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Dalesconols Built Via Cascade Reaction

Judicious use of protecting groups and a clever cascade sequence lead to immunosuppressant natural products

by Bethany Halford
July 5, 2010 | A version of this story appeared in Volume 88, Issue 27

Through the judicious use of protecting groups and the application of a clever cascade sequence, chemists at Columbia University have accomplished the first total syntheses of dalesconols A and B (Angew. Chem. Int. Ed., DOI: 10.1002/anie.201002264). These natural products, which have been cultured from various fungi, have proven to be potent immunosuppressants in initial assays, performing nearly as well as the drug cyclosporine A, but with reduced cytotoxicity. To construct the dalesconols’ unprecedented skeleton of seven fused rings of various sizes, Columbia’s Scott A. Snyder, Trevor C. Sherwood, and Audrey G. Ross envisioned a single cascade sequence—a Friedel-Crafts cyclization initiated by ionization of a hydroxyl group and a subsequent oxidative C–C bond-forming event—that would crochet together a precursor containing five of the rings and create two more rings in the process. But getting the cascade to work as they planned took considerable effort. “The main challenge,” the researchers write, “was that subtle alteration of reaction conditions or the mere alteration or absence of a single protecting group afforded a number of unanticipated skeletal rearrangements.”


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