High Enantiomeric Excess Research Articles

Autonomous Chiral Microswimmers with Self‐mixing Capabilities for Highly Efficient Enantioselective Synthesis

AbstractThe development of chiral catalysts plays a very important role in various areas of chemical science. Heterogeneous catalysts have the general advantage of allowing a more straightforward separation from the products. One specific case of heterogeneous catalysis is electrocatalysis, being potentially a green chemistry approach. However, a typical drawback is that the redox conversion of molecules occurs only at the electrode/electrolyte interface, and not in the bulk of the electrolyte. The second limitation is that the electrodes have to be physically connected to a power supply to induce the desired reactions. To circumvent these problems, we propose here a complementary approach by replacing macroscopic electrodes with an ensemble of self‐propelled redox active microswimmers. They move autonomously in solution while transforming simultaneously a prochiral starting compound into a specific enantiomer with a very high enantiomeric excess, accompanied by a significantly increased production rate of the favorite enantiomer.

Autonomous Chiral Microswimmers with Self-mixing Capabilities for Highly Efficient Enantioselective Synthesis.

The development of chiral catalysts plays a very important role in various areas of chemical science. Heterogeneous catalysts have the general advantage of allowing a more straightforward separation from the products. One specific case of heterogeneous catalysis is electrocatalysis, being potentially a green chemistry approach. However, a typical drawback is that the redox conversion of molecules occurs only at the electrode/electrolyte interface, and not in the bulk of the electrolyte. The second limitation is that the electrodes have to be physically connected to a power supply to induce the desired reactions. To circumvent these problems, we propose here a complementary approach by replacing macroscopic electrodes with an ensemble of self-propelled redox active microswimmers. They move autonomously in solution while transforming simultaneously a prochiral starting compound into a specific enantiomer with a very high enantiomeric excess, accompanied by a significantly increased production rate of the favorite enantiomer.

Asymmetric Total Synthesis of a Bioactive Lignanamide Using a 5‐endo‐tet‐Type Cyclization of Activated Cyclopropylcarbinols and Synthetic Support for the Reaction Mechanism

AbstractThe first enantioselective total synthesis of a bioactive lignanamide was achieved with high enantiomeric excess. Key synthetic steps include an organocatalytic enantioselective cyclopropanation and a Lewis‐acid‐mediated chirality‐transferring 5‐endo‐tet‐type cyclization that proceeds with a very high degree of stereoinduction. The proposed mechanism of the key reaction is supported by the experimental results. Based on these experimental results, the 5‐endo‐tet‐type cyclization of a cyclopropylcarbinol proceeds predominantly via an SN1 mechanism with high trans‐selectivity, which arises from the steric hindrance of the neighboring substituent. Minor pathways include the anchimeric participation of (i) the oxygen atom of the benzoyl group in an SN2 mechanism and/or (ii) a benzene‐coordinated transition state in an SN1‐like mechanism.

Enantioselective (8+3) Cycloadditions by Activation of Donor-Acceptor Cyclopropanes Employing Chiral Brønsted Base Catalysis.

A novel enantioselective (8+3) cycloaddition between donor–acceptor cyclopropanes and heptafulvenoids catalysed by a chiral bifunctional Brønsted base is described. Importantly, the reaction, which leverages an anionic activation strategy, is divergent from prototypical Lewis‐acid activation protocols. A series of cyclopropylketones react with tropones affording the desired (8+3) cycloadducts in high yield and enantiomeric excess. For barbiturate substituted heptafulvenes, the (8+3) cycloaddition with cyclopropylketones proceeds in good yield, excellent diastereoselectivity and high enantiomeric excess. The experimental work is supported by DFT calculations, which indicate that the bifunctional organocatalyst activates both the donor–acceptor cyclopropane and tropone; the reaction proceeds in a step‐wise manner with the ring‐closure being the stereodetermining step.

Enantioselective (8+3) Cycloadditions by Activation of Donor–Acceptor Cyclopropanes Employing Chiral Brønsted Base Catalysis

AbstractA novel enantioselective (8+3) cycloaddition between donor–acceptor cyclopropanes and heptafulvenoids catalysed by a chiral bifunctional Brønsted base is described. Importantly, the reaction, which leverages an anionic activation strategy, is divergent from prototypical Lewis‐acid activation protocols. A series of cyclopropylketones react with tropones affording the desired (8+3) cycloadducts in high yield and enantiomeric excess. For barbiturate substituted heptafulvenes, the (8+3) cycloaddition with cyclopropylketones proceeds in good yield, excellent diastereoselectivity and high enantiomeric excess. The experimental work is supported by DFT calculations, which indicate that the bifunctional organocatalyst activates both the donor–acceptor cyclopropane and tropone; the reaction proceeds in a step‐wise manner with the ring‐closure being the stereodetermining step.

