Synthetic Steps Research Articles

Palladium-catalyzed cascade of aza-Wacker and Povarov reactions of aryl amines and 1,6-dienes for hexahydro-cyclopenta[b]quinoline framework

Palladium catalyzed tandem reaction represents a one-pot synthetic approach to efficiently synthesize complex functionalized molecules while reducing synthetic steps, aligning with the principles of green chemistry. However, achieving a direct cascade of the aza-Wacker and Povarov reactions in one-pot synthesis presents a challenge due to substrate compatibility issues between the two reactions. In this work, we describe an aza-Wacker/Povarov reaction employing a highly electrophilic palladium catalyst, which effectively converts anilines and 1,6-dienes into hexahydro-cyclopenta[b]quinolines. The optimized conditions yield up to 79%, with a diastereoselectivity > 20:1. Substrate range testing reveals compatibility with various sensitive functional groups, and successful late-stage modifications are performed on several natural products and drug molecules, demonstrating the versatility and practicality of the method. Additionally, a preliminary investigation into the reaction mechanism suggests an aza-Wacker process followed by a Povarov process.

Enantioselective synthesis of γ-chiral amides via copper-catalyzed reductive relay hydroaminocarbonylation

Chiral amides are common and effective structural motifs found in many pharmaceuticals and biologically active molecules. Despite their importance, existing synthetic methods are predominantly employed for the synthesis of α-amides and β-amides. The synthesis of remote chiral amides, characterized by distal stereocenters, typically requires intricate synthetic steps conducted under demanding conditions. Here, we present a general procedure for the copper-catalyzed enantioselective synthesis of γ-chiral amides, employing a reductive relay hydroaminocarbonylation strategy with trisubstituted allylic benzoates and hydroxylamine electrophiles. This approach demonstrates a wide substrate scope with excellent enantioselectivity and regioselectivity, thus providing access to challenging enantioenriched γ-chiral amides.

Creation of an aluminum matrix composite with a core-shell carbide reinforcing phase with improved strength characteristics using selective laser sintering

Abstract The development of methods for printing metal matrix composites with a ceramic reinforcing phase is an urgent task in materials science. The production of new MMCs with dispersed filling in additive technology facesproblems that are difficult to solve within the hardware framework of the method. Our research group proposed the approach to the production of MMCs using ceramic-metal core-shell particles, with a matrix soluble shell. It makes possible to develop a universal sequence of synthetic steps used to introduce reinforcing ceramic particles into an Al matrix. The introduction of metal-layer coated ceramic particles into the metal matrix allows maximal contact during sintering between the matrix and the reinforcing phase due to improved phases wettability. As a result, a technique was developed for printing a composite using selective laser melting based on an Al powder matrix (50 µm) and reinforcing core-shell carbide particles (TiC/Ni) with varying reinforcement degrees and improved strength characteristics.

Synthesis of hexafluorovaline-containing di- and tripeptides

A new strategy for the synthesis of peptides incorporating racemic hexafluorovaline (hfVal) is presented. The synthetic pathway relies on the anti-Michael addition of benzyl amine derivatives to ad hoc prepared β-bis-trifluoromethyl-acryloyl-α-amino esters which proceeds in mild condition, high yields, even if with low stereocontrol. The following elaboration of the intermediates, namely deprotection of the benzyl moiety and coupling with α-amino esters allowed us to synthetize the targeted tripeptides in four overall synthetic steps, resulting in a synthetic pathway more favorable respect to those appeared in literature based on the synthesis and isolation of racemic Boc-hfVal-OH (eight synthetic steps).

New Dephenylated Analogues of (–)-Goniofufurone: Optimization of Synthesis from l-Xylose

AbstractNatural products containing highly oxygenated furanofuranone fragments are known for their potent biological activity, but also for their challenging total synthesis. In this study, the synthesis of five novel dephenylated (–)-goniofufurone analogues was completed and their cytotoxic activity against eight malignant and one normal human cell line was evaluated. Compared with previous syntheses of similar analogues, the synthesis was carried out starting from l-xylose, resulting in improved yields and a reduced number of synthetic steps for three divergent intermediates.

