Acyloin Research Articles

A Novel 2-Methylimidazole Promoted Oxyacyloxylation of α-Hydroxy Ketones and Anhydrides: An Easy Access to α-Acyloxy Ketones

An efficient and operationally simple method for the synthesis of α-acyloxy ketones through the readily available 2-methylimidazole-promoted reaction of α-hydroxy ketones and anhydrides is developed. In the reaction, the anhydrides act as both a substrate and a solvent. The new method features good substrate tolerance, mild reaction conditions, readily accessible starting materials, and excellent yields, providing facile and green access to the targets. Importantly, the reaction also avoids the use of reagents with pungent odors, such as pyridine, in traditional esterification, which may promote the development of organocatalysis using nitrogen-containing heterocyclic compounds as catalysts.

Synergistic Rh(II)- and Zn(II)-Catalyzed [3 + 3] Annulation of Diazoenals and α-Hydroxy Ketones for the Direct Synthesis of 2H-Pyrans, A Gateway Toward γ-Pyrones.

A new synergistic Rh(II)/Zn(II)-catalyzed [3 + 3] annulation has been developed between diazoenals and α-hydroxy ketones enabling the direct synthesis of 4-formyl-2H-pyrans. The reaction involves the formation of protic oxonium ylides from highly electrophilic Rh-enalcarbenoids followed by Zn-templated regioselective intramolecular aldol condensation. Subsequent investigations demonstrated that 4-formyl-2H-pyrans are unique precursors of γ-pyrones. The γ-pyrones were obtained via Et3N-mediated oxidative deformylation. Further, the triflic-acid-promoted double Schmidt reaction of 4-formyl-2H-pyrans provides synthetically important carboxamide-substituted 4-cyano 2H-pyrans.

Significantly enhanced specific activity of Bacillus subtilis (2,3)-butanediol dehydrogenase through computer-aided refinement of its substrate-binding pocket

(2,3)-Butanediol dehydrogenases (BDHs) are widely utilized for the stereoselective interconversion between α-hydroxy ketones and vicinal diols to produce various functional building blocks. In this study, to enhance the specific activity towards (R)-phenyl-1,2-ethanediol (1a) for 2-hydroxyacetophenone (1b), the substrate-binding pocket of a Bacillus subtilis BDH (BsBDHA) was refined through site-directed mutagenesis. Based on molecular docking simulations, 14 residues were identified and subjected to alanine scanning mutagenesis. After screening, two residues, His42 and Gly292, were singled out for partial site-saturation mutagenesis. The results revealed that BsBDHAH42A and BsBDHAG292A displayed high activities of 3.21 and 1.97 U/mg, respectively. Employing combinatorial mutagenesis, a superior mutant, BsBDHAI49L/V266L/G292A, was developed, exhibiting significantly enhanced specific activity and catalytic efficiency towards (R)-1a, achieving 14.81 U/mg and 4.47 mM−1 s−1, respectively, which were 27.4- and 55.9-fold higher than those of BsBDHA. Further substrate spectrum analysis revealed that the superior mutant displayed increased specific activities for (R)-2a–6a by 1.4- to 10.3-fold. The integration of BsBDHAI49L/V266L/G292A into a three-enzymatic cascade for the synthesis of 1b effectively elevated the yield from 58.1 to 82.4%. Molecular mechanism analysis indicated that the mutation-induced changes in intermolecular forces resulted in a higher frequency of reactive conformations for (R)-1a in BsBDHAI49L/V266L/G292A compared to BsBDHA.

Highly efficient synthesis and photochromic properties of a pentacyclic N-heterocyclic carbonyl-based dithienylethene

Given that the photochromic functional materials possess outstanding phototropic color-change properties, the attention being paid to this field is progressively intensifying. The development of N-heterocyclic carbonyl photoswitching materials, harnessing dithienylethene site for photochromism, typically involves a complex multi-step synthesis process, which substrate diversification and the complexity of the preparation process are confronted with various challenges. Herein, we present a straightforward synthetic methodology for the preparation of photochromic 4,5-bis(2,5-dimethylthiophen-3-yl)-1,3-diphenyl-1,3-dihydro-2H-imidazol-2-one (1o) via reprogramming the synthesis pathway of dithienylethene-containing imidazolone using 1,3-diphenylurea. The current method demonstrates efficient reaction between α-hydroxy ketone and 1,3-diphenylurea in high yield, thereby enabling direct and straightforward one-step cyclization. The grown crystal sample of the targeted 1o has undergone single crystal X-ray diffraction analysis to elucidate its structural information. The ring-open (o-isomer) and ring-closed (c-isomer) forms showing remarkable fatigue resistance and high contrast visual color changes, can be effortlessly interconverted through the alternating irradiation of UV/vis light. To illustrate the electronic structure of the isomers, thorough analyses of the frontier molecular orbital based on TD-DFT calculations were conducted.

