Cascade Reaction Research Articles

Stereodivergent Construction of 1,5/1,7-Nonadjacent Tetrasubstituted Stereocenters Enabled by Pd/Cu-Cocatalyzed Asymmetric Heck Cascade Reaction.

The construction of chiral motifs containing nonadjacent stereocenters in an enantio- and diastereoselective manner has long been a challenging task in synthetic chemistry, especially with respect to their stereodivergent synthesis. Herein, we describe a protocol that enables the enantio- and diastereoselective construction of 1,5/1,7-nonadjacent tetrasubstituted stereocenters through a Pd/Cu-cocatalyzed Heck cascade reaction. Notably, a C=C bond relay strategy involving the shift of the π-allyl palladium intermediate was successfully applied in the asymmetric construction of 1,7-nonadjacent stereocenters. The current method allows for the efficient preparation of chiral molecules bearing two privileged scaffolds, oxindoles and non-natural α-amino acids, with good functional group tolerance. The full complement of the four stereoisomers of products bearing 1,5/1,7-nonadjacent stereocenters could be readily accessed by a simple combination of two chiral metal catalysts with different enantiomers.

Establishing an Artificial Pathway for the Biosynthesis of Octopamine and Synephrine.

In this study, we designed an artificial pathway composed of tyramine β-hydroxylase (TBH) and phenylethanolamine N-methyltransferase (PNMT) for the biosynthesis of both octopamine and synephrine. As most TBH and PNMT originate from eukaryotic animals and plants, the heterologous expression and identification of functional TBH and PNMT are critical for establishing the pathway in mode microorganisms like Escherichia coli. Here, three TBHs were evaluated, and only TBH from Drosophila melanogaster was successfully expressed in the soluble form in E. coli. Its expression was promoted by evaluating the effects of different expression strategies. The specific enzyme activity of TBH was optimized up to 229.50 U·g-1, and the first step in the biosynthetic pathway was successfully established and converted tyramine to synthesize 0.10 g/L of octopamine. Furthermore, the second step to produce synephrine from octopamine was developed by screening PNMT, enhancing enzyme activity, and optimizing reaction conditions, with a maximum synephrine production of 2.02 g/L. Finally, based on the optimization of the reaction conditions for each individual reaction, the one-pot cascade reaction for synthesizing synephrine from tyramine was constructed by combining the TBH and PNMT. The synthetic synephrine reached 30.05 mg/L with tyramine as substrate in the two-step enzyme cascade system. With further optimization and amplification, the titers of octopamine and synephrine were increased to 0.45 and 0.20 g/L, respectively, with tyramine as substrate. This work was the first achievement of the biosynthesis of octopamine and synephrine to date.

One‐Pot Synthesis of 2‐Aminothiophenes by Au(I)‐Catalyzed Cascade Reaction Including Hydrothiolation, Thio‐Claisen Rearrangement, and Cycloisomerization

AbstractThe cascade reaction of ynamides with propargyl thiols by Au(I) catalysis involving regioselective hydrothiolation, thio‐Claisen rearrangement, and cycloisomerization to generate 2‐aminothiophenes in a one‐pot manner is described. In this reaction, the selection of reaction temperature is crucial, with the initial step, namely hydrothiolation, conducted at a low temperature (40 °C), followed by the subsequent reaction requiring an increase in temperature (>110 °C). Furthermore, it was revealed that multi‐substituted anilines could be synthesized from the resulting 2‐aminothiophenes.

Main Group-Catalyzed Cationic Claisen Rearrangements via Vinyl Carbocations.

We report a catalytic C-O coupling/Claisen cascade reaction enabled by interception of vinyl carbocations with allyl ethers. The reaction utilizes commercially available borate salts as catalysts and is effective at constructing sterically hindered C-C bonds. The reaction mechanism is studied experimentally and computationally to support a charge-accelerated [3,3] rearrangement of a silyloxonium cation. Our reaction is also applied to the highly stereoselective synthesis of fully substituted vinyl ethers.

