Low Loading Asymmetric Catalysis with Helical Chiral Oligoureas – HCO_for_LLAC

The approaches used to address the different tasks are detailed below:
-Task 1: Design and Synthesis of Urea-Based Catalysts
Led by Partner 1, this task focuses on the design, synthesis, and optimization of helical urea-based catalysts, including a detailed structural analysis of the synthesized catalysts. Various modifications will be introduced into the catalyst sequences—such as isosteric replacements of urea to tune NH properties at the catalytic site, selective blocking of hydrogen bond donor sites, variations in oligomer length, and adjustments to side-chain orientations—to fine-tune the sequence-structure-activity relationship in catalysis. Structural characterization by X-ray diffraction will provide precise insights into the impact of these modifications on helical folding, as well as on the accessibility and relative positioning of the catalytic sites.
-Task 2: Asymmetric Molecular Transformations
Coordinated by Partners 1 and 4, this task expands the scope of reactions and substrates, including Michael addition and other more complex transformations. Three main categories of reactions have been considered to evaluate the catalytic potential of urea-based foldamers:
(i) C-nucleophile additions to carbonyl compounds (aldehydes and ketones), imines, and electron-deficient olefins,
(ii) Cycloaddition reactions, and
(iii) Coupling reactions with halogenated substrates.
This task also explores the potential of solid-supported foldamers as heterogeneous, reusable flow-catalysts, building on previous findings that oligoureas retain their folded structure when immobilized on a solid support.
-Task 3: Enantioselective Organocatalytic Polymerization
Led by Partner 2, this task investigates foldamer-mediated asymmetric polymerization of methyl methacrylate (MMA) and D,L-lactide (LA). The objective is to transfer the chirality of urea-based catalysts to the polymer backbone, leading to syndiotactic PMMA and chiral PLA without the use of metals. The physicochemical properties of the resulting polymers and mechanistic aspects of the process will be analyzed to optimize the effect of foldamers on polymerization outcomes.
-Task 4: Mechanistic Studies
Coordinated by Partner 3, this task focuses on elucidating the catalytic mechanisms of oligoureas through structural analysis, kinetic studies, and DFT calculations. Natural Bond Orbital (NBO) analysis will provide insights into the electronic nature of the catalytic site, while comprehensive reaction profiles will be established to identify transition states and guide the design of more efficient and selective catalysts.

This ANR project has benefited from the excellent complementarity and commitment of the partners involved.

As part of Task 1, Partner 1 designed and prepared a library of novel foldamers to precisely study the sequence/structure/catalytic property relationship and generate molecular diversity for exploring new catalytic transformations. Several key features of the reference catalyst (oligourea 1 from JACS 2017) were modified, including the nature of the electron-withdrawing terminal group, the interaction site, the sequence (nature and position of side chains on the helix surface), and the length of the main-chain. To date, around twenty sequences have been synthesized in solution, partly within the framework of an international PhD in collaboration with the University of the Basque Country (UPV/EHU), co-funded by Idex Bordeaux and co-supervised with Partner 4. Structural data obtained by X-ray diffraction for a representative set of these catalysts provided highly precise insights into the modifications of the catalytic site.

Evaluation of these sequences in Task 2, focusing on the reference reaction (Michael addition of 1,3-dicarbonyl compounds to nitroolefins and cascade reactions), revealed that sequence 1 remains the most efficient in terms of conversion and enantiomeric control. However, exploring other reactions by modifying either the electrophile or the nucleophile (such as a Mannich-type reaction with ketimines derived from isatin) led to the identification of more effective catalysts within the library. A detailed study of the structure-activity relationship in catalysis is currently being drafted for publication.

The work conducted by Partner 2 (PhD thesis of M. Zaky at LCPO, funded by this ANR project) within Task 3 aimed to investigate the chirality transfer from urea- and thiourea-based organocatalysts to polymer backbones via stereoselective reactions. Efforts were primarily focused on the ring-opening polymerization of rac-lactide. Excellent results were obtained using a phosphazene-type organic superbase in combination with (thio)urea catalysts. These studies have led to three publications.

The final part of the project was dedicated to using theoretical chemistry to rationalize the catalytic mechanism. This work (PhD thesis of M. Toledo at IPREM, funded by this ANR project) provided insights into how nucleophilic and electrophilic species interact with the two catalytic sites of the foldamer and how this interaction leads to the observed excellent enantiomeric control. Part of this theoretical chemistry work has been published in J. Org. Chem..

Several follow-up initiatives are being considered to build upon the work carried out within HCO_for_LLAC, and new funding opportunities have been explored. The objectives we aim to pursue as a continuation of this ANR project are as follows:

(i) Expanding catalyst screening to other reactions, such as anion-binding catalysis.

(ii) Advancing supported catalysis to enable reuse of the catalysts. This involves grafting several of the most promising catalysts onto solid supports and employing them in the reactions developed in solution.

(iii) Broadening the scope of foldamer screening for rac-lactide polymerization, particularly by exploring new foldamer-based helical strategies to catalyze the formation of PLA with enhanced properties such as stereocomplexes.

(iv) Extending the theoretical chemistry approach used to study catalyst reactivity to other foldamers and reactions.

New funding has been secured by consortium members to ensure the continuity of this project and the development of these new objectives:ective construction of carbon-carbon bonds and asymmetric polymerization.

The work carried out during the HCO_for_LLAC project resulted in the publication of six articles in peer-reviewed international journals, explicitly acknowledging the support of the ANR (ANR-18-CE07-0018). Several other articles are currently in preparation or being drafted for submission in 2025 and 2026. Part of this research has been presented at invited international conferences by members of the consortium. FInally, three PhD thesis have been defended (under the supervision of Partners 1-4, respectively) out of which two were funded by this ANR program and one was an international PhD between partners 1 and 4 supported by the Univ. Bordeaux.

Organocatalysis is a rapidly expanding methodology enabling challenging chemical transformations to be performed in the broad context of sustainable chemistry (metal-free procedures, catalyst recycling…) in line with Challenge 3, CS07 of the ANR Work Program 2018. Despite major achievements, organocatalysts generally suffer from low rate acceleration and turnover and the need for relatively high amounts to achieve good conversion and selectivity. This project which involves three academic laboratories in France and one in Spain, with a strong and unique complementarity, is aimed at developing original catalytic systems utilizing the chiral micro-environment of oligourea helices to catalyze challenging asymmetric transformations at (very) low catalyst loading. Particular attention will be paid to mechanistic studies to elucidate the mode of action of these helical oligomers with the aim to optimize their performance and further expand their reaction and substrate scope.