Racemization Catalyst Research Articles

Topology of Gemini‐shaped Hexagonal Heterojunction for Efficient Stereoconvergent Transformation via Dynamic Kinetic Resolution

AbstractDespite recent advances in the combination of kinetic resolution and racemization for efficient stereoconvergent transformation, the poor stability and limited reaction activities of the products restrict their wide application in industrial production. To overcome these problems, Gemini‐shaped hexagons with para‐heterojunctions for one‐dimensional and two‐dimensional supramolecular polymers were designed via hydrogen‐bonding adhesion by racemization catalyst 1 and kinetic resolution 2 in this work. The polymers from the assembly of Gemini‐shaped hexagons exhibit rapid catalytic behaviour with efficient selectivity for the desired configuration in the synthesis of tertiary alcohols with contiguous stereocenters through dynamic kinetic resolution for the nanoscale heterojunctions of dissimilar catalysts. Among them, the developed 2D polymers gave outstanding enantioselectivities and diastereoselectivities (>99 % ee, 20 : 1 dr) through the cooperation of adjacent dissimilar catalysts. The heterojunctions varying dimensions and distances of dissimilar catalysts provide new insight for increasing the enantioselectivity of chiral organocatalysts.

Topology of Gemini-shaped Hexagonal Heterojunction for Efficient Stereoconvergent Transformation via Dynamic Kinetic Resolution.

Despite recent advances in the combination of kinetic resolution and racemization for efficient stereoconvergent transformation, the poor stability and limited reaction activities of the products restrict their wide application in industrial production. To overcome these problems, Gemini-shaped hexagons with para-heterojunctions for one-dimensional and two-dimensional supramolecular polymers were designed via hydrogen-bonding adhesion by racemization catalyst 1 and kinetic resolution 2 in this work. The polymers from the assembly of Gemini-shaped hexagons exhibit rapid catalytic behaviour with efficient selectivity for the desired configuration in the synthesis of tertiary alcohols with contiguous stereocenters through dynamic kinetic resolution for the nanoscale heterojunctions of dissimilar catalysts. Among them, the developed 2D polymers gave outstanding enantioselectivities and diastereoselectivities (>99 % ee, 20 : 1 dr) through the cooperation of adjacent dissimilar catalysts. The heterojunctions varying dimensions and distances of dissimilar catalysts provide new insight for increasing the enantioselectivity of chiral organocatalysts.

Overcoming the Limitations of Transition-Metal Catalysis in the Chemoenzymatic Dynamic Kinetic Resolution (DKR) of Atropisomeric Bisnaphthols.

Chemoenzymatic dynamic kinetic resolution (DKR), combining a metal racemization catalyst with an enzyme, has emerged as an elegant solution to transform racemic substrates into enantiopure products, while compatibility of dual catalysis is the key issue. Conventional solutions have utilized presynthesized metal complexes with a fixed and bulky ligand to protect the metal from the enzyme system; however, this has been generally limited to anionic ligands. Herein, we report our strategy to solve the compatibility issue by employing a reliable ligand that firmly coordinates in situ to the metal. Such a reliable ligand offers π* orbitals, allowing additional metal-to-ligand d-π* back-donation, which can significantly enhance coordination effects between the ligand and metal. Therefore, we developed an efficient DKR method to access chiral BINOLs from racemic derivatives under dual copper and enzyme catalysis. In cooperation with lipase LPL-311-Celite, the DKR of BINOLs was successfully realized with a copper catalyst via in situ coordination of BCP (L8) to CuCl. A series of functionalized C 2- and C 1-symmetric chiral biaryls could be synthesized in high yields with good enantioselectivity. The racemization mechanism was proposed to involve a radical-anion intermediate, which allows the axial rotation with a dramatic decrease of the rotation barrier.