Adventures in the Chemistry of Multicomponent and Domino Reactions

AbstractThe present personalized account summarizes various cyclization reactions, including multicomponent and domino processes, which are directed towards the synthesis of complex heterocyclic products. Domino Knoevenagel/hetero‐Diels‐Alder reactions provide a synthesis of annulated quinol‐2‐ones. The combination of Knoevenagel reactions with [3+2] cycloadditions of nitrogen ylides afford complex spiroheteriocyclic products. Domino Knoevenagel/enamine cyclization reactions result in the formation of condensed purine analogues. Formal [3+3] cyclizations of pyridinium salts allow for a rapid assembly of bridged heterocyclic systems and include the employment of thioxindoles and cyclohexane‐1,3‐diones as dinucleophilic building blocks. The formal [3+3] cyclization of thioxindoles with fluoroaroyl chlorides, such as 2‐fluorobenzoyl chlorides and 2‐chloropyridine‐3‐carboxylic chloride, give rise to the synthesis of condensed benzothiophenes. The cyclization of heterocyclic enamines with diimines and triazines afford various purine analogues by domino [4+2]/retro [4+2] reactions. The formal [3+3] cyclization of 2,4,6‐tris(trifluoromethyl)‐1,3,5‐triazine with 1,3‐bis(silyloxy)‐1,3‐butadienes afford, depending on the conditions, 2,6‐bis(trifluoromethy)pyrid‐4‐ones or triazaadamantanone derivatives. Heating of 2‐ethynylpyridines with electron‐rich dienes afforded 2‐(2‐methoxyphenyl)pyridines by a domino [4+2]/retro [4+2] process. The reaction of 2‐ethynylpyridines with enones afforded indolizines by a formal [3+3] cyclization. The reaction of trifluoromethyl‐substituted 1,3‐diketones with lithiated alkynes afforded 3‐hydroxy‐pent‐4‐yn‐1‐ones. Formal [5+1] cyclization of the latter with urea afforded trifluoromethyl‐substituted pyridines. The Pd catalyzed formal [3+2] cyclizations of 2,3‐dihalopyridines with imines afforded a series of regioisomeric 4‐ and 7‐azaindoles.

Stereoselective Synthesis of Polysubstituted Dihydropyrroles via 1,5-Addition and N-1,4-Addition Cascade.

An unprecedented 1,5-addition/N-1,4-addition cascade reaction is established via palladium hydride catalysis. A variety of polysubstituted dihydropyrrole skeletons are constructed in high yield and with exclusively >20 : 1 diastereoselectivity. An enantioselective protocol of this design is also developed to provide a novel access to enantioenriched dihydropyrroles.

Endogenous mRNA-Driven "One-To-More" Signal Amplification of DNA Probe for Intracellular miR155 Sensing.

The detection of specific intracellular microRNAs could be potentially helpful in understanding the underlying mechanisms of cancer metastasis and invasion. MiRNAs are usually present in lower expression levels, especially in early stage of cancer. Here, we proposed a "one-to-more" amplification strategy for miRNA imaging, by virtue of DNA strand displacements with dual-amplification. This approach involves leveraging high-abundance endogenous mRNA as fuel strand to drive cascade reactions between DNA strands for amplification, enabling the monitoring of low-abundance intracellular microRNA155. Notably, in comparison to the traditional "one-to-one" signal triggering mode, our "one-to-more" amplification strategy led to a remarkable 11.8-fold increase in fluorescence signal. Our approach not only demonstrates a high sensitivity and specificity in detecting miR155, but also allows for discrimination of miR155 expression levels in different cell lines. With the advantages of intracellular signal amplification and reduced background signal, this approach holds substantial potential in the early diagnosis of cancer.

Aquivion-based spray freeze-dried composite materials for the cascade production of γ-valerolactone.

The development of multifunctional catalysts is a necessary step to effectively carry out cascade reactions, such as that from furfural to γ-valerolactone. This research effort faces the challenge posed by the intrinsic limit of how many kinds of catalytic sites a single material can bear. In this work, the application of Spray-Freeze Drying (SFD) as a synthetic technique for the preparation of a wide range of composite multi-functional catalysts is reported. Herein we show that by the proper combination of Aquivion as a highly active Brønsted acid catalyst and metal oxides as Lewis acids (LAS) enable to achieve highly unique efficient and effective dual acid composite catalysts that are able to carry out the cascade reaction from furfural to γ-valerolactone. The dual catalytic system comprised of Aq/ZrO2 with 30% polymer content prepared via spray-freeze drying exhibited GVL yields of 25% after only 2 h at 180 °C and a remarkably high productivity of 4470 µmolGVL gCat-1 h-1, one of the highest reported results. Mechanistic studies based on experimental and advanced characterisation and spectroscopic techniques, such as, SEM, TEM, 15N MAS NMR and 19F MAS NMR indicate that activity arises from the proper tuning of BAS/LAS acidic properties.

