Retro-aldol Reaction Research Articles

One-Pot Catalytic Cascade for the Depolymerization of the Lignin β-O-4 Motif to Non-phenolic Dealkylated Aromatics.

Aromatic monomers obtained by selective depolymerization of the lignin β-O-4 motif are typically phenolic and contain (oxygenated) alkyl substitutions. This work reveals the potential of a one-pot catalytic lignin β-O-4 depolymerization cascade strategy that yields a uniform set of methoxylated aromatics without alkyl side-chains. This cascade consists of the selective acceptorless dehydrogenation of the γ-hydroxy group, a subsequent retro-aldol reaction that cleaves the Cα-Cβ bond, followed by in situ acceptorless decarbonylation of the formed aldehydes. This three-step cascade reaction, catalyzed by an iridium(I)-BINAP complex, resulted in 75 % selectivity for 1,2-dimethoxybenzene from G-type lignin dimers, alongside syngas (CO : H2≈1.4 : 1). Applying this method to a synthetic G-type polymer, 11 wt % 1,2-dimethoxybenzene was obtained. This versatile compound can be easily transformed into 3,4-dimethoxyphenol, a valuable precursor for pharmaceutical synthesis, through an enzymatic catalytic approach. Moreover, the hydrodeoxygenation potential of 1,2-dimethoxybenzene offers a pathway to produce valuable cyclohexane or benzene derivatives, presenting enticing opportunities for sustainable chemical transformations without the necessity for phenolic mixture upgrading via dealkylation.

Conversion of Phorbol into Des-D-Ring Tricycle and Crotonianoid B via Peroxidation Reaction.

Phorbol (1) has a tetracyclic ABCD-ring and is readily isolable from a natural source. We previously synthesized 1 and 16 structurally related natural products using common ABC-ring intermediate 2. Here we report a new synthetic route to 2 using 1 as a starting material. Key features of the synthesis are chemoselective removal of the D-ring via cyclopropane opening, peroxidation, and retro-aldol reactions. The high utility of the peroxidation was further demonstrated in the first synthesis of crotonianoid B (9).

Direct Analysis of Complex Reaction Mixtures: Formose Reaction.

Complex reaction mixtures, like those postulated on early Earth, present an analytical challenge because of the number of components, their similarity, and vastly different concentrations. Interpreting the reaction networks is typically based on simplified or partial data, limiting our insight. We present a new approach based on online monitoring of reaction mixtures formed by the formose reaction by ion-mobility-separation mass-spectrometry. Monitoring the reaction mixtures led to large data sets that we analyzed by non-negative matrix factorization, thereby identifying ion-signal groups capturing the time evolution of the network. The groups comprised ≈300 major ion signals corresponding to sugar-calcium complexes formed during the formose reaction. Multivariate analysis of the kinetic profiles of these complexes provided an overview of the interconnected kinetic processes in the solution, highlighting different pathways for sugar growth and the effects of different initiators on the initial kinetics. Reconstructing the network's topology further, we revealed so far unnoticed fast retro-aldol reaction of ketoses, which significantly affects the initial reaction dynamics. We also detected the onset of sugar-backbone branching for C6 sugars and cyclization reactions starting for C5 sugars. This top-down analytical approach opens a new way to analyze complex dynamic mixtures online with unprecedented coverage and time resolution.

Facile synthesis of N-acetylglycine from chitin-derived N-acetylmonoethanolamine

The effective conversion of renewable chitin and its derivatives to organonitrogen chemicals is of significance. N-acetylmonoethanolamine (NMEA) is a compound that can be produced from N-acetylglucosamine (NAG, the monomer of chitin) via successive retro-aldol and hydrogenation reactions. Here we report the aerobic oxidation of NMEA to N-acetylglycine in O2 using cheap Fe(NO3)3⋅9H2O, TEMPO, and KCl. The effects of catalysts, additives, and reaction conditions on the N-acetylglycine synthesis were investigated. Under optimized conditions, a 62.1% yield of N-acetylglycine with almost full conversion was obtained.