Enantioselective Trost alkynylation with 2E,4E-5-bromo-2,4-pentadienal

The synthetically useful aldehyde 2E,4E-5-bromo-2,4-pentadienal was subjected to the enantioselective Trost alkynylation protocol, yielding highly functionalized propargylic secondary alcohols in an enantioselective manner. In most cases, the isolated yields and enantiomeric excess of the products were modest to high, but several products were formed in both high yields and enantiomeric excess.

Diisopropyl Malonate as Acylating Agent in Kinetic Resolution of Chiral Amines with Lipase B from Candida antarctica

Activity of diisopropyl malonate (2) as a novel acylating agent was investigated in kinetic resolution (KR) of various racemic amines [(±)-1a-d] catalyzed by lipase B from Candida antarctica. Diisopropyl malonate (2) proved to be effective acylating agent with four racemic amines [(±)-2-aminoheptane, (±)-1-methoxy-2-propylamine, (±)-1-phenylethylamine and (±)-4-phenylbutan-2-amine; (±)-1a-d, respectively] selected for this study. The lipase-catalyzed acylation of the amines (±)-1a-d with 2 proceeded with good conversions (44.9–52.1%) and provided the expected (R)-amides [(R)-3a-d] in moderate to excellent yields (51–98%) with high enantiomeric excess (ee(R)-3a-d 92.0–99.9%) after 4 h reaction time under mild reaction conditions in batch mode. The best conversion (50%) combined with high enantiomeric purity (ee(R)-2d > 99%ee) was achieved in the KR from racemic 2-aminoheptane (±)-1a. The four novel (R)-amides [(R)-3a-d] were isolated and properly characterized.

Chemical Composition, Enantiomeric Distribution and Anticholinesterase and Antioxidant Activity of the Essential Oil of Diplosthephium juniperinum.

The aim of this study was to extract and identify the chemical compounds of Diplosthephium juniperinum essential oil (EO) from Ecuador and to assess its anticholinesterase and antioxidant properties. The EO chemical composition was determined by GC–MS. A total of 74 constituents of EO were identified, representing 97.27% in DB-5ms and 96.06% in HP-INNOWax of the total EO. The major constituents (>4.50%) identified were: α-pinene (21.52, 22.04%), geranyl acetate (10.54, 7.78%), silphiper-fol-5-ene (8.67, 7.38%), α-copaene (8.26, 8.18%), 7-epi-silphiperfol-5-ene (4.93, 5.95%), and germacrene D (4.91, 6.00%). Enantioselective analysis of the volatile fraction of D. juniperinum showed: (+)-α-pinene as a pure enantiomer and 5 pairs of enantiomeric compounds. Among them, (−)-β-Pinene and (−)-Germacrene D presented a high enantiomeric excess of 93.23 and 84.62%, respectively, while (−)-α-Thujene, (−)-Sabinene and (S)-4-Terpineol with a lower enantiomeric excess of 56.34, 47.84 and 43.11%, respectively. A moderate inhibitory effect was observed for Acetylcholinesterase (AChE) and Butyrylcholinesterase (BuChE) enzymes with IC50 values of 67.20 ± 7.10 and 89.00 ± 9.90 µg/mL, respectively. A lower antioxidant potential was observed for the EO measured through DPPH and ABTS radical scavenging assays with SC50 values of 127.03 and >1000 µg/mL, respectively. To the best of our knowledge, this is the first report of the chemical composition, enantiomeric distribution and, anticholinesterase and antioxidant potential of the EO of D. juniperinum. As future perspective, further in-vivo studies could be conducted to confirm the anticholinesterase potential of the EO.

The asymmetric Henry reaction as synthetic tool for the preparation of the drugs linezolid and rivaroxaban.

The human drugs – the antibiotic linezolid (1) and the anticoagulant rivaroxaban (2) – belong among modern pharmaceutics, which contain an oxazolidine-2-one moiety bearing a stereogenic center. The chirality of these drugs is a fundamental attribute for their biological activity. Herein, one of the efficient asymmetric syntheses of these drugs was studied in detail. Highly enantioselective catalysts were tested in the key step of the synthetic procedure, i.e., the asymmetric Henry reaction, under different reaction conditions, using several starting aldehydes. The corresponding nitroaldols as chiral intermediates in the syntheses of these drugs were obtained in high yields and enantiomeric excesses of up to 91% ee.

