Unveiling the mechanism for selective cleavage of C-C bonds in sugar reactions on tungsten trioxide-based catalysts.

Conversion of naturally occurring sugars, the most abundant biomass resources on Earth, to fuels and chemicals provides a sustainable and carbon-neutral alternative to the current fossil resource-based processes. Tungsten-based catalysts (e.g., WO3) are efficient for selectively cleaving C-C bonds of sugars to C2,3 oxygenate intermediates (e.g., glycolaldehyde) that can serve as platform molecules with high viability and versatility in the synthesis of various chemicals. Such C-C bond cleavage follows a mechanism distinct from the classical retro-aldol condensation. Kinetic, isotope 13C-labeling, and spectroscopic studies and theoretical calculations, reveal that the reaction proceeds via a surface tridentate complex as the critical intermediate on WO3, formed by chelating both α- and ß-hydroxyls of sugars, together with the carbonyl group, with two adjacent tungsten atoms (W-O-W) contributing to the ß-C-C bond cleavage. This mechanism provides insights into sugar chemistry and enables the rational design of catalytic sites and reaction pathways toward the efficient utilization of sugar-based feedstocks.

Synthesis of ω-Chloroalkyl Aryl Ketones via C-C Bond Cleavage of tert-Cycloalkanols with Tetramethylammonium Hypochlorite.

An oxidative C-C bond cleavage of tert-cycloalkanols with tetramethylammonium hypochlorite (TMAOCl) has been developed. TMAOCl is easy to prepare from tetramethylammonium hydroxide, and the combination of TMAOCl and AcOH effectively promoted the C-C bond cleavage in a two-phase system without additional phase-transfer reagents. Unstrained tert-cycloalkanols were transformed into ω-chloroalkyl aryl ketones in moderate to excellent yields under metal-free and mild reaction conditions.

Diverse enzymatic chemistry for propionate side chain cleavages in tetrapyrrole biosynthesis.

Tetrapyrroles represent a unique class of natural products that possess diverse chemical architectures and exhibit a broad range of biological functions. Accordingly, they attract keen attention from the natural product community. Many metal-chelating tetrapyrroles serve as enzyme cofactors essential for life, while certain organisms produce metal-free porphyrin metabolites with biological activities potentially beneficial for the producing organisms and for human use. The unique properties of tetrapyrrole natural products derive from their extensively modified and highly conjugated macrocyclic core structures. Most of these various tetrapyrrole natural products biosynthetically originate from a branching point precursor, uroporphyrinogen III, which contains propionate and acetate side chains on its macrocycle. Over the past few decades, many modification enzymes with unique catalytic activities, and the diverse enzymatic chemistries employed to cleave the propionate side chains from the macrocycles, have been identified. In this review, we highlight the tetrapyrrole biosynthetic enzymes required for the propionate side chain removal processes and discuss their various chemical mechanisms. ONE-SENTENCE SUMMARY: This mini-review describes various enzymes involved in the propionate side chain cleavages during the biosynthesis of tetrapyrrole cofactors and secondary metabolites.

A Chiral Relay Race: Stereoselective Synthesis of Axially Chiral Biaryl Diketones through Ring-Opening of Optical Dihydrophenan-threne-9,10-diols.

We report herein a point-to-axial chirality transfer reaction of optical dihydrophenanthrene-9,10-diols for the synthesis of axially chiral diketones. Two sets of conditions, namely a basic tBuOK/air atmosphere and an acidic NaClO/n-Bu4NHSO4, were developed to oxidatively cleave the C-C bond, resulting in the formation of axially chiral biaryl diketones. Finally, brief synthetic applications of the obtained chiral aryl diketones were demonstrated.

Recent Advances in Molecule Synthesis Involving C-C Bond Cleavage of Ketoxime Esters.

