Poor Enantioselectivity Research Articles

Selective Stereoretention of Carbohydrates upon C−C Cleavage Enabling D‐Glyceric Acid Production with High Optical Purity over a Ag/γ‐Al2O3 Catalyst

AbstractChiral carboxylic acid production from renewable biomass by chemocatalysis is vitally important for reducing our carbon footprint, but remains underdeveloped. We herein establish a strategy that make use of a stereogenic center of biomass to achieve a rare example of D‐glyceric acid production with the highest yield (86.8 %) reported to date as well as an excellent ee value (>99 %). Unlike traditional asymmetric catalysis, chiral catalysts/additives are not required. Ample experiments combined with quantum chemical calculations established the origins of the stereogenic center and catalyst performance. The chirality at C4 in D‐xylose was proved to be retained and successfully delivered to C2 in D‐glyceric acid during C−C cleavage. The remarkable cooperative‐roles of Ag+ and Ag0 in the constructed Ag/γ‐Al2O3 catalyst are disclosed as the crucial contributors. Ag+ was responsible for low‐temperature activation of D‐xylose, while Ag0 facilitated the generation of active O* from O2. Ag+ and active O* cooperatively promoted the precise cleavage of the C2−C3 bond, and more importantly O* allowed the immediate fast oxidization of the D‐glyceraldehyde intermediate to stabilize D‐glyceric acid, thereby inhibiting the side reaction that induced racemization. This strategy makes a significant breakthrough in overcoming the limitation of poor enantioselectivity in current chemocatalytic conversion of biomass.

Selective Stereoretention of Carbohydrates upon C-C Cleavage Enabling D-Glyceric Acid Production with High Optical Purity over a Ag/γ-Al2O3 Catalyst.

Chiral carboxylic acid production from renewable biomass by chemocatalysis is vitally important for reducing our carbon footprint, but remains underdeveloped. We herein establish a strategy that make use of a stereogenic center of biomass to achieve a rare example of D-glyceric acid production with the highest yield (86.8 %) reported to date as well as an excellent ee value (>99 %). Unlike traditional asymmetric catalysis, chiral catalysts/additives are not required. Ample experiments combined with quantum chemical calculations established the origins of the stereogenic center and catalyst performance. The chirality at C4 in D-xylose was proved to be retained and successfully delivered to C2 in D-glyceric acid during C-C cleavage. The remarkable cooperative-roles of Ag+ and Ag0 in the constructed Ag/γ-Al2O3 catalyst are disclosed as the crucial contributors. Ag+ was responsible for low-temperature activation of D-xylose, while Ag0 facilitated the generation of active O* from O2. Ag+ and active O* cooperatively promoted the precise cleavage of the C2-C3 bond, and more importantly O* allowed the immediate fast oxidization of the D-glyceraldehyde intermediate to stabilize D-glyceric acid, thereby inhibiting the side reaction that induced racemization. This strategy makes a significant breakthrough in overcoming the limitation of poor enantioselectivity in current chemocatalytic conversion of biomass.

Quantum Mechanical Elucidation on [3+2] cycloaddition reaction of aryl nitrile oxide with cyclopentenones

The [3 + 2] cycloaddition (32CA) reaction of benzonitrile oxide (BNO) with 4-substituted 4-hydroxy-2-cyclopentenone has been investigated using molecular electron density theory (MEDT) at the Density Functional Theory (DFT) B3LYP/6-31G (d), M06/6-311G (d,p) and M06-2X/6–311++G (d,p) levels. The present theoretical computations indicate that the reaction of BNO with 4-substituted 4-hydroxy-2-cyclopentenones is via [3 + 2] cycloaddition, where the three atom component (TAC) chemo-selectively adds across the alkene functionality in the 2-cyclopentenones (Path A). Analysis of the electrophilic PA+ and nucleophilic PA− Parr functions at the different reaction sites in the alkene counterpart indicates that the aryl nitrile oxides add across the atomic centers with the highest Mulliken atomic spin densities. The results reported in this study are in good agreement with previous experimental work. The GEDT calculations unravel the low polar character of the [3 + 2] cycloaddition reactions. This reaction occurs with poor enantioselectivity, but a high degree of stereo-, peri-, diastereo, and regioselectivity is seen for the reaction of the BNO with 4-hydroxy-4-methyl-2-cyclopentenones. The regioselectivity of the reactions is the same in all the solvents investigated.

