Chiral Ligands Research Articles

Enantioselective remote methylene C-H (hetero)arylation of cycloalkane carboxylic acids.

Stereoselective construction of γ- and δ-stereocenters in carbonyl compounds is a pivotal objective in asymmetric synthesis. Here, we report chiral bifunctional oxazoline-pyridone ligands that enable enantioselective palladium-catalyzed remote γ-C-H (hetero)arylations of free cycloalkane carboxylic acids, which are essential carbocyclic building blocks in organic synthesis. The reaction establishes γ-tertiary and α-quaternary stereocenters simultaneously in up to >99% enantiomeric excess, providing access to a wide range of cyclic chiral synthons and bioactive molecules. The sequential enantioselective editing of two methylene C-H bonds can be achieved by using chiral ligands with opposite configuration to construct carbocycles containing three chiral centers. Enantioselective remote δ-C-H (hetero)arylation is also realized to establish δ-stereocenters that are particularly challenging to access using classical methodologies.

Chiroptical Activity Amplification of Chiral Metal Nanoclusters via Surface/Interface Solidification.

It remains a grand challenge to amplify the chiroptical activity of chiral metal nanoclusters (NCs) although it is desirable for fundamental research and practical application. Herein, we report a strategy of surface/interface solidification (SIS) for enhancing the chiroptical activity of gold NCs. Structural analysis of [Au19(2R,4R/2S,4S-BDPP)6Cl2]3+ (BDPP is 2,4-bis(diphenylphosphino)pentane) clusters reveals that one of the interfacial gold atoms is flexible between two sites and large space is present on the surface, thus hampering chirality transfer from surface chiral ligands to metal core and leading to low chiroptical activity. Following SIS by filling the flexible sites and replacing chlorides with thiolate ligands affords another pair of [Au20(2R,4R/2S,4S-BDPP)6(4-F-C6H4S)2]4+, which shows a more compact and organized structure and thus an almost 40-fold enhancement of chiroptical activity. This work not only provides an efficient approach for amplifying the chiroptical activity of metal nanoclusters but also highlights the significance of achiral components in shaping chiral nanostructures.

Enantioselective Synthesis of Heteroatom-Linked Non-Biaryl Atropisomers.

Atropisomers hold significant fascination, not only for their prevalence in natural compounds but also for their biological importance and wide-ranging applications as chiral materials, ligands, and organocatalysts. While biaryl and heterobiaryl atropisomers are commonly studied, the enantioselective synthesis of less abundant heteroatom-linked non-biaryl atropisomers presents a formidable challenge in modern organic synthesis. Unlike classical atropisomers, these molecules allow rotation around two bonds, resulting in low barriers to enantiomerization through concerted bond rotations. In recent years the discovery of new configurationally stable rare non-biaryl scaffolds such as aryl amines, aryl ethers and aryl sulfones as well as innovative methodologies to control their configuration have been disclosed in the literature and constitute the topic of this minireview.

Enantioselective Synthesis of Heteroatom‐Linked Non‐Biaryl Atropisomers

Atropisomers hold significant fascination, not only for their prevalence in natural compounds but also for their biological importance and wide‐ranging applications as chiral materials, ligands, and organocatalysts. While biaryl and heterobiaryl atropisomers are commonly studied, the enantioselective synthesis of less abundant heteroatom‐linked non‐biaryl atropisomers presents a formidable challenge in modern organic synthesis. Unlike classical atropisomers, these molecules allow rotation around two bonds, resulting in low barriers to enantiomerization through concerted bond rotations. In recent years the discovery of new configurationally stable rare non‐biaryl scaffolds such as aryl amines, aryl ethers and aryl sulfones as well as innovative methodologies to control their configuration have been disclosed in the literature and constitute the topic of this minireview.

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.

Asymmetric Transfer Hydrogenation of Stable NH Imines for the Synthesis of Enantiopure α‐Chiral Primary Amines

Asymmetric Transfer Hydrogenation of Stable <scp>NH</scp> Imines for the Synthesis of Enantiopure <scp>α‐Chiral</scp> Primary Amines

Carbene-Catalyzed Atroposelective Construction of Chiral Diaryl Ethers.

Atropoisomeric chemotypes of diaryl ethers-related scaffolds are prevalent in naturally active compounds. Nevertheless, there remains considerable research to be carried out on the catalytic asymmetric synthesis of these axially chiral molecules. In this instance, we disclose an N-heterocyclic carbene (NHC)-catalyzed synthesis of axially chiral diaryl ethers via atroposelective esterification of dialdehyde-containing diaryl ethers. NHC desymmetrization produces axially chiral diaryl ether atropisomers with high yields and enantioselectivities in moderate circumstances. Chiral diaryl ether compounds may be precursors for highly functionalized diaryl ethers with bioactivity and chiral ligands for asymmetric catalysis.

