Excellent Enantioselectivities Research Articles

Asymmetric 1,4-Addition of Diarylphosphine Oxides to α, β-Unsaturated 2-Acyl Imidazoles.

Here we introduce a metal-free, catalytic and enantioselective strategy from α,β-unsaturated 2-acyl imidazoles to the chiral phosphorous 2-acyl imidazoles. Interestingly, this methodology was catalyzed by the classical and commercial oxazaborolidine under mild conditions. This strategy features a wide range of substrates scope with good yields and excellent enantioselectivities. The possible mechanism further suggests the key of this reaction through the cleavage of diarylphosphine oxides using Frustrated Lewis Pairs theory.

Regioselective and Enantioselective Nickel-Catalyzed Intermolecular Reductive Coupling of Aliphatic Alkenes with Imines.

Unactivated aliphatic alkenes are particularly desirable as starting materials because they are readily accessible in large quantities, but the enantioselective intermolecular reductive coupling of unactivated alkenes with imines is challenging. In this paper, we report a method for nickel-catalyzed intermolecular reductive coupling reactions between aliphatic alkenes and imines to yield chiral amines with excellent enantioselectivities and good linear selectivities. The reaction conditions are compatible with a broad range of aliphatic alkenes, including those derived from bioactive molecules. The success of this method can be attributed to the use of newly developed monodentate chiral spiro phosphine ligands.

Organocatalytic skeletal reorganization for enantioselective synthesis of S-stereogenic sulfinamides

The enantioselective synthesis of S-stereogenic sulfinamides has garnered considerable attention due to their structural and physicochemical properties. However, catalytic asymmetric synthesis of sulfinamides still remains daunting challenges, impeding their broad application in drug discovery and development. Here, we present an approach for the synthesis of S-stereogenic sulfinamides through peptide-mimic phosphonium salt-catalyzed asymmetric skeletal reorganization of simple prochiral and/or racemic sulfoximines. This methodology allows for the facile access to a diverse array of substituted sulfinamides with excellent enantioselectivities, accommodating various substituent patterns through desymmetrization or parallel kinetic resolution process. Mechanistic experiments, coupled with density functional theory calculations, clarify a stepwise pathway involving ring-opening and ring-closing processes, with the ring-opening step identified as crucial for achieving stereoselective control. Given the prevalence of S-stereogenic centers in pharmaceuticals, we anticipate that this protocol will enhance the efficient and precise synthesis of relevant chiral molecules and their analogs, thereby contributing to advancements in drug discovery.

Catalytic (4+2) Annulation via Regio- and Enantioselective Interception of in-situ Generated Alkylgold Intermediate.

A regio- and stereoselective stepwise (4+2) annulation of N-propargylamides and α,β-unsaturated imines/ketones has been accomplished with synergetic catalysis by a combination of a gold-complex and a chiral quinine-derived squaramide (QN-SQA), leading to highly functionalized chiral tetrahydropyridines/dihydropyrans in good to high yields with generally excellent enantioselectivity. Mechanistic studies and DFT calculations indicate that the in-situ formed alkylgold species is the key intermediate in this transformation, and the amide group served as a traceless directing group in this highly selective transformation. This method complements the enantioselective (4+2) annulation of allene reagents, providing the formal internal C-C π-bond cycloaddition products, which is challenging and remains elusive.

Co-Immobilization of ADH and GDH on Metal-Organic-Framework: An Effective Biocatalyst for Asymmetric Reduction of Ketones.

Chiral alcohols are not only important building blocks of various bioactive natural compounds and pharmaceuticals, but can serve as synthetic precursors for other valuable organic chemicals, thus the synthesis of these products is of great importance. Bio-catalysis represents one effective way to obtain these molecules, however, the weak stability and high cost of enzymes often hinder its broad application. In this work, we designed a biological nanoreactor by embedding alcohol dehydrogenase (ADH) and glucose dehydrogenase (GDH) in metal-organic-framework ZIF-8. The biocatalyst ADH&GDH@ZIF-8 could be applied to the asymmetric reduction of a series of ketones to give chiral alcohols in high yields (up to 99 %) and with excellent enantioselectivities (>99 %). In addition, the heterogeneous biocatalyst could be recycled and reused at least four times with slight activity decline. Moreover, E. coli containing ADH and GDH was immobilized by ZIF-8 to form biocatalyst E. coli@ZIF-8, which also exhibits good catalytic behaviours. Finally, the chiral alcohols are further converted to marketed drugs (R)-Fendiline, (S)-Rivastigmine and NPS R-568 respectively.

