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Molecular Recognition with Urea-based Foldamers : From Anion Receptors to Bioinspired Organocatalysts – UREKAT

Functional biomimetic helices

Molecular recognition with helical urea-based foldamers

Anion recognition and development of new catalysts

Although the project stands primarily in foldamer research, it is characterized by a strong interplay with the field of artificial anion receptors and H-bond mediated organocatalysis. Translating structure information into function certainly represents one of the most fascinating issues in the field of foldamers. <br />The main goal of the UREKAT project is the development of a helical platform with intrinsic recognition motifs for H-bond mediated anion binding and catalysis. The project is largely based on the use of discrete urea oligomers of general formula –[NH-CH(R)-CH2-NH]n- and thiourea congeners. These urea oligomers adopt a robust 2.5-helical fold stabilized by remote intramolecular three-centred H-bond interactions between backbone ureas. The four urea NHs free not involved into intramolecular interactions, at the extremity of the helix, build a cleft, intrinsically chiral, that could be suitable for binding anions or neutral molecules such as carbonyls. In addition, the stacking of urea along the helix axis gives rise to a macrodipole whose positive pole is located close to this recognition site. One way to evaluate the influence of the macrodipole of the helix on molecular recognition processes is to modify the length, thus the polarity, of the helix. <br />Taken together, the specific objectives of the project are to analyze the anion (or ligand) binding modes, to document the origin of anion-binding selectivity in these systems, to establish the relationship between the structure and the catalytic efficiency, as well as between the structure and the stereochemical outcome of catalyzed reactions.<br />

In this project, we propose to go beyond the current state of the art in the field of foldamer applications, by taking advantage of two unique features of the helical urea backbone, i.e. the presence of: (1) a preformed binding site consisting of two urea head groups presented in an intrinsically chiral environment at one end of the helix (2) a macrodipole moment along the helix axis with a positive pole close to the binding site which could contribute to cooperative ligand binding.
The first part of the project will be devoted to the design and synthesis of urea-based oligomers ranging in size from 4-10 units, starting from a pool of activated carbamates (urea formation) or thiocarbamates (thiourea formation). These oligomers will then be evaluated for helical folding and tested both qualitatively and quantitatively for their anion binding properties using solution phase titrations (NMR, ITC…) and cristallogenesis techniques. In parallel, the helical foldamers will be tested for their organocatalysis properties with two different applications: the organocatalysis of asymmetric reactions using model substrates such as the Michael reactions of nitroolefins and the organocatalysis of Ring-Opening Polymerization (ROP) of lactide for which a collaboration with the team of Didier Bourissou in Toulouse will be undertaken.

So far, a variety of urea-based oligomers with different lengths and N-terminal parts have been produced. These oligomers have been used for the two main objectives of the project: the molecular recognition of various anions and the exploration of their organocatalytic properties. Concerning the first part, NMR titration studies gave us access to binding constants and showed the influence of different parameters on the anion/oligourea interaction: the data suggest different binding modes depending on the anion and the terminal part of the oligourea helix. Overall, the results show that the interaction is site-specific and that the helicity is largely unaffected upon binding. Concerning the second part of the project, the oligoureas have been applied as enantioselective catalysts for the Michael reaction of 1,3-dicarbonyl compounds (e.g. malonates) to nitroolefins and the results have shown enantioselectivity comparable or higher than classical urea-based catalyst such as Takemoto’s at much lower charge of catalyst (0.1 mol%)

Despite the high affinity and site-specificity of the interaction of anions with the oligourea helices, some systems have been shown to be more complex than others suggesting cooperativity or conformational changes that need to be investigated. Furthermore, crystallization of the complexes remain a challenge as the anions are likely to interfere with the global packing of the oligourea helices. The introduction of a countercation in the backbone of the helices may overcome this difficulty. In future development of the studies undertaken in the second part of the project, we plan to extend catalysis to other reactions such as addition of carbon nucleophiles to nitroalkenes, nitro-Mannich reactions, or transfer hydrogenation. Another very interesting extension of this work will be to evaluate the potential of solid-supported oligourea foldamers as reusable catalysts.

A publication in a peer-reviewed journal has been published in 2013 on the helical structuration of various urea-based oligomers (Angew. Chem. Int Ed. 2013, 52, 4147-51). Another one has been published in 2015 on anion recognition properties of oligoureas (Anion recognition by aliphatic helical oligoureas; V. Diemer, L. Fischer, B. Kauffmann, G. Guichard, Chem. Eur. J. 2016, 22, 15684–15692.);
Concerning organocatalysis properties of oligoureas a patent has been registered in 2015 (U.S. Provisional Application 62/182,997 ; Title: Bioinspired catalysis using oligourea helical foldamers; Filing Date: June 22, 2015, Inventors: S. Goudreau, G. Guichard, L. Fischer, A. Salaün, V. Diemer, D. Bécart) and a manuscript is in preparation.

The UREKAT proposal focuses on Foldamers and on the challenging issue in the field of connecting structure and function. By taking its original inspiration both from biological and artificial chemical systems, the project proposes to develop, evaluate and optimize synthetic helical molecules bearing intrinsic anion-binding and/or catalytic properties (evaluated in asymmetric reactions and Ring-Opening Polymerization (ROP)). The project will concentrate on enantiopure, aliphatic, helically folded urea-oligomers, a non-oligoamide class of foldamers whose structures have recently been characterized at atomic resolution (Fischer et al. Angew. Chem. Int. Ed. 2010).

The motivation to set-up this project stems from (1) the importance of protein anion recognition processes in biology (anion channels / transporters, enzymatic reactions) and the role of H-bond mediated interactions in conferring selectivity, (2) the finding that approaches based on ureas and thioureas have become prevalent in the design of synthetic anion receptors and hydrogen-bonding organocatalysts, (3) the robustness of the intramolecular three-centred H-bonding scheme in oligoureas that stabilize the helical fold, and (4) the versatility of this class of foldamers which bear an isostructural relationship with helix forming gamma-peptides.

Oligoureas have been shown to be very effective in terms of interaction with biomolecules and for possible biomedical applications. In particular, helices designed to mimic host-defense peptides disrupt bacterial cell membranes and display potent antimicrobial activities. In UREKAT, we propose to go beyond the current state of the art in the field of foldamer applications, by taking advantage of two unique features of the helical urea backbone, i.e. the presence of: (1) a preformed binding site consisting of two urea head groups presented in an intrinsically chiral environment at one end of the helix (2) a macrodipole moment along the helix axis with a positive pole close to the binding site which could contribute to cooperative ligand binding. Properties such as anion selectivity and affinity, ligand binding, catalytic efficiency will be modulated and tuned by variation in capping groups, nature of side chains, and helix length and by discrete substitution of thiourea for urea.

Short-chain helices such as those delivered by the end of the project, suitable for binding anions and H-bond mediated catalysis may be seen as a first step towards the design of more complex folded architectures mimicking more closely the structure and function of proteins, and enzymes in particular.

This fundamental research program will be performed at the Institut Européen de Chimie et Biologie (IECB) in Bordeaux (France) which offers a very suitable environment in terms of facilities and complementary scientific expertises for the applicant.

Project coordinator

Madame Lucile Fischer (CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION AQUITAINE LIMOUSIN) – l.fischer@iecb.u-bordeaux.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

CBMN, UMR 5248 CNRS- Université Bordeaux I CENTRE NATIONAL DE LA RECHERCHE SCIENTIFIQUE - DELEGATION AQUITAINE LIMOUSIN

Help of the ANR 355,101 euros
Beginning and duration of the scientific project: - 36 Months

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