Synthetic Approach Research Articles

Acetal-thiol Click-like Reaction: Facile and Efficient Synthesis of Dynamic Dithioacetals and Recyclable Polydithioacetals.

Dithioacetals are heavily used in organic, material and medical chemistries, and exhibit huge potential to synthesize degradable or recyclable polymers. However, the current synthetic approaches of dithioacetals and polydithioacetals are overwhelmingly dependent on external catalysts and organic solvents. Herein, we disclose a catalyst- and solvent-free acetal-thiol click-like reaction for synthesizing dithioacetals and polydithioacetals. High conversion, higher than acid catalytic acetal-thiol reaction, can be achieved. High universality was confirmed by monitoring the reactions of linear and cyclic acetals (including renewable bio-sourced furan-acetal) with aliphatic and aromatic thiols, and the reaction mechanism of monomolecular nucleophilic substitution (SN1) and auto-protonation (activation) by thiol was clarified by combining experiments and density functional theory computation. Subsequently, we utilize this reaction to synthesize readily recyclable polydithioacetals. By simple heating and stirring, linear polydithioacetals with w of ~110 kDa were synthesized from acetal and dithiol, and depolymerization into macrocyclic dithioacetal and repolymerization into polydithioacetal can be achieved; through reactive extrusion, a semi-interpenetrating polymer dynamic network with excellent mechanical properties and continuous reprocessability was prepared from poly(vinyl butyral) and pentaerythritol tetrakis(3-mercaptopropionate). This green and high-efficient synthesis method for dithioacetals and polydithioacetals is beneficial to the sustainable development of chemistry.

Pyrazolidinone-Aided Ru(II)-Catalyzed Regioselective C-H Annulation with Allenes.

Regioselective annulation of allenes via C-H activation represents an elegant synthetic approach toward the construction of valuable scaffolds. Considering the importance of allenes, herein we developed an unprecedented Ru(II)-catalyzed highly regioselective redox-neutral C-H activation/(4 + 1)-annulation of 1-arylpyrazolidinones employing allenyl acetates to access pyrazolo[1,2-a]indazol-1-one derivatives. Additionally, allenyl cyclic carbonates, which were never tested in C-H activation, were utilized to construct a similar class of heterocycles having a pendent alcohol functionality. Notably, double C-H functionalization was achieved by a simple modification of reaction conditions. The synthetic significance of this methodology is underscored by late-stage modification of natural products, broad substrate scope, gram-scale synthesis, and postfunctionalizations.

Co-Ti Bimetallic Complex-Induced Phase Modulation of Co@Black TiO2 for Catalytic Hydrogenation of Cinnamaldehyde.

Transition-metal-doped black titania, primarily in the anatase phase, shows promise for redox reactions, water splitting, hydrogen generation, and organic pollutant removal, but exploring other titania phases for broader catalytic applications is underexplored. This study introduces a synthetic approach using a Co-Ti bimetallic complex bridged by a 1,10-phenanthroline-5,6-dione ligand as a precursor for the synthesis of cobalt-doped black titania [Co@L2N@b-TiO2]. The synthesis involves precise control of pyrolysis conditions, yielding a distinct structure dominated by the rutile phase over anatase, with active cobalt encapsulated within a nitrogen-doped graphitic layer, primarily as Co0 rather than CoII and CoIII. The synthesized material is employed for the selective hydrogenation of cinnamaldehyde (CAL) to cinnamyl alcohol (COL) under industrially viable conditions. The efficiency and selectivity of Co@L2N@b-TiO2 was compared with other catalysts, including cobalt-doped rutile TiO2 (Co@r-TiO2), anatase TiO2 (Co@a-TiO2), and black titania (Co@b-TiO2) as well as materials pyrolyzed under different atmospheres and temperatures, materials with phenanthroline ligands, and materials lacking any ligands. The superior performance of Co@L2N@b-TiO2 is attributed to its high surface area, stable Co0 within the nitrogen-doped graphitic layer, and composition of rutile and anatase phases of TiO2 and Ti2O3 (referred to as RAT), along with the synergistic interaction between RAT and Co0. These factors significantly influence the efficiency and selectivity of COL over hydrocinnamaldehyde (HCAL) and hydrocinnamyl alcohol (HCOL), indicating potential for broader applications beyond catalysis, particularly in designing of black titania-based materials.

