Platform For Synthesis Research Articles

Enzyme-particle Complexes Facilitate Pickering Interfacial Biocatalysis.

Pickering interfacial biocatalysis (PIB), where biocatalysts stabilize emulsions through carrier coupling or polymer grafting, has emerged as a powerful platform for organic synthesis due to its ability to accommodate water-insoluble substrates within enzymatic cascade reactions. PIB provides a large interfacial area for two-phase reactions, reducing diffusional resistance and enhancing transformation efficiency. The performance of PIB relies heavily on enzyme-particle conjugates, which serve a dual function: stabilizing the emulsion and acting as the active biocatalysts in the system. In this Concept, we discuss the latest advancements, current challenges, and future directions in the development of protein-particle conjugates for PIB.

Improved electrochemical performances of cobalt molybdate electrode using Gd3+ dopant and redox additive electrolyte: a simple synthesis platform

Improved electrochemical performances of cobalt molybdate electrode using Gd3+ dopant and redox additive electrolyte: a simple synthesis platform

Synthesis of Clickable Isotactic Poly(vinyl ether)s through Organocatalytic Stereoselective Cationic Copolymerization.

By virtue of the high reliability of click chemistry, polymers with clickable groups provide a useful platform for the rapid synthesis of polymer materials with diverse functionalities and architectures. However, the polymerization of clickable vinyl monomers with a concurrent regulation on tacticity remains underdeveloped. Herein, we report the successful development of a stereoselective cationic copolymerization of C-C triple bond-containing vinyl ethers with simple alkyl vinyl ethers by employing confined Brønsted acid as catalyst, which allows for the synthesis of alkyne-functionalized vinyl ether copolymers with high isotacticity (up to 90% m), controlled molecular weight, and variable content of C-C triple bonds. Further transformation of the pendant clickable alkyne groups via thiol-yne click reactions and copper(I)-catalyzed alkyne-azide cycloaddition reaction enables a modular access to isotactic polymers with various functional groups.

A Well-Coupled Supramolecular System Accelerates Photophosphorylation.

Supramolecular assembly allows multiple chemical/bio-components integrated as one system for cascade biochemical reactions. Herein the graphitic carbon nitrides (g-C3N4) as photocatalyst trapped in a dipeptide hydrogel covering adenosine triphosphate (ATP) synthase accelerates the photophosphorylation through ATP synthesis. Self-assembled N-fluorenylmethoxycarbonyl diphenylalanine (Fmoc-FF) as nanofibrils to allow g-C3N4 nanosheets are embedded as a complex Fmoc-FF/g-C3N4 hydrogel. Fmoc-FF gel exhibits good electronic coupling with g-C3N4, which enables a photo-induced proton generation. The transmembrane proton gradient can be established by ATP synthase-lipid reconstituted on the surface of the Fmoc-FF/g-C3N4 hydrogel to enhance the ATP synthesis. It indicates that the Fmoc-FF/g-C3N4/ATP synthase-lipid film can possess a longer-term ATP production capability and allow repeated immersion for sustained ATP production. Such a hydrogel-supported ATP synthesis platform is achieved by a procedure at a larger scale.

A Well‐Coupled Supramolecular System Accelerates Photophosphorylation

AbstractSupramolecular assembly allows multiple chemical/bio‐components integrated as one system for cascade biochemical reactions. Herein the graphitic carbon nitrides (g‐C3N4) as photocatalyst trapped in a dipeptide hydrogel covering adenosine triphosphate (ATP) synthase accelerates the photophosphorylation through ATP synthesis. Self‐assembled N‐fluorenylmethoxycarbonyl diphenylalanine (Fmoc‐FF) as nanofibrils to allow g‐C3N4 nanosheets are embedded as a complex Fmoc‐FF/g‐C3N4 hydrogel. Fmoc‐FF gel exhibits good electronic coupling with g‐C3N4, which enables a photo‐induced proton generation. The transmembrane proton gradient can be established by ATP synthase‐lipid reconstituted on the surface of the Fmoc‐FF/g‐C3N4 hydrogel to enhance the ATP synthesis. It indicates that the Fmoc‐FF/g‐C3N4/ATP synthase‐lipid film can possess a longer‐term ATP production capability and allow repeated immersion for sustained ATP production. Such a hydrogel‐supported ATP synthesis platform is achieved by a procedure at a larger scale.