Biosynthesis of the benzylpyrrolidine precursor in anisomycin by a unique ThDP-dependent enzyme

Anisomycin (compound 1), a multifunctional pyrrolidine antibiotic, primarily inhibits protein biosynthesis by binding to the ribosome. Upon binding to the ribosome, the para-phenol moiety of anisomycin inserts completely into the hydrophobic crevice of the A-site and blocks the access of the incoming aminoacyl-tRNAs, disrupting peptide bond formation. Hence, the para-methoxyphenyl group serves as a starting point for developing novel anisomycin analogs with potent antifungal and insecticidal properties. However, the activation and condensation mechanism of phenylpyruvic acid has not yet been elucidated. In this study, genetic manipulations of aniP and its homologue siAniP confirmed their indispensable role in 1 biosynthesis. Bioinformatics analysis suggested that AniP and siAniP function as transketolase. siAniP was found to catalyzed condensation between 4-hydroxyphenylpyruvic acid (3) and glyceraldehyde (GA), initiating pyrrolidine synthesis. siAniP was specific for aromatic keto acids and tolerant of aliphatic and aromatic aldehydes, and was able to catalyze the asymmetric intermolecular condensation of two keto acids, leading to the formation of 24 α-hydroxy ketone. To the best of our knowledge, siAniP is the first TK that catalyzes the transfer of a C2 ketol and symmetrical intermolecular coupling using aromatic keto acids as donor substrates. Structural analysis, docking model construction, and site-directed mutagenesis identified that I220, H275, R322 and W391 were crucial for substrate binding. Moreover, sequence similarity network (SSN)-based genome neighborhood network (GNN) analyses of AniP suggested the widespread occurrence of the AniP-like-mediated reaction in the biosynthesis of 1 and its analogs, particularly in the assembly of benzylpyrrolidine. These findings not only expand the repertoire of TKs but also provide a potent biocatalyst that could be used for the structural innovation of 1 and its derivatives.

Synthesis of α-hydroxy ketones through novel one-pot multi-enzyme cascade system from racemic epoxides

α-Hydroxy ketones, highly versatile building blocks, present challenges for their green and efficient synthesis. Based on thermodynamic analysis, a novel in vitro one-pot multi-enzyme cascade system was designed for synthesizing 2-hydroxyacetophenone (1c) from racemic styrene oxide (1a). This system incorporated a Rhodotorula paludigena epoxide hydrolase (RpEHL360V) for the enantioconvergent hydrolysis of rac-1a to (R)-phenyl-1,2-ethanediol (1b), a Bacillus subtilis (2,3)-butanediol dehydrogenase (BsBDHAI49L/V266L/G292A) for the subsequent oxidation to 1c, and a Lactobacillus casei lactate dehydrogenase (LcLDH1) for the reduction of pyruvate to lactate, thereby facilitating coenzyme recycling and shifting the reaction's thermodynamic equilibrium. After optimizing the reaction conditions, the system reached its highest efficiency using cell-free extracts of RpEHL360V (4.0 U/mL), BsBDHAI49L/V266L/G292A (0.3 U/mL), and LcLDH1 (0.1 U/mL), along with 4 mM NADH and 200 mM sodium pyruvate as cofactor and cosubstrate, respectively, in a Na2HPO4-NaH2PO4 buffer (100 mM, pH 8.0) at 30 °C. Under these conditions, the system catalyzed the conversion of 50 mM rac-1a to 1c with a total yield of 73.1 % and a maximum space-time yield of 10.7 mmol/L/h within 24 h. Furthermore, this one-pot system was applied to catalyze 20 mM of rac-4-chlorostyrene oxide and 1,2-epoxyhexane, successfully synthesizing two corresponding α‑hydroxy ketones, each with a space-time yield of 0.7 mmol/L/h, demonstrating the system's efficacy for the production of α‑hydroxy ketones.