The Real-Time Impact of the War on Russian Imports: A Synthetic Control Method Approach

The Real-Time Impact of the War on Russian Imports: A Synthetic Control Method Approach

Pyrazole Paradigms: Unveiling Synthetic Pathways and Unraveling Anti-Cancer Potential.

This review investigates the synthetic methods and anti-cancer activities of pyrazole compounds. Various synthetic approaches, including traditional organic synthesis and microwaveassisted synthesis, have been used to change the pyrazole core structure, resulting in new compounds with improved pharmacological properties. The paper also covers the mechanisms of action that underpin pyrazole derivatives' anti-cancer characteristics, focusing on interactions with major molecular targets implicated in cancer growth and proliferation. SAR insights help to rationally develop novel anti-cancer drugs. In conclusion, the review emphasizes the versatility of pyrazole derivatives as scaffolds for the discovery and development of new anti-cancer medicines. By understanding synthesis routes and unravelling anti-cancer potential, this study hopes to encourage new research endeavours focused on leveraging the therapeutic advantages of pyrazole paradigms in the fight against cancer.

An Enzymatic Prodrug-like Route to Thio and Selenoamides.

6-Thioguanine (6TG) is a clinically used antitumor agent that was rationally designed as a DNA-targeting antimetabolite, but it also occurs naturally. 6TG is a critical virulence factor produced by Erwinia amylovorans, a notorious plant pathogen that causes fire blight of pome fruit trees. The biosynthesis of the rare thioamide metabolite involves an adenylating enzyme (YcfA) and a sulfur-mobilizing enzyme (YcfC), but the mechanism of sulfur transfer and putative intermediates have remained elusive. Through dissection and in vitro reconstitution of the thionation process using diverse substrates, we uncover an intermediate, prodrug-like thio-conjugate and elucidate the precise enzyme functions. YcfA not only adenylates GMP but also transfers the mercapto group of l-cysteine to the activated carbonyl. A designated C-S lyase (YcfC) then cleaves the resulting S-adduct to yield the thioamide. This pathway is distinct from canonical tRNA sulfur modifications and known enzymatic peptide thionations. By exploring a wide range of substrate surrogates, we exploited the tolerance of the enzyme pair to produce even a seleno analogue. This study provides valuable insight into a previously unexplored area of bacterial thioamide formation and lays the groundwork for synthetic biology approaches to produce thioamide antimetabolites.

Rapid access to divergent fused polycycles via one-pot A3 coupling and intramolecular Diels-Alder reaction.

Divergent nitrogen-containing fused polycyclic ring systems are constructed from simple starting materials via a one-pot aldehyde-alkyne-amine (A3) coupling and intramolecular Diels-Alder reaction. This domino reaction directly furnishes linear 5/5/5 and 5/5/6, or nonlinear 5/5/6/5, polycyclic rings containing an oxa-bridged fused 5/5 bicycle and a 1,6-enyne substructure. One-step derivation of the oxa-bridged 5/5 bicycle leads to a polyfunctionalized 5/5 bicycle with tetrahydrofuran fused back-to-back to pyrroline or a 6/5 bicycle with the hexahydro-1H-isoindole structure, while cycloisomerizing the enyne substructure adds an extra fused 5-membered ring to afford functionalized linear 5/5/5/5 or 5/5/5/5/5 fused ring systems from selected substrates. In addition, the one-pot product can be designed so that the alkyne moiety is hydroalkoxylated to form an additional heterocyle in a linear 5/5/5/6 or nonlinear 5/5/6/5/5 ring system. This diversity-oriented synthetic approach thus allows rapid access to an under-explored structural space for discovery of new biological or non-biological activities or functions.

