A Combined Kinetic and Thermodynamic Approach for the Interpretation of Continuous‐Flow Heterogeneous Catalytic Processes

The heterogeneous proline‐catalyzed aldol reaction was investigated under continuous‐flow conditions by means of a packed‐bed microreactor. Reaction‐progress kinetic analysis (RPKA) was used in combination with nonlinear chromatography for the interpretation, under synthetically relevant conditions, of important mechanistic aspects of the heterogeneous catalytic process at a molecular level. The information gathered by RPKA and nonlinear chromatography proved to be highly complementary and allowed for the assessment of optimal operating variables. In particular, the determination of the rate‐determining step was pivotal for optimizing the feed composition. On the other hand, the competitive product inhibition was responsible for the unexpected decrease in the reaction yield following an apparently obvious variation in the feed composition. The study was facilitated by a suitable 2D instrumental arrangement for simultaneous flow reaction and online flow‐injection analysis.     

Development of a Continuous‐Flow System for Asymmetric Hydrogenation Using Self‐Supported Chiral Catalysts

Well‐designed, self‐assembled, metal–organic frameworks were constructed by simple mixing of multitopic MonoPhos‐based ligands ( 3 ; MonoPhos=chiral, monodentate phosphoramidites based on the 1,1′‐bi‐2‐naphthol platform) and [Rh(cod)₂]BF₄ (cod=cycloocta‐1,5‐diene). This self‐supporting strategy allowed for simple and efficient catalyst immobilization without the use of extra added support, giving well‐characterized, insoluble (in toluene) polymeric materials ( 4 ). The resulting self‐supported catalysts ( 4 ) showed outstanding catalytic performance for the asymmetric hydrogenation of a number of α‐dehydroamino acids ( 5 ) and 2‐aryl enamides ( 7 ) with enantiomeric excess (ee) ranges of 94–98 % and 90–98 %, respectively. The linker moiety in 4 influenced the reactivity significantly, albeit with slight impact on the enantioselectivity. Acquisition of reaction profiles under steady‐state conditions showed 4 h and 4 i to have the highest reactivity (turnover frequency (TOF)=95 and 97 h^?1 at 2 atm, respectively), whereas appropriate substrate/catalyst matching was needed for optimum chiral induction. The former was recycled 10 times without loss in ee (95–96 %), although a drop in TOF of approximately 20 % per cycle was observed. The estimation of effective catalytic sites in self‐supported catalyst 4 e was also carried out by isolation and hydrogenation of catalyst–substrate complex, showing about 37 % of the Rh^I centers in the self‐supported catalyst 4 e are accessible to substrate 5 c in the catalysis. A continuous flow reaction system using an activated C/ 4 h mixture as stationary‐phase catalyst for the asymmetric hydrogenation of 5 b was developed and run continuously for a total of 144 h with >99 % conversion and 96–97 % enantioselectivity. The total Rh leaching in the product solution is 1.7 % of that in original catalyst 4 h .     

A Carbon Nanotube Confinement Strategy to Implement Homogeneous Asymmetric Catalysis in the Solid Phase

A readily recyclable asymmetric catalyst has been developed based on the self‐assembly of a homogeneous catalyst in a fibrous network of multiwalled carbon nanotubes (MWNTs). Dimerization of an amide‐based chiral ligand with a suitable spacer allows for the efficient formation of a heterogeneous catalyst by self‐assembly on addition of Er(OiPr)₃. The self‐assembly proceeds in the MWNT fibrous network and small clusters of assembled catalyst are confined in the MWNTs, producing an easily handled solid‐phase catalyst. The resulting MWNT‐confined catalyst exhibits a good catalytic performance in a catalytic asymmetric Mannich‐type reaction, which can be conducted in a repeated batch system and in a continuous‐flow platform.     

Bimetallic Gold(I)/Chiral N,N′‐Dioxide Nickel(II) Asymmetric Relay Catalysis: Chemo‐ and Enantioselective Synthesis of Spiroketals and Spiroaminals

A highly efficient asymmetric cascade reaction between keto esters and alkynyl alcohols and amides is reported. The success of the reaction was attributed to the combination of chiral Lewis acid N,N′‐dioxide nickel(II) catalysis with achiral π‐acid gold(I) catalysis working as an asymmetric relay catalytic system. The corresponding spiroketals and spiroaminals were synthesized in up to 99 % yield, 19:1 d.r., and more than 99 % ee under mild reaction conditions. Control experiments suggest that the N,N′‐dioxide ligand was essential for the formation of the spiro products.     

