Synthetic Building Research Articles

Non-Reciprocity, Metastability, and Dynamic Reconfiguration in Co-Assembly of Active and Passive Particles.

Living organisms often exhibit non-reciprocal interactions where the forces acting on the objects are not equal in magnitude or opposite in direction. The combination of reciprocal and non-reciprocal interactions between synthetic building blocks remains largely unexplored. Here, out-of-equilibrium assemblies of non-motile isotropic passive and metal-patched motile active particles are formed by overlapping bulk interactions with directed self-propulsion. An external alternating current (AC) electric field generates concurrent dipolar and induced-charge electrophoretic forces between the particles which are evaluated using microscopy. The interaction force measurements allow to determine the degree of reciprocity in interactions, which is tunable by designing the active particle and its trajectory. While linearly-propelled active particles evade assembly with passive particles, helically propelled active particles form active-passive clusters with dynamic reconfiguration and long-lived metastability. Large clusters display programmable fluctuations and reconfigurability by controlling the fraction of active particles. The study establishes principles of integrating reciprocal and non-reciprocal interactions in guided colloidal assembly of reconfigurable metastable structures.

Decatungstate-Photocatalyzed Transformations of 2-Bromo-3,3,3-trifluoropropene for Selective Synthesis of Z/E-β-CF3-Enones.

Condition-controlled switchable and divergent transformations of cost-effective 2-bromo-3,3,3-trifluoropropene (BTP) and aldehydes were realized using a decatungstate (TBADT)-photocatalyzed strategy. The hydroacylated products, i.e., β,β-Br,CF3-ketones, can be applied as highly functionalized synthetic building blocks for the selective synthesis of (Z/E)-β-CF3-enones. Utilizing this methodology, a broad range of commercially available aromatic and aliphatic aldehydes as well as numerous complex aldehydes, such as lily aldehyde, cyclamen aldehyde, citronellal, vanillin, and aldehydes containing bioactive moieties, including ibuprofen, gemfibrozil, naproxen, flurbiprofen, oleic acid, and aspirin, may be proficiently employed in this transformative process.

Noncanonical Amino Acid Incorporation in Animals and Animal Cells.

Noncanonical amino acids (ncAAs) are synthetic building blocks that, when incorporated into proteins, confer novel functions and enable precise control over biological processes. These small yet powerful tools offer unprecedented opportunities to investigate and manipulate various complex life forms. In particular, ncAA incorporation technology has garnered significant attention in the study of animals and their constituent cells, which serve as invaluable model organisms for gaining insights into human physiology, genetics, and diseases. This review will provide a comprehensive discussion on the applications of ncAA incorporation technology in animals and animal cells, covering past achievements, current developments, and future perspectives.

Enantioselective Deoxygenative Amino-Cyanation of Carboxylic Acids via Ti-Multicatalysis.

Carboxylic acids are valued synthetic building blocks that offer shelf life stability, structural diversity, and wide commercial availability. Despite the remarkable synthetic utility of carboxylic acids, a direct enantioselective deoxygenative functionalization of carboxylic acids remains rare. We present enantioselective deoxygenative amino-cyanation of carboxylic acids using a novel TiIV-multicatalytic system that catalytically modified each C-O bond of carboxylic acid to C-C, C-N, and C-H bonds, generating enantio-enriched chiral α-amino nitriles (up to 98:2 er).

PAMAM-Calix-Dendrimers: Third Generation Synthesis and Impact of Generation and Macrocyclic Core Conformation on Hemotoxicity and Calf Thymus DNA Binding.

Background/Objectives: Current promising treatments for many diseases are based on the use of therapeutic nucleic acids, including DNA. However, the list of nanocarriers is limited due to their low biocompatibility, high cost, and toxicity. The design of synthetic building blocks for creating universal delivery systems for genetic material is an unsolved problem. In this work, we propose PAMAM dendrimers with rigid thiacalixarene core in various conformations, i.e., PAMAM-calix-dendrimers, as a platform for a supramolecular universal constructor for nanomedicine. Results: Third generation PAMAM dendrimers with a macrocyclic core in three conformations (cone, partial cone, and 1,3-alternate) were synthesized for the first time. The obtained dendrimers were capable of binding and compacting calf thymus DNA, whereby the binding efficiency improved with increasing generation, while the influence of the macrocyclic core was reduced. A dramatic effect of the macrocyclic core conformation on the hemolytic activity of PAMAM-calix-dendrimers was observed. Specifically, a notable reduction in hemotoxicity was associated with a decrease in compound amphiphilicity. Conclusions: We hope the results will help reduce financial and labor costs in developing new drug delivery systems based on dendrimers.

