A Single Enzyme in Enantiocomplementary Synthesis of ß-Nitroalcohols: Bidirectional Catalysis by Hydroxynitrile Lyase.

A single enzyme, Baliospermum montanum hydroxynitrile lyase (BmHNL), without alteration, enabled bidirectional catalysis in enantiocomplementary synthesis of chiral ß-nitroalcohols. BmHNL catalyzed promiscuous Henry (24 examples) and retro-Henry reaction (22 examples) provided up to >99% and 50% conversion to (S)- and (R)-ß-nitroalcohols respectively, while both cases displayed up to >99% ee. The broad substrate scope and high stereoselectivity of BmHNL represents its synthetic applications in sustainable production of diverse chiral ß-nitroalcohols. Kinetic parameters of BmHNL was determined for Henry and retro-Henry reaction, which reveals poor catalytic efficiency for both the promiscuous transformations, however, the former has better efficiency than the latter. Practical applicability of the biocatalyst and transformation was illustrated by preparative scale synthesis of chiral intermediates of (S)-Tembamide, and (S)-Micanozole.

Evaluation of the enantioselectivity of new chiral ligands based on imidazolidin-4-one derivatives.

The new chiral ligands I-III based on derivatives of imidazolidin-4-one were synthesised and characterised. The catalytic activity and enantioselectivity of their corresponding copper(II) complexes were studied in asymmetric Henry reactions. It was found that the enantioselectivity of these catalysts is overall very high and depends on the relative configuration of the ligand used; cis-configuration of ligand affords the nitroaldols with major enantiomer S- (up to 97% ee), whereas the application of ligands with trans-configuration led to nitroaldols with major R-enantiomer (up to 96% ee). The "proline-type" ligand IV was also tested in asymmetric aldol reactions. Under the optimised reaction conditions, aldol products with enantioselectivities of up to 91% ee were obtained.

Rationally introducing non-canonical amino acids to enhance catalytic activity of LmrR for Henry reaction.

The use of enzymes to catalyze Henry reaction has advantages of mild reaction conditions and low contamination, but low enzyme activity of promiscuous catalysis limits its application. Here, rational design was first performed to identify the key amino acid residues in Henry reaction catalyzed by Lactococcal multidrug resistance Regulator (LmrR). Further, non-canonical amino acids were introduced into LmrR, successfully obtaining variants that enhanced the catalytic activity of LmrR. The best variant, V15CNF, showed a 184% increase in enzyme activity compared to the wild type, and was 1.92 times more effective than the optimal natural amino acid variant, V15F. Additionally, this variant had a broad substrate spectrum, capable of catalyzing reactions between various aromatic aldehydes and nitromethane, with product yielded ranging from 55 to 99%. This study improved enzymatic catalytic activity by enhancing affinity between the enzyme and substrates, while breaking limited types of natural amino acid residues by introducing non-canonical amino acids into the enzyme, providing strategies for molecular modifications.

Click nanosponge - A novel amine-rich ß-cyclodextrin-based crosslinked polymer for heterogeneous catalysis.

Cyclodextrin-based nanosponges are promising materials for heterogeneous catalysis due to their inherent synthetic versatility, tunable porosity and nontoxicity. In this work, a primary amine-rich ß-cyclodextrin nanosponge was synthesized via click imine condensation reaction between 1,6-hexamethylamine-functionalized ß-cyclodextrin (CDAM) and glutaraldehyde (GLT) to afford CDGLAM, in mild conditions. The crosslinked polymer exhibited a BET surface area of 36.39 m2 g-1, an average pore diameter of 3.09 nm (as assessed by the BJH method), and thermal stability up to 253 °C. CDGLAM was tested as heterogeneous catalyst for the metal-free Henry and Knoevenagel reactions, between aromatic aldehydes and nitromethane or ethyl cyanoacetate, respectively, affording the products in moderate to very high yields. These results show the ease of preparation of ß-CD-based nanosponges from a green chemistry perspective, as well as their potential for future use in catalytic systems.

Asymmetric Henry Reaction Using Cobalt Complexes with Bisoxazoline Ligands Bearing Two Fluorous Tags.

The effect of the presence of fluorous tags in bisoxazoline ligands on the stereoselectivity of the cobalt-catalyzed asymmetric Henry reaction was investigated. In contrast to the stereoselectivity obtained with conventional nonfluorous ligands, using bisoxazoline bidentate ligands featuring two fluorous tags in adjacent positions on the aromatic ring yielded a reversed stereoselectivity. The stereoselectivity also reversed when the fluorous tags were replaced with alkyl chains of equivalent length, albeit to a considerably lesser degree, highlighting the effect of the fluorous tags.

Synthesis and Characterization of New Triazole-Bispidinone Scaffolds and Their Metal Complexes for Catalytic Applications.

