Catalytic Oxidation of Benzoins by Hydrogen Peroxide on Nanosized HKUST-1: Influence of Substituents on the Reaction Rates and DFT Modeling of the Reaction Path.

In this research, the oxidation of a series of benzoins, R-C(=O)-CH(OH)-R, where R = phenyl, 4-methoxyphenyl, 4-bromophenyl, and 2-naphthyl, by hydrogen peroxide in the presence of nanostructured HKUST-1 (suspension in acetonitrile/water mixture) was studied. The respective benzoic acids were the only products of the reactions. The initial average reaction rates were experimentally determined at different concentrations of benzoin, H2O2 and an effective concentration of HKUST-1. The sorption of the isotherms of benzoin, dimethoxybenzoin and benzoic acid on HKUST-1, as well as their sorption kinetic curves, were measured. The increase in H2O2 concentration expectedly led to an acceleration of the reaction. The dependencies of the benzoin oxidation rates on the concentrations of both benzoin and HKUST-1 passed through the maxima. This finding could be explained by a counterplay between the increasing reaction rate and increasing benzoin sorption on the catalyst with the increase in the concentration. The electronic effect of the substituent in benzoin had a significant influence on the reaction rate, while no relation between the size of the substrate molecule and the rate of its oxidation was found. It was confirmed by DFT modeling that the reaction could pass through the Baeyer-Villiger mechanism, involving an attack by the HOO- anion on the C atom of the activated C=O group.

Influence of Pore Size in Benzoin Condensation of Furfural Using Heterogenized Benzimidazole Organocatalysts.

A designed N-heterocyclic carbene (NHC) catalyst was covalently anchored on a range of mesoporous and hierarchical supports, to study the influence of pore size in the benzoin condensation of furfural. The structural and spectroscopic characteristics of the anchored catalysts were investigated, also with the help of molecular dynamics simulations, in order to rationalize the degree of stability and recyclability of the heterogenized organocatalysts. Quantitative yields (99 %) and complete recyclability were maintained after several cycles, vindicating the design rationale.

Carbene-Catalyzed Activation of C-Si Bonds for Chemo- and Enantioselective Cross Brook-Benzoin Reaction.

The first carbene-catalyzed asymmetric chemoselective cross silyl benzoin (Brook-Benzoin) reaction has been developed. Key steps of this reaction involve activation of the carbon-silicon bond of an acylsilane by a chiral N-heterocyclic carbene (NHC) catalyst to form a silyl acyl anion intermediate. These acyl anions then undergo an addition reaction with indole aldehydes in a highly chemo- and enantioselective manner to afford α-silyloxy ketones with excellent optical purities. The reaction mechanism of this cross Brook-Benzoin reaction was investigated through both experimental and computational methods. The chiral α-hydroxy ketone derivatives obtained by this approach show promising, agrochemically interesting activity against harmful plant bacteria.

Accessing Diverse Cross-Benzoin and α-Siloxy Ketone Products via Acyl Substitution Chemistry.

An approach to diverse cross-benzoin and α-siloxy ketone products which leverages a simple yet underutilized C-C bond disconnection strategy is reported. Acyl substitution of readily accessible α-siloxy Weinreb amides with organolithium compounds enables access to a broad scope of aryl, heteroaryl, alkyl, alkenyl, and alkynyl derivatives. Enantiopure benzoins can be accessed via a chiral pool approach, and the utility of accessible cross-benzoins and α-siloxy ketones is highlighted in a suite of downstream synthetic applications.

Microbial Synthesis of (S)- and (R)-Benzoin in Enantioselective Desymmetrization and Deracemization Catalyzed by Aureobasidium pullulans Included in the Blossom Protect™ Agent.

In this study, we examined the Aureobasidium pullulans strains DSM 14940 and DSM 14941 included in the Blossom Protect™ agent to be used in the bioreduction reaction of a symmetrical dicarbonyl compound. Both chiral 2-hydroxy-1,2-diphenylethanone antipodes were obtained with a high enantiomeric purity. Mild conditions (phosphate buffer [pH 7.0, 7.2], 30 °C) were successfully employed in the synthesis of (S)-benzoin using two different methodologies: benzyl desymmetrization and rac-benzoin deracemization. Bioreduction carried out with higher reagent concentrations, lower pH values and prolonged reaction time, and in the presence of additives, enabled enrichment of the reaction mixture with (R)-benzoin. The described procedure is a potentially useful tool in the synthesis of chiral building blocks with a defined configuration in a simple and economical process with a lower environmental impact, enabling one-pot biotransformation.

Total Synthesis of (+)-Hyacinthacine A1 Using a Chemoselective Cross-Benzoin Reaction and a Furan Photooxygenation-Amine Cyclization Strategy.

