Sequential Ring Opening Research Articles

Development of Fully Degradable Phosphonium-Functionalized Amphiphilic Diblock Copolymers for Nucleic Acids Delivery.

To expand the range of functional polymer materials to include fully hydrolytically degradable systems that bear bioinspired phosphorus-containing linkages both along the backbone and as cationic side chain moieties for packaging and delivery of nucleic acids, phosphonium-functionalized polyphosphoester-block-poly(l-lactide) copolymers of various compositions were synthesized, fully characterized, and their self-assembly into nanoparticles were studied. First, an alkyne-functionalized polyphosphoester-block-poly(l-lactide) copolymer was synthesized via a one pot sequential ring opening polymerization of an alkyne-functionalized phospholane monomer, followed by the addition of l-lactide to grow the second block. Second, the alkynyl side groups of the polyphosphoester block were functionalized via photoinitiated thiol–yne radical addition of a phosphonium-functionalized free thiol. The polymers of varying phosphonium substitution degrees were self-assembled in aqueous buffers to afford formation of well-defined core–shell assemblies with an average size ranging between 30 and 50 nm, as determined by dynamic light scattering. Intracellular delivery of the nanoparticles and their effects on cell viability and capability at enhancing transfection efficiency of nucleic acids (e.g., siRNA) were investigated. Cell viability assays demonstrated limited toxicity of the assembly to RAW 264.7 mouse macrophages, except at high polymer concentrations, where the polymer of high degree of phosphonium functionalization induced relatively higher cytotoxicity. Transfection efficiency was strongly affected by the phosphonium-to-phosphate (P+/P–) ratios of the polymers and siRNA, respectively. The AllStars Hs Cell Death siRNA complexed to the various copolymers at a P+/P– ratio of 10:1 induced comparable cell death to Lipofectamine. These fully degradable nanoparticles might provide biocompatible nanocarriers for therapeutic nucleic acid delivery.

Construction of 4‐Isochromanones through Cu(OTf)2‐Catalysed Sequential C=O and C–O Bond Formation

A new strategy for the facile and efficient synthesis of 4‐isochromanones has been developed. The reaction involves a Cu(OTf)2‐catalysed sequential reaction of epoxides carrying electron‐deficient alkenes using the solvent DMSO as the oxidant. The single‐step process involves a sequential oxidative ring opening of epoxides and an oxa‐Michael addition where one new C=O bond and one new C–O bond are created. The advantages of this approach include high efficiency, a broad substrate scope, and mild conditions.

Biodegradable silica rubber core-shell nanoparticles and their stereocomplex for efficient PLA toughening

In the effort to overcome the shortcomings such as brittleness and poor mechanical stability, and increase the competitive edge of renewable poly(lactic acid) PLA over conventional petroleum-based thermoplastics, silica rubber core-shell nanoparticles for effective PLA toughening were successfully synthesized by sequential ring opening polymerization (ROP). The core-shell structure was designed with silica as inner core, P(CL-mLA) as ‘rubber’ middle layer and terminal PDLA chains (SiO2-r-PDLA), to facilitate the stereocomplex formation with PLLA matrix for enhanced interface control. The PLLA/SiO2-r-PDLA nanocomposites were fabricated through solution blending-injection molding process. Nuclear magnetic resonance (1H NMR and 13C NMR) results confirmed the presence of grafted ’rubber’ and PDLA chains from the surface of silica particle. In addition, PLLA/SiO2-r-PDLA nanocomposites showed tremendous improvement in thermal and mechanical properties using differential scanning calorimetry (DSC) and tensile testing, respectively. Besides the formation of stereocomplex in the nanocomposites, a detailed study on the melt stability of these stereocomplex nanocomposites revealed a ‘memorized’ stereocomplex behavior, i.e., having the ability to perfectly reassemble after re-crystallization from melt (melt memory effect), when rubber segment is present. Finally, structure-deformation mechanisms were studied using scanning electron microscopy (SEM) and small angle x-ray scattering (SAXS). From SAXS, crazing was clearly observed whereas SEM revealed fibrillated structures. Thus, crazing and fibrillation are the key deformation mechanisms in PLLA/SiO2-r-PDLA system. The exciting new fillers could open up new horizons for PLA advanced composites applications.

