Catalytic Asymmetric Aza-Electrophilic Additions of 1,1-Disubstituted Styrenes.

Electrophilic addition of alkenes is a textbook reaction that plays a pivotal role in organic chemistry. In the past decades, catalytic asymmetric variants of this important type of reaction have witnessed great achievements by the development of novel catalytic systems. However, enantioselective aza-electrophilic additions of unactivated alkenes, which could provide a transformative strategy for the preparation of synthetically significant nitrogen-containing compounds, still remain a formidable challenge. Herein, we have developed unprecedented Au(I)/NHC-catalyzed asymmetric aza-electrophilic additions of unactivated 1,1-disubstituted styrenes by the utilization of readily available dialkyl azodicarboxylates as electrophilic nitrogen sources. Based on this approach, a series of transformations, including [2 + 2] cycloaddition, intermolecular 1,2-oxyamination, and several types of intramolecular hydrazination-induced cyclizations, have been realized. These transformations provide a previously unattainable platform for the divergent synthesis of hydrazine derivatives, which could also be converted to other nitrogen-containing chiral synthons. Experimental and computational studies support the idea that carbocation intermediates are involved in reaction pathways.

Enantioselective Cross-[4 + 2]-Cycloaddition/Decarboxylation of 2-Pyrones by Cooperative Catalysis of the Pd(0)/NHC Complex and Chiral Phosphoric Acid.

Here, we describe a cooperative Pd(0)/chiral phosphoric acid catalytic system that allows us to realize the first chemo-, regio-, and enantioselective sequential cross-[4 + 2]-cycloaddition/decarboxylation reaction between 2-pyrones and unactivated acyclic 1,3-dienes. The key to the success of this transformation is the utilization of an achiral N-heterocyclic carbene (NHC) as the ligand and a newly developed chiral phosphoric acid as the cocatalyst. Experimental investigations and computational studies support the idea that the Pd(0)/NHC complex acts as a π-Lewis base to increase the nucleophilicity of 1,3-dienes via η2 coordination, while the chiral phosphoric acid simultaneously increases the electrophilicity of 2-pyrones by hydrogen bonding. By this synergistic catalysis, the sequential cross-[4 + 2]-cycloaddition and decarboxylation reaction proceeds efficiently, enabling the preparation of a wide range of chiral vinyl-substituted 1,3-cyclohexadienes in good yields and enantioselectivities. The synthetic utility of this reaction is demonstrated by synthetic transformations of the product to various valuable chiral six-membered carbocycles.

Chiral Bis(binaphthyl) Cyclopentadienyl Ligands for Rhodium-Catalyzed Desymmetrization of Diarylmethanes via Selective Arene Coordination.

Owing to substantial advances in the past several decades, transition-metal-catalyzed asymmetric reactions have garnered considerable attention as pivotal methods for constructing chiral molecules from abundant, readily available achiral counterparts. These advances are largely attributed to the development of chiral ligands that control stereochemistry through steric repulsion and other noncovalent interactions between the ligands and functional groups or prochiral centers on the substrates. However, stereocontrol weakens dramatically with increasing distance between the reaction site and the functional group or prochiral center. Herein, we report a symphonic strategy for remote stereocontrol of Rh(III)-catalyzed asymmetric benzylic C-H bond addition reactions of diarylmethanes in which the two aryl motifs differ at the meta and/or para position. Specifically, catalysts bearing a new type of chiral cyclopentadienyl (Cp) ligand differentiate between the two aromatic rings of the diarylmethane by arene-selective η6 coordination, setting up an opportunity for ligand-controlled stereoselective benzylic deprotonation and subsequent stereoselective addition to the 1,1-bis(arylsulfonyl)ethylene.

Asymmetric Dearomatization of Indoles with Azodicarboxylates via Cascade Electrophilic Amination/Aza-Prins Cyclization/Phenonium-like Rearrangement.

Herein, we report a highly efficient synthesis of enantioenriched aza-[3.3.1]-bicyclic enamines and ketones, a class of structural cores in many natural products, via asymmetric dearomatization of indoles with azodicarboxylates. The reaction is initiated by electrophilic amination and followed by aza-Prins cyclization/phenonium-like rearrangement. A newly developed fluorine-containing chiral phosphoric acid displays excellent activity in promoting this cascade reaction. The absence or presence of water as the additive directs the reaction pathway toward either enamine or ketone products in high yields (up to 93%) with high enantiopurity (up to 98% ee). Comprehensive density functional theory (DFT) calculations reveal the energy profile of the reaction and the origins of enantioselectivity and water-induced chemoselectivity.

Explicit Mechanism of Rh(I)-Catalyzed Asymmetric C-H Arylation and Facile Synthesis of Planar Chiral Ferrocenophanes.

Mechanism-guided reaction development is a well-appreciated research paradigm in chemistry since the merging of mechanistic knowledge would accelerate the discovery of new synthetic methods. Low-valent transition metals such as Pd(0)- and Rh(I)-catalyzed C-H arylation with aryl (pseudo)halides is among the enabling reactions for the exclusive cross-coupling of two different aryl partners. However, different from the situation of Pd(0)-catalysis, the mechanism of Rh(I)-catalyzed C-H arylation is underexplored. The sequence of the elementary steps of aryl C-H activation and oxidative addition of aryl (pseudo)halides remains unclear. Herein, we report comprehensive experimental and computational studies toward explicit mechanistic understandings of Rh(I)-catalyzed intermolecular asymmetric C-H arylation between 2-pyridinylferrocenes and aryl bromides. The identification of each elementary step in the catalytic cycle and the structural characterization of the key intermediates and transition states allow the rational design and development of challenging intramolecular reactions. The successful realization of this reaction mode set the foundation for the facile synthesis of planar chiral [m]ferrocenophanes (m = 6-8), a class of rarely explored target molecules with strained structures and intriguing molecular topology.