Stereoselective Transaminase‐Mediated Synthesis of Serotonin and Melatonin Receptor Agonists

AbstractTransaminase enzymes have significant potential for the stereoselective synthesis of drugs or drug precursors. Here, starting from one prochiral β‐tetralone, a short and efficient chemoenzymatic synthesis of four agonists of the serotonin/melatonin receptors have been developed. The key step is the stereoselective transamination of the prochiral ketone to produce both enantiomers of 8‐methoxy‐2‐aminotetraline in high yields and enantiomeric excesses. This was followed by either amidation to give the 8‐methoxy‐2‐acetimidotetralines or several facile chemical steps to the 8‐hydroxy‐2‐aminodipropyltetralines.magnified image

Mechanoenzymology in the Kinetic Resolution of β-Blockers: Propranolol as a Case Study.

Recent advances in biotechnology, protein engineering, and enzymatic immobilization have made it possible to carry out biocatalytic transformations through alternative non-conventional activation strategies. In particular, mechanoenzymology (i.e., the use of the mechanical force produced by milling or grinding to activate a biotransformation) has become a new area in so-called "green chemistry", reshaping key fundaments of biocatalysis and leading to the exploration of enzymatic transformations under more sustainable conditions. Significantly, numerous chiral active pharmaceutical ingredients have been synthesized via mechanoenzymatic methods, boosting the use of biocatalysis in the synthesis of chiral drugs. In this regard and aiming to widen the scope of the young field of mechanoenzymology, a dual kinetic resolution of propranolol precursors was explored. The biocatalytic methodology mediated by Candida antarctica Lipase B (CALB) and activated by mechanical force allowed the isolation of both enantiomeric precursors of propranolol with high enantiomeric excess (up to 99% ee), complete conversion (c = 50%), and excellent enantiodifferentiation (E > 300). Moreover, the enantiomerically pure products were used to synthesize both enantiomers of the β-blocker propranolol with high enantiopurity.

Chirality of proteinoid nanoparticles made of lysine and phenylalanine

AbstractProteinoid nanoparticles composed of l‐lysine and l‐phenylalanine were prepared and showed enantioselective adsorption of l‐amino acids at various pH values, emphasizing the chiral nature of the particles. The adsorption was examined using circular dichroism, isothermal titration calorimetry and ζ‐potential measurements. Positively charged ammonium moieties on the proteinoid surface are most likely responsible for the enantioselective adsorption owing to their chirality which originates from l‐lysine. Accordingly, a higher enantiomeric excess was found for amino acids such as alanine with a more negative charge.

Atroposelective Kinetic Resolution of 8H-Indeno[1,2-c]thiophen-8-ols via Pd-Catalyzed C-C Bond Cleavage Reaction.

The present work demonstrates a palladium-catalyzed kinetic resolution/ring-opening reaction of 8H-indeno[1,2-c]thiophen-8-ols. The reaction proceeds in a highly regioselective manner, and both optically active thiophene-phenyl atropisomers and stereogenic 8H-indeno[1,2-c]thiophen-8-ols were obtained with high enantiomeric excesses. The synthetic applications of the obtained thiophenyl atropisomers were briefly investigated.

Ethylenediamine-β-cyclodextrin modified graphene oxide nanocomposite membranes for highly efficient chiral separation of tryptophan and propranolol enantiomers

The separation of racemic drugs remains significance and challenge for pharmaceutical production. Recently, chiral drugs permeation separation based on membrane is a promising technology with advantages of energy efficient, continuous operation and cost-effectiveness. Herein, ethylenediamine-β-cyclodextrin (EDA-β-CD) mixed matrix membranes (EDA-β-CD MMMs) and EDA-β-CD modified graphene oxide thin-film nanocomposite membranes (GO/EDA-β-CD TFNMs) were fabricated via precipitation phase inversion and interfacial polymerization process, respectively. The corresponding membrane structure and GO nanosheets were characterized by SEM, TEM, ATR FT-IR, EA. Subsequently, the water flux, BSA rejection and stability of the membranes were studied. Moreover, enantioseparation performances of GO/EDA-β-CD TFNMs and EDA-β-CD MMMs toward (DL)-tryptophan (Trp) and (RS)-propranolol (Prop) were examined. Results showed that the GO/EDA-β-CD TFNMs exhibited extraordinary enantioselectivity, which remained high percent enantiomeric excess (ee.%) of Trp (100.00%) and Prop (75.34%). GO nanosheets with a multilayer structure and an interlayer spacing not only provided bonding site of EDA-β-CD but also improved permeation flux of the membrane. Finally, molecular docking technology was used to study the separation mechanism of the membranes. These findings demonstrate that GO/EDA-β-CD TFNMs might possess possibilities of high permeability and high enantioselectivity for chiral drugs separation.

