Amine Additives Greatly Expand the Scope of Asymmetric Hydrosilylation of Imines

Slow addition of a primary amine to the reaction mixture greatly increases the scope of the titanium-catalyzed asymmetric reduction of imines 1 . An important added feature of this method is that chiral secondary amines 2 can be obtained in much higher optical purity (up to 99 % ee) than would be predicted from the E:Z ratios of the starting imines 1 .     

Desymmetrization of 1,4‐Pentadien‐3‐ol by the Asymmetric 1,3‐Dipolar Cycloaddition of Azomethine Imines

Desymmetrization of the divinyl carbinol 1,4‐pentadien‐3‐ol was accomplished by the asymmetric 1,3‐dipolar cycloaddition of azomethine imines based on a magnesium‐mediated, multinucleating chiral reaction system utilizing diisopropyl (R,R)‐tartrate as the chiral auxiliary. The corresponding optically active trans‐pyrazolidines, each with three contiguous stereogenic centers, were obtained with excellent regio‐, diastereo‐, and enantioselectivity, with results as high as 99 % ee. This reaction was shown to be applicable to both aryl‐ and alkyl‐substituted azomethine imines. The use of a catalytic amount of diisopropyl (R,R)‐tartrate was also effective when accompanied by the addition of MgBr₂.     

Iridium‐Catalyzed Asymmetric Hydrogenation of Imines

We have evaluated a wide range of iridium complexes derived from chiral oxazoline‐based N,P ligands for the asymmetric hydrogenation of imines and identified three efficient catalysts. These catalysts are readily synthesized by straightforward convenient routes and are air and moisture stable. In the reduction of acetophenone N‐arylimines and related acyclic substrates, excellent enantioselectivities (up to 96 % ee) were obtained by using 0.1–0.5 mol % of catalyst at ?20 °C and 5–50 bar hydrogen pressure.     

Organocatalytic asymmetric [3 + 3] annulation of isatin N,N'-cyclic azomethine imines with enals: Efficient approach to functionalized spiro N-heterocyclic oxindoles

An unprecedented chiral secondary amine-catalyzed [3 + 3] annulation of isatin N,N'-cyclic azomethine imines with α,β-unsaturated aldehydes was developed. This strategy allowed the construction of structurally novel spiro N-heterocyclic oxindole derivatives in good yields (up to 91%) and good to excellent enantioselectivities (up to >99% ee), albeit with modest diastereoselectivities (up to 3.1:1 dr).     

A Powerful Chiral Phosphoric Acid Catalyst for Enantioselective Mukaiyama–Mannich Reactions

A new BINOL‐derived chiral phosphoric acid bearing 2,4,6‐trimethyl‐3,5‐dinitrophenyl substituents at the 3,3′‐positions was developed. The utility of this chiral phosphoric acid is demonstrated by a highly enantioselective (ee up to >99 %) and diastereoselective (syn/anti up to >99:1) asymmetric Mukaiyama–Mannich reaction of imines with a wide range of ketene silyl acetals. Moreover, this method was successfully applied to the construction of vicinal tertiary and quaternary stereogenic centers with excellent diastereo‐ and enantioselectivity. Significantly, BINOL‐derived N‐triflyl phosphoramide constitutes a complementary catalyst system that allows the title reaction to be applied to more challenging imines without an N‐(2‐hydroxyphenyl) moiety.     

Nickel(II)‐Catalyzed Enantioselective 1,3‐Dipolar Cycloaddition of Azomethine Imines with Alkylidene Malonates

We demonstrated an asymmetric 1,3‐dipolar cycloaddition of azomethine betaines with alkylidene malonates by using a chiral N,N′‐dioxide–Ni^II complex as a catalyst. Both aromatic‐ and aliphatic‐substituted alkylidene malonates were found to be suitable for the reaction. A range of trans‐pyrazolone derivatives was exclusively obtained with excellent yields (up to 99 % yield) and good enantioselectivities (up to 97 % ee) under mild reaction conditions. The reaction could be carried out on a gram scale with the good results being maintained. Control experiments were performed to elucidate the specific diastereoselectivity of the reaction. The formation of single trans isomers was dominated by secondary orbital interactions between the ester groups of the dipolarophile and the azomethine imine. On the basis of the experimental results and previous reports, a possible catalytic model was assumed.     