Cp*Co(III)-Catalyzed Enantioselective Hydroarylation of Unactivated Terminal Alkenes via C-H Activation.

Enantioselective hydroarylation of unactivated terminal akenes constitutes a prominent challenge in organic chemistry. Herein, we reported a Cp*Co(III)-catalyzed asymmetric hydroarylation of unactivated aliphatic terminal alkenes assisted by a new type of tailor-made amino acid ligands. Critical to the chiral induction was the engaging of a novel noncovalent interaction (NCI), which has seldomly been disclosed in the C-H activation area, arising from the molecular recognition among the organocobalt(III) intermediate, the coordinated alkene, and the well-designed chiral ligand. A broad range of C2-alkylated indoles were obtained in high yields and excellent enantioselectivities. DFT calculations revealed the reaction mechanism and elucidated the origins of chiral induction in the stereodetermining alkene insertion step.

Succinate induces skeletal muscle fiber remodeling via SUNCR1 signaling.

The conversion of skeletal muscle fiber from fast twitch to slow-twitch is important for sustained and tonic contractile events, maintenance of energy homeostasis, and the alleviation of fatigue. Skeletal muscle remodeling is effectively induced by endurance or aerobic exercise, which also generates several tricarboxylic acid (TCA) cycle intermediates, including succinate. However, whether succinate regulates muscle fiber-type transitions remains unclear. Here, we found that dietary succinate supplementation increased endurance exercise ability, myosin heavy chain I expression, aerobic enzyme activity, oxygen consumption, and mitochondrial biogenesis in mouse skeletal muscle. By contrast, succinate decreased lactate dehydrogenase activity, lactate production, and myosin heavy chain IIb expression. Further, by using pharmacological or genetic loss-of-function models generated by phospholipase Cß antagonists, SUNCR1 global knockout, or SUNCR1 gastrocnemius-specific knockdown, we found that the effects of succinate on skeletal muscle fiber-type remodeling are mediated by SUNCR1 and its downstream calcium/NFAT signaling pathway. In summary, our results demonstrate succinate induces transition of skeletal muscle fiber via SUNCR1 signaling pathway. These findings suggest the potential beneficial use of succinate-based compounds in both athletic and sedentary populations.

Low-Temperature Nickel-Catalyzed C-N Cross-Coupling via Kinetic Resolution Enabled by a Bulky and Flexible Chiral N-Heterocyclic Carbene Ligand.

The transition-metal-catalyzed C-N cross-coupling has revolutionized the construction of amines. Despite the innovations of multiple generations of ligands to modulate the reactivity of the metal center, ligands for the low-temperature enantioselective amination of aryl halides remain a coveted target of catalyst engineering. Designs that promote one elementary reaction often create bottlenecks at other steps. We here report an unprecedented low-temperature (as low as -50 °C), enantioselective Ni-catalyzed C-N cross-coupling of aryl chlorides with sterically hindered secondary amines via a kinetic resolution process (s factor up to >300). A bulky yet flexible chiral N-heterocyclic carbene (NHC) ligand is leveraged to drive both oxidative addition and reductive elimination with low barriers and control the enantioselectivity. Computational studies indicate that the rotations of multiple σ-bonds on the C2 -symmetric chiral ligand adapt to the changing needs of catalytic processes. We expect this design would be widely applicable to diverse transition states to achieve other challenging metal-catalyzed asymmetric cross-coupling reactions.

Towards Data-Driven Design of Asymmetric Hydrogenation of Olefins: Database and Hierarchical Learning.

Asymmetric hydrogenation of olefins is one of the most powerful asymmetric transformations in molecular synthesis. Although several privileged catalyst scaffolds are available, the catalyst development for asymmetric hydrogenation is still a time- and resource-consuming process due to the lack of predictive catalyst design strategy. Targeting the data-driven design of asymmetric catalysis, we herein report the development of a standardized database that contains the detailed information of over 12000 literature asymmetric hydrogenations of olefins. This database provides a valuable platform for the machine learning applications in asymmetric catalysis. Based on this database, we developed a hierarchical learning approach to achieve predictive machine leaning model using only dozens of enantioselectivity data with the target olefin, which offers a useful solution for the few-shot learning problem and will facilitate the reaction optimization with new olefin substrate in catalysis screening.

Direct Synthesis of Ketones from Methyl Esters by Nickel-Catalyzed Suzuki-Miyaura Coupling.

The direct conversion of alkyl esters to ketones has been hindered by the sluggish reactivity of the starting materials and the susceptibility of the product towards subsequent nucleophilic attack. We have now achieved a cross-coupling approach to this transformation using nickel, a bulky N-heterocyclic carbene ligand, and alkyl organoboron coupling partners. 65 alkyl ketones bearing diverse functional groups and heterocyclic scaffolds have been synthesized with this method. Catalyst-controlled chemoselectivity is observed for C(acyl)-O bond activation of multi-functional substrates bearing other bonds prone to cleavage by Ni, including aryl ether, aryl fluoride, and N-Ph amide functional groups. Density functional theory calculations provide mechanistic support for a Ni0 /NiII catalytic cycle and demonstrate how stabilizing non-covalent interactions between the bulky catalyst and substrate are critical for the reaction's success.