Enantioselective Catalysis Research Articles

Catalytic Enantioselective Synthesis of Axially Chiral Imidazoles by Cation-Directed Desymmetrization.

Axially chiral five-membered heterobiaryls synthesized by enantioselective catalysis typically feature large ortho-substituents or a heteroatom in the chiral axis to maintain a stable configuration. Herein we report a cation-directed catalytic enantioselective desymmetrization method that enables rapid access to axially chiral imidazoles with the basic nitrogen at the ortho position and efficiently integrates π-stacking moieties to ensure a stable axial configuration for further applications. The process is operationally simple, is highly enantioselective, and can be performed on the gram scale. The majority of the products are obtained in >90% ee, but interestingly even those with only moderate ee can readily be enriched to near optical purity by selective racemate crystallization. Together with a mild phosphine oxide reduction method, axially chiral imidazoles such as StackPhos and its derivatives are readily prepared in high yield and excellent enantioselectivity on the gram scale. The method also enables the preparation of new chiral non-phosphine-bearing imidazoles.

Desymmetrization and Parallel Kinetic Resolution of 1-Ethynylcyclobutanols via Asymmetric Cooperative Gold Catalysis.

Enantioselective gold catalysis remains a challenging area of research. By harnessing gold-ligand cooperation in the presence of a chiral bifunctional phosphine ligand featuring a novel 3'-phosphine oxide moiety, highly enantioselective desymmetrization of 1-ethynylcyclobutanols is achieved, permitting access to chiral α-methylenecyclopentanones featuring a diverse array of chiral quaternary and tertiary centers. This cooperative gold catalysis also enables parallel kinetic resolution in gold catalysis, delivering cyclopentanone regioisomers with excellent enantiomeric excesses. DFT calculations of the transition states support the distinct mechanism of asymmetric induction via controlling the conformation of the bound substrate and hence dictating the ring bond undergoing migration.

Atroposelective Synthesis of Planar-Chiral Indoles via Carbene Catalyzed Macrocyclization.

Indole-based planar-chiral macrocycles are widely found in natural products and bioactive molecules. However, in sharp contrast to the preparation of indole-based axially chiral structures, the enantioselective catalysis of indole-based planar-chiral macrocycles is still a formidable task so far. Here we report an N-heterocyclic carbene (NHC)-catalyzed intramolecular atroposelective macrocyclization of 3-carboxaldehyde indole/pyrroles, featuring with broad substrate scope and good functional group tolerance, and allowing for a rapid access to diverse indole/pyrrole-based planar-chiral macrocycles with various tether-lengths (10-16 members) in good yields and with excellent enantioselectivities. Importantly, the indole-based macrocyclic structures with both planar and axial chirality were directly and efficiently obtained through this protocol with excellent enantioselectivities and diastereoselectivities. In addition, these synthesized planar-chiral macrocycles offer many possibilities for chemists to develop new catalysts or ligands, as well as new reactions.

Atroposelective Synthesis of Planar‐Chiral Indoles via Carbene Catalyzed Macrocyclization

AbstractIndole‐based planar‐chiral macrocycles are widely found in natural products and bioactive molecules. However, in sharp contrast to the preparation of indole‐based axially chiral structures, the enantioselective catalysis of indole‐based planar‐chiral macrocycles is still a formidable task so far. Here we report an N‐heterocyclic carbene (NHC)‐catalyzed intramolecular atroposelective macrocyclization of 3‐carboxaldehyde indole/pyrroles, featuring with broad substrate scope and good functional group tolerance, and allowing for a rapid access to diverse indole/pyrrole‐based planar‐chiral macrocycles with various tether‐lengths (10–16 members) in good yields and with excellent enantioselectivities. Importantly, the indole‐based macrocyclic structures with both planar and axial chirality were directly and efficiently obtained through this protocol with excellent enantioselectivities and diastereoselectivities. In addition, these synthesized planar‐chiral macrocycles offer many possibilities for chemists to develop new catalysts or ligands, as well as new reactions.

