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.

Pd(II)-Catalyzed atroposelective C-H olefination: synthesis of enantioenriched N-aryl peptoid atropisomers.

Herein, we reported the synthesis of enantioenriched N-aryl peptoid atropisomers via Pd(II)-catalyzed atroposelective C-H olefination using the easily accessible L-pyroglutamic acid (L-pGlu-OH) as the chiral ligand. A series of optically active N-aryl peptoid atropisomers were obtained in synthetically useful yields with high enantioselectivities.

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.

Synthesis of Chiral Diarylmethylamines by Cobalt-Catalyzed Enantioselective C-H Alkoxylation.

Chiral diarylmethylamines (DAMA) are important structural motifs widely present in pharmaceuticals, natural products, and chiral ligands. Herein, we reported a highly enantioselective synthesis of chiral DAMAs via cobalt-catalyzed enantioselective C-H alkoxylation strategy. The reaction features easy operation, the use of earth-abundant and cost-efficient cobalt(II) catalyst, and readily available ligand. A range of chiral DAMAs were efficiently synthesized in high yields with excellent enantioselectivities (up to 90 % yield and up to 99 % ee) through desymmetrization and parallel kinetic resolution. Moreover, this protocol was also compatible with the synthesis of chiral benzylamines via kinetic resolution.

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.

Single-Step Synthesis of Atropisomers with Vicinal C-C and C-N Diaxes by Cobalt-Catalyzed Atroposelective C-H Annulation.

The atroposelective synthesis of atropisomers with vicinal diaxes remains rare and challenging, due to the steric influence between the two axes and their unique topology. Herein, we disclose a single-step construction of atropisomers with vicinal C-C and C-N chiral diaxes by cyclopentadiene (Cp)-free cobalt-catalyzed intramolecular atroposelective C-H annulation, providing the desired diaxial atropisomers of unique structures with decent stereocontrols of both axes (up to >99 % ee and 70 : 1 dr). The optically pure products bearing fluorophores show circular polarized luminescence (CPL) properties, being candidate materials for potential CPL applications. Atropisomerization experiments and density function theory (DFT) calculations are conducted to study the rotational barriers and rotation pathways of the diaxes.

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.

Pd(II)-Catalyzed Atroposelective C-H Allylation: Synthesis of Enantioenriched N-Aryl Peptoid Atropisomers.

A Pd-catalyzed atroposelective C-H allylation with 1,1-disubstituted alkenes was developed for the synthesis of enantioenriched N-aryl peptoid atropisomers via ß-H elimination using commercially available and inexpensive L-pGlu-OH as a chiral ligand. Exclusive allylic selectivity was achieved. Additionally, a series of enantioenriched N-aryl peptoid atropisomers were obtained in synthetically useful yields with excellent enantioselectivities (up to 90% yield and 97% ee).

Synthesis of Chiral Sulfoxides via Pd(II)-Catalyzed Enantioselective C-H Alkynylation/Kinetic Resolution of 2-(Arylsulfinyl)pyridines.

A Pd(II)-catalyzed enantioselective C-H alkynylation of 2-(arylsulfinyl)pyridines via kinetic resolution using cheap and commercially available l-pGlu-OH as a chiral ligand is reported. A wide range of 2-(arylsulfinyl)pyridines were compatible with this protocol, giving the alkynylation products and recovered sulfoxides in high yields with high enantioselectivities (up to 99% ee). Furthermore, the enantioenriched products can be easily transformed to several other types of chiral sulfoxide scaffolds with the retention of enantiopurity.

Atroposelective synthesis of N-aryl peptoid atropisomers via a palladium(ii)-catalyzed asymmetric C-H alkynylation strategy.

The introduction of chirality into peptoids is an important strategy to determine a discrete and robust secondary structure. However, the lack of an efficient strategy for the synthesis of structurally diverse chiral peptoids has hampered the studies. Herein, we report the efficient synthesis of a wide variety of N-aryl peptoid atropisomers in good yields with excellent enantioselectivities (up to 99% yield and 99% ee) by palladium-catalyzed asymmetric C-H alkynylation. The inexpensive and commercially available l-pyroglutamic acid was used as an efficient chiral ligand. The exceptional compatibility of the C-H alkynylation with various peptoid oligomers renders this procedure valuable for peptoid modifications. Computational studies suggested that the amino acid ligand distortion controls the enantioselectivity in the Pd/l-pGlu-catalyzed C-H bond activation step.

Enantioselective Synthesis of Atropisomeric Anilides via Pd(II)-Catalyzed Asymmetric C-H Olefination.

