Late-Stage C(sp²)-C(sp³) Diversification via Nickel Oxidative Addition Complexes

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Catalysis

Background:

• Drug discovery often faces challenges in accessing novel chemical space, particularly with high C(sp3) fractions.
• Traditional nickel-catalyzed reactions can be limited in scope and require specialized ligands.

Purpose of the Study:

• To introduce nickel oxidative addition complexes (Ni-OACs) as a versatile platform for rapid lead candidate generation.
• To explore the potential of Ni-OACs in accessing new chemical space beyond C(sp2)-C(sp3) couplings.
• To demonstrate an automated diversification process for expediting drug discovery.

Main Methods:

• Synthesis and characterization of Ni-OACs derived from drug-like molecules.
• Evaluation of Ni-OACs in various bond-forming reactions, including C(sp2)-C(sp3) couplings.
• Development and implementation of an automated diversification workflow.

Main Results:

• Ni-OACs enable rapid generation of lead candidates with enhanced C(sp3) fraction.
• Ni-OACs demonstrate broad applicability in diverse bond formations, surpassing conventional Ni-catalyzed methods.
• The automated diversification process highlights the robustness and efficiency of the Ni-OAC platform.

Conclusions:

• Ni-OACs provide a powerful and generalizable strategy for accessing novel chemical entities.
• This platform significantly accelerates the design-make-test-analyze (DMTA) cycle in drug discovery.
• Ni-OACs represent a promising new gateway for medicinal chemistry and lead optimization.