Iron(II)-Catalyzed 1,2-Diamination of Styrenes Installing a Terminal NH2 Group Alongside Unprotected Amines.

1,2-Diamination of alkenes represents an attractive way to generate differentiated vicinal diamines, which are prevalent motifs in biologically active compounds and catalysts. However, existing methods are usually limited in scope and produce diamines where one or both nitrogens are protected, adding synthetic steps for deprotection and further N-functionalization to reach a desired target. Furthermore, the range of amino groups that can be introduced at the internal position is fairly limited. Here we describe a 1,2-diamination of styrenes that directly installs a free amino group at the terminal position and a wide variety of unprotected nitrogen nucleophiles (primary or secondary alkyl or aromatic amines, sulfoximines, N-heterocycles, and ammonia surrogate) at the internal position. Two complementary sets of conditions encompass electronically activated and deactivated styrenes with diverse substitution patterns and functional groups. Moreover, this strategy can be extended to the 1,2-aminothiolation of styrenes.

Iron(II)‐Catalyzed 1,2‐Diamination of Styrenes Installing a Terminal NH2 Group Alongside Unprotected Amines

1,2‐Diamination of alkenes represents an attractive way to generate differentiated vicinal diamines, which are prevalent motifs in biologically active compounds and catalysts. However, existing methods are usually limited in scope and produce diamines where one or both nitrogens are protected, adding synthetic steps for deprotection and further N‐functionalization to reach a desired target. Furthermore, the range of amino groups that can be introduced at the internal position is fairly limited. Here we describe a 1,2‐diamination of styrenes that directly installs a free amino group at the terminal position and a wide variety of unprotected nitrogen nucleophiles (primary or secondary alkyl or aromatic amines, sulfoximines, N‐heterocycles, and ammonia surrogate) at the internal position. Two complementary sets of conditions encompass electronically activated and deactivated styrenes with diverse substitution patterns and functional groups. Moreover, this strategy can be extended to the 1,2‐aminothiolation of styrenes.

Cucurbit[8]uril-modulated discrete pyrene dimers fluorescent sensor for nitroaromatic compounds and latent fingerprints visualization

As a promising class of luminescent materials, π-conjugated organic aromatic molecules are usually subject to aggregation-caused quenching (ACQ) effect, which limits their wide application. Currently, obtaining structurally visualized solid luminescent materials of polycyclic aromatic hydrocarbons (PAHs) without complex synthetic purification steps remains a challenging topic. Herein, we focus on the supramolecular assembly strategy to constructed a solid fluorescent material (HPTS@Q[8]@Rb+) by co-assembling cucurbit[8]uril (Q[8]) with 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) and rubidium ions based on the coordination and outer surface interactions of Q[8]. HPTS@Q[8]@Rb+ exhibited good fluorescence properties with quantum yields of 2.28 % and 73.15 % in solid state and aqueous suspensions, respectively, providing a good sensing platform for nitroaromatic compounds (NACs), especially for 2,4,6-trinitrophenol (PA) and 4-nitroaniline (4-NA) with remarkable quenching constants (KSV=4.06×104 M−1 for PA and KSV=2.95×104 M−1 for 4-NA) in working range of 0–3.33×104 M and 0–5.0×104 M, respectively. Moreover, a fluorescent fingerprint powder was prepared by combining montmorillonite (MMT) for high-resolution visualization of latent fingerprints (LFPs) without substrate limitation. This study demonstrates the synthesis of Q[n]-based fluorescent material, the anion-rich aromatic compounds can be used as potential moieties for assembly with Q[n], providing a facile and promising approach to develop PAHs-based luminescent materials. This supramolecular self-assembly strategy provides a fundamental design principle for the creation of diverse functional crystalline solid materials.

