High Enantioselectivity Research Articles

B(C6F5)3/CPA-Catalyzed Aza-Diels-Alder Reaction of 3,3-Difluoro-2-Aryl-3H-indoles and Unactivated Dienes.

Here we report B(C6F5)3/CPA-catalyzed enantioselective aza-Diels-Alder reaction of 3,3-difluoro-2-Aryl-3H-indoles with unactivated dienes to access chiral 10,10-difluoro-tetrahydropyrido[1,2-a]indoles. This protocol allows the formation of pyrazole-based C2-quaternary indolin-3-ones with high enantioselectivities and regioselectivities. Moreover, gram-scale synthesis of the 10,10-difluoro-tetrahydropyrido[1,2-a]indole skeleton was successfully achieved without any reduction in both yield and enantioselectivity.

Electrochemical Asymmetric Radical Functionalization of Aldehydes Enabled by a Redox Shuttle.

Aminocatalysis is a well-established tool that enables the production of enantioenriched compounds under mild conditions. Its versatility is underscored by its seamless integration with various synthetic approaches. While the combination of aminocatalysis with metal catalysis, photochemistry, and stoichiometric oxidants has been extensively explored, its synergy with electrochemical activation remains largely unexplored. Herein, we present the successful merger of electrochemistry and aminocatalysis to perform SOMO-type transformations, expanding the toolkit for asymmetric electrochemical synthesis. The methodology harnesses electricity to drive the oxidation of catalytically generated enamines, which ultimately partake in enantioselective radical processes, leading to α-alkylated aldehydes. Crucially, mechanistic studies highlight how this electrochemical strategy is enabled by the use of a redox shuttle, 4,4'-dimethoxybiphenyl, to prevent catalyst degradation and furnishing the coveted compounds in good yield and high enantioselectivity.

Catalytic Eoconvergent C(sp3)−N Coupling to Access Chiral Amines: A Concept Review

AbstractNitrogen containing compounds like chiral amines have been widely used in synthetic medicines, biomass, and fine chemical products because of their particularly valuable motifs and exceedingly broad range of functionality. Enantioconvergent synthesis of chiral amines has high atomic economy and enantioselectivity with theoretically 100 % yield of enantioenriched products. In this concept article, we hope to provide a further understanding of chiral amines enantioconvergent synthesis methodology with an introduction of recent progresses in enantioconvergent amination reactions catalyzed by early transition metals and facilitate the development of enantioconvergent C(sp3)−N coupling for benign and efficient preparation of highly valuable chiral nitrogen‐containing units.

Chiral P,N,N‐Ligands for Asymmetric Hydrogenation

The chiral P,N,N‐ligands represented a new type of tridentate ligand developed in recent years and displayed wide utilities in asymmetric catalysis. In the past decades, numerous chiral P,N,N‐ligands with ferrocene, phenethylamine and spiro backbones were synthesized by addition of an aminopyridine, imidazole or diamines coordinating group. These chiral tridentate P,N,N‐ligands showed excellent performance in the ruthenium, iridium, manganese, or cobalt‐catalyzed asymmetric hydrogenations. A wide range of substrates, including simple ketones, α‐halogenated ketones, α‐hydroxy ketones, α‐ or β‐amino ketones, α‐, γ‐, or δ‐keto acids, α‐ or β‐keto amides, β‐ or δ‐keto esters, α‐ or β‐enones, olefins, imines, quinolines and indoles, could be hydrogenated to afford the corresponding chiral products with high yields and enantioselectivities. In this review, progress on the asymmetric hydrogenation of C=O, C=N, C=C bonds with chiral tridentate P,N,N‐ligands was summarized.

Insights into the Enantioselective Au(I)‐Catalyzed Reactions between 2‐Alkynyl Ketones and Naphthols using the TCDC approach

The CPAPhosAuCl bifunctional complexes catalyse the enantioselective tandem cycloisomerization‐nucleophilic addition reactions between 2‐alkynylenones and naphthols, where naphthols behave mainly as O‐nucleophiles. The inherent acidity of the catalysts induces then the isomerization of the O‐addition‐ into the C‐addition products with concomitant decrease of their enantiomeric excesses. In depth mechanistic studies have provided insights into these processes. Subsequently, the undesired racemization pathways could be suppressed by using substituted naphthols as nucleophiles, which delivered a large series of chiral bicyclic furanes in high enantioselectivities.

Enantioselective and Band-Gap Modulation in Photocatalysis of Metal-Free Chiral Carbon Dots.