The synthetic strategies of oxime derivatives participating in radical-type reactions have been rapidly developed in the last few decades. Among them, the N-O bond cleavage of oxime esters leading to formation of nitrogen-centered radicals triggers adjacent C-C bond cleavage to produce carbon-centered free radicals, which has been virtually used in organic synthesis in recent years. Herein, we summarized the radical reactions involving oxime N-O bond and C-C bond cleavage through this special reaction form, including those from acyl oxime ester derivatives and cyclic ketoxime ester derivatives. These contents were systematically classified according to different reaction types. In this review, the free radical reactions involving acyl oxime esters and cyclic ketoxime esters after 2021 were included, with emphasis on the substrate scope and reaction mechanism.

Unusual Reactivities of ortho-Hydroxy-ß-nitrostyrene.

Nitrostyrene derivatives are widely used in organic syntheses as a substrate for Michael addition, photoisomerization and cycloaddition. In contrast, ortho-hydroxy derivatives exhibit unusual behaviors in these reactions. Conjugate addition proceeded upon treatment of the ortho-hydroxy-ß-nitrostyrene with an amine; however, subsequent C-C bond cleavage readily occurred to afford the corresponding imine. Moreover, conversion of the trans-isomer to a cis-isomer did not occur efficiently, even when UV light was irradiated. We studied these unusual behaviors of ß-nitrostyrene, focusing on the role of the ortho-hydroxy group.

A requirement for an active proton delivery network supports a compound I-mediated C-C bond cleavage in CYP51 catalysis.

CYP51 enzymes (sterol 14α-demethylases) are cytochromes P450 that catalyze multistep reactions. The CYP51 reaction occurs in all biological kingdoms and is essential in sterol biosynthesis. It removes the 14α-methyl group from cyclized sterol precursors by first forming an alcohol, then an aldehyde, and finally eliminating formic acid with the introduction of a Δ14-15 double bond in the sterol core. The first two steps are typical hydroxylations, mediated by an electrophilic compound I mechanism. The third step, C-C bond cleavage, has been proposed to involve either compound I (i.e. FeO3+) or, alternatively, a proton transfer-independent nucleophilic ferric peroxo anion (compound 0, i.e. Fe3+O2-). Here, using comparative crystallographic and biochemical analyses of WT human CYP51 (CYP51A1) and its D231A/H314A mutant, whose proton delivery network is destroyed (as evidenced in a 1.98-Å X-ray structure in complex with lanosterol), we demonstrate that deformylation of the 14α-carboxaldehyde intermediate requires an active proton relay network to drive the catalysis. These results indicate a unified, compound I-based mechanism for all three steps of the CYP51 reaction, as previously established for CYP11A1 and CYP19A1. We anticipate that our approach can be applied to mechanistic studies of other P450s that catalyze multistep reactions, such as C-C bond cleavage.

C=C Bond Oxidative Cleavage of BODIPY Photocages by Visible Light.

Photocages for protection and the controlled release of bioactive compounds have been widely investigated. However, the vast majority of these photocages employ the cleavage of single bonds and high-energy ultraviolet light. The construction of a photoactivation system that uses visible light to cleave unsaturated bonds still remains a challenge. Herein, we report a regioselective oxidative cleavage of C=C bonds from a boron-dipyrrolemethene (BODIPY)-based photocage by illumination at 630 nm, resulting in a free aldehyde and a thiol fluorescent probe. This strategy was demonstrated in live HeLa cells, and the generated α-formyl-BODIPY allowed real-time monitoring of aldehyde release in the cells. In particular, it is shown that a mannose-functionalized photocage can target HepG2 cells.

Selective synthesis of α-organylthio esters and α-organylthio ketones from ß-keto esters and sodium S-organyl sulfurothioates under basic conditions.

We described herein a selective method to prepare α-organylthio esters and α-organylthio ketones by the reaction of ß-keto esters with sodium S-benzyl sulfurothioate or sodium S-alkyl sulfurothioate (Bunte salts) under basic conditions in toluene as the solvent at 100 °C. When 4 equivalents of a base were used, a series of differently substituted α-thio esters were obtained with up to 90% yield. On the other hand, employing 2 equivalents of a base, α-thio ketones were achieved after 18 h under air. Furthermore, after a shorter reaction time, the isolation of keto-enol tautomers was possible, revealing them as significant intermediates for the mechanism elucidation.