Solid‐Phase‐Supported Chemoenzymatic Synthesis and Analysis of Chondroitin Sulfate Proteoglycan Glycopeptides

AbstractProteoglycans (PGs), consisting of glycosaminoglycans (GAGs) linked with the core protein through a tetrasaccharide linkage region, play roles in many important biological events. The chemical synthesis of PG glycopeptides is extremely challenging. In this work, the enzymes required for synthesis of chondroitin sulfate (CS) PG (CSPG) have been expressed and the suitable sequence of enzymatic reactions has been established. To expedite CSPG synthesis, the peptide acceptor was immobilized on solid phase and the glycan units were directly installed enzymatically onto the peptide. Subsequent enzymatic chain elongation and sulfation led to the successful synthesis of CSPG glycopeptides. The CS dodecasaccharide glycopeptide was the longest homogeneous CS glycopeptide synthesized to date. The enzymatic synthesis was much more efficient than the chemical synthesis of the corresponding CS glycopeptides, which could reduce the total number of synthetic steps by 80 %. The structures of the CS glycopeptides were confirmed by mass spectrometry analysis and NMR studies. In addition, the interactions between the CS glycopeptides and cathepsin G were studied. The sulfation of glycan chain was found to be important for binding with cathepsin G. This efficient chemoenzymatic strategy opens new avenues to investigate the structures and functions of PGs.

Solid-Phase-Supported Chemoenzymatic Synthesis and Analysis of Chondroitin Sulfate Proteoglycan Glycopeptides.

Proteoglycans (PGs), consisting of glycosaminoglycans (GAGs) linked with the core protein through a tetrasaccharide linkage region, play roles in many important biological events. The chemical synthesis of PG glycopeptides is extremely challenging. In this work, the enzymes required for synthesis of chondroitin sulfate (CS) PG (CSPG) have been expressed and the suitable sequence of enzymatic reactions has been established. To expedite CSPG synthesis, the peptide acceptor was immobilized on solid phase and the glycan units were directly installed enzymatically onto the peptide. Subsequent enzymatic chain elongation and sulfation led to the successful synthesis of CSPG glycopeptides. The CS dodecasaccharide glycopeptide was the longest homogeneous CS glycopeptide synthesized to date. The enzymatic synthesis was much more efficient than the chemical synthesis of the corresponding CS glycopeptides, which could reduce the total number of synthetic steps by 80 %. The structures of the CS glycopeptides were confirmed by mass spectrometry analysis and NMR studies. In addition, the interactions between the CS glycopeptides and cathepsin G were studied. The sulfation of glycan chain was found to be important for binding with cathepsin G. This efficient chemoenzymatic strategy opens new avenues to investigate the structures and functions of PGs.

Highly soluble and crossover-free all-organic redox pair using N-heterocycle-linked TEMPO and two-electron-capable bipyridinium towards high performance aqueous flow batteries

Aqueous organic redox flow batteries (AORFBs) are the brilliant technologies for safe and sustainable stationary energy storage. However, the cross-contamination, limited cell voltage, and inferior cycling stability remain challenges. Herein, the N-heterocycle-substituted TEMPO (TMP-TEMPO) and pyrrolidinium-/ammonium-grafted bipyridinium ([PyrTMAV]Cl4) redox pair with multiple charges are designed for high-performance AORFBs. The whole material preparation is relatively simple and only needs two or three synthetic steps. The TMP-TEMPO and [PyrTMAV]Cl4 show high aqueous solubility of 2.4 M and 1.71 M, respectively, excellent electrochemical reversibility, and fast redox kinetics. Notably, the introduction of multiple charges into the active materials can produce a strong Gibbs-Donnan effect with ion exchange membranes, thus preventing the permeability of molecules through the membrane and avoiding the cross-contamination of active molecules. By using the crossover-free TMP-TEMPO and two-electron [PyrTMAV]Cl4 redox pair, the assembled two-electron AORFBs at an electron concentration of 0.2 M exhibit stable battery performancein environments with O2 contents of both 10 ppm and 100 ppm with a capacity retention of over 99 % per day for hundreds of cycles (268 and 310 cycles), and a high energy efficiency of ∼89 % and Coulombic efficiency of ∼100 %. Furthermore, the AORFB achieves a high capacity of ∼37.4 Ah L−1 at an ultra-high electron concentration of 1.5 M, while maintaining a capacity retention rate of ∼99.7 % over 138 cycles and a theoretical capacity utilization rate of 93 %. The versatile molecular design for TMP-TEMPO and [PyrTMAV]Cl4 can be easily extended to the synthesis of various amino-functionalized TEMPO and asymmetric bipyridinium derivatives.

