Confinement of peptide sequences in Porous Macroligand for Asymmetric Catalysis – PoMAC

To achieve it, PoMAC conceives microporous solids rationally functionalized with peptides sequences acting both as enzyme-like stereoselective pocket and as ligand for organometallic catalysts. The stereoselective pocket confined inside micropores shall generate chiral constraints on the second coordination sphere of the heterogenized chiral catalyst to enhance the enantioselectivity of transfer hydrogenation reactions.
The PoMAC bifunctional approach is unprecedented in heterogeneous catalysis.
PoMAC will reach its objective by implementing a multidisciplinary methodology departing from the state-of-the-art on peptides grafting in porous solids, tandem organometallic functionalization, computational chemistry and heterogeneous asymmetric catalysis.
Molecularly defined porous solids with permanent and tunable porosity represent the most suitable platforms for peptides and organometallics heterogenization targeted in PoMAC. Metal-Organic Frameworks (MOF) and Conjugated Microporous Polymers (CMP) will be used as organo-based matrix for the heterogenization of such active sites. Advantageously, these host matrixes present various chemical and structural properties, tailored to accomplish enantioselective application in PoMAC. The success of the PoMAC project lies on this original multimaterial approach.
Moreover, the organometallic chemistry methodology applied on peptide-functional porous solids is unprecedented in the field of molecular catalyst heterogenization pioneered by the PoMAC partners.
A transverse study is devoted to the understanding of the host-guest interactions through cutting-edge computational chemistry study including DFT and Molecular Dynamics in multifunctional hybrid solids. PoMAC aims at generating fundamental knowledge, rationale and design principles on the structure-properties of the {host-peptide-catalyst} triad with a focus on its molecular recognition capabilities thanks to a thorough computational chemistry investigation.

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Résultats de traduction
The predictions, obtained by calculation, supported by experimental data fully rationalize the catalytic properties and highlight the crucial role of MOF as a macroligand acting on the first coordination sphere of the metal but also on its second coordination sphere (at the manner of a metalloenzyme) to promote the enantioselectivity of a chiral molecular catalyst.
More generally, the ability to provide a structure-reactivity relationship at the molecular level within a functionalized MOF opens up avenues for developing a predictive framework making it possible to achieve the same level of rationalization in the design of a heterogeneous chiral catalyst as that developed for molecular systems.

So far, atomic-level structures of PoMAC solids are not accessible experimentally using routine techniques such as conventional powder X-ray diffraction due to the spatial disorder of the active species (peptides, catalyst) immobilized in the solids. The complexity of these composite systems hence imposes a robust sequential computational approach, tightened here to NMR experiments. The computational study in PoMAc aims at providing constructs of functionalized MOF and CMP and at the assessment of the molecular recognition in PoMAC solids.
The knowledge generated on multifunctional catalysts conception, heterogeneous molecular recognition and reaction optimization in asymmetric synthesis of high value added molecules will have a strong impact on the materials and catalysis scientific community. It will provide opportunities for future industrial pharmaceutics and cosmetics development, ensuring a significant socio-economic impact of the PoMAc project.

“Synthetic and computational assessment of a chiral metal–organic framework catalyst for predictive asymmetric transformation”, Canivet et al., Chem. Sci., 2020, 11, 8800-8808 et HAL Id : hal-02935289, version 1

How can one dispose of the undesired enantiomer from a mixture in drugs to prevent side-effects? This is a major challenge for pharmaceutics. Indeed, chiral molecules represent 56% of the drugs marketed, and although enantiomers have the same chemical structure, they usually exhibit different physiological properties, making their separation crucial.
To prepare enantiopure molecules, conventional asymmetric syntheses, even when benefiting from the tremendous selectivity of enzymes, suffer from multiple steps processes and several purifications.
The one-step direct asymmetric synthesis of chiral molecules shall unlock these issues but remains unprecedented in nature and in synthetic systems.
PoMAC aims at the 100% enantioselective, one-step and waste-free production of chiral drug building blocks though highly asymmetric transfer hydrogenation of functional ketones and imines of industrial relevance.
To achieve it, PoMAC conceives microporous solids rationally functionalized with peptides sequences acting both as enzyme-like stereoselective pocket and as ligand for organometallic catalysts. The stereoselective pocket confined inside micropores shall generate chiral constraints on the second coordination sphere of the heterogenized chiral catalyst to enhance the enantioselectivity of transfer hydrogenation reactions. The synergy between stereoselective molecular recognition and catalysis shall lead to 100% yield for 100% enantiopure target molecules.
The PoMAC bifunctional approach is unprecedented in heterogeneous catalysis.
PoMAC will reach its objective by implementing a multidisciplinary methodology departing from the state-of-the-art on peptides grafting in porous solids, tandem organometallic functionalization, computational chemistry and heterogeneous asymmetric catalysis.
Molecularly defined porous solids with permanent and tunable porosity represent the most suitable platforms for peptides and organometallics heterogenization targeted in PoMAC. Metal-Organic Frameworks (MOF) and Conjugated Microporous Polymers (CMP) will be used as organo-based matrix for the heterogenization of such active sites. Advantageously, these host matrixes present various chemical and structural properties, tailored to accomplish enantioselective application in PoMAC. The success of the PoMAC project lies on this original multimaterial approach.
Moreover, the organometallic chemistry methodology applied on peptide-functional porous solids is unprecedented in the field of molecular catalyst heterogenization pioneered by the PoMAC partners.
A transverse study is devoted to the understanding of the host-guest interactions through cutting-edge computational chemistry study including DFT and Molecular Dynamics in multifunctional hybrid solids. PoMAC aims at generating fundamental knowledge, rationale and design principles on the structure-properties of the {host-peptide-catalyst} triad with a focus on its molecular recognition capabilities thanks to a thorough computational chemistry investigation. So far, atomic-level structures of PoMAC solids are not accessible experimentally using routine techniques such as conventional powder X-ray diffraction due to the spatial disorder of the active species (peptides, catalyst) immobilized in the solids. The complexity of these composite systems hence imposes a robust sequential computational approach, tightened here to NMR experiments. The computational study in PoMAc aims at providing constructs of functionalized MOF and CMP and at the assessment of the molecular recognition in PoMAC solids.
The knowledge generated on multifunctional catalysts conception, heterogeneous molecular recognition and reaction optimization in asymmetric synthesis of high value added molecules will have a strong impact on the materials and catalysis scientific community. It will provide opportunities for future industrial pharmaceutics and cosmetics development, ensuring a significant socio-economic impact of the PoMAc project.