Dynamic Kinetic Resolution of 2‐Hydroxybiaryl Atropisomers via Lipase‐Catalyzed Enantioselective O‐Acylation

AbstractThe increasing interest in axially chiral biaryl moieties, which are prevalent in chiral ligands, organocatalysts, and bioactive molecules, has raised the need for developing novel efficient synthetic methods for these types of molecules. In addition to the currently available methods, such as kinetic resolution, desymmetrization and enantio‐ and diastereo‐selective biaryl coupling, we herein report a lipase‐catalyzed dynamic kinetic resolution (DKR) of racemic 2‐hydroxybiaryls through enantioselective O‐acylation. This method features the production of enantiomerically enriched atropisomers (89 %–98 % ee) in 91 %–99 % yields from eleven racemates. Notably, the DKR proceeds without any racemization catalyst since in situ‐racemization was achieved by easy rotation about the biaryl axis of the substrates. The enzymatic O‐acylation then furnished conformationally stable biaryl‐containing esters, in which the increased steric bulkiness of the O‐acyl moiety suppresses the rotation, i. e., racemization, under the reaction conditions of 35–50 °C. This experimental study was accompanied by a computational determination of the rotational barrier of substrates and products. The choice of suitable substrates with a significant difference in their rotational barrier compared to that of their products turned out to be the key to an efficient implementation of this method.

Crystallization-Induced Diastereomeric Transformation of Chiral Ozanimod Key Intermediate Using Homogeneous Ir-Based Racemization Catalyst

Crystallization-Induced Diastereomeric Transformation of Chiral Ozanimod Key Intermediate Using Homogeneous Ir-Based Racemization Catalyst

Imidazolidine‐pyrroloimidazolone Pyridine‐Ni(acac)2 complex Catalyzed Asymmetric Darzens Reaction of Isatins with Phenacyl Chlorides: A Chiral Amplification Effect

With phenacyl chlorides as simple nucleophilic species, the asymmetric Darzens reaction of isatins using Ni(acac)2 as the Lewis acid and imidazolidine‐pyrroloimidazolone pyridine as the ligand is reported. In the presence of 1 mol% of catalyst, diverse spiro‐epoxyoxindoles with two new contiguous stereocenters were afforded in 82‐99% yields, >20:1 dr, and 91‐99% ee. Chiral spiro‐epoxyoxindoles could undergo ring‐opening reactions in further transformations. The developed method was applied to the derivatization of complex molecules including indomethacin, gemfibrozil, and febuxostat‐derived α‐chloroketones. A strong positive nonlinear effect was observed, which was caused by the precipitation of a less‐soluble racemic catalyst complex.

Chemoenzymatic Dynamic Kinetic Resolution Protocol with an Immobilized Oxovanadium as a Racemization Catalyst.

An excellent compatible and cost-effective dynamic kinetic resolution (DKR) protocol has been developed by combining a novel immobilized oxovanadium racemization catalyst onto cheap diatomite (V-D) with an immobilized lipase LA resolution catalyst onto a macroporous resin (LA-MR). V-D was prepared via grinding immobilization, which may become a promising alternative for the immobilization of metals, especially precious metals due to its low cost, high efficiency, easy separation, and large reaction interface. The DKR afforded high yield (96.1%), e.e. (98.67%), and Sel (98.28%) under optimal conditions established using response surface methodology as follows: the amount of V-D 10.83 mg, reaction time 51.2 h, and temperature 48.1 °C, respectively, indicating that all the reactions in the DKR were coordinated very well. The DKR protocol was also found to have high stability up to six reuses. V-D exhibited excellent compatibility with LA-MR because the lipase immobilized onto MR did not physically contact with the vanadium species immobilized onto diatomite, thus avoiding inactivation. Considering that lipase, oxovanadium, diatomite, and MR used are relatively inexpensive, and the adsorption or grinding immobilization is simple, the LA-V-MD DKR by coupling LA-MR with V-D is a cost-effective and promising protocol for chiral secondary alcohols.

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.