Chiral Diselenophosphoric Acids for Ion Pair Catalysis: A Novel Approach to Enhance Both Proton Donating and Proton Accepting Properties.

The activation of poorly reactive substrates via strong chiral acids is a central topic in asymmetric ion pair catalysis these days. Despite highly successful scaffolds such as N-triflylphosphoramides, these catalysts either lack C2-symmetry or provide multiple H-bond acceptor sites, leading to lower ee values for certain reactions. We present BINOL-based diselenophosphoric acids (DSA) as an extremely promising alternative. Using an intertwined approach of synthesis and NMR studies, we developed a synthetic approach to DSA with up to 98% NMR yield. The obtained acids provide both very high proton donor and proton acceptor properties, a bifunctionality, which is key to catalytic applications. Indeed, first reactivity test proved the much higher acidity of DSA and its ability to initiate Mukaiyama-Mannich reaction and protodesilylation of silyl ethers. Together with their C2-symmetry, the single donor and single acceptor situation, the decreased tendency of self-association, and the straightforward synthesis with potential 3,3'-substitution, the DSA provide all features ideal for the further development of ion pair catalysis.

An ambipolar PEDOT-perfluorinated porphyrin electropolymer: application as an active material in energy storage systems.

The development of functional organic materials is crucial for the advancement of various fields, such as optoelectronics, energy storage, sensing, and biomedicine. In this context, we successfully prepared a stable ambipolar perfluoroporphyrin-based polymeric film by electrochemical synthesis. Our strategy involved the synthesis of a novel tetra-pentafluorophenyl porphyrin covalently linked to four 3,4-ethylenedioxythiophene (EDOT) moieties. The resulting monomer, EDOT-TPPF16, was obtained through a straightforward synthetic approach with a good overall yield. The unique molecular structure of EDOT-TPPF16 serves a dual function, with EDOT moieties allowing electropolymerization for polymeric film formation, while the electron-acceptor porphyrin core enables electrochemical reduction and electron transport. The electrochemical polymerization permits the polymer (PEDOT-TPPF16) synthesis and film formation in a reproducible and controllable manner in one step at room temperature. Spectroelectrochemical experiments confirmed that the porphyrin retained its optoelectronic properties within the polymeric matrix after the electrochemical polymerization. The obtained polymeric material exhibited stable redox capabilities. Current charge-discharge cycles and electrochemical impedance spectroscopy of the electrochemically generated organic film demonstrated that the polymer could be applied as a promising active material in the development of supercapacitor energy storage devices.

Carbene-Catalyzed Enantioselective Addition of Sulfinate to Ketones.

A carbene-catalyzed enantioselective addition of sulfinate to ketones between 2-benzoylbenzaldehyde and sulfonyl chloride is disclosed. Up to now, the carbon and heteroatom nucleophiles have effectively undergone catalytic enantioselective addition to carbonyl molecules to introduce functionalities and chirality. Sulfone, as an important class of sulfur-containing functional groups, represents highly valuable motifs in medicines and natural products. It remains undeveloped for the catalytic asymmetric addition of sulfinate to carbonyls. Herein we disclosed the first catalytic enantioselective addition of sulfinate to ketones for the synthesis of sulfones via N-heterocyclic carbene (NHC) catalysis. The sulfonyl chloride behaves both as an oxidant and as a nucleophilic substrate in this carbene-catalyzed process. Experimental studies suggested that the Breslow intermediate can be SET oxidized by sulfonyl chloride to generate the sulfonyl radical. This novel synthetic approach for the asymmetric addition of sulfinate to carbonyls can also be used to modify the commercially available functional molecules.

Enabling nucleophilic reactivity in molecular calcium fluoride complexes.