Chiral Lewis Acid-Catalyzed Norrish Type II Cyclization to Synthesize α-Oxazolidinones via Enantioselective Protonation

Chiral Lewis Acid-Catalyzed Norrish Type II Cyclization to Synthesize α-Oxazolidinones via Enantioselective Protonation

Organocatalytic Enantioselective α-Bromination of Aldehydes with N-Bromosuccinimide.

Despite the wealth of existing organocatalytic, enantioselective transformations, the α-bromination of aldehydes remains a challenging reaction. The four examples reported to date require expensive, inconvenient brominating agents to achieve the desired products in excellent yields and enantioselectivities. The preferred brominating agent, N-bromosuccinimide (NBS), has been repeatedly discarded for these reactions because it results in low yields and relatively poor enantioselectivities. We describe a methodology that uses NBS and performs excellently with low catalyst loadings, short reaction times, and mild temperatures.

Inherently Chiral 6,7-Diphenyldibenzo[ e,g ][1,4]diazocine: Enantioselective Synthesis and Application as a Ligand Platform

Inherently Chiral 6,7-Diphenyldibenzo[ <i>e,g</i> ][1,4]diazocine: Enantioselective Synthesis and Application as a Ligand Platform

Highly Chiral Selective Resolution in Pillar[6]arenes Functionalized Microchannel Membranes.

High flux microchannel membranes have the potential for large scale separations. However, it is prevented by poor enantioselectivity. Therefore, the development of a high-enantioselective microchannel membrane is of great importance for large scale chiral separations. In this work, chiral gold nanoparticles are incorporated into the microchannel membrane to astringe the large pores and improve the enantioselectivity. Here, the gold nanoparticles are functionalized by l-phenylalanine-derived pil-lararenes (l-Phe-P6@AuNPs) as the chiral receptor of R-phenylglycinol (R-PGC) over its enantiomer. This chiral Au NPs coated microchannel membrane (l-Phe-P6@AuNPs microchannel) shows a selectivity of 5.40 for R-PGC and a flux of 140.35 nmol·cm-2·h-1, where the enantioselectivity is improved, ensuring its flux. Compared with the enantioselectivity and flux of nanochannel membranes reported in literatures, the l-Phe-P6@AuNPs microchannel has the advantage for enantioselectivity and flux for chiral separation.

Intramolecular Partners in Asymmetric Catalysis Copolymerization: Highly Enantioselective and Controllable at Enhanced Temperatures and Low Loadings.

Asymmetric copolymerization of meso-epoxide and anhydride is a powerful strategy for preparing various isotactic polyesters with two contiguous stereogenic centers. However, the previous binary systems suffered from slow rates at low loadings, poor enantioselectivities and transesterification reactions at enhanced temperatures. Herein, we report novel dinuclear aluminium complexes with multiple chiralities and ammonium salts anchored on ligand frameworks. These bifunctional catalysts exhibit high activities and enantioselectivities for epoxides/anhydrides copolymerizations at harsh conditions via intramolecularly synergistic catalysis, affording polyesters with unprecedented molecular weights and narrow distributions. Notably, no transesterification reactions were observed, significantly different from the binary catalyst/cocatalyst pairs. This study represents a rare example regarding temperature-independent asymmetric induction for preparing chiral polymers from achiral monomers.

Intramolecular Partners in Asymmetric Catalysis Copolymerization: Highly Enantioselective and Controllable at Enhanced Temperatures and Low Loadings

AbstractAsymmetric copolymerization of meso‐epoxide and anhydride is a powerful strategy for preparing various isotactic polyesters with two contiguous stereogenic centers. However, the previous binary systems suffered from slow rates at low loadings, poor enantioselectivities and transesterification reactions at enhanced temperatures. Herein, we report novel dinuclear aluminium complexes with multiple chiralities and ammonium salts anchored on ligand frameworks. These bifunctional catalysts exhibit high activities and enantioselectivities for epoxides/anhydrides copolymerizations at harsh conditions via intramolecularly synergistic catalysis, affording polyesters with unprecedented molecular weights and narrow distributions. Notably, no transesterification reactions were observed, significantly different from the binary catalyst/cocatalyst pairs. This study represents a rare example regarding temperature‐independent asymmetric induction for preparing chiral polymers from achiral monomers.

