Soluble Polymer Support Research Articles

PEG-Supported Hypervalent Iodine Reagent for Sulfonamide Synthesis

AbstractA reusable and recoverable PEG-supported hypervalent iodine reagent is reported. This hypervalent iodine reagent, immobilized in a soluble polymer support, was easily prepared in six steps from PEG-OH 2000. This reagent was successfully applied in a mild sulfonamide synthesis using a sulfinate salt and an amine in up to 95% yield. The use of the soluble polymer allowed a facile workup procedure and reaction monitoring, by simple precipitation and filtration of the reagent, with an easy recovery and subsequent re-oxidation and reuse. This approach greatly improves the sustainability of this sulfonamide synthesis method, avoiding frequent preparation of reagents and generation of waste during the purification steps.

Scalable One-Pot-Liquid-Phase Oligonucleotide Synthesis for Model Network Hydrogels.

Solid-phase oligonucleotide synthesis (SPOS) based on phosphoramidite chemistry is currently the most widespread technique for DNA and RNA synthesis but suffers from scalability limitations and high reagent consumption. Liquid-phase oligonucleotide synthesis (LPOS) uses soluble polymer supports and has the potential of being scalable. However, at present, LPOS requires 3 separate reaction steps and 4-5 precipitation steps per nucleotide addition. Moreover, long acid exposure times during the deprotection step degrade sequences with high A content (adenine) due to depurination and chain cleavage. In this work, we present the first one-pot liquid-phase DNA synthesis technique which allows the addition of one nucleotide in a one-pot reaction of sequential coupling, oxidation, and deprotection followed by a single precipitation step. Furthermore, we demonstrate how to suppress depurination during the addition of adenine nucleotides. We showcase the potential of this technique to prepare high-purity 4-arm PEG-T20 (T = thymine) and 4-arm PEG-A20 building blocks in multigram scale. Such complementary 4-arm PEG-DNA building blocks reversibly self-assemble into supramolecular model network hydrogels and facilitate the elucidation of bond lifetimes. These model network hydrogels exhibit new levels of mechanical properties (storage modulus, bond lifetimes) in DNA bonds at room temperature (melting at 44 °C) and thus open up pathways to next-generation DNA materials programmable through sequence recognition and available for macroscale applications.

Pd-Catalyzed Functionalization of Aryl Amines on a Soluble Polymer Support

AbstractHerein we report the use of a soluble polymer support PEG-2000 on Pd-catalyzed reactions to improve the functionalization of aromatic amines and the synthesis of N-heterocycles. Compatibility of metal-catalyzed reactions for assembling privileged structures such as functionalized anilines were studied. PEG-supported anilines were found to be suitable substrates for Pd-catalyzed N-arylation, Sonogashira and Heck reactions. PEGylated substrates were prepared in yields up to 94%. This work consists on a proof of concept on the use of PEGylated anilines on Pd-catalyzed cross-coupling reactions. Indole core was attained in 82% and 62% yields, via two different routes.

Sequence-defined vinyl sulfonamide click nucleic acids (VS-CNAs) and their assembly into dynamically responsive materials.

Synthetic DNA analogues are of great interest for their application in information storage, therapeutics, and nanostructured materials, yet are often limited in scalability. Vinyl sulfonamide click nucleic acids (VS-CNAs) have been developed to overcome this limitation using the highly efficient thiol-Michael 'click' reaction. Utilizing all four nucleobases, sequence-defined click nucleic acids (CNAs) were synthesized using a simple and scalabale solution-phase approach. Employing a polyethylene glycol (PEG) support, synthesis of the CNA sequence, GATTACA, was achieved in high yields. CNA crosslinked hydrogels were assembled using multiarm PEG-CNAs resulting in materials that dynamically respond to temperature, strain, and competitive sequences.

(Invited) DNA Quadruplex Hydrogels: An Application of Synthetic DNA As Bulk Material

DNA is a water-soluble and biodegradable polymer, which forms right-handed double helices and carries genetic information in life. Because of its high structure regularity and sequence programmability, DNA has been used as a key component in development of functional nanomaterial. Despite such success in nanoscience, reports on application of DNA to typical material, i.e. hydrogels, are very few, except for some excellent achievements, because preparation of DNA in gram scales usually requires unreasonable costs. One solution for this problem is liquid-phase DNA synthesis method developed by Bonora et al. They used monofunctional MeO-PEG as a soluble polymeric support, which enables coupling reaction of phosphoramidite monomers in liquid phase and can be easily precipitated by ether addition for product separation. We have applied this system to synthesize DNA-PEG-DNA tri-block copolymer in grams, and successfully prepared biodegradable PEG hydrogels by using higher-order DNA structures, such as G-quadruplexes, for cross-linking points. Aqueous solution of a tri-block copolymer bearing multiple guanosines at the ends, for example, immediately turns into gel upon addition of Na+ or K+ ions at reasonable concentration. Various body-related fluids such as PBS, artificial saliva, sweat, or tear can trigger gelation. The resulting hydrogels are self-healable since the crosslinking points are stable but still reversible structure. Moreover, introduction of toehold sequence realized complete control of such sol-gel transition by the addition of complementary DNA strand.