Asymmetric 1,n‐Remote Aminoacetoxylation of Unactivated Internal Alkenes Enabled by Palladium Catalysis**

A palladium ‐catalyzed asymmetric 1,n‐remote aminoacetoxylation of cis‐alkenes has been developed using PhI(OAc)2 as oxidant, providing the acetoxylated lactams with excellent enantioselectivities under mild reaction conditions. The sterically hindered pyridine‐oxazoline (Pyox) L3 with a tert‐butyl group in oxazoline ring and propyl group in C6 position of pyridinyl is vital for the reaction, where the former is good for asymmetric aminopalladation step and the latter for the chain walking process. The enantioenriched lactam products were proven to be good building blocks for the synthesis of azabicycles.

Asymmetric 1,n-Remote Aminoacetoxylation of Unactivated Internal Alkenes Enabled by Palladium Catalysis*.

A palladium -catalyzed asymmetric 1,n-remote aminoacetoxylation of cis-alkenes has been developed using PhI(OAc)2 as oxidant, providing the acetoxylated lactams with excellent enantioselectivities under mild reaction conditions. The sterically hindered pyridine-oxazoline (Pyox) L3 with a tert-butyl group in oxazoline ring and propyl group in C6 position of pyridinyl is vital for the reaction, where the former is good for asymmetric aminopalladation step and the latter for the chain walking process. The enantioenriched lactam products were proven to be good building blocks for the synthesis of azabicycles.

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.

Ionic Hydrogen Bond-Assisted Catalytic Construction of Nitrogen Stereogenic Center via Formal Desymmetrization of Remote Diols.

The control of noncarbon stereogenic centers is of profound importance owing to their enormous interest in bioactive compounds and chiral catalyst or ligand design for enantioselective synthesis. Despite various elegant approaches have been achieved for construction of S-, P-, Si- and B-stereocenters over the past decades, the catalyst-controlled strategies to govern the formation of N-stereogenic compounds have garnered less attention. Here, we disclose the first organocatalytic approach for efficient access to a wide range of nitrogen-stereogenic compounds through a desymmetrization approach. Intriguingly, the pro-chiral remote diols, which are previously not well addressed with enantiocontrol, are well differentiated by potent chiral carbene-bound acyl azolium intermediates. Preliminary studies shed insights on the critical importance of the ionic hydrogen bond (IHB) formed between the dimer aggregate of diols to afford the chiral N-oxide products that feature a tetrahedral nitrogen as the sole stereogenic element with good yields and excellent enantioselectivities. Notably, the chiral N-oxide products could offer an attractive strategy for chiral ligand design and discovery of potential antibacterial agrochemicals.

Ionic Hydrogen Bond‐Assisted Catalytic Construction of Nitrogen Stereogenic Center via Formal Desymmetrization of Remote Diols

The control of noncarbon stereogenic centers is of profound importance owing to their enormous interest in bioactive compounds and chiral catalyst or ligand design for enantioselective synthesis. Despite various elegant approaches have been achieved for construction of S‐, P‐, Si‐ and B‐stereocenters over the past decades, the catalyst‐controlled strategies to govern the formation of N‐stereogenic compounds have garnered less attention. Here, we disclose the first organocatalytic approach for efficient access to a wide range of nitrogen‐stereogenic compounds through a desymmetrization approach. Intriguingly, the pro‐chiral remote diols, which are previously not well addressed with enantiocontrol, are well differentiated by potent chiral carbene‐bound acyl azolium intermediates. Preliminary studies shed insights on the critical importance of the ionic hydrogen bond (IHB) formed between the dimer aggregate of diols to afford the chiral N‐oxide products that feature a tetrahedral nitrogen as the sole stereogenic element with good yields and excellent enantioselectivities. Notably, the chiral N‐oxide products could offer an attractive strategy for chiral ligand design and discovery of potential antibacterial agrochemicals.