Endogenous Group‐Directed Late‐Stage C−H Functionalization of Peptides

AbstractPeptides are diverse in terms of their functional groups and side‐chain functionalities, and late‐stage C−H functionalization plays a crucial role in their design. Approaches for such synthesis require pre‐installation and post‐removal of the directing group (DG). In recent times, chemical methods have been developed, focusing on the external DG‐free C−H functionalization of peptides. These approaches utilize the inherent native functionality of peptides as DG to simplify synthetic routes, reducing synthetic steps, waste generation, enhancing sustainability, cost‐effectiveness, and operational flexibility. Such approaches facilitate late‐stage C−H functionalization of both natural and unnatural amino acid‐containing peptides.

Expanding Color Control of Anodically Coloring Electrochromes Based on Electron-Rich 1,4-Dihydropyrrolo[3,2-b]pyrroles.

Anodically coloring electrochromes have received attention in recent years as high-contrast alternatives to cathodically coloring electrochromes due to their superior optical contrast during electrochemical switching. While current systems represent significant progress for organic electrochromics, it is necessary to expand the structural diversity of these materials while simultaneously reducing the hazards associated with synthetic protocols. With these considerations in mind, a family of 1,4-dihydropyrrolo[3,2-b]pyrrole (DHPP) chromophores with varying functionalities along the 2,5-axis was envisioned to accomplish these goals. After predicting different absorbance traits as oxidized molecules with time-dependent density functional theory, DHPP chromophores with varying peripheral functionalities were synthesized in a single aerobic synthetic step via an iron-catalyzed multicomponent reaction and characterized as high-contrast chromophores. In solution, the DHPP chromophores absorb in the ultraviolet region of the electromagnetic spectrum, resulting in color-neutral L*a*b* color coordinates of ∼100, 0, 0. Upon chemical oxidation, each molecule transitions to absorb at various points across the visible spectrum based on the extent of electron-donating ability and can display five distinct colors. Importantly, the chromophores are redox-active and display switching capabilities with an applied electrochemical potential. In conjunction with building fundamental insights into molecular design of DHPP chromophores, the results and synthetic simplicity of DHPPs make them compelling materials for color-controlled high-contrast electrochromes.

Green Approach Toward Triazole Forming Reactions for Developing Anticancer Drugs.

Compounds containing triazole have many significant applications in the dye and ink industry, corrosion inhibitors, polymers, and pharmaceutical industries. These compounds possess many antimicrobial, antioxidant, anticancer, antiviral, anti-HIV, antitubercular, and anticancer activities. Several synthetic methods have been reported for reducing time, minimizing synthetic steps, and utilizing less hazardous and toxic solvents and reagents to improve the yield of triazoles and their analogues synthesis. Among the improvement in methods, green approaches towards triazole forming biologically active compounds, especially anticancer compounds, would be very important for pharmaceutical industries as well as global research community. In this article, we have reviewed the last five years of green chemistry approaches on click reaction between alkyl azide and alkynes to install 1,2,3-triazole moiety in natural products and synthetic drug-like molecules, such as in colchicine, flavanone cardanol, bisphosphonates, thiabendazoles, piperazine, prostanoid, flavonoid, quinoxalines, C-azanucleoside, dibenzylamine, and aryl-azotriazole. The cytotoxicity of triazole hybrid analogues was evaluated against a panel of cancer cell lines, including multidrug-resistant cell lines.

