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.
An unprecedented low‐temperature, asymmetric Ni‐catalyzed C−N cross‐coupling of sterically hindered secondary amines with aryl chlorides via kinetic resolution is reported. A bulky yet flexible, chiral NHC ligand enables both low barrier oxidative addition and reductive elimination and high levels of enantiocontrol. Computational studies indicate that multiple σ‐bond rotations of the C2‐symmetric chiral NHC adapt to the changing needs of catalytic processes.
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.
Methyl esters are shown to participate in intermolecular Suzuki–Miyaura cross‐coupling reactions. Due to the mild nature of organoboron reagents, the product ketones are inert to the reaction conditions, avoiding over reactivity issues prominent with more aggressive organometallic nucleophiles.
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.
A concise and divergent approach for the total syntheses of four cembrane diterpenoids, namely (+)‐sarcophytin, (+)‐chatancin, (−)‐3‐oxochatancin, and (−)‐pavidolide B, has been developed, and it ...also led to the structural revision of (−)‐isosarcophytin. The key steps of the strategy feature a double Mukaiyama Michael addition/elimination, a Helquist annulation, two substrate‐controlled facial‐selective hydrations, and a pinacol rearrangement. The described syntheses not only achieved these natural products in an efficient manner, but also provided insight into the biosynthetic relationship between the two different skeletons.
Efficient access: A concise and divergent approach for the total syntheses of four cembranoids, namely (+)‐sarcophytin, (+)‐chatancin, (−)‐3‐oxochatancin, and (−)‐pavidolide B, was developed. The key features of the efficient strategy entail a double Mukaiyama–Michael addition/elimination, a Helquist annulation, two facial‐selective hydrations, and a pinacol rearrangement.
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.
A standardized database including over 12000 literature transformations was created to provide the data basis for the AI design of asymmetric hydrogenation of olefins. The developed hierarchical learning strategy can provide a predictive model in the early stage of catalysis screening where limited data is available.
Herein we report a highly enantioselective kinetic resolution of tertiary benzyl alcohols via palladium/chiral norbornene cooperative catalysis. With simple aryl iodides as the resolution reagent, a ...wide range of readily available racemic tertiary benzyl alcohols are applicable to this method. Both chiral tertiary benzyl alcohols and benzocchromene products are obtained in good to excellent enantioselectivities (selectivity factor up to 544). The appealing synthetic utility of the obtained enantioenriched tertiary alcohols is demonstrated by the facile preparation of several valuable chiral heterocycles. Preliminary mechanism studies include DFT calculations to explain the origin of enantiodiscrimination and control experiments to uncover the formation of a transient axial chirality during the kinetic resolution step.
A highly enantioselective kinetic resolution of tertiary benzyl alcohols via palladium/chiral norbornene cooperative catalysis is developed. Simple aryl iodides are used as the resolution reagent. Both enantioenriched tertiary benzyl alcohols and benzocchromene products are obtained in good to excellent enantioselectivities. The synthetic applications are demonstrated by the facile synthesis of diversified biorelevant heterocycles.
The asymmetric allylic alkylation (AAA), which features employing active allylic substrates, has historical significance in organic synthesis. The allylic C–H alkylation is principally more atom- and ...step-economic than the classical allylic functionalizations and thus can be considered a transformative variant. However, asymmetric allylic C–H alkylation reactions are still scarce and yet underdeveloped. Herein, we have found that Z/E- and regioselectivities in the Pd-catalyzed asymmetric allylic C–H alkylation of 1,4-dienes are highly dependent on the type of nucleophiles. A highly stereoselective allylic C–H alkylation of 1,4-dienes with azlactones has been established by palladium-chiral phosphoramidite catalysis. The protocol proceeds under mild conditions and can accommodate a wide scope of substrates, delivering structurally divergent α,α-disubstituted α-amino acid surrogates in high yields and excellent levels of diastereo-, Z/E-, regio-, and enantioselectivities. Notably, this method provides key chiral intermediates for an efficient synthesis of lepadiformine marine alkaloids. Experimental and computational studies on the reaction mechanism suggest a novel concerted proton and two-electron transfer process for the allylic C–H cleavage and reveal that the Z/E- and regioselectivities are governed by the geometry and coordination pattern of nucleophiles.
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.
Transition metal‐catalyzed amide C−N bond activation has emerged as a powerful strategy to utilize amides in synthetic transformations. The key mechanistic basis for the rational design of amide ...reagents is the structure‐activity relationship of amide C−N bond activation. In this work, the controlling factors of Ni/PCy3‐catalyzed amide C−N bond activation barrier are elucidated with density functional theory (DFT) calculations and distortion/interaction analysis. We found that the substrate distortion is the key factor that differentiates the amide reactivity in the C−N bond activation. The substrate distortion of amide is associated with two distinctive structure‐activity relationships. The general planar amides undergo a classic three‐membered ring oxidative addition to cleave the C−N bond, in which the C−N heterolytic bond dissociation energy has a linear relationship with the activation barrier. The twisted amides have a chelation‐assisted transition state for the amide C−N bond cleavage, and the twisted angle τ can serve as a predictive parameter for the reactivity of the twisted amides. The understanding of the structure‐activity relationship of amide C−N bond activation provides a rational and predictive basis for future reaction designs involving transition metal‐catalyzed amide C−N bond activation.
Computational catalysis: The structure‐activity relationship and the key controlling factors of amide activation barriers were elucidated by DFT calculation and distortion/interaction analysis.
Reports on digital complete dentures (CDs) are increasing. However, systematic reviews on their accuracy and influencing factors are lacking.
The purpose of this systematic review was to evaluate the ...accuracy of digital CDs and to summarize influencing factors.
An electronic search of the English language literature from January 2009 to October 2019 was performed in the database PubMed/MEDLINE, with the results enriched by manual searches and citation mining. Factors investigated in the selected articles included the fabrication technique, type of computer-aided design and computer-aided manufacturing (CAD-CAM) system, shape of reference model, long-term service, analytical method, and statistical indicators.
A total of 522 articles were identified, of which 14 in vitro articles met the inclusion criteria. Eight articles compared the adaptation of the denture base between digital and conventional methods, 4 studies evaluated the occlusal discrepancies, 4 compared the trueness or adaptation of the denture fabricated with CAD-CAM milling and 3D printing, 1 compared the denture adaptation with 4 different CAD-CAM systems, and 2 evaluated the adaptation of the denture base before and after incubation in artificial saliva.
Most of the studies reported clinically acceptable values for the occlusal trueness and adaptation of digital CDs. The digital CDs showed similar or better adaptation than conventionally fabricated CDs, and the greatest misfit of the intaglio surface was reported in the posterior palatal seal area and border seal area. The fabrication technique, CAD-CAM system, and long-term service were statistically significant in relation to denture accuracy. Clarification is needed concerning the accuracy of digital CDs according to the shape of the cast, the parameters related to the CAD-CAM process, the analytical method, and the statistical indicators. No clear conclusions can be drawn about the superiority of CAD-CAM milling and 3D printing regarding denture accuracy.