Polystyrene-Supported Aminocatalyst Derived from Diarylprolinol for Asymmetric α-Amination of Aldehydes

A new class of polystyrene-supported aminocatalysts with a triazole linker from diphenyl prolinol were developed. Their catalytic activity was tested in the asymmetric α-amination of aldehydes. The substrate scope of this catalysis was studied under the optimized reaction conditions. The reusability of the polystyrene-supported aminocatalyst was demonstrated up to four cycles. Based on the reaction results, a reaction mechanism was proposed for the asymmetric α-amination of aldehydes.     

Asymmetric Synthesis of Indoline from Achiral Phthalimide Involving Crystallization-Induced Deracemization

Asymmetric synthesis was performed by combining the photochemical reaction of an achiral substrate followed by crystallization-induced deracemization. The results indicated that a fused indoline produced by photochemical intramolecular δ-hydrogen abstraction and cyclization of N-(5-chloro-2-methylphenyl)phthalimide crystallized as a racemic conglomerate. Since this substrate has an aminal skeleton, racemization involving a ring-opening and ring-closing equilibrium process occurred under suitable conditions. Efficient racemization was observed in acetone containing a catalytic base, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Crystallization-induced dynamic deracemization by Viedma ripening from racemic indoline was performed with an excellent enantioselectivity of 99 % ee. Furthermore, one-pot asymmetric synthesis of the indoline was achieved by the photochemical reaction of achiral phthalimide followed by continuous attrition-enhanced deracemization converging to 99 % ee of enantiomeric crystals. This is the first example of asymmetric expression and amplification by photochemical hydrogen abstraction and crystallization-induced dynamic deracemization.     

From a Sequential to a Concurrent Reaction in Aqueous Medium: Ruthenium‐Catalyzed Allylic Alcohol Isomerization and Asymmetric Bioreduction

The ruthenium‐catalyzed redox isomerization of allylic alcohols was successfully coupled with the enantioselective enzymatic ketone reduction (mediated by KREDs) in a concurrent process in aqueous medium. The overall transformation, formally the asymmetric reduction of allylic alcohols, took place with excellent conversions and enantioselectivities, under mild reaction conditions, employing commercially and readily available catalytic systems, and without external coenzymes or cofactors. Optimization resulted in a multistep approach and a genuine cascade reaction where the metal catalyst and biocatalyst coexist from the beginning.     

Merging Electrosynthesis and Bifunctional Squaramide Catalysis in the Asymmetric Detrifluoroacetylative Alkylation Reactions

An enantioselective bifunctional squaramide-catalyzed detrifluoroacetylative alkylation reaction has been developed under electrochemical conditions. The unified strategy based on this key tandem methodology has been divergently explored for the asymmetric synthesis of fluorine-containing target molecules with good stereocontrol (up to 95 % ee). Furthermore, this asymmetric catalytic reaction combines the benefits of electrosynthesis and organocatalysis for the preparation of biologically relevant products containing C-F tertiary stereogenic centers.     

Enantioselective Continuous‐Flow Production of 3‐Indolylmethanamines Mediated by an Immobilized Phosphoric Acid Catalyst

A polystyrene‐supported 1,1’‐bi‐2‐naphthol derived phosphoric acid has been synthesized and applied in the enantioselective Friedel–Crafts reaction of indoles and sulfonylimines. The immobilized catalyst was highly active and selective, and gave rise to a broad range of 3‐indolylmethanamines (19 examples) in high yields and excellent enantioselectivities (up to 98 % enantiomeric excess) after short reaction times under very convenient reaction conditions (RT in dichloromethane). Moreover, repeated recycling (14 cycles) was possible with no substantial loss in catalytic performance and the system could be adapted to a continuous‐flow operation (6 h). Finally, the applicability of the system was further confirmed by rapid access to a library of compounds with three points of diversity in a single continuous‐flow experiment that involved sequential pumping of different substrate combinations.     

Catalytic and Mechanistic Developments of the Nickel(II) Pincer Complex-Catalyzed Hydroarsination Reaction

Synthetic challenges have significantly slowed the development of the catalytic asymmetric hydroarsination reaction despite it being a highly attractive C−As bond formation methodology. In addition, there is a poor understanding of the main reaction steps in such reactions which limit further development in the field. Herein, key intermediates of the hydroarsination reaction catalyzed by a PCP Ni^II-Cl pincer complex are presented upon investigating the reaction with DFT calculations, conductivity measurements, NMR spectroscopy, and catalytic screening. The novel Ni–Cl–As interaction proposed was then contrasted against known Ni^II-catalyzed hydrophosphination reactions to highlight dissimilarities between them even though P and As share a close group relationship. Lastly, the asymmetric hydroarsination of nitroolefins was further developed to furnish a library of chiral organoarsines in up to 99 % yield and 80 % ee under mild conditions (−20 °C to RT) between 5 to 210 mins.     

