Condensation Reagent Research Articles

One-Step Synthesis of Sugar Nucleotides.

The chemical synthesis of sugar nucleotides requires a multistep procedure to ensure a selective reaction. Herein, sugar nucleotides were synthesized in one step using 2-chloro-1,3-dimethylimidazolinium chloride as the condensation reagent. The products were obtained in yields of 12-30%, and the yields were increased to 35-47% by the addition of a tuning reagent. NMR identification of the sugar nucleotides showed that mainly 1,2-trans-glycosides were present. The reported method represents a one-step route to sugar nucleotides from commercially available materials.

Development of Hydrophilic Polyacrylamide Gel-Based Condensing Reagents Comprised of Chlorotriazine.

Hydrophilic polyacrylamide gel-based triazine-type condensing reagents, PAG-Trz-Cl, have been developed. PAG-Trz-Cls were synthesized using a chlorotriazine with an acrylamide moiety, acrylamide, and N,N'-methylenebisacrylamide via both precipitation and solution polymerization. Because PAG-Trz-Cls adequately swell in aqueous media, the amidation between polar carboxylic acids and amines afforded the corresponding amides in good yields.

A triple-combination nanotechnology platform based on multifunctional RNA hydrogel for lung cancer therapy

Conventional cancer combination therapy usually involves systemic delivery of anticancer drugs which may lead to the destruction of normal cells and physiological toxicity due to the lack of targeting ability and toxicity of drug carriers. In the present study, a triple combination nanosystem of gene therapy, chemotherapy and phototherapy delivered by multifunctional RNA nanohydrogels (RNA NHs) was established. By taking the advantages of DNA nanotechnology and rolling circle transcription (RCT), three lung cancer inhibitor microRNA (let-7a, microRNA 34a, microRNA 145) hairpins were integrated in one RNA NH nanoparticle, leading to the simultaneous silencing of three targeted mRNAs. Meanwhile, RNA NH carried doxorubicin (DOX, a chemotherapy drug) as well as 5,10,15,20-tetrakis (1-methylpyridinium-4-yl) porphyrin (TMPyP4, a photosensitizer) and delivered these drugs to cancer cells. It was demonstrated that lung cancer inhibitor microRNAs integrated in RNA NHs, DOX and TMPyP4 could play a synergistic anti-cancer role in multi-drug resistance cancer cells. Under the action of aptamer sequence S6 that was modified with cholesterol, the resulting RNA NHs were condensed to feasible size without the assistance of polyelectrolyte condensation reagents and showed cancer-specific cellular targeting. Subsequently, thousands of copies of miRNA together with chemotherapy drug as well as photosensitizer were delivered to cancer cells specifically, and an ideal synergistic treatment effect was achieved in vivo, thus playing a combined role of gene therapy, chemotherapy and phototherapy. Through this study, it can be concluded that the triple combination therapy nanosystem can overcome the multidrug resistance caused by the malfunction of genes in chemotherapy and shows a great potential in the field of multifunctional synergistic cancer treatment.

First Total Synthesis of Neostrictinin

Herein, we describe the first total synthesis of neostrictinin, a natural ellagitannin bearing a (R)‐hexahydroxydiphenoyl (HHDP) bridge between the 4‐ and 6‐oxygens of d‐glucose. Among the multitude of 4,6‐O‐HHDP bridged ellagitannins, (R)‐axial chirality of the HHDP bridge is quite rare as it is less stable than the corresponding (S)‐isomer. The labile bridge was constructed using a two‐step bislactonization that involved: (1) monoacylation of the primary alcohol of ethyl 2,3‐O‐benzyl‐1‐thio‐β‐d‐glucopyranoside using protected (R)‐hexahydroxydiphenic anhydride and (2) intramolecular lactonization of the obtained seco acid by treatment with a Mukaiyama condensation reagent (2‐chloro‐N‐methylpyridinium iodide) and 2,6‐lutidine. Structural confirmation of the synthesized neostrictinin and the preparation of its epimer are also reported.