Calcium fluoride is the ultimate source of all fluorochemicals. Current synthetic approaches rely on the use of HF, generated from naturally occurring fluorspar and sulfuric acid. Methods for constructing E-F bonds directly from CaF2 have long been frustrated by its high lattice energy, low solubility and impaired fluoride ion nucleophilicity. Little fundamental understanding of the reactivity of Ca-F moieties is available to guide methodology development; well-defined molecular species containing Ca-F bonds are extremely rare, and existing examples are strongly aggregated and evidence no nucleophilic fluoride delivery. Here, by contrast, we show that by targeting anionic systems of the type [Ln(X)2CaF]-, monomeric calcium fluoride complexes containing single Ca-F bonds can be synthesized, including via routes involving fluoride abstraction from existing C-F bonds. Comparative structural and spectroscopic studies of mono- and dinuclear systems allow us to define structure-activity relationships for E-F bond formation from molecular calcium fluorides.

Stereodivergent Synthesis of 1,4-Dicarbonyl Compounds through Sulfonium Rearrangement: Mechanistic Investigation, Stereocontrolled Access to γ-Lactones and γ-Lactams, and Total Synthesis of Paraconic Acids.

Although simple γ-lactones and γ-lactams have received considerable attention from the synthetic community, particularly due to their relevance in biological and medicinal contexts, stereoselective synthetic approaches to more densely substituted derivatives remain scarce. The in-depth study presented herein, showcasing a straightforward method for the stereocontrolled synthesis of γ-lactones and γ-lactams, builds on and considerably expands the stereodivergent synthesis of 1,4-dicarbonyl compounds by a ynamide/vinyl sulfoxide coupling. A full mechanistic and computational study of the rearrangement was conducted, uncovering the role of all of the reaction components and providing a rationale for stereoselection. The broad applicability of the developed tools to streamlining synthesis is demonstrated by concise enantioselective total syntheses of (+)-nephrosteranic acid, (+)-rocellaric acid, and (+)-nephromopsinic acid.

A Recent Trends on Green Synthesis and Bioactivity of Imidazole

Imidazole is a five-membered, planar heterocyclic ring made up of 3C, 2N, and N in the 1st and 3rd places. Purine, histamine, histidine, and nucleic acid are only a few significant natural compounds that contain the imidazole ring. It is utilised as a cure to optimize the solubility and bioavailability properties of proposed weakly soluble lead compounds since it is an aromatic chemical that is polar and ionizable and so improves the pharmacokinetic features of lead molecules. Derivatives of imidazole have a special place in medicinal chemistry. An essential synthesis technique in the process of discovering new drugs is the integration of the imidazole nucleus. Due to the remarkable therapeutic efficacy of medications related to imidazole, medicinal chemists have been inspired to create numerous innovative chemotherapy agents. This review summarized the work that has been done in recent years about different synthetic approaches of imidazole derivatives and their potential activity as anti-HIV, anticancer, anticovid, antifungal, antidiabetic, antidepressant, antioxidant, and antituberculosis.

Hybrid Machine Learning and Geostatistical Methods for Gap Filling and Predicting Solar-Induced Fluorescence Values

Sun-induced chlorophyll fluorescence (SIF) has proven to be advantageous in estimating gross primary production, despite the lack of a stable relationship. Satellite-based SIF measurements at Level 2 offer comprehensive global coverage and are available in near real time. However, these measurements are often limited by spatial and temporal sparsity, as well as discontinuities. These limitations primarily arise from incomplete satellite trajectories. Additionally, variability in cloud cover and periodic issues specific to the instruments can compromise data quality. Two families of methods have been developed to address data discontinuity: (1) machine learning-based gap-filling techniques and (2) geostatistical techniques (various forms of kriging). The former techniques utilize the relationships between ancillary data and SIF, while the latter usually rely on the available SIF data recordings and their covariance structure to provide estimates at unsampled locations. In this study, we create a synthetic approach for SIF gap filling by hybridizing the two approaches under the umbrella of kriging with external drift. We performed leave-one-out cross-validation of the OCO-2 SIF retrieval aggregates for the entire year of 2019, comparing three methods: ordinary kriging, ML-based estimation using ancillary data, and kriging with external drift. The Mean Absolute Error (MAE) for ML, ordinary kriging, and the hybrid approach was found to be 0.1399, 0.1318, and 0.1183 mW m2 sr−1 nm−1, respectively. We demonstrate that the performance of the hybrid approach exceeds both parent techniques due to the incorporation of information from multiple resources. This use of multiple datasets enriches the hybrid model, making it more robust and accurate in handling the spatio-temporal variability and discontinuity of SIF data. The developed framework is portable and can be applied to SIF retrievals at various resolutions and from various sources (satellites), as well as extended to other satellite-measured variables.