Regioselectivity Switch between Enantioselective 1,2- and 1,4-Addition of Allyl Aryl Ketones with 2,3-Dioxopyrrolidines.

A vinylogous addition reaction of allyl aryl ketones with good yields and excellent regioselectivity catalyzed by squaramide catalysts has been developed. A series of chiral tertiary alcohols and bicyclic pyrrolidones could be synthesized in good to excellent yields, enantioselectivities, and diaseteroselectivities. Both experimental results and DFT calculations indicate that 1,2-addition reaction is favorable when the reaction is employed at a lower temperature, while the 1,4-addition/cyclization pathway is favorable when the reaction is employed at a higher temperature. Furthermore, the formation of compound 4 can potentially arise from either the 1,4-addition/cyclization pathway or retro-aldol reaction of compound 3, followed by subsequent 1,4-addition/cyclization.

Unveiling Photodegradation and Photosensitization Mechanisms of Unconjugated Pterins.

Unconjugated pterins are ubiquitous molecules participating in countless enzymatic processes and potentially involved in the photosensitization of singlet oxygen, amino acids, and nucleotides. Following electronic excitation with UV-A light, some of these pterins degrade, producing hydrogen peroxide as the main side product. This process, that is known to take place in vivo, contributes to oxidative stress and melanocyte destruction in vitiligo. In this work, we present for the first time mechanistic insight to the formation of transient triplet species which simultaneously trigger Type I and Type II photosensitizing processes and the initiation of degradation processes. Our calculations reveal that photodegradation of 6-biopterin, which accumulates in the skin of vitiligo patients, leads to 6-formylpterin via retro-aldol reaction, and subsequently to 6-carboxypterin through a water-mediated aldehyde oxidation. Additionally, we show that the changes in the photosensitizing potential of these systems with pH come from the modulation of their excited-state redox potentials.

Biomimetic Catalytic Retro-Aldol Reaction Using a Cation-Binding Catalyst: A Promising Route to Axially Chiral Biaryl Aldehydes.

Here we describe a biomimetic catalytic retro-aldol reaction of racemic α-substituted β-hydroxy ketones utilizing a chiral oligoEG cation-binding catalyst as a type-II aldolase mimic. Our investigation of various aldol substrates has demonstrated that our biomimetic retro-aldol protocol enables rapid access to highly enantiomerically enriched aldols with a selectivity factor (s) of up to 70. Additionally, we have demonstrated the synthetic strategy's feasibility for accessing diverse and valuable axially chiral aldehydes.

Selective Production of Glycolic Acid from Cellulose Promoted by Acidic/Redox Polyoxometalates via Oxidative Hydrolysis

The direct conversion of cellulose to glycolic acid (GA) with a high yield of up to 75% is realized using acidic/redox polyoxometalates (POMs) as catalysts in a one-pot reaction. Analysis of the reaction pathway and mechanism for the three POMs H3PMo12O40 (H3PMo), H3PW12O40 (H3PW), and H5PMo10V2O40 (H5PMoV2) by density functional theory calculations and experiments shows that H3PMo is especially promising. Activation of O2 to •O2– and 1O2 via one-electron transfer assists the depolymerization process of cellulose by acidic/redox H3PMo. The reduced form [PMo10VIMo2VO39]5– plays a crucial role in GA production due to its high activity and ability to stabilize the intermediates of the retro-aldol reaction. H3PMo was furthermore complexed by the ionic liquid 1-(3-sulfonic group) propyl-3-methyl imidazolium (MIMPS), which enables easy recovery from the reaction solution due to temperature-responsive properties of the complexes. [MIMPS]H2PMo provides an outstanding GA selectivity of 61% under aerobic conditions and is comparable to the homogeneous H3PMo. Activity and selectivity to GA could be improved to 100 and 75%, respectively, by performing the reaction in the microwave at 190 °C for 2 min. The work deepens the insight on cellulosic biomass transformation over POMs by acidic/oxidative synergetic catalysis and contributes to the effort of designing highly active, selective, and multifunctional catalysts.