Gram-Scale Synthesis of (R)-P-Chlorophenyl-1,2-Ethanediol at High Concentration by a Pair of Epoxide Hydrolases.

(R)-p-chlorophenyl-1,2-ethanediol (pCPED) is an important intermediate for the synthesis of (R)-eliprodil that is widely applied in the treatment of ischemic stroke. To prepare (R)-pCPED with high enantiomeric excess (ee p) and yield via the enantioconvergent hydrolysis of racemic styrene oxide (rac-pCSO) at high concentration, the bi-enzymatic catalysis was designed and investigated by a pair of epoxide hydrolases, a mutant (PvEH1Z4X4-59) of Phaseolus vulgaris EH1 and a mutant (RpEHF361V) of Rhodotorula paludigena RpEH. Firstly, the maximum allowable concentration of rac-pCSO was confirmed. Subsequently, the addition mode and the weight ratio of two Escherichia coli cells were optimized. Finally, under the optimized reaction conditions—the cell weight ratio 20:1 of E. coli/pveh1z4x4-59 to E. coli/rpeh F361V, a simultaneous addition mode, and reaction temperature at 25°C—300 mM rac-pCSO in the 100 ml 4% (v/v) Tween-20/phosphate buffer system (100 mM, pH 7.0) was completely hydrolyzed within 5 h, affording (R)-pCPED with 87.8% ee p, 93.4% yield, and 8.63 g/L/h space–time yield (STY). This work would be an efficient technical strategy for the preparation of chiral vicinal diols at industrial scale.

Optimization of asymmetric reduction conditions of 2-bromo-1-(naphthalen-2-yl)ethanone by Enterococcus faecium BY48 biocatalyst with A-optimal design-embedded model.

Aromatic α-halohydrins, especially 2-haloethanols, which are a common pharmacological precursor, may be readily transformed to chiral β-adrenergic receptor blockers. Studies including the synthesis of (S)-2-bromo-1-(naphthalen-2-yl)ethanol ((S)-2), an α-halohydrin, in high conversion, enantiomeric excess (ee), and yield by biocatalytic asymmetric reduction of 2-bromo-1-(naphthalen-2-yl)ethanone (1) are still insufficient. Moreover, asymmetric reduction of substrate 1 using a mathematical optimization method is not explored in the current literature. In this article, the four asymmetric bioreduction conditions, which are (1) pH, (2) temperature, (3) incubation period, and (4) agitation speed, of substrate 1 were optimized to obtain (S)-2 with A-optimal design-embedded model in the presence of Enterococcus faecium BY48. Optimum bioreduction conditions were determined by the A-optimal design-embedded model as follows: pH = 7, temperature = 25°C, incubation period = 24 h, and agitation speed = 200 rpm. And then, it was suggested that (S)-2 could be obtained with 98.88% ee and 100% conversion rate (cr) under these optimum conditions. As a result of the experimental reaction performed under the optimization conditions suggested by the model, (S)-2 was obtained with 99% ee and 100% cr. The study revealed that E.faecium BY48 could be used as a biocatalyst in asymmetric reduction reactions. Also, the A-optimal design-embedded model could have the great potential to obtain the optimum asymmetric bioreduction conditions.

An Engineered Cholesterol Oxidase Catalyses Enantioselective Oxidation of Non-steroidal Secondary Alcohols.

The enantioselective oxidation of 2° alcohols to ketones is an important reaction in synthetic chemistry, especially if it can be achieved using O2‐driven alcohol oxidases under mild reaction conditions. However to date, oxidation of secondary alcohols using alcohol oxidases has focused on activated benzylic or allylic substrates, with unactivated secondary alcohols showing poor activity. Here we show that cholesterol oxidase (EC 1.1.3.6) could be engineered for activity towards a range of aliphatic, cyclic, acyclic, allylic and benzylic secondary alcohols. Additionally, since the variants demonstrated high (S)‐selectivity, deracemisation reactions were performed in the presence of ammonia borane to obtain enantiopure (R)‐alcohols.