Enantioselective Construction of Vicinal Tetrasubstituted Stereocenters by the Mannich Reaction of Silyl Ketene Imines with Isatin‐Derived Ketimines

A highly enantioselective Mannich reaction of silyl ketene imines with isatin‐derived ketimines has been realized by using a chiral N,N′‐dioxide/Zn^II catalyst. A variety of β‐amino nitriles containing congested vicinal tetrasubstituted stereocenters were obtained with excellent outcomes (up to 98 % yield, >19:1 d.r. and 99 % ee). Based on the experimental investigations, a possible transition state has been proposed to explain the origin of the asymmetric induction.     

Catalytic Biomimetic Asymmetric Reduction of Alkenes and Imines Enabled by Chiral and Regenerable NAD(P)H Models

The development of biomimetic chemistry based on the NAD(P)H with hydrogen gas as terminal reductant is a long‐standing challenge. Through rational design of the chiral and regenerable NAD(P)H analogues based on planar‐chiral ferrocene, a biomimetic asymmetric reduction has been realized using bench‐stable Lewis acids as transfer catalysts. A broad set of alkenes and imines could be reduced with up to 98 % yield and 98 % ee, likely enabled by enzyme‐like cooperative bifunctional activation. This reaction represents the first general biomimetic asymmetric reduction (BMAR) process enabled by chiral and regenerable NAD(P)H analogues. This concept demonstrates catalytic utility of a chiral coenzyme NAD(P)H in asymmetric catalysis.     

Self‐Supported Chiral Titanium Cluster (SCTC) as a Robust Catalyst for the Asymmetric Cyanation of Imines under Batch and Continuous Flow at Room Temperature

A robust heterogeneous self‐supported chiral titanium cluster (SCTC) catalyst and its application in the enantioselective imine‐cyanation/Strecker reaction is described under batch and continuous processes. One of the major hurdles in the asymmetric Strecker reaction is the lack of availability of efficient and reusable heterogeneous catalysts that work at room temperature. We exploited the readily hydrolyzable nature of titanium alkoxide to synthesize a self‐supported chiral titanium cluster (SCTC) catalyst by the controlled hydrolysis of a preformed chiral titanium‐alkoxide complex. The isolated SCTC catalysts were remarkably stable and showed up to 98 % enantioselectivity (ee) with complete conversion of the imine within 2 h for a wide variety of imines at room temperature. The heterogeneous catalysts were recyclable more than 10 times without any loss in activity or selectivity. The robustness, high performance, and recyclability of the catalyst enabled it to be used in a packed‐bed reactor to carry out the cyanation under continuous flow. Up to 97 % ee and quantitative conversion with a throughput of 45 mg h^?1 were achieved under optimized flow conditions at room temperature in the case of benzhydryl imine. Furthermore, a three‐component Strecker reaction was performed under continuous flow by using the corresponding aldehydes and amines instead of the preformed imines. A good product distribution was obtained for the formation of amino nitriles with ee values of up to 98 %. Synthetically useful ee values were also obtained for challenging α‐branched aliphatic aldehyde by using the three‐component continuous Strecker reaction.     

Chiral Bis(imidazolidine)‐Derived NCN Pincer Rh Complex for Catalytic Asymmetric Mannich Reaction of Malononitrile with N‐Boc Imines

Chiral bis(imidazolidine)‐derived NCN–rhodium complexes ([PhBidine‐RhX₂] and [tBu‐PhBidine‐RhX₂]) were prepared by a C?H insertion method, and the structures were unequivocally determined by X‐ray crystallographic analysis. The [tBu‐PhBidine‐Rh(OAc)₂] complex smoothly catalyzed an asymmetric Mannich reaction of malononitrile with N‐Boc imines to give products in up to 94 % ee, which are useful for the synthesis of chiral α‐amino acids.     

Kinetic resolutions of azomethine imines via copper-catalyzed [3 + 2] cycloadditions

An effective method has been developed for the kinetic resolution of racemic azomethine imines via [3 + 2] cycloadditions with alkynes catalyzed by a chiral copper complex. Efficient kinetic resolution is observed for a variety of N1 and C5 substituents on the dipole, thereby furnishing a wide array of useful enantioenriched azomethine imines, which can readily be transformed into monocyclic and bicyclic pyrazolidinones.     