Photocontrolled Synthesis of Abiotic Sequence-Defined Oligo(Phosphodiester)s.

A photoregulated phosphoramidite iterative process is studied for the synthesis of non-natural, digitally encoded oligo(phosphodiester)s. The oligomers are prepared using two reactive phosphoramidite monomers containing a 2-(2-nitrophenyl)propoxycarbonyl (NPPOC) protected OH group. The stepwise synthesis is performed on an OH-functional soluble polystyrene support, which allows recycling by precipitation in a nonsolvent. Repeating cycles involving phosphoramidite coupling, oxidation of phosphite to phosphate, and NPPOC deprotection by light irradiation at λ = 365 nm are performed in order to prepare oligomers with different lengths and sequences. Synthesis is conducted on a micromolar scale and good recycling yields are obtained in all cases. The use of a soluble polymer support allows an in-depth characterization of the NPPOC photo-deprotection step by 1 H NMR, UV spectroscopy, and size exclusion chromatography, and thus identification of optimal synthesis conditions. After cleavage from the support, the oligo(phosphodiester)s are characterized by tandem mass spectrometry, which confirms preparation of uniform sequence-coded oligomers.

Novel Globular Polymeric Supports for Membrane-Enhanced Peptide Synthesis

Membrane-enhanced peptide synthesis (MEPS), a technique that combines liquid-phase peptide synthesis (LPPS) with organic solvent nanofiltration (OSN), has emerged as a new methodology to tackle current challenges in solid-phase peptide synthesis (SPPS), the current strategy of choice for the preparation of peptides. This new technology platform is scalable beyond kilogram scale, automatable, and compatible with established Fmoc chemistry, as it combines chemistry in solution with expedient membrane purification. Here we screened novel highly rejected soluble polymeric supports and studied their application for the preparation of a model peptide. Our findings make a significant contribution to the development of MEPS.

Synthesis of oligoarylacetylenes with defined conjugated sequences using tailor-made soluble polymer supports.

Due to their strong tendency to self-aggregate, unfunctionalized oligoarylacetylenes are difficult to synthesize. Here, tailored polystyrene soluble supports, prepared by atom transfer radical polymerization and post-polymerization modification, were tested for preparing sequence-defined oligoarylacetylenes. Controlled aromatic sequences were obtained by iterative Sonogarisha coupling, using phenyl- and pyridine-based building-blocks.

Supported Catalysts Useful in Ring-Closing Metathesis, Cross Metathesis, and Ring-Opening Metathesis Polymerization.

Ruthenium and molybdenum catalysts are widely used in synthesis of both small molecules and macromolecules. While major developments have led to new increasingly active catalysts that have high functional group compatibility and stereoselectivity, catalyst/product separation, catalyst recycling, and/or catalyst residue/product separation remain an issue in some applications of these catalysts. This review highlights some of the history of efforts to address these problems, first discussing the problem in the context of reactions like ring-closing metathesis and cross metathesis catalysis used in the synthesis of low molecular weight compounds. It then discusses in more detail progress in dealing with these issues in ring opening metathesis polymerization chemistry. Such approaches depend on a biphasic solid/liquid or liquid separation and can use either always biphasic or sometimes biphasic systems and approaches to this problem using insoluble inorganic supports, insoluble crosslinked polymeric organic supports, soluble polymeric supports, ionic liquids and fluorous phases are discussed.

Optimal ATRP-Made Soluble Polymer Supports for Phosphoramidite Chemistry.

