Total synthesis of 13-desmethyl spirolide C – SPIROSYN
Spiroimines were synthesized using an asymmetric allylic decarboxylation and a cycloaddition reaction [3 +2] / dediazotation under microwave irradiation as key reactions .
Bis spiroketals were prepared from 1,4-diketones obtained by a reaction of sila-Stetter applied to enones and acylsilanes functionalized.
Optically active butenolides have been prepared by catalytic enantioselective vinylogous Mukaiyama-Michael addition of 2-silyloxyfurans to cyclic unsaturated oxo esters.
New methods and original synthetic approaches have been developed to access the scaffolds of 13-desmethyl spirolide C. Methods that allowed the efficient synthesis of spiroimines and bis-spiroketals have been applied to more functionalized substrates. The South fragment, the C10-C24- bis-spiroketal of 13-desmethyl spirolide C was obtained. Access to the North fragment was more difficult. Obtaining the North fragment will allow us to access 13-desmethyl spirolide C. Optically active butenolides have been synthesized. The pharmacophore of 13-desmethyl spirolide C was also identified. It is the spiroimine scaffold. This result was achieved through a collaboration with a neurobiologist established during the project.
Functionalization of a spiroimine precursor is being studied in the laboratory,
1- Rambla, M.; Duroure, L.; Chabaud, L.; Guillou, C. Enantioselective Synthesis of Spiroimines by Asymmetric Decarboxylative Alkylation/Isomerization/[3+2]-Cycloaddition Reaction of Azidoalkenes Eur. J. Org. Chem. 2014, 34, 7716-20.
2- Duroure, L.; Jousseaume, T.; Aráoz, R.; Barre, E.; Retailleau, P.; Chabaud, L. ; Molgó,J. ; Guillou, C. 6,6-Spiroimine Analogs of (–)-Gymnodimine A : Synthesis and Biological Evaluation on Nicotinic Acetylcholine Receptors. Org. Biomol. Chem. 2011, 23, 8112-18.
3- Alonso E.; Otero, P.; Vale, C.; Alfonso, A.; Antelo, A.; Giménez-Llort, L.; Chabaud, L.; Guillou, C.; Botana, L. M. Bioavailability of 13-desmethyl spirolide-C and improvement of Alzheimer disease markers in vivo observed by Proton magnetic resonance spectroscopy and immunoblotting analysis. Curr. Alzheimer Res. 2013, 10, 279-89.
4-Labarre-Lainé, J.; Beniazza, R., Desvergnes, V.; Landais, Y. Convergent access to bis-spiroacetals through a sila-Stetter-ketalization cascade. Org. Lett. 2013, 15, 4706-9.
5- Labarre-Lainé, J.; Periñan, I.; Desvergnes, V.; Landais, Y. Synthesis of the C10-C24-bis-spiroacetal core of 13-desmethyl spirolide C based on a sila-Stetter-acetalization process. Chem. Eur. J. 2014, 20, 9336-41.
6- Jusseau, X.; Retailleau, P.; Chabaud, L.; Guillou, C. Catalytic Enantioselective Vinylogous Mukaiyama–Michael Addition of 2-Silyloxyfurans to Cyclic Unsaturated Oxo Esters J. Org. Chem., 2013, 78, 2289-300. Highlighted in Synfacts 2013, 9, 645 et Synfacts 2013, 9, 761.
7- Jusseau, X.; Chabaud, L.; Guillou, C. Synthesis of ?-butenolides and a,ß-unsaturated ?-butyrolactams by addition of vinylogous nucleophiles to Michael acceptors Tetrahedron, 2014, 70, 2595-2615. Invited review
Some marine phycotoxins (spirolides, gymnodimines, pinnatoxins and pteriatoxins) produced by toxic dinoflagellates can be transferred and concentrated in shellfish edible tissues, and by vectorial transport they reach marine animals and humans. In 2005, spirolides have been detected in oysters and mussels in the Arcachon bay (France), and sanitary authorities have banned their commercialization causing heavy losses to the 350 shellfish farms around. Up to recently the presence of marine toxins was detected by the injection of extracts of shellfishes or oysters in laboratory mice, whose death reflected presence of the toxins. This test, that was highly criticized because of its low specificity and sensitivity, was abandoned in January 2010.
To date, no toxicological study has been conducted to determine the long-term impact of spirolides on human health. One of the reasons is that natural spirolides can only be isolated in very low amounts, not sufficient for thorough biological studies.
Because of their complex chemical structures and their biological properties, some spirolides and gymnodimine have been the subject of extensive fondamental research. Recently it has been shown that 13-desmethyl spirolide C was the most active of the spirolide family presenting a potent antagonist effect on nicotinic acetylcholine receptors with only little specificity for a particular receptor subtype. Spirolide fragments were synthesized by several groups but no total synthesis of a spirolide has been described to date.
The objective of this research program is to achieve the total synthesis of 13-desmethyl spirolide C using an original synthetic strategy by developing new, convergent and efficient methods to build up the north and south fragments of 13-desmethyl spirolide C. The north fragment includes a spiroimine skeleton that will be synthesized by mean of an asymmetric decarboxylative allylation and a [3+2]- cycloaddition of an azide and a double bond. The south fragment characterized by a bis-spiroketal will be synthesized by using a sila-Stetter reaction. The north and south fragments will be assembled through a Nozaki-Hiyama-Kishi coupling and the macrocyle form by a ring closing metathesis.
The results obtained during this program will contribute to the development of new methodological methods in organic synthesis to access original architectures. It should ultimately provide an access to larger amount of rare complex marine macrocycles and afford, to biologists, sufficient amount of a new biological tool to carry out toxicological studies. Finally, it should also, as a long term objective, contribute to the development o f a new test, more sensitive,
Project coordination
Catherine GUILLOU (CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE ILE-DE-FRANCE SECTEUR SUD) – guillou@icsn.cnrs-gif.fr
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
Partner
CNRS-ICSN CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION REGIONALE ILE-DE-FRANCE SECTEUR SUD
Université de bordeaux 1 UNIVERSITE BORDEAUX I
Help of the ANR 399,422 euros
Beginning and duration of the scientific project:
September 2011
- 48 Months