Planar Chiral Rhodium Complex Based on the Tetrahydrofluorenyl Core for Enantioselective Catalysis.

A simple four-step route to a chiral tetrahydrofluorenyl rhodium catalyst from naturally occurring (-)-α-pinene was developed. Our approach does not use multistep and time-consuming procedures such as chiral HPLC or diastereomeric resolution. The key to success lies in the face-selective coordination of rhodium to the sterically hindered tetrahydrofluorenyl ligand, giving only one diastereomeric complex. This catalyst proved to be highly efficient for asymmetric C-H annulation of aryl hydroxamates with alkenes (yield up to 95%, 91% ee) at low loading (up to 0.4 mol % based on Rh).

Geometric Control and Optical Properties of Intrinsically Chiral Plasmonic Nanomaterials.

Intrinsically chiral plasmonic nanomaterials exhibit intriguing geometry-dependent chiroptical properties, which is due to the combination of plasmonic features with geometric chirality. Thus, chiral plasmonic nanomaterials have become promising candidates for applications in biosensing, asymmetric catalysis, biomedicine, photonics, etc. Recent advances in geometric control and optical tuning of intrinsically chiral plasmonic nanomaterials have further opened up a unique opportunity for their widespread applications in many emerging technological areas. Here, the recent developments in the geometric control of chiral plasmonic nanomaterials are reviewed with special attention given to the quantitative understanding of the chiroptical structure-property relationship. Several important optical spectroscopic tools for characterizing the optical chirality of plasmonic nanomaterials at both ensemble and single-particle levels are also discussed. Three emerging applications of chiral plasmonic nanomaterials, including enantioselective sensing, enantioselective catalysis, and biomedicine, are further highlighted. It is envisioned that these advanced studies in chiral plasmonic nanomaterials will pave the way toward the rational design of chiral nanomaterials with desired optical properties for diverse emerging technological applications.

Bottom‐Up Assembly of Inorganic Particle‐Based Chiroptical Materials

AbstractChiral artificial nanosystems constructed from inorganic nanoparticles brought about a paradigm shift in chiral sensing, enantioselective catalysis, chiral polarization engineering, and chiral emission due to their strong light–matter interaction and their precisely engineered properties. Especially bottom‐up approaches hold great potential for the inexpensive, scalable production of plasmonic, excitonic, and upconversion chiral materials. This perspective first reviews the state‐of‐the‐art fabrication schemes: chiral molecule‐induced chirality, chiral nanoparticle growth, and assembly of chiral superstructures from achiral building blocks. Next, the emerging field of dynamically tunable chiroptical materials, promising for adaptive thin‐film optics, display technologies, and information encoding, is explored. Here, the strength of chiral assemblies based on their rich tuning mechanisms and their ability for geometrical reconfiguration is highlighted. Finally, promising future directions and opportunities in the field of active chiroptical materials are discussed.

Catalytic Enantioselective Nucleophilic Addition to Arynes by a New Quaternary Guanidinium Salt-Based Phase-Transfer Catalyst.

Owing to the mild generation methods, arynes have been widely used in synthetic chemistry. However, achieving asymmetric organocatalytic reactions with arynes remains a formidable and infrequent challenge, primarily because these neutral and transient species tend to spontaneously quench. To address this issue, a solid-liquid phase-transfer strategy is devised in which the generation speed of arynes could be controlled by the in situ generated fluoride-based chiral phase-transfer catalyst. In this study, we present a catalytic enantioselective nucleophilic addition reaction involving arynes, utilizing an amino amide-based guanidinium salt QG•X. Furthermore, we demonstrate the broad compatibility of this reaction with various arynes and cyclic/acyclic β-keto amides, leading to the creation of diverse α-aryl quaternary stereocenters with good stereoselectivity. Mechanistic investigations have uncovered the potential involvement of a chiral intramolecular cationic-anionic pair and HF during the ion exchange between QG•X and CsF for nucleophile activation and aryne generation. Additionally, DFT calculations suggested that the observed high levels of enantioselectivity can be attributed to steric repulsion and the cumulative noncovalent interactions between the catalysts and substrates.

