Enantioselective C(sp²)-C(sp³) Bond Construction by Ni Catalysis

Area of Science:

• Organometallic Chemistry
• Catalysis
• Synthetic Organic Chemistry

Background:

• Palladium catalysis has long dominated cross-coupling reactions.
• Nickel catalysis offers unique advantages for C(sp3) center formation, including facile single-electron transfer and rapid reductive elimination.
• Reductive cross-coupling (RCC) utilizes two electrophiles and an external reductant, enabling the use of stable starting materials and offering good functional group tolerance.

Purpose of the Study:

• To develop highly enantioselective nickel-catalyzed reductive cross-coupling (RCC) reactions.
• To investigate the factors governing enantioinduction and electrophile activation in Ni-catalyzed RCCs.
• To expand the scope and understanding of asymmetric Ni-catalyzed RCCs for complex molecule synthesis.

Main Methods:

• Systematic investigation of chiral ligands for controlling selectivity in Ni-catalyzed RCCs.
• Exploration of various reductants, including heterogeneous (Mn0), homogeneous (tetrakis(dimethylamino)ethylene - TDAE), and electrochemical methods.
• Mechanistic studies to elucidate electrophile activation and radical generation pathways.
• Application of Ni-catalyzed RCCs to C(sp3) electrophiles such as benzylic chlorides, N-hydroxyphthalimide (NHP) esters, and alpha-chloro esters/nitriles.

Main Results:

• Development of methods for enantioselective Ni-catalyzed RCCs using diverse C(sp3) electrophiles.
• Identification of specific chiral ligands crucial for achieving high cross-selectivity and enantioselectivity.
• Demonstration of efficient reduction using various methods, including TDAE and electrochemistry.
• Highlighting the role of ligand properties in influencing reaction rates and mechanisms.

Conclusions:

• Chiral ligand selection is pivotal for achieving high enantioselectivity in Ni-catalyzed RCCs.
• Understanding mechanistic factors like electrophile activation and radical generation is key to optimizing these reactions.
• This work provides valuable insights for developing new asymmetric Ni-catalyzed RCC methods and expanding their substrate scope.