A Chiral, Dendralenic C–H Acid

AbstractWe report the synthesis of a chiral dendralenic C–H acid, which contains three unsubstituted binaphthyl moieties. This motif and an achiral variant can be made from their corresponding bis(sulfone) precursors in one step. Despite the presence of the enantiopure binaphthyl backbone, the newly designed chiral C–H acid showed only poor enantioselectivity in a Mukaiyama aldol reaction. First attempts toward the synthesis of 3,3′-hexasubstituted binaphthyl-based dendralenic acids are also reported.

Organocatalytic Stereoselective [8+2] Cycloaddition of Tropones with Azlactones

Organocatalytic Stereoselective [8+2] Cycloaddition of Tropones with Azlactones

Discovery and Design of Family VIII Carboxylesterases as Highly Efficient Acyltransferases.

Promiscuous acyltransferase activity is the ability of certain hydrolases to preferentially catalyze acyl transfer over hydrolysis, even in bulk water. However, poor enantioselectivity, low transfer efficiency, significant product hydrolysis, and limited substrate scope represent considerable drawbacks for their application. By activity‐based screening of several hydrolases, we identified the family VIII carboxylesterase, EstCE1, as an unprecedentedly efficient acyltransferase. EstCE1 catalyzes the irreversible amidation and carbamoylation of amines in water, which enabled the synthesis of the drug moclobemide from methyl 4‐chlorobenzoate and 4‐(2‐aminoethyl)morpholine (ca. 20 % conversion). We solved the crystal structure of EstCE1 and detailed structure–function analysis revealed a three‐amino acid motif important for promiscuous acyltransferase activity. Introducing this motif into an esterase without acetyltransferase activity transformed a “hydrolase” into an “acyltransferase”.

Synthesis, characterization and catalytic performance in enantioselective reactions by mesoporous silica materials functionalized with chiral thiourea-amine ligand

Chiral heterogeneous catalysts have been synthesized by grafting of silyl derivatives of (1R, 2R)- or (1S, 2S)-1,2-diphenylethane-1,2-diamine on SBA-15 mesoporous support. The mesoporous material SBA-15 and so-prepared chiral heterogeneous catalysts were characterized by a combination of different techniques such as X-ray diffractometry (XRD), Fourier transform infrared (FT-IR), thermogravimetric analysis (TGA), field emission scanning electron microscopy (FESEM), and Brunauer–Emmett–Teller (BET) surface area. Results showed that (1R, 2R)- and (1S, 2S)-1,2-diphenylethane-1,2-diamine were successively immobilized on SBA-15 mesoporous support. Chiral heterogeneous catalysts and their homogenous counterparts were tested in enantioselective transfer hydrogenation of aromatic ketones and enantioselective Michael addition of acetylacetone to β-nitroolefin derivatives. The catalysts demonstrated notably high catalytic conversions (up to 99%) with moderate enantiomeric excess (up to 30% ee) for the heterogeneous enantioselective transfer hydrogenation. The catalytic performances for enantioselective Michael reaction showed excellent activities (up to 99%) with poor enantioselectivities. Particularly, the chiral heterogeneous catalysts could be readily recycled for Michael reaction and reused in three consecutive catalytic experiments with no loss of catalytic efficacies.

Copper-Catalyzed Enantioselective Trifluoromethylthiolation of Secondary Propargyl Sulfonates

Although trifluoromethylthiolated compounds have privileged applications in pharmaceuticals and agrochemicals, efficient strategies for the asymmetric construction of Csp3–SCF3 bonds are limited. S...

Significant improvement of the enantioselectivity of a halohydrin dehalogenase for asymmetric epoxide ring opening reactions by protein engineering.

Halohydrin dehalogenases (HHDHs) have attracted much attention due to their ability to synthesize enantiomerically enriched epoxides and β-haloalcohols. However, most of the HHDHs exhibit low enantioselectivity. Here, a HHDH from the alphaproteobacteria isolate 46_93_T64 (AbHHDH), which shows only poor enantioselectivity in the catalytic resolution of rac-PGE (E = 9.9), has been subjected to protein engineering to enhance its enantioselectivity. Eight mutants (R89K, R89Y, V137I, P178A, N179Q, N179L, F187L, F187A) showed better enantioselectivity than the wild type. The best single mutant N179L (E = 93.0) showed a remarkable 9.4-fold increase in the enantioselectivity. Then, the single mutations were combined to produce the double, triple, quadruple, and quintuple mutants. Among the combinational mutants, the best variant (R89Y/N179L) showed an increased E value of up to 48. The E values of the variants N179L and R89Y/N179L for other epoxides 2-7 were 12.2 to > 200, which showed great improvement compared to 1.2 to 10.5 for the wild type. Using the variant N179L, enantiopure (R)-PGE with > 99% ee could be readily prepared, affording a high yield and a high concentration.