N-Heterocyclic Carbene Catalyzed Reassembly of Dibenzyl Ethers: Facile Access to α-Hydroxy Ketones

AbstractA novel one-pot cascade process of oxidation-initiated, N-heterocyclic carbene catalyzed, reintegration of dibenzyl ethers has been developed for the first time. This protocol allows straightforward access to α-hydroxy ketones from dibenzyl ethers. It is noteworthy that the present method is the first attempt to synthesize benzoin from dibenzyl ether.

Identification of Kibdelomycin and Related Biosynthetic Gene Clusters and Characterization of the C-Branching of Amycolose.

Many bacterial natural products contain C-branched sugars, including components from the outer cell wall or antibiotically active metabolites. The enzymatic C-branching of keto sugars leading to longer side chains (≥C2) is catalyzed by thiamine diphosphate (ThDP)-dependent enzymes. Chiral tertiary α-hydroxy ketones are formed in this process. The ThDP-dependent enzymes that catalyze C-branching reactions belong to one of three enzymatic superfamilies: decarboxylases, transketolases, and α-ketoacid dehydrogenases 2, but branching of keto sugars has only been demonstrated for decarboxylases. In this study, we showed that an α-ketoacid dehydrogenase is responsible for C-branching of the deoxyketo sugar amycolose in the biosynthesis of kibdelomycin in Kibdelosporangium sp. MA7385. In addition, we characterized an amino transferase in the same biosynthetic gene cluster (BGC) that accepts a sterically demanding tertiary α-hydroxy ketone in a downstream reaction. Subsequently, we identified approximately 400 similar BGCs in silico, suggesting that there is a large diversity of possible ThDP-dependent enzymes catalyzing the C-branching of keto sugars and subsequent modifications.

Modulating regioselectivity of CYP107J3-catalyzed isophorone hydroxylation by disrupting the hydrophobic balance of the substrate binding pocket

4-Hydroxyisophorone (4HIP) is an oxygenated intermediate derived from isophorone, serving as an important flavor and fragrance and chiral synthon of pharmaceutical drugs. In this study, a newly identified P450CYP107J3 from Bacillus cereus was found to prefer 4-hydroxylation of isophorone (80% regioselectivity) with 4HIP as the predominant product (59% product proportion). Bioinformatic analyses, including homologous modelling and molecular docking, reveal that four potential “hotspot” residues (L98, T300, M401 and V296) located on both sides of the substrate in the active pocket may control regioselectivity. By introducing polar residues to these hotspots to disrupt the hydrophobic balance, significant improvement in C4-regioselectivity was achieved by variants of L98, T300, and M401, with the most effective L98N exhibiting a notable enhancement of 93% C4-regioselectivity including 81% of 4HIP. Following, the double mutant L98N-M401F further improved both C4-regioselectivity (97%) and the proportion of 4HIP (86%). Remarkably, variant V296T essentially shifted regioselectivity from 4HIP to 6-hydroxyisophorone (6HIP) with an 80% preference for the latter, indicating the crucial role of V296 in controlling regioselectivity. Subsequently, the mechanism of regioselectivity of isophorone hydroxylation catalyzed by CYP107J3 was revealed by computational analysis. Furthermore, we demonstrated the generality of conserved hotspots L98 and V296 in mediating regioselectivity control in the CYP107J family members like CYP107J1 and CYP107J5. Overall, our study not only expands the biocatalytic toolbox for producing 4HIP and the α-hydroxy ketone 6HIP but also provides efficient engineering strategy and knowledge for the regioselectivity control of P450s in potential applications.

One-Pot N-α-C(sp3)–H Bond Functionalisation Cascade for the Synthesis of Polysubstituted Imidazoles

AbstractA one-pot eco-friendly oxidative N-α-C(sp3)–H bond functionalisation of arylmethylamines for the synthesis of tetrasubstituted imidazoles is demonstrated. The substrate scope of these amines has been well-explored with different substrates, such as 1,2-diketones, an α-hydroxy ketone and phenylacetophenone. In the presence of FeCl3 catalyst and green oxidant O2, the easily accessible substrates afforded tetrasubstituted imidazoles in up to 94% yield.

Multifunctional Biomass-Based Ionic Liquids/CuCl-Catalyzed CO2-Promoted Hydration of Propargylic Alcohols: A Green Synthesis of α-Hydroxy Ketones.