Enantioselective Access to β-Amino Carbonyls via Ni-Catalyzed Formal Olefin Hydroamidation.

We herein describe a Ni-catalyzed formal hydroamidation of readily available α,β-unsaturated carbonyl compounds to afford valuable chiral β-amino acid derivatives (up to >99:1 e.r.) using dioxazolones as a robust amino source. A wide range of alkyl-substituted olefins conjugated to esters, amides, thioesters, and ketones were successfully amidated at the β-position with excellent enantioselectivity for the first time. Combined experimental and computational mechanistic studies supported our working hypothesis that this unconventional β-amidation of unsaturated carbonyl substrates can be attributed to the polar-matched migratory olefin insertion of an (amido)(Cl)NiII intermediate, in situ generated from the dioxazolone precursor.

Enantioselective Alkylation of Aldehydes with Organoborons Enabled by Nickel/N‐Heterocyclic Carbene Catalysis†

Comprehensive SummaryTransition‐metal‐catalyzed asymmetric alkylation of aldehydes represents a straightforward strategy for the synthesis of chiral secondary alcohols. However, efficient methods using organoborons as coupling reagents are rare. Herein, we report a highly enantioselective nickel‐catalyzed alkylation reaction of aldehydes, using readily available alkylborons as nucleophiles. A wide variety of chiral secondary alcohols were prepared from commercially available aldehydes with high yields. The key to the excellent enantioselectivity and chemoselectivity was the employment of a bulky C2‐symmetric chiral NHC ligand. This protocol features excellent enantiocontrol, mild conditions, and good functional group compatibility.

Enantioselective Dearomatization of Pyridinium Salts by Copper‐Catalyzed C4‐Selective Addition of Silicon Nucleophiles

A copper‐catalyzed C4‐selective addition of silicon nucleophiles released from an Si–B reagent to prochiral pyridinium triflates is reported. The dearomatization proceeds with excellent enantioselectivity using Cu(CH3CN)4PF6 as the precatalyst and (R,R)‐Ph‐BPE as the chiral ligand. A carbonyl group at C3 is required, likely acting a weak group to preorganize and direct the nucleophilc attack towards C4. The resulting 4‐silylated 1,4‐dihydropyridines can be further converted into functionalized piperidine derivatives.

Enantioselective Dearomatization of Pyridinium Salts by Copper-Catalyzed C4-Selective Addition of Silicon Nucleophiles.

A copper-catalyzed C4-selective addition of silicon nucleophiles released from an Si-B reagent to prochiral pyridinium triflates is reported. The dearomatization proceeds with excellent enantioselectivity using Cu(CH3CN)4PF6 as the precatalyst and (R,R)-Ph-BPE as the chiral ligand. A carbonyl group at C3 is required, likely acting a weak group to preorganize and direct the nucleophilc attack towards C4. The resulting 4-silylated 1,4-dihydropyridines can be further converted into functionalized piperidine derivatives.

Pd-catalyzed asymmetric Larock reaction for the atroposelective synthesis of N─N chiral indoles.

Atropisomeric indoles defined by a N─N axis are an important class of heterocycles in synthetic and medicinal chemistry and material sciences. However, they remain heavily underexplored due to limited synthetic methods and challenging stereocontrol over the short N─N bonds. Here, we report highly atroposelective access to N─N axially chiral indoles via the asymmetric Larock reaction. This protocol leveraged the powerful role of chiral phosphoramidite ligand to attenuate the common ligand dissociation in the original Larock reaction, forming N─N chiral indoles with excellent functional group tolerance and high enantioselectivity via palladium-catalyzed intermolecular annulation between readily available o-iodoaniline and alkynes. The multifunctionality in the prepared chiral indoles allowed diverse post-coupling synthetic transformations, affording a broad array of functionalized chiral indoles. Experimental and computational studies have been conducted to explore the reaction mechanism, elucidating the enantio-determining and rate-limiting steps.

Switchable divergent synthesis of chiral indole derivatives via catalytic asymmetric dearomatization of 2,3-disubstituted indoles.