Pd-Catalyzed Enantioselective Desymmetrizing 1,7-Enyne Cycloisomerization of Alkyne-Tethered Cyclopentenes.

An enantioselective Pd-catalyzed intramolecular desymmetrizing cycloisomerization of N-(cyclopent-3-en-1-yl)propiolamides has been developed by employing a new chiral phosphoramidite ligand. A series of structurally unique bridged azabicycles are achieved in moderate to excellent yields with good E/Z selectivity and high enantioselectivity. Synthetic transformations are conducted to demonstrate the practical utility of this reaction.

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.

Recent advances in catalytic asymmetric synthesis

Asymmetric catalysis stands at the forefront of modern chemistry, serving as a cornerstone for the efficient creation of enantiopure chiral molecules characterized by their high selectivity. In this review, we delve into the realm of asymmetric catalytic reactions, which spans various methodologies, each contributing to the broader landscape of the enantioselective synthesis of chiral molecules. Transition metals play a central role as catalysts for a wide range of transformations with chiral ligands such as phosphines, N-heterocyclic carbenes (NHCs), etc., facilitating the formation of chiral C-C and C-X bonds, enabling precise control over stereochemistry. Enantioselective photocatalytic reactions leverage the power of light as a driving force for the synthesis of chiral molecules. Asymmetric electrocatalysis has emerged as a sustainable approach, being both atom-efficient and environmentally friendly, while offering a versatile toolkit for enantioselective reductions and oxidations. Biocatalysis relies on nature’s most efficient catalysts, i.e., enzymes, to provide exquisite selectivity, as well as a high tolerance for diverse functional groups under mild conditions. Thus, enzymatic optical resolution, kinetic resolution and dynamic kinetic resolution have revolutionized the production of enantiopure compounds. Enantioselective organocatalysis uses metal-free organocatalysts, consisting of modular chiral phosphorus, sulfur and nitrogen components, facilitating remarkably efficient and diverse enantioselective transformations. Additionally, unlocking traditionally unreactive C-H bonds through selective functionalization has expanded the arsenal of catalytic asymmetric synthesis, enabling the efficient and atom-economical construction of enantiopure chiral molecules. Incorporating flow chemistry into asymmetric catalysis has been transformative, as continuous flow systems provide precise control over reaction conditions, enhancing the efficiency and facilitating optimization. Researchers are increasingly adopting hybrid approaches that combine multiple strategies synergistically to tackle complex synthetic challenges. This convergence holds great promise, propelling the field of asymmetric catalysis forward and facilitating the efficient construction of complex molecules in enantiopure form. As these methodologies evolve and complement one another, they push the boundaries of what can be accomplished in catalytic asymmetric synthesis, leading to the discovery of novel, highly selective transformations which may lead to groundbreaking applications across various industries.

Chiral Heterometallic Cu8Ln4 Complexes with Enantiopure Schiff Base Ligands: Synthesis, Structural, Spectroscopic and Magnetic Studies.

The enantiomerically pure Schiff base ligands H2L-S and H2L-R yield chiral heterometallic dodecanuclear complexes of the form [Cu8Ln4(OH)8(OMe)4(O2CBut)8(L-S or L-R)4(H2O)4] where LnIII=Gd (1S), Tb (2S), Dy (3S, 3R), Ho (4S, 4R), Er (5S) or Y (6S, 6R) and H2L=(S or R)-2-{[(1-hydroxypropan-2-yl)imino]methyl}-6-methoxyphenol. The complexes are isomorphous and crystallize in the non-centrosymmetric polar space group C2 in enantiomeric conformation. The chirality of the Schiff base ligands originates from the respective S- or R- enantiomer of 2-aminopropan-1-ol, is imparted to the complexes and to the crystals that belong to non-centrosymmetric space group. The chirality and enantiomeric conformation of all complexes are retained in dmso solutions as confirmed by Circular Dichroism spectra which consist of mirror images, expected for enantiomeric pairs. All complexes consist of four distorted cubane-like subunits [Cu2Ln2(μ3-OH)2(μ3-OMe)(μ3-OR)], which share the LnIII ions and result in a cyclic distorted tetragonal arrangement; each edge of the {LnIII 4} quadrilateral is occupied by two μ-OH- ions that further bridge to a CuII ion. Magnetic susceptibility measurements revealed ferromagnetic interactions for 3S with LnIII=Dy and antiferromagnetic interactions for all other complexes. AC susceptibility data of 3S under 1 kOe external dc field indicate slow magnetic relaxation phenomena below 2 K.

