Dynamic Kinetic Resolution Process Research Articles

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.

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.

RuPHOX-Ru Catalyzed Asymmetric Cascade Hydrogenation of 3-Substituted Chromones for the Synthesis of Corresponding Chiral Chromanols​.

An efficient RuPHOX-Ru catalyzed asymmetric cascade hydrogenation of 3-substituted chromones has been achieved under mild reaction conditions, affording the corresponding chiral 3-substituted chromanols in high yields with excellent enantio- and diastereoselectivities (up to 99% yield, >99% ee and >20:1 dr). Control reactions and deuterium labelling experiments revealed that a dynamic kinetic resolution process occurs during the subsequent hydrogenation of the C=O double bond, which is responsible for the high performance of the asymmetric cascade hydrogenation. The resulting products allow for several transformations and it was shown that the protocol provides a practical and alternative strategy for the synthesis of chiral 3-substituted chromanols and their derivatives.

N-Heterocyclic carbene-catalyzed enantioselective synthesis of planar-chiral cyclophanes via dynamic kinetic resolution

Planar-chiral cyclophanes have gained considerable concerns for drug discovery due to their unique conformational strain and 3D structure. However, the enantioselective synthesis of planar-chiral cyclophanes is a long-standing challenge for the synthetic community. We herein describe an N-heterocyclic carbene (NHC)-catalyzed asymmetric construction of planar-chiral cyclophanes. This transformation occurs through a dynamic kinetic resolution (DKR) process to convert racemic substrates into planar-chiral macrocycle scaffolds in good to high yields with high to excellent enantioselectivities. The ansa chain length and aromatic ring substituent size is crucial to achieve the DKR approach. Controlled experiments and DFT calculations were performed to clarify the DKR process.

Asymmetric Hydrogenation of Racemic 2-Substituted Indoles via Dynamic Kinetic Resolution: An Easy Access to Chiral Indolines Bearing Vicinal Stereogenic Centers.

The asymmetric hydrogenation (AH) of N-unprotected indoles is a straightforward, yet challenging method to access biologically interesting NH chiral indolines. This method has for years been limited to 2/3-monosubstituted or 2,3-disubstituted indoles, which produce chiral indolines bearing endocyclic chiral centers. Herein, we have reported an innovative Pd-catalyzed AH of racemic α-alkyl or aryl-substituted indole-2-acetates using an acid-assisted dynamic kinetic resolution (DKR) process, affording a range of structurally fascinating chiral indolines that contain exocyclic stereocenters with excellent yields, diastereoselectivities, and enantioselectivities. Mechanistic studies support that the DKR process relies on a rapid interconversion of each enantiomer of racemic substrates, leveraged by an acid-promoted isomerization between the aromatic indole and nonaromatic exocyclic enamine intermediate. The reaction can be performed on a gram scale, and the products can be derivatized into non-natural β-amino acids via facile debenzylation and amino alcohol upon reduction.

NHC-Catalyzed Chemo- and Enantioselective Reaction between Aldehydes and Enals for Access to Axially Chiral Arylaldehydes.

A chiral carbene-catalyzed chemo- and enantioselective reaction with racemic biaryl aldehydes and α-bromoenals is developed for access to axially chiral 2-arylbenzaldehydes through atroposelective dynamic kinetic resolution (DKR) processes. This atroposelective DKR strategy can tolerate a broad scope of substrates with diverse functionalities. The axially chiral 2-aryl benzaldehyde products generally afford moderate to good yields and enantioselectivities. The axially chiral molecules afforded from the current approach are variable through simple transformations to afford axially chiral functional molecules with excellent optical purities.

Carbene-Catalyzed Direct O-Functionalization of Ketone: Atroposelective Access to Non-C2-Symmetric Binaphthyls.

Disclosed here is NHC-catalyzed direct intermolecular trapping of the ketone oxygen atom with the acyl azolium intermediate. The overall reaction is a dynamic kinetic resolution process that converts ketone to the corresponding enol ester with well-controlled axial chirality. Our reaction eventually affords non-C2-symmetric binaphthyl derivatives with important applications, such as in the area of asymmetric catalysis.

