Platform For Synthesis Research Articles

Comparative Evaluation of the Asymmetric Synthesis of (S)-Norlaudanosoline in a Two-Step Biocatalytic Reaction with Whole Escherichia coli Cells in Batch and Continuous Flow Catalysis

Opioids are important analgesics, and their pharmaceutical application is increasing worldwide. Many opioids are based on benzylisoquinoline alkaloids (BIA) and are still industrially produced from Papaver somniferum (opium poppy). (S)-norlaudanosoline ((S)-NLS) is a complex BIA and an advanced intermediate for diverse pharmaceuticals. The efficient synthesis of this scaffold could pave the way for a plant-independent synthesis platform. Although a promising biocatalytic route to (S)-NLS using norcoclaurine synthase (NCS) and ω-transaminase (TAm) has already been explored, the cost-effectiveness of this process still needs much improvement. Therefore, we investigated whether the synthesis could also be performed using whole cells to avoid the use of (partially) purified enzymes. With an optimized mixing ratio of TAm- and NCS-containing cells in batch biotransformations, 50 mM substrate was converted within 3 h with more than 90% yield and a high enantiomeric excess of the product (95%). To further increase the space–time yield, the cells were immobilized to enable their retainment in fixed-bed reactors. A comparison of glass beads, Diaion HP-2MG and alginate revealed that the addition of Diaion during bacterial growth led to the most active immobilisates. To facilitate sustained production of (S)-NLS, a fixed-bed setup was constructed based on lithographically printed columns from biocompatible PRO-BLK 10 plastic. The continuous production at two scales (5 mL and 50 mL columns) revealed insufficient system stability originating from biocatalyst leaching and inactivation. Thus, while the use of whole cells in batch biotransformations represents an immediate process improvement, the transfer to flow catalysis needs further optimization.

Direct Observation of Triplet States in the Isomerization of Alkenylboronates by Energy Transfer Catalysis.

Alkenylboronates are versatile building blocks for stereocontrolled synthesis owing to the traceless nature of the boron group that can be leveraged to achieve highly selective geometric isomerization. Using thioxanthone as an inexpensive photocatalyst, the photoisomerization of these species continues to provide an expansive platform for stereodivergent synthesis, particularly in the construction of bioactive polyenes. Although mechanistic investigations are consistent with light-driven energy transfer, direct experimental evidence remains conspicuously absent. Herein, we report a rigorous mechanistic investigation using two widely used alkenylboronates alongside relevant reference compounds. Through the combination of irradiation experiments, transient absorption spectroscopic studies, kinetic modeling, and DFT calculations with all isomers of the model compounds, it has been possible to unequivocally detect and characterize the perpendicular triplet generated by energy transfer. Our results serve not only as a blueprint for mechanistic studies that are challenging with organic sensitizers, but these guidelines delineated have also enabled the development of more sustainable reaction conditions: for the first time, efficient organocatalytic isomerization under sunlight irradiation has become feasible.

Towards Low-Temperature CVD Synthesis and Characterization of Mono- or Few-Layer Molybdenum Disulfide.

Molybdenum disulfide (MoS2) transistors are a promising alternative for the semiconductor industry due to their large on/off current ratio (>1010), immunity to short-channel effects, and unique switching characteristics. MoS2 has drawn considerable interest due to its intriguing electrical, optical, sensing, and catalytic properties. Monolayer MoS2 is a semiconducting material with a direct band gap of ~1.9 eV, which can be tuned. Commercially, the aim of synthesizing a novel material is to grow high-quality samples over a large area and at a low cost. Although chemical vapor deposition (CVD) growth techniques are associated with a low-cost pathway and large-area material growth, a drawback concerns meeting the high crystalline quality required for nanoelectronic and optoelectronic applications. This research presents a lower-temperature CVD for the repeatable synthesis of large-size mono- or few-layer MoS2 using the direct vapor phase sulfurization of MoO3. The samples grown on Si/SiO2 substrates demonstrate a uniform single-crystalline quality in Raman spectroscopy, photoluminescence (PL), scanning electron microscopy (SEM), atomic force microscopy (AFM), X-ray photoelectron spectroscopy (XPS), and scanning transmission electron microscopy. These characterization techniques were targeted to confirm the uniform thickness, stoichiometry, and lattice spacing of the MoS2 layers. The MoS2 crystals were deposited over the entire surface of the sample substrate. With a detailed discussion of the CVD setup and an explanation of the process parameters that influence nucleation and growth, this work opens a new platform for the repeatable synthesis of highly crystalline mono- or few-layer MoS2 suitable for optoelectronic application.