Genome mining integrating semi-rational protein engineering and nanoreactor design: roadmap for a robust biocatalyst for industrial resolution of Vince lactam.

Biomanufacturing of chemicals using biocatalysts is an attractive strategy for the production of valuable pharmaceuticals since it is usually more economical and has a much-reduced environmental impact. However, there are often challenges such as their thermal instability that should be overcome before a newly discovered enzyme is eventually translated into industrial processes. In this work, we describe a roadmap for the development of a robust catalyst for industrial resolution of Vince lactam, a key intermediate for the synthesis of carbocyclic-nucleoside-related pharmaceuticals. By a genome mining strategy, a new (+)-γ-lactamase (MiteL) from Microbacterium testaceum was successfully discovered and biochemically characterized. In vitro studies showed that the enzyme exhibited high activity but poor enantioselectivity (E = 6.3 ± 0.2) toward racemic Vince lactam, and thus, it is not suitable for industrial applications. Based on structural modeling and docking studies, a semi-rational engineering strategy combined with an efficient screening method was then applied to improve the enantioselectivity of MiteL. Several mutants with significant shifting stereoselectivity toward (-)-γ-lactam were obtained by site-saturation mutagenesis. Synergy effects led to the final mutant F14D/Q114R/M117L, which enabled efficient acquisition of (-)-γ-lactam with a high E value (> 200). The mutant was biochemically characterized, and the docking studies suggested a plausible mechanism for its improved selectivity. Finally, a sunflower-like nanoreactor was successfully constructed to improve the mutant's robustness via protein supramolecular self-assembly. Thus, the synergism between semi-rational protein engineering and self-assembling immobilization enabled construction of a nanoreactor with superior properties, which can be used for resolution of Vince lactam in large scale.

Importance of the Reducing Agent in Direct Reductive Heck Reactions

AbstractThe role of the reductant in the palladium N‐heterocyclic carbene (NHC) catalyzed reductive Heck reaction and its effect on the mechanism of the reaction is reported. For the first time in this type of transformation, the palladium‐NHC‐catalyzed reductive Heck reaction was shown to proceed in the presence of LiOMe and iPrOH even at 10 °C to give the products very efficiently in excellent yields and with exceptional chemoselectivities. This study shows that the reaction proceeds through two distinct mechanisms that depend on the nature of the reducing agent. In the presence of a protic solvent or acidic medium the reaction undergoes protonation to yield the reduced product, whereas in the absence of proton source, it proceeds through the insertion of the reductant followed by reductive elimination. The kinetic data reveal that the oxidative addition is the rate‐determining step in the reaction. The reaction profiles show first‐order kinetics in aryl iodide and Pd and zero‐order kinetics in LiOMe, benzylideneacetone, and the excess amount of NHC ligand. In addition, the reaction progress kinetic analysis shows that neither catalyst decomposition nor product inhibition occurs during the reaction. DFT calculations of the key steps confirm that the oxidative addition step is the rate‐determining step in the reaction. Deuterium‐labeling experiments indicate that the product is formed by the protonation of the Pd−Calkyl bond of the intermediate formed after enone insertion into the Pd−CAr bond. Application of chiral NHC ligands in the asymmetric reductive Heck reaction only results in poor enantioselectivities (enantiomeric excess up to 20 %) and is also substrate specific. DFT calculations suggest that the migration of the aryl group to the alkene of the substrate is the enantioselectivity‐determining step of the reaction. It is further shown that if the steric bulk at the enone is small (a methyl group), the two transition state barriers from [PdII(L2)(ArI)(enone)] species Cre and Csi, which have the re and si face of the enone substrate coordinated to Pd, are very similar, in line with the experimental results. With a slightly larger group (an isopropyl substituent) a significant difference in energy barriers is calculated (2.6 kcal mol−1), and in the experiment this product is formed with a modest enantiomeric excess (up to 20 %).

Recombinant expression and characterisation of the oxygen-sensitive 2-enoate reductase from Clostridium sporogenes.