Efficient Hydrogenation of Glucose to Polyols over Hydrotalcite-Derived PtNi Alloy Catalyst under Mild Conditions

Polyols are important biomass-based building blocks for chemical production. In this work, a hydrotalcite-derived PtNi alloy catalyst (PtNi/HT) was prepared with high metal dispersion under microwave-assisted synthesis and employed for glucose hydrogenation, where 95.7% of glucose was converted with 90.1% selectivity into polyols at 393 K in water. The PtNi/HT was stable and could be recycled for at least five runs for glucose. Lower reaction temperatures (333–373 K) contributed to glucose hydrogenation to hexitols, while higher reaction temperatures (373–413 K) facilitated the C–C activation of glucose to generate more polyols with less carbon (C2–C4). The Ptδ−–Niδ+ pair on PtNi/HT contributed to both H2 activation and adsorption of the aldehyde group in glucose hydrogenation. The basic support of PtNi/HT can efficiently catalyze the glucose isomerization and retro-aldol reaction in the aqueous phase. This study advocates a green approach for sustainable biorefinery of readily available glucose into value-added chemicals.

Hydrothermal Reactions of Biomass-Derived Platform Molecules: Mechanistic Insights into 5-Hydroxymethylfurfural (5-HMF) Formation during Glucose and Fructose Decomposition

The study investigates the primary reaction mechanisms of hydrothermal decomposition of glucose and fructose at 150–225 °C under various initial pH conditions (i.e., with an initial pH of 3–7) to reveal the formation mechanism of 5-hydroxymethylfurfural (5-HMF) from glucose and fructose. The results clearly show that dehydration to produce 5-HMF is not a primary reaction during hydrothermal decomposition of both glucose and fructose under noncatalytic conditions, indicating that 5-HMF cannot be directly produced from either glucose or fructose in water (with an initial pH of ∼7). In the presence of formic acid, dehydration to produce 5-HMF becomes a primary reaction during the hydrothermal decomposition of both glucose and fructose. The selectivity of dehydration reaction to produce 5-HMF increases with reducing the initial pH, i.e., up to ∼40% for glucose decomposition at 175 °C and ∼49% for fructose decomposition at 150 °C when the initial pH reduces to 3. Further kinetic analyses show that the rate constants of isomerization and retro-aldol condensation reactions almost remain unchanged under all initial pH conditions, while the rate constants of dehydration reactions to produce 5-HMF and levoglucosan increase almost linearly with the hydrogen ion concentration at the reaction temperature. This leads to increases in the selectivities of dehydration reactions, at the expense of other primary reactions. Our data also clearly indicate that dehydration reactions are acid-catalyzed reactions, while organic acid has almost no effect on isomerization and retro-aldol condensation reactions. Since organic acids can be formed at the early stage of sugar decomposition, this study provides the first experimental evidence in the field to clarify the formation mechanism of 5-HMF during sugar hydrothermal decomposition.

Construction of an autocatalytic reaction cycle in neutral medium for synthesis of life-sustaining sugars.