Wireless Electrochemical Reactor for Accelerated Exploratory Study of Electroorganic Synthesis.

Electrosynthesis is an emerging tool to construct value-added fine chemicals under mild and sustainable conditions. However, the complex apparatus required impedes the facile development of new electrochemistry in the laboratory. Herein, we proposed and demonstrated the concept of wireless electrochemistry (Wi-eChem) based on wireless power transfer technology. The core of this concept is the dual-function wireless electrochemical magnetic stirrer that provides an electrolysis driving force and mixing simultaneously in a miniaturized form factor. This Wi-eChem system allowed electrochemists to execute electrochemical reactions in a manner similar to traditional organic chemistry without handling wire connections. The controllability, reusability, and versatility were validated with a series of modern electrosynthesis reactions, including electrodecarboxylative etherification, electroreductive olefin-ketone coupling, and electrochemical nickel-catalyzed oxygen atom transfer reaction. Its remarkably simplified operation enabled its facile integration into a fully automated robotic synthesis platform to achieve autonomous parallel electrosynthesis screening.

DNA-Programmed Lipid Nanoreactors for Synthesis of Carbohydrate Mimetics by Fusion of Aqueous Sub-attoliter Compartments.

Lipid nanoreactors are biomimetic reaction vessels (nanoreactors) that can host aqueous or membrane-associated chemical and enzymatic reactions. Nanoreactors provide ultra-miniaturization from atto- to zeptoliter volumes per reaction vessel with the major challenge of encoding and spatio-temporal control over reactions at the individual nanoreactor or population level, thereby controlling volumes several orders of magnitude below advanced microfluidic devices. We present DNA-programmed lipid nanoreactors (PLNs) functionalized with lipidated oligonucleotides (LiNAs) that allow programming and encoding of nanoreactor interactions by controlled membrane fusion, exemplified for a set of carbohydrate mimetics with mono- to hexasaccharide azide building blocks connected by click-chemistry. Programmed reactions are initiated by fusion of distinct populations of nanoreactors with individually encapsulated building blocks. A focused library of triazole-linked carbohydrate-Cy5 conjugates formed by strain-promoted azide-alkyne cycloadditions demonstrated LiNA-programmed chemistry, including two-step reaction schemes. The PLN method is developed toward a robust platform for synthesis in confined space employing fully programmable nanoreactors, applicable to multistep synthesis for the generation of combinatorial libraries with subsequent analysis of the molecules formed, based on the addressability of the lipid nanoreactors.

Pd-Catalyzed Homologation of Arylboronic Acids as a Platform for the Diversity-Oriented Synthesis of Benzylic C–X Bonds

AbstractWe report a synthetic platform for the formation of benzylic C–X bonds. Benzylboronic acid pinacol (Bpin) esters are useful synthetic intermediates but are commercially uncommon, leading to preparations that typically rely upon stoichiometric metalation. Pd-catalyzed formal homologation of arylboronic acids provides access to these compounds that, in turn, allow the formation of C–C, C–O, and C–N bonds from Pd- and Cu-mediated cross-coupling or oxidative processes. This affords a wide variety of benzylic alcohols, diarylmethanes, benzyl amines, and benzyl ethers. Limitations are disclosed, and the utility is further demonstrated by the generation of analogues of meclizine.

