High Enantioselectivity Research Articles

Asymmetric C–H Dehydrogenative Alkenylation via a Photo-induced Chiral α‑Imino Radical Intermediate

The direct alkenylation with simple alkenes stands out as the most ideal yet challenging strategy for obtaining high-valued desaturated alkanes. Here we present a direct asymmetric dehydrogenative α-C(sp3)-H alkenylation of carbonyls based on synergistic photoredox-cobalt-chiral primary amine catalysis under visible light. The ternary catalytic system enables the direct coupling of β-keto-carbonyls and alkenes through a cooperative radical addition-dehydrogenation process involving a chiral α-imino radical and Co(II)-metalloradical intermediate. A catalytic H-transfer process involving nitrobenzene is engaged to quench in situ generated cobalt hydride species, ensuring a chemoselective alkenylation in good yields and high enantioselectivities.

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.

Solvent-Switchable Remote C-H Activation via 1,4-Palladium Migration Enables Site-Selective C-P Bond Formation: A Tool for the Synthesis of P-Chiral Phosphinyl Imidazoles.

Solvent-switchable and site-selective phosphorylation of imidazoles at the C2 or C5 position of the imidazole ring was achieved via 1,4-palladium migration. P-Chiral tert-butyl(aryl)phosphine oxides were cross-coupled to 1-(2-bromophenyl)-1H-imidazoles with high enantiospecificity, thereby leading to a novel class of chiral imidazole-based phosphine oxides. As proof of concept, reduction of an analogue yielded the corresponding P-chiral 2-phosphinyl imidazole ligand, which was shown to induce high enantioselectivity in the formation of axially chiral molecules synthesized via Pd-catalyzed Suzuki-Miyaura cross-coupling.

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.

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.

A Homochiral Porous Organic Cage‐Polymer Membrane for Enantioselective Resolution

AbstractMembrane‐based enantioselective separation is a promising method for chiral resolution due to its low cost and high efficiency. However, scalable fabrication of chiral separation membranes displaying both high enantioselectivity and high flux of enantiomers is still a challenge. Here, we report the preparation of homochiral porous organic cage (CC3‐R)‐based enantioselective thin‐film‐composite membranes using polyamide (PA) as the matrix, where fully organic and solvent‐processable cage crystals have good compatibility with the polymer scaffold. The hierarchical CC3‐R channels consist of chiral selective windows and inner cavities, leading to favorable chiral resolution and permeation of enantiomers; the CC3‐R/PA composite membranes display an enantiomeric excess (ee) of 95.2% for R‐(+)‐limonene over S‐(‐)‐limonene and a high flux of 99.9 mg h−1 m−2. This work sheds light on the use of homochiral porous organic cages for preparing enantioselective membranes and demonstrates a new route for the development of next‐generation chiral separation membranes.This article is protected by copyright. All rights reserved

Isothiourea‐Catalysed Acylative Dynamic Kinetic Resolution of Tetra‐substituted Morpholinone and Benzoxazinone Lactols

The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) of tetra‐substituted lactols is a recognised synthetic challenge. In this manuscript, a highly enantioselective isothiourea‐catalysed acylative DKR of tetra‐substituted morpholinone and benzoxazinone‐derived lactols is reported. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 89%, 99:1 er) observed across a broad range of substrate derivatives incorporating substitution at N(4) and C(2), di‐ and spirocyclic substitution at C(5)‐ and C(6)‐position, as well as benzannulation (>35 examples in total). The DKR process is amenable to scale‐up on a 1 g laboratory scale. The factors leading to high selectivity in this DKR process have been probed through computation, with an N‐C=O•••isothiouronium interaction identified as key to producing ester products in highly enantioenriched form.

Enantioselective Synthesis of Tetra-substituted 3-Hydroxyphthalide Esters by Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution.

A general and highly enantioselective method for the preparation of tetra-substituted 3-hydroxyphthalide esters via isothiourea-catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2S,3R)-HyperBTM (5 mol%) as the catalyst, the scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields observed (>40 examples, up to 99%, 99:1 er). Substitution of the aromatic core within the 3-hydroxyphthalide skeleton, as well as aliphatic and aromatic substitution at C(3)-, is readily tolerated. A diverse range of anhydrides, including those from bioactive and pharmaceutically relevant acids, can also be used. The high enantioselectivity observed in this DKR process has been probed computation, with a key substrate heteroatom donor O•••acyl-isothiouronium interaction identified through DFT analysis as necessary for enantiodiscrimination.

Enantioselective Synthesis of Tetra‐substituted 3‐Hydroxyphthalide Esters by Isothiourea‐Catalysed Acylative Dynamic Kinetic Resolution

A general and highly enantioselective method for the preparation of tetra‐substituted 3‐hydroxyphthalide esters via isothiourea‐catalysed acylative dynamic kinetic resolution (DKR) is reported. Using (2S,3R)‐HyperBTM (5 mol%) as the catalyst, the scope and limitations of this methodology have been extensively probed, with high enantioselectivity and good to excellent yields observed (>40 examples, up to 99%, 99:1 er). Substitution of the aromatic core within the 3‐hydroxyphthalide skeleton, as well as aliphatic and aromatic substitution at C(3)‐, is readily tolerated. A diverse range of anhydrides, including those from bioactive and pharmaceutically relevant acids, can also be used. The high enantioselectivity observed in this DKR process has been probed computation, with a key substrate heteroatom donor O•••acyl‐isothiouronium interaction identified through DFT analysis as necessary for enantiodiscrimination.