Merging Aerobic Oxidation and Enamine Catalysis in the Asymmetric α‐Amination of β‐Ketocarbonyls Using N‐Hydroxycarbamates as Nitrogen Sources

We describe herein an unprecedented asymmetric α‐amination of β‐ketocarbonyls under aerobic conditions. The process is enabled by a simple chiral primary amine through the coupling of a catalytic enamine ester intermediate and a nitrosocarbonyl (generated in situ) derived from N‐hydroxycarbamate. The reaction features high chemoselectivity and excellent enantioselectivity for a broad range of substrates.     

Asymmetric Dearomative Fluorination of 2-Naphthols with a Dicarboxylate Phase-Transfer Catalyst

A linked dicarboxylate phase-transfer catalyst enables smooth asymmetric dearomative fluorination of 2-naphthols with Selectfluor under mild conditions to give the corresponding 1-fluoronaphthalenone derivatives in a highly enantioselective manner. This reaction, which is compatible with a range of functional groups, is the first example of catalytic asymmetric fluorination of 2-naphthols, and is expected to be useful in the synthesis of bioactive molecules.     

Biphasic asymmetric hydroformylation and hydrogenation by water-soluble rhodium and ruthenium complexes of sulfonated (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl in ionic liquids

A biphasic catalytic system with water-soluble rhodium complexes of sulfonated (R)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (labeled as (R)-BINAPS) in ionic liquid BMI·BF₄ has been developed for the asymmetric hydroformylation of vinyl acetate under mild conditions. The corresponding ruthenium complexes have been investigated for the biphasic asymmetric hydrogenation of dimethyl itaconate. The biphasic asymmetric hydroformylation of vinyl acetate provided 28.2% conversion and 55.2% enantiomeric excess when BMI·BF₄–toluene was used as the reaction medium at 333 K and 1.0 MPa for 24 h. The biphasic asymmetric hydrogenation of dimethyl itaconate in BMI·BF₄–ⁱPrOH at 333 K and 2.0 MPa afforded 65% enantiomeric excess with an activity similar to the homogenous analogs. Both biphasic catalytic systems with (R)-BINAPS ligand could be reused several times without significantly decrease in the activity, enantio- and regio-selectivities. The effects of properties of ionic liquid, molar ratio of ligand to rhodium, temperature, pressure and reaction time have been discussed.     

Asymmetric Dearomative Fluorination of 2‐Naphthols with a Dicarboxylate Phase‐Transfer Catalyst

A linked dicarboxylate phase‐transfer catalyst enables smooth asymmetric dearomative fluorination of 2‐naphthols with Selectfluor under mild conditions to give the corresponding 1‐fluoronaphthalenone derivatives in a highly enantioselective manner. This reaction, which is compatible with a range of functional groups, is the first example of catalytic asymmetric fluorination of 2‐naphthols, and is expected to be useful in the synthesis of bioactive molecules.     

Continuous‐Flow Synthesis and Derivatization of Aziridines through Palladium‐Catalyzed C(sp3)−H Activation

A continuous‐flow synthesis of aziridines by palladium‐catalyzed C(sp³)?H activation is described. The new flow reaction could be combined with an aziridine‐ring‐opening reaction to give highly functionalized aliphatic amines through a consecutive process. A predictive mechanistic model was developed and used to design the C?H activation flow process and illustrates an approach towards first‐principles design based on novel catalytic reactions.     

Catalytic Asymmetric Dearomatization of Indolyl Dihydropyridines through an Enamine Isomerization/Spirocyclization/Transfer Hydrogenation Sequence

A highly efficient synthesis of enantioenriched spiroindolines by catalytic asymmetric dearomatization of indolyl dihydropyridines through a chiral phosphoric acid catalyzed enamine isomerization/spirocyclization/transfer hydrogenation sequence has been developed. This reaction proceeds under mild reaction conditions, affording novel spiroindolines in good yields (up to 88 %) with excellent enantioselectivity (up to 97 % ee). DFT calculations provide insights into the reaction mechanism as well as the origin of stereochemistry.     