Modular Access to Tetrasubstituted N−H Pyrroles by Catalytic 1,3‐Dipolar Cycloaddition of Azomethine Ylides and α,β‐Ynones

AbstractThe development of efficient synthetic strategies for the preparation of tetrasubstituted N−H pyrrole derivatives, especially in an environmentally benign fashion is important yet challenging. Herein, we report a copper(II)‐catalyzed tandem reaction involving 1,3‐dipolar cycloaddition of α,β‐ynones and glycine iminoesters, followed by copper(II)‐promoted oxidative (air) dehydrogenative aromatization, allowing de novo access to tetrasubstituted N−H pyrroles in up to 81 % yield under green reaction conditions. A possible reaction pathway is tentatively proposed. Finally, fully substituted pyrroles are available by N‐alkylation, and a preliminary phase‐transfer catalytic asymmetric N‐alkylation was also studied to give an axially chiral pyrrole.

Modular Cascade of Flow Reactors: Continuous Flow Synthesis of Water-Insoluble Diazo Dyes in Aqueous System.

Continuous flow synthesis is pivotal in dye production to address batch-to-batch variations. However, synthesizing water-insoluble dyes in an aqueous system poses a challenge that can lead to clogging. This study successfully achieved the safe and efficient synthesis of azo dyes by selecting and optimizing flow reactor modules for different reaction types in the two-step reaction and implementing cascade cooperation. Integrating continuous flow microreactor with continuous stirred tank reactor (CSTR) enabled the continuous flow synthesis of Sudan Yellow 3G without introducing water-soluble functional groups or using organic solvents to enhance solubility. Optimizing conditions (acidity/alkalinity, temperature, residence time) within the initial modular continuous flow reactor resulted in a remarkable 99.5% isolated yield, 98.6% purity, and a production rate of 2.90 g · h-1. Scaling-up based on different reactor module characteristics further increased the production rate to 74.4 g·h-1 while maintaining high yield and purity. The construction of this small 3D-printing modular cascaded reactor and process scaling-up provide technical support for continuous flow synthesis of water-insoluble dyes, particularly high-market-share azo dyes. Moreover, this versatile methodology proves applicable to continuous flow processes involving various homogeneous and heterogeneous reaction cascades.

Modified Janus silica-based sheets stable stimulus-responsive Pickering emulsion: An excellent recycling platform for tandem reaction

To accommodate the advancement of green chemistry and further enhance hydrogen utilization efficiency and organic compound conversion in reactions, a smart Pickering emulsion stabilized by modified Janus silica particles was successfully prepared for the tandem reaction of ammonia borane hydrolysis and organic hydrogenation reduction. The emulsion has been confirmed to possess high stability and rapid stimulus responsiveness. The high stability and large oil-water interface area of Pickering emulsions, along with their low energy demulsification method, provide an excellent reaction platform and catalyst in situ recovery strategy for tandem reactions. Moreover, the anisotropy of Janus particles facilitates the progression of tandem reactions, mitigating the waste associated with "sacrifice" mechanisms and averting hydrogen loss. Experimental results demonstrate that even when the molar amount of hydrogen released from ammonia borane is comparable to that of organic compounds, organic compounds still achieve a conversion rate of 99 %, with a hydrogen utilization efficiency 3–4 times higher than that of conventional two-phase systems. By simply adjusting the pH, the catalyst can be recovered in situ for the next cycle. Even after 5 cycles, a high conversion rate of organic compounds is maintained.

Complex Droplet Microreactor for Highly Efficient and Controllable Esterification and Cascade Reactions.

A highly efficient complex emulsion microreactor has been successfully developed for multiphasic water-labile reactions, providing a powerful platform for atom economy and spatiotemporal control of reaction kinetics. Complex emulsions, composing a hydrocarbon phase (H) and a fluorocarbon phase (F) dispersed in an aqueous phase (W), are fabricated in batch scale with precisely controlled droplet morphologies. A biphasic esterification reaction between 2-bromo-1,2-diphenylethane-1-ol (BPO) and perfluoro-heptanoic acid (PFHA) is chosen as a reversible and water-labile reaction model. The conversion reaches up to 100 % under mild temperature without agitation, even with nearly equivalent amounts of reactants. This efficiency surpasses all reported single emulsion microreactors, i. e., 84~95 %, stabilized by various emulsifiers with different catalysts, which typically necessitate continuous stirring, a high excess of one reactant, and/or extended reaction time. Furthermore, over 3 times regulation threshold in conversion rate is attained by manipulating the droplet morphologies, including size and topology, e. g., transition from completely engulfed F/H/W double to partially engulfed (F+H)/W Janus. Addition-esterification, serving as a model for triple phasic cascade reaction, is also successfully implemented under agitating-free and mild temperature with controlled reaction kinetics, demonstrating the versatility and effectiveness of the complex emulsion microreactor.