Enantioselective organocatalytic synthesis of axially chiral aldehyde-containing styrenes via SNAr reaction-guided dynamic kinetic resolution

The precise and efficient construction of axially chiral scaffolds, particularly toward the aryl-alkene atropoisomers with impeccably full enantiocontrol and highly structural diversity, remains greatly challenging. Herein, we disclose an organocatalytic asymmetric nucleophilic aromatic substitution (SNAr) reaction of aldehyde-substituted styrenes involving a dynamic kinetic resolution process via a hemiacetal intermediate, offering a novel and facile way to significant axial styrene scaffolds. Upon treatment of the aldehyde-containing styrenes bearing (o-hydroxyl)aryl unit with commonly available fluoroarenes in the presence of chiral peptide-phosphonium salts, the SNAr reaction via an exquisite bridged biaryl lactol intermediate undergoes smoothly to furnish a series of axially chiral aldehyde-containing styrenes decorated with various functionalities and bioactive fragments in high stereoselectivities (up to >99% ee) and complete E/Z selectivities. These resulting structural motifs are important building blocks for the preparation of diverse functionalized axial styrenes, which have great potential as efficient and privileged chiral ligands/catalysts in asymmetric synthesis.

ArPNO-Catalyzed Acylative Dynamic Kinetic Resolution of 3-Hydroxyphthalides: Access to Enantioenriched Phthalidyl Esters.

A chiral 4-aryl-pyridine-N-oxide nucleophilic organocatalyst was used to synthesize chiral phthalidyl ester prodrugs by the acylative dynamic kinetic resolution process. By using the 3,5-dimethylphenyl-derived ArPNO catalyst, the phthalidyl esters were obtained in up to 97% yield with 97% ee at room temperature. Two phthalidyl esters of prodrugs, talosalate and talmetacin, were generated. By control experiments and density functional theory calculations, an acyl transfer mechanism was proposed.

Ir‐Catalyzed Enantioselective Synthesis of gem‐Diborylalkenes Enabled by 1,2‐Boron Shift

AbstractAsymmetric cross‐couplings based on 1,2‐carbon migration from B‐ate complexes have been developed efficiently to access valuable organoboronates. However, enantioselective reactions triggered by 1,2‐boron shift have remained to be unaddressed synthetic challenge. Here, Ir‐catalyzed asymmetric allylic alkylation enabled by 1,2‐boron shift was developed. In this reaction, we disclosed that excellent enantioselectivities were achieved through an interesting dynamic kinetic resolution (DKR) process of allylic carbonates at the elevated temperature. Notably, the highly valuable (bis‐boryl)alkenes have enabled an array of diversifications to access versatile molecules. Extensive experimental and computational studies were conducted to elucidate the reaction mechanism of DKR process and clarify the origin of excellent enantioselectivities.

Ir-Catalyzed Enantioselective Synthesis of gem-Diborylalkenes Enabled by 1,2-Boron Shift.

Asymmetric cross-couplings based on 1,2-carbon migration from B-ate complexes have been developed efficiently to access valuable organoboronates. However, enantioselective reactions triggered by 1,2-boron shift have remained to be unaddressed synthetic challenge. Here, Ir-catalyzed asymmetric allylic alkylation enabled by 1,2-boron shift was developed. In this reaction, we disclosed that excellent enantioselectivities were achieved through an interesting dynamic kinetic resolution (DKR) process of allylic carbonates at the elevated temperature. Notably, the highly valuable (bis-boryl)alkenes have enabled an array of diversifications to access versatile molecules. Extensive experimental and computational studies were conducted to elucidate the reaction mechanism of DKR process and clarify the origin of excellent enantioselectivities.

Enantioselective Intramolecular Hydroacylation of Alkynes by Rhodium Catalysis through Dynamic Kinetic Resolution. Front Cover Picture: (Adv. Synth. Catal. 20/2023)

The front cover picture illustrates a rhodium-catalyzed enantioselective hydroacylation of racemic alkynals having a substituent at the α-position of the carbonyl group. Mechanistic studies revealed that hydroacylation occurs preferentially from one enantiomer of the racemic substrate via a dynamic kinetic resolution (DKR) process. The picture shows an outline of the DKR process by using an illustration of soccer, in which the player getting the good ball (i. e., enantiomer) successfully scores a goal. Details can be found in the Communication by Yoshihiro Sato and co-workers (Y. Oonishi, K. Takagishi, Y.-M. Liu, Y. Sato, Adv. Synth. Catal. 2023, 365, XXXX–XXXX; DOI: 10.1002/adsc.202300206).

Enantioselective Intramolecular Hydroacylation of Alkynes by Rhodium Catalysis through Dynamic Kinetic Resolution.

The front cover picture illustrates a rhodium-catalyzed enantioselective hydroacylation of racemic alkynals having a substituent at the α-position of the carbonyl group. Mechanistic studies revealed that hydroacylation occurs preferentially from one enantiomer of the racemic substrate via a dynamic kinetic resolution (DKR) process. The picture shows an outline of the DKR process by using an illustration of soccer, in which the player getting the good ball (i. e., enantiomer) successfully scores a goal. Details can be found in the Communication by Yoshihiro Sato and co-workers (Y. Oonishi, K. Takagishi, Y.-M. Liu, Y. Sato, Adv. Synth. Catal. 2023, 365, XXXX–XXXX; DOI: 10.1002/adsc.202300206).