Green synthesis of bimetallic Pd[sbnd]Ag alloy nanoparticles supported on polydopamine-functionalized kaolin for catalytic reduction of 4-nitrophenol and organic dyes

A green and universal synthesis strategy was demonstrated for preparation of bimetallic PdAg alloy nanoparticles supported on polydopamine-functionalized kaolin (kaolin-PDA-PdAg), where bimetallic PdAg alloy was synthesized by co-reduction of Na2PdCl4 and AgNO3 with sodium citrate. Characterization results, including TEM results and XPS results, confirmed that bimetallic PdAg was alloying state and kaolin-PDA-PdAg was successfully synthesized through mussel-inspired chemistry. The kaolin-PDA-PdAg nanocomposite exhibited excellent catalytic activity and performance towards reduction of 4-nitrophenol, whose rate constant was found to be 3.46 min−1 under condition of high concentration (10 mM) of 4-nitrophenol. Besides, kaolin-PDA-PdAg nanocomposite showed high catalytic performance for methyl orange and safranine-T as well. The high catalytic activity of kaolin-PDA-PdAg could be elucidated by electronic effect and synergistic effect of bimetallic PdAg alloy. These results suggest that kaolin-PDA-PdAg composites could be applied as high-efficiency catalysts for reduction of 4-nitrophenol and degradation of organic dyes. Furthermore, abundance and low-priced of raw materials kaolin, green and versatility of synthetic method endow kaolin-PDA-PdAg composites with broad application prospects. Strategy of bimetallic PdAg alloy anchored on kaolin in this text could provide an efficient platform for synthesis of bimetallic alloy nanoparticles loaded on various materials.

Controlled mixing during colloidal quantum dot synthesis: A proxy-concept based on equivalent parameters

Mixing is a key process parameter during liquid phase particle synthesis that requires special attention, in particular for scalable process and reactor development. This issue is especially pressing for advanced materials where on the one hand multifunctional properties require products of utmost quality, while on the other hand only few strategies for process design are yet developed. One material class in this context is quantum dot (QD) nanocrystals. By making use of automation and high throughout (HT) experimentation, we could recently demonstrate qualitatively the role of mixing on focusing and defocusing during QD synthesis by hot injection. In this work, we demonstrate the application of HT methodologies to investigate the effect of mixing as an important process parameter during process optimization and scale up. We performed reaction optimization by screening a multi-parameter design space using design of experiments (DoE) and machine learning (ML). We developed a so-called cold model as proxy that is based on equivalent mixing times (EMTs) derived from a competing parallel reaction system. Experimentally, we realized a fully automated approach using a HT platform for particle synthesis. The final dataset (128 experiments for model development including repeats and 29 experiments for prediction testing) was combined with DoE and complimented with machine learning. By doing so, with DoE, we could reduce the number of experiments required to develop a predictive, statistical knowledge base for EMTs at ambient conditions. Finally, we demonstrated the applicability of EMTs for two defined stirrer geometries to fine tune the widths of the particle size distribution and photoluminescence of QDs at increasing reaction volumes from 20 mL to 80 mL. This opens the door towards scalable processes for QDs at increased reaction volumes while maintaining product quality.

The Power of Automation in Polymer Chemistry: Precision Synthesis of Multiblock Copolymers with Block Sequence Control.

Machines can revolutionize the field of chemistry and material science, driving the development of new chemistries, increasing productivity, and facilitating reaction scale up. The incorporation of automated systems in the field of polymer chemistry has however proven challenging owing to the demanding reaction conditions, rendering the automation setup complex and costly. There is an imminent need for an automation platform which uses fast and simple polymerization protocols, while providing a high level of control on the structure of macromolecules via precision synthesis. This work combines an oxygen tolerant, room temperature polymerization method with a simple liquid handling robot to automatically prepare precise and high order multiblock copolymers with unprecedented livingness even after many chain extensions. The highest number of blocks synthesized in such a system is reported, demonstrating the capabilities of this automated platform for the rapid synthesis and complex polymer structure formation.

Luteal Lipid Droplets: A Novel Platform for Steroid Synthesis.