Trizaine-based dehydrative condensation reagents bearing carbon-substituents

Herein, we report on the synthesis of alkyl-, aryl-, and alkynyl-substituted chlorotriazines and their ammonium salts, and demonstrate their utility in dehydrative condensation reactions. Although the electrophilicity of these reagents is mainly dependent on the hybridization of the carbon-substituents, it was found that bulky 2,6-dimethylphenyl group-substituted reagents resulted in the highest product yields because of a slight increase in reagent electrophilicity and/or steric hindrance favorable for desired dehydrative condensation reactions.

Development of Triazinone-Based Condensing Reagents for Amide Formation

Novel triazinone-based condensing reagents have been developed. The palladium-catalyzed O-N allylic rearrangement of 2-(allyloxy)-4,6-dichloro-1,3,5-triazine and subsequent regioselective substitution using alcohols and an amine afforded chlorotriazinones, which can be readily converted using N-methylmorpholine into the corresponding condensing reagents. The condensation of carboxylic acids and amines using these reagents proceeded to afford the desired amides in good yields. In comparison with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride, the newly synthesized triazinone-based condensing reagents exhibited higher reactivity.

Moldable Material from ε-Poly-l-lysine and Lignosulfonate: Mechanical and Self-Healing Properties of a Bio-Based Polyelectrolyte Complex.

A moldable material from a natural cationic polyelectrolyte, ε-poly-l-lysine (ε-PL), was prepared by mixing with two lignosulfonates a reagent for research (L-SO3Na) and a commercially available purified lignosulfonate (Pearllex NP). The obtained ε-PL/lignosulfonate complexes demonstrated the ability to be tuned from a rigid form, such as polystyrene or poly(methyl methacrylate), to a soft elastomer form such as silicone by varying the lignosulfonate species and composition. The maximum toughness of the complex (8.4 MJ/m3) was superior to that of ε-PL or lignosulfonate-derived polyelectrolyte complexes. In addition, the ε-PL/lignosulfonate complex showed self-healing properties due to the many reversible ionic bonds in the complex. The preparation process for the novel complex was simple, involving the mixing and drying of an aqueous solution of the polyelectrolyte without any extra reagents (organic solvents, condensation reagents, and cross-linker). Thus, given these many advantages and the excellent biodegradability of the components, the ε-PL/lignosulfonate complex is expected to be useful as a sustainable structural material.

Synthesis of Piperidines via Intramolecular Hydride Transfer from α‐Amino sp3 Carbon Atoms to Ethenetricarboxylate‐Derived Fragments and Further Cyclization

AbstractThe cyclization of amides derived from ethenetricarboxylic acid bearing tert‐amino groups has been examined. The amides were efficiently converted to piperidine derivatives (2‐piperidones) upon heating in a polar solvent (e. g., DMSO or DMF) via intramolecular hydride transfer and subsequent ring closure. The reaction was less efficient in the presence of a Lewis acid. The reactivity varies depending on the alkyl substituents of tert‐amino groups, probably due to steric effects. The hydride transfer/cyclization mechanism was investigated by DFT calculations. The reaction of the carboxylic acid and relatively bulky diamines such as diisopropyl‐substituted diamine in the presence of amide condensation reagents at 60 °C gave the piperidine derivatives in a one‐pot reaction. The reaction of the diisopropylamine substituted piperidine product with primary amines gave secondary amine‐substituted piperidines.

Solid-Phase Synthesis of Oligopeptides Containing Sterically Hindered Amino Acids on Nonswellable Resin Using 3-Nitro-1,2,4-triazol-1-yl-tris(pyrrolidin-1-yl)phosphonium Hexafluorophosphate (PyNTP) as the Condensing Reagent.

Peptides are still difficult to synthesize when they contain sterically hindered amino acids, such as α,α-disubstituted amino acids and N-substituted amino acids. In this study, solid-phase syntheses of oligopeptides containing multiple α-aminoisobutyric acid (Aib) residues were performed in high yields by using a nonswellable resin as the solid-support and 3-nitro-1,2,4-triazol-1-yl-tris(pyrrolidin-1-yl)phosphonium hexafluorophosphate (PyNTP) as the condensing reagent.

Retraction of "Asymmetric Synthesis of Apratoxin E".