Enantioselective Intramolecular Hydroacylation of Alkynes by Rhodium Catalysis through Dynamic Kinetic Resolution

AbstractRhodium‐catalyzed enantioselective hydroacylation of racemic alkynals having a substituent at the α‐position of the carbonyl group is described. This reaction can be applied for the wide range of substrates (22 examples), and mechanistic studies revealed that a dynamic kinetic resolution (DKR) process occurs during the hydroacylation, giving various cyclic ketones in 47–93% yields with 59:41 to 97:3 er from racemic starting materials.

Rh-Catalyzed Sequential Asymmetric Hydrogenations of 3-Amino-4-Chromones Via an Unusual Dynamic Kinetic Resolution Process.

Rh-catalyzed sequential asymmetric hydrogenations of 3-amino-4-chromones have been achieved for the first time via an unprecedented dynamic kinetic resolution under neutral conditions, providing (S,R)-3-amino-4-chromanols in high yields (up to 98%) with excellent enantio- and diastereoselectivities (up to 99.9% ee and 20:1 dr). The mechanistic studies based on control experiments and density functional theory (DFT) calculations suggest that the dynamic kinetic resolution process for the intermediate enantiomers generated in the first hydrogenation step proceeded via a stereomutation (or called chiral assimilation) pathway from an undesired enantiomer to the desired enantiomer rather than via traditional racemization of the undesired enantiomer. The protocol can be performed on a gram scale with a relatively low catalyst loading and offers a practical and convenient pathway for synthesizing a series of bioactive chromanols and their derivatives.

Chalcogen bond-guided conformational isomerization enables catalytic dynamic kinetic resolution of sulfoxides

Conformational isomerization can be guided by weak interactions such as chalcogen bonding (ChB) interactions. Here we report a catalytic strategy for asymmetric access to chiral sulfoxides by employing conformational isomerization and chalcogen bonding interactions. The reaction involves a sulfoxide bearing two aldehyde moieties as the substrate that, according to structural analysis and DFT calculations, exists as a racemic mixture due to the presence of an intramolecular chalcogen bond. This chalcogen bond formed between aldehyde (oxygen atom) and sulfoxide (sulfur atom), induces a conformational locking effect, thus making the symmetric sulfoxide as a racemate. In the presence of N–heterocyclic carbene (NHC) as catalyst, the aldehyde moiety activated by the chalcogen bond selectively reacts with an alcohol to afford the corresponding chiral sulfoxide products with excellent optical purities. This reaction involves a dynamic kinetic resolution (DKR) process enabled by conformational locking and facile isomerization by chalcogen bonding interactions.

An Environmentally Sustainable Synthesis of Enantioenriched CF3‐Chromanol, Indanol and Tetralol Derivatives by Rh‐Catalyzed Asymmetric Transfer Hydrogenation

AbstractThe Rh(III)‐catalyzed asymmetric reduction of α‐trifluoromethyl ketones through transfer hydrogenation was developed under mild conditions to access a series of enantioenriched cis‐trifluoromethyl alcohols via a dynamic kinetic resolution process. The reaction was efficiently performed in the green solvent 2‐MeTHF with HCO2H/Et3N (1 : 1) as the hydrogen source. High yields, alongside excellent diastereo‐ and enantioselectivities were obtained for the synthesis of CF3‐chromanol, CF3‐indanol and CF3‐tetralol derivatives.

Highly Enantioselective Synthesis of N‐Unprotected Unnatural α‐Amino Acid Derivatives by Ruthenium‐Catalyzed Direct Asymmetric Reductive Amination

AbstractAn unprecedented highly enantioselective Ru‐catalyzed direct asymmetric reductive amination of α‐keto amides with ammonium salts has been disclosed, efficiently offering valuable enantioenriched N‐unprotected unnatural α‐amino acid derivatives bearing a broad range of aryl or alkyl α‐substituents. This protocol features easily accessible substrates, good functional‐group tolerance and excellent enantiocontrol, making it a good complementary approach to the known methods. Moreover, this method is also applicable to the preparation of N‐unprotected unnatural α‐amino acid derivatives containing an additional stereogenic center at the β‐position through a dynamic kinetic resolution (DKR) process. Convenient transformations of the obtained products into chiral N‐unprotected unnatural α‐amino acids, drug intermediates, peptides, and organocatalysts/ligands further showcase the utility of this method.