Progesterone is an essential steroid hormone that is required to initiate and maintain pregnancy in mammals and serves as a metabolic intermediate in the synthesis of endogenously produced steroids, including sex hormones and corticosteroids. Steroidogenic luteal cells of the corpus luteum have the tremendous capacity to synthesize progesterone. These specialized cells are highly enriched with lipid droplets that store lipid substrate, which can be used for the synthesis of steroids. We recently reported that hormone-stimulated progesterone synthesis by luteal cells requires protein kinase A-dependent mobilization of cholesterol substrate from lipid droplets to mitochondria. We hypothesize that luteal lipid droplets are enriched with steroidogenic enzymes and facilitate the synthesis of steroids in the corpus luteum. In the present study, we analyzed the lipid droplet proteome, conducted the first proteomic analysis of lipid droplets under acute cyclic adenosine monophosphate (cAMP)-stimulated conditions, and determined how specific lipid droplet proteins affect steroidogenesis. Steroidogenic enzymes, cytochrome P450 family 11 subfamily A member 1 and 3 beta-hydroxysteroid dehydrogenase (HSD3B), were highly abundant on lipid droplets of the bovine corpus luteum. High-resolution confocal microscopy confirmed the presence of active HSD3B on the surface of luteal lipid droplets. We report that luteal lipid droplets have the capacity to synthesize progesterone from pregnenolone. Lastly, we analyzed the lipid droplet proteome following acute stimulation with cAMP analog, 8-Br-cAMP, and report increased association of HSD3B with luteal lipid droplets following stimulation. These findings provide novel insights into the role of luteal lipid droplets in steroid synthesis.

Ruthenium Complex Hydride Catalyst as a Platform for Ammonia Synthesis: The Effect of Alkali or Alkaline Earth Elements

Ruthenium Complex Hydride Catalyst as a Platform for Ammonia Synthesis: The Effect of Alkali or Alkaline Earth Elements

Activation of N−O σ Bonds with Transition Metals: A Versatile Platform for Organic Synthesis and C−N Bonds Formation**

AbstractN−O σ bonds containing compounds are versatile substrates for organic synthesis under transition metal catalysis. Their ability to react through both polar (oxidative addition, formation of metallanitrene, nucleophilic substitution) and radical pathways (single electron transfer, homolytic bond scission) have triggered the development of various synthetic methodologies, particularly toward synthesizing nitrogen‐containing compounds. In this review, we discuss the different modes of activation of N−O bonds in the presence of transition metal catalysts, emphasizing the experimental and computational mechanistic proofs in the literature to help to design new synthetic pathways toward the synthesis of C−N bonds.

Radical thioesterification via nickel-catalysed sensitized electron transfer

Multi-catalytic reaction modes have attracted widespread attention in synthetic chemistry. The merger of nickel catalysis with photoredox catalysis has offered a powerful platform for synthesis of molecules with attractive properties. Nonetheless, the conceptual development of nickel-catalysed, sensitized electron transfer is of pivotal relevance, but is still greatly limited. Here we describe the development of a radical cross-thioesterification process by nickel-catalysed sensitized electron transfer. The strategy can produce diverse methyl thioesters, which are not only found in natural products, materials and pharmaceuticals but also are widespread precursors in synthetic chemistry and biological processes. This catalytic mode features high chemoselectivity, good functional group tolerance and excellent scalability. Perhaps more important was the finding that various drugs and amino acids were successfully functionalized in this system. Experimental studies, nanosecond transient spectroscopic analysis, and density functional theory calculations reveal that the merger of photocatalytic electron transfer, energy transfer and nickel catalysis plays an essential role in this radical thioesterification reaction.