Reversing the directionality of reactions between non-oxidative pentose phosphate pathway and glycolytic pathway boosts mycosporine-like amino acid production in Saccharomyces cerevisiae

BackgroundMycosporine-like amino acids (MAAs) are a class of strongly UV-absorbing compounds produced by cyanobacteria, algae and corals and are promising candidates for natural sunscreen components. Low MAA yields from natural sources, coupled with difficulties in culturing its native producers, have catalyzed synthetic biology-guided approaches to produce MAAs in tractable microbial hosts like Escherichia coli, Saccharomyces cerevisiae and Corynebacterium glutamicum. However, the MAA titres obtained in these hosts are still low, necessitating a thorough understanding of cellular factors regulating MAA production.ResultsTo delineate factors that regulate MAA production, we constructed a shinorine (mycosporine-glycine-serine) producing yeast strain by expressing the four MAA biosynthetic enzymes from Nostoc punctiforme in Saccharomyces cerevisiae. We show that shinorine is produced from the pentose phosphate pathway intermediate sedoheptulose 7-phosphate (S7P), and not from the shikimate pathway intermediate 3-dehydroquinate (3DHQ) as previously suggested. Deletions of transaldolase (TAL1) and phosphofructokinase (PFK1/PFK2) genes boosted S7P/shinorine production via independent mechanisms. Unexpectedly, the enhanced S7P/shinorine production in the PFK mutants was not entirely due to increased flux towards the pentose phosphate pathway. We provide multiple lines of evidence in support of a reversed pathway between glycolysis and the non-oxidative pentose phosphate pathway (NOPPP) that boosts S7P/shinorine production in the phosphofructokinase mutant cells.ConclusionReversing the direction of flux between glycolysis and the NOPPP offers a novel metabolic engineering strategy in Saccharomyces cerevisiae.

The Socio-Economic Impact of an Abrupt Loss of Oil: A Synthetic Control Approach in the Case of Sudan

With the secession of South Sudan in 2011, the Republic of Sudan experienced a sudden loss of more than 70% of its oil reserves. Few countries have experienced such a dramatic macroeconomic adjustment within a short period of time. While earlier studies have explored the socio-economic impacts of oil discoveries, little is known about what happens in the case of an abrupt reversal of an oil windfall. We make use of the synthetic control method to isolate the effects of such an abrupt oil loss. We find little evidence of oil-induced socio-economic effects with the exception of higher unemployment.

Helically Chiral π-Expanded Azocines Through Regioselective Beckmann Rearrangement and Their Charged States.

