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ABSOLUte asymmetric synthesis by means of CATalysts supported on extremely chirally-amplified supramolecular scaffolds – AbsoluCat

A general approach towards absolute asymmetric syntheses achieved by rational design

A general approach towards absolute asymmetric syntheses achieved by rational design. All industrial processes rely on chiral precursors to produce new chiral compounds and this paradigm is a severe limitation of asymmetric synthesis. Absolute asymmetric synthesis, i.e. the preparation of enantiopure compounds without the help of any chiral species, is still very limited. A general approach towards absolute asymmetric syntheses would thus constitute an important breakthrough.

Absolute asymmetric synthesis by means of Catalysts supported on extremely chirally-amplified supramolecular scaffolds (AbsoluCat)

The challenge of achieving absolute asymmetric catalysis in a rational and predictable manner was achieved by dissociating the catalytic and symmetry breaking / chirality amplification phenomena required for the emergence of single chirality. More precisely, asymmetric metal catalysts have been supported on a supramolecular polymer helical scaffold formed by the assembly of low-molecular weight monomers (Figure). On the one hand, chirality amplification is controlled at the level of the interacting monomers and serves as a tool to control the handedness of the supramolecular helices. On the other hand, catalysis is achieved by intrinsically achiral catalytic centres located at the periphery of the assemblies. Chirality transfer between the chirally-amplified assemblies and the catalyst leads to asymmetric induction for the catalytic reaction (enantioselective catalysis). Absolutely asymmetric catalysis can be achieved with such systems thanks to the possibility to implement chiral sources in infinitesimal amounts in various types of asymmetric reactions.

The aim of the AbsoluCat project was to design a chemical system by means of which absolute asymmetric synthesis will be achieved in a rational and predictable manner. Our strategy to tackle this challenge was to dissociate the catalytic and symmetry breaking / chirality amplification phenomena required for the emergence of single chirality. It can be achieved by supporting asymmetric metal catalysts on a supramolecular polymer scaffold formed by the assembly of low-molecular weight monomers. Hydrogen-bonded supramolecular polymers that are known to form dynamic inherently chiral helices upon self-assembly are perfectly suitable for this purpose. Three different platforms have been selected
which differ by their assembly properties, their stability, their geometry, and their intrinsic sensibility to chiral perturbation. These plaforms are: benzene-1,3,5-tricarboxamide (BTA, induction/amplification of chirality through the sergeants-and-soldiers effect), triarylamine trisamides (TATA, induction/amplification of chirality through the sergeants-and-soldiers effect and cicurlarly-polarized light) and carbonyl-bridged triarylamine trisamides (CBT, induction/amplification of chirality through the sergeants-and-soldiers effect). Two strategies have been selected to get single-handed supramolecular helices: i) the addition of an enantiopure but catalytically-inactive molecule, referred to as a sergeant, and ii) chiral induction by CPL. In the former case, the proportion of sergeants able to induce a single handedness to supramolecular helices embedding the soldiers dictates the extent of chirality amplification through the sergeants-and-soldiers (S&S) principle. Extremely chirally amplified assemblies have been reported in the literature for which a very small of sergeants (1% or lower) was sufficient to get homochiral helices. CPL has also been reported as the suitable chiral source to generate chirally biased TATA assemblies. Our efforts have been devoted to implement these strategies (S&S effect and CPL) to asymmetric reactions. Towards this goal, achiral phosphine-functionalized monomers were mixed with sergeants for induction of chirality through the S&S effect or polymerized in presence of CPL. Chirality transfer between the chirally-amplified assemblies and the catalytic sites led to asymmetric induction for the catalytic reaction (enantioselective catalysis). Several reactions of reference have been targeted to demonstrate the feasibility of the concept. Finally, a range of analytical techniques has been performed to confirm the correlation between the structure of the assemblies and the outcome of the catalytic reaction.

In the framework of theAbsoluCat project, it has been demonstrated that an enantiopure but catalytically-inactive molecule, referred to as the sergeant, on the order of 2.5% or less is sufficient to provide homochiral helical catalysts which in turn provided highly enantioenriched products (=75% of enantiomeric excess) in two reactions of reference. The fraction (relative to the ligand) and the catalytic loading (relatively to the substrate) of the sergeant are ca. 50 times lower and equal, respectively, to those employed for the best chirally amplified catalysts reported previously. The concept was demonstrated for two copper-catalyzed reactions but can probably be expanded to other asymmetric synthesis in order to produce industrially relevant intermediates. Scientific production. The implementation of asymmetric catalysts with very low amount of chiral species has been published in a very high impact factor journal (J.Am.Chem.Soc.). The same concept has been applied successfully to a second reaction (manuscript in preparation). The originality of this class of asymmetric catalysts was recognized by an invitation to contribute to a special issue in ChemCatChem dealing with “New Concepts in Homogeneous Catalysis”, a review in Chem. Soc. Rev. and two book chapters including one in « Supramolecular Catalysis : New Directions and Developments”, co-edited by P. W. N. M. van Leeuwen and M. Raynal (Wiley). The AbsoluCat project is a fundamental research project, supervised by Matthieu Raynal at Sorbonne Université (Paris) – Institut Parisien de Chimie Moléculaire. Experiments have been mainly conducted by Ahmad Hammoud during his PhD and by Pamela Aoun as postdoctoral research associate, but has involved multiple collaborations with other scientists. The project starts in October 2016 and lasts for 48 months. It was funded by ANR, at an eligible cost of 251586 euros, and a total cost of 408505 euros.