Chiral N,O‐Ligand/[Cu(OAc)2]‐Catalyzed Asymmetric Construction of 4‐Aminopyrrolidine Derivatives by 1,3‐Dipolar Cycloaddition of Azomethine Ylides with α‐Phthalimidoacrylates

A protocol to access useful 4‐aminopyrrolidine‐2,4‐dicarboxylate derivatives has been developed. A variety of chiral N,O‐ligands derived from 2,3‐dihydroimidazo[1,2‐a]pyridine motifs have been evaluated in the asymmetric 1,3‐dipolar cycloaddition of azomethine ylides to α‐phthalimidoacrylates. Reactions catalyzed by copper in combination with ligand 7‐Cl‐DHIPOH provided the highest level of stereoselectivity for the 1,3‐dipolar cycloaddition reaction. The reaction tolerates both β‐substituted and β‐unsubstituted α‐phthalimidoacrylate as dipolarophiles, affording the corresponding quaternary 4‐aminopyrrolidine cycloadducts with excellent diastereo‐ (>98:2 d.r.) and enantioselectivities (up to 97 % ee). Removal of the phthalimido protecting group can be accomplished by a simple NaBH₄ reduction. Theoretical calculations employing DFT methods show this cycloaddition reaction is likely to proceed through a stepwise mechanism and the stereochemistry was also theoretically rationalized.     

Asymmetric Synthesis of Bicyclic Pyrazolidinones through Alkaloid-Catalyzed [3+2]-Cycloadditions of Ketenes and Azomethine Imines

A versatile asymmetric synthesis of bicyclic pyrazolidinones through alkaloid-catalyzed formal [3+2]- and [3+2+2]-cycloadditions of ketenes with azomethine imines is described. The methodology was found to be tolerant of ketene and a variety of monosubstituted ketenes (R=alkyl, OAc). The products were formed in good to excellent yields (71–99 % for 24 examples, 39 examples in all), with good to excellent diastereoselectivity in many cases (dr 3 : 1 to 27 : 1 for 22 examples), and with excellent enantioselectivity for most examples (≥93 % ee for 34 products). In the case of most disubstituted ketenes, the reaction proceeded through a [3+2+2]-cycloaddition to form structurally interesting bicyclic pyrazolo-oxadiazepinediones with moderate diastereoselectivity (dr up to 3.7 : 1) and as racemic mixtures (3 examples). The method represents the first unambiguous example of an enantioselective reaction between ketenes and a 1,3-dipole.     

Stereo‐ and Chemodivergent NHC‐Promoted Functionalisation of Arylalkylketenes with Chloral

Stereo‐ and chemodivergent enantioselective reaction pathways are observed upon treatment of alkylarylketenes and trichloroacetaldehyde (chloral) with N‐heterocyclic carbenes, giving selectively either β‐lactones (up to 88:12 dr, up to 94 % ee) or α‐chloroesters (up to 94 % ee). Either 2‐arylsubstitution or an α‐branched iPr alkyl substituent within the ketene favours the chlorination pathway, allowing chloral to be used as an electrophilic chlorinating reagent in asymmetric catalysis.     

Organocatalytic Asymmetric Mannich-Type Reaction of Isocyanoacetates with N-(2-Benzothiazolyl)imines

An organocatalytic asymmetric synthesis of directly linked benzothiazole-dihydroimidazoles with two adjacent tertiary-quaternary stereocenters through a Mannich-type reaction of isocyanoacetates with N-(2-benzothiazolyl)imines is disclosed. When employing bifunctional dihydroquinine-derived squaramide as catalyst, moderate to excellent yields (up to 97 % yield), moderate diastereoselectivities and excellent enantioselectivities (up to >99 % ee) were obtained for a variety of substrates. In addition, the transformation of the resulted directly linked benzothiazole-dihydroimidazole into highly functionalized α,β-diamino esters was also demonstrated.     