We report the shortest synthesis of glycosidase inhibitor (+)-hyacinthacine A1 using a highly chemoselective N-heterocyclic carbene-catalyzed cross-benzoin reaction as well as a furan photooxygenation-amine cyclization strategy. This is the first such cyclization on a furylic alcohol, an unprecedented reaction due to the notorious instability of the formed intermediates. The photooxygenation strategy was eventually incorporated into a three-step one-pot process that formed the requisite pyrrolizidine framework of (+)-hyacinthacine A1.

Photochemical α-Cleavage Reaction of 3',5'-Dimethoxybenzoin: A Combined Time-Resolved Spectroscopy and Computational Chemistry Study.

Benzoin is one of the most commonly used photoinitiators to induce free radical polymerization. Here, improved benzoin properties could be accomplished by the introduction of two methoxy substituents, leading to the formation of 3',5'-dimethoxybenzoin (DMB) which has a higher photo-cleavage quantum yield (0.54) than benzoin (0.35). To elucidate the underlying reaction mechanisms of DMB and obtain direct information of the transient species involved, femtosecond transient absorption (fs-TA) and nanosecond transient absorption (ns-TA) spectroscopic experiments in conjunction with density functional theory/time-dependent density functional theory (DFT/TD-DFT) calculations were performed. It was found that the photo-induced α-cleavage (Norrish Type I reaction) of DMB occurred from the nπ* triplet state after a rapid intersystem crossing (ISC) process (7.6 ps), leading to the generation of phenyl radicals on the picosecond time scale. Compared with Benzoin, DMB possesses two methoxy groups which are able to stabilize the alcohol radical and thus result in a stronger driving force for cleavage and a higher quantum yield of photodissociation. Two stable conformations (cis-DMB and trans-DMB) at ground state were found via DFT calculations. The influence of the intramolecular hydrogen bond on the α-cleavage of DMB was elaborated.

Anti-Inflammatory and Anti-Apoptotic Effects of Stybenpropol A on Human Umbilical Vein Endothelial Cells.

Inflammation is a key mediator in the progression of atherosclerosis (AS). Benzoinum, a resin secreted from the bark of Styrax tonkinensis, has been widely used as a form of traditional Chinese medicine in clinical settings to enhance cardiovascular function, but the active components of the resin responsible for those pharmaceutical effects remain unclear. To better clarify these components, a new phenylpropane derivative termed stybenpropol A was isolated from benzoinum and characterized via comprehensive spectra a nalysis. We further assessed how this phenylpropane derivative affected treatment of human umbilical vein endothelial cells (HUVECs) with tumor necrosis factor-α (TNF-α). Our results revealed that stybenpropol A reduced soluble intercellular cell adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), interleukin-8 (IL-8), and interleukin-1ß (IL-1ß) expression by ELISA, inhibited apoptosis, and accelerated nitric oxide (NO) release in TNF-α-treated HUVECs. We further found that stybenpropol A decreased VCAM-1, ICAM-1, Bax, and caspase-9 protein levels, and increased the protein levels of Bcl-2, IKK-ß, and IκB-α. This study identified a new, natural phenylpropane derivative of benzoinum, and is the first to reveal its cytoprotective effects in the context of TNF-α-treated HUVECs via regulation of the NF-κB and caspase-9 signaling pathways.

Cu(II)-Catalyzed C-N Coupling of (Hetero)aryl Halides and N-Nucleophiles Promoted by α-Benzoin Oxime.

We first reported the new application of a translate metal chelating ligand α-benzoin oxime for improving Cu-catalyzed C-N coupling reactions. The system could catalyse coupling reactions of (hetero)aryl halides with a wide of nucleophiles (e.g., azoles, piperidine, pyrrolidine and amino acids) in moderate to excellent yields. The protocol allows rapid access to the most common scaffolds found in FDA-approved pharmaceuticals.

Efficient and Selective Carboligation with Whole-Cell Biocatalysts in Pickering Emulsion.

Pickering emulsions (PEs) are particle-stabilized multiphase systems with promising features for synthetic applications. Described here is a novel, simplified set-up employing catalytically active whole cells for simultaneous emulsion stabilization and synthetic reaction. In the stereoselective carboligation of benzaldehyde to (R)-benzoin catalyzed by a benzaldehyde lyase in E. coli, the set-up yielded maximum substrate conversion within very short time, while economizing material demand and waste. Formation and activity of freshly produced PEs were enhanced when the catalytic whole cells were covered with hydrophobic silicone prior to PE formation. Benchmarked against other easy-to-handle whole-cell biocatalysts in pure organic solvent, neat substrate, an aqueous emulsion in substrate, and a micro-aquatic system, respectively, the cell-stabilized PE outperformed all other systems by far.

Facile Transfer of Reverse Micelles from the Organic to the Aqueous Phase for Mimicking Enzyme Catalysis and Imaging-Guided Cancer Therapy.