Isothiourea-Catalysed Acylative Dynamic Kinetic Resolution of Tetra-substituted Morpholinone and Benzoxazinone Lactols.

The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) of tetra-substituted lactols is a recognised synthetic challenge. In this manuscript, a highly enantioselective isothiourea-catalysed acylative DKR of tetra-substituted morpholinone and benzoxazinone-derived lactols is reported. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 89%, 99:1 er) observed across a broad range of substrate derivatives incorporating substitution at N(4) and C(2), di- and spirocyclic substitution at C(5)- and C(6)-position, as well as benzannulation (>35 examples in total). The DKR process is amenable to scale-up on a 1 g laboratory scale. The factors leading to high selectivity in this DKR process have been probed through computation, with an N-C=O•••isothiouronium interaction identified as key to producing ester products in highly enantioenriched form.

Engineered Phenylalanine Ammonia‐Lyases for the Enantioselective Synthesis of Aspartic Acid Derivatives

Biocatalytic hydroamination of alkenes is an efficient and selective method to synthesize natural and unnatural amino acids. Phenylalanine ammonia‐lyases (PALs) have been previously engineered to access a range of substituted phenylalanines and heteroarylalanines, but their substrate scope remains limited, typically including only arylacrylic acids. Moreover, the enantioselectivity in the hydroamination of electron‐deficient substrates is often poor. Here, we report the structure‐based engineering of PAL from Planctomycesbrasiliensis (PbPAL), enabling preparative‐scale enantioselective hydroaminations of previously inaccessible yet synthetically useful substrates, such as amide‐ and ester‐containing fumaric acid derivatives. Through the elucidation of cryo‐electron microscopy (cryo‐EM) PbPAL structure and screening of the structure‐based mutagenesis library, we identified the key active site residue L205 as pivotal for dramatically enhancing the enantioselectivity of hydroamination reactions involving electron‐deficient substrates. Our engineered PALs demonstrated exclusive a‐regioselectivity, high enantioselectivity, and broad substrate scope. The potential utility of the developed biocatalysts was further demonstrated by a preparative‐scale hydroamination yielding tert‐butyl protected l‐aspartic acid, widely used as intermediate in peptide solid‐phase synthesis.

Engineered Phenylalanine Ammonia-Lyases for the Enantioselective Synthesis of Aspartic Acid Derivatives.

Biocatalytic hydroamination of alkenes is an efficient and selective method to synthesize natural and unnatural amino acids. Phenylalanine ammonia-lyases (PALs) have been previously engineered to access a range of substituted phenylalanines and heteroarylalanines, but their substrate scope remains limited, typically including only arylacrylic acids. Moreover, the enantioselectivity in the hydroamination of electron-deficient substrates is often poor. Here, we report the structure-based engineering of PAL from Planctomycesbrasiliensis (PbPAL), enabling preparative-scale enantioselective hydroaminations of previously inaccessible yet synthetically useful substrates, such as amide- and ester-containing fumaric acid derivatives. Through the elucidation of cryo-electron microscopy (cryo-EM) PbPAL structure and screening of the structure-based mutagenesis library, we identified the key active site residue L205 as pivotal for dramatically enhancing the enantioselectivity of hydroamination reactions involving electron-deficient substrates. Our engineered PALs demonstrated exclusive a-regioselectivity, high enantioselectivity, and broad substrate scope. The potential utility of the developed biocatalysts was further demonstrated by a preparative-scale hydroamination yielding tert-butyl protected l-aspartic acid, widely used as intermediate in peptide solid-phase synthesis.

A New Approach in Lipase-Octyl-Agarose Biocatalysis of 2-Arylpropionic Acid Derivatives

The use of lipase immobilized on an octyl-agarose support to obtain the optically pure enantiomers of chiral drugs in reactions carried out in organic solvents is a great challenge for chemical and pharmaceutical sciences. Therefore, it is extremely important to develop optimal procedures to achieve a high enantioselectivity of the biocatalysts in the organic medium. Our paper describes a new approach to biocatalysis performed in an organic solvent with the use of CALB-octyl-agarose support including the application of a polypropylene reactor, an appropriate buffer for immobilization (Tris base—pH 9, 100 mM), a drying step, and then the storage of immobilized lipases in a climatic chamber or a refrigerator. An immobilized lipase B from Candida antarctica (CALB) was used in the kinetic resolution of (R,S)-flurbiprofen by enantioselective esterification with methanol, reaching a high enantiomeric excess (eep = 89.6 ± 2.0%). As part of the immobilization optimization, the influence of different buffers was investigated. The effect of the reactor material and the reaction medium on the lipase activity was also studied. Moreover, the stability of the immobilized lipases: lipase from Candida rugosa (CRL) and CALB during storage in various temperature and humidity conditions (climatic chamber and refrigerator) was tested. The application of the immobilized CALB in a polypropylene reactor allowed for receiving over 9-fold higher conversion values compared to the results achieved when conducting the reaction in a glass reactor, as well as approximately 30-fold higher conversion values in comparison with free lipase. The good stability of the CALB-octyl-agarose support was demonstrated. After 7 days of storage in a climatic chamber or refrigerator (with protection from humidity) approximately 60% higher conversion values were obtained compared to the results observed for the immobilized form that had not been stored. The new approach involving the application of the CALB-octyl-agarose support for reactions performed in organic solvents indicates a significant role of the polymer reactor material being used in achieving high catalytic activity.