Zeolite-catalyzed Transformation of Glucose: A Review

Background: Isomerization of glucose to fructose is recognized as one of the key reactions for the transformation of cellulosic biomass, a potent substitution for the depleting petroleum resources. Zeolites are among the most useful catalysts for the isomerization process and substantial achievements have been achieved thus far. A state-of-the-art review is given within this content, and catalytic mechanisms and competitive reactions are discussed as well. Methods: We performed a comprehensive search of literatures and the qualities of retrieved papers were appraised using standard tools. Literatures that represent the substantial findings are highlighted reflecting the progresses made with regard to the isomerization of glucose to fructose catalyzed by zeolites. Results: Substantial achievements have been made with regard to the zeolite-catalyzed isomerization of glucose to fructose. The joint experimental-computational studies provide insightful clues to reaction mechanisms; e.g., the isomerization reaction proceeds in sequence of pyranose ring opening, hydride shift from C2 to C1 (rate-decisive) and furanose ring closure while the epimerization reaction is characterized by the intramolecular 1,2-carbon shift; Both of the defects SnOH and proximate silanol promote significantly the isomerization reaction while proximate silanol disfavors the epimerization reaction. Conclusion: On basis of the fruitful catalytic results obtained thus far, two outlets are put forward that should be given priority with regard to the utilization of cellulosic biomass, as the combination of the isomerization reaction with other catalytic processes and the exploitation of the direct transformation of cellulosic biomass to platform chemicals. Keywords: Cellulosic biomass, Lewis acidic zeolites, catalysis, isomerization, reaction mechanism, transformation.

A Boron Protecting Group Strategy for 1,2-Azaborines

Upon reaction with either molecular oxygen or di-tert-butylperoxide in the presence of a simple copper(I) salt and an alcohol, a range of 1,2-azaborines readily exchange B-alkyl or B-aryl moieties for B-alkoxide fragments. This transformation allows alkyl and aryl groups to serve for the first time as removable protecting groups for the boron position of 1,2-azaborines during reactions that are not compatible with the easily modifiable B-alkoxide moiety. This reaction can be applied to synthesize a previously inaccessible BN isostere of ethylbenzene, a compound of interest in biomedical research. A sequence of epoxide ring opening using N-deprotonated 1,2-azaborines followed by an intramolecular version of the boron deprotection reaction can be applied to access the first examples of BN isosteres of dihydrobenzofurans and benzofurans, classes of compounds that are important to medicinal chemistry and natural product synthesis.

Expedient Synthesis of 1,5-Diketones by Rhodium-Catalyzed Hydroacylation Enabled by C-C Bond Cleavage.

A rhodium-catalyzed intermolecular hydroacylation reaction of vinyl cyclobutanols with non-chelating aldehydes has been developed. This reaction offers a new and atom-economical approach for the selective preparation of 1,5-diketones in high yields. Experimental data suggest a sequential ring-opening, transfer hydrogenation, and hydroacylation mechanism. We propose that aldehyde decarbonylation is avoided by the formation of a novel rhodium enolate species that also accounts for the compatibility of a broad range of aldehydes and its anti-Markovnikov selectivity.

Reductive Deamination by Benzyne for Deoxy Sugar Synthesis Through a Domino Reaction.

Benzyne was developed as a reducing agent in the key step of converting amino sugars and ketoses into deoxy sugars, which occur widely in natural products. Many deoxy sugars exhibit antibiotic and anticancer activities, and furthermore, they play essential biological roles. By treatment with CS2 and then Ac2O, amino sugars and ketoses were converted into the corresponding 1,3‐thiazolidine‐2‐thiones. In the key step, these intermediates were treated with 2‐trimethylsilylphenyl triflate (2.0 equiv.) and CsF (3.0 equiv.) in MeCN at 25 °C to produce acyclic enol acetates in 60–63 % yields. Saponification of the enol acetates with NaOMe/MeOH followed by intramolecular cyclization afforded the target 2‐deoxy sugars. The key step of the reductive deamination involved a domino 1,2‐elimination/[3+2]‐cycloaddition/retro [3+2]‐ring‐opening sequence. The generality of this new method was proven by the use of various substrates, including pentoses, hexoses, monosaccharides, disaccharides, aldoses, and ketoses.