Remote Selective Cross‐Dehydrogenative Coupling Reactions of Aryl C−H Bonds with Carboxylic Acids at Room Temperature

AbstractAn efficient Pd(II)‐catalyzed remote selective cross‐dehydrogenative coupling of broadly useful synthetic building blocks biphenyl Weinreb amides with carboxylic acids is developed. This acetoxylation protocol is performed under room temperature using N‐fluorobenzene‐sulfonimide (NFSI) as the oxidant, exhibiting a wide range of functional group tolerance and affording δ‐position‐ selective products up to 85 % yield. Notably, a diverse set of carboxylic acid‐containing drugs is also found to be compatible under the current reaction conditions. Preliminary mechanistic studies indicate that this reaction presumably proceeds through a seven‐membered palladacycle intermediate.

Development of ketalized unsaturated saccharides as multifunctional cysteine-targeting covalent warheads

Multi-functional cysteine-targeting covalent warheads possess significant therapeutic potential in medicinal chemistry and chemical biology. Herein, we present novel unsaturated and asymmetric ketone (oxazolinosene) scaffolds that selectively conjugate cysteine residues of peptides and bovine serum albumin under normal physiological conditions. This unsaturated saccharide depletes GSH in NCI-H1299 cells, leading to anti-tumor effects in vitro. The acetyl group of the ketal moiety on the saccharide ring can be converted to other carboxylic acids in a one-pot synthesis. In this way, the loaded acid can be click-released during cysteine conjugation, making the oxazolinosene a potential multifunctional therapeutic agent. The reaction kinetic model for oxazolinosene conjugation to GSH is well established and was used to evaluate oxazolinosene reactivity. The aforementioned oxazolinosenes were stereoselectively synthesized via a one-step reaction of nitriles with saccharides and conveniently converted into a series of α, β-unsaturated ketone N-glycosides as prevalent synthetic building blocks. The reaction mechanisms of oxazolinosene synthesis were investigated through calculations and validated with control experiments. Overall, these oxazolinosenes can be easily synthesized and developed as cysteine-targeted covalent warheads carrying useful click-releasing groups.

Ligand‐Controlled Copper‐Catalyzed Halo‐Halodifluoromethylation of Alkenes and Alkynes Using Fluorinated Carboxylic Anhydrides

AbstractPolyhalogenated molecules are often found as bioactive compounds in nature and are used as synthetic building blocks. Fluoroalkyl compounds hold promise for the development of novel pharmaceuticals and agrochemicals, as the introduction of fluoroalkyl groups is known to improve lipophilicity, membrane permeability, and metabolic stability. Three‐component 1,2‐halo‐halodifluoromethylation reactions of alkenes are useful for their synthesis. However, general methods enabling the introduction of halodifluoromethyl (CF2X) and halogen (X’) groups in the desired combination of X and X’ are lacking. To address this gap, for the first time, we report a three‐component halo‐halodifluoromethylation of alkenes and alkynes using combinations of commercially available fluorinated carboxylic anhydrides ((CF2XCO)2O, X=Cl and Br) and alkali metal halides (X’=Cl and Br). In situ prepared fluorinated diacyl peroxides were identified as important intermediates, and the use of appropriate bipyridyl‐based ligands and a copper catalyst was essential for achieving high product selectivity. The synthetic utility of the polyhalogenated products was demonstrated by exploiting differences in the reactivities of their C−X and C−X’ bonds to achieve selective derivatization. Finally, the reaction mechanism and ligand effect were investigated using experimental and theoretical methods to provide important insights for the further development of catalytic reactions.

Ligand-Controlled Copper-Catalyzed Halo-Halodifluoromethylation of Alkenes and Alkynes Using Fluorinated Carboxylic Anhydrides.

Polyhalogenated molecules are often found as bioactive compounds in nature and are used as synthetic building blocks. Fluoroalkyl compounds hold promise for the development of novel pharmaceuticals and agrochemicals, as the introduction of fluoroalkyl groups is known to improve lipophilicity, membrane permeability, and metabolic stability. Three-component 1,2-halo-halodifluoromethylation reactions of alkenes are useful for their synthesis. However, general methods enabling the introduction of halodifluoromethyl (CF2X) and halogen (X') groups in the desired combination of X and X' are lacking. To address this gap, for the first time, we report a three-component halo-halodifluoromethylation of alkenes and alkynes using combinations of commercially available fluorinated carboxylic anhydrides ((CF2XCO)2O, X=Cl and Br) and alkali metal halides (X'=Cl and Br). In situ prepared fluorinated diacyl peroxides were identified as important intermediates, and the use of appropriate bipyridyl-based ligands and a copper catalyst was essential for achieving high product selectivity. The synthetic utility of the polyhalogenated products was demonstrated by exploiting differences in the reactivities of their C-X and C-X' bonds to achieve selective derivatization. Finally, the reaction mechanism and ligand effect were investigated using experimental and theoretical methods to provide important insights for the further development of catalytic reactions.