Epoxide-based TFC membranes with tunable performance in the tight nanofiltration range

Membrane technology offers promise as a breakthrough separation technology in many applications, but is frequently limited by the chemical stability of currently available membrane materials. Recently developed membranes utilizing epoxide-based chemistry have shown great potential as intrinsically stable thin-film composite membranes in water-based applications. However, as these membranes are in their infancy, many synthesis parameters are still to be explored. In this study, the versatility of epoxide chemistry is exploited to demonstrate its potential to serve as a new platform for membrane synthesis, even beyond the field of aqueous applications. It is proven here how the membrane performance can be tailored in a controllable way between 20 – 85% NaCl rejection with a water permeance between 0.5 – 3 L m−2 h−1 bar−1 by simply selecting epoxide monomers and initiators of different size and functionality. A systematic increase in water permeance and salt passage was observed for epoxide monomers that exhibit a lower functionality and a lower number of aromatic groups, while a threshold nucleophilicity and aliphatic chain length of the initiator are required to obtain a salt-selective layer. This work demonstrates the possibility to easily and predictably tune membrane performance in the tight nanofiltration range, while simultaneously achieving a better understanding of the synthesis-structure-performance relationship of this new class of promising membranes.

Population balance modeling of InP quantum dots: Experimentally enabled global optimization to identify unknown material parameters

Despite great progress in the synthetic chemistry of InP QDs, a predictive model to describe their temporal formation is still missing. In this work, we introduce a population balance model incorporating liquid phase reactions, homogeneous nucleation and reaction-limited growth of InP supported with the highly reproducible and reliable experimental data acquired from an automated robotic synthesis platform. A comparison between experimental kinetic data (different initial concentrations and temperatures) and simulations was made. The proposed model describes the temporal evolution of solid concentration, particle diameter and particle size distribution very well. The quantitative agreement between experiments and simulations was only achieved by global optimization to identify unknown and hardly measurable material parameters and kinetic constants such as surface energy, growth rate constants or activation energies. We see this model rendering the first step towards the development of more refined models that enable rigorous optimization and control of the production process for III-V semiconductors.

Debris:Machine learning, archive archaeology, digital audio waste

This article fragments and processesDebris, a project developed to formalise the creative recycling of digital audio byproducts.Debrisbegan as an open call for electronic compositions that take as their point of departure gigabytes of audio material generated through training and calibratingDemiurge, an audio synthesis platform driven by machine learning. TheDebrisproject led us down rabbitholes of structural analysis: what does it mean to work with digital waste, how is it qualified, and what new relationships and methodologies do this foment? To chart the fluid boundaries ofDebrisand pin down its underlying conceptualisation of sound, this article introduces a framework ranging from archaeomusicology to intertextuality, from actor-network theory to Deleuzian assemblage, from Adornian constellation to swarm intelligence to platform and network topology. This diversity of approaches traces connective frictions that may allow us to understand, from the perspective ofDebris, what working with soundmeansunder the regime of machine intelligence. How has machine intelligence fundamentally altered the already shaky diagram connecting humans, creativity and history? We advise the reader to approach the text as a multisensory experience, listening toDebriswhile navigating the circuitous theoretical alleys below.

Enantioselective Synthesis of cis-Decalins by Merging the Birch Reduction and Inverse-Electron-Demand Diels-Alder Reaction.

Herein, we show the combination of the Birch reduction of readily available anisole derivatives and the catalytic asymmetric inverse-electron-demand Diels-Alder reaction of 2-pyrones can serve as a powerful platform for the diverse synthesis of synthetically important cis-decalin scaffolds. Enabled by a well-modified chiral bis(oxazoline) ligand/Cu(II) complex, a wide range of polysubstituted cis-decalin scaffolds with up to six continuous stereocenters was generated efficiently. The synthetic potential of this method is demonstrated by the concise synthesis of sesquiterpene (+)-occidentalol and a key intermediate for seven triterpenes. Mechanistic studies suggest the in situ formed 1,3-cyclohexadienes are the key intermediates, and efficient kinetic resolution occurs when C2 and/or C3 substituted 1,4-cyclohexadienes are utilized as substrates. DFT calculations elucidate the Diels-Alder reaction proceeds in a stepwise fashion, and reveal the originations of the stereoselectivities.

