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

Abstract

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.

Rocaglamide, silvestrol and structurally related bioactive compounds from Aglaia species

“…In 2012, Frontier and coworkers 49 disclosed the total synthesis of (±)-rocaglamide ( 1 ) while the Magnus group 50 reported a formal synthesis of (±)-methyl rocaglate ( 42 ). Both approaches utilized a Nazarov cyclization as the key step for the preparation of the tricyclic rocaglamide core.…”

Flavaglines: Potent Anticancer Drugs that Target Prohibitins and the Helicase eIF4A

“…Flavagline synthesis remains a challenge as the compounds have two contiguous quaternary chiral centers and cis aryl groups on adjacent carbons of a strained cyclopentane ring. Since most of these efforts have already been reviewed, we will discuss only the most recent developments in this field [3,4,12].…”

Cycloaromatization Protocol for Synthesis of Polysubstituted Phenol Derivatives: Method Development and Mechanistic Studies

“…1 H NMR and 13 C NMR spectroscopy were performed at ambient temperature. 2-Bromocyclohex-1-enecarbaldehyde, 12 phenylboronic acid– d 5 , 13 and 4,6-dimethoxy-2-(4-methoxyphenyl)benzofuran-3-carbaldehyde ( 5a ) 1b were prepared according to literature procedures.…”

“…We recently reported our synthetic efforts toward the synthesis of the cytostatic natural product (±)-rocaglamide 1 , in which the key step was an oxidation-initiated Nazarov cyclization 2 of a benzofuryl allene intermediate. During these studies, we found that treatment of propargylic ether 1a with a substoichiometric amount of Triton B® in DMSO was the most effective way to isomerize 1a to terminal allene 2 (Scheme 1).…”