Kinetic Resolution Research Articles

Synthesis of Axially Chiral QUINAP Derivatives by Ketone-Catalyzed Enantioselective Oxidation.

QUINAPs have emerged as a pivotal class of axially chiral compounds with remarkable features in the stereoinduction of diverse enantioselective transformations. Despite their significant achievements, the confined substrate range and extravagant price still pose challenges, limiting their broader utilization. Herein, we have achieved the first atroposelective oxidation of N-atom using a chiral ketone catalyst. This innovative approach allows the kinetic resolution of QUINAPOs, resulting in both the unreacted substrates and their corresponding N-oxides with excellent enantiocontrol. Importantly, the enantioenriched products can be easily converted to the QUINAP targets without any loss of stereochemical integrity. Mechanistic investigations indicate that dioxirane, generated through the oxidation of ketone with oxone, acts as the active catalytic species. Furthermore, we have successfully extended this catalytic system to the kinetic resolution of QUINOLs and the dynamic kinetic transformation of pyridine analogs of QUINAPO possessing a labile stereogenic axis. The practicality of the developed protocol is further demonstrated by the successful application of QUINAPO N-oxide as a Lewis base catalyst in a series of enantioselective transformations.

Synthesis of Axially Chiral QUINAP Derivatives by Ketone‐Catalyzed Enantioselective Oxidation

AbstractQUINAPs have emerged as a pivotal class of axially chiral compounds with remarkable features in the stereoinduction of diverse enantioselective transformations. However, the confined substrate range and extravagant price still pose challenges, limiting their broader utilization. Herein, we describe the first atroposelective oxidation of an N atom using a chiral ketone catalyst, allowing the kinetic resolution of QUINAPOs to give both the unreacted substrates and their corresponding N‐oxides with excellent enantioselectivity. Importantly, the enantioenriched products can be readily converted into the QUINAP targets without any loss of stereochemical integrity. Mechanistic investigations indicate that a dioxirane, generated through the oxidation of the ketone with oxone, acts as the active catalytic species. Furthermore, we have successfully extended this catalytic system to the kinetic resolution of QUINOLs and the dynamic kinetic transformation of pyridine analogues of QUINAPO possessing a labile stereogenic axis. The practicality of the developed protocol is further demonstrated by the successful application of QUINAPO N‐oxide as a Lewis base catalyst in a series of enantioselective transformations.

First Asymmetric Total Synthesis of Salinosporamides D and I Using Memory of Chirality and Dynamic Kinetic Resolution

The first total synthesis of (–)‐salinosporamide D was achieved using d‐serine as the sole chiral source. This approach stands out for its application of the principles of memory of chirality and dynamic kinetic resolution in the intramolecular aldol reaction of serine‐derived oxazolidines. These strategies enabled the rapid construction of a pyrrolidinone core and installation of contiguous stereocenters. The key intermediate was readily obtained, culminating the asymmetric total synthesis of salinosporamide D. The total synthesis of salinosporamides A and I was also achieved using the same chemistry.

Lipase/H2SO4‐Cocatalyzed Dynamic Kinetic Resolution of Alcohols in Pickering Emulsion

AbstractThis study reports the first chemoenzymatic dynamic kinetic resolution (DKR) of racemic sec‐alcohols by simultaneously using immobilized lipase and aqueous sulfuric acid as catalysts for kinetic resolution and racemization, respectively. The nanoparticle‐stabilized phase separation in a Pickering emulsion enabled the use of these inherently incompatible catalysts in a single vessel. The racemization reaction in the aqueous sulfuric acid solution significantly suppressed the dehydrative side reactions that form alkenes and dimeric ethers, which are often observed in racemization using Brønsted/Lewis acids or oxovanadium compounds in organic solvents. The efficacy of the Pickering emulsion was confirmed by the significantly lower catalytic performance in DKR without emulsification. This method achieved high yields and high optical purities in the production of a wide range of sec‐alcohols.

Sugar-Assisted Kinetic Resolutions in Metal/Chiral Amine Co-Catalyzed α-Allylations and [4+2] Cycloadditions: Highly Enantioselective Synthesis of Sugar and Chromane Derivatives.

Functionalized triose-, furanose and chromane-derivatives were synthesized by the titled reactions. The sugar-assisted kinetic resolution/C-C bond-forming cascade processes generate a functionalized sugar derivative with a quaternary stereocenter in a highly enantioselective fashion (up to >99 % ee) by using a simple combination of metal and chiral amine co-catalysts. Notably, the interplay between the chiral sugar substrate and the chiral amino acid derivative allowed for the construction of a functionalized sugar product with high enantioselectivity (up to 99 %) also when using a combination of racemic amine catalyst (0 % ee) and metal catalyst.

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.

