Molecular Engineering

Asymmetric Synthesis of QAA and incorporation into peptides

1,3-DC reactions between chiral aspartic nitrones and vinyl ethers provide isoxazolidinyl adducts able to be transformed into valuable bis-aspartic acid derivatives : ester (B) or aldehyde (C) :

The anhydride D efficiently produced from ester B acts as a synthetic platform for the generation of a variety of enantiopure QAA (E) featuring two extendable aspartic side chains,

From the aldehyde C, a robust pathway to the cyclic QAA derivative F was disclosed, which was found to act as a powerful beta-turn inducing agent when incorporated into a peptide.

Researchers

• Mathieu Laurent
• Arnaud Martel
• Gilles Dujardin

Related papers

• Zhang, P. Cividino, J.-F. Poisson, P. Shpak-Kraievskyi, M. Y. Laurent, A. Martel, G. Dujardin, S. Py Org. Lett., 2014, 16, 1936.
• Zhang, S. Chewchanwuttiwong, R. Hadade, M. Y. Laurent, A. Martel, J. Lhoste, S. Py,  G. Dujardin submitted to J. Org. Chem.

Synthesis of symmetrical QAA

A straightforward synthesis of α,α-disubstituted α-amino acids was stiudied. The key step of this process relies on the efficient double addition of Grignard reagents to acyl cyanohydrins to provide N-acyl amino alcohols selectively in good yields. The chemoselectivity of the reaction was modulated by the nature of the acyl moiety. Different amino acids were prepared, including the particularly simple divinylglycine, which is not easily accessible by using conventional methods.

Researchers

• Fabien Boeda
• Morwenna Pearson-Long
• Philippe Bertus

Related papers

• A short Access to α,α-Disubstituted α-Amino Acids from Acyl Cyanohydrins

• Boukattaya, J. Caillé, H. Ammar, F. Rouzier, F. Boeda, M. S. M. Pearson-Long, P. Bertus Synthesis 2016, 48(6), 906-916.

Synthesis of Constrained Lysine Derivatives

The Ti-mediated cyclopropanation reaction of nitriles using unsaturated Grignard reagents was found to be strongly dependent on the nature of the substrate and the solvent in terms of reactivity, yield and diastereoselectivity. The most useful result was obtained from benzyloxyacetonitrile  and 4-pentenylmagnesium bromide, affording both the cis and the trans isomers in pure form. Ever if it is not diastereoselective, the simplicity of the method, using easily available substrates and reagents, and the easy separation of stereoisomers makes this method attractive for the preparation of constrained aminoacids. The synthetic utility of the obtained cyclopropylamines was thus illustrated by the synthesis of orthogonally protected 2,3-methanoaminoacids bearing an amino side chain with variable length, suitable for peptidic synthesis.

Researchers

• Fabien Boeda
• Morwenna Pearson-Long
• Philippe Bertus

Related papers

• Ti-Mediated Cyclopropanation of Nitriles with Unsaturated Grignard Reagents: Application to the Synthesis of Constrained Lysine Derivatives
• Forcher, N. Clousier, A. Beauseigneur, P. Setzer, F. Boeda, M. S. M. Pearson-Long, P. Karoyan, J. Szymoniak, P. Bertus Synthesis 2015, 47(7), 992-1006.

• F. Taber, Org. Chem. Highlights 2015, December 14.

The access a wide variety of original stereocontrolled N-heterocycles in one step starting from similar substrates employing a tunable and atom economic domino process is the goal of this project. The modularity of the domino process based both on the functionalization of the substrates and the experimental conditions employed allow the access to a variety of polycyclic systems from commercially available compounds. This project is supported by the anticipation of the outcome involved via a rational approach based on DFT calculations.

Researchers

• Arnaud Martel
• Mathieu Laurent

Related papers

• Le Goff, R.; Martel, A.; Sanselme, M.; Lawson, A. M.; Daïch, A.; Comesse, S. Chem. - Eur. J. 2015, 21 (7), 2966.

• El Bouakher, R. Le Goff, J. Tasserie, J. Lhoste, A. Martel, S. Comesse, Org. Lett. 2016, 18, 2383-2386.

• El Bouakher, A.; Tasserie, J.; Le Goff, R.; Lhoste, J.; Martel, A.; Comesse, S. J. Org. Chem. 2017, 82 (11), 5798.

Heteromultifunctional cross-linking reagents are molecules of great importance for bioconjugation, diagnosis, therapy and layer functionalization. Despite their attractiveness, a few structures displaying more than 2 different functionalities are described. The project aims at synthesizing new heteromultifunctional linkers displaying up to four functional groups able to undergo bioorthogonal modifications, in respect to the concept of click chemistry.  The strategy to access this valuable compounds includes environmental and industrial considerations and is based on a novel double functionalization of nitriles using zinc chemistry.

By aiming application in diagnostic imaging, therapy and even theranostic, this project is developed in collaboration with Raphaël Tripier (CEMCA, Université de Bretagne Occidentale) and the start-up EasyChelators for the grafting of saturated azamacrocycles able to chelate cations (64Cu and 67Cu for positron emission tomography or targeted nuclear medicine for instance).

Researchers

• Fabien Boeda
• Morwenna Pearson-Long
• Philippe Bertus

Related papers

• Polyfunctional compounds, methods for their preparing same and uses thereof

Composés multifonctionnels, leurs procédés de préparation et leurs utilisations, Bertus, L. Fontaine, M. S. M. Pearson-Long, F. Boeda, J. Caillé, V. Gaignet

• Demande de brevet n° FR2016-57227, déposée le 27 juillet 2016

WO 2017-EP66675, 4 juillet 2017

Publication : Patent WO 2018/019527A, publiée le 01 février 2018

Researchers

• Arnaud Martel
• Gilles Dujardin
• Oxides and Fluorides Team
• Sagrario Pascual (POL)
• Jean-Marc Grenèche (PSC)