Ligating Catalytically Active Peptides onto Microporous Polymers: A General Route Toward Specifically-Functional High Surface Area Platforms.

A versatile post-synthetic modification strategy to functionalize a high surface area microporous network (MPN-OH) by bio-orthogonal inverse electron-demand Diels-Alder (IEDDA) ligation is presented. While the polymer matrix is modified with a readily accessible norbornene isocyanate (Nor-NCO), a series of functional units presenting the robust asymmetric 1,2,4,5-tetrazine (Tz) allows easy functionalization of the MPN by chemoselective Nor/Tz ligation. A generic route is demonstrated, modulating the internal interfaces by introducing carboxylates, amides or amino acids as well as an oligopeptide d-Pro-Pro-Glu organocatalyst. The MPN-Pz-Peptide construct largely retains the catalytic activity and selectivity in an enantioselective enamine catalysis, demonstrates remarkable availability in different solvents, offers heterogeneous organocatalysis in bulk and shows stability in recycling settings.

Interplay of Computation and Experiment in Enantioselective Catalysis: Rationalization, Prediction, and─Correction?

Interplay of Computation and Experiment in Enantioselective Catalysis: Rationalization, Prediction, and─Correction?

Inverse design of chiral functional films by a robotic AI-guided system

Artificial chiral materials and nanostructures with strong and tuneable chiroptical activities, including sign, magnitude, and wavelength distribution, are useful owing to their potential applications in chiral sensing, enantioselective catalysis, and chiroptical devices. Thus, the inverse design and customized manufacturing of these materials is highly desirable. Here, we use an artificial intelligence (AI) guided robotic chemist to accurately predict chiroptical activities from the experimental absorption spectra and structure/process parameters, and generate chiral films with targeted chiroptical activities across the full visible spectrum. The robotic AI-chemist carries out the entire process, including chiral film construction, characterization, and testing. A machine learned reverse design model using spectrum embedded descriptors is developed to predict optimal structure/process parameters for any targeted chiroptical property. A series of chiral films with a dissymmetry factor as high as 1.9 (gabs ~ 1.9) are identified out of more than 100 million possible structures, and their feasible application in circular polarization-selective color filters for multiplex laser display and switchable circularly polarized (CP) luminescence is demonstrated. Our findings not only provide chiral films with the highest reported chiroptical activity, but also have great fundamental value for the inverse design of chiroptical materials.

Highly Enantioselective Synthesis of Pharmaceuticals at Chiral-Encoded Metal Surfaces.

Enantioselective catalysis is of crucial importance in modern chemistry and pharmaceutical science. Although various concepts have been used for the development of enantioselective catalysts to obtain highly pure chiral compounds, most of them are based on homogeneous catalytic systems. Recently, we successfully developed nanostructured metal layers imprinted with chiral information, which were applied as electrocatalysts for the enantioselective synthesis of chiral model compounds. However, so far such materials have not been employed as heterogeneous catalysts for the enantioselective synthesis of real pharmaceutical products. In this contribution, we report the asymmetric synthesis of chiral pharmaceuticals (CPs) with chiral imprinted Pt-Ir surfaces as a simple hydrogenation catalyst. By fine-tuning the experimental parameters, a very high enantioselectivity (up to 95 % enantiomeric excess) with good catalyst stability can be achieved. The designed materials were also successfully used as catalytically active stationary phases for the continuous asymmetric flow synthesis of pharmaceutical compounds. This illustrates the possibility of producing real chiral pharmaceuticals at such nanostructured metal surfaces for the first time.

Total synthesis of [13 C2 ]-labeled phytosiderophores of the mugineic and avenic acid families.