Photodriven chiral catalysis is the combination of photocatalysis and chiral catalysis and is considered one of the cleanest and most efficient methods for the synthesis of chiral compounds or drugs. Furthermore, due to the potential metal contamination associated with most metal-based catalysts, metal-free chiral photocatalysts are ideal candidates. In this work, we demonstrate that metal-free chiral carbon dots (CDs) exhibit size-dependent enantioselective photocatalytic activity. Using serine as the raw material, chiral CDs with well-defined structures and average sizes of 2.22, 3.01, 3.70, 4.77, and 7.21 nm were synthesized using the electrochemical method. These chiral CDs possess size-dependent band gaps and exhibit photoresponsive enantioselective catalytic activity toward the oxidation of dihydroxyphenylalanine (DOPA). Under light-assisted conditions, chiral CDs (L72, 500 μg/mL) exhibit high selectivity (selectivity factor: 2.07) and maintain a certain level of catalytic activity (1.34 μM/min) even at a low temperature of 5 °C. The high catalytic activity of the chiral CDs arises from their photoelectrons reducing O2 to generate O2-, as the active oxygen species for DOPA oxidation. The high enantioselectivity of the chiral CDs is attributed to their differential adsorption capabilities toward DOPA enantiomers. This study provides a new approach for designing metal-free chiral photocatalysts with high enantioselectivity.

Kinetic Resolution of Cyclic Tertiary Alcohols with Lipase A from Candida antarctica

Enzyme‐catalyzed acylative kinetic resolution (KR) and dynamic kinetic resolution (DKR) of racemic primary and secondary alcohols have been widely reported to produce esters with high enantiomeric purity. In contrast, similar KRs of tertiary alcohols have been reported for only a limited range of substrates and require prolonged reaction times of several days. To gain deeper insight into the substrate scope and increase the process efficiency, we examined the reaction conditions using commercially available immobilized lipase A from Candida antarctica and found that the addition of the heterogeneous, inorganic base sodium carbonate significantly increased the reaction rate while maintaining high enantioselectivity. The use of vinyl hexanoate as the acyl donor provided esters that were stable during chromatography purification. The optimized reaction conditions were then successfully applied to a range of cyclic tertiary alcohols containing tetralin, dihydroindene, chromane, and thiochromane skeletons having, in part, a substituent on the aromatic ring. In this study on the structure–reactivity relationship of enzymatic KR‐type reactions, we achieved >30% conversion for various tertiary alcohols in 24 h at 25 °C, producing optically active esters with 88–99% ee.

Copper-Catalyzed Enantioselective 1,2-Allylation of Azadienes with Allylboronates.

Catalytic asymmetric 1,2-allylation of aurone-derived azadienes is very difficult to achieve due to the driving force for aromatization and the greater steric hindrance of 1,2-addition compared with 1,4-addition. By taking advantage of the ability of nitrogen ligated metal complexes, we successfully demonstrated the first example of copper-catalyzed 1,2-allylation of azadienes with allylboronates for the highly enantioselective synthesis of homoallylic amines. Meanwhile, the enantioenriched 1,4-addition products could also be obtained through a subsequent 3,3-sigmatropic rearrangement of the 1,2-addition products. Extensive DFT calculations were carried out to elucidate the origins of high regioselectivity (1,2- vs 1,4-) and enantioselectivity.

Covalent Organic Frameworks Based Photoenzymatic Nano‐reactor for Asymmetric Dynamic Kinetic Resolution of Secondary Amines

AbstractBio‐catalysis represents a highly efficient and stereoselective method for the synthesis of valuable chiral compounds, however, the poor stability and limited reaction types of free enzymes restrict their wide application in industrial production. In this work, to overcome these problems, a multifunctional photoenzymatic nanoreactor CALB@COF‐Ir was developed through the encapsulation of Candida antarctica lipase B (CALB) in a photosensitive covalent organic framework COF‐Ir. This bio‐nanocluster serves as efficient catalysts in asymmetric dynamic kinetic resolution (DKR) of secondary amines to give a series of chiral amines in high yields (up to 99 %) and enantioselectivities (up to 99 % ee). The well‐designed COF‐Ir not only acts as safety cover to prevent CALB from deactivation but promotes racemization of secondary amines via photo‐induced hydrogen atom transfer (HAT) process. Photoelectric characterization and TDDFT calculation revealed that (ppy)2Ir units in COF‐Ir play crucial role in this photocatalytic system which enhance its photo‐redox properties through facilitating the separation between photoelectrons (e−) and holes (h+). Furthermore, the heterogeneous photoenzymatic nanoreactor could be recycled for five rounds with slight decline of catalytic reactivity.