Green Dynamic Kinetic Resolution—Stereoselective Acylation of Secondary Alcohols by Enzyme-Assisted Ruthenium Complexes

Dynamic kinetic resolution allows for the synthesis of enantiomerically pure asymmetric alcohols. Cyclopentadienyl-derived ruthenium catalysts were immobilized with an ionic liquid, [BMIM][NTf2], on multiwall carbon nanotubes and used for the racemization of chiral secondary alcohols. This successful approach was combined with the enantioselective enzymatic acylation of secondary alcohols (1-phenylethanol and 1-(1-naphthyl)ethanol) using Novozyme® 435. The resulting catalytic system of the ruthenium racemization catalysts and enzymatic acylation led to chiral esters being obtained by dynamic kinetic resolution. The immobilized catalytic system in the ionic liquid gave the same activity of >96% yield within 6 h and a selectivity of 99% enantiomeric excess as the homogeneous system, while allowing for the convenient separation of the desired products from the catalyst. Additionally, the process can be regarded as green, since the efficient reuse of the catalytic system was demonstrated.

Enantiodivergent Chemoenzymatic Dynamic Kinetic Resolution: Conversion of Racemic Propargyl Alcohols into Both Enantiomers.

Natural lipases typically recognize enantiomers of alcohols based on the size differences of substituents near the carbinol moiety and selectively react with the R enantiomers of secondary alcohols. Therefore, lipase-catalyzed dynamic kinetic resolution (DKR) of racemic secondary alcohols produces only R enantiomers. We report herein a method for obtaining S enantiomers by DKR of secondary 3-(trialkylsilyl)propargyl alcohols by using a well-known R-selective Pseudomonas fluorescens lipase in combination with a racemization catalyst VMPS4, in which the silyl group reverses the size relationship of substituents near the carbinol moiety. We have already reported R-selective DKR of the corresponding propargyl alcohols without substituents on the ethynyl terminal carbon, and the presence of an easily removable silyl group has enabled us to produce both enantiomers of propargyl alcohols in high chemical yields and with high enantiomeric excess. In addition, immobilization of the lipase on Celite was found to be important for achieving a high efficiency of the DKR.

Solid-State Deracemization via Temperature Cycles in Continuous Operation: Model-Based Process Design.

Solid-state deracemization via temperature cycles converts a racemic crystal mixture into an enantiopure product by periodic cycling of the temperature in the presence of a racemization catalyst. A continuous counterpart of this conventional batch-operated process is proposed that can be performed in mixed suspension mixed product removal crystallizers (MSMPRCs). More specifically, three different configurations are described to perform periodic forcing via temperature cycles, which differ from each other in the type of the feed and in the withdrawal system. We have developed a model by extending our recent population balance equation model of batch solid-state deracemization via temperature cycles, and we exploit this tool to analyze the start-up and periodic steady-state behavior. Moreover, we compare the performance of the different configurations based on the selected key performance indicators, namely, average periodic steady-state enantiomeric excess and productivity. The process with solution feed yields pure enantiomers, while the solid and suspension-fed process alternatives result in highly enantiomerically enriched crystals. We further design an MSMPRC cascade to overcome this purity limitation. This work discusses guidelines on how to transform the batch process of temperature cycles into a continuous operation, which enables stable, unattended operation and chiral crystal production with consistent product quality.

Perylene Bisimide Cyclophanes as Biaryl Enantiomerization Catalysts─Explorations into π-π Catalysis and Host-Guest Chirality Transfer.

The racemization of axially chiral biaryls is a fundamental step toward transforming kinetic resolutions into dynamic kinetic resolutions (DKRs). The high enantiomerization barriers of many biaryl compounds of synthetic relevance, however, may render DKR strategies challenging. Here, we computationally explore the potential of a para-xylene bridged perylene bisimide cyclophane to serve as a conceptually transferrable biaryl enantiomerization catalyst for fundamental biphenyl and binaphthyl scaffolds, as well as the versatile reagent 1,1'-binaphthyl-2,2'-diol and a precursor to the heterobiaryl ligand QUINAP. The calculated enantiomerization barriers of the different biaryls decrease by 19.8-73.2% upon complexation, suggesting that the cyclophane may form an effective biaryl racemization catalyst. We find that these observed barrier reductions predominantly originate from a combination of transition structure stabilization through π-π stacking interactions between the shape-complementary transition structures and catalyst, as well as ground-state destabilization of the less complementary reactants, indicating a generalizable strategy toward biaryl racemization catalysis. In exploring all enantiomerization pathways of the biaryls under consideration, we further find a systematic enantiomer- and conformer-dependent chirality transfer from biaryl to cyclophane in host-guest complexes.