The steroid side-chain-cleaving aldolase Ltp2-ChsH2DUF35 is a thiolase superfamily member with a radically repurposed active site.

An aldolase from the bile acid-degrading actinobacterium Thermomonospora curvata catalyzes the C-C bond cleavage of an isopropyl-CoA side chain from the D-ring of the steroid metabolite 17-hydroxy-3-oxo-4-pregnene-20-carboxyl-CoA (17-HOPC-CoA). Like its homolog from Mycobacterium tuberculosis, the T. curvata aldolase is a protein complex of Ltp2 with a DUF35 domain derived from the C-terminal domain of a hydratase (ChsH2DUF35) that catalyzes the preceding step in the pathway. We determined the structure of the Ltp2-ChsH2DUF35 complex at 1.7 Å resolution using zinc-single anomalous diffraction. The enzyme adopts an αßßα organization, with the two Ltp2 protomers forming a central dimer, and the two ChsH2DUF35 protomers being at the periphery. Docking experiments suggested that Ltp2 forms a tight complex with the hydratase but that each enzyme retains an independent CoA-binding site. Ltp2 adopted a fold similar to those in thiolases; however, instead of forming a deep tunnel, the Ltp2 active site formed an elongated cleft large enough to accommodate 17-HOPC-CoA. The active site lacked the two cysteines that served as the nucleophile and general base in thiolases and replaced a pair of oxyanion-hole histidine residues with Tyr-246 and Tyr-344. Phenylalanine replacement of either of these residues decreased aldolase catalytic activity at least 400-fold. On the basis of a 17-HOPC-CoA -docked model, we propose a catalytic mechanism where Tyr-294 acts as the general base abstracting a proton from the D-ring hydroxyl of 17-HOPC-CoA and Tyr-344 as the general acid that protonates the propionyl-CoA anion following C-C bond cleavage.

Copper-catalyzed aerobic radical C-C bond cleavage of N-H ketimines.

We report herein studies on copper-catalyzed aerobic radical C-C bond cleavage of N-H ketimines. Treatment of N-H ketimines having an α-sp(3) hybridized carbon under Cu-catalyzed aerobic reaction conditions resulted in a radical fragmentation with C-C bond cleavage to give the corresponding carbonitrile and carbon radical intermediate. This radical process has been applied for the construction of oxaspirocyclohexadienones as well as in the electrophilic cyanation of Grignard reagents with pivalonitrile as a CN source.

Flavonoids Biotransformation by Human Gut Bacterium Dorea sp. MRG-IFC3 Cell-Free Extract.

Human gut bacterium Dorea sp. MRG-IFC3 is unique in that it is capable of metabolizing puerarin, an isoflavone C-glycoside, whereas it shows broad substrate glycosidase activity for the various flavonoid O-glycosides. To address the question on the substrate specificity, as well as biochemical characteristics, cell-free biotransformation of flavonoid glycosides was performed under various conditions. The results showed that there are two different enzyme systems responsible for the metabolism of flavonoid C-glycosides and O-glycosides in the MRG-IFC3 strain. The system responsible for the conversion of puerarin was inducible and comprised of two enzymes. One enzyme oxidizes puerarin to 3"-oxo-puerarin and the other enzyme converts 3"-oxo-puearin to daidzein. The second enzyme was only active toward 3"-oxo-puerarin. The activity of puerarin conversion to daidzein was enhanced in the presence of Mn2+ and NAD+. It was concluded that the puerarin C-deglycosylation by Dorea sp. MRG-IFC3 possibly adopts the same biochemical mechanism as the strain PUE, a species of Dorea longicatena.

Laser flash photolysis and quantum chemical studies of UV degradation of pharmaceutical drug chloramphenicol: Short-lived intermediates, quantum yields and mechanism of photolysis.

