Development of new sp3 C–H carboxylation strategies via interrupted Ni-catalyzed chain-walking catalysis

Informations projet

CARBO-CHAIN

N° de convention de subvention: 101105032

DOI

10.3030/101105032

Projet clôturé

Date de signature de la CE 6 Mars 2023

Date de début 1 Avril 2023

Date de fin 31 Mars 2025

Financé au titre de

• Marie Skłodowska-Curie Actions (MSCA)

Coût total

Aucune donnée

Contribution de l’UE

€ 181 152,96

Coordonné par

FUNDACIO INSTITUT CATALA D'INVESTIGACIO QUIMICA
Spain

Periodic Reporting for period 1 - CARBO-CHAIN (Development of new sp3 C–H carboxylation strategies via interrupted Ni-catalyzed chain-walking catalysis)

Période du rapport: 2023-04-01 au 2025-03-31

Résumé du contexte et des objectifs généraux du projet

The use of catalysts to control the synthesis of architecturally complex molecules is a key aspect in organic chemistry. Not only does this concept impact strongly on the arena of natural product synthesis but also the continued development of chemical biology, medicinal chemistry, and material science. A particularly important endeavor is the ability to rapidly access complex sp3 architectures – currently a need in medicinal chemistry programs given that such motifs contribute to clinical success – from simple precursors, as it constitutes a unique tool for streamlining the access to target leads in the drug discovery pipeline. While originally designed to control the topology of polymers, catalytic chain-walking reactions have recently offered new vistas for targeting unfunctionalized sp3 C–H sites by formally translocating the metal catalyst throughout the alkyl side-chain. Bulk alkenes and alkyl halides can be functionalized at remote sp3 sites in a regioconvergent manner, generating added-value products of interest in medicinal chemistry. , Despite the significant progress made with late- or noble transition metals, the ability of nickel catalysts to adopt one- or two-electron pathways have positioned this affordable first-row metal at the forefront of this emerging field. This project aims to identify and study the identity of the nickel complexes responsible for the multiple β–H elimination and Ni-insertion at sp3 carbon fragments (aka chain-walking mechanism). The knowledge generated will provide a strong foundation for the development of new reactions and functionalizations in a more rational manner, including its long-term application into asymmetric C–C bond forming reactions.

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

This two-year period funded by the MSCA-PF scheme enabled the development of different research lines in the area of nickel catalysis and C–H functionalization. Nitrous oxide, an inert greenhouse gas, was repurposed as a mild oxidant in synthetic chemistry, performing a regioselective nickel-catalyzed oxygen-atom transfer into C(sp2)–H bonds while releasing nitrogen, an excellent and benign leaving group in line with the EU green chemistry principles. This work is now published (10.1021/jacs.3c07018). The challenge of developing an asymmetric C–C bond formation using nickel chain-walking catalysis was also explored. The priorly reported C(sp3)–C(sp3) coupling (10.1021/jacs.2c12915) was conducted in an enantioselective manner by using substituted cyclohexenes as substrates. By virtue of nickel migration, and depending on the chiral ligand of choice, different C–H bonds of the cycloalkane ring could be successfully functionalized in good yields, regioselectivities and enantioselectivities. This work will be shortly summarised and send for publication. The prior knowledge of the fellow in amine synthesis and C–H functionalization catalyzed a new synthetic methodology for the direct functionalization of C–H bonds using photochemical conditions. By introducing a bromide atom as a chemical handle, products could be subsequently functionalized in various scenarios, including cross-coupling and nucleophilic substitution reactions. This work is also published (10.1002/anie.202406485). Apart from research articles, the fellow also wrote a perspective about regiodivergent strategies in nickel chain-walking scenarios (10.1021/jacsau.3c00617) an opinion article (10.1038/s44160-024-00586-6) and supervised a master student.

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)

Repurposing harmful greenhouse gases as reagents for unconventional chemical reactions is a great synthetic challenge worth of further investigation. The research conducted during this fellowship serves as the cornerstone for new oxidative transformations to arise in the area of C-H functionalization reactions, with foreseen long-term applications in the market, after further extensive research. On the other hand, medicinal chemists are in desperate need for new and robust asymmetric sp3-sp3 coupling of two different carbon fragments. This fellowship also dedicated extensive efforts in developing a regiodivergent scenario targeting different C-H bonds of a molecule by careful choice of a suitable ligand. The exquisite regioselectivity, diastereoselectivity, and enantioselectivity of the products obtained set the standard for further research in the area of C-C coupling, with potential scalability to industrial drug synthesis in the future. Lastly, the selective bromination of amines under acidic conditions sparked interest among the industrial community for the C - H functionalization of ring-strained motifs. This research has opened a collaboration with Janssen in developing a flow-chemistry photocatalyzed reaction for accessing new chemical vectors in highly sp3 hybridized molecules.

CARBO-CHAIN summary