The first objective of the AbsoluCat project, i.e. pushing the limits of the sergeants-and-soldiers (S&S) principle applied to catalysis, has been reached. Optimal selectivities for two reactions of reference have been achieved with a fraction of sergeants relatively to the ligand of 0.25% (for the hydrosilylation) and 2.5% (for the hydroamination). Key for the success of the approach was the evaluation of different types of BTA ligands and conditions, including the counterintuitive beneficial effect of an achiral additive. The second objective, i.e. asymmetric catalysis with a chirally-amplified scaffold generated by CPL, remains unsolved. Our investigations indicated that induction of supramolecular chirality in helical assemblies by CPL is likely a very subtle and intricate process that will require deeper experimental investigation and a better understanding of the underlying mechanism.

Peer-reviewed papers:
[1] Y. Li, L. Bouteiller, M. Raynal* ChemCatChem, 2019, 11, 5212-5226, dx.doi.org/10.1002/cctc.201901246, hal.sorbonne-universite.fr/hal-02303651/document Invitation, Special Issue on New Concepts in Homogeneous Catalysis.
[2] Y. Li, A. Hammoud, L. Bouteiller, M. Raynal* J. Am. Chem. Soc., 2020, 142, 5676-5688, pubs.acs.org/doi/10.1021/jacs.9b13157, hal.sorbonne-universite.fr/hal-02877177/document
[3] P. Aoun, A. Hammoud, M.A. Martínez-Aguirre, L. Bouteiller, M. Raynal*, submitted
[4] Q. Sallembien, L. Bouteiller, J. Crassous,* M. Raynal*, in preparation
Book chapters:
[1] M. Raynal,* A Vidal-Ferran* « Supramolecular Regulation in Asymmetric Catalysis” in Topics in Enantioselective Catalysis: Recent Achievements and Future Challenges, Ed. by A. Marinetti, World Scientific, ISBN: 978-981-124-842-9, expected release: Dec. 2021, www.worldscientific.com/worldscibooks/10.1142/12589.
[2] L. Bouteiller, M. Raynal* “Supramolecular Helical Catalysts” in Supramolecular Catalysis: New Directions and Developments, Ed. by P. W. N. M. van Leeuwen and M. Raynal, Wiley-VCH GmbH, ISBN: 978-352-734-902-9, expected release: Jan. 2022, www.wiley-vch.de/en/areas-interest/natural-sciences/chemistry-11ch/catalysis-11ch4/supramolecular-catalysis-978-3-527-34902-9

Absolute asymmetric synthesis, i.e. the preparation of enantiopure compounds without the help of any chiral species, is a topic of considerable interest in chemical sciences given its connexion with the emergence of homochirality on Earth and its potential applications for the elaboration of synthetic methods. AbsoluCat relies on the design of homogenous catalysts which consist of metal complexes supported on a supramolecular polymer scaffold. Intrinsically achiral catalytic centres will be located in the chiral environment provided by extremely chirally-amplified hydrogen-bonded assemblies. Chirality transfer between the chirally-amplified assemblies and the metal catalyst will lead to asymmetric induction for the catalytic reaction (enantioselective catalysis). Achieving high level of asymmetric induction for the reaction (ca. 80% e.e.) with either a tiny amount of chiral monomers (0.2 %) or only circularly-polarized light, acting as the chiral biases, will constitute the two proofs of concept to be demonstrated in the framework of this project. The copper-catalysed hydrosilylation of 4-nitroacetophenone will be selected as the reaction of reference for the implementation of these proofs of concept. Then, these new synthetic methodologies will be applied for the preparation of a series of precursors en route to a drug blockbuster (L-DOPA, Parkinson disease) and an antidepressive drug candidate (GSK1360707F). Such asymmetric catalysts supported on extremely chirally-amplified scaffolds will considerably extend the scope and practical usefulness of absolute asymmetric synthesis.

Project coordination

MATTHIEU RAYNAL (Institut Parisien de Chimie Moléculaire)

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

IPCM Institut Parisien de Chimie Moléculaire

Help of the ANR 251,586 euros
Beginning and duration of the scientific project: September 2017 - 36 Months

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