Reverse micelles (RMs) with confined water pools have been applied in many fields. However, the water insolubility of RMs seriously limits the scope of their application, especially those needed to operate in aqueous environments. Here, we report the first successful transfer of RMs from the organic phase to water phase without disturbing their confined water pools and hydrophobic alkyl region. This transfer was achieved by virtue of a mild host-guest interaction between the hydrophobic tails of interfacial cross-linked reverse micelles (ICRMs) and the hydrophobic cavity of (2-hydroxypropyl)-ß-cyclodextrin (HP-ß-CD). Benefitting from the maintained confined water pools and the hydrophobic scaffold, the obtained water-soluble ICRMs served as multifunctional nanoplatforms for enzyme-mimicking catalysis and image-guided cancer therapy, which were impossible for normal RMs lacking water solubility or confined pool-buried water-soluble nanoparticles without a hydrophobic alkyl chain. This mild transfer approach thus surmounts the application obstacle of RMs and opens up new avenues for their application in aqueous environments.

Supramolecular chirality and crystallization from biocatalytic self-assembly in lipidic cubic mesophases.

Biocatalytic self-assembly in a nanoconfined environment is widely used in nature to construct complex structures that endow special characteristics to life. There is tremendous interest in mimicking such bottom-up processes to fabricate functional materials. In this study, we have investigated a novel biomimetic scaffold based on lipidic cubic mesophases (LCMs), which provide a special nanoconfined environment for biocatalytic self-assembly and subsequent formation of organic crystals. (R)-Benzoin generated in situ from benzaldehyde in a reaction catalyzed by the enzyme benzaldehyde lyase (BAL) exhibits - when confined within LCMs - enhanced chirality compared to (R)-benzoin in solution or (R)-benzoin-doped LCMs. We infer that a metastable state is formed under kinetic control that displays enhanced supramolecular chirality. As they age, these metastable structures can further grow into thermodynamically stable crystals. The biomimetic, nanoconfined environment provided by the LCMs plays a key role in the development of supramolecular chirality and subsequent crystallization.

Ligand-Based Drug Design: Synthesis and Biological Evaluation of Substituted Benzoin Derivatives as Potential Antitumor Agents.

BACKGROUND: Phosphoinositide 3-kinase α (PI3Kα) has emerged as a promising target for anticancer drug design. OBJECTIVES: Target compounds were designed to investigate the effect of the p-OCH3 motifs on ligand/PI3Kα complex interaction and antiproliferative activity. METHODS: Synthesis of the proposed compounds, biological examination tests against human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines, along with Glide docking studies. RESULTS: A series of 1,2-bis(4-methoxyphenyl)-2-oxoethyl benzoates was synthesized and characterized by means of FT-IR, 1H and 13C NMR, and by elemental analysis. Biological investigation demonstrated that the newly synthesized compounds exhibit antiproliferative activity in human colon adenocarcinoma (HCT-116), breast adenocarcinoma (MCF-7), and breast carcinoma (T47D) cell lines possibly via inhibition of PI3Kα and estrogen receptor alpha (ERα). Additionally, results revealed that these compounds exert selective inhibitory activity, induce apoptosis, and suppress VEGF production. Compound 3c exhibited promising antiproliferative activity in HCT-116 interrogating that hydrogen bond-acceptor mediates ligand/PI3Kα complex formation on m- position. Compounds 3e and 3i displayed high inhibitory activity in MCF-7 and T47D implying a wide cleft discloses the o-attachment. Furthermore, compound 3g exerted selective inhibitory activity against T47D. Glide docking studies against PI3Kα and ERα demonstrated that the series accommodate binding to PI3Kα and/or ERα. CONCLUSION: The series exhibited a potential antitumor activity in human carcinoma cell lines encoding PI3Kα and/or ERα.

Photolabile Linkers for Solid-Phase Synthesis.

Photolabile linkers are the subjects of intense research because they allow the release of the target molecule simply by irradiation. Photochemical release of synthesis products is often facilitated without additional reagents under mild reaction conditions, which may even be environmentally friendly and appealing in the context of greener chemistry. The mild conditions also allow for applications of released material in subsequent biological screening experiments, where contamination with cleavage reagents would be detrimental. This Review pays attention to the increasing number of photolabile linkers developed for solid-phase synthesis and release and covers: (i) o-nitrobenzyloxy linkers, (ii) o-nitrobenzylamino linkers, (iii) α-substituted o-nitrobenzyl linkers, (iv) o-nitroveratryl linkers, (v) phenacyl linkers, (vi) p-alkoxyphenacyl linkers, (vii) benzoin linkers, (viii) pivaloyl linkers, and (ix) other photolabile linkers.

