Each year, there are many cases of seafood poisoning in humans worldwide1. Among the various toxins isolated that contribute to these poisonings2,3, the chlorosulpholipids are particularly intriguing because of their structural and stereochemical complexity4,5,6,7,8,9,10,11,12. The mechanism of biological activity remains unknown and, although chlorosulpholipids are associated with membranes in the organisms from which they are isolated, little is understood about their role within biological membranes. The lack of availability of the natural products has impaired more in-depth biochemical studies. So far, none of the chlorosulpholipids have been obtained from total synthesis, and efficient routes to their synthesis would be desirable for the preparation of material for pharmacological characterization and proper evaluation of the risk to human health. Despite the notable advances in the science of organic synthesis, reliable methods for stereoselective construction of polychlorinated acyclic substrates are lacking, although some preliminary investigations have appeared13,14,15. Here we report the synthesis of a chlorosulpholipid cytotoxin, leading to confirmation of the proposed structure and the discovery of unanticipated reactivity of polychlorinated hydrocarbons. The concise synthetic approach should enable the preparation of material in sufficient quantities to facilitate biological studies.
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We thank M.-O. Ebert for acquisition and discussion of the NMR data needed for J-based configuration analysis as well as W. B. Schweizer for the X-ray crystallographic analysis. C.N. thanks the Stiftung Stipendien-Fonds des Verbandes der Chemischen Industrie for a Kekulé-Fellowship. This research was supported by the Swiss National Science Foundation and ETH Zürich. We are grateful for support for our program from F. Hoffmann-La Roche, Eli Lilly and Boehringer Ingelheim.
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Nilewski, C., Geisser, R. & Carreira, E. Total synthesis of a chlorosulpholipid cytotoxin associated with seafood poisoning. Nature 457, 573–576 (2009). https://doi.org/10.1038/nature07734
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