Kinetic regularities of resolution of amines racemates in the acylation reaction with chiral N‐protected amino acids esters

AbstractIn this work, the kinetic and stereochemical regularities of the kinetic resolution of the 1‐phenylethylamine racemate in the acylation reaction under the action of optically active 4‐nitrophenyl ester of N‐protected phenylalanine in 2‐propanol and 1,4‐dioxane were studied. Kinetic measurements were carried out using UV spectroscopy. The studies of the reaction series made it possible to establish the reaction orders with respect to the reagents, as well as the kinetic regularities of the enantioselective acylation. It is shown that different kinetic schemes of the reaction take place in protic and aprotic solvents. Based on the experimental data on the reaction kinetics of both the individual enantiomers and the amine racemate, the enantioselectivity values of the acylation are calculated. It has been found that the nature of the solvent and the reagents ratio strongly affect the selectivity of kinetic resolution. Practical recommendations on the conditions of preparative kinetic resolution of amines by amino acid derivatives using the acylation reaction are proposed.

Nickel-catalyzed kinetic resolution to achieve P-chiral phosphine oxides and sec-phosphine oxides

Nickel-catalyzed kinetic resolution to achieve P-chiral phosphine oxides and sec-phosphine oxides

On the Ability of the N-O Bond to Support a Stable Stereogenic Axis: Peptide-Catalyzed Atroposelective N-Oxidation.

During studies of atroposelective, peptide-catalyzed N-oxidations of pyridines, we observed lower-than-expected barriers to atropisomerization for these stereodynamic processes under the reaction conditions. Mechanistic studies indicate a hydrogen bond-assisted racemization mechanism intrinsic to both the starting materials and products. We also identified a protonation-dependent barrier to rotation that operates for the starting materials alone. Nonetheless, several substrates were amenable to atroposelective N-oxidations via kinetic resolution, yielding krel values of up to 12.6 and the isolation of one N-oxide with >99:1 er after recrystallization.

Co-Immobilization of a Multi-Enzyme Cascade: (S)-Selective Amine Transaminases, l-Amino Acid Oxidase and Catalase.

An enzyme cascade was established previously consisting of a recycling system with an l-amino acid oxidase (hcLAAO4) and a catalase (hCAT) for different α-keto acid co-substrates of (S)-selective amine transaminases (ATAs) in kinetic resolutions of racemic amines. Only 1 mol % of the co-substrate was required and l-amino acids instead of α-keto acids could be applied. However, soluble enzymes cannot be reused easily. Immobilization of hcLAAO4, hCAT and the (S)-selective ATA from Vibrio fluvialis (ATA-Vfl) was addressed here. Immobilization of the enzymes together rather than on separate beads showed higher reaction rates most likely due to fast co-substrate channeling between ATA-Vfl and hcLAAO4 due to their close proximity. Co-immobilization allowed further reduction of the co-substrate amount to 0.1 mol % most likely due to a more efficient H2 O2 -removal caused by the stabilized hCAT and its proximity to hcLAAO4. Finally, the co-immobilized enzyme cascade was reused in 3 cycles of preparative kinetic resolutions to produce (R)-1-PEA with high enantiomeric purity (97.3 %ee). Further recycling was inefficient due to the instability of ATA-Vfl, while hcLAAO4 and hCAT revealed high stability. An engineered ATA-Vfl-8M was used in the co-immobilized enzyme cascade to produce (R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine, an apremilast-intermediate, with a 1,000 fold lower input of the co-substrate.

Desymmetrization and Kinetic Resolution of Endoperoxides Using a Bifunctional Organocatalyst.

Bifunctional thiourea/amine organocatalysts have been used for the desymmetrization of meso-endoperoxides using the Kornblum-DeLaMare reaction, giving 4-hydroxyketones in 78-98% yields with ≤98:2 enantioselectivity. The influence of the catalyst structure, solvent, and temperature was examined. The most promising catalyst was applied to the kinetic resolution of racemic endoperoxides to give enantioenriched materials (≤99:1 er).

Kinetic Resolution of Electron-Deficient Bromohydrins via Copper(II)-Catalyzed C-C Bond Cleavage.

Herein, we report a nonenzymatic kinetic resolution (KR) of α,β-unsaturated ketone-derived bromohydrins (up to s = 211) with N-bromosuccinimide (NBS) in the presence of a chiral Cu(II)-Box catalyst via the C-C bond cleavage of the fast reacting enantiomer. A one-pot synthesis-KR approach of the same has also been realized with excellent enantioselectivities (up to 99% ee). Both protocols are found to be effective for a variety of substrates, leading to enantioenriched bromohydrins. The synthetic utility of this process has been demonstrated by exploring a new strategy to convert the resolved enantiomer to an optically active epoxide.

A Flash Thermal Racemization Protocol for the Chemoenzymatic Dynamic Kinetic Resolution and Stereoinversion of Chiral Amines

A Flash Thermal Racemization Protocol for the Chemoenzymatic Dynamic Kinetic Resolution and Stereoinversion of Chiral Amines

Synthesis of P-Stereogenic Phosphinamides via Pd(II)-Catalyzed Enantioselective C-H Alkynylation.