Practical access to (S)-heterocyclic aromatic acetates via CAL-B/Na2CO3-deacylation and Mitsunobu reaction protocol

Herein, we report the preparation of enantiomerically pure forms of 2,3-dihydrobenzofuran-3-ol (1), chroman-4-ol (2), thiochroman-4-ol (3), 1-(furan-2-yl) ethanol (5) and 1-(thiophen-2-yl) ethanol (6), through a kinetic resolution catalysed by Candida antarctica lipase B/Na2CO3 hydrolysis sequence in organic media. The (R)-furnished alcohols and the (S)-remained acetates are recovered enantiopures (ee >99%, E ≫ 200, Conv = 50%). Those ideal enzymatic kinetic resolution (EKRs) are well incorporated to the Mitsunobu inversion protocol in a one pot procedure to give (S)-heterocyclic acetates (1a–3a) in good to high enantiomeric excess (88%–92% ee). Whilst, the (S)-heteroaromatic acetates (5a and 6a) are given with moderate enantiomeric excess (51%–62% ee). All the (S)-acetates are given in good isolated chemical yields (>80%) allowing to overcome the maximum of 50% yield which could be usually reached in a regular kinetic resolution processes.

Exploring the enzyme-catalyzed synthesis of isotope labeled cyclopropanes.

Cyclopropanes are commonly employed structural moieties in drug design since their incorporation is often associated with increased target affinity, improved metabolic stability, and increased rigidity to access bioactive conformations. Robust chemical cyclopropanation procedures have been developed which proceed with high yield and broad substrate scope, and have been applied to labeled substrates. Recently, engineered enzymes have been shown to perform cyclopropanations with remarkable diastereoselectivity and enantioselectivity, but this biocatalytic approach has not been applied to labeled substrates to date. In this study, the use of enzyme catalysis for the synthesis of labeled cyclopropanes was investigated. Two readily available enzymes, a modified CYP450 enzyme and a modified Aeropyrum pernix protoglobin, were investigated for the cyclopropanation of a variety of substituted styrenes. For this biocatalytic transformation, the enzymes required the use of ethyl diazoacetate. Due to the highly energetic nature of this molecule, alternatives were investigated. The final optimized cyclopropanation was successfully demonstrated using n‐hexyl diazoacetate, resulting in moderate to high enantiomeric excess. The optimized procedure was used to generate labeled cyclopropanes from 13C‐glycine, forming all four labeled stereoisomers of phosphodiesterase type‐IV inhibitor, MK0952. These reactions provide a convenient and effective biocatalytic route to stereoselective 13C‐labeled cyclopropanes and serve as a proof‐of‐concept for generating stereoselective labeled cyclopropanes.

A Convenient Route to New (Radio)Fluorinated and (Radio)Iodinated Cyclic Tyrosine Analogs.

The use of radiolabeled non-natural amino acids can provide high contrast SPECT/PET metabolic imaging of solid tumors. Among them, radiohalogenated tyrosine analogs (i.e., [123I]IMT, [18F]FET, [18F]FDOPA, [123I]8-iodo-L-TIC(OH), etc.) are of particular interest. While radioiodinated derivatives, such as [123I]IMT, are easily available via electrophilic aromatic substitutions, the production of radiofluorinated aryl tyrosine analogs was a long-standing challenge for radiochemists before the development of innovative radiofluorination processes using arylboronate, arylstannane or iodoniums salts as precursors. Surprisingly, despite these methodological advances, no radiofluorinated analogs have been reported for [123I]8-iodo-L-TIC(OH), a very promising radiotracer for SPECT imaging of prostatic tumors. This work describes a convenient synthetic pathway to obtain new radioiodinated and radiofluorinated derivatives of TIC(OH), as well as their non-radiolabeled counterparts. Using organotin compounds as key intermediates, [125I]5-iodo-L-TIC(OH), [125I]6-iodo-L-TIC(OH) and [125I]8-iodo-L-TIC(OH) were efficiently prepared with good radiochemical yield (RCY, 51–78%), high radiochemical purity (RCP, >98%), molar activity (Am, >1.5–2.9 GBq/µmol) and enantiomeric excess (e.e. >99%). The corresponding [18F]fluoro-L-TIC(OH) derivatives were also successfully obtained by radiofluorination of the organotin precursors in the presence of tetrakis(pyridine)copper(II) triflate and nucleophilic [18F]F− with 19–28% RCY d.c., high RCP (>98.9%), Am (20–107 GBq/µmol) and e.e. (>99%).