We, herein, report the synthesis of 13 C2 -labeled natural products from the mugineic acid and avenic acid family. These phytosiderophores ("plant iron carriers") are built up from non-proteinogenic amino acids and play a key role in micronutrient uptake in gramineous plants. In this work, two central building blocks are prepared from labeled starting materials (13 C2 -bromoacetic acid, 13 C2 -glycine) and further employed in our recently reported divergent, branched synthetic strategy delivering eight isotopically labeled phytosiderophores. The required labeled building blocks (13 C2 -l-allylglycine and a related hydroxylated derivative) were prepared via enantioselective phase-transfer catalysis and enantio- and diastereoselective aldol condensation with a chiral auxiliary, respectively, both potentially valuable themselves for other synthetic routes toward labeled (natural) products.

Diastereodivergent Catalysis.

Alongside enantioselective catalysis, synthetic chemists are often confronted by the challenge of achieving catalyst control over the relative configuration to stereodivergently access desired diastereomers. Typically, these approaches iteratively or simultaneously control multiple stereogenic units for which dual catalytic methods comprising sequential, relay, and synergistic catalysis emerged as particularly efficient strategies. In this Perspective, the benefits and challenges of catalyst-controlled diastereodivergence in the construction of carbon stereocenters are discussed on the basis of illustrative examples. The concepts are then transferred to diastereodivergent catalysis for atropisomeric systems with twofold and higher-order stereogenicity as well as diastereodivergent catalyst control over E- and Z-configured alkenes.

Advances in Versatile Chiral Ligands for Asymmetric Gold Catalysis

The formation of valuable chiral skeletons through asymmetric gold catalysis has made considerable progress due to the unrivaled affinity of gold complexes with multiple carbon–carbon bonds. The renaissance of chiral ligands in recent decades has enabled the elaborate design of chiral gold complexes, which are of great significance to control chiral formation in these catalytic reactions. Therefore, this review intends to highlight the design and central role of versatile chiral ligands in asymmetric gold catalysis. Specifically, the seminal applications of various chiral ligands with representative examples in various gold-catalyzed asymmetric reactions are comprehensively explored. In addition, the reaction mechanisms are mentioned when the crucial interactions between ligands and activated substrates are introduced. Furthermore, the applications of enantioselective gold catalysis in the construction of chiral functional organic materials and drug molecules are also presented.

Direct covalent immobilizaion of chiral phosphines to hollow mesoporous polystyrene nanospheres (HMPNs) for efficient heterogeneous enantioselective [2+3] cycloaddition

Low-cost and convenient strategy for the direct covalent immobilizaion of chiral phosphines into structurally superior solid supports is desirable for efficient heterogeneous enantioselective catalysis. In this paper, a universal and convenient method for the direct covalent immobilization of chiral phosphines into HMPNs is developed via Friedel-Craft alkylation to fabricate supported chiral phosphines at a low cost. Using (S)-2,2´-bis(diphenylphosphino)-1,1´-binaphthyl [(S)-BINAP] and (R,R)-diphenylbis-[(o-anisyl)-methylenephosphine] [(R,R)-DIPAMP] as examples, the as-fabricated HMPNs-supported (S)-BINAP and (R,R)-DIPAMP, namely BINAP@HMPNs and DIPAMP@HMPNs, possess a well-shaped spherical morphology with hollow interior and thin mesoporous shell, enabling reactants to easily access to catalytic sites. In enantioselective [2+3] cycloaddition, DIPAMP@HMPNs exhibits good yields (70–86 %) with excellent enantioselectivities (94–98 %ee). Furthermore, DIPAMP@HMPNs shows a good mechanical stability of spherical morphology and mesoporous structure in its reuses. Moreover, the oxidation of DIPAMP leads to the gradual deactivation of DIPAMP@HMPNs including yield and enantioselectivity, which can be restored by the reduction of tetramethyldisiloxane (TMDS)/Ti(OiPr)4.