Atropisomeric anilides have received tremendous attention as a novel class of chiral compounds possessing restricted rotation around an N-aryl chiral axis. However, in sharp contrast to the well-studied synthesis of biaryl atropisomers, the catalytic asymmetric synthesis of chiral anilides remains a daunting challenge, largely due to the higher degree of rotational freedom compared to their biaryl counterparts. Here we describe a highly efficient catalytic asymmetric synthesis of atropisomeric anilides via Pd(II)-catalyzed atroposelective C-H olefination using readily available L-pyroglutamic acid as a chiral ligand. A broad range of atropisomeric anilides were prepared in high yields (up to 99% yield) and excellent stereoinduction (up to >99% ee) under mild conditions. Experimental studies indicated that the atropostability of those anilide atropisomers toward racemization relies on both steric and electronic effects. Experimental and computational studies were conducted to elucidate the reaction mechanism and rate-determining step. DFT calculations revealed that the amino acid ligand distortion is responsible for the enantioselectivity in the C-H bond activation step. The potent applications of the anilide atropisomers as a new type of chiral ligand in Rh(III)-catalyzed asymmetric conjugate addition and Lewis base catalysts in enantioselective allylation of aldehydes have been demonstrated. This strategy could provide a straightforward route to access atropisomeric anilides, one of the most challenging types of axially chiral compounds.

Wide-field optical design for a 60 m submillimeter telescope.

We present a practical wide-field optical design for a 60 m aperture submillimeter telescope, which is currently under conceptual design study in China. The telescope is specified to operate over a wavelength range of 0.65-3 mm and provide a wide field of view (FOV) of 1° in diameter. We designed an F/6 Ritchey Chrétien (RC) system with a quasi-planar tertiary corrector, which cancels all spherical, coma, and astigmatism aberrations. It also achieves a good balance among the mirror sizes, central obscuration, and focal-plane curvature. The problems of focal surface curvature and nontelecentricity are treated in the subfield instrumental design, which employs a simple silicon wedge prism to obtain flat and telecentric focal planes for each subfield instrument module. Our studies show that by such a design, more than ${{10}^5}$105 detector pixels can be efficiently and uniformly fed at the shortest wavelength band with Strehl ratios above 0.85 across the entire 1° FOV. Several practical issues related to the telescope optics are also discussed.

Pd(II)-Catalyzed Tandem Enantioselective Methylene C(sp3 )-H Alkenylation-Aza-Wacker Cyclization to Access ß-Stereogenic γ-Lactams.

Herein, we describe an unprecedented cascade reaction to ß-stereogenic γ-lactams involving Pd(II)-catalyzed enantioselective aliphatic methylene C(sp3 )-H alkenylation-aza-Wacker cyclization through syn-aminopalladation. Readily available 3,3'-substituted BINOLs are used as chiral ligands, providing the corresponding γ-lactams with broad scope and high enantioselectivities (up to 98 % ee).

Synthesis of Axially Chiral Styrenes through Pd-Catalyzed Asymmetric C-H Olefination Enabled by an Amino Amide Transient Directing Group.

The atroposelective synthesis of axially chiral styrenes remains a formidable challenge due to their relatively lower rotational barriers compared to the biaryl atropoisomers. Herein, we describe the construction of axially chiral styrenes through PdII -catalyzed atroposelective C-H olefination, using a bulky amino amide as a transient chiral auxiliary. Various axially chiral styrenes were produced with good yields and high enantioselectivity (up to 95 % yield and 99 % ee). Carboxylic acid derivatives of the resulting axially chiral styrenes showed superior enantiocontrol over the biaryl counterparts in CoIII -catalyzed enantioselective C(sp3 )-H amidation of thioamide. Mechanistic studies suggest that C-H cleavage is the enantioselectivity-determining step.

Recent advances in the synthesis of axially chiral biaryls via transition metal-catalysed asymmetric C-H functionalization.

Axially chiral biaryl motifs are widely present in natural products and pharmaceuticals. Moreover, they have been broadly used as privileged ligands in asymmetric catalysis. Over the past few decades, the efficient synthesis of axially chiral biaryls has been a research topic of great interest. This feature article will provide an overview of recent advances in the synthesis of these chiral skeletons via transition metal-catalysed asymmetric C-H functionalization.

Synthesis of Chiral Aldehyde Catalysts by Pd-Catalyzed Atroposelective C-H Naphthylation.

Chiral aldehyde catalysis opens new avenues for the activation of simple amines. However, the lack of easy access to structurally diverse chiral aldehyde catalysts has hampered the development of this cutting-edge field. Herein, we report a Pd-catalyzed atroposelective C-H naphthylation with 7-oxabenzonorbornadienes for the preparation of axially chiral biaryls with excellent enantioselectivities (up to >99 % ee). This reaction is scalable and robust, which serves as a key step to provide a rapid access to axially chiral aldehyde catalysts through a three-step C-H functionalization sequence. These chiral aldehydes exhibit better activities and enantioselectivities than the previously reported organocatalysts in the asymmetric activation of glycine derived amides and dipeptides. Moreover, preliminary investigation also discloses that the aldehyde catalyst can effectively override the intrinsic facial selectivity of chiral dipeptide substrates, showcasing the strong chiral induction ability of this type of novel aldehyde catalysts.