Five-component synthesis of dihydropyridines based on diketene

A novel five-component strategy involving commercially available diketene, primary amines, malononitrile and various benzaldehydes for the synthesis of densely functionalized 1,4-dihydropyridines in good yields was achieved. The reaction pathway involves a sequential ring-opening of diketene/enamine formation/Knoevenagel-condensation/Michael addition and 6-exo-tet cyclization, resulting in multiple bond-formation events including two C–C and three C–N bonds ultimately leading to the formation of the respective 1,4-dihydropyridines.

Stereoselective Total Syntheses of Polyacetylene Plant Metabolites via Ester-Tethered Ring Closing Metathesis.

Total syntheses of five naturally occurring polyacetylenes from three different plants are described. These natural products have in common an E,Z-configured conjugated diene linked to a di- or triyne chain. As the key method to stereoselectively establish the E,Z-diene part, an ester-tethered ring-closing metathesis/base-induced eliminative ring opening sequence was used. The results presented herein do not only showcase the utility of this tethered RCM variant but have also prompted us to suggest that the originally assigned absolute configurations of chiral polyacetylenes from Atractylodes macrocephala should be revised or at least reconsidered.

ZnBr2-Mediated Cascade Reaction of o-Alkoxy Alkynols: Synthesis of Indeno[1,2-c]chromenes.

A Lewis acid-mediated cascade annulation of o-alkoxy alkynols in the presence of ZnBr2 has been developed. The cascade cyclization proceeds through a 5-exo-dig cyclization followed by a Friedel-Crafts reaction and ring-opening sequence to synthesize indeno[1,2-c]chromenes. This protocol provides a broad substrate scope in moderate to good yields with high regioselectivity. The reaction with benzo-fused cycloalkyl ketones gave an unexpected alkyne C-C bond cleavage resulting in fused polycycles.

Triblock copolymers based on ε-caprolactone and trimethylene carbonate for the 3D printing of tissue engineering scaffolds.

Biodegradable PCL-b-PTMC-b-PCL triblock copolymers based on trimethylene carbonate (TMC) and ε-caprolactone (CL) were prepared and used in the 3D printing of tissue engineering scaffolds. Triblock copolymers of various molecular weights containing equal amounts of TMC and CL were prepared. These block copolymers combine the low glass transition temperature of amorphous PTMC (approximately -20°C) and the semi-crystallinity of PCL (glass transition approximately -60°C and melting temperature approximately 60°C). PCL-b-PTMC-b-PCL triblock copolymers were synthesized by sequential ring opening polymerization (ROP) of TMC and ε-CL. From these materials, films were prepared by solvent casting and porous structures were prepared by extrusion-based 3D printing. Films prepared from a polymer with a relatively high molecular weight of 62 kg/mol had a melting temperature of 58°C and showed tough and resilient behavior, with values of the elastic modulus, tensile strength and elongation at break of approximately 120 MPa, 16 MPa and 620%, respectively. Porous structures were prepared by 3D printing. Ethylene carbonate was used as a crystalizable and water-extractable solvent to prepare structures with microporous strands. Solutions, containing 25 wt% of the triblock copolymer, were extruded at 50°C then cooled at different temperatures. Slow cooling at room temperature resulted in pores with widths of 18 ± 6 μm and lengths of 221 ± 77 μm, rapid cooling with dry ice resulted in pores with widths of 13 ± 3 μm and lengths of 58 ± 12 μm. These PCL-b-PTMC-b-PCL triblock copolymers processed into porous structures at relatively low temperatures may find wide application as designed degradable tissue engineering scaffolds. In this preliminary study we prepared biodegradable triblock copolymers based on 1,3-trimethylene carbonate and ε-caprolactone and assessed their physical characteristics. Furthermore, we evaluated their potential as melt-processable thermoplastic elastomeric biomaterials in 3D printing of tissue engineering scaffolds.