P-Stereogenic phosphinamides represent important structural elements in chiral organocatalysts and bioactive compounds. Herein, we report Pd(II)-catalyzed enantioselective C-H alkynylation using cheap commercially available l-pyroglutamic acid as a chiral ligand. A range of structurally diverse P-stereogenic phosphinamides was prepared in good yields with high enantioselectivities via desymmetrization and kinetic resolution. A tailor-made congested directing group, N-ethyl-N-(3-methylpyridin-2-yl)amino, was crucial for the reactivity.

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.

Chiral Modification of Ferrite Nanoparticles for Oxidative Kinetic Resolution of Benzoins

AbstractWe report the surface modification of ferrite nanoparticles (MFe2O4 NPs; M= Mn, Fe, Co, Ni, Cu, Zn) with chiral surfactants derived from cinchona alkaloids. The successful synthesis of chiral ferrites were characterized using powder X‐ray diffraction (PXRD), X‐ray photoelectron spectroscopy (XPS), Atomic force microscopy (AFM), Thermogravimetric analysis (TGA) and vibrating sample magnetometer (VSM). These chiral materials were highly active in the oxidative kinetic resolution (OKR) of racemic benzoins. Remarkably gemini surfactant modified Fe3O4 NPs were found to be a potential candidate in the OKR and (R)‐benzoin was isolated with 97% enantiomeric excess (ee). The sustainability of our catalyst has been demonstrated in the gram scale synthesis of (R)‐furoin (93% ee). The recyclability studies have also been performed and found that it could be recyclable with decrease in ee.

Chemoenzymatic Synthesis of Tenofovir.

We report on novel chemoenzymatic routes toward tenofovir using low-cost starting materials and commercial or homemade enzyme preparations as biocatalysts. The biocatalytic key step was accomplished either via stereoselective reduction using an alcohol dehydrogenase or via kinetic resolution using a lipase. By employing a suspension of immobilized lipase from Burkholderia cepacia (Amano PS-IM) in a mixture of vinyl acetate and toluene, the desired (R)-ester (99% ee) was obtained on a 500 mg scale (60 mM) in 47% yield. Alternatively, stereoselective reduction of 1-(6-chloro-9H-purin-9-yl) propan-2-one (84 mg, 100 mM) catalyzed by lyophilized E. coli cells harboring recombinant alcohol dehydrogenase (ADH) from Lactobacillus kefir (E. coli/Lk-ADH Prince) allowed one to reach quantitative conversion, 86% yield and excellent optical purity (>99% ee) of the corresponding (R)-alcohol. The key (R)-intermediate was transformed into tenofovir through "one-pot" aminolysis-hydrolysis of (R)-acetate in NH3-saturated methanol, alkylation of the resulting (R)-alcohol with tosylated diethyl(hydroxymethyl) phosphonate, and bromotrimethylsilane (TMSBr)-mediated cleavage of the formed phosphonate ester into the free phosphonic acid. The elaborated enzymatic strategy could be applicable in the asymmetric synthesis of tenofovir prodrug derivatives, including 5'-disoproxil fumarate (TDF, Viread) and 5'-alafenamide (TAF, Vemlidy). The molecular basis of the stereoselectivity of the employed ADHs was revealed by molecular docking studies.

Cover Picture: Discovery and Engineering of an Ene‐reductase for Kinetic Resolution and Cascade Reduction of Hajos‐Parrish/Wieland‐Miescher Ketones (Adv. Synth. Catal. 17/2023)

Cover Picture: Discovery and Engineering of an Ene‐reductase for Kinetic Resolution and Cascade Reduction of Hajos‐Parrish/Wieland‐Miescher Ketones (Adv. Synth. Catal. 17/2023)

Dynamic Kinetic Resolution of 2‐(Quinolin‐8‐yl)Benzaldehydes: Atroposelective Iridium‐Catalyzed Transfer Hydrogenative Allylation

AbstractAn atroposelective Ir‐catalyzed dynamic kinetic resolution (DKR) of 2‐(quinolin‐8‐yl)benzaldehydes/1‐naphthaldehydes by transfer hydrogenative coupling of allyl acetate is disclosed. The allylation reaction takes place with simultaneous installation of central and axial chirality, reaching high diastereoselectivities and excellent enantiomeric excesses when ortho‐cyclometalated iridium‐DM‐BINAP is used as the catalyst. The racemization of the substrates occurs through a designed transient Lewis acid‐base interaction between the quinoline nitrogen atom and the aldehyde carbonyl group.

Dynamic Kinetic Resolution of 2-(Quinolin-8-yl)Benzaldehydes: Atroposelective Iridium-Catalyzed Transfer Hydrogenative Allylation.

An atroposelective Ir-catalyzed dynamic kinetic resolution (DKR) of 2-(quinolin-8-yl)benzaldehydes/1-naphthaldehydes by transfer hydrogenative coupling of allyl acetate is disclosed. The allylation reaction takes place with simultaneous installation of central and axial chirality, reaching high diastereoselectivities and excellent enantiomeric excesses when ortho-cyclometalated iridium-DM-BINAP is used as the catalyst. The racemization of the substrates occurs through a designed transient Lewis acid-base interaction between the quinoline nitrogen atom and the aldehyde carbonyl group.