Chiral Alcohols Research Articles

Merging High‐Pressure Syngas Metal Catalysis and Biocatalysis in Tandem One‐Pot Processes for the Synthesis of Nonchiral and Chiral Alcohols from Alkenes in Water

AbstractWhile simultaneously proceeding reactions are among the most fascinating features of biosynthesis, this concept of tandem processes also offers high potential in the chemical industry in terms of less waste production and improved process efficiency and sustainability. Although examples of one‐pot chemoenzymatic syntheses exist, the combination of completely different reaction types is rare. Herein, we demonstrate that extreme “antipodes” of the “worlds of catalysis”, such as syngas‐based high‐pressure hydroformylation and biocatalyzed reduction, can be combined within a tandem‐type one‐pot process in water. No significant deactivation was found for either the biocatalyst or the chemocatalyst. A proof‐of‐concept for the one‐pot process starting from 1‐octene was established with >99 % conversion and 80 % isolated yield of the desired alcohol isomers. All necessary components for hydroformylation and biocatalysis were added to the reactor from the beginning. This concept has been extended to the enantioselective synthesis of chiral products by conducting the hydroformylation of styrene and an enzymatic dynamic kinetic resolution in a tandem mode, leading to an excellent conversion of >99 % and an enantiomeric ratio of 91 : 9 for (S)‐2‐phenylpropanol. The overall process runs in water under mild and energy‐saving conditions, without any need for intermediate isolation.

Efficient bioreduction of 4-phenyl-2-butanone to drug precursor (S)-4-phenyl-2-butanol by a whole-cell biocatalyst using a novel hybrid design technique

Asymmetric synthesis is a critical tactic in pharmaceutical industries for creating chiral medications as it allows an enantiomer to be obtained in synthetic chemistry. The asymmetric bioreduction processes by biocatalysts have shown significant potential in producing chiral alcohols. The amount of substrate and the production method of the biocatalytic synthesis of (S)-4-phenyl-2-butanol ((S)-2) are not still desired levels. Furthermore, the biocatalytic asymmetric reduction of 4-phenyl-2-butanone (1) to (R)- or (S)-4-phenyl-2-butanol did not use any mathematical modeling techniques. In this study, the asymmetric bioreduction of 1 was carried out in this work employing Lactobacillus paracasei BD71 biocatalyst and a novel hybrid design-based optimization approach. By using the hybrid design technique, the optimal circumstances were discovered to be pH = 7, temperature = 29 °C, incubation period = 66 h, and agitation speed = 189 rpm. Also, the enantiomeric excess (ee) and conversion could be 99.15 % and 98.19 %, respectively. Next, (S)-2 was acquired to be ee: 99 %, conversion: >99 %, and yield: 97 % from the optimum bioreduction conditions. Furthermore, 14.08 g of 1 under optimal conditions was entirely transformed into (S)-2 (13.84 g, 97 % isolated yield). This study is the first research attempt to use a biocatalyst and an innovative and new hybrid design-based optimization approach to fabricate enantiopure (S)-2 at a high gram scale. This work has successfully demonstrated that the new hybrid design-based optimization technique is applicable to biocatalytic asymmetric reduction processes.

Enhanced catalytic efficiency for chiral alcohol pharmaceutical intermediate production using polyacrylic acid (PAA)-based nano-bienzyme conjugates at the organic-buffer biphasic interface

Nano-bienzyme conjugates (nano-BECs) for catalysing one-pot reactions can simplify the reaction process and improve the efficiency of biocatalytic reactions. In this work glucose dehydrogenase (GDH) and Candida parapsilosis secondary alcohol dehydrogenase (CpSADH) were immobilised with polyacrylic acid (PAA) to form two types of PAA-based nano-BECs (2-S, 2-P), which achieved in situ regeneration of NADH for the production of chiral alcohols in oil-water biphasic systems, such as the key chiral pharmaceutical intermediate of (S)-1-(3-trifluoromethylphenyl)ethanol ((S)-TMPE). At a substrate concentration of 100 mM 3-trifluoromethylacetophenone (TMAP), the conversion catalyzed by nano BEC was 98.2 % in dipentyl phthalate-phosphate buffer biphasic system. In contrast, the conversion was only 39.5 % and 38.9 % in the PB buffer and 8.4 % and 7.7 % in dipentyl phthalate system. The experiments on kinetic constants demonstrated that the catalytic efficiencies (Kcat/Km) of nano-BECs (2-S, 2-P) were enhanced by 6.7-fold and 7-fold, respectively, compared to free CpSADH. Additionally, nano-BECs showed stronger coenzyme regeneration ability. Under optimal reaction conditions, nano-BECs achieved 96.2 % conversion of TMAP to (S)-TMPE in an organic-buffer system with e.e. > 99.6 % at 300 mM substrate concentration. This research expands the potential applications of polymers and proteins, and offers valuable insights into the synergistic effects of PAA on bienzyme catalytic systems in biocatalysis.

