, as well as the characterization of undesired reaction pathways
available to the Nazarov cyclization product. A sequence of experiments
that led to an understanding of the unexpected reactivity of this
key intermediate is described, which culminated in the successful
total synthesis of (+)-rocaglamide.