‘Ene’-reductases have attracted significant attention for the preparation of chemical intermediates and biologically active products. To date, research has been focussed primarily on Old Yellow Enzyme-like proteins, due to their ease of handling, whereas 2-enoate reductases from clostridia have received much less attention, because of their oxygen sensitivity and a lack of suitable expression systems. A hypothetical 2-enoate reductase gene, fldZ, was identified in Clostridium sporogenes DSM 795. The encoded protein shares a high degree of homology to clostridial FMN- and FAD-dependent 2-enoate reductases, including the cinnamic acid reductase proposed to be involved in amino acid metabolism in proteolytic clostridia. The gene was cloned and overexpressed in Escherichia coli. Successful expression depended on the use of strictly anaerobic conditions for both growth and enzyme preparation, since FldZ was oxygen-sensitive. The enzyme reduced aromatic enoates, such as cinnamic acid or p-coumaric acid, but not short chain unsaturated aliphatic acids. The β,β-disubstituted nitroalkene, (E)-1-nitro-2-phenylpropene, was reduced to enantiopure (R)-1-nitro-2-phenylpropane with a yield of 90 %. By contrast, the α,β-disubstituted nitroalkene, (E)-2-nitro-1-phenylpropene, was reduced with a moderate yield of 56 % and poor enantioselectivity (16 % ee for (S)-2-nitro-1-phenylpropane). The availability of an expression system for this recombinant clostridial 2-enoate reductase will facilitate future characterisation of this unusual class of ‘ene’-reductases, and expand the biocatalytic toolbox available for enantioselective hydrogenation of carbon-carbon double bonds.

Chemo‐ and Stereoselective Cytochrome P450‐BM3‐Catalyzed Sulfoxidation of 1‐Thiochroman‐4‐ones Enabled by Directed Evolution

AbstractDirected evolution utilizing an unconventional approach to saturation mutagenesis has been applied to cytochrome P450‐BM3 as a catalyst in the asymmetric sulfoxidation of 1‐thiochroman‐4‐one and two derivatives thereof with complete chemoselectivity as well as (S)‐ and (R)‐selectivity on an optional basis. Whereas wild‐type P450‐BM3 shows in the case of the parent compound poor enantioselectivity in slight favor of the (S)‐sulfoxide (er=75:25), (S)‐selectivity was enhanced to er=93:7, while reversal of enantioselectivity favoring the (R)‐sulfoxide was also achieved (er=7:93). Two derivatives of the parent substrate underwent similar stereoselective sulfoxidation reactions. Sulfoxides of this type are of potential pharmaceutical interest. This biocatalytic approach nicely complements synthetic methods.magnified image

Cinchona-Alkaloids Based Isoselenazolones: Synthesis and Their Catalytic Reactivity in Asymmetric Bromolactonization of Alkenoic Acid

A series of chiral isoselenazolones have been synthesized and characterized by multinuclear (1H, 13C, and 77Se) NMR, mass spectrometry, and single crystal X-ray crystallography. Catalytic reactivity of synthesized chiral isoselenazolones was studied in the enantioselective bromolactonization of alkenoic acids using N-bromosuccinimide as a source of bromine. A series of alkenoic acid underwent bromolactonization successfully in the presence of 10 mol% of chiral isoselenazolone catalyst and excellent yields of bromolactones were obtained with high diastereoselectivity and moderate enantioselectivity. Isoselenazolone catalyst derived from quininamine afforded bromolactones in 82–94 % yield with 1−47 % enantioselectivity while rest of the isoselenazolones derived from simple chiral (S)-phenylethyl, and (S)-naphthylethyl, quinidin, and cinchonidin-amine afforded poor enantioselectivity in the bromolactonization reaction. Furthermore, isoselenazolone having Se–N bond gave best enantioselectivity in the bromolactonization of 5-phenyl-4-pentenoic acid as compared to the isothiazolone having S–N bond. Also isoselenazolone gave best enantioselectivity than the corresponding methyl selenide and diselenide bearing the same quininamine auxiliary in the organoselenium catalyst. Crystal structure and enantioselectivity outcome in bromolactonization on similar isoselenazolone catalysts; quininamine based (intramolecular Se…N distance 3.56 A, ee 47 %); cinchonidinamine based (Se…N distances 3.80 A, ee 17 %), and 7-methyl-amide and quininamine based (Se…N distances 3.72 A, ee 28 %) suggests that intramolecular Se…N interaction could be the crucial parameter for the enantioselectivity outcome of the reaction.