Resin-Immobilized Palladium Acetate and Alcohol Dehydrogenase for Chemoenzymatic Enantioselective Synthesis of Chiral Diarylmethanols.

The enantioselective synthesis of chiral diarylmethanols is highly desirable in synthetic chemistry and the pharmaceutical industry, but it remains challenging, especially in terms of green and sustainable production. Herein, a resin-immobilized palladium acetate catalyst was fabricated with high activity, stability, and reusability in Suzuki cross-coupling reaction of acyl halides with boronic acids, and the coimmobilization of alcohol dehydrogenase and glucose dehydrogenase on resin supports was also conducted for asymmetric bioreduction of diaryl ketones. Experimental results revealed that the physicochemical properties of the resins and the immobilization modes played important roles in affecting their catalytic performances. These two catalysts enabled the construction of a chemoenzymatic cascade for the enantioselective synthesis of a series of chiral diarylmethanols in high yields (83-90%) and enantioselectivities (87-98% ee). In addition, the asymmetric synthesis of the antihistaminic and anticholinergic drugs (S)-neobenodine and (S)-carbinoxamine was also achieved from the chiral diarylmethanol precursors, demonstrating the synthetic utility of the chemoenzymatic cascade.

Three-Component Radical Cross-Coupling: Asymmetric Vicinal Sulfonyl-Esterification of Alkenes Involving Sulfur Dioxide.

A novel catalytic system for radical cross-coupling reactions based on copper and chiral Pyridyl-bis(imidazole) (PyBim) ligandsis described. It overcomes the challenges of chemoselectivity and enantioselectivity, achieving a highly enantioselective vicinal sulfonyl-esterification reaction of alkenes involving sulfur dioxide. This strategy involves the use of earth-abundant metal catalyst, mild reaction conditions, a broad range of substrates (84 examples), high yields (up to 97% yield), and exceptional control over enantioselectivity. The reaction system is compatible with different types of radical precursors, including O-acylhydroxylamines, cycloketone oxime esters, aryldiazonium salts, and drug molecules. Chiral ligand PyBim is identified as particularly effective in achieving the desired high enantioselectivity. Mechanistic studies reveal that copper/PyBim system plays a vital role in C─O coupling, employing an outer-sphere model. In addition, the side arm effect of ligand is observed.

Rhodium(I)/Chiral Diene Complexes Catalyzed Asymmetric Desymmetrization of Alkynyl-Tethered 2,5-Cyclohexadienones Through an Arylative Cyclization Cascade.

Cis-hydrobenzofurans, cis-hydroindoles, and cis-hydrindanes, privileged structural motifs found in numerous biologically active natural and synthetic compounds, are efficiently prepared by a Rh(I)-catalyzed cascade syn-arylation/1,4-addition protocol. This approach starts with the regioselective syn-arylation of the alkyne tethered to 2,5-hexadienone moieties, using a chiral Rh(I) catalyst generated in situ from a chiral bicyclo[2.2.1]hepatadiene ligand L4f. By forging two new carbon-carbon bonds and introducing two chiral centers, the resulting alkenylrhodium species undergoes desymmetrization via an intramolecular 1,4-addition reaction, delivering annulated products with high yields and enantioselectivities.

Manganese Pentacarbonyl Bromide as Regeneration Catalyst Enabled Biomimetic Asymmetric Reduction.

Using readily available manganese pentacarbonyl bromide as a regeneration catalyst, biomimetic asymmetric reduction of imines including quinoxalinones, benzoxazinones, and benzoxazine has been successfully developed in the presence of transfer catalyst chiral phosphoric acids, providing the chiral amines with high yields and enantioselectivities.