Radical Fluorosulfonamidation: A Facile Access to Sulfamoyl Fluorides.

Recently, the introduction of fluorosulfonyl (-SO2F) groups have attracted considerable research interests, as this moiety could often afford enhanced activities and new functions in the context of chemical biology and drug discovery. Herein, we report the design and synthesis of 1-fluorosulfamoyl-pyridinium (FSAP) salts, which could serve as an effective photoredox-active precursor to fluorosulfamoyl radicals and enable the direct radical C-H fluorosulfonamidation of a variety of (hetero)arenes. This method features mild conditions, visible light, broad substrate scope, good group tolerance, etc., and a metal-free protocol is also viable by using organic photocatalysts. Further, FSAP can also be applied to the radical functionalization of alkenes via 1,2-difunctionalization, radical distal migration, tandem radical-polar crossover reactions, etc. In addition, a formal C-H methylamination of (hetero)arenes by combining this radical C-H fluorosulfonamidation with subsequent hydrolysis as well as product derivatization are also demonstrated.

Porous Prussian blue nanolayers formed in situ on Fe-MOFs-modified electrode surfaces by electrochemically triggered dual-templating effect for ultrasensitive detection of lead ions and Staphylococcus aureus

In this study, introducing Fe-MOFs as reactants to the electrode surface creates a novel mode for modulating interface performance that can lead to rapid enrichment of reactants in the proximity of electrodes by electrochemical-induced confinement effect. A facile, controllable, and room temperature electrochemical approach utilizes Fe-MOFs as nanotemplates to produce porous Prussian blue (PB) nanolayers on the electrode surfaces. Unlike conventional chemical conversion that needs a supply of exogenous acid regents, the electrochemical method creates a solid acidic condition in the oxygen evolution reaction cycle to release Fe3+ from the Fe-MOFs, improving conversion efficiency and electrochemical activity of PB. Furthermore, small oxygen bubbles generated by splitting H2O near the electrodes are also good templates, promoting the formation of porous structures that can increase effective surface area and mass-transfer efficiency. As a conceptional application, using Fe-MOFs as self-sacrificial tags, an ultrasensitive electrochemical platform with triple amplification is developed to detect Pb2+ and S. aureus based on DNAzyme-CHA cascade reaction. The designed platform shows low detection limits of 8.5 fM and 1 CFU/mL for Pb2+ and S. aureus, respectively. Moreover, the platform has high selectivity, stability and reproducibility, and also shows satisfactory recovery rates when validated using actual samples.

Diastereo- and Enantioselective Chemodivergent Three-Component Cascade Reactions via Gold and Carbene Sequential Catalysis

Diastereo- and Enantioselective Chemodivergent Three-Component Cascade Reactions via Gold and Carbene Sequential Catalysis

Improving the enzymatic activity and stability of N-carbamoyl hydrolase using deep learning approach

BackgroundOptically active D-amino acids are widely used as intermediates in the synthesis of antibiotics, insecticides, and peptide hormones. Currently, the two-enzyme cascade reaction is the most efficient way to produce D-amino acids using enzymes DHdt and DCase, but DCase is susceptible to heat inactivation. Here, to enhance the enzymatic activity and thermal stability of DCase, a rational design software “Feitian” was developed based on kcat prediction using the deep learning approach.ResultsAccording to empirical design and prediction of “Feitian” software, six single-point mutants with high kcat value were selected and successfully constructed by site-directed mutagenesis. Out of six, three mutants (Q4C, T212S, and A302C) showed higher enzymatic activity than the wild-type. Furthermore, the combined triple-point mutant DCase-M3 (Q4C/T212S/A302C) exhibited a 4.25-fold increase in activity (29.77 ± 4.52 U) and a 2.25-fold increase in thermal stability as compared to the wild-type, respectively. Through the whole-cell reaction, the high titer of D-HPG (2.57 ± 0.43 mM) was produced by the mutant Q4C/T212S/A302C, which was about 2.04-fold of the wild-type. Molecular dynamics simulation results showed that DCase-M3 significantly enhances the rigidity of the catalytic site and thus increases the activity of DCase-M3.ConclusionsIn this study, an efficient rational design software “Feitian” was successfully developed with a prediction accuracy of about 50% in enzymatic activity. A triple-point mutant DCase-M3 (Q4C/T212S/A302C) with enhanced enzymatic activity and thermostability was successfully obtained, which could be applied to the development of a fully enzymatic process for the industrial production of D-HPG.