Development of benzoxazole deoxybenzoin oxime and acyloxylamine derivatives targeting innate immune sensors and xanthine oxidase for treatment of gout.

Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and anti-acute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD.

Intramolecular Benzoin Reaction Catalyzed by Benzaldehyde Lyase from Pseudomonas Fluorescens Biovar I.

Intramolecular benzoin reactions catalyzed by benzaldehyde lyase from Pseudomonas fluorescens biovar I (BAL) are reported. The structure of the substrates envisaged for this reaction consists of two benzaldehyde derivatives linked by an alkyl chain. The structural requirements needed to achieve the intramolecular carbon-carbon bond reaction catalyzed by BAL were established. Thus, a linker consisting of a linear alkyl chain of three carbon atoms connected through ether-type bonds to the 2 and 2' positions of two benzaldehyde moieties, which could be substituted with either Cl, Br, or OCH3 at either the 3 and 3' or 5 and 5' positions, were suitable substrates for BAL. Reactions with 61-84 % yields of the intramolecular product and ee values between 64 and 98 %, were achieved.

Thermodynamic Activity-Based Interpretation of Enzyme Kinetics.

The experimentally determined Michaelis constant Km results from a combination of two effects: the recognition of the substrate by the enzyme and the interactions between substrate and solvent. For a solvent-independent analysis of substrate specificity, the thermodynamic activity of the substrate, rather than its concentration, must be considered.

Regio- and Stereoselective Aliphatic-Aromatic Cross-Benzoin Reaction: Enzymatic Divergent Catalysis.

The catalytic asymmetric synthesis of chiral 2-hydroxy ketones by using different thiamine diphosphate dependent enzymes, namely benzaldehyde lyase from Pseudomonas fluorescens (PfBAL), a variant of benzoylformate decarboxylase from Pseudomonas putida (PpBFD-L461A), branched-chain 2-keto acid decarboxylase from Lactococcus lactis (LlKdcA) and a variant of pyruvate decarboxylase from Acetobacter pasteurianus (ApPDC-E469G), was studied. Starting with the same set of substrates, substituted benzaldehydes in combination with different aliphatic aldehydes, PfBAL and PpBFD-L461A selectively deliver the (R)- and (S)-2-hydroxy-propiophenone derivatives, respectively. The (R)- and (S)-phenylacetylcarbinol (1-hydroxy-1-phenylacetone) derivatives are accessible in a similar way using LlKdcA and ApPDC-E469G, respectively. In many cases excellent stereochemical purities (>98 % enantiomeric excess) could be achieved. Hence, the regio- and stereochemistry of the product in the asymmetric aliphatic-aromatic cross-benzoin reaction can be controlled solely by choice of the appropriate enzyme or enzyme variant.

Synthesis of 2-(methylsulfonyl)-5-(4-(methylsulfonyl) phenyl)-4-phenyl-1H-[5-(14)C]imidazole, a selective COX-2 inhibitor, via asymmetrical benzoins.

4,5-Diarylimidazoles labeled with carbon-14 in the 5-position of the imidazole ring were prepared as a part of three-step sequence from 2-hydroxy-1-(4-(methylthio)phenyl)-2-phenyl[1-(14) C]ethanone as a key synthetic intermediate which has been synthesized from potassium [(14) C]cyanide.

Heterofunctional Magnetic Metal-Chelate-Epoxy Supports for the Purification and Covalent Immobilization of Benzoylformate Decarboxylase From Pseudomonas Putida and Its Carboligation Reactivity.

In this study, the combined use of the selectivity of metal chelate affinity chromatography with the capacity of epoxy supports to immobilize poly-His-tagged recombinant benzoylformate decarboxylase from Pseudomonas putida (BFD, E.C. 4.1.1.7) via covalent attachment is shown. This was achieved by designing tailor-made magnetic chelate-epoxy supports. In order to selectively adsorb and then covalently immobilize the poly-His-tagged BFD, the epoxy groups (300 µmol epoxy groups/g support) and a very small density of Co(2+)-chelate groups (38 µmol Co(2+)/g support) was introduced onto magnetic supports. That is, it was possible to accomplish, in a simple manner, the purification and covalent immobilization of a histidine-tagged recombinant BFD. The magnetically responsive biocatalyst was tested to catalyze the carboligation reactions. The benzoin condensation reactions were performed with this simple and convenient heterogeneous biocatalyst and were comparable to that of a free-enzyme-catalyzed reaction. The enantiomeric excess (ee) of (R)-benzoin was obtained at 99 ± 2% for the free enzyme and 96 ± 3% for the immobilized enzyme. To test the stability of the covalently immobilized enzyme, the immobilized enzyme was reused in five reaction cycles for the formation of chiral 2-hydroxypropiophenone (2-HPP) from benzaldehyde and acetaldehyde, and it retained 96% of its original activity after five reaction cycles.