One-pot synthesis of PLA-b-PHEA via sequential ROP and RAFT polymerizations

A block copolymer library of polylactide and poly(2-hydroxyethyl acrylate) was prepared via sequential ring opening polymerization and RAFT polymerization in a one-pot approach.

Regioselective O-Sulfonylation of N,N-Bis(2-hydroxyalkyl)tosylamides as a Synthetic Key Step to Enantiopure Morpholines.

The synthesis of enantiopure 2,6-disubstituted morpholines was realized through sequential ring opening of two different optically pure oxiranes by a tosylamide, under solid-liquid phase-transfer catalysis (SL-PTC) conditions, mono-O-sulfonylation of the resulting tosylamido-2,2'-diol, and cyclization to the morpholine. The crucial step, the regioselective formation of the monosulfonate, was controlled by taking advantage of the different stereo, electronic, and coordination properties of the oxirane-derived side chains in the diol backbone. As an application of this protocol, a new morpholine-3-carboxamide was synthesized starting from threonine.

ChemInform Abstract: [5 + 2] Cycloaddition of 2‐(2‐Aminoethyl)oxiranes with Alkynes via Epoxide Ring‐Opening: A Facile Access to Azepines.

A new FeCl3 and BF3 ⋅OEt2 co-catalyzed tandem hetero-[5+2] cycloaddition of 2-(2-aminoethyl)oxiranes with a wide range of alkynes, including terminal alkynes and alkyl-substituted internal alkynes is presented. This is the first example of rapid and facile production of diverse 2,3-dihydro-1H-azepines through a sequence of epoxide ring-opening, annulation, and dehydroxylation with broad substrate scope and exquisite selectivity control.

Dereplication of Flavonoid Glycoconjugates from Adenocalymma imperatoris-maximilianii by Untargeted Tandem Mass Spectrometry-Based Molecular Networking.

The interpretation of large datasets acquired using high performance liquid chromatography coupled with tandem mass spectrometry represents one of the major challenges in natural products research. Here we propose the use of molecular networking to rapid identify the known secondary metabolites from untargeted MS/MS analysis of Adenocalymma imperatoris-maximilianii plant extracts. The leaves, stems and roots of A.imperatoris-maximilianii were extracted using different solvents according to Snyder selectivity triangle. The samples were analyzed by HPLC coupled with ion trap mass spectrometer in a collision-induced dissociation MS/MS configuration in both positive and negative electrospray ionization modes. Molecular networking simultaneously organized the spectra by cosine similarity. The chemical identification was performed based on the systematic study of the main fragmentation pathways observed for the resulting network. The untargeted tandem mass spectrometry-based molecular networking allowed for the identification of 63 metabolites, mainly mono-, di- and tri-, C- and/or O-glycosyl flavones. Molecular networking was capable not only to dereplicate known flavonoids, but also to point out related prenyl derivatives, described for the first time in Adenocalymma species. The gas-phase reaction route to form the characteristic [M-H2O-(30/60/90)]+ fragments in C-glycosyl flavones was suggested as sequential sugar ring opening followed by retro-aldol elimination involving aldose-ketose isomerization. The use of molecular networking with LC-CID-MS/MS assisted the identification of various isomeric and isobaric flavonoid glycoconjugates by establishing clusters according to the fragmentation similarities. Additionally, the proposed cross-ring sugar cleavages can contribute to the identification of C-glycosides by MS/MS analysis.