Organic Electrosynthesis: A Promising Green Tool in Solving Key Steps for the Total Synthesis of Complex Natural Products

Abstract: Electro-organic synthesis, an atom-efficient, sustainable, mild process, permits an ecofriendly and elegant green path to synthesize structurally complex, still valuable molecules, avoiding the use of conventional harsh oxidizing and reducing agents and long-route reaction protocols. Being one of the oldest forms of reaction setups in a laboratory, it deals with fundamental redox chemistry through the direct application of electrical potential. Here flow of electrons acts as an oxidizing agent at the anode at the same time reducing agent at the cathode, depending upon the requirement of the reaction. Simultaneously, it minimizes the generation of reagent waste during the reaction. However, electrifying organic synthesis plays more than preventing the waste footprint. This technology provides an alternative roadmap through nonclassical bond disconnections to access desired target molecules by cutting down a number of steps with the formation of apparently looking difficult bonds with excellent regio-, chemo-and stereoselectivity. Hence, it emerges as an alternative and attractive technique for the contemporary synthetic communities. Consequently, in recent years, multiple milestones have been achieved in the electro-organic synthesis of fascinating natural products through oxidative C-C bond formation, C-H/N-H functionalization, very rare oxidative N-N dimerization, RCDA dimerization, etc. Thus, synthesis of extremely complex natural products through finding new electro-synthetic route as a key methodology have become one of the alluring synthetic targets to synthetic chemists because of their versatile utilities in medicine, agriculture, food, and cosmetic industry. This review presents advances in electrochemistry in the total synthesis of 20 complex natural products reported since 2013. Enabling synthetic steps are analyzed alongside innate advantages as well as future prospects are speculated.

Mechanochemical and Microwave Multistep Organic Reactions

Abstract: The development of more sustainable chemical reactions and processes has been the focus of recent research activities. Advances in the field of organic synthesis have led to the emergence of new methodologies and techniques involving non-conventional energy sources. These include the applications of mechanical energy (mechanochemistry) and microwave radiation (MW) methods. This article reviews the advances in multistep organic synthesis of biologically relevant organic molecules using mechanochemistry and microwave techniques. Among them, various heterocyclic molecules (with nitrogen, oxygen, and sulphur atoms), amides, and peptides have been synthesized by multistep mechanochemical or MW reactions. Performing multiple synthetic steps using more sustainable methods shows cumulative advantages over multistep processes under conventional conditions in terms of reduced solvent use, shorter reaction times, better turnovers, and reaction yields. Simplification of protocols by carrying out two or more reaction steps in the same reaction vessel is another advantage of multistep syntheses.

Phenothiazine Embedded Dithiasmaragdyrins.

Two different types of novel phenothiazine-embedded dithiasmaragdyrins containing one phenothiazine ring, two thiophene rings and two pyrrole rings connected via three meso carbons and two direct bonds in the macrocyclic framework were synthesized over the sequence of synthetic steps starting with phenothiazine. Three examples of phenothiazine-embedded dithiasmaragdyrins were synthesized by condensing appropriate phenothiazine-based pentapyrrane with pentafluorobenzaldehyde and two examples of phenothiazine sulfone embedded dithiasmaragdyrins were synthesized by condensing phenothiazine-based diol with appropriate meso-aryl dipyrromethane under mild acid-catalysed conditions. 1D&2D NMR studies revealed that the thiophene rings adopted inverted orientation in phenothiazine sulfone embedded dithiasmaragdyrins whereas in phenothiazine-embedded dithiasmaragdyrins, the thiophene rings were in normal orientation. Both types of macrocycles exhibit nonaromatic absorption features and showed panchochromic absorption features in its neutral and protonated forms. The electrochemical studies indicated that the phenothiazine-embedded dithiasmaragdyrins were more electron-rich compared to phenothiazine sulfone embedded dithiasmaragdyrins. DFT studies revealed that both types of dithiasmaragdyrins exhibit significantly distorted structures and TD-DFT studies support the experimental observations.