Autocatalytic mechanisms in carbon metabolism, such as the Calvin cycle, are responsible for the biological assimilation of CO2 to form organic compounds with complex structures, including sugars. Compounds that form C-C bonds with CO2 are regenerated in these autocatalytic reaction cycles, and the products are concurrently released. The formose reaction in basic aqueous solution has attracted attention as a nonbiological reaction involving an autocatalytic reaction cycle that non-enzymatically synthesizes sugars from the C1 compound formaldehyde. However, formaldehyde and sugars, which are the substrate and products of the formose reaction, respectively, are consumed in Cannizzaro reactions, particularly under basic aqueous conditions, which makes the formose reaction a fragile sugar-production system. Here, we constructed an autocatalytic reaction cycle for sugar synthesis under neutral conditions. We focused on the weak Brønsted basicity of oxometalate anions such as tungstates and molybdates as catalysts, thereby enabling the aldol reaction, retro-aldol reaction, and aldose-ketose transformation, which collectively constitute the autocatalytic reaction cycle. These bases acted on sugar molecules of substrates together with sodium ions of a Lewis acid to promote deprotonation under neutral conditions, which is the initiation step of the reactions forming an autocatalytic cycle, whereas the Cannizzaro reaction was inhibited. The autocatalytic reaction cycle established using this abiotic approach is a robust sugar production system. Furthermore, we found that the synthesized sugars work as energy storage substances that sustain microbial growth despite their absence in nature.

Hydrothermal conversion of fructose to lactic acid and derivatives: Synergies of metal and acid/base catalysts

With increasing strict regulation on single-use plastics, lactic acid (LA) and alkyl lactates, as essential monomers for bio-degradable polylactic acid (PLA) plastic products, have gained worldwide attention in both academia and industry. While LA is still dominantly produced through fermentation processes from start, chemical synthesis from cellulosic biomass remains a grand challenge, owing to poor selectivity in activating C-H and C-C bonds in sugar molecules. To our best knowledge, recent publications have been focused on hydrothermal conversion of glucose to LA, while this review summarizes the highlights on direct thermal conversion of fructose as starting material to LA and derivatives. In particular, the synergies of metal/metal cations and acid/base catalysts will be critically revised on retro-aldol and dehydration reactions. This work will provide insights into rational design of active and selective catalysts for the production of carboxylic acids from biomass feedstocks.

Cross β Amyloid Nanotubes Demonstrate Promiscuous Catalysis in a Chemical Reaction Network via Co-option.

In Darwin's warm pond rich with nutrients, lesser number of early catalytic machineries with modest capabilities were able to demonstrate promiscuity by catalyzing diverse biochemical transformations important for protometabolism. Herein, we report catalytically promiscuous amyloid-based short peptide assemblies that could concomitantly catalyse three metabolically important yet orthogonal reactions. The surface exposed catalytic dyads featuring lysines and imidazoles were utilized for C=N condensation via dynamic covalent linkages and modulation of protonation events, respectively. Further, the peptide assemblies could promiscuously catalyse hydrolysis as well as retro-aldol reactions, that could be co-opted to facilitate C=N bond formation, either by a feedforward-driven reaction network or by replenishing depleted substrates. The catalytic diversity of short peptide based promiscuous β-sheet folds suggests their possible role in promoting the protometabolic network in early earth.

T211K substitution in Pseudomonas putida phenylserine aldolase improves catalytic efficiency towards l-threo-4-nitrophenylserine with reversed stereoselectivity

Phenylserine aldolase from Pseudomonas putida (PSALD) catalyzes the conversion of glycine and 4-nitrobenzaldehyde to 4-nitrophenylserine with unsatisfactory enantioselectivity at the Cβ position. In this report, mutations adjacent to the substrate-binding pocket of PSALD were introduced using site-directed mutagenesis to improve product stereoselectivity. The activity of the variants towards native substrates l-threonine and l-allo-threonine decreased by 2- to 10-fold in the retro-aldol reaction when compared with that of wild-type (WT) PASLD. In particular, the T211K mutant biosynthesizes l-erythro-4-nitrophenylserine from glycine and 4-nitrobenzaldehyde as substrates with improved catalytic efficiency and reversed product stereoselectivity. This mutant synthesized l-erythro-4-nitrophenylserine with diastereoselectivity (de) of 84% and a conversion of 57%, whereas WT PSALD yielded a de of 5% and a conversion of 14%. In order to study the binding force between proteins and ligands, thermodynamic parameters were calculated by fluorescence spectroscopy. The determined thermodynamic parameters (ΔH = −76.52 kJ·mol–1, ΔS = −0.16 kJ·mol–1·K–1 and ΔG = −28.48 kJ·mol–1) indicate that the T211K mutation alters hydrogen bonds between PSALD and 4-nitrophenylserine. Molecular dynamics simulations elucidated the formation of a hydrogen bond between the amino group of T211K and the nitro group of 4-nitrophenylserine, which enhances the interaction between the mutant and product. This agent modifies the stereo-preference of threonine aldolases for the preparation of desired chiral β-hydroxy-α-amino acids by protein engineering.