Miktoarm star copolymers from D-(−)-salicin core aggregated into dandelion-like structures as anticancer drug delivery systems: synthesis, self-assembly and drug release

The β-glucoside-based heterofunctional initiator was used in the synthesis of well-defined eight-armed miktopolymers by sequential ring opening polymerization (ROP) of ε-caprolactone (CL) and atom transfer radical (co)polymerization (ATRP) of methyl methacrylate (MMA) and/or tert-butyl methacrylate (tBMA). Consequently, methacrylic acid (MAA) repeating units were introduced via selective cleavage of pendant tert-butyl protecting groups. Both the amphiphilic copolymers and miktoarm copolymers were self-assembled at 37°C and pH 7.4. The aggregates of miktoarm polymers were larger than that formed by polymethacrylate homoarm stars (≥250nm vs ≤200nm). The critical aggregation concentrations (CAC) of (mikto)stars were relatively low (0.006–0.411mg/mL) and decreased with the increase in MAA fraction content. Both MAA-based mikto- and homoarmed (co)polymers with shorter arms exhibited lower doxorubicin (DOX) loading capacity, whereas camptothecin (CPT) was encapsulated preferably by miktostars. The kinetic profiles of drug release showed that the rate of release was higher at acidic environment (pH 5.0) than in neutral pH. In the most cases the studied miktopolymer systems demonstrated the well-controlled delivery of the model anticancer drugs, which can be adjusted by structural parameters of polymeric carriers.

Versatile design of amphiphilic glycopolypeptides nanoparticles for lectin recognition

The understanding of glycopolymer-based nanostructures formation and their lectin binding properties are of great interest to the development of drug delivery systems and other biological applications. Herein, glycosylated polypeptides were synthesized from a clickable poly(l-lysine)-b-poly(benzyl-l-glutamate) copolypeptide, obtained by a sequential ring opening polymerization. The clickable poly(l-lysine) chain was completely functionalized by introducing galactose and lactose moieties on the copolypeptide's hydrophilic block, aiming specific lectin recognition. Spheres, pearl-necklace and worm-like structures prepared from poly(l-lysine)-b-poly(benzyl-l-glutamate) copolypeptides were obtained after nanoprecipitation, depending on the hydrophilic block functionalization and the hydrophobic block length. Specific interaction between the sugars on the micelles' surface with RCA120 lectin was observed with the PBLG40-based nano-structures. However, unexpected and unspecific interactions were observed with some nanostructures, showing the importance of the chemical functionalization and nanostructure stabilization. Such a synthetic approach can be used to develop any other amphiphilic and biofunctional polypeptide-based copolymers and nanoparticles.

5+2] Cycloaddition of 2-(2-Aminoethyl)oxiranes with Alkynes via Epoxide Ring-Opening: A Facile Access to Azepines.

A new FeCl3 and BF3 ⋅OEt2 co-catalyzed tandem hetero-[5+2] cycloaddition of 2-(2-aminoethyl)oxiranes with a wide range of alkynes, including terminal alkynes and alkyl-substituted internal alkynes is presented. This is the first example of rapid and facile production of diverse 2,3-dihydro-1H-azepines through a sequence of epoxide ring-opening, annulation, and dehydroxylation with broad substrate scope and exquisite selectivity control.

Transition metal free intramolecular approach for the synthesis of cyclopenta[b]chromene derivatives from phenol substituted fulvene derived azabicyclic olefins

A facile route towards the synthesis of cyclopentene fused chromene derivatives from strained phenol substituted fulvene derived bicyclic hydrazines is described. The reaction is proceeding through base catalyzed sequential intramolecular ring opening and ring closure of azabicyclic olefins. The transition metal free method provides an easy access to biologically relevant fused chromene ring system under relatively mild reaction conditions.

ChemInform Abstract: Silver‐Promoted Oxidative Ring Opening/Alkynylation of Cyclopropanols: Facile Synthesis of 4‐Yn‐1‐ones.

A new silver-promoted oxidative ring opening/alkynylation of cyclopropanols with ethynylbenziodoxolones (EBX) is described. This method enables the formation of alkylated alkynes via a sequence of ring opening and alkynylation. Control experiments support a radical mechanism in this silver-promoted method.