An efficient method for asymmetric synthesis of apratoxin E 2 is described in this report. The chiral lactone 8, recycled from the degradation of saponin glycosides, was utilized to prepare the non-peptide fragment 6. In addition to this “from nature to nature” strategy, olefin cross-metathesis (CM) was applied as an alternative approach for the formation of the double bond. Moreover, pentafluorophenyl diphenylphosphinate was found to be an efficient condensation reagent for the macrocyclization.

π-conjugated naphthodithiophene homopolymers bearing alkyl/alkylthio-thienyl substituents: facile synthesis using hexamethylditin and their charge-transport and photovoltaic properties

Two π-conjugated naphtho[1,2-b:5,6-b']dithiophene (NDT)-based homopolymers functionalized with alkyl-thienyl or alkylthio-thienyl side chains were designed and synthesized via palladium-catalyzed dehalogenative polycondensation using hexamethylditin as the condensation reagent. Their photophysical properties and device performances for organic field-effect transistors and organic solar cells were systematically studied. Replacing lateral alkyl-thienyl substituents with alkylthio-thienyl ones led to better photoabsorption properties and a deeper-lying HOMO energy level of the resulting NDT homopolymers. The alkylthio-thienyl-functionalized NDT homopolymer showed a higher hole mobility and superior photovoltaic properties compared with the alkyl-thienyl homolog. Two new π-conjugated naphtho[1,2-b:5,6-b']dithiophene (NDT)-based homopolymers functionalized with alkyl-thienyl or alkylthio-thienyl side chains were synthesized and characterized. To simplify the synthetic route, we performed the palladium-catalyzed dehalogenative polycondensation using hexamethylditin as the condensation reagent. The alkylthio-thienyl-functionalized NDT-based homopolymer exhibited a higher hole mobility in organic field-effect transistors (OFETs) and higher power conversion efficiency in organic solar cells (OSCs), compared to alkyl-thienyl-functionalized one.

Asymmetric Synthesis of Apratoxin E

An efficient method for asymmetric synthesis of apratoxin E 2 is described in this report. The chiral lactone 8, recycled from the degradation of saponin glycosides, was utilized to prepare the non-peptide fragment 6. In addition to this "from nature to nature" strategy, olefin cross-metathesis (CM) was applied as an alternative approach for the formation of the double bond. Moreover, pentafluorophenyl diphenylphosphinate was found to be an efficient condensation reagent for the macrocyclization.

A RNA nanotechnology platform for a simultaneous two-in-one siRNA delivery and its application in synergistic RNAi therapy.

Incorporating multiple copies of two RNAi molecules into a single nanostructure in a precisely controlled manner can provide an efficient delivery tool to regulate multiple gene pathways in the relation of mutual dependence. Here, we show a RNA nanotechnology platform for a two-in-one RNAi delivery system to contain polymeric two RNAi molecules within the same RNA nanoparticles, without the aid of polyelectrolyte condensation reagents. As our RNA nanoparticles lead to the simultaneous silencing of two targeted mRNAs, of which biological functions are highly interdependent, combination therapy for multi-drug resistance cancer cells, which was studied as a specific application of our two-in-one RNAi delivery system, demonstrates the efficient synergistic effects for cancer therapy. Therefore, this RNA nanoparticles approach has an efficient tool for a simultaneous co-delivery of RNAi molecules in the RNAi-based biomedical applications, and our current studies present an efficient strategy to overcome multi-drug resistance caused by malfunction of genes in chemotherapy.

ChemInform Abstract: Synthetic Study on the T3P®‐Promoted One‐Pot Preparation of 1‐Substituted‐3,4‐dihydro‐β‐carbolines by the Reaction of Tryptamine with Carboxylic Acids.

AbstractA one‐pot procedure for the synthesis of 1‐substituted‐3,4‐dihydro‐β‐carbolines from tryptamine and the corresponding aliphatic and (hetero)aromatic carboxylic acids using T3P as the condensation reagent is reported.

Asymmetric synthesis of emericellamide B

Asymmetric total synthesis of emericellamide B (9.4%, 17 longest linear steps) is detailed in this report. In this synthetic route, the highly methylated (2R,3R,4S,6S)-3-hydroxy-2,4,6-trimethyldodecanoic acid (HTMD) unit was effectively prepared through the asymmetric methylation, Wittig and Horner–Wadsworth–Emmons reaction. Moreover, pentafluorophenyl diphenylphophinate (FDPP) proved to be an effective condensation reagent for the macrolactamization between C14 and C18.