Diverse polycyclic polyprenylated acylphloroglucinols with anti-neuroinflammatory activity from Hypericum beanii

A phytochemical investigation on the roots of Hypericum beanii resulted in the isolation of six new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperberlones A-F, along with fourteen known analogues. The structural characterization of these compounds was carried out by analyzing the HRESIMS data, 1D and 2D NMR spectroscopic data, electronic circular dichroism (ECD) calculations, and gauge-independent atomic orbital (GIAO) NMR calculations. Hyperberlone A (1) was a caged PPAP with a rare tricyclo[4.3.1.03,8]decane carbon skeleton. It was deduced to be biosynthetically generated from hyperbeanol C (8) through key Paternò-Büchi reaction, radical cascade cyclizations, and retro-aldol reaction. Compounds 4, 6, 7, 9, 14, and 16 exhibited significant nitric oxide (NO) production inhibitory effects in lipopolysaccharide (LPS)-induced BV-2 microglial cells with IC50 values of 6.11–25.28 μM. Moreover, compound 4 significantly decreased the expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in LPS-induced BV-2 microglia, as well as the phosphorylation of JNK.

Three enzymes of Rhizobium radiobacter involved in the novel metabolism of two naturally occurring bioactive oxidative derivatives of l-isoleucine.

Rhizobium radiobacter C58 was found to convert 4-hydroxyisoleucine (HIL) and 2-amino-3-methyl-4-ketopentanoate (AMKP), bioactive oxidative derivatives of l-isoleucine, in both cases producing 2-aminobutyrate. Three native enzymes involved in these metabolisms were purified by column chromatography and successfully identified. In this strain, HIL was converted to acetaldehyde and 2-aminobutyrate by coupling action of the transaminase rrIlvE and the aldolase HkpA. AMKP was also converted to acetate and 2-aminobutyrate by coupling action of rrIlvE and a hydrolase DkhA. In the multi-enzymatic reactions, HkpA catalyzes the retro-aldol reaction of 4-hydroxy-3-methyl-2-ketopentanoate into acetaldehyde and 2-ketobutyrate, and DkhA catalyzes hydrolytic cleavage of the carbon-carbon bond of 2,4-diketo-3-methylpentanoate into acetate and 2-ketobutyrate. rrIlvE catalyzes reversible transamination between HIL and 4-hydroxy-3-methyl-2-ketopentanoate, AMKP and 2,4-diketo-3-methylpentanoate, and 2-ketobutyrate and 2-aminobutyrate. The results suggested that the conversion activity of Rhizobium bacteria plays an important role in the complex biological metabolic networks associated with HIL and AMKP.

Synthesis of highly active solid base catalysts of SrO-ZrO2 and SrO-SiO2 by solid–liquid interface reactions of hydrated strontium hydroxide with metal alkoxides

