CE07 - Chimie moléculaire

HAT-induced sequential catalytic enantioselective C-alkylations of native diols – BO-HAT

Free radicals as molecular scalpels to the synthesis of complex molecules.

This project aims to combine two types of molecular catalysis to convert readily available diols into complex and valuable molecules in a fast and controlled process. This approach would provide a more direct access to biologically relevant compounds while adressing some fundamental challenges as the selective functionalisation of poorly reactive C-H bonds.

Fast increase of molecular complexity by surgical functionalisation of diols.

More than ever, the discovery and development of original molecular scaffolds displaying therapeutic properties (antiviral, antibiotics, antitumor and others) are major concerns in our society. Nature remains an inexhaustible reservoir of biologically relevant molecules and the formation of such complex compounds is ensured by strickingly efficient enzymatic processes. Indeed, enzymatic pools are able to control both the shape of the carbon backbone, the correct positioning of chemical functions with the good oxidation degree and the three-dimensional layout of the different bonds. At the opposite, forging such molecules in laboratory or industry remains a major challenge in modern organic synthesis. This issue, combined to environmental concerns, had led organic pactitioners to design highly efficient synthetic pathways displaying limited costs, numbers of steps and amount of waste while increasing quickly the molecular complexity from simple and abundant substrates. As enzymes, the efficiency of such reactions requires a perfect control of the selectivity. As a matter of fact, setting up methodologies allowing the selective cleavage of a single C-H bonds (often numerous in organic molecules) to convert it in a new C-C bond without the need of intermediate and superfluous transformations, is an appealing goal of this research area. In this framework, the present project aims to convert simple diols in complex molecules through successive C-H bond cleavage/C-C bond formation sequences. The challenging selective cleavage of a defined C-H and the geometrical control of the new-formed C-C bond will be adressed by an original combination of catalysts mimicking enzymes.

Free radicals are chemical species displaying a single electron on their valence shell. As a result, free radicals are high-energy intermediates able to break poorly reactive C-H bonds via elementary steps known as hydrogen atom transfers (HAT). Due to the high reactivity of open-shell species, HAT are mostly unselective and, at first glance, poorly relevant to achieve the surgical functionalisation of diols. However, we envision to combine the catalytic generation (by visible light of electrochemistry) of free radicals with a second catalyst ensuring the selective activation of precise C-H bonds of diol substrates. In other words, the role of this last catalyst will be to direct the action of the HAT catalyst toward one type of C-H bonds. The new radical intermediate resulting from the HAT will quickly react with alkenes to form a new C-C bond. A carreful worl related to the structure of the «targeting catalyst« should allow to control the geometry of the new-formed C-C bond (chirality). In the meantime, harnessing this reactivity in sequential processes would allow the divergent functionalisation of both ends of diols, then increasing quickly the molecular complexity in a limited number of steps.

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Organic synthesis is an essential development content in many fields of our modern society (therapeutics, agrochemistry, cosmetics, energies...). In order to reduce the environmental footprint of organic chemistry, the development of new synthetic approaches allowing the selective functionnalization of simple or complex molecules is highly appealing. In this framework, the present project aims to set up an efficient methodology ensuring ghe selective cleavage of C-H bonds from unprotected diols to create new C-C bond while controling the chirality of the final products. This double selectivity will be ensured by the design of new boron-based catalysts and the reactions will harness visible light and electricity as clean energy sources. The methodology should provide polyhydroxylated compounds, highly suitable in the synthesis of bioactive molecules.

Project coordination

Jérémy Merad (INSTITUT DE CHIMIE ET BIOCHIMIE MOLECULAIRES ET SUPRAMOLECULAIRES)

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

ICBMS INSTITUT DE CHIMIE ET BIOCHIMIE MOLECULAIRES ET SUPRAMOLECULAIRES

Help of the ANR 181,440 euros
Beginning and duration of the scientific project: November 2020 - 42 Months

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