Design and Synthesis of Spirochroman‐2‐on‐4,1'‐indan‐7'‐ol and Its Application for Synthesizing Chiral Monophosphinite Ligands†

Comprehensive SummaryThe design and synthesis of spirochroman‐2‐on‐4,1'‐indan‐7'‐ol (SCIOL) and its application for synthesizing chiral monophosphinite ligands are reported. The synthesis features a tandem double Friedel‐Crafts reaction/lactonization to construct the spiro framework and the desired racemic SCIOL was obtained via 6 steps with a total yield of 44.5%. Using an inclusion resolution with N‐benzylcinchonidinium chloride, the optical SCIOL could be obtained in good yields on a gram scale. The preliminary studies indicated that the corresponding chiral spiro monophosphinite ligands exhibit high catalytic activity and enantioselectivity (up to 94% ee) in the rhodium‐catalyzed asymmetric hydrogenation of N‐acetyl dehydroamino esters. These outcomes highlight the significant potential of SCIOL as a useful framework for the development of chiral spiro ligands.

Turning on Asymmetric Catalysis of Achiral Metal-Organic Frameworks by Imparting Chiral Microenvironment.

The development of heterogeneous asymmetric catalysts has attracted increasing interest in synthetic chemistry but mostly relies on the immobilization of homogeneous chiral catalysts. Herein, a series of chiral metal-organic frameworks (MOFs) have been fabricated by anchoring similar chiral hydroxylated molecules (catalytically inactive) with different lengths onto Zr-oxo clusters in achiral PCN-222(Cu). The resulting chiral MOFs exhibit regulated enantioselectivity up to 83 % ee in the asymmetric ring-opening of cyclohexene oxide. The chiral molecules furnished onto the catalytic Lewis sites in the MOF create multilevel microenvironment, including the hydrogen interaction between the substrate and the chiral -OH group, the steric hindrance endowed by the benzene ring on the chiral molecules, and the proximity between the catalytic sites and chiral molecules confined in the MOF pores, which play crucial roles and synergistically promote chiral catalysis. This work nicely achieves heterogeneous enantioselective catalysis by chiral microenvironment modulation around Lewis acid sites.

Turning on Asymmetric Catalysis of Achiral Metal‐Organic Frameworks by Imparting Chiral Microenvironment

AbstractThe development of heterogeneous asymmetric catalysts has attracted increasing interest in synthetic chemistry but mostly relies on the immobilization of homogeneous chiral catalysts. Herein, a series of chiral metal–organic frameworks (MOFs) have been fabricated by anchoring similar chiral hydroxylated molecules (catalytically inactive) with different lengths onto Zr‐oxo clusters in achiral PCN‐222(Cu). The resulting chiral MOFs exhibit regulated enantioselectivity up to 83 % ee in the asymmetric ring‐opening of cyclohexene oxide. The chiral molecules furnished onto the catalytic Lewis sites in the MOF create multilevel microenvironment, including the hydrogen interaction between the substrate and the chiral −OH group, the steric hindrance endowed by the benzene ring on the chiral molecules, and the proximity between the catalytic sites and chiral molecules confined in the MOF pores, which play crucial roles and synergistically promote chiral catalysis. This work nicely achieves heterogeneous enantioselective catalysis by chiral microenvironment modulation around Lewis acid sites.

Forging Medium Rings via I(I)/I(III)-Catalyzed Diene Carbofunctionalization.

A main-group catalysis-based strategy to access 8-membered carbocycles via the direct carbofunctionalization of 2-phenethyl-substituted 1,3-dienes is disclosed. Through the intervention of an I(I)/I(III) catalysis cycle, the synthesis of densely functionalized, fluorinated benzocyclooctenes can be achieved in an operationally simple manner. Modulating the oxidation/activation regime, and the external nucleophile, the process has been extended to unify the challenging cyclization with formation of allylic C-O, C-N, and C-C bonds (>30 examples). Derivatization of the product benzocyclooctenes is demonstrated together with X-ray conformational analysis, preliminary validation of enantioselective catalysis and a scalable resolution protocol.