Using methods of time-resolved and stationary photolysis, HPLC-MS and quantum-chemical calculations by the DFT method, the mechanism of direct UV photolysis of the antibiotic chloramphenicol (CAP) was established. For the first time, short-lived intermediates formed during photolysis were detected. The primary photoprocess is the cleavage of the ß-C-C bond relative to the aromatic system with the formation of 4-nitrobenzylalcohol radical and residual aliphatic radical. The first radical in deoxygenated solutions predominantly transforms into para-nitrobenzaldehyde and its secondary photolysis products. In the presence of oxygen, the aromatic radical and para-nitrobenzaldehyde are transformed into para-nitrosobenzoic and para-nitrobenzoic acids as a result of reaction with reactive oxygen species (ROS). Formation of ROS is provoked by reactions of aliphatic radical with dissolved oxygen, so this radical is very important for CAP degradation. The quantum yield of direct photolysis of CAP is ∼3% and does not depend on the presence of dissolved oxygen and on the change of the excitation wavelength in the range of 254-308 nm. Obtained data are important for further understanding of the transformation pathways of CAP and similar PPCP in natural and wastewaters under the action of sunlight and artificial UV radiation.

Regioselective synthesis of 2,3-disubstituted indoles via interrupted Heyns rearrangement involving C-C bond cleavage.

A novel metal free, Brønsted acid mediated and operationally simple strategy has been developed for regioselective synthesis of 2,3-disubstituted indoles from α-hydroxyketones and o-aminoaryl ketones in excellent yields. The reaction proceeds via interrupted Heyns rearrangement through the generation of aminoenol intermediate followed by intramolecular trapping and aromatization with C-C bond cleavage and release of corresponding ester. The mechanism was further supported by the identification of ester in GCMS and reaction of cyclic α-hydroxydimethylketal, which afforded ester tethered indole derivative.

C-Glycoside-Metabolizing Human Gut Bacterium, Dorea sp. MRG-IFC3.

Biochemical gut metabolism of dietary bioactive compounds is of great significance in elucidating health-related issues at the molecular level. In this study, a human gut bacterium cleaving C-C glycosidic bond was screened from puerarin conversion to daidzein, and a new, gram-positive C-glycoside-deglycosylating strain, Dorea sp. MRG-IFC3, was isolated from human fecal sample under anaerobic conditions. Though MRG-IFC3 biotransformed isoflavone C-glycoside, it could not metabolize other C-glycosides, such as vitexin, bergenin, and aloin. As evident from the production of the corresponding aglycons from various 7-O-glucosides, MRG-IFC3 strain also showed 7-O-glycoside cleavage activity; however, flavone 3-O-glucoside icariside II was not metabolized. In addition, for mechanism study, C-glycosyl bond cleavage of puerarin by MRG-IFC3 strain was performed in D2O GAM medium. The complete deuterium enrichment on C-8 position of daidzein was confirmed by 1H NMR spectroscopy, and the result clearly proved for the first time that daidzein is produced from puerarin. Two possible reaction intermediates, the quinoids and 8-dehydrodaidzein anion, were proposed for the production of daidzein-8d. These results will provide the basis for the mechanism study of stable C-glycosidic bond cleavage at the molecular level.

Unraveling the electrophilic oxygen-mediated mechanism for alcohol electrooxidation on NiO.

Aqueous organic electrosynthesis such as nucleophile oxidation reaction (NOR) is an economical and green approach. However, its development has been hindered by the inadequate understanding of the synergy between the electrochemical and non-electrochemical steps. In this study, we unravel the NOR mechanism for the primary alcohol/vicinal diol electrooxidation on NiO. Thereinto, the electrochemical step is the generation of Ni3+-(OH)ads, and the spontaneous reaction between Ni3+-(OH)ads and nucleophiles is an electrocatalyst-induced non-electrochemical step. We identify that two electrophilic oxygen-mediated mechanisms (EOMs), EOM involving hydrogen atom transfer (HAT) and EOM involving C-C bond cleavage, play pivotal roles in the electrooxidation of primary alcohol to carboxylic acid and the electrooxidation of vicinal diol to carboxylic acid and formic acid, respectively. Based on these findings, we establish a unified NOR mechanism for alcohol electrooxidation and deepen the understanding of the synergy between the electrochemical and non-electrochemical steps during NOR, which can guide the sustainable electrochemical synthesis of organic chemicals.