Co-Immobilization of ADH and GDH on Metal-Organic-Framework: An Effective Biocatalyst for Asymmetric Reduction of Ketones.

Chiral alcohols are not only important building blocks of various bioactive natural compounds and pharmaceuticals, but can serve as synthetic precursors for other valuable organic chemicals, thus the synthesis of these products is of great importance. Bio-catalysis represents one effective way to obtain these molecules, however, the weak stability and high cost of enzymes often hinder its broad application. In this work, we designed a biological nanoreactor by embedding alcohol dehydrogenase (ADH) and glucose dehydrogenase (GDH) in metal-organic-framework ZIF-8. The biocatalyst ADH&GDH@ZIF-8 could be applied to the asymmetric reduction of a series of ketones to give chiral alcohols in high yields (up to 99 %) and with excellent enantioselectivities (>99 %). In addition, the heterogeneous biocatalyst could be recycled and reused at least four times with slight activity decline. Moreover, E. coli containing ADH and GDH was immobilized by ZIF-8 to form biocatalyst E. coli@ZIF-8, which also exhibits good catalytic behaviours. Finally, the chiral alcohols are further converted to marketed drugs (R)-Fendiline, (S)-Rivastigmine and NPS R-568 respectively.

Chemoenzymatic Sequential Catalysis with Carbonic Anhydrase for the Synthesis of Chiral Alcohols from Alkanes, Alkenes, and Alkynes

Chemoenzymatic Sequential Catalysis with Carbonic Anhydrase for the Synthesis of Chiral Alcohols from Alkanes, Alkenes, and Alkynes

Enantioselective Alkylation of Aldehydes with Organoborons Enabled by Nickel/N‐Heterocyclic Carbene Catalysis†

Comprehensive SummaryTransition‐metal‐catalyzed asymmetric alkylation of aldehydes represents a straightforward strategy for the synthesis of chiral secondary alcohols. However, efficient methods using organoborons as coupling reagents are rare. Herein, we report a highly enantioselective nickel‐catalyzed alkylation reaction of aldehydes, using readily available alkylborons as nucleophiles. A wide variety of chiral secondary alcohols were prepared from commercially available aldehydes with high yields. The key to the excellent enantioselectivity and chemoselectivity was the employment of a bulky C2‐symmetric chiral NHC ligand. This protocol features excellent enantiocontrol, mild conditions, and good functional group compatibility.

Design of 3D-Printed Heterogeneous Reactor Systems To Overcome Incompatibility Hurdles when Combining Metal and Enzyme Catalysis in a One-Pot Process.

Combining chemo- and biocatalysis enables the design of novel economic and sustainable one-pot processes for the preparation of industrial chemicals, preferably proceeding in water. While a range of proofs-of-concept for the compatibility of such catalysts from these two different "worlds of catalysis" have recently been demonstrated, merging noncompatible chemo- and biocatalysts for joint applications within one reactor remained a challenge. A conceptual solution is compartmentalization of the catalytic moieties by heterogenization of critical catalyst components, thus "shielding" them from the complementary noncompatible catalyst, substrate or reagent. Exemplified for a one-pot process consisting of a metal-catalyzed Wacker oxidation and enzymatic reduction as noncompatible individual reactions steps, we demonstrate that making use of 3D printing of heterogeneous materials containing Cu as a critical metal component can overcome such incompatibility hurdles. The application of a 3D-printed Cu-ceramic device as metal catalyst component allows an efficient combination with the enzyme and the desired two-step transformation of styrene into the chiral alcohol product with high overall conversion and excellent enantioselectivity. This compartmentalization concept based on 3D printing of heterogenized metal catalysts represents a scalable methodology and opens up numerous perspectives to be used as a general tool also for other related chemoenzymatic research challenges.

