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

Abstract

After decades of palladium dominating the realm of transition-metal-catalyzed cross-coupling, recent years have witnessed exciting advances in the development of new nickel-catalyzed cross-coupling reactions to form C(sp³) centers. Nickel possesses distinct properties compared with palladium, such as facile single-electron transfer to C(sp³) electrophiles and rapid C–C reductive elimination from Ni^III. These properties, among others, make nickel particularly well-suited for reductive cross-coupling (RCC) in which two electrophiles are coupled and an exogenous reductant is used to turn over the metal catalyst. Ni-catalyzed RCCs use readily available and stable electrophiles as starting materials and exhibit good functional group tolerance, which makes them appealing for applications in the synthesis of complex molecules. Building upon the foundational work in Ni-catalyzed RCCs by the groups of Kumada, Durandetti, Weix, and others, as well as the advancements in Ni-catalyzed enantioselective redox-neutral cross-couplings led by Fu and co-workers, we initiated a program to explore the feasibility of developing highly enantioselective Ni-catalyzed RCCs. Our research has also been driven by a keen interest in unraveling the factors contributing to enantioinduction and electrophile activation as we seek new avenues for advancing our understanding and further developing these reactions.

In the first part of this Account, we organize our reported methods on the basis of the identity of the C(sp³) electrophiles, including benzylic chlorides, N-hydroxyphthalimide (NHP) esters, and α-chloro esters and nitriles. We highlight how the selection of specific chiral ligands plays a pivotal role in achieving high cross-selectivity and enantioselectivity. In addition, we show that reduction can be accomplished not only with heterogeneous reductants, such as Mn⁰, but also with the soluble organic reductant tetrakis(dimethylamino)ethylene (TDAE), as well as electrochemically. The use of homogeneous reductants, such as TDAE, is well suited for studying the mechanism of the transformation. Although this Account primarily focuses on RCCs, we also highlight our work using trifluoroborate (BF₃K) salts as radical precursors for enantioselective dual-Ni/photoredox systems.

At the end of this Account, we summarize the relevant mechanistic studies of two closely related asymmetric reductive alkenylation reactions developed in our laboratory and provide a context between our work and related mechanistic studies by others. We discuss how the ligand properties influence the rates and mechanisms of electrophile activation and how understanding the mode of C(sp³) radical generation can be used to optimize the yield of an RCC. Our research endeavors to offer insights on the intricate mechanisms at play in asymmetric Ni-catalyzed RCCs with the goal of using the rate of electrophile activation to improve the substrate scope of enantioselective RCCs. We anticipate that the insights we share in this Account can provide guidance for the development of new methods in this field.

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