A strategy allowing the switchable divergent synthesis of chiral indole derivatives was established via chiral phosphoric acid-catalyzed asymmetric dearomatization of 2,3-disubstituted indoles using naphthoquinone monoimines as electrophiles. The products were switched between chiral indolenines and fused indolines according to the post-processing conditions. Both two types of products were obtained in good to high yields with generally excellent enantioselectivities. NaBH4 was found to work as a promoter as well as a reductant in the cyclization process leading to fused indolines.

Atroposelective Construction of Naphthylpyrazoles by Chiral Phosphoric Acid Catalyzed Enantioselective Cross‐Coupling of Pyrazoles with Naphthoquinone Esters

AbstractThe catalytic asymmetric reaction of 5‐aminopyrazoles with naphthoquinone esters has been established. A wide range of unprecedented axially chiral naphthylpyrazole derivatives (29 examples) have been synthesized in moderate to excellent yields (up to 99 % yield) with excellent enantioselectivities (up to 99 % ee) by utilizing chiral phosphoric acid as a catalyst. This protocol features mild reaction conditions, a broad substrate scope, good scalability and facile derivatization. Moreover, preliminary mechanistic investigation was conducted to elucidate the mechanism.

De novo Synthesis of Chiral 3,4‐DihydroquinazolinesviaOne‐Pot Enantioselective Ugi‐Azide/Cyclization Sequences†

Comprehensive SummaryHerein, we reported a precise de novo synthesis of chiral 3,4‐dihydroquinazoline frameworks via a one‐pot anionic stereogenic‐at‐cobalt(III) complex‐catalyzed enantioselective Ugi‐azide/Pd‐catalyzed cyclization sequence. This powerful protocol involves 5 components and 2 catalytic systems, delivering chiral 3,4‐dihydroquinazolines with excellent enantioselectivities (up to 94% ee). The preliminary antifungal experiments suggest that both Ugi‐adducts and 3,4‐dihydroquinazolines have great potential in inhibiting plant pathogens such as Trichoderma viride and Fusarium graminearum.

Sparteine Thiourea: The Synthesis of an N Chiral Bispidine-Quinolizidine-Derived Organocatalyst and Applications in Asymmetric Synthesis of Dihydropyrano[c]chromenes.

Bispidine, a bridged bicyclic diamine, has been widely utilized as a rigid scaffold in chiral chelating ligands in asymmetric synthesis. In particular, a chiral bispidine-quinolizidine hybrid, such as sparteine, was utilized in asymmetric synthesis involving a metal, exhibiting superior catalytic activity. In this study, we report the design and synthesis of a series of sparteine-derived organocatalysts and the utilization of these catalysts in tandem Michael addition-cyclization reactions. These catalysts have shown excellent catalytic reactivity and enantioselectivity, and the corresponding dihydropyrano[c]chromenes have been prepared in ≤99% yield and ≤99% ee with a low catalyst loading. The recycled catalysts maintain a good catalytic performance even after four cycles, and a gram-scale reaction with a 1% catalyst loading is also performed, providing the product in 96% yield and 98% ee.

Design of 3D-Printed Heterogeneous Reactor Systems To Overcome Incompatibility Hurdles when Combining Metal and Enzyme Catalysis in a One-Pot Process.

Combining chemo- and biocatalysis enables the design of novel economic and sustainable one-pot processes for the preparation of industrial chemicals, preferably proceeding in water. While a range of proofs-of-concept for the compatibility of such catalysts from these two different "worlds of catalysis" have recently been demonstrated, merging noncompatible chemo- and biocatalysts for joint applications within one reactor remained a challenge. A conceptual solution is compartmentalization of the catalytic moieties by heterogenization of critical catalyst components, thus "shielding" them from the complementary noncompatible catalyst, substrate or reagent. Exemplified for a one-pot process consisting of a metal-catalyzed Wacker oxidation and enzymatic reduction as noncompatible individual reactions steps, we demonstrate that making use of 3D printing of heterogeneous materials containing Cu as a critical metal component can overcome such incompatibility hurdles. The application of a 3D-printed Cu-ceramic device as metal catalyst component allows an efficient combination with the enzyme and the desired two-step transformation of styrene into the chiral alcohol product with high overall conversion and excellent enantioselectivity. This compartmentalization concept based on 3D printing of heterogenized metal catalysts represents a scalable methodology and opens up numerous perspectives to be used as a general tool also for other related chemoenzymatic research challenges.