Environmental modulation of chiral prolinamide catalysts for stereodivergent conjugate addition

Synthetic chiral catalysts generally rely on proximal functional groups or ligands for chiral induction. Enzymes often employ environmental chirality to achieve stereoselectivity. Environmentally controlled catalysis has benefits such as size and shape selectivity but is underexplored by chemists. We here report molecularly imprinted nanoparticles (MINPs) that utilized their environmental chirality to either augment or reverse the intrinsic selectivity of a chiral prolinamide cofactor. The latter ability allowed the catalyst to produce products otherwise disfavored in the conjugate addition of aldehyde to nitroalkene. The catalysis occurred in water at room temperature and afforded γ-nitroaldehydes with excellent yields (up to 94%) and ee (>90% in most cases). Up to 25:1 syn/anti and 1:6 syn/anti ratios were achieved through a combination of catalyst-derived and environmentally enabled selectivity. The high enantioselectivity of the MINP also made it possible for racemic catalysts to perform asymmetric catalysis, with up to 80% ee for the conjugate addition.

In depth analysis of heterogeneous catalysts for the chemoenzymatic dynamic kinetic resolution of β-amino esters

The chemoenzymatic dynamic kinetic resolution of β-amino esters is established after detailed evaluation of metal-based heterogeneous catalysts for racemization and enzyme catalysts for kinetic resolution.

Preparation of racemic α-amino acid standards for accurate mass spectrometric analysis via racemization catalyzed by a hydrophobic pyridoxal derivative

Racemic α-amino acid standards for chiral metabolomics were prepared from l-α-amino acids using a hydrophobic pyridoxal derivative, namely 3-hydroxy-2-methyl-5-((octyloxy)methyl)isonicotinaldehyde (OPy), as the racemization catalyst. Among the 19 tested proteinogenic amino acids, 13 (including the generally unstable asparagine, glutamine, and tryptophan) underwent efficient racemization/epimerization under mildly basic conditions at room temperature, while solid-phase extraction allowed for effective and simple catalyst removal and amino acid recovery, obviating the need for chromatographic separation and recrystallization. Isotopically labeled racemic amino acids are commonly employed as internal standards for highly accurate mass spectrometric analysis. However, as isotopically labeled d-amino acids are often unavailable or highly expensive, the developed method was used to prepare racemic labeled amino acids, which were shown to enhance the repeatability and accuracy of d,l-amino acid quantitation in human urine by liquid chromatography-mass spectrometry (LC-MS). Given that our method should also be applicable to non-proteinogenic α-amino acids and the N-termini of peptides, the present study is expected to accelerate the development of LC-MS-based chiral metabolomics.

Asymmetric Synthesis of Biaryl Diols via Dynamic Kinetic Resolution

We have developed a protocol incuding dynamic kinetic resolution as the key step for the asymmetric synthesis of biaryl diol stereoisomers. The two aryl alkanols as the starting materials were cross‐coupled by palladium catalysis to give dl‐ and meso‐diol, which were then subject to chemoenzymatic dynamic kinetic resolution (DKR) for the transformation into single stereoisomeric diol diester. Diol diester was finally deacylated to give the corresponding biaryl diol stereoisomer. The chemoenzymatic DKR was performed with a ruthenium‐based racemization catalyst and a (R)‐selective lipoprotein lipase. Total 17 (R,R)‐diols including 7 C2‐symmetric diols were synthesized with excellent enantiopurities (>99% ee).