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.

Chiral Self-Sorting, Spontaneous Resolution, and Hierarchical Self-Assembly in Metal-Organic Cages.

The ability to collectively program chiral recognition and the hierarchical self-assembly of molecular and supramolecular building blocks into complex higher-order superstructures is a significant goal in supramolecular chemistry. Metal-organic cages are excellent model systems to examine chiral self-sorting and build hierarchical self-assembly. Herein, details on how limiting the conformational flexibility and incorporating hydrogen bonding functional groups in the ligands can influence chiral self-sorting and hierarchical self-assembly of metal-organic cages are reported. The urea-functionalized axially chiral bis-pyridyl ligands afford high-fidelity in chiral self-sorting in Pd2L4 cages, when they have fewer conformations. Ligand L1, with more conformations, affords mixture of heterochiral and homochiral cages (≈70:30). Among them, the heterochiral cage adopts unusual twisted conformation and self-assembles into 2D sheets, linked by anion coordination between urea and nitrate. Ligand L2, with fewer conformations, affords homochiral cages via high-fidelity chiral self-sorting. The choice of counter anions influences further self-sorting in the solid state: racemate with PF6 - and spontaneously resolves conglomerate with BF4 -. Urea-BF4 hydrogen bonding directs hierarchical self-assembly of the Pd2L4 metal-organic cages into super-cubic networks. The study introduces a new approach in hierarchical self-assembly of metal-organic cages into higher-order networks aided by hydrogen bonding anion coordination with functional ligands.

Oxidovanadium(V) Schiff Base Complexes Derived from Chiral 3-amino-1,2-propanediol Enantiomers: Synthesis, Spectroscopic Studies, Catalytic and Biological Activity.

Oxidovanadium(V) complexes, [(+)VOL1-5] and [(-)VOL1-5], with chiral tetradentate Schiff bases, which are products of monocondensation of S(‒)-3-amino-1,2-propanediol or R(+)-3-amino-1,2-propanediol with salicylaldehyde derivatives, have been synthesized. Different spectroscopic methods, viz. 1H and 51V NMR, IR, UV-Vis, and circular dichroism, as well as elemental analysis, have been used for their detailed characterization. Furthermore, the epoxidation of styrene, cyclohexene, and two monoterpenes, S(‒)-limonene and (‒)-α-pinene, using two oxidants, aqueous 30% H2O2 or tert-butyl hydroperoxide (TBHP) in decane, has been studied with catalytic amounts of all complexes. Finally, biological cytotoxicity studies have also been performed with these oxidovanadium(V) compounds for comparison with cis-dioxidomolybdenum(VI) Schiff base complexes with the same chiral ligands, as well as to determine the cytoprotection against the oxidative damage caused by 30% H2O2 in the HT-22 hippocampal neuronal cells in the range of their 10-100 μM concentration.

ß‐Phenethylamine Synthesis via Latent Dual Electrophilicity of N‐Pyridinium Aziridines

ß‐Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N‐pyridinium aziridines as latent dual electrophiles for the synthesis of ß‐phenethylamines. Bromide‐promoted ring opening generates ß‐halopyridinium amines. Selective Ni‐catalyzed C–C cross‐coupling between organozinc nucleophiles and the benzylic C–Br electrophile affords a diverse family of ß‐functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni‐catalyzed reductive N–N bond activation within the b‐functionalized phenethylamino‐pyridinium salts furnishes the products of formal olefin carboamination. Other reductive N–N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N‐centered radical chemistry. The developed reaction sequence can be implemented in the context of complex molecules and natural product derivatives. Together, the described results provide a general and modular synthesis of ß‐phenethylamines and significantly expand the utility of N‐pyridinium aziridines as linchpins in chemical synthesis

ß-Phenethylamine Synthesis via Latent Dual Electrophilicity of N-Pyridinium Aziridines.

ß-Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N-pyridinium aziridines as latent dual electrophiles for the synthesis of ß-phenethylamines. Bromide-promoted ring opening generates ß-halopyridinium amines. Selective Ni-catalyzed C-C cross-coupling between organozinc nucleophiles and the benzylic C-Br electrophile affords a diverse family of ß-functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni-catalyzed reductive N-N bond activation within the b-functionalized phenethylamino-pyridinium salts furnishes the products of formal olefin carboamination. Other reductive N-N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N-centered radical chemistry. The developed reaction sequence can be implemented in the context of complex molecules and natural product derivatives. Together, the described results provide a general and modular synthesis of ß-phenethylamines and significantly expand the utility of N-pyridinium aziridines as linchpins in chemical synthesis.