Bispidines are a family of ligands that plays a pivotal role in various areas of coordination chemistry, with applications in medicinal chemistry, molecular catalysis, coordination polymers synthesis, and molecular magnetism. In the present work, triazole moieties were introduced using the CuAAC click-reaction, with the aim of expanding the number of coordination sites on the bispidine core. The 1,2,3-triazole rings were thus synthesized on propargyl-derived bispidines after reaction with different alkyl azides. The new class of triazole-bispidines was characterized, and their chelation capabilities were evaluated with different metals through NMR titration, ESI-MS spectrometry, and single-crystal X-ray diffraction (SC-XRD). Finally, the suitability of these molecules as metal ligands for the catalytic Henry reaction was demonstrated with copper and zinc.

Enantioselective Synthesis of Chiral 2-Nitroallylic Amines via Cooperative Cation-Binding Catalysis.

Chiral allylic amines are valuable building blocks for biologically important compounds and natural products. In this study, we present the use of cooperative cation-binding catalysis as an efficient method for synthesizing chiral allylic amines. By utilizing a chiral oligoEG and potassium fluoride as a cation-binding catalyst and base, respectively, a wide range of biologically relevant chiral 2-nitroallylic amines are obtained with excellent enantioselectivities (up to >99 % ee) through the organocatalytic asymmetric aza-Henry-like reaction of ß-monosubstituted and ß,ß-disubstituted nitroalkenes with α-amidosulfones as imine precursors. Extensive experimental studies are presented to illustrate plausible mechanisms. Preliminary use of a chiral 2-nitroallylic amine as a Michael acceptor demonstrated its potential application for diversity-oriented synthesis of bioactive compounds.

Heterogeneous Photoredox Catalysis Based on Silica Mesoporous Material and Eosin Y: Impact of Material Support on Selectivity of Radical Cyclization.

Heterogenization of the photocatalyst appears to be a valuable solution to reach sustainable processes. Rapid and efficient synthesis of supported photocatalyst is still a remaining challenge and the choice of the support material is crucial. The present study aims at preparing a new generation of hybrid inorganic/organic photocatalysts based on silica mesoporous material and Eosin Y. These results highlight the influence of non-covalent interactions between the material support and the reagent impacting the selectivity of the reaction.

Enantioselective Henry Reaction Catalyzed by Chiral Piperazine Derivatives.

A series of novel tridentate Schiff bases is synthesized from piperazine-amine and substituted salicylaldehydes, and characterized by spectroscopic methods. These chiral ligands were used to catalyze the addition of nitromethane to various aldehydes in the presence of Cu(II) ions under ambient conditions in good yields (98%) and high enantioselectivities (9:91 er).

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.

Enzyme engineering improves catalytic efficiency and enantioselectivity of hydroxynitrile lyase for promiscuous retro-nitroaldolase activity.

Protein engineering to improve promiscuous catalytic activity is important for biocatalytic application of enzymes in green synthesis. We uncovered the significance of binding site residues in Arabidopsis thaliana hydroxynitrile lyase (AtHNL) for promiscuous retro-nitroaldolase activity. Engineering of AtHNL has improved enantioselective retro-nitroaldolase activity, a synthetically important biotransformation, for the production of enantiopure ß-nitroalcohols having absolute configuration opposite to that of the stereopreference of the HNL. The variant F179A has shown âˆ¼ 12 fold increased selectivity towards the retro-nitroaldol reaction over cyanogenesis, the natural activity of the parent enzyme. Screening of the two saturation libraries of Phe179 and Tyr14 revealed several variants with higher kcat, while F179N showed âˆ¼ 2.4-fold kcat/Km than the native enzyme towards retro-nitroaldol reaction. Variants F179N, F179M, F179W, F179V, F179I, Y14L, and Y14M have shown > 99% ee in the preparation of (S)-2-nitro-1-phenylethanol (NPE) from the racemic substrate, while F179N has shown the E value of 138 vs. 81 by the wild type. Our molecular docking and dynamics simulations (MDS) studies results provided insights into the molecular basis of higher enantioselectivity by the F179N toward the retro-nitroaldolase activity than the other mutants. Binding energy calculations also showed the higher negative binding free energy in the case of F179N-(R)-NPE compared to other complexes that support our experimental low Km by the F179N for NPE. A plausible retro-nitroaldol reaction mechanism was proposed based on the MDS study of enzyme-substrate interaction.

Asymmetric Henry Reaction of Trifluoromethyl Enones with Nitromethane Using a N,N-Dibenzyl Diaminomethylenemalononitrile Organocatalyst.