Highly dispersed SrO in amorphous ZrO2 or SiO2, SrO–ZrO2, and SrO–SiO2 mixed oxides were synthesized by applying the solid–liquid interface reaction of Sr(OH)2•8 H2O in the solid phase with an equal number of moles of Zr(OC3H7)4 or with twice the number of Si(OC2H5)4 moles dissolved in 2-propanol. After heat treating at 723 K, the SrO–ZrO2 catalyst exhibited a higher activity than the conventional solid base MgO catalyst for the base-catalyzed retroaldol reaction of diacetone alcohol. The catalytic activity of SrO–ZrO2 was higher by a factor of 1.5 than that of MgO prepared by the thermal decomposition of hydrated magnesium oxalate (MgC2O4•2H2O). By contrast, the highest activity of SrO–SiO2 obtained by thermal activation at 673 K was much lower than that of MgO. The active SrO–ZrO2 catalyst was composed of catalytically inactive species of SrZrO3, and small amounts of Sr(OH)2 and SrCO3. The expected active species of SrO was not detected in powder X-ray diffraction analysis in any sample. The formation of SrO in small crystal size dispersed in amorphous ZrO2 was strongly expected. Similar results were obtained in the SrO–SiO2 sample. An active site formed on SrO–ZrO2 surface is proposed.

Synthesis of a Solid Base Catalyst Formed from Zinc(II) Acetylacetonate and Consisting of MgO Modified with ZnO

Solid base catalysts consisting of MgO modified with 10 mol% ZnO (ZnO/MgO) were prepared by depositing zinc(II) acetylacetonate (Zn(acac)2) in polar and nonpolar organic solvents on the surface of MgO and Mg(OH)2. The process was followed by thermal decomposition in air at 773 K over a period of 3 h. The activity of MgO modified with Zn(acac)2 for base-catalyzed retroaldol reaction (the decomposition of diacetone alcohol (4-hydroxy-4-methyl-2-pentanone) to acetone) at 299 K was higher than the activity of unmodified MgO prepared by thermal decomposition of Mg(OH)2. The activity of the catalysts prepared by depositing Zn(acac)2 on Mg(OH)2 was lower than that of unmodified MgO. Analysis of X-ray diffraction patterns revealed the presence of highly intense peaks, which were assigned to the ZnO units in the samples with high catalytic activity. ZnO was deposited in the form of large particles on the surface of MgO in the catalysts with high activity.

Facile synthesis of δ-ketoesters via formal two-carbon insertion into β-ketoesters

A formal two-carbon insertion into β-ketoesters with vinylmetal has been developed for the rapid synthesis of δ-ketoesters. This method features high efficiency, simple operation, and mild conditions without the usage of bases and catalysts. The reaction is postulated to proceed via a tandem process involving nucleophilic addition of vinylmetal to ketone, retro-aldol reaction to give an enolate anion and an enone, and finally Michael addition of these two intermediates.

Structural and Mechanistic Bases for StnK3 and Its Mutant-Mediated Lewis-Acid-Dependent Epimerization and Retro-Aldol Reactions

β-Methyl amino acids are important building units contributing to diversification of natural products, of which stereoselectivity and reaction fidelity are critical issues but far from conclusive. StnK3 is an enzyme mediating the chirality-inversion between (2S,3R) and (2S,3S) β-methyltryptophan. Here, we report that StnK3 is a novel Fe3+-dependent epimerase, in which the iron is structurally held by a 3-His-1-Glu tetrad alongside an α-keto acid bidentate from the substrate to form a six-coordinate octahedral complex. In addition to recognizing β-methylindolepyruvate (β-MeInPy), this given setting increases β-C acidity of the substrate facilitating its enolization; subsequent epimerization is implemented by inverse protonation utilizing a hidden coordination-switching device through an unprecedented two-base internal return mechanism. Beyond that, StnK3 exhibits an additional proofreading activity, where the immature substrate indolepyruvate (InPy) is cleaved to indole aldehyde by a retro-aldol reaction, thereby avoiding futile cycling but assuring reaction fidelity. Based on this, mutant H27A converts the epimerase remarkably to a full-duty retro-aldolase that breaks the C–C bond of β-MeInPy instead of InPy to 3-acetylindole at catalytic scope. The discovery of new reactions and elucidation of committed mechanisms not only help crack how the regio- and enantioselectivity is implemented but also lay a foundation to aid design of new biocatalysts/reactions for the synthesis of industrially or medicinally useful chemicals.