Stereospecific Asymmetric Synthesis of Tertiary Allylic Alcohol Derivatives by Catalytic [2,3]‐Meisenheimer Rearrangements

Chiral acyclic tertiary allylic alcohols are very important synthetic building blocks, but their enantioselective synthesis is often challenging. A major limitation in catalytic asymmetric 1,2‐addition approaches to ketones is the enantioface differentiation by steric distinction of both ketone residues. Herein we report the development of a catalytic asymmetric Meisenheimer rearrangement to overcome this problem, as it proceeds in a stereospecific manner. This allows for high enantioselectivity also for the formation of products in which the residues at the generated tetrasubstituted stereocenter display a similar steric demand. Low catalyst loadings were found to be sufficient and the reaction conditions were mild enough to tolerate even highly reactive functional groups, such as an enolizable aldehyde, a primary tosylate, or an epoxide. Our investigations suggest an intramolecular rearrangement pathway.     

Asymmetric Catalysis with Heterobimetallic Compounds

This review focuses on a new concept in catalytic asymmetric reactions that was first realized for the use of heterobimetallic complexes. As these heterobimetallic complexes function as both a Brønsted base and as a Lewis acid, just like an enzyme, they make possible a variety of efficient catalytic asymmetric reactions. This heterobimetallic concept should prove to be applicable to a variety of new asymmetric catalyses. The first part of this review describes the development of rare-earth–alkali metal complexes such as LnM₃tris(binaphthoxide) complexes (LnMB, Ln = rare-earth metal, M = alkali metal), which are readily prepared from the corresponding rare-earth trichlorides or rare-earth isopropoxides, and their application to catalytic asymmetric synthesis. By using a catalytic amount of LnMB complexes several asymmetric reactions proceed efficiently to give the corresponding desired products in up to 98% ee: LnLB-catalyzed asymmetric nitroaldol reactions (L = Li), LnSB-catalyzed asymmetric Michael reactions (S ? Na), and LnPB-catalyzed asymmetric hydrophosphonylations of either imines or aldehydes (P ? K). Applications of these heterobimetallic catalysts to the syntheses of several biologically and medicinally important compounds are also described. Spectral analyses and computational simulations of the asymmetric reactions catalyzed by the heterobimetallic complexes reveal that the two different metals play different roles to enhance the reactivity of both reaction partners and to position them. From mechanistic considerations, a useful activation of the heterobimetallic catalyses was realized by addition of alkali metal reagents. The second part describes the development of another type of heterobimetallic catalysts featuring Group 13 elements such as Al and Ga as the central metal. Among them, the AlLibis(binaphthoxide) complex (ALB) is an effective catalyst for asymmetric Michael reactions, tandem Michael–aldol reactions, and hydrophosphonylation of aldehydes.     

Catalytic Enantioselective and Regioselective [3+3] Cycloadditions Using 2‐Indolylmethanols as 3 C Building Blocks

The first catalytic asymmetric cycloaddition using 2‐indolylmethanols as 3C building blocks has been established by a chiral phosphoric acid‐catalyzed enantioselective and regioselective [3+3] cycloaddition of 2‐indolylmethanols with azomethine ylides, which constructed biologically important tetrahydro‐γ‐carboline frameworks in high yields and excellent enantioselectivities (up to 83 % yield, 99:1 e.r.). This reaction not only represents the first application of 2‐indolylmethanols as 3C building blocks in catalytic asymmetric cycloadditions, but also has established an abnormal regioselectivity in indolylmethanol‐involved transformations.     

Chiral‐Zn(NTf2)2‐Complex‐Catalyzed Diastereo‐ and Enantioselective Direct Conjugate Addition of Arylacetonitriles to Alkylidene Malonates

Chiral N,N′‐dioxide/Zn(NTf₂)₂ complexes were demonstrated to be highly effective in the direct asymmetric conjugate addition of arylacetonitriles to alkylidene malonates under mild conditions. A wide range of substrates were tolerated to afford their corresponding products in moderate‐to‐good yields with high diastereoselectivities (82:18–>99:1 d.r.) and enantioselectivities (81–99 % ee). The reactions performed well, owing to the high Lewis acidity of the metal triflimidate and a ligand‐acceleration effect. The N,N′‐dioxide also benefited the deprotonation process as a Brønsted base. The catalytic reaction could be performed on the gram‐scale with retention of yield, diastereoselectivity, and enantioselectivity. The products that contained functional groups were ready for further manipulation. In addition, a possible catalytic model was proposed to explain the origin of the asymmetric induction.