Design von 3D‐gedruckten heterogenen Reaktorsystemen zur Überwindung von Inkompatibilitätshürden bei der Kombination von Metall‐ und Enzym‐Katalyse in einem Eintopf‐Prozess

AbstractDie Kombination von Chemo‐ und Biokatalyse ermöglicht die Entwicklung neuartiger ökonomischer und nachhaltiger Eintopfverfahren für die Herstellung von Industriechemikalien, welche vorzugsweise in Wasser ablaufen. Während kürzlich anhand einer Reihe von Beispielen der Nachweis für die Kompatibilität solcher Katalysatoren aus diesen beiden unterschiedlichen “Welten der Katalyse” aufgezeigt wurde, blieb die Zusammenführung nicht kompatibler Chemo‐ und Biokatalysatoren für gemeinsame Anwendungen in einem Reaktor eine Herausforderung. Eine konzeptionelle Lösung besteht in der Kompartimentierung der katalytischen Einheiten durch Heterogenisierung kritischer Katalysatorkomponenten, wodurch diese von dem komplementären, nicht kompatiblen Katalysator, Substrat oder Reagenz “abgeschirmt” werden. Am Beispiel eines Eintopfverfahrens, das aus einer Metall‐katalysierten Wacker‐Oxidation und einer enzymatischen Reduktion als nicht‐kompatible Einzelreaktionsschritte besteht, zeigen wir, dass durch den Einsatz des 3D‐Drucks von heterogenen, die kritische Metallkomponente Kupfer enthaltenden Materialien solche Hürden der Inkompatibilität überwinden werden können. Der Einsatz eines 3D‐gedruckten Cu‐Keramikgerüsts als Metallkatalysator‐Komponente ermöglicht eine effiziente Kombination mit dem Enzym und die gewünschte zweistufige Umwandlung von Styrol in das chirale Alkoholprodukt mit hohem Gesamtumsatz und exzellenter Enantioselektivität. Dieses auf 3D‐Druck heterogenisierter Metallkatalysatoren basierende Konzept zur Kompartimentierung stellt eine skalierbare Methodik dar und eröffnet zahlreiche Perspektiven im Hinblick auf dessen Nutzung als allgemeiner Lösungsansatz auch für weitere verwandte chemoenzymatische Forschungsherausforderungen.

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.

Enantioselective and divergent construction of chiral amino alcohols and oxazolidin-2-ones via Ir-f-phamidol-catalyzed dynamic kinetic asymmetric hydrogenation

Enantioselective and divergent construction of chiral amino alcohols and oxazolidin-2-ones via Ir-f-phamidol-catalyzed dynamic kinetic asymmetric hydrogenation

Protein engineering of lipase A from Candida antarctica to improve esterification of tertiary alcohols.

Chiral tertiary alcohols are important organic compounds in science as well as in industry. However, their preparation in enantiomerically pure form is still a challenge due to their complex structure and steric hindrances compared with primary and secondary alcohols, so kinetic resolution could be an attractive approach. Lipase A from Candida antarctica (CAL-A) has been shown to catalyze the enantioselective esterification of various tertiary alcohols with excellent enantioselectivity but low activity. Here we report a mutagenesis study by rational design to improve CAL-A activity against tertiary alcohols. Single mutants of CAL-A were selected, expressed, immobilized and screened for esterification of the tertiary alcohol 1,2,3,4-tetrahydronaphthalene-1-ol. A double mutant V278S+S429G showed a 1.5-fold higher reaction rate than that of the wild type CAL-A, while maintaining excellent enantioselectivity.

Synthesis of Optically Pure Cyclometalated Iridium(III) Complex‐Peptide Hybrids and Their Anticancer Activity.

We report on the synthesis of optically pure cyclometalated iridium(III) complex‐peptide hybrids as amphiphilic peptide conjugates (IPH‐ACs) from Δ‐ and Λ‐Ir(tpyCO2H)3 (tpy: 2‐(4’‐tolyl)pyridine) by optical resolution via diastereomeric intermediates conjugated with the chiral alcohol, (1R,2R)‐2‐aminocyclohexanol ((R,R)‐11). Spectroscopic spectra of the optically pure IPH‐ACs that were prepared from Δ‐ and Λ‐Ir(tpyCO2H)3 are reported. It was found that both optically pure IPH‐ACs induce paraptotic cell death in Jurkat cells and the EC50 values were evaluated by MTT assays. We also performed TEM analyses of Jurkat cells treated with Λ‐13 to observe morphological changes that occurred, and cytoplasmic vacuolization, a characteristic feature of paraptosis, was observed. The intracellular uptake of IPH‐ACs by the cells measured by ICP‐MS (inductively coupled plasma‐mass spectrometry) was higher for the Λ‐forms and the EC50 values of the Λ‐forms were slightly lower than those of the Δ‐IPH‐ACs. The intrinsic cytotoxicity of the IPH‐ACs, taking into account the fact that the intracellular uptake and the intrinsic cytotoxicity is almost equal for the Δ‐ and Λ‐forms, suggests that the difference in cytotoxicity against Jurkat cells is due to the selectivity in the intracellular uptake of each stereoisomer.