Signal‐Amplifying Biohybrid Material Circuits for CRISPR/Cas‐Based Single‐Stranded RNA Detection

AbstractThe functional integration of biological switches with synthetic building blocks enables the design of modular, stimulus‐responsive biohybrid materials. By connecting the individual modules via diffusible signals, information‐processing circuits can be designed. Such systems are, however, mostly limited to respond to either small molecules, proteins, or optical input thus limiting the sensing and application scope of the material circuits. Here, a highly modular biohybrid material is design based on CRISPR/Cas13a to translate arbitrary single‐stranded RNAs into a biomolecular material response. This system exemplified by the development of a cascade of communicating materials that can detect the tumor biomarker microRNA miR19b in patient samples or sequences specific for SARS‐CoV. Specificity of the system is further demonstrated by discriminating between input miRNA sequences with single‐nucleotide differences. To quantitatively understand information processing in the materials cascade, a mathematical model is developed. The model is used to guide systems design for enhancing signal amplification functionality of the overall materials system. The newly designed modular materials can be used to interface desired RNA input with stimulus‐responsive and information‐processing materials for building point‐of‐care suitable sensors as well as multi‐input diagnostic systems with integrated data processing and interpretation.

N-Heteroocyclic Carbenes and N-Heterocycles as Synthetic Reagents and Building Blocks.

N-Heterocyclic carbenes (NHCs) have become important tools in modern synthetic chemistry due to their versatility as organocatalysts and ligands in organometallic complexes. Since their first isolation and characterization, NHCs have demonstrated significant utility in various catalytic processes, offering advantages such as strong σ-electron donation and the ability to stabilize reactive intermediates. However, beyond their well-documented roles in catalysis, the potential of NHCs as stoichiometric reagents and synthetic building blocks remains an underexplored yet promising area. This Mini-review aims to shed light on these lesser-known applications of NHCs and their N-heterocyclic precursors or derivatives in organic synthesis. Furthermore, we discuss how the unique electronic and steric properties of NHCs can be harnessed to develop new synthetic methodologies or construct interesting organic frameworks. By highlighting these emerging uses, we hope to encourage further research into the non-catalytic applications of NHCs, broadening their scope and impact in synthetic chemistry.

Selective hydrogenation of nitro compounds to amines by coupled redox reactions over a heterogeneous biocatalyst

Cleaner synthesis of amines remains a key challenge in organic chemistry because of their prevalence in pharmaceuticals, agrochemicals and synthetic building blocks. Here, we report a different paradigm for chemoselective hydrogenation of nitro compounds to amines, under mild, aqueous conditions. The hydrogenase enzyme releases electrons from H2 to a carbon black support which facilitates nitro-group reduction. For 30 nitroarenes we demonstrate full conversion (isolated yields 78 – 96%), with products including pharmaceuticals benzocaine, procainamide and mesalazine, and 4-aminophenol – precursor to paracetamol (acetaminophen). We also showcase gram-scale synthesis of procainamide with 90% isolated yield. We demonstrate potential for extension to aliphatic substrates. The catalyst is highly selective for reduction of the nitro group over other unsaturated bonds, tolerant to a wide range of functional groups, and exhibits excellent stability in reactions lasting up to 72 hours and full reusability over 5 cycles with a total turnover number over 1 million, indicating scope for direct translation to fine chemical manufacturing.

Synthesis of 2‐Aminopyridine Derivatives via a Tandem CuAAC/Ring‐Cleavage/[4+2]‐Cycloaddition/Rearrangement Reaction Sequence

Abstract2H‐Azirines are an important class of small‐ring heterocycle that have been employed as versatile synthetic building blocks. Herein, a one‐pot CuAAC/ring‐cleavage/[4+2]‐cycloaddition/rearrangement reaction sequence involving terminal ynones, sulfonyl azides and 2H‐azirines is reported that leads to 2‐aminopyridine derivatives. In the first step, highly reactive N‐sulfonyl α‐acylketenimines are generated, via a CuAAC/ring‐cleavage process, from sulfonyl azides and terminal ynones and these undergo inverse electron‐demand Diels–Alder cycloaddition reactions with 2H‐azirines to form (isolable) 1,3‐oxazines that themselves undergo base‐promoted ring‐cleavage and rearrangement reactions to afford the title compounds.

Catalytic asymmetric synthesis of 1,2-diamines.