Facile cleavage of C-C bond: conversion of pyrane derivative to 1,3-oxazin derivative.

A cascade reaction that involves a unique C-C bond cleavage has been discovered. This protocol affords an unusual and facile method for the synthesis of 1,3-oxazin derivatives under mild conditions.

Metal-Free Catalysis in C-C Single-Bond Cleavage: Achievements and Prospects.

This review article emphasizes the C-C bond cleavage in organic synthesis via metal-free approach. Conventional organic synthesis mainly deals with the reactive π bonds and polar σ bonds. In contrast, the ubiquitous C-C single bonds are inherently stable and are less reactive, which poses a challenge to synthetic chemists. Although inert, such C-C single-bond cleavage reactions have gained attention amongst synthetic chemists, as they provide unique and more straightforward routes, with significantly fewer steps. Several review articles have been reported regarding the activation and cleavage of C-C bonds using different transition metals. However, given the high cost and toxicity of many of these metals, the development of strategies under metal-free conditions is of utmost importance. Though many research articles have been published in this area, no review article has been reported so far. Herein, we discuss the reactions in a more concise way from the year 2012 to today, with emphasis on important reactions. Mechanisms of all the reactions are also well addressed. We believe that this review will be beneficial for the readers who work in this field.

Quantum Mechanical Investigation of the Oxidative Cleavage of the C-C Backbone Bonds in Polyethylene Model Molecules.

Recalcitrant plastic waste has caused serious global ecological problems. There is an urgent need to develop environmentally friendly and efficient methods for degrading the highly stable carbon skeleton structure of plastics. To that end, we used a quantum mechanical calculation to thoroughly investigate the oxidative scission of the carbon-carbon (C-C) backbone in polyethylene (PE). Here, we studied the reaction path of C-C bond oxidation via hydroxyl radical in PE. The flexible force constants and fuzzy bond orders of the C-C bonds were calculated in the presence of one or more carbocations in the same PE carbon chain. By comparison, the strength of the C-C bond decreased when carbocation density increased. However, the higher the density of carbocations, the higher the total energy of the molecule and the more difficult it was to be generated. The results revealed that PE oxidized to alcohol and other products, such as carboxylic acid, aldehyde and ketone, etc. Moreover, the presence of carbocations was seen to promote the cleavage of C-C backbones in the absence of oxygen.

Enzymatic Characterization and Comparison of Two Steroid Hydroxylases CYP154C3-1 and CYP154C3-2 from Streptomyces Species.

Bacterial cytochrome P450 (CYP) enzymes are responsible for the hydroxylation of diverse endogenous substances with a heme molecule used as a cofactor. This study characterized two CYP154C3 proteins from Streptomyces sp. W2061 (CYP154C3-1) and Streptomyces sp. KCCM40643 (CYP154C3-2). The enzymatic activity assays of both CYPs conducted using heterologous redox partners' putidaredoxin and putidaredoxin reductase showed substrate flexibility with different steroids and exhibited interesting product formation patterns. The enzymatic characterization revealed good activity over a pH range of 7.0 to 7.8 and the optimal temperature range for activity was 30 to 37°C. The major product was the C16-hydroxylated product and the kinetic profiles and patterns of the generated hydroxylated products differed between the two enzymes. Both enzymes showed a higher affinity toward progesterone, with CYP154C3-1 demonstrating slightly higher activity than CYP154C3-2 for most of the substrates. Oxidizing agents (diacetoxyiodo) benzene (PIDA) and hydrogen peroxide (H2O2) were also utilized to actively support the redox reactions, with optimum conversion achieved at concentrations of 3 mM and 65 mM, respectively. The oxidizing agents affected the product distribution, influencing the type and selectivity of the CYP-catalyzed reaction. Additionally, CYP154C3s also catalyzed the C-C bond cleavage of steroids. Therefore, CYP154C3s may be a good candidate for the production of modified steroids for various biological uses.