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Metal-catalyzed remote functionalization of aliphatic amines and amides triggered by photocatalytic sp3 C-H activation

Project description

Breaking obstinate bonds to create novel biologically active compounds

Isolated carbon-hydrogen (C-H) bonds are highly stable and their activation is a bit of a Holy Grail in synthetic chemistry. Functionalisation is becoming an increasingly powerful tool for applications as varied as crop protection and drug discovery. However, despite major advances, C-H activation is still a challenge and novel catalysts are needed. PHOTO-WALK is developing an innovative strategy for remote functionalisation of C-H bonds in a variety of naturally occurring and biologically active compounds of particular importance to the pharmaceutical industry. The technique will enable access to C-H sites unreachable with current methods, and could open the door to completely novel compounds with impact on a variety of diseases.

Objective

Activation of traditionally inert bonds has attracted great attention in the last decades and impressive advancements have been achieved in the catalytic functionalization of CH bonds.
Although the great number of catalytic methodologies for the transformation at sp2 CH sites, manipulation of the corresponding sp3 CH bonds remains largely confined to activated allylic and benzylic positions or to sites within reach of an existing directing group. Transition metal-catalyzed olefin isomerization has provided an outstanding tool for remote functionalization of sp3 CH bonds but it requires the use of prefunctionalized molecules, bearing a component or an alkyl bromide. On the other hand, photocatalysis has emerged as a novel strategy for sp3 CH activation but it is limited to the functionalization at the or positions with respect to a heteroatom. PHOTO-WALK will merge the photocatalytic activation of sp3 CH bonds with a Ni-catalyzed chain-walking process, disclosing a completely novel triggering event for the remote functionalization of unactivated aliphatic amines and amides. The approach will overcome the limitations of current strategies for remote functionalization, allowing transformations at sp3 CH sites unreachable by current photocatalytic methods and employing hydrocarbon feedstocks (aliphatic amines and amides) lacking of C=C or C-halide handles. Three functionalizations have been envisioned to increase molecular complexity by forging new C(sp2)–C(sp3) and C(sp3)–C(sp3) bonds: i) remote carboxylation, ii) remote arylation and iii) remote alkylation. PHOTO-WALK has the potential to be applied to the late-stage derivatization of pharmaceuticals, enabling the exploration of uncharted chemical spaces and offering the opportunity for structural diversification in drug discovery.

Coordinator

FUNDACIO PRIVADA INSTITUT CATALA D'INVESTIGACIO QUIMICA
Net EU contribution
€ 160 932,48
Address
AVENIDA PAISSOS CATALANS 16
43007 Tarragona
Spain

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Region
Este Cataluña Tarragona
Activity type
Research Organisations
Links
Total cost
€ 160 932,48