α-Hydroxy ketones are a class of vital organic skeletons that generally exist in a variety of natural products and high-value chemicals. However, the traditional synthetic route for their production involves toxic Hg salts and corrosive H2SO4 as catalysts, resulting in harsh conditions and the undesired side reaction of Meyer-Schuster rearrangement. In this study, CO2-promoted hydration of propargylic alcohols was achieved for the synthesis of various α-hydroxy ketones. Notably, this process was catalyzed using an environmentally friendly and cost-effective biomass-based ionic liquids/CuCl system, which effectively eliminated the side reaction. The ionic liquids utilized in this system are derived from natural biomass materials, which exhibited recyclability and catalytic activity under 1 bar of CO2 pressure without volatile organic solvents or additives. Evaluation of the green metrics revealed the superiority of this CuCl/ionic liquid system in terms of environmental sustainability. Further mechanistic investigation attributed the excellent performance to the ionic liquid component, which exhibited multifunctionality in activating substrates, CO2 and the Cu component.

Visible-light-induced Ritter-type amidation of α-hydroxy ketones in the selective synthesis of α,α-diamido and monoamido ketones.

Visible light-induced, transition metal-free oxidative dehydroxylation and C-H amidation of α-hydroxy ketones involving Ritter-type amidation has been developed, leading to the selective synthesis of α,α-diamido- and α-monoamido ketones with tunable selectivity as well as broad substrate tolerance.

A Chemo-Enzymatic Approach for Preparing Efinaconazole with High Optical Yield.

Herein, we present a novel and ecofriendly biocatalytic approach for synthesizing efinaconazole (7), a clinically used antifungal agent. This method involves utilizing benzaldehyde lyase (BAL) to catalyze the crucial benzoin condensation step in the ketone precursor. Treating 2,4-difluorobenzaldehyde with BAL in the presence of thiamin-diphosphate (ThDP) and Mg2+ resulted in the formation of α-hydroxy ketone which then underwent the preparation of 7. This innovative approach not only provides a greener alternative but also offers significant advantages over the traditional chemical process. Through our efforts and development work, we have established efficient and scalable procedures that enable the production of 7 in a moderate 38% yield.

Direct Deoxygenation of α-Hydroxy and α,β-Dihydroxy Ketones Using a Silyl Lithium Reagent.

A reliable method for the one-step direct deoxygenation of α-hydroxy ketones has been developed using a silyl lithium reagent and acetic anhydride. The method is metal-catalyst-free and does not require prefunctionalization of the hydroxy group prior to its removal. Deoxygenation of different primary, secondary, and tertiary alcohols was carried out with up to 98% isolated yield. Additionally, double deoxygenation was achieved when the present method was applied to α,β-dihydroxy ketones to access the corresponding enones in a single step.

The photoinitiator of bifunctional α-hydroxy ketone with long-wavelength in photopolymerization under UV-LEDs

α-hydroxy ketone photoinitiators have been widely used in the photopolymerization industry, such as coating, ink and adhesive, for they have high initiating activity, good thermal stability, and yellowing resistance. However, few works have been reported in developing α-hydroxy ketone photoinitiators that match the absorption of long wavelength LEDs. In this work, a new bifunctional α-hydroxy ketone photoinitiator, (1,4-phenylene) bis (4-hydroxy-4-methylpent-1-en-3-one) (B-HMP), was synthesized and characterized. B-HMP exhibited excellent absorption among the wavelength of 300– 400 nm due to the introduction of unsaturated double bonds which could be employed to match 365/405 nm LEDs. From the results of electron spin resonance spin-trapping (EPR-ST) and steady-state photolysis investigations, the mechanism of the generation of radicals of B-HMP may be via not only the cleavage of CC bonds, but also intermolecular hydrogen abstraction. The efficiency of photopolymerization of B-HMP and triethanolamine (TEOA) was better than those of B-HMP alone because of the synergistic effect. Furthermore, the B-HMP/TEOA had a significantly yellowing resistance property.