Synthesis of a A2B3-type Hyperbranched Copolymers Based on a 3-Armed Unimolecular 4-N-Methylbenzamide Pentamer and Poly(propylene oxide)

Abstract A novel hyperbranched copolymer (HBCP), with a number-average molecular weight from 11000 to 25000, was successfully prepared by the direct condensation polymerization of a unimolecular 3-armed 4-N-methylbenzamide pentamer (TMA-3MAB5) as a hard segment (B3 monomer), with amine-functionalized poly(propylene oxide) (PPOx) (x: degree of polymerization, 32 or 64) (A2 monomer) at both ends as a soft segment, and investigated its possibility as a thermoplastic elastomer. The highly pure B3 molecule, TMA-3MAB5, was quantitatively obtained by the step-growth reaction of 4-(N-methylamino)benzoic acid (MAB) using thionyl chloride as the condensation reagent and trimesic acid (TMA) as the core molecule in N-methylpyrrolidone (NMP) at 20 °C for 0.5 h for each step. The HBCP showed two glass transitions corresponding to imperfectly segregated PPO-rich and polybenzamide hard segment-rich domains, and the film showed good mechanical properties (Young’s Modulus TM 0.25–4.0 MPa, elongation at break EB 133–1470%), which were controlled by the fraction of the hard segment.

Preparation of Photocrosslinked Fish Elastin Polypeptide/Microfibrillated Cellulose Composite Gels with Elastic Properties for Biomaterial Applications

Photocrosslinked hydrogels reinforced by microfibrillated cellulose (MFC) were prepared from a methacrylate-functionalized fish elastin polypeptide and MFC dispersed in dimethylsulfoxide (DMSO). First, a water-soluble elastin peptide with a molecular weight of ca. 500 g/mol from the fish bulbus arteriosus was polymerized by N,N′-dicyclohexylcarbodiimide (DCC), a condensation reagent, and then modified with 2-isocyanatoethyl methacrylate (MOI) to yield a photocrosslinkable fish elastin polypeptide. The product was dissolved in DMSO and irradiated with UV light in the presence of a radical photoinitiator. We obtained hydrogels successfully by substitution of DMSO with water. The composite gel with MFC was prepared by UV irradiation of the photocrosslinkable elastin polypeptide mixed with dispersed MFC in DMSO, followed by substitution of DMSO with water. The tensile test of the composite gels revealed that the addition of MFC improved the tensile properties, and the shape of the stress–strain curve of the composite gel became more similar to the typical shape of an elastic material with an increase of MFC content. The rheology measurement showed that the elastic modulus of the composite gel increased with an increase of MFC content. The cell proliferation test on the composite gel showed no toxicity.

非共平面的に芳香環が集積した分子群に関する特異な反応挙動の解析とその空間構造の特徴解明

The polyaromatic ketone compounds having non-coplanarly aromatic-ring-accumulated structure have been studied from the viewpoint of uniqueness and specificity in reaction behavior and characteristics in spatial organization. Synthesis of 1-aroylated and 1,8-diaroylated derivatives of 2,7-dimethoxynaphthalene was successfully performed by the action of arenecarboxylic acids or their chlorides with the aid of adequate acidic mediator: Lewis/Brønsted acid or direct condensation reagent. The aroylation shows distinct dependence on acidic mediator employed. The product distribution among 1-aroyl-, 1,8-diaroyl-, and 3-aroylnaphthalenes is strongly affected by the kind of acidic mediator. With the aid of the monitoring of the time-course of the product distribution, interconversion from the 1-aroylated- and 1,8-diaroylated derivatives to the 3-aroylated one is revealed. These reaction behaviors including acid-strength-dependent reversibility are well interpreted from the nature of highly congested non-coplanar geometry of the polyaromatic ketone products. By the separate reaction of the isolated aryl-aryl ketones, the acid-mediated retro-aroylation of aromatic ketone molecules is confirmed. Moreover, the aroylated 2,7-dimethoxynaphthalene homologues/analogues show susceptible ether scission of the methyl ether moiety adjacent to aroyl substituents. These unique and specific reaction behavior compared to conventional aromatic ketones and aromatic methyl ether is interpreted due to the non-coplanarly situated carbonyl group of the aroyl moieties against naphthalene ring with essentially perpendicular situation. The spatial organization of these compounds has been investigated with expectation of useful information for clarification of reactivity-structure relationship analysis and elucidation of structure determining factors. On the basis of the X-ray crystal structure analysis of about 80 homologous/analogous compounds and NMR spectroscopic study including variable temperature measurement, both the protocols of determination of single molecular and packing structures in crystal and analysis of bond rotation behavior in solution were undertaken. The structure characteristics about symmetric nature of the single molecule, stabilizing intermolecular interaction, and alignment of molecules in crystal and the rotation capability of the bonds in solution were discussed to clarify the determining factors for spatial organization and reaction behavior of the non-coplanarly aromatic-ring-accumulated compounds and to design the molecular materials having such type of spatial organization in the future.