Enantioselective Synthesis of cis‐Decalins by Merging the Birch Reduction and Inverse‐Electron‐Demand Diels–Alder Reaction

AbstractHerein, we show that the combination of the Birch reduction of readily available anisole derivatives and the catalytic asymmetric inverse‐electron‐demand Diels–Alder reaction of 2‐pyrones can serve as a powerful platform for the diverse synthesis of synthetically important cis‐decalin scaffolds. Enabled by a well‐modified chiral bis(oxazoline) ligand/CuII complex, a wide range of polysubstituted cis‐decalin scaffolds with up to six contiguous stereocenters were generated efficiently. The synthetic potential of this method is demonstrated by the concise synthesis of the sesquiterpene (+)‐occidentalol and a key intermediate for seven triterpenes. Mechanistic studies suggest the 1,3‐cyclohexadienes formed in situ are the key intermediates, and efficient kinetic resolution occurs when C2‐ and/or C3‐substituted 1,4‐cyclohexadienes are utilized as substrates. DFT calculations elucidated that the Diels–Alder reaction proceeds in a stepwise fashion and revealed the origins of the stereoselectivities.

Anthraquinone-Polyaniline-Integrated Textile Platforms for In Situ Electrochemical Production of Hydrogen Peroxide for Microbial Deactivation.

Hydrogen peroxide (H2O2) is a versatile and effective disinfectant against common pathogenic bacteria such as Escherichia coli (E. coli). Electrochemical H2O2 generation has been studied in the past, but a lack of studies exists on miniaturized electrochemical platforms for the on-demand synthesis of H2O2 for antibacterial applications. In this article, a chemically modified cotton textile platform capable of in situ H2O2 production is demonstrated for E. coli deactivation. The cotton textile was modified by layer-by-layer coating with conductive carbon nanotubes/cellulose nanocrystals (CNT/CNC) and a polymer of polyaniline (PANI) decorated with anthraquinone (AQ), designated as the AQ@PANI@CNT/CNC@textile antibacterial patch. The AQ@PANI@CNT/CNC@textile antibacterial textile patch H2O2 production capabilities were evaluated using both electrochemical and colorimetric methods. The AQ@PANI@CNT/CNC@textile antibacterial patch electrochemically produced H2O2 concentrations up to 209 ± 25 µM over a 40 min period and displayed a log reduction of 3.32 for E. coli over a period of 2 h. The AQ@PANI@CNT/CNC@textile antibacterial patch offers promise for use as a self-disinfecting pathogen control platform.

Understanding target-specific effects of antidepressant drug pollution on molluscs: A systematic review protocol.

The environmental prevalence of widely prescribed human pharmaceuticals that target key evolutionary conserved biomolecules present across phyla is concerning. Antidepressants, one of the most widely consumed pharmaceuticals globally, have been developed to target biomolecules modulating monoaminergic neurotransmission, thus interfering with the endogenous regulation of multiple key neurophysiological processes. Furthermore, rising prescription and consumption rates of antidepressants caused by the burgeoning incidence of depression is consistent with increasing reports of antidepressant detection in aquatic environments worldwide. Consequently, there are growing concerns that long-term exposure to environmental levels of antidepressants may cause adverse drug target-specific effects on non-target aquatic organisms. While these concerns have resulted in a considerable body of research addressing a range of toxicological endpoints, drug target-specific effects of environmental levels of different classes of antidepressants in non-target aquatic organisms remain to be understood. Interestingly, evidence suggests that molluscs may be more vulnerable to the effects of antidepressants than any other animal phylum, making them invaluable in understanding the effects of antidepressants on wildlife. Here, a protocol for the systematic review of literature to understand drug target-specific effects of environmental levels of different classes of antidepressants on aquatic molluscs is described. The study will provide critical insight needed to understand and characterize effects of antidepressants relevant to regulatory risk assessment decision-making, and/or direct future research efforts. The systematic review will be conducted in line with the guidelines by the Collaboration for Environmental Evidence (CEE). A literature search on Scopus, Web of Science, PubMed, as well as grey literature databases, will be carried out. Using predefined criteria, study selection, critical appraisal and data extraction will be done by multiple reviewers with a web-based evidence synthesis platform. A narrative synthesis of outcomes of selected studies will be presented. The protocol has been registered in the Open Science Framework (OSF) registry with the registration DOI: 10.17605/OSF.IO/P4H8W.