Asymmetric Dearomatization of Indoles through Cobalt-Catalyzed Enantioselective C-H Functionalization Enabled by Photocatalysis.

Photocatalysis holds a pivotal position in modern organic synthesis, capable of inducing novel reactivities under mild and environmentally friendly reaction conditions. However, the merger of photocatalysis and transition-metal-catalyzed asymmetric C-H activation as an efficient and sustainable method for the construction of chiral molecules remains elusive and challenging. Herein, we develop a cobalt-catalyzed enantioselective C-H activation reaction enabled by visible-light photoredox catalysis, providing a synergistic catalytic strategy for the asymmetric dearomatization of indoles with high levels of enantioselectivity (96% to >99% ee). Mechanistic studies indicate that the excited photocatalyst was quenched by divalent cobalt species in the presence of Salox ligand, leading to the formation of catalytically active chiral Co(III) complex. Moreover, stoichiometric reactions of cobaltacycle intermediate with indole suggest that the irradiation of visible light also play a critical role in the dearomatization step.

Cobalt-Catalyzed Domino Transformations via Enantioselective C-H Activation/Nucleophilic [3 + 2] Annulation toward Chiral Bridged Bicycles.

Selective synthesis of chiral bridged (hetero)bicyclic scaffolds via asymmetric C-H activation constitutes substantial challenges due to the multiple reactivities of strained bicyclic structures. Herein, we develop the domino transformations through an unprecedented cobalt-catalyzed enantioselective C-H activation/nucleophilic [3 + 2] annulation with symmetrical bicyclic alkenes. The methods offer straightforward access to a wide range of chiral molecules bearing [2.2.1]-bridged bicyclic cores with four and five consecutive stereocenters in a single step. Two elaborate salicyloxazoline (Salox) ligands were synthesized based on the rational design and mechanistic understanding. The well-defined chiral pockets generated from asymmetric coordination around the trivalent cobalt catalyst direct the orientation of bicyclic alkenes, leading to excellent enantioselectivity.

Cobalt-Catalyzed Enantioselective C-H Carbonylation towards Chiral Isoindolinones.

Transition metal-catalyzed enantioselective C-H carbonylation with carbon monoxide, an essential and easily available C1 feedstock, remains challenging. Here, we disclosed an unprecedented enantioselective C-H carbonylation catalyzed by inexpensive and readily available cobalt(II) salt. The reactions proceed efficiently through desymmetrization, kinetic resolution, and parallel kinetic resolution, affording a broad range of chiral isoindolinones in good yields with excellent enantioselectivities (up to 92 % yield and 99 % ee). The synthetic potential of this method was demonstrated by asymmetric synthesis of biological active compounds, such as (S)-PD172938 and (S)-Pazinaclone. The resulting chiral isoindolinones also serve as chiral ligands in cobalt-catalyzed enantioselective C-H annulation with alkynes to construct phosphorus stereocenter.

Cobalt-Catalyzed Enantioselective C-H Annulation of Benzylamines with Alkynes: Application to the Modular and Asymmetric Syntheses of Bioactive Molecules.

The transition metal-catalyzed enantioselective C-H functionalization strategy has revolutionized the logic of natural product synthesis. However, previous applications have heavily relied on the use of noble metal catalysts such as rhodium and palladium. Herein, we report the efficient synthesis of C1-chiral 1,2-dihydroisoquinolines (DHIQs) via enantioselective C-H/N-H annulation of picolinamides with alkynes catalyzed by a more sustainable and cheaper 3d metal catalyst, cobalt(II) acetate tetrahydrate. A wide range of enantiomerically enriched DHIQs were obtained in good yields with excellent enantioselectivities (up to 98% yield and >99% ee). The robustness and synthetic potential of this method were demonstrated by the modular and asymmetric syntheses of several tetrahydroisoquinoline alkaloids, including (S)-norlaudanosine, (S)-laudanosine, (S)-xylopinine, (S)-sebiferine, and (S)-cryptostyline II, and the asymmetric syntheses of key intermediates of (+)-solifenacin, FR115427, and (+)-NPS R-568.

Synthesis of Axially Chiral Biaryls through Cobalt(II)-Catalyzed Atroposelective C-H Arylation.