Total Synthesis of Ryanodane Diterpenoids Garajonone and 3‐epi‐Garajonone

AbstractRyanodane diterpenes are structurally complex natural products that are well‐known for their high degree of oxidation and the challenges associated with synthesizing them within the terpene class. Herein, we present a two‐stage synthetic strategy that draws inspiration from the broad biosynthesis of terpenes, allowing us to achieve the first chemical synthesis of garajonone, a ryanodane diterpenoid that occurs naturally at low abundance, as well as its epimer, 3‐epi‐garajonone. The key to this success lies in the rapid construction of the carbon framework of the target molecule by employing an early‐stage palladium‐catalyzed Heck/carbonylative esterification cascade annulation, followed by successive late‐stage selective redox manipulation to establish the desired oxidation state of the molecule. This research not only showcases the synthesis of garajonone and its epimer but also provides a platform for the chemical synthesis of other members and analogs of this complex diterpenoid family.

Total Synthesis of Ryanodane Diterpenoids Garajonone and 3-epi-Garajonone.

Ryanodane diterpenes are structurally complex natural products that are well-known for their high degree of oxidation and the challenges associated with synthesizing them within the terpene class. Herein, we present a two-stage synthetic strategy that draws inspiration from the broad biosynthesis of terpenes, allowing us to achieve the first chemical synthesis of garajonone, a ryanodane diterpenoid that occurs naturally at low abundance, as well as its epimer, 3-epi-garajonone. The key to this success lies in the rapid construction of the carbon framework of the target molecule by employing an early-stage palladium-catalyzed Heck/carbonylative esterification cascade annulation, followed by successive late-stage selective redox manipulation to establish the desired oxidation state of the molecule. This research not only showcases the synthesis of garajonone and its epimer but also provides a platform for the chemical synthesis of other members and analogs of this complex diterpenoid family.

Photobiocatalytic Platform for the Efficient Enantio-Divergent Synthesis of β-Fluoromethylated Ketones.

β-Fluoromethyl (CH2F, CHF2, and CF3)-substituted chiral ketones are essential moieties and are vital building blocks in pharmaceutical and agrochemistry. However, general and convenient methods for enantio-diverse access to diverse β-fluoromethylated ketones are lacking, hindering the further development of these functional moieties. In this study, we developed an ene-reductase-based photobiocatalytic platform for efficient synthesis of enantio-divergent β-fluoromethylated chiral ketones. Our method highlights substrate-type diversity, excellent enantioselectivity, enzymatic enantio-divergent synthesis, as well as a dicyanopyrazine (DPZ)-type photosensitizer for biocompatible olefin E/Z isomerization in enzymatic stereoconvergent olefin asymmetric reduction, thereby providing a general photobiocatalytic solution to diverse β-fluoromethylated chiral ketones.

Selective CO2 Reduction Electrocatalysis Using AgCu Nanoalloys Prepared by a "Host-Guest" Method.

Multimetallic nanoalloy catalysts have attracted considerable interest for enhancing the efficiency and selectivity of many electrochemically driven chemical processes. However, the preparation of homogeneous bimetallic alloy nanoparticles remains a challenge. Here, we present a room-temperature and scalable, host-guest approach for synthesis of dilute Cu in Ag alloy nanoparticles. In this approach, an ionic silver bromide precursor harboring exogenous Cu cations is reduced to yield ∼20 nm diameter AgCu alloy nanoparticles wherein the % Cu loading can be tuned precisely. AgCu nanoparticles with a 5% nominal loading of Cu exhibit peak activity (-0.23 mA/cm2 normalized partial current density) and selectivity (83.2% faradaic efficiency) for CO product formation from electrocatalytic reduction of CO2 at mild overpotentials. These AgCu nanoalloys exhibit a higher mass activity compared to Ag- and Cu-containing nanomaterials used for similar electrocatalytic transformations. Our host-guest synthesis platform holds promise for production of other nanoalloys with relevance in electrocatalysis and optics.