A novel N,N-dibenzyl diaminomethylenemalononitrile organocatalyst efficiently promoted asymmetric Henry reactions of trifluoromethyl enones with nitromethane, affording corresponding highly functionalized products in high yields with excellent enantioselectivities (up to 90% ee). This study is the first to report the successful example of the asymmetric 1,2-additions of nitromethane to trifluoromethyl enones.

Guanidine-Amide-Catalyzed Aza-Henry Reaction of Isatin-Derived Ketimines: Origin of Selectivity and New Catalyst Design.

Density functional theory (DFT) calculations were performed to investigate the mechanism and the enantioselectivity of the aza-Henry reaction of isatin-derived ketimine catalyzed by chiral guanidine-amide catalysts at the M06-2X-D3/6-311+G(d,p)//M06-2X-D3/6-31G(d,p) (toluene, SMD) theoretical level. The catalytic reaction occurred via a three-step mechanism: (i) the deprotonation of nitromethane by a chiral guanidine-amide catalyst; (ii) formation of C-C bonds; (iii) H-transfer from guanidine to ketimine, accompanied with the regeneration of the catalyst. A dual activation model was proposed, in which the protonated guanidine activated the nitronate, and the amide moiety simultaneously interacted with the ketimine substrate by intermolecular hydrogen bonding. The repulsion of CPh3 group in guanidine as well as N-Boc group in ketimine raised the Pauli repulsion energy (∆EPauli) and the strain energy (∆Estrain) of reacting species in the unfavorable si-face pathway, contributing to a high level of stereoselectivity. A new catalyst with cyclopropenimine and 1,2-diphenylethylcarbamoyl as well as sulfonamide substituent was designed. The strong basicity of cyclopropenimine moiety accelerated the activation of CH3NO2 by decreasing the energy barrier in the deprotonation step. The repulsion between the N-Boc group in ketimine and cyclohexyl group as well as chiral backbone in the new catalyst raised the energy barrier in C-C bond formation along the si-face attack pathway, leading to the formation of R-configuration product. A possible synthetic route for the new catalyst is also suggested.

Metal-Organic Frameworks as Versatile Heterogeneous Solid Catalysts for Henry Reactions.

Metal-organic frameworks (MOFs) have become one of the versatile solid materials used for a wide range of applications, such as gas storage, gas separation, proton conductivity, sensors and catalysis. Among these fields, one of the more well-studied areas is the use of MOFs as heterogeneous catalysts for a broad range of organic reactions. In the present review, the employment of MOFs as solid catalysts for the Henry reaction is discussed, and the available literature data from the last decade are grouped. The review is organized with a brief introduction of the importance of Henry reactions and structural properties of MOFs that are suitable for catalysis. The second part of the review discusses the use of MOFs as solid catalysts for the Henry reaction involving metal nodes as active sites, while the third section provides data utilizing basic sites (primary amine, secondary amine, amides and urea-donating sites). While commenting on the catalytic results in these two sections, the advantage of MOFs over other solid catalysts is compared in terms of activity by providing turnover number (TON) values and the structural stability of MOFs during the course of the reaction. The final section provides our views on further directions in this field.

Immobilized Arabidopsis thaliana Hydroxynitrile Lyase-Catalyzed Retro-Henry Reaction in the Synthesis of (S)-ß-Nitroalcohols.

Enantiopure ß-nitroalcohols are versatile intermediates used in the synthesis of important pharmaceuticals and chiral synthons. In this article, immobilized Arabidopsis thaliana HNL (AtHNL)-catalyzed preparation of (S)-ß-nitroalcohols from their racemic mixtures via retro-Henry reaction was studied. AtHNL used in biocatalysis was immobilized by physical adsorption in inexpensive celite®545. Under optimized biocatalytic conditions, the total turnover number of the catalyst has improved 2.3-fold for (S)-2-nitro-1-phenylethanol (NPE) synthesis, than free enzyme catalysis. This study reported for the first time celite-AtHNL-catalyzed retro-Henry reaction at low pH. At pH 4.5 and 5.0, 62% ee and 41% conversion, and 97% ee and 42% conversion of (S)-NPE were obtained respectively, while the free enzyme inactivates at pH < 5.0. The increased catalytic efficiency and pH stability of the catalyst could be possibly due to increased stability of AtHNL by immobilization. A dozen of racemic ß-nitroalcohols were converted into their corresponding (S)-ß-nitroalcohols using this reaction; among them, eight were not tested earlier. The immobilized enzyme has showed broad substrate selectivity in the retro-Henry reaction, and products were obtained up to 98.5% ee.

Rationally design and chemical modification: Getting a new and efficient biocatalyst for Henry reaction.

