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

• Published in: Journal of organic chemistry Vol. 77; no. 4; pp. 1891 - 1908
• Main Authors: Malona, John A, Cariou, Kevin, Spencer, William T, Frontier, Alison J
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 17.02.2012; Amer Chemical Soc
• Subjects: Alicyclic compounds; Alicyclic compounds, terpenoids, prostaglandins, steroids; Alkadienes - chemistry; Anti-Inflammatory Agents - chemical synthesis; Antineoplastic agents; Antineoplastic Agents, Phytogenic - chemical synthesis; Benzofurans - chemical synthesis; Benzofurans - chemistry; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Chemistry; Chemistry, Organic; Cyclization; Cyclopentanes - chemistry; Exact sciences and technology; General aspects; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Insecticides - chemical synthesis; Ketones - chemistry; Magnetic Resonance Spectroscopy; Medical sciences; Molecular Structure; Organic chemistry; Oxidation-Reduction; Pharmacology. Drug treatments; Physical Sciences; Preparations and properties; Science & Technology; Stereoisomerism; ROCAGLAMIDE DERIVATIVES; KETONES; VINYLALLENES; CHEMISTRY; BIOMIMETIC APPROACH; ALLENE EPOXIDATION; OXYALLYL CATIONS; ARYL; STEREOSELECTIVE-SYNTHESIS; EFFICIENT; Antineoplastic agent; Insecticide; Targeting; Pesticides; Antiinflammatory agent; Natural compound; Total synthesis; Characterization; Reaction mechanism; Cations; Oxidation; Chemical reactivity; Chemical synthesis; Cyclopentane derivatives; Heterocyclic compound
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo202366c

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.