Molecular syntheses largely rely on time- and labour-intensive prefunctionalization strategies. In contrast, C-H activation represents an increasingly powerful approach that avoids lengthy syntheses of prefunctionalized substrates, with great potential for drug discovery, the pharmaceutical industry, material sciences, and crop protection, among others. The enantioselective functionalization of omnipresent C-H bonds has emerged as a transformative tool for the step- and atom-economical generation of chiral molecular complexity. However, this rapidly growing research area remains dominated by noble transition metals, prominently featuring toxic palladium, iridium and rhodium catalysts. Indeed, despite significant achievements, the use of inexpensive and sustainable 3d metals in asymmetric C-H activations is still clearly in its infancy. Herein, we discuss the remarkable recent progress in enantioselective transformations via organometallic C-H activation by 3d base metals up to April 2019.

Enantioselective C-H Activation with Earth-Abundant 3d Transition Metals.

Recent advances in Cpx MIII catalysis (M=Co, Rh, Ir) have enabled a variety of enantioselective C(sp2 )-H functionalization reactions, but enantioselective C(sp3 )-H functionalization is still largely unexplored. We describe an asymmetric C(sp3 )-H amidation of thioamides using an achiral CoIII /chiral carboxylic acid hybrid catalytic system, which provides easy and straightforward access to chiral β-amino thiocarbonyl and β-amino carbonyl building blocks with a quaternary carbon stereocenter.

Enantioselective C(sp3)–H Amidation of Thioamides Catalyzed by a CobaltIII/Chiral Carboxylic Acid Hybrid System

Transition-metal-catalysed direct C(sp3)−H functionalization of primary aliphatic amines is an attractive – but elusive – process that could provide efficient access to biologically and pharmaceutically important compounds. Now, a palladium-catalysed γ-arylation of primary alkylamines is achieved using an inexpensive, catalytic and transient directing group.

Site-Selective C−H Arylation of Primary Aliphatic Amines Enabled by a Catalytic Transient Directing Group

Chiral cations have been used extensively as organocatalysts, but their application to rendering transition metal-catalyzed processes enantioselective remains rare. This is despite the success of the analogous charge-inverted strategy in which cationic metal complexes are paired with chiral anions. We report here a strategy to render a common bipyridine ligand anionic and pair its iridium complexes with a chiral cation derived from quinine. We have applied these ion-paired complexes to long-range asymmetric induction in the desymmetrization of the geminal diaryl motif, located on a carbon or phosphorus center, by enantioselective C-H borylation. In principle, numerous common classes of ligand could likewise be amenable to this approach.

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Enantioselective remote C-H activation directed by a chiral cation

Direct catalytic modifications of carbon–hydrogen (C H) bonds, ubiquitous in organic molecules, represent a powerful strategy in organic synthesis. In the past decade, chemists have focused on the development of sustainable methods for functionalization of inert C H bonds using cost-effective earth-abundant 3d transition-metal catalysts. To fully harness the potential of this technology, however, it is essential to control the stereoselectivity of the C H functionalization processes. This review describes developments in the emerging area of enantioselective functionalization of C H bonds by 3d transition-metal catalysts proceeding via inner-sphere C H activation.

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Enantioselective C-H Bond Functionalizations by 3d Transition-Metal Catalysts

Reported is an achiral Cpx RhIII /chiral carboxylic acid catalyzed asymmetric C-H alkylation of diarylmethanamines with a diazomalonate, followed by cyclization and decarboxylation to afford 1,4-dihydroisoquinolin-3(2H)-one. Secondary alkylamines as well as nonprotected primary alkylamines underwent the transformation with high enantioselectivities (up to 98.5:1.5 e.r.) by using a newly developed chiral carboxylic acid as the sole source of chirality to achieve enantioselective C-H cleavage by a concerted metalation-deprotonation mechanism.

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Chiral Carboxylic Acid Enabled Achiral Rhodium(III)-Catalyzed Enantioselective C−H Functionalization

Enantioselective C(sp3)–H functionalization reactions using high-valent group 9 metal catalysts with cyclopentadienyl ligands have been achieved by the introduction of appropriate chiral carboxylic...

Development of Pseudo-C2-symmetric Chiral Binaphthyl Monocarboxylic Acids for Enantioselective C(sp3)–H Functionalization Reactions under Rh(III) Catalysis

Ru(II)-catalyzed enantioselective C–H functionalization reactions of sulfoximines with sulfoxonium ylides are described. The combination of [RuCl2(p-cymene)]2 and a pseudo-C
 2-symmetric binaphthyl monocarboxylic acid furnished the S-chiral products in 76:24–92:8 er.

Luqing Lin

Papers

Chiral Carboxylic Acid Enabled Achiral Rhodium(III)-Catalyzed Enantioselective C−H Functionalization

Development of Pseudo-C2-symmetric Chiral Binaphthyl Monocarboxylic Acids for Enantioselective C(sp3)–H Functionalization Reactions under Rh(III) Catalysis

Ru(II)/chiral carboxylic acid-catalyzed enantioselective C–H functionalization of sulfoximines