The asymmetric catalytic synthesis of 1,2-diamines has received considerable interest, especially in the last ten years, due to their presence in biologically active compounds and their applications for the development of synthetic building blocks, chiral ligands and organocatalysts. Synthetic strategies based on C-N bond-forming reactions involve mainly (a) ring opening of aziridines and azabenzonorbornadienes, (b) hydroamination of allylic amines, (c) hydroamination of enamines and (d) diamination of olefins. In the case of C-C bond-forming reactions are included (a) the aza-Mannich reaction of imino esters, imino nitriles, azlactones, isocyano acetates, and isothiocyanates with imines, (b) the aza-Henry reaction of nitroalkanes with imines, (c) imine-imine coupling reactions, and (d) reductive coupling of enamines with imines, and (e) [3+2] cycloaddition with imines. C-H bond forming reactions include hydrogenation of CN bonds and C-H amination reactions. Other catalytic methods include desymmetrization reactions of meso-diamines.

DABCO‐catalyzed highly regioselective synthesis of novel 4H‐pyrano[2,3‐b]quinoline derivatives: One‐pot three‐component reaction

AbstractA regioselective synthesis of 4H‐pyrano[2,3‐b]quinoline derivatives via DABCO‐mediated Knoevenagel condensation/heterocyclization sequence has been executed. In this way some new fused heterocyclic compounds were synthesized from 2‐chloroquinoline‐3‐carbaldehyde as a versatile and efficient synthetic building block. The one‐pot three‐component reaction of 2‐chloroquinoline‐3‐carbaldehyde and diverse cyclic active methylenes for construction of highly substituted quinolines scaffold has been accomplished under mild condition. The strategy included herein shows significant advantages, including a facile process with easy purification, excellent yields, wide applicability, available substrates, and cost‐effective/eco‐friendly solvent and catalyst.

Total Synthesis of Lissodendoric Acid A

AbstractWe describe a full account of our synthetic strategy leading to the first total synthesis of the manzamine alkaloid lissodendoric acid A . These efforts demonstrate that strained cyclic allenes are valuable synthetic building blocks and can be employed efficiently in total synthesis.

Total Synthesis of Lissodendoric Acid A.

We describe a full account of our synthetic strategy leading to the first total synthesis of the manzamine alkaloid lissodendoric acid A . These efforts demonstrate that strained cyclic allenes are valuable synthetic building blocks and can be employed efficiently in total synthesis.

Generating synthetic building electrical load profiles using machine learning based on the CRISP-ML(Q) framework

Abstract This study presents a machine learning application for generating synthetic building electrical load profiles. The implementation followed the Cross Industry Standard Process for the development of Machine Learning Applications with Quality assurance methodology, or CRISP-ML(Q) framework, to ensure a systematic machine learning development process. The model training performance was evaluated using the mean absolute error (MAE), root mean squared error (RSME), and coefficient of determination (R2) which were observed to be 0.0739, 0.1119, and 0.5728, respectively. These metrics remained consistent during the model testing phase, suggesting robust model performance. During the initial simulation experiment, the MAE and RMSE of the generated synthetic load profile were found to be 0.014 and 0.016, respectively, underscoring high model accuracy. Additional evaluation experiments showed that the developed machine learning application can generate realistic building load profiles using high-level parameters such as building type, average daily load, and peak demand. This study can aid in the development of demand-side management strategies and building energy management systems by providing realistic building electrical load profiles especially when real-world data is limited. For future work, researchers can consider integrating additional model features, refining data processing methods, and developing an agile version of the CRISP-ML(Q) framework.

Lignin‐Based Multilamellar Aggregates for Removing Ofloxacin Antibiotic: A Dissipative Particle Dynamics Simulation Study

AbstractLignin, a renewable aromatic polymer, has great potential as a synthetic building block for functional materials. The effects of quaternary ammonic methylation of alkali lignin (AL) on the morphologies and ofloxacin antibiotic (OA) removal application from water are investigated by using the dissipative particle dynamics (DPD) simulation method. Untreated AL can form spherical aggregates, but the phenylpropane units of untreated AL and loaded broad‐spectrum OA molecules are randomly distributed in aggregates. However, if quaternary ammonic groups are grafted onto all orthopositions of the phenolic hydroxyl groups (100‐QAMAL), then multilamellar spherical aggregates are obtained and OA molecules are entrapped in the aggregates. To prepare multilamellar spherical aggregates with an ordered and regular layered structure, <15 v% of 100‐QAMAL and low molecular weights of AL (≈4700–9400 Da) are suggested to be used. Lignin‐based multilamellar spherical aggregates can be adopted as potential functional carriers for removing pollutant OA from water.

Cover Picture

The cover image portrays the asymmetric synthesis of dihydrospirotryprostatin B, achieved through a chiral pool strategy utilizing readily available tryptamine‐ynamide. This tryptamine‐ynamide was constructed from three synthetic building blocks: L‐tryptophan, methyl‐L‐proline ester, and bromoalkyne. For a comprehensive understanding of this process, refer to the article authored by Liu et al., pages 1355—1359.image