A robust biocatalyst for green Henry reaction was achieved. Based on the fact that Henry reaction requires a base for proton transfer, we firstly proposed that the catalytic triad of lipase could play this role. The distance between the substrate and the catalytic center and the surrounding amino acid interaction network were used as the criterion. Benzaldehyde and nitromethane were used as the model reaction, RNL (Lipase from Rhizopus niveus) was considered to be the best Henry reaction catalyst via a molecular dynamics simulation. Then experiments demonstrated that RNL has a yield of 48 % using model substrate in water. Further, in order to increase product yield, the chemical modifier 1, 2-cyclohexanedione (CHD) was used to modify Arg on RNL. As a result, RNL (CHD) increased the activity of catalyzing Henry reaction and had a broad spectrum of substrates, the yield of the product was as high as 67-99 %.

Photophysical Properties and Heterogeneous Photoredox Catalytic Activities of Ru(bpy)3 @InBTB Metal-Organic Framework (MOF).

Metal-organic frameworks (MOFs) with negatively charged frameworks are suitable for selectively encapsulating cationic guest ions via a cation-exchange process. Encapsulating photoactive [RuL3 ]2+ polypyridine complexes into the preorganized mesoscale channels of a MOF is a good method for stabilizing the excited states of the complexes. Three new RuL3 @InBTB MOFs were prepared by encapsulating cationic [Ru(bpy)3 ]2+ (bpy=2,2'-bipyridine), [Ru(phen)3 ]2+ (phen=1,10-phenanthroline), and [Ru(bpz)3 ]2+ (bpz=2,2'-bipyrazine) into the mesopores of a three-dimensional (3D) InBTB MOF (H3 BTB=1,3,5-benzenetribenzoic acid). The photophysical properties of the resulting materials were investigated by photoluminescence (PL) analysis. The photoredox catalytic activities were also investigated for the aza-Henry reaction, hydrogenation of dimethyl maleate, and decomposition of methyl orange under visible light irradiation at room temperature. RuL3 @InBTB MOFs were found to be very stable and highly recyclable photoredox catalytic systems.

Asymmetric Organocatalyzed Aza-Henry Reaction of Hydrazones: Experimental and Computational Studies.

The first asymmetric catalyzed aza-Henry reaction of hydrazones is presented. In this process, quinine was used as the catalyst to synthesize different alkyl substituted ß-nitrohydrazides with ee up to 77 %. This ee was improved up to 94 % by a further recrystallization and the opposite enantiomer can be obtained by using quinidine as the catalyst, opening exciting possibilities in fields in which the control of chirality is vital, such as the pharmaceutical industry. Additionally, experimental and ab initio studies were performed to understand the reaction mechanism. The experimental results revealed an unexpected secondary kinetic isotope effect (KIE) that is explained by the calculated reaction pathway, which shows that the protonation of the initial hydrazone and the C-C bond forming reaction occur during a concerted process. This concerted mechanism makes the catalysis conceptually different to traditional base-promoted Henry and aza-Henry reactions.

The Stereoselective Nitro-Mannich Reaction in the Synthesis of Active Pharmaceutical Ingredients and Other Biologically Active Compounds.

The nitro-Mannich (aza-Henry) reaction, in which a nitroalkane and an imine react to form a ß-nitroamine, is a versatile tool for target-oriented synthesis. Although the first stereoselective reaction was developed only 20 years ago, and enantioselective and diastereoselective versions for the synthesis of non-racemic compounds soon after, there are nowadays a variety of reliable methods which can be used for the synthesis of APIs and other biologically active substances. Hence many anticancer drugs, antivirals, antimicrobials, enzyme inhibitors and many more substances, containing C-N bonds, have been synthesized using this reaction. Several transition metal complexes and organocatalysts were shown to be compatible with the presence of a wide range of functional groups in these molecules, and very high levels of asymmetric induction have been achieved in some cases. The reaction has also been applied in cascade processes. The structural diversity of the products, ranging from simple heterocycles or azabicycles to complex alkaloids, iminosugars, amino acids or diamino acids and phosphonates, shows the versatility of the nitro-Mannich reaction and its potential for future developments.

Asymmetric Henry Reaction of 2-Acylpyridine N-Oxides Catalyzed by a Ni-Aminophenol Sulfonamide Complex: An Unexpected Mononuclear Catalyst.

The asymmetric Henry reaction of 2-acylpyridine N-oxide remains a challenge as N-oxides generally act as competitive catalyst inhibitors or displace activating ligands. A novel variable yield (up to 99%) asymmetric Henry reaction of 2-acypyridine N-oxides catalyzed by a Ni-aminophenol sulfonamide complex with good to excellent enantioselectivity (up to 99%) has been developed. Mechanistic studies suggest that the unique properties of the electron-pairs of N-oxides for complexation with Ni makes the unexpected mononuclear complex, rather than the previously reported dinuclear complex, the active species.