Biocatalytic alkylation: fitting enzymes for selective C-C bond formations

Informations projet

BioAlk

N° de convention de subvention: 949910

DOI

10.3030/949910

Projet clôturé

Date de signature de la CE 1 Septembre 2020

Date de début 1 Janvier 2021

Date de fin 31 Decembre 2025

Financé au titre de

• EXCELLENT SCIENCE - European Research Council (ERC)

Coût total

€ 1 625 000,00

Contribution de l’UE

€ 1 625 000,00

Coordonné par

TECHNISCHE UNIVERSITEIT DELFT
Netherlands

Periodic Reporting for period 3 - BioAlk (Biocatalytic alkylation: fitting enzymes for selective C-C bond formations)

Période du rapport: 2024-01-01 au 2025-06-30

Résumé du contexte et des objectifs généraux du projet

Alkylation, in particular carbon-carbon (C-C) bond formation, is one of the most important and challenging synthetic transformations in chemistry. Current chemical approaches for C-alkylation require the use of expensive and toxic transition metals with complex ligands that have limited selectivity. Developing sustainable methods for the controlled formation of C-C bonds with regio- and stereospecificity in high yields has the potential to change organic chemistry and provide access to new molecules. Enzymes, Nature’s catalysts that enhance reaction rates, can selectively catalyze such reactions, with current limitations due to high energy co-substrates and the requirement for specific starting materials, sometimes leading to undesired side products, therefore unsustainable to upscale. Funded by the European Research Council, the BioAlk project aims at overcoming these challenges by developing the synthetic potential of key oxidoreductase and transferase enzymes towards the sustainable selective production of highly valuable compounds through C-C bond formation.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

Biocatalytic asymmetric reduction of alkenes in organic solvent is attractive for enantiopurity and product isolation, yet remains under developed. We demonstrated the robustness of an ene reductase immobilised on Celite for the reduction of activated alkenes in micro-aqueous organic solvent. Full conversion was obtained in methyl t-butyl ether, avoiding hydrolysis and racemisation of products. The immobilised ene reductase showed reusability and a scale-up demonstrated its applicability (doi 10.1039/d3cy00541k).

Chiral N-heterocycles are a common motif in many active pharmaceutical ingredients; however, their synthesis often relies on the use of heavy metals. In recent years, several biocatalytic approaches have emerged to reach enantiopurity. Here, we describe the asymmetric synthesis of 2-substituted pyrrolidines and piperidines, starting from commercially available ω-chloroketones by using transaminases, which has not yet been comprehensively studied. Analytical yields of up to 90% and enantiomeric excesses of up to >99.5% for each enantiomer were achieved, which has not previously been shown for bulky substituents. Our biocatalytic approach was applied to synthesize (R)-2-(p-chlorophenyl)pyrrolidine on a 300 mg scale, affording 84% isolated yield, with >99.5% ee (doi 10.1021/jacsau.3c00103).

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

We characterised flavin-dependent ene reductases and nicotinamide-dependent double bond reductases and transferases for their reductive and alkylating properties and expect to provide new insights for their use to catalyse C-C bond.