A Data Science-Guided Approach for the Development of Nickel-Catalyzed Homo-Diels-Alder Reactions

Area of Science:

• Organic Chemistry
• Catalysis
• Synthetic Methodology

Background:

• The homo-Diels-Alder (hDA) reaction is an underutilized method for creating bridged bicyclic systems.
• Nickel catalysis offers a convergent route, but its application in hDA reactions requires further investigation.

Purpose of the Study:

• To investigate ligand effects in Ni-catalyzed hDA reactions using a monophosphine descriptor library.
• To develop enantioselective conditions for hDA reactions with both acyclic and cyclic dienophiles.
• To expand the synthetic utility of hDA reactions for accessing complex molecular architectures.

Main Methods:

• Utilized the kraken monophosphine descriptor library to screen ligands.
• Employed classification models to identify key ligand effects for reactivity.
• Applied reaction space design and Bayesian optimization to develop new reaction conditions.
• Investigated mechanistic aspects including the role of Ni(I) species.

Main Results:

• Identified key ligand effects governing Ni-catalyzed hDA reactions.
• Discovered (S)-AntPhos as a chiral ligand for enantioselective hDA of acyclic dienophiles.
• Developed novel conditions compatible with cyclic dienophiles, overcoming previous limitations.
• Demonstrated the transformation of cycloadducts into bicycloheptane structures via cyclopropane cleavage.

Conclusions:

• Successfully expanded the scope of Ni-catalyzed hDA reactions to include cyclic substrates.
• Established a method for rapidly accessing structurally complex scaffolds from simple starting materials.
• Highlighted the potential of Ni-catalyzed hDA reactions as a powerful tool in synthetic chemistry.