Laboratoire de Méthodologies et Synthèse de Produits Naturels

Research

This is an overview of our research themes. We focus on the development of new methodologies, mainly involving hypervalent iodine-mediated dearomatizations of electrons-rich aromatics, and new syntheses of complex natural compounds.

Aromatic ring Umpolung concept

Everybody knows the aliphatic Umpolung concept which involves thioacetal transformations or the Stetter reaction. However, if we want to transpose that concept to aromatic ring chemistry, we first have to consider one of the most important reaction in this domain : The aromatic electrophilic substitution. In that case, an electron-rich aromatic, like a phenol, reacts with an electrophile to give the substituted compound 2. (Scheme 1).

Yet, an oxydative activation allows to produce the highly electrophilic specie 3, which can now react with a nucleophile to give the substituted compound 4. So in one case, the aromatic ring 1 acts as a nucleophile, whereas in the other case, it acts as an electrophile. The transformation is consequently right in agreement with the Umpolung concept.

conceptumpolung1

Scheme 1 : Aromatic ring Umpolung concept (1/2).

The activation can be done with a hypervalent iodine reagent, such as DIB (Scheme 2), in perfluorated solvents like HFIP. Those conditions were developed by Pr. Kita in Japan. It is a single electron transfer process, which means that the iodine takes two electrons from the oxygen on the phenol 5. It results the formation of a positive charge on the oxygen. The latter, being an electron-withdrawing atom, don't tolerate that charge and delocalizes it into the ring, either in ortho position or in para position, leading to the phenoxonium ion 6.
At this stage, two reactional pathways are possible. In a first time, if a hindered nucleophile is used (typically a carbon-based nucleophile), the attack in ortho position is preferred, in order to minimize steric interactions (Way a). It results the formation of the enone 7, which can easily rearomatize to give the substituted phenol 8. In the other hand, if a small nucleophile or a hetero-nucleophile is used, the attack in para position is favored, probably due to the stability of the carbocation at this position (Way b). It results the formation of the prochiral dienone 9.
It can be noted that compounds 8 and 9 are quite different, and regarding the Way b, the sleeping insaturations of the phenol are converted into more reactive and functionalizable insaturations.

conceptumpolung2

Schéma 2 : Aromatic ring Umpolung concept (2/2).

We believe that compounds resulting from these transformations can represent key intermediates in organic synthesis. That's the reason why the Canesi Group - Laboratoire de Méthodologies et Synthèse de Produits Naturels focuses both on the development of new synthetic methodologies based on the aromatic ring Umpolung concept and on their applications in total syntheses.

Development of new methodologies

# Cross coupling without metals


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Scheme 3 : Coupling between N-Aryl Methanesulfonamide derivatives and thiophene derivatives.


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Scheme 4 : Oxydative cycloadditions and cross coupling on non-activated benzene derivatives.

# [3+2] cycloadditions


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Scheme 5 : [3+2] cycloaddtions between substituted phenols and allylsilane.


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Scheme 6 : [3+2] cycloadditions between substituted phenols and furane.

# Oxydative transpositions


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Scheme 7 : Oxydative Wagner-Meerwein transpositions.


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Scheme 8 : 1,3-Alkyne and 1,3-Allyl transpositions.


# Oxydative polycyclisations


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Scheme 9 : Oxydative bicyclisations.


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Scheme 10 : Oxydative tricyclisations.


Natural products synthesis

# Yet synthesized natural compounds


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Schéma 11 : Synthesis of Fortucine.


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Schema 12 : Synthesis of (+/-)-Aspidospermidine.


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Scheme 13 : Synthesis of (-)-Platensimycin.


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Scheme 14 : Synthesis of Acetylaspidoalbidine.


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Scheme 15 : Synthesis of (+/-)-Mesembrine and (+/-)-4,5-dihydro-4'-O-methylsceletenone.


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Scheme 16 : Synthesis of Panacene.


# Our targets


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Scheme 17 : Some targeted natural compounds.