A Bulky Chiral N-Heterocyclic Carbene Palladium Catalyst Enables Highly Enantioselective Suzuki–Miyaura Cross-Coupling Reactions for the Synthesis of Biaryl Atropisomers

Abstract

Axially chiral biaryl scaffolds are essential structural units in chemistry. The asymmetric Pd-catalyzed Suzuki–Miyaura cross-coupling reaction has been widely recognized as one of the most practical methods for constructing atropisomers of biaryls. However, longstanding challenges remain in this field. For example, substrate scope is often narrow and specialized, functional groups and heterocycles can lead to reduced reactivity and selectivity, bulky ortho-substituents are usually needed, and reported methods are generally inapplicable to tetra-ortho-substituted biaryls. We have developed an unprecedented highly enantioselective N-heterocyclic carbene (NHC)-Pd catalyzed Suzuki–Miyaura cross-coupling reaction for the synthesis of atropisomeric biaryls. These reactions enable efficient coupling of aryl halides (Br, Cl) or aryl triflates with various types of aryl boron compounds (B­(OH)2, Bpin, Bneo, BF3K), tolerate a remarkably broad scope of functional groups and heterocycles (>41 examples), employ low loading of catalyst (0.2–2 mol %), and proceed under mild conditions. The protocol provided general and efficient access to various atropisomeric biaryls and heterobiaryls in excellent enantioselectivities (up to 99% ee) with no need of using bulky ortho-substituted substrates and was effective for the synthesis of tetra-ortho-substituent biaryls. Moreover, the method was successfully applied to the diastereo- and enantioselective synthesis of atropisomeric ternaphthalenes. Critical to the success of the reaction is the development and application of an extremely bulky C 2-symmetric chiral NHC, (R,R,R,R)-DTB-SIPE, as the ligand for palladium. To the best of our knowledge, this is the first highly enantioselective (>90% ee) example of a chiral NHC-metal-catalyzed C­(sp2)–C­(sp2) cross-coupling reaction.

Chiral N-heterocyclic Carbene Gold Complexes: Synthesis and Applications in Catalysis

“…Although some advances have been achieved using phosphine ligands, their tedious synthesis and, in some cases, intrinsic ease of oxidation excludes practical applications on a large scale. In contrast, the rigid structure of NHCs (N-heterocyclic carbenes) provides an excellent opportunity to form stable gold complexes with a well-defined chiral environment, as was proven in the case of other metals, such as palladium [26][27][28][29], ruthenium [30][31][32][33] or copper [34][35][36][37][38][39][40][41][42]. Moreover, adequately planned structure of NHC ligands allows for tuning of their electronic and steric properties, which is not easily achievable in the case of phosphines [43,44].…”

Transient-axial-chirality controlled asymmetric rhodium-carbene C(sp2)-H functionalization for the synthesis of chiral fluorenes

“…On the other hand, the axial chirality has been found in a variety of rotation-hindered molecules [32][33][34][35][36][37][38][39] , such as BINAP and BINOL derivatives, which have been widely used as privileged ligands or catalysts in asymmetric catalysis [40][41][42][43][44][45] . Inspired by the unique structures of these chiral ligands with axial chirality, we…”

Enantioselective Synthesis of Atropisomers with Multiple Stereogenic Axes

“…In 2019, Shi and co-workers described the first highly enantioselective N-heterocyclic carbene (NHC)-Pd-catalyzed Suzuki-Miyaura cross-coupling reaction for the synthesis of atropisomeric biaryls. [13] Av ariety of axially chiral biaryls, heterobiaryls,a nd tetra-ortho-substituted biaryls were efficiently prepared in high yields with excellent levels of enantiocontrol from readily available substrates.T hese reactions tolerate aw ide scope of heterocycles and functional groups,employ low catalyst loading, and proceed under mild conditions.I na ddition to this broad substrate scope,t he authors also demonstrated the possible access to ternaphthalenes 5a,b via ad ouble Suzuki-Miyaura cross-coupling between dibromonaphthalene 3 and naphthylboronic acid 8 (Scheme 4). Key to the success of the reaction was the development and application of the very bulky C 2 -symmetric chiral NHC ligand L2 for the Pd catalyst.…”