Highly efficient synthesis of axially chiral biaryl amines through cobalt-catalyzed atroposelective C-H arylation using easily accessible cobalt(II) salt and salicyloxazoline ligand has been reported. This methodology provides a straightforward and sustainable access to a broad range of enantioenriched biaryl-2-amines in good yields (up to 99 %) with excellent enantioselectivities (up to 99 % ee). The synthetic utility of the unprecedented method is highlighted by its scalability and diverse transformations.

Base-Promoted Electrochemical CoII -catalyzed Enantioselective C-H Oxygenation.

Metalla-electrocatalyzed C-H oxygenation represents one of the most straightforward and sustainable approaches to access valuable oxygenated molecules. Despite the significant advances, the development of enantioselective electrochemical C-H oxygenation reaction is very challenging and remains elusive. Herein, we described the first electrochemical CoII -catalyzed enantioselective C-H alkoxylation. A broad range of enantioenriched alkoxylated phosphinamides were obtained in good yields with excellent enantioselectivities (up to 98 % yield and >99 % ee). An unusual cobalt(III) alcohol complex was prepared and fully characterized, which was proven to be a key intermediate of this C-H alkoxylation reaction. Mechanistic studies revealed that the oxidation of CoIII to CoIV was facilitated by a base and the whole process proceeded through a cobalt(III/IV/II) catalytic cycle.

Enantio- and Regioselective Electrooxidative Cobalt-Catalyzed C-H/N-H Annulation with Alkenes.

In recent years, the merging of electrosynthesis with 3d metal catalyzed C-H activation has emerged as a sustainable and powerful technique in organic synthesis. Despite the impressive advantages, the development of an enantioselective version remains elusive and poses a daunting challenge. Herein, we report the first electrooxidative cobalt-catalyzed enantio- and regioselective C-H/N-H annulation with olefins using an undivided cell at room temperature (up to 99 % ee). t Bu-Salox, a rationally designed Salox ligand bearing a bulky tert-butyl group at the ortho-position of phenol, was found to be crucial for this asymmetric annulation reaction. A strong cooperative effect between t Bu-Salox and 3,4,5-trichloropyridine enabled the highly enantio- and regioselective C-H annulation with the more challenging α-olefins without secondary bond interactions (up to 96 % ee and 97 : 3 rr). Cyclovoltametric studies, and the preparation, characterization, and transformation of cobaltacycle intermediates shed light on the mechanism of this reaction.

Cobalt/Salox-Catalyzed Enantioselective Dehydrogenative C-H Alkoxylation and Amination.

The past decade has witnessed a rapid progress in asymmetric C-H activation. However, the enantioselective C-H alkoxylation and amination with alcohols and free amines remains elusive. Herein, we disclose the first enantioselective dehydrogenative C-H alkoxylation and amination enabled by a simple cobalt/salicyloxazoline (Salox) catalysis. The use of cheap and readily available cobalt(II) salts as catalysts and Saloxs as chiral ligands provides an efficient method to access P-stereogenic compounds in excellent enantioselectivities (up to >99 % ee). The practicality of this protocol is demonstrated by gram-scale preparation and further derivatizations of the resulting P-stereogenic phosphinamides, which offering a flexible asymmetric alternative to access P-stereogenic mono- and diphosphine chiral ligands. Preliminary mechanistic studies on the enantioselective C-H alkoxylation reaction suggest that a cobalt(III/IV/II) catalytic cycle might be involved.

Cobalt/Salox-Catalyzed Enantioselective C-H Functionalization of Arylphosphinamides.

Previous methods on CoIII -catalyzed asymmetric C-H activation rely on the use of tailor-made cyclopentadienyl-ligated CoIII complexes, which require lengthy steps for the preparation. Herein, we report an unprecedented enantioselective C-H functionalization enabled by a simple cobalt/salicyloxazoline (Salox) catalysis. The chiral Salox ligands can be easily prepared in one step from salicylonitrile and chiral amino alcohols. A broad range of P-stereogenic compounds were synthesized in high yields with excellent enantioselectivities (45 examples, up to 99 % yield and >99 % ee). The isolation and characterization of several intermediates provided insights into the generation of active catalytic cobalt species, the action of Salox, and the mode of stereocontrol.