Light Induced Cobalt(III) Carbene Radical Formation from Dimethyl Malonate As Carbene Precursor.

Radical-type carbene transfer catalysis is an efficient method for the direct functionalization of C-H and C=C bonds. However, carbene radical complexes are currently formed via high-energy carbene precursors, such as diazo compounds or iodonium ylides. Many of these carbene precursors require additional synthetic steps, have an explosive nature, or generate halogenated waste. Consequently, the utilization of carbene radical catalysis is limited by specific carbene precursors that access the carbene radical intermediate. In this study, we generate a cobalt(III) carbene radical complex from dimethyl malonate, which is commercially available and bench-stable. EPR and NMR spectroscopy were used to identify the intermediates and showed that the cobalt(III) carbene radical complex is formed upon light irradiation. In the presence of styrene, carbene transfer occurred, forming cyclopropane as the product. With this photochemical method, we demonstrate that dimethyl malonate can be used as an alternative carbene precursor in the formation of a cobalt(III) carbene radical complex.

Efficient Catalyst-Free One-Pot Synthesis of Polysaccharide-Polypeptide Hydrogels in Aqueous Solution.

The preparation of polysaccharide-peptide hydrogels usually involves multiple synthetic steps, thus reducing the effectiveness and practicality of these approaches. Inspired by recent discoveries in aqueous N-carboxyanhydride (NCA) ring-opening polymerization (ROP) and ring-opening polymerization-induced nanogelation, we present an aqueous one-pot strategy to prepare polysaccharide-polypeptide hydrogels. In this study, water-soluble polysaccharide carboxymethyl chitosan is used as the macromolecular initiator to prepare polysaccharide-polypeptide copolymers through the aqueous ROP of NCA. The catalyst-free approach afforded hydrogels with properties that could be controlled by adjusting the type and amount of NCA used, with the elastic modulus ranging from 50 Pa to 18000 Pa. The hydrogen bond-cross-linked hydrogel exhibited self-healing and injectable properties. Morphology characterization revealed that micelles were formed in the early stage of reaction, suggesting that the polymerization follows an aqueous ring-opening polymerization-induced self-assembly (ROPISA) mechanism and that aggregation of micelles during the reaction caused the gelation. Moreover, the hydrogels displayed high swelling ratios (>95% water content), and hemolysis and cytotoxicity experiments demonstrated that the hydrogels had excellent biocompatibility, indicating their potential in medical applications.

Triflic Acid-Assisted Regioselective Bromination of Quinoxaline Derivatives Enables a Facile Synthesis of Polymer PTQ10.

Poly[(thiophene)-alt-(6,7-difluoro-2(2-hexyldecyloxy)quinoxaline)] (PTQ10) emerges as a promising candidate for donor materials in organic solar cells (OSCs) due to its high efficiency, simplified synthesis, and cost-effectiveness. The acceptor unit of PTQ10 is derived from the alkylation of 5,8-dibromo-6,7-difluoroquinoxaline-2-ol, emphasizing the importance of its economical synthesis for commercial viability. This study investigates triflic acid-assisted regioselective bromination of quinoxaline derivatives and proposes an alternative synthetic pathway for PTQ10. The developed route benefits from concise synthetic steps, a dependable procedure, and high overall yield. Starting with the condensation of 4,5-difluorobenzene-1,2-diamine with ethyl oxoacetate to yield 6,7-difluoroquinoxaline-2-ol, subsequent triflic acid-assisted regioselective bromination produces 5,8-dibromo-6,7-difluoroquinoxaline-2-ol in high yield. Alkylation under Mitsunobu reaction conditions yields 5,8-dibromo-6,7-difluoro-2-(2-hexyldecyloxy)quinoxaline, followed by polymerization with 2,5-distannylated thiophene under Stille reaction conditions to afford PTQ10. This research provides insights into efficient synthetic strategies for PTQ10, advancing its potential for commercial application in OSCs.