Inside Back Cover

Simple reaction, useful chemistry. The electron donor‐acceptor complex (EDA) photochemistry provides a simple and efficient platform for organic synthesis. A general EDA complex strategy formed by readily accessible thiophenolate anion and oxime ester successfully realizes the diverse synthesis of thioethers under visible light irradiation. Such a strategy could also enable a thiol‐catalysis for the synthesis of phenanthridines. More details are discussed in the article by Zhong et al. on pages 2751—2756. image

Sustainable and Advanced LED-Implanted Microfluidic Photoreactor with Coupled Optical Fiber Enabling Efficient Photocatalytic Synthesis Beside Online Reaction Progress Monitoring.

The conventional methods for the photoinduced synthesis of benzimidazoles may need further improvement regarding a safer and energy-efficient synthesis platform with in-process monitoring for maximum yield within a much reduced reaction time. This work describes the use of a novel optofluidic Lab-on-a-Chip technology for safer, energy-efficient, and expedited synthesis of benzimidazole derivatives in excellent yields along with real-time quantitative measurement during product formation. This innovative method involves synthesis within LED-embedded microfluidic reactors, allowing for rapid synthesis of benzimidazole derivatives via photoinduced condensation cyclization reactions of aryl aldehydes and o-phenylenediamines using a Rose Bengal/fluorescein photocatalyst. It results in good to excellent yields (85-94%) in a notably shorter period of time (10 min) as compared to that for the batch protocol reaction (2-3 h). The incorporation of a reaction-monitoring microfluidic device precisely connected to the microfluidic reactor (microreactor) unit successfully avoids interference from light sources, ensuring consistent UV-vis spectroscopic observations of the produced benzimidazole derivatives. This LED-embedded microfluidic device's capability of photoinduced synthesis, along with real-time spectroscopic analysis, represents a promising breakthrough in organic synthesis. The proposed approach minimizes the potential for accidents, prevents waste of chemicals, maximizes atom economy, and designs an energy-efficient synthesis route, along with real-time in-process monitoring.

Algorithm-Driven Robotic Discovery of Polyoxometalate-Scaffolding Metal-Organic Frameworks.

The experimental exploration of the chemical space of crystalline materials, especially metal-organic frameworks (MOFs), requires multiparameter control of a large set of reactions, which is unavoidably time-consuming and labor-intensive when performed manually. To accelerate the rate of material discovery while maintaining high reproducibility, we developed a machine learning algorithm integrated with a robotic synthesis platform for closed-loop exploration of the chemical space for polyoxometalate-scaffolding metal-organic frameworks (POMOFs). The eXtreme Gradient Boosting (XGBoost) model was optimized by using updating data obtained from the uncertainty feedback experiments and a multiclass classification extension based on the POMOF classification from their chemical constitution. The digital signatures for the robotic synthesis of POMOFs were represented by the universal chemical description language (χDL) to precisely record the synthetic steps and enhance the reproducibility. Nine novel POMOFs including one with mixed ligands derived from individual ligands through the imidization reaction of POM amine derivatives with various aldehydes have been discovered with a good repeatability. In addition, chemical space maps were plotted based on the XGBoost models whose F1 scores are above 0.8. Furthermore, the electrochemical properties of the synthesized POMOFs indicate superior electron transfer compared to the molecular POMs and the direct effect of the ratio of Zn, the type of ligands used, and the topology structures in POMOFs for modulating electron transfer abilities.

From lab to industry: Scaling-up Fe-Ni bimetallic nano oxygen carrier for mid-temperature methane chemical looping reforming