Optimizing the Yield of a Pure Enantiomer by Integrating Chiral SMB Chromatography and Racemization. Part 2: Theory

We address the purification of the target enantiomer of a chiral compound from its racemic mixture, through simulated moving bed (SMB) chromatography either as a standalone or combined with the recycle and racemization of the undesired enantiomer. We carry out a comparative assessment of the two processes with focus on the role of the racemization kinetics, on the effect of the selectivity of the chiral stationary phase, and of the upstream symmetric synthesis of the racemate. The analysis is general thanks to the methods adopted for the optimal design of the integrated process (with racemization) and for the sizing of the SMB unit, as well as for the use of the four generalized Langmuir adsorption isotherms. In this way, we determine quantitative criteria that show that the standalone SMB process outperforms the integrated process when the performance of the racemization catalyst or the chiral stationary phase is poor and the racemic feed is inexpensive.

Enantioselective Conjugate Addition of Catalytically Generated Zinc Homoenolate

We report herein an enantioselective conjugate addition reaction of a zinc homoenolate, catalytically generated via ring opening of a cyclopropanol, to an α,β-unsaturated ketone. The reaction is promoted by a zinc aminoalkoxide catalyst generated from Et2Zn and a chiral β-amino alcohol to afford 1,6-diketones, which undergo, upon heating, intramolecular aldol condensation to furnish highly substituted cyclopentene derivatives with good to high enantioselectivities. The reaction has proved applicable to various 1-substituted cyclopropanols as well as chalcones and related enones. The chiral amino alcohol has proved to enable ligand-accelerated catalysis of the homoenolate generation and its conjugate addition. Positive nonlinear effects and lower reactivity of a racemic catalyst have been observed, which can be attributed to a stable and inactive heterochiral zinc aminoalkoxide dimer.

Engineering and Performance of Ruthenium Complexes Immobilized on Mesoporous Siliceous Materials as Racemization Catalysts

Dynamic kinetic resolution (DKR) is one of the most attractive routes to enantioselective synthesis, and ruthenium complexes are often applied as racemization catalysts. Two substituted cyclopentadienyl ruthenium complexes were immobilized covalently and non-covalently on mesoporous silica of mesocellular foam (MCF) and Santa Barbara Amorphous (SBA)-15 type functionalized with a 3 carbon spacer and 4-(chloromethyl)-N-amidobenzoate moiety. The catalysts were studied in a model reaction of secondary alcohol racemization. The immobilization decreased catalyst activity, considerably more for SBA-15 than for MCFs, and complete racemization of 1-phenylethanol was achieved within 24 h with the MCF-supported catalyst. The catalyst could be recovered and reused, thus paving the way for further development of the DKR process. The synthesized materials were fully characterized by Fourier-transform infrared spectroscopy analysis, thermogravimetry analysis, inductively cou-pled plasma optical emission spectrometry, and nitrogen adsorption at 77 K.

Enantioselective extraction of unprotected amino acids coupled with racemization

Scalable and economical methods for the production of optically pure amino acids, both natural and unnatural, are essential for their use as synthetic building blocks. Currently, enzymatic dynamic kinetic resolution (DKR) underpins some of the most effective processes. Here we report the development of enantioselective extraction coupled with racemization (EECR) for the chirality conversion of underivatized amino acids. In this process, the catalytic racemization of amino acids in a basic aqueous solution is coupled with the selective extraction of one enantiomer into an organic layer. Back-extraction from the organic layer to an acidic aqueous solution then completes the deracemization of the amino acid. The automation of the EECR process in a recycling flow reactor is also demonstrated. Continuous EECR is made possible by the sterically hindered chiral ketone extractant 5, which prevents the coextraction of the copper racemization catalyst because of its nonplanar geometry. Furthermore, the extractant 5 unexpectedly forms imines with amino acids faster and with greater enantioselectivity than less bulky derivatives, even though 5 cannot participate in intramolecular resonance-assisted hydrogen bonding. These features may allow EECR to challenge the preponderance of enzymatic DKR in the production of enantiomerically enriched amino acids.