Conformational preferences, lattice energies and receptor binding in a series of α-hydroxy ketones and α-fluoro ketones in supramolecular space

Conformational preferences, lattice energies and receptor binding in a series of α-hydroxy ketones and α-fluoro ketones in supramolecular space

Transition-Metal-Free and Selective Deconstructive Carbonyl Olefination of α-Hydroxy Ketones: A Complementary Approach to Knoevenagel Reaction

AbstractWhile the carbonyl olefination has been extensively studied and well documented, use of α-hydroxy ketones as precursors for the carbonyl olefination is not reported, till date. Herein, a transition-metal-free and selective Knoevenagel-type deconstructive carbonyl olefination of α-hydroxy ketones using arylacetonitriles under mild reaction conditions is presented. The reaction affords valuable scaffolds of acrylonitriles with the use of α-hydroxy ketones as precursors for carbonyl olefination.

Chemo-enzymatic synthesis of chiral precursor molecules with chiral ring hydroxyenone and acetoxyenone structures

A biocatalytic transformation has the potential to perform organic reactions that are quite challenging to achieve with synthetic organic chemistry. They also catalyze these reactions with a chemo and enantio selective manner. The discovery and development of new chemoenzymatic methods for the synthesis of these chiral structures is essential to the production of a wide range of bioactive compounds. In this study, two important pharmaceutical precursors were synthesized chemoenzymatically and subjected to biocatalytic conversions with different dehydrogenases. One of these compound is an α-acetoxy enone structure 4-methoxy-2-oxacyclohex-3-enyl acetate and the other is an α-hydroxy ketone 6-hydroxy-3-methoxycycyclohex-2-enone. To obtain these pharmaceutical precursors, 3-methoxy-cyclohex-2-enone was prepared using 1,3-diketone as a starting material. After obtaining this material, α-acetoxy enone was synthesized by chemical acetylation and α-hydroxy ketone prepared by enzymatic deacetylation. The structure of these products was elucidated by NMR analysis. In addition, biocatalytic reduction reactions involving the enzymes galactitol dehydrogenase (GatDH), shikimate dehydrogenase (SDH) and diaphorase were carried out with these products.

The O2-Mediated Cross-Dehydrogenative Coupling: Rose Bengal-Catalyzed Direct Oxidative α-Acyloxylation of Ketones.

A general and facile approach for the direct oxidative α-acyloxylation of ketones using molecular oxygen as the oxidant is developed. This method avoids the use of excessive peroxides and expensive metal catalysts, affording a variety of α-acyloxylated ketones in satisfactory yields. Experimental studies indicate that the reaction proceeds via a radical pathway. Additionally, α-hydroxy ketones could be obtained by changing the solvent.

Optimized enantioselective (S)-2-hydroxypropiophenone synthesis by free- and encapsulated-resting cells of Pseudomonas putida

BackgroundAromatic α-hydroxy ketones, such as S-2-hydroxypropiophenone (2-HPP), are highly valuable chiral building blocks useful for the synthesis of various pharmaceuticals and natural products. In the present study, enantioselective synthesis of 2-HPP was investigated by free and immobilized whole cells of Pseudomonas putida ATCC 12633 starting from readily-available aldehyde substrates. Whole resting cells of P. putida, previously grown in a culture medium containing ammonium mandelate, are a source of native benzoylformate decarboxylase (BFD) activity. BFD produced by induced P. putida resting cells is a highly active biocatalyst without any further treatment in comparison with partially purified enzyme preparations. These cells can convert benzaldehyde and acetaldehyde into the acyloin compound 2-HPP by BFD-catalyzed enantioselective cross-coupling reaction.ResultsThe reaction was carried out in the presence of exogenous benzaldehyde (20 mM) and acetaldehyde (600 mM) as substrates in 6 mL of 200 mM phosphate buffer (pH 7) for 3 h. The optimal biomass concentration was assessed to be 0.006 g dry cell weight (DCW) mL− 1. 2-HPP titer, yield and productivity using the free cells were 1.2 g L− 1, 0.56 g 2-HPP/g benzaldehyde (0.4 mol 2-HPP/mol benzaldehyde), 0.067 g 2-HPP g− 1 DCW h− 1, respectively, under optimized biotransformation conditions (30 °C, 200 rpm). Calcium alginate (CA)–polyvinyl alcohol (PVA)-boric acid (BA)-beads were used for cell entrapment. Encapsulated whole-cells were successfully employed in four consecutive cycles for 2-HPP production under aerobic conditions without any noticeable beads degradation. Moreover, there was no production of benzyl alcohol as an unwanted by-product.ConclusionsBioconversion by whole P. putida resting cells is an efficient strategy for the production of 2-HPP and other α-hydroxyketones.Graphical abstract