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Total synthesis of a chlorosulpholipid cytotoxin associated with seafood poisoning

Nature volume 457, pages 573–576 (2009)Cite this article

Abstract

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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Figure 1: Structurally characterized docosane, tetracosane and pentadecane chlorosulpholipids that originate from microalgae.
Figure 2: Initial synthetic studies of chlorosulpholipid 5.
Figure 3: Total synthesis of chlorosulpholipid cytotoxin 5.
Figure 4: Determination of the relative configuration of epoxyalcohol 18.

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Acknowledgements

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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  1. Laboratorium für Organische Chemie, ETH Zürich, CH-8093 Zürich, Switzerland ,

    Christian Nilewski, Roger W. Geisser & Erick M. Carreira

Authors
  1. Christian Nilewski
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  2. Roger W. Geisser
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  3. Erick M. Carreira
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Correspondence to Erick M. Carreira.

Additional information

Supplementary crystallographic data for this paper has been deposited at the Cambridge Crystallographic Data Centre under deposition numbers CCDC 711103 and CCDC 711104. These data can be obtained free of charge from http://www.ccdc.cam.ac.uk/data_request/cif.

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Supplementary Information

This file contains Supplementary Methods and Supplementary Data. The operating frequencies of some of the NMR spectrometers were corrected on 4th Feb 2009. (PDF 1119 kb)

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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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