Chemical looping methane reforming has emerged as a promising avenue to produce blue hydrogen. Currently, satisfactory CH4 conversion and H2 productivity typically requires reaction temperature above 800 °C, bringing challenges for industrial reactor design and energy conservation. To realize high chemical looping methane reforming performance at low temperature, a Fe-Ni bimetallic nano oxygen carrier was presented, along with the workflow and platform for scaled-up synthesis of the oxygen carrier. On account of the synergy of nanoscale Fe-Ni species, the operating temperature could be lowered to 500–600 °C. The lab-scale oxygen carrier converted >90 % CH4 and produced 3.5 H2 per CH4 molecule with 80–82 % outlet H2 purity at 575–600 °C. The 10-kg scale synthesized oxygen carrier powder exhibited >90 % CH4 conversion, >78 % H2 purity and produced 2.8–3.5 H2 per CH4, with performance penalty from scaling up controlled within 5 %. After shaping and calcination, the 10-kg oxygen carrier beads still produced 2.8 H2 from per CH4 molecule with >70 % H2 purity. Longevity test revealed the 10-kg powder and beads as stable in phase, morphology, and redox activity over 110 cycles. Experiments of variable operating conditions found that the 10-kg oxygen carriers can meet industrial requirements of H2 production at >550 °C, with low steam/carbon ratio favored by 10-kg beads. Further analysis attributed the performance distinction of 10-kg beads to its lower surface area, reduction extent and steam affinity, compared to those of the lab-scale and 10-kg powders. These findings contributed to the mid-temperature chemical looping methane reforming by bridging laboratory practices and industrial application.

Re-imagen: Generating coherent background activity in synthetic scenario-based forensic datasets using large language models

Due to legal and privacy-related restrictions, the generation of synthetic data is recommended for creating datasets for digital forensic education and training. One challenge when synthesizing scenario-based forensic data is the creation of coherent background activity besides evidential actions. This work leverages the creative writing abilities of large language models (LLMs) to generate personas and actions that describe the background usage of a device consistent with the created persona. These actions are subsequently converted into a machine-readable format and executed on a virtualized device using VM control automation. We introduce Re-imagen, a framework that combines state-of-the-art LLMs and a recent unintrusive GUI automation tool to produce synthetic disk images that contain arguably coherent “wear-and-tear” artifacts that current synthesis platforms lack. While, for now, the focus is on the coherence of the generated background activity, we believe that the proposed approach is a step toward more realistic synthetic disk image generation.

Photoredox-Catalyzed Carbamoyl Radical-Initiated Dearomative Spirocyclization To Access Spiro-Cyclohexadiene Oxindoles.

The sustainable construction of spirocyclic compounds is important to the scientific community and the pharmaceutical industries. Herein, we demonstrate a carbamoyl radical-initiated intramolecular dearomative spirocyclization to access the spiro-cyclohexadiene oxindoles under visible light irradiation, which constitutes the first example of accessing the I-substituted derivatives that facilitate diversified transformations. Additionally, the scalability, late-stage modification of drugs, and significant antitumor activity of the products demonstrate the novel spirocyclic synthesis platform for expediting drug development.

Unlocking Oxetane Potential: Modular Synthetic Platform for the Concise Synthesis of Acyclic Oligo-Isoprenoids and Terpenoids.

Terpenes occupy a unique place among the secondary metabolites due to their broad utility and extraordinary structural diversity. Their synthesis via polyene cyclization, either biomimetic or enzymatic, represents the cutting edge of modern synthetic chemistry. However, these endeavors have been inherently tied to the availability of natural and non-natural acyclic polyene starting materials. Herein, we report an oxetane-based platform for the modular construction of oxygenated polyolefins with precise geometric control. This "tail-to head" iterative method leverages the site-selective cross-metathesis of terminal olefins to form an alkylidene oxetane moiety and the regioselective ring opening of alkenyl-oxetanes for chain elongation. In addition, the unique and peculiar propensity of alkylidene oxetane fragment in various reactions was also revealed and exploited for site-selective functionalization, cyclization, and as a protecting group in polyenes.

Intranasal immunization with CPAF combined with cyclic-di-AMP induces a memory CD4 T cell response and reduces bacterial burden following intravaginal infection with Chlamydia muridarum.

Chlamydia trachomatis (Ct) is the most common bacterial sexually transmitted infection globally, and a vaccine is urgently needed to stop transmission and disease. Chlamydial Protease Activity Factor (CPAF) is an immunoprevalent and immunodominant antigen for CD4 T cells and B cells, which makes it a strong vaccine candidate. Due to the tolerogenic nature of the female genital tract (FGT) and its lack of secondary lymphoid tissue, effective induction of protective cell-mediated immunity will likely require potent and safe mucosal adjuvants. To address this need, we produced CPAF in a cell-free protein synthesis platform and adjuvanted it with the TLR9-agonist CpG1826, STING (stimulator of interferon genes) agonist cyclic-di-AMP (CDA), and/or the squalene oil-in-water nanoemulsion, AddaS03. We determined that intranasal immunization with CPAF plus CDA was well tolerated in female mice, induced CD4 T cells that produced IL-17A or IFNγ, significantly reduced bacterial shedding, and shortened the duration of infection in mice intravaginally challenged with Chlamydia muridarum . These data demonstrate the potential for CDA as a mucosal adjuvant for vaccines against Chlamydia genital tract infection.

