Total Synthesis of (+)-Schweinfurthins B and E

• Published in: Journal of organic chemistry 2009-09, Vol.74 (18), p.6965-6972
• Main Authors: Topczewski, Joseph J, Neighbors, Jeffrey D, Wiemer, David F
• Format: Article
• Language: English
• Subjects: Alkenes - chemistry; Antineoplastic Agents - chemical synthesis; Benzaldehydes - chemistry; Benzene Derivatives - chemistry; Benzoquinones - chemistry; Boranes - chemistry; Chemistry; Cyclization; Epoxy Compounds - chemistry; Ethers - chemistry; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with o, s, se, te hetero atom and condensed derivatives; Models, Chemical; Noncondensed benzenic compounds; Organic chemistry; Oxidation-Reduction; Preparations and properties; Stereoisomerism; Stilbenes - chemical synthesis
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo901161m

The first total synthesis of (+)-schweinfurthin B, a potent and differentially active cytotoxic agent, has been accomplished. Completion of the synthesis required just 16 steps in the longest linear sequence from commercially available vanillin. Key synthetic transformations included a Shi epoxidation and an efficient cascade cyclization initiated by treatment of the resulting epoxide with BF3·OEt2. Furthermore, use of a methyl ether as a stable protecting group for benzylic alcohols dramatically increased the efficiency of the overall sequence. The benzylic ether can be removed from this electron-rich aromatic system through oxidation with DDQ that provided the desired aldehyde intermediate in quantitative yield and shortened the synthetic sequence. Introduction of the A-ring diol in the required cis stereochemistry then became viable through a short sequence highlighted by an aldol condensation with benzaldehyde to introduce an olefin as a latent carbonyl group at the C-3 position. This synthesis established for the first time the absolute stereochemistry of the natural product, and provides access to material on a scale that will advance biological studies. The total synthesis of the closely related compound (+)-schweinfurthin E also is reported.