We report a synthetic approach to p-expanded [6]helicenes incorporating tropone and azocine units in combination with a 5-membered ring, which exhibit intriguing structural, electronic, and chiroptical properties. The regioselective Beckmann rearrangement allows the isolation of helical scaffolds containing 8-membered lactam, azocine, and amine units. As shown by X-ray crystallographic analysis, the incorporation of tropone or azocine units leads to highly distorted [6]helicene moieties, with distinct packing motifs in the solid state. The compounds exhibit promising optoelectronic properties with considerable photoluminescence quantum yields and tunable emission wavelengths depending on the relative position of the nitrogen center within the polycyclic framework. Separation of the enantiomers by chiral high-performance liquid chromatography (HPLC) allowed characterization of their chiroptical properties by circular dichroism (CD) and circularly polarized luminescence (CPL) spectroscopy. The azocine compounds feature manifold redox chemistry, allowing for the characterization of the corresponding radical anions and cations as well as the dications and dianions, with near-infrared (NIR) absorption bands extending beyond 3000nm. Detailed theoretical studies provided insights into the aromaticity evolution upon reduction and oxidation, suggesting that the steric strain prevents the azocine unit from undergoing aromatization, while the indene moiety dominates the observed redox chemistry.

Helically Chiral π‐Expanded Azocines Through Regioselective Beckmann Rearrangement and Their Charged States

We report a synthetic approach to p‐expanded [6]helicenes incorporating tropone and azocine units in combination with a 5‐membered ring, which exhibit intriguing structural, electronic, and chiroptical properties. The regioselective Beckmann rearrangement allows the isolation of helical scaffolds containing 8‐membered lactam, azocine, and amine units. As shown by X‐ray crystallographic analysis, the incorporation of tropone or azocine units leads to highly distorted [6]helicene moieties, with distinct packing motifs in the solid state. The compounds exhibit promising optoelectronic properties with considerable photoluminescence quantum yields and tunable emission wavelengths depending on the relative position of the nitrogen center within the polycyclic framework. Separation of the enantiomers by chiral high‐performance liquid chromatography (HPLC) allowed characterization of their chiroptical properties by circular dichroism (CD) and circularly polarized luminescence (CPL) spectroscopy. The azocine compounds feature manifold redox chemistry, allowing for the characterization of the corresponding radical anions and cations as well as the dications and dianions, with near‐infrared (NIR) absorption bands extending beyond 3000 nm. Detailed theoretical studies provided insights into the aromaticity evolution upon reduction and oxidation, suggesting that the steric strain prevents the azocine unit from undergoing aromatization, while the indene moiety dominates the observed redox chemistry.

Enantioselective construction of stereogenic-at-sulfur(IV) centres via catalytic acyl transfer sulfinylation.

Chiral sulfur pharmacophores are crucial for drug discovery in bioscience and medicinal chemistry. While the catalytic asymmetric synthesis of sulfoxides and sulfinate esters with stereogenic-at-sulfur(IV) centres is well developed, the synthesis of chiral sulfinamides remains challenging, which has primarily been attributed to the high nucleophilicity and competing reactions of amines. In this study, we have developed an efficient methodology for the catalytic asymmetric synthesis of chiral sulfinamides and sulfinate esters by the sulfinylation of diverse nucleophiles, including aromatic amines and alcohols, using our bifunctional chiral 4-arylpyridine N-oxides as catalysts. The remarkable results are a testament to the efficiency, versatility and broad applicability of the developed synthetic approach, serving as a valuable tool for the synthesis of sulfur pharmacophores. Mechanistic experiments and density functional theory calculations revealed that the initiation and stereocontrol of this reaction are induced by an acyl transfer catalyst. Our research provides an efficient approach for the construction of optically pure sulfur(IV) centres.

Contribution of the Strategic Economic Plan to Singapore’s Long-term Growth: A Synthetic Control Approach

<p class="MsoNormal" style="margin-top: 12pt; text-align: justify;"><span lang="EN-US" style="font-family: 'times new roman', times, serif; font-size: 14pt;">We assess the impact of the Strategic Economic Plan on Singapore’s long-term GDP per capita. To our knowledge, we are the first to evaluate the effect of the 1991 plan on Singapore’s successful growth trajectory using methodologies aimed at causal identification. In other words, this article applies the Synthetic Control method and World Bank data from 1970 to 2018. We estimate an average increase of 6,641.71 US$ in Singapore’s GDP per capita. Results remain robust to placebo and leave-one-out tests and the Synthetic Difference-in-Differences method.</span></p>