Tuning Mechanical Characteristics and Permeability of Alginate Hydrogel by Polyvinyl Alcohol and Deep Eutectic Solvent Addition.

Alginate-based hydrogels are widely utilized for various applications, including enzyme immobilization and the development of drug delivery systems, owing to their advantageous characteristics, such as low toxicity, high availability and cost-effectiveness. However, the broad applicability of alginate hydrogels is hindered by their limited mechanical and chemical stability, as well as their poor permeability to hydrophobic molecules. In this study, we addressed the mechanical properties and chemical resistance of alginate hydrogels in a high-pKa environment by the copolymerization of alginate with polyvinyl alcohol (PVA). The addition of PVA resulted in a threefold improvement in the shear modulus of the copolymeric hydrogel, as well as enhanced chemical resistance to (S)-α-methylbenzylamine, a model molecule with a high pKa value. Furthermore, we addressed the permeability challenge by introducing a betaine-propylene glycol deep eutectic solvent (DES) into the PVA-alginate copolymer. This led to an increased permeability for ethyl 3-oxobutanoate, a model molecule used for bioreduction to chiral alcohols. Moreover, the addition of the DES resulted in a notable improvement of the shear modulus of the resulting hydrogel. This dual effect highlights the role of the DES in achieving the desired improvement of the hydrogel as an immobilization carrier.

Asymmetric Hydrogenative Coupling of Indoles with Unsaturated Ketones Enabled by Copper/Ruthenium Relay Catalysis

AbstractA relay catalytic system is developed for the asymmetric hydrogenative coupling of indoles with α,β-unsaturated ketones, affording enantioenriched chiral γ-indole alcohols with broad substrate scope and excellent enantioselectivities (32 examples, up to >99% ee). Mechanistic studies suggest that the relay catalytic system consists of copper-catalyzed alkylation and ruthenium-catalyzed asymmetric hydrogenation.

Enzymatic kinetic resolution of an intermediate alcohol of the drug Tegoprazan using lipase from Thermomyces lanuginosus

An enzymatic approach for the synthesis of intermediate alcohol of the drug tegoprazan in 99% ee at 20 °C in hexane has been developed utilizing commercially available immobilized Thermomyces lanuginosus lipase (TL lipase) as a biocatalyst and vinyl acetate as a acyl donor. This method involves the enantioselective esterification of (RS)-5,7-difluorochroman-4-ol with vinyl acetate using TL Lipase. This enzymatic approach provides the (S)-chiral alcohol in 44% yield with 99% enantiomeric excess (ee) and the (R)-acetate in 43% yield and >99% ee. It is a sustainable approach for the synthesis of enantiopure tegoprazan intermediate, contributing to the advancement of green chemistry. The recovered TL lipase was reused in 13 subsequent runs without loss of activity.

Engineering diaryl alcohol dehydrogenase KpADH reveals importance of retaining hydration shell in organic solvent tolerance.

Alcohol dehydrogenases (ADHs) are synthetically important biocatalysts for the asymmetric synthesis of chiral alcohols. The catalytic performance of ADHs in the presence of organic solvents is often important since most prochiral ketones are highly hydrophobic. Here, the organic solvent tolerance of KpADH from Kluyveromyces polyspora was semi-rationally evolved. Using tolerant variants obtained, meticulous experiments and computational studies were conducted to explore properties including stability, activity and kinetics in the presence of various organic solvents. Compared with WT, variant V231D exhibited 1.9-fold improvement in ethanol tolerance, while S237G showed a 6-fold increase in catalytic efficiency, a higher , as well as 15% higher tolerance in 7.5% (v/v) ethanol. Based on 3 × 100 ns MD simulations, the increased tolerance of V231D and S237G against ethanol may be ascribed to their enhanced ability in retaining water molecules and repelling ethanol molecules. Moreover, 6.3-fold decreased KM value of V231D toward hydrophilic ketone substrate confirmed its capability of retaining hydration shell. Our results suggest that retaining hydration shell surrounding KpADH is critical for its tolerance to organic solvents, as well as catalytic performance. This study provides useful guidance for engineering organic solvent tolerance of KpADH and other ADHs.

New Strategy for the Synthesis of Some Valuable Chiral 1,3-Diols with High Enantiomeric Purity: New Organocatalyst, Asymmetric Aldol Reaction, and Reduction.