Automated Production of [68Ga]Ga-Desferrioxamine B on Two Different Synthesis Platforms.

Background/Objectives: PET imaging of bacterial infection could potentially provide added benefits for patient care through non-invasive means. [68Ga]Ga-desferrioxamine B-a radiolabelled siderophore-shows specific uptake by human-pathogenic bacteria like Staphylococcus aureus or Pseudomonas aeruginosa and sufficient serum stability for clinical application. In this report, we present data for automated production of [68Ga]Ga-desferrioxamine B on two different cassette-based synthesis modules (Modular-Lab PharmTracer and GRP 3V) utilising commercially obtainable cassettes together with a licensed 68Ge/68Ga radionuclide generator. Methods: Quality control, including the determination of radiochemical purity, as well as a system suitability test, was set up via RP-HPLC on a C18 column. The two described production processes use an acetic acid/acetate buffer system with ascorbic acid as a radical scavenger for radiolabelling, yielding ready-to-use formulations with sufficient activity yield. Results: Batch data analysis demonstrated radiochemical purity of >95% by RP-HPLC combined with ITLC and excellent stability up to 2 h after synthesis. Specifications for routine production were set up and validated with four masterbatches for each synthesis module. Conclusions: Based on this study, an academic clinical trial for imaging of bacterial infection was initiated. Both described synthesis methods enable automated production of [68Ga]Ga-desferrioxamine B in-house with high reproducibility for clinical application.

Selective reductive conversion of CO2 to CH2-bridged compounds by using a Fe-functionalized graphene oxide-based catalyst

Anthropogenic climate change drastically affects our planet, with CO2 being the most critical gaseous driver. Despite the existing carbon dioxide capture and transformation, there is much need for innovative carbon dioxide hydrogenation catalysts with excellent selectivity. Here, we present a fast, effective, and sustainable route for coupling diverse alcohols, amines and amides with CO2 via heterogenization of a natural metal-based homogeneous catalyst through decorating on functionalized graphene oxide (GO). Combined synthetic, experimental, and theoretical studies unravel mechanistic routes to convergent 4‑electron reduction of CO2 under mild conditions. We successfully replace the toxic and expensive ruthenium species with inexpensive, ubiquitously available and recyclable iron. This iron-based functionalized graphene oxide (denoted as Fe@GO-EDA, where EDA represents ethylenediamine) functions as an efficient catalyst for the selective conversion of CO2 into a formaldehyde oxidation level, thus opening the door for interesting molecular structures using CO2 as a C1 source. Overall, this work describes an intriguing heterogeneous platform for the selective synthesis of valuable methylene-bridged compounds via 4‑electron reduction of CO2.

Pressure-induced generation of heterogeneous electrocatalytic metal hydride surfaces for sustainable hydrogen transfer

Metal hydrides are crucial intermediates in numerous catalytic reactions. Intensive efforts have been dedicated to constructing molecular metal hydrides, where toxic precursors and delicate mediators are usually involved. Herein, we demonstrate a facile pressure-induced methodology to generate a cost-effective heterogeneous electrocatalytic metal hydride surface for sustainable hydrogen transfer. Taking carbon dioxide (CO2) electroreduction as a model system and zinc (Zn), a well-known carbon monoxide (CO)-selective catalyst, as a model catalyst, we showcase a homogeneous-type hydrogen atom transfer process induced by heterogeneous hydride surfaces, enabling direct hydrogenation pathways traditionally considered “prohibited”. Specifically, the maximal Faradaic efficiency for formate is enhanced by ~fivefold to 83% under ambient conditions. Experimental and theoretical analyses reveal that unlike the distal hydrogenation route for CO2 to CO over pristine Zn, the Zn hydride surface enables direct hydrogenation at the carbon site of CO2 to form formate. This work provides a promising material platform for sustainable synthesis.