Enantio- and Diastereoselective Total Synthesis of Belzutifan Enabled by Rh-Catalyzed Hydrogenation.

Herein, we report a nine-step synthesis of belzutifan enabled by a novel Rh-catalyzed asymmetric hydrogenation to install the contiguous fluorinated stereocenters with high enantioselectivity. Moreover, the final ketone reduction in the synthesis proceeds with high diastereoselectivity, leading to the expedient assembly of the stereotriad. In contrast to the original 16-step synthesis, this route avoids a lengthy bromination-oxidation sequence and introduces the sulfone functionality via nucleophilic aromatic substitution, obviating the need for transition metal catalysis.

Chiral zwitterionic stationary phases based on Cinchona alkaloids and dipeptides: Application in chiral separation of dipeptides under reversed phase conditions

Chromatographic behavior of novel chiral stationary phases with bonded selectors based on Cinchona alkaloids modified with dipeptides was studied using dipeptides as probe molecules. Buffer-free and salt containing hydro-organic solutions were used as the mobile phases. The selectors exhibit pseudoenantiomeric behavior with respect to the L/D or LL/DD enantiomers and do not behave so with respect to the LD/DL enantiomers. The alkaloid part of the selectors is the driver of enantioselectivity, while the dipeptide substituent plays a modulating role. The quinidine-based selectors demonstrate stronger adsorption affinity and higher enantioselectivity as compared to the quinine-based selectors. The dipeptide analytes containing a glycyl fragment are weaker retained and their enantiomers are worse separated comparing to dipeptides with both units being larger amino acids. Moreover, a phenyl group in the structure of a dipeptide analyte facilitates enantioseparation. The effect of the mobile phase composition on retention depends on the hydrophobicity of an analyte. Hydrophobic dipeptides are better eluted by methanol-rich solvents, hydrophilic dipeptides are better eluted with water-rich solvents, and dipeptides with an intermediate hydrophobicity demonstrate a U-shaped or more complicated dependence of the retention factor on the percentage of methanol. Even a small buffer addition to the mobile phase decreases retention, but the ion-exchange mechanism was not confirmed. The effect of an electrolyte is rather due to the shielding of the charged groups of the selector reducing thereby electrostatic interaction between the selector and analyte. Efficiency of the novel columns is comparable to that of other brush-type chiral columns, the highest achieved number of the theoretical plates per 1 m varying between 30,000 and 40,000.

Nickel-Catalyzed Enantioselective Reductive Arylation of Common Ketones.

A nickel complex of chiral bisoxazolines catalyzed the stereoselective reductive arylation of ketones in high enantioselectivity. A range of common acyclic and cyclic ketones reacted without the aid of directing groups. Mechanistic studies using isolated complex of a chiral bis(oxazoline) (L)Ni(Ar)Br revealed that Mn reduction was not needed, while Lewis acidic titanium alkoxides were critical to ketone insertion.

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

AbstractEnzyme‐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.

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

AbstractThe 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.

Chiral supramolecular catalysts of helical nanoribbon: more twist, higher enantioselectivity

Chiral supramolecular catalysts of helical nanoribbon: more twist, higher enantioselectivity

Diastereo-divergent synthesis of chiral hindered ethers via a synergistic calcium(II)/gold(I) catalyzed cascade hydration/1,4-addition reaction.

Hindered ethers are ubiquitous in natural products and bioactive molecules. However, developing an efficient method for the stereocontrolled synthesis of all stereoisomers of chiral hindered ethers is highly desirable but challenging. Here we show a strategy that utilizes in situ-generated water as a nucleophile in an asymmetric cascade reaction involving two highly reactive intermediates, 3-furyl methyl cations and ortho-quinone methides (o-QMs), to synthesize chiral hindered ethers. The Ca(II)/Au(I) synergistic catalytic system enables the control of diastereoselectivity and enantioselectivity by selecting suitable chiral phosphine ligands in this cascade hydration/1,4-addition reaction, affording all four stereoisomers of a diverse range of chiral tetra-aryl substituted ethers with high diastereoselectivities (up to >20/1) and enantioselectivities (up to 95% ee). This work provides an example of chiral Ca(II)/Au(I) bimetallic catalytic system controlling two stereogenic centers via a cascade reaction in a single operation.