Engineering the enantioselectivity of a novel imine reductase from Streptomyces viridochromogenes for the dynamic kinetic reductive amination of cyclic β-ketoester

N-substituted β-amino esters as an important class of chiral amines, are widely used as building blocks in pharmaceuticals. A novel imine reductase SvIRED was identified through gene mining from Streptomyces viridochromogenes with high enantioselectivity of > 99 % ee (1R, 2S), 95 % de (cis:trans), towards 2-oxocyclohexane-1-carboxylate and cyclopropylamine. SvIRED exhibited the highest activity at pH 7.0 and 40 °C. A variety of amine donors could be used by SvIRED and produce chiral N-substituted β-amino esters with different enantioselectivity. Employing methylamine (i) and pyrrolidine (n) as amine donors, SvIRED exhibited reversed enantioselectivity of 23 % ee (1S, 2R) and 79 % ee (1S, 2R) respectively. Through alanine scanning, M183 and H244 were identified with remarkable roles in governing enantioselectivity towards i and n. Compared with WT SvIRED, the enantioselectivity of M183A was inverted to ee value of >99 % (1R, 2S) and de value of >99 % (cis:trans) towards i, and the enantioselectivity of H244A was inverted to ee value of 88 % (1R, 2S) and de value of >99 % (cis:trans) towards n. Interaction analysis indicated the orientation of ester group was vital for manipulation of enantioselectivity. This study provides novel Imine reductase mutants for enantioselective synthesis of N-substituted β-amino esters with different amine donors.

A concise and scalable chemoenzymatic synthesis of prostaglandins

Prostaglandins have garnered significant attention from synthetic chemists due to their exceptional biological activities. In this report, we present a concise chemoenzymatic synthesis method for several representative prostaglandins, achieved in 5 to 7 steps. Notably, the common intermediate bromohydrin, a radical equivalent of Corey lactone, is chemoenzymatically synthesized in only two steps, which allows us to complete the synthesis of prostaglandin F2α in five steps on a 10-gram scale. The chiral cyclopentane core is introduced with high enantioselectivity, while the lipid chains are sequentially incorporated through a cost-effective process involving bromohydrin formation, nickel-catalyzed cross-couplings, and Wittig reactions. This cost-efficient synthesis route for prostaglandins holds the potential to make prostaglandin-related drugs more affordable and facilitate easier access to their analogues.

Nickel-Catalyzed Hydrofluorination in Unactivated Alkenes: Regio- and Enantioselective C-F Bond Formation.

Catalytic formation of a regio- and enantioselective C-F bond chiral center from readily available alkenes is a crucial goal, yet it continues to pose significant challenges in organic synthesis. Here, we report the regioselective formation of C-F bonds facilitated by NiH catalysis and a coordination directing strategy that enables precise hydrofluorination of both terminal and internal alkenes. Notably, we have optimized this methodology to achieve high enantioselectivity in creating aliphatic C-F stereogenic centers especially with β,γ-alkenyl substrates, using a tailored chiral Bn-BOx ligand. Another pivotal finding in our research is the identification of the (+)-nonlinear effect under optimized conditions, allowing for high enantioselectivity even with moderately enantiomerically enriched chiral ligands. Given the significant role of fluorine in pharmaceuticals and synthetic materials, this research offers essential insights into the regioselective and enantioselective formation of C-F bond chiral centers, paving the way for the efficient production of valuable fluorinated compounds.

Nickel-Catalyzed Atroposelective C-H Alkylation Enabled by Bimetallic Catalysis with Air-Stable Heteroatom-Substituted Secondary Phosphine Oxide Preligands.

The catalytic asymmetric construction of axially chiral C-N atropisomers remains a formidable challenge due to their low rotational barriers and is largely reliant on toxic, cost-intensive, and precious metal catalysts. In sharp contrast, we herein describe the first nickel-catalyzed atroposelective C-H alkylation for the construction of C-N axially chiral compounds with the aid of a chiral heteroatom-substituted secondary phosphine oxide (HASPO)-ligated Ni-Al bimetallic catalyst. A wide range of alkenes, including terminal and internal alkenes, were well compatible with the reaction, providing a variety of benzimidazole derivatives in high yields and enantioselectivities (up to 97:3 e.r.). The key to success was the identification of novel HASPOs as highly effective chiral preligands. Mechanistic studies revealed the catalyst mode of action, and in-depth data science analysis elucidated the key features of the responsible chiral preligands in controlling the enantioselectivity.

Enantioselective [2π + 2σ] Cycloadditions of Bicyclo[1.1.0]butanes with Vinylazaarenes through Asymmetric Photoredox Catalysis.

