SpiroSynth · Total Synthesis of 13-Desmethyl Spirolide C

Total Synthesis of 13-Desmethyl Spirolide C

Spirolides and their congeners (gymnodimines, pinnatoxins and pteriatoxins) are novel macrocyclic imine phycotoxins produced by the dinoflagellate Alexandrium ostenfeldii, isolated from the digestive glands of mussels, scallops and phytoplankton Usually micro-organism concentration rapidly increases in the months of June and July, causing dinoflagellate blooms. Bivalve mollusks (clams, mussels, oysters or scallops) feed from these harmful dinoflagellates and get contaminated. Shellfish can then concentrate these phycotoxins in their tissues and act as vectors for transferring these toxic chemical compounds to crabs, fishs, birds, marine mammals and ultimately to humans, thus menacing wild life and human health. Hence, shellfish poisoning constitutes a threat to public health and also to the shellfish industry. Although recent studies showed that molecular targets of 13-desmethyl spirolide C are nicotinic acetylcholine receptors (nAChR) and revealed that the toxin is a potent antagonist of nAChR in the subnanomolar range to date, no toxicological studies have been carried out to evaluate the long term impact of spirolides on human health. Our objective was thus to provide a straightforward access to 13-desmethyl spirolide C in order to get sufficient quantities to perform such biological tests. The results obtained during this program have contributed to the development of new methodological methods in organic synthesis. In particular, we set up a straightforward access to the bis-spiroketal fragment of 13-desmethyl spirolide (south-fragment), via the formation of a functionalized 1,4 diketones using an efficient organocatalyzed sila-Stetter reaction. The convergent sila-Stetter-acidic spiroketalisation carried out through a one-pot sequence was also worked out providing various bis-spiroketal skeletons. This methodology was then applied successfully to the synthesis of C10-C24 bis-spiroketal fragment of the title spirolide C. Efforts have also focused on the elaboration of the spiroimine North-fragment. Model reactions showed that a Diels-Alder strategy was able to afford the desired skeleton. Work is now underway to finalize the functionalization of the spiroimine moiety and to connect the different fragments en route to the total synthesis of 13-desmethyl spirolide C. Studies performed during this training period are part of a more general strategy aimed at preparing important neurotoxins present in shellfish, and constituting a threat for human health. No total synthesis of spirolides has ever been described and it is hoped that these developments will help at identifying the biological targets of these toxins and evaluate their lasting consequences on human health. This work has led to a publication in a journal of international audience: Synthesis of the C10-C24-Bis-spiroacetal Core of 13-Desmethyl Spirolide C, Based on a sila-Stetter-acetalization Process. J. Labarre-Lainé, I. Periñan, V. Desvergnes, Y. Landais Chemistry: A. European Journal 2014, 20, 9336-9341. This work has also been presented in two international congresses: 1. A Convergent Access to Spirolides Bis-Spiroketal using the Sila-Stetter Reaction. I. Perinan, J. Labarre-Lainé, R. Beniazza, V. Desvergnes, Y. Landais, Journée de Chimie Organique (JCO), 2013 september 24-26th, Palaiseau, France. 2. Toward the total synthesis of the 13-Desmethyl Spirolide C. A. Guthertz, J. Labarre-Lainé, I. Periñan, V. Desvergnes, Y. Landais, 15th French American Chemical Society Symposium, 2014 June 1-5th, Avignon, France. Finally, an interview of Dr. Perinan, the recruited researcher, was performed by the university of Bordeaux communication office. Such interviews and articles are communicated through the university web site to university members and members of local authorities. These studies effectively have local consequences as some of the targeted neurotoxins have been isolated on the sea side, in the Bordeaux region.

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