Chiral 1,3-diols are highly valuable molecules used in industries such as pharmaceuticals, cosmetics, and agriculture. Therefore, in this study, a new strategy was developed to synthesize enantiomerically pure (>99% ee) 1,3-diols. New chiral 1,3-diols (5a-5q) with high enantiomeric purity were synthesized from aldol products chiral 1,3-keto alcohols (4a-4q), which are aldol products with different structures. Chiral 1,3-keto alcohols (4a-4q) were synthesized by a new asymmetric aldol method in the first step. This method was developed using a new proline-derived organocatalyst (3g) and Cu(OTf)2 as an additive in DMSO-H2O for the first time. Almost >99% ee was obtained using our developed aldol procedure. In the second step, original chiral diols (5a-5q) of high enantiomeric purity were obtained by asymmetric reduction of chiral keto alcohols with chiral oxazaborolidine reagents. In this way, a two-step asymmetric reaction was developed for chiral 1,3-diol enantiomers with high enantiomeric purity. The structures of all the original chiral compounds obtained were elucidated by infrared and nuclear magnetic resonance spectroscopy, mass spectrometry, and elemental analysis methods. Their enantiomeric excesses were determined by the chiral high-performance liquid chromatography method. Both keto alcohols and their corresponding chiral diols synthesized can be used as chiral starting materials and chiral source materials or intermediates in the synthesis of many biologically active molecules, or they can be used as chiral ligands in asymmetric synthesis, serving as organocatalysts.

Catalytic Enantioselective Alkyne Addition to Nitrones Enabled by Tunable Axially Chiral Imidazole-Based P,N-Ligands.

Although catalytic enantioselective alkyne addition is an established method for the synthesis of chiral propargylic alcohols and amines, addition to nitrones presents unique challenges, and no general chiral catalyst system has been developed. In this manuscript, we report the first Cu-catalyzed enantioselective alkyne addition to nitrones utilizing tunable axially chiral imidazole-based P,N-ligands. Our approach effectively overcomes difficulties in both reactivity and selectivity, resulting in a simple Cu-catalyzed protocol. The reaction accommodates a wide range of nitrones and alkynes, enabling the streamlined synthesis of chiral propargyl N-hydroxylamines via the enantioselective C-C bond formation. A diverse array of optically active nitrogen-containing compounds, including chiral hydroxylamines, can be accessed directly through facile transformations of the reaction products.

Synthesis and Application of a New Class of Planar and Centrally Chiral Ferrocenyl Amino Alcohol Ligands

AbstractA family of ferrocenyl amino alcohols (14 examples) has been prepared from the corresponding planar chiral ketones and evaluated as a new class of chiral ligands for asymmetric ethyl‐ and phenylzinc additions to aldehydes. The highly enantioselective synthesis of these ligands is facile, scalable, robust and relies on the use of cheaply available starting materials. Asymmetric ethyl additions proceeded smoothly at ambient temperature, with reaction times as short as 1 hour furnishing the desired products in up to 90 % yield and 99 % ee. The corresponding phenyl additions afforded products in up to 81 % yield and 88 % ee. The observed stereochemical outcome for the addition of diethylzinc was rationalized and the key proposed transition state was supported by an analysis of the X‐ray structures of a series of amino alcohol ligands.

Identification of a potent palladium-aryldiphosphine catalytic system for high-performance carbonylation of alkenes

The development of stable and efficient ligands is of vital significance to enhance the catalytic performance of carbonylation reactions of alkenes. Herein, an aryldiphosphine ligand (L11) bearing the [Ph2P(ortho-C6H4)]2CH2 skeleton is reported for palladium-catalyzed regioselective carbonylation of alkenes. Compared with the industrially successful Pd/1,2-bis(di-tert-butylphosphinomethyl)benzene catalyst, catalytic efficiency catalyzed by Pd/L11 on methoxycarbonylation of ethylene is obtained, exhibiting better catalytic performance (TON: >2,390,000; TOF: 100,000 h−1; selectivity: >99%) and stronger oxygen-resistance stability. Moreover, a substrate compatibility (122 examples) including chiral and bioactive alkenes or alcohols is achieved with up to 99% yield and 99% regioselectivity. Experimental and computational investigations show that the appropriate bite angle of aryldiphosphine ligand and the favorable interaction of 1,4-dioxane with Pd/L11 synergistically contribute to high activity and selectivity while the electron deficient phosphines originated from electron delocalization endow L11 with excellent oxygen-resistance stability.