Protocells Featuring Membrane-Bound and Dynamic Membraneless Organelles.

Living cells, especially eukaryotic ones, use multicompartmentalization to regulate intra- and extracellular activities, featuring membrane-bound and membraneless organelles. These structures govern numerous biological and chemical processes spatially and temporally. Synthetic cell models, primarily utilizing lipidic and polymeric vesicles, have been developed to carry out cascade reactions within their compartments. However, these reconstructions often segregate membrane-bound and membraneless organelles, neglecting their collaborative role in cellular regulation. To address this, we propose a structural design incorporating microfluidic-produced liposomes housing synthetic membrane-bound organelles made from self-assembled poly(ethylene glycol)-block-poly(trimethylene carbonate) nanovesicles and synthetic membraneless organelles formed via temperature-sensitive elastin-like polypeptide phase separation. This architecture mirrors natural cellular organization, facilitating a detailed examination of the interactions for a comprehensive understanding of cellular dynamics.

Tandem Four-Component Reaction to Access Fused Polycycles Exhibiting Aggregation-Enhanced Through-Space Charge Transfer Emission.

Rapid construction of new fluorescence emitters is essential in advancing synthetic luminescent materials. This study illustrated a piperidine-promoted reaction of chiral dialdehyde with benzoylacetonitrile and malonitrile, leading to the formation of the 6/6/7 fused cyclic product in good yield. The proposed reaction mechanism involves a dual condensation/cyclization process, achieving the formation of up to six bonds for fused polycycles. The single crystal structure analysis revealed that the fused cyclic skeleton contains face-to-face naphthyl and cyanoalkenyl motifs, which act as the electronic donor and acceptor, respectively, potentially resulting in through-space charge transfer (TSCT) emission. While the TSCT emissions were weak in solution, a notable increase in luminescence intensity was observed upon aggregation, indicating bright fluorescent light. A series of theoretical analyses further supported the possibility of spatial electronic communication based on frontier molecular orbitals, the distance of charge transfer, and reduced density gradient analysis. This work not only provides guidance for the one-step synthesis of complex polycycles, but also offers valuable insights into the design of aggregation-enhanced TSCT emission materials.

Construction of Two-Dimensional Organometallic Coordination Networks with Both Organic Kagome and Semiregular Metal Lattices on Au(111).

Two-dimensional metal-organic networks (2D MONs) having heterogeneous coordination nodes (HCNs) could exhibit excellent performance in catalysis and optoelectronics because of the unbalanced electron distribution of the coordinating metals. Therefore, the design and construction of 2D MONs with HCNs are highly desirable but remain challenging. Here, we report the construction of 2D organometallic coordination networks with an organic Kagome lattice and a semiregular metal lattice on Au(111) via the in situ formation of HCNs. Using a bifunctional precursor 1,4-dibromo-2,5-diisocyanobenzene, the coordination of isocyano with Au adatom on a room-temperature Au(111) yielded metal-organic coordination chains with isocyano-Au-isocyano nodes. In contrast, on a high-temperature Au(111), a selective debromination/coordination cascade reaction occurred, affording 2D organometallic coordination networks with phenyl-Au-isocyano nodes. By combining scanning tunneling microscopy and density functional theory calculations, we determined the structures of coordination products and the nature of coordination nodes, demonstrating a thermodynamically favorable pathway for forming the phenyl-Au-isocyano nodes.

Colorimetric/SERS dual-mode sensing of glucose based on cascade reaction of peroxidase-like Au@Pt/Fe-DACDs nanozyme

Colorimetric/SERS dual-mode sensing of glucose based on cascade reaction of peroxidase-like Au@Pt/Fe-DACDs nanozyme