Here we present a highly enantioselective [2π + 2σ] photocycloaddition of bicyclo[1.1.0]butanes (BCBs). The reaction uses a variety of vinylazaarenes as partners and is catalyzed by a polycyclic aromatic hydrocarbon (PAH)-containing chiral phosphoric acid as a bifunctional chiral photosensitizer. A wide array of pharmaceutically important bicyclo[2.1.1]hexane (BCH) derivatives have been synthesized with high yields, enantioselectivity, and diastereoselectivity. In addition to the diverse 1-ketocarbonyl-3-substituted BCBs, α/β-substituted vinylazaarenes are compatible with such an unprecedented photoredox catalytic pathway, resulting in the successful assembly of an all-carbon quaternary stereocenter or two adjacent tertiary stereocenters on the product.

Chiral Memory in Dynamic Transformation from Porous Organic Cages to Covalent Organic Frameworks for Enantiorecognition Analysis.

The preservation of chirality during a transformation process, known as the "chiral memory" effect, has garnered significant attention across multiple research disciplines. Here, we first report the retention of the original chiral structure during dynamic covalent chemistry (DCC)-induced structural transformation from porous organic cages into covalent organic frameworks (COFs). A total of six two-dimensional chiral COFs constructed by entirely achiral building blocks were obtained through the DCC-induced substitution of chiral linkers in a homochiral cage (CC3-R or -S) using achiral amine monomers. Homochirality of these COFs resulted from the construction of 3-fold-symmetric benzene-1,3,5-methanimine cores with a propeller-like configuration of one single-handedness throughout the cage-to-COF transformation. The obtained chiral COFs can be further utilized as fluorescence sensors or chiral stationary phases for gas chromatography with high enantioselectivity. The present study thus highlighted the great potential to expand the scope of functional chiral materials via DCC-induced crystal-to-crystal transformation with the chiral memory effect.

Enantioselective Zirconium-catalyzed Transformations

Abstract: The cheaper and less-toxic metals of Group 4 compared with common metals used in catalysis are increasingly applied in catalysis, resulting in the development of many novel greener transformations. Zirconium is abundant, non-toxic, and exhibits a remarkably diversified chemical reactivity among these metals. Since the first asymmetric zirconium-catalyzed reaction disclosed by Nugent in 1992, a wide variety of chiral zirconium catalysts have been proven to be capable of promoting many types of highly enantioselective transformations, spanning from standard reactions, such as Friedel‒Crafts reactions, cycloadditions, aldol reactions, Mannich reactions, epoxidations, nucleophilic additions to carbonyl compounds and derivatives, cyanations, ring-opening reactions, hydroxylations, hydroformylations, carboaluminations among others, to more modern and complex domino and tandem processes. This review aims to collect the major progress achieved in the field of enantioselective transformations of all types promoted by chiral zirconium catalysts, covering the literature since the beginning of 2003 and illustrating the power of these non-toxic catalysts to provide high enantioselectivity in almost all kinds of asymmetric organic reactions. It is divided into ten parts, focussing consecutively on enantioselective Friedel‒Crafts reactions, cycloadditions, aldol reactions, Mannich reactions, epoxidations, additions of alkylzinc reagents to imines, cyanations, ring-opening reactions, hydroxylations, and domino/ tandem reactions. The diversity of these transformations well reflects that of the products synthesized. For example, chiral indole and pyrrole derivatives were prepared from Friedel‒Crafts reactions; pyranones, pyridones and pyrazolidines from cycloadditions; β-hydroxy α-diazo carbonyl compounds, βhydroxy (thio)esters and β-hydroxy-α-amino acid derivatives from aldol reactions; β-amino (thio)esters from Mannich reactions; functionalized epoxides from epoxidations; amines from additions of alkylzinc reagents to imines; amino nitriles from cyanations; 1,2-diamines and β-vinyloxy alcohols from ring-opening processes; 2- hydroxy 1-indanones from hydroxylations; various amines, 1,3-anti-diol monoesters, β-amino esters, α,βdihydroxy acid derivatives, α-amino ketones, indoles, cyclopentane and aryl α-aminophosphonates from domino/ tandem reactions. Furthermore, the utility of these novel methodologies was demonstrated in the total synthesis of numerous essential bioactive products, such as (+)-prelactone C, (+)-9-deoxygoniopypyrone, (+)- coniine, vancomycin, (+)-fusarisetin A, mycolipenic acid, onchidin, indoxacarb, tachykinin receptor antagonists, cerebroprotecting agent MS-153, and L-erythro-sphingosine. The advances achieved in the last three decades demonstrate that the non-toxicity, abundance, and efficiency of zirconium make its application in catalysis suiting the growing demand for more environmentally benign processes, offering the real opportunity to replace other toxic and expensive metals in the near future.