Development of Photo-Controlled Molecular Shuttle Utilizing ATP Driven Motor Kinesin

The ATP driven motor kinesin has many possibilities for the application to the molecular machines. Previously, we introduced photochromic molecules into the functional key region of the kinesin as a photo-switch and tried to control the function of kinesin by ultraviolet (UV) and visible (VIS) light irradiations. The kinesin mutant S275C modified with thiol reactive azobenzene derivative exhibited photo-controlled ATPase activity correlating to photo isomerization of photochromic molecules.In this study, we tried to prepare the photo-controlled molecular shuttles using kinesin and liposome modified with photochromic molecule.We prepared the kinesin motor domain (K355) mutant that has a single cysteine at neck linker region and His-tag at C-terminal. Subsequently the kinesin mutant was dimerized with photochromic bifunctional cross-linker, azobenzene dimaleimide (ABDM). And the photo-reversible regulation of the ATPase and motor activities of the kinesin dimer cross-linked with ABDM was studied.We also tried to develop photo-responsive vesicle composed of photochromic molecules as a cargo for the photo-controlled kinesin. Diacyl glycerol was coupled with carboxypropyl-spiropyran to be phospholipid analogue using carbonyldiimidazole condensation reagent. The spiropyran moiety performs photo-reversible isomerization between hydrophobic spiro form and merocyanine zwitterion form upon visible light and ultraviolet light, respectively. Therefore, it is expected that the merocyanine form of the mimic phospholipid results in formation liposome like vesicle. The photo-reversible formation of the vesicle was studied using water-soluble fluorescent probe.

Liquid chromatography/tandem mass spectrometry with fluorous derivatization method for selective analysis of sialyl oligosaccharides.

A separation-oriented derivatization method using a specific fluorous affinity between perfluoroalkyl-containing compounds was applied to selective liquid chromatography/tandem mass spectrometric (LC/MS/MS) analysis of sialyl oligosaccharides. The perfluoroalkyl-labeled sialyl oligosaccharides could be selectively retained on an LC column with the perfluoroalkyl-modified stationary phase and effectively distinguished from non-derivatized species. Sialyl oligosaccharides (3'-sialyllactose, 6'-sialyllactose, sialyllacto-N-tetraose a, sialyllacto-N-tetraose b, sialyllacto-N-tetraose c, and disialyllacto-N-tetraose) were derivatized with 4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoroundecylamine via amidation in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (condensation reagent). The obtained derivatives were directly injected onto the fluorous LC column without any pretreatments and then detected by positive electrospray ionization MS/MS. The method enabled accurate determination of the sialyl oligosaccharides in biological samples such as human urine and human milk, because there was no interference with matrix-induced effects during LC/MS/MS analysis. The limits of detection of the examined sialyl oligosaccharides, defined as signal-to-noise (S/N) = 3, were in the range 0.033-0.13 nM. Accuracy in the range 95.6-108% was achieved, and the precision (relative standard deviation) was within 9.4%. This method enabled highly selective and sensitive analysis of sialyl oligosaccharides, enabling accurate measurement of even their trace amounts in biological matrices. The proposed method may prove to be a powerful tool for the analysis of various sialyl oligosaccharides.