Deracemization By Simultaneous Bio‐oxidative Kinetic Resolution and Stereoinversion

Deracemization, that is, the transformation of a racemate into a single product enantiomer with theoretically 100 % conversion and 100 % ee, is an appealing but also challenging option for asymmetric synthesis. Herein a novel chemo‐enzymatic deracemization concept by a cascade is described: the pathway involves two enantioselective oxidation steps and one non‐stereoselective reduction step, enabling stereoinversion and a simultaneous kinetic resolution. The concept was exemplified for the transformation of rac‐benzylisoquinolines to optically pure (S)‐berbines. The racemic substrates were transformed to optically pure products (ee>97 %) with up to 98 % conversion and up to 88 % yield of isolated product.     

Catalytic Atroposelective Synthesis of Axially Chiral Azomethine Imines and Neuroprotective Activity Evaluation

Azomethine imines, as a prominent class of 1,3-dipolar species, hold great significance and potential in organic and medicinal chemistry. However, the reported synthesis of centrally chiral azomethine imines relies on kinetic resolution, and the construction of axially chiral azomethine imines remains unexplored. Herein, we present the synthesis of axially chiral azomethine imines through copper- or chiral phosphoric acid catalyzed ring-closure reactions of N′-(2-alkynylbenzylidene)hydrazides, showcasing high efficiency, mild conditions, broad substrate scope, and excellent enantioselectivity. Furthermore, the biological evaluation revealed that the synthesized axially chiral azomethine imines effectively protect dorsal root ganglia (DRG) neurons by inhibiting apoptosis induced by oxaliplatin, offering a promising therapeutic approach for chemotherapy-induced peripheral neuropathy (CIPN). Remarkably, the (S)- and (R)-atropisomers displayed distinct neuroprotective activities, underscoring the significance of axial stereochemistry.     

Organocatalytic Enantioselective Conia‐Ene‐Type Carbocyclization of Ynamide Cyclohexanones: Regiodivergent Synthesis of Morphans and Normorphans

Described herein is an organocatalytic enantioselective desymmetrizing cycloisomerization of arylsulfonyl‐protected ynamide cyclohexanones, representing the first metal‐free asymmetric Conia‐ene‐type carbocyclization. This method allows the highly efficient and atom‐economical construction of a range of valuable morphans with wide substrate scope and excellent enantioselectivity (up to 97 % ee). In addition, such a cycloisomerization of alkylsulfonyl‐protected ynamide cyclohexanones can lead to the divergent synthesis of normorphans as the main products with high enantioselectivity (up to 90 % ee). Moreover, theoretical calculations are employed to elucidate the origins of regioselectivity and enantioselectivity.     

Solvent‐Dependent Asymmetric Synthesis of Alkynyl and Monofluoroalkenyl Isoindolinones by CpRhIII‐Catalyzed C−H Activation

The asymmetric synthesis of alkynyl and monofluoroalkenyl isoindolinones from N‐methoxy benzamides and α,α‐difluoromethylene alkynes is enabled by C?H activation with a chiral CpRh^III catalyst. Remarkably, product formation is solvent‐dependent; alkynyl isoindolinones are afforded in MeOH (up to 86 % yield, 99.6 % ee) whereas monofluoroalkenyl isoindolinones are generated in ⁱPrCN (up to 98:2 Z/E, 93 % yield, 86 % ee). Mechanistic studies revealed chiral allene and E‐configured alkenyl rhodium species as reaction intermediates. The latter is transformed into the corresponding Z‐configured monofluoroalkene upon protonation in the ⁱPrCN system and into an alkyne by an unusual anti β‐F elimination in the MeOH system. Notably, kinetic resolution processes occur in this reaction. Despite the moderate enantiocontrol for the formation of the chiral allene, the Z‐monofluoroalkenyl isoindolinones and alkynyl isoindolinones were obtained in good enantiopurities by one or two sequential kinetic resolution processes.     

Asymmetric Synthesis of 2,3‐Dihydropyrroles by Ring‐Opening/Cyclization of Cyclopropyl Ketones Using Primary Amines

The asymmetric ring‐opening/cyclization of cyclopropyl ketones with primary amine nucleophiles was catalyzed by a chiral N,N′‐dioxide/scandium(III) complex through a kinetic resolution process. A broad range of cyclopropyl ketones and primary amines are suitable substrates of this reaction. The corresponding products were afforded in excellent enantioselectivities and yields (up to 97 % ee and 98 % yield) under mild reaction conditions. This method provides a promising access to chiral 2,3‐dihydropyrroles as well as an effective procedure for the kinetic resolution of 2‐substituted cyclopropyl ketones.