Soluble polystyrene supports with optimal molecular structures for iterative phosphoramidite chemistry were prepared by atom-transfer radical polymerization (ATRP) and subsequent chain-end modification steps. The controlled radical polymerization of styrene was first performed in the presence of an 9-fluorenylmethoxycarbonyl (Fmoc)-protected amino-functional ATRP initiator. Soluble supports of different molecular weight were prepared. Size-exclusion chromatography and NMR analysis indicated formation of well-defined polymers with controlled chain lengths and narrow dispersity. After synthesis, the bromo ω end group of the ATRP polymer was removed by dehalogenation in the presence of tributyltin hydride, and the Fmoc protecting group of the α moiety was subsequently cleaved with piperidine. The resulting α-primary amine was afterwards treated with a linker containing a carboxyl group, a cleavable ester site, and a dimethoxytrityl-protected hydroxyl group to afford ideal soluble supports for phosphoramidite chemistry. NMR analysis indicated that these chain-end modifications were quantitative. The supports were tested for the synthesis of a non-natural sequence-defined oligophosphates. High-resolution ESI-MS analysis of the cleaved oligomers indicated formation of uniform species, and thus confirmed the efficiency of the ATRP-made soluble polymer supports. In addition, the synthesis of a thymidine-loaded soluble support was achieved.

Microwave Controlled Reductive Cyclization: A Selective Synthesis of Novel Benzimidazole-alkyloxypyrrolo[1,2-a]quinoxalinones.

An efficient cascade synthesis of novel benzimidazole linked alkyloxypyrrolo[1,2-a]quinoxalinones was explored on soluble polymer support under microwave irradiation. Two exclusive protocols have been developed for the partial and full reductive cyclization by controlling the microwave energy. Commencing from the same substrate, ortho nitro pyrrol carboxylates, N-hydroxy pyrroloquinoxalinones were obtained by partial reductive cyclization (60 °C, 7 min), and the synthesis of pyrroloquinoxalinones was accomplished by full reductive cyclization (85 °C, 12 min). This method represents the first synthesis of N-hydroxy pyrroloquinoxalinones using Pd/C and ammonium formate as reducing agents. Further employing a variety of alkyl bromides, the obtained pyrroloquinoxalinones were transformed to their corresponding O- and N-alkylated analogues to deliver the diversified, novel molecular entities.

Debromination of ATRP-made Wang soluble polymer supports

This article describes two convenient methods for removing the ω-terminal bromine atom of well-defined soluble polymer supports prepared by atom transfer radical polymerization (ATRP). The targeted soluble supports are linear polystyrene chains that contain an acid-labile p-alkoxybenzyl ester linker (i.e. Wang linker) at their α-chain end. These polymers are synthesized by ATRP using a fluorenylmethoxycarbonyl (Fmoc)-protected amino functional ATRP initiator, namely 3-(Fmoc-amino)propyl 2-bromoisobutyrate. After polymerization and before Wang functionalization, the bromine-atom of the ATRP-made soluble supports was removed. Two different debromination approaches were considered. The first one consists in reducing the terminal alkyl bromide in the presence of a trialkyltin hydride. This method can be applied directly in the ATRP medium at the end of the polymerization or can be performed on a purified polymer sample. The latter conditions were found to be more suitable. It was also observed that the use of tributyltin hydride in the absence of additional radical initiator led to the best results. Indeed, well-defined polymer supports with controlled chain-length, molecular weight distribution and fully dehalogenated chain-ends were obtained. The second dehalogenation approach consisted in removing the terminal bromide by nucleophilic substitution with sodium azide. Afterwards, the formed terminal azide group was reacted with 1-pentyne by copper-catalyzed azide-alkyne 1, 3-dipolar Huisgen cycloaddition. This method was also found to be valid for preparing bromine-free polystyrene supports. After ω-chain-end debromination, Fmoc-deprotection was performed on the α-chain-end and the resulting amine function was reacted with 4-(hydroxymethyl)phenoxyacetic acid. Further esterification of the Wang linker is also possible.

A pH-responsive soluble polymer-based homogeneous system for fast and highly efficient N-glycoprotein/glycopeptide enrichment and identification by mass spectrometry.

Liquid phase homogeneous reactions using soluble polymer supports have found numerous applications in homogeneous catalysis and organic synthesis because of their advantages of no interface mass transfer limitation and a high conversion rate. However, their application in analytical separation is limited by the inefficient/inconvenient recovery of the target molecules from the extremely complex biological samples. Here, we report a stimuli-responsive polymer system for facile and efficient enrichment of trace amounts of biomolecules from complex biological samples. The soluble polymer supports provide a homogeneous reaction system with fast mass transfer and facilitate interactions between the supports and the target molecules. More importantly, the stimuli-responsive polymers exhibit reversible self-assembly and phase separation under pH variations, which leads to facial sample recovery with a high yield of the target biomolecules. The stimuli-responsive polymer is successfully applied to the enrichment of low abundant N-glycoproteins/glycopeptides, which play crucial roles in various key biological processes in mammals and are closely correlated with the occurrence, progression and metastasis of cancer. N-Glycoprotein is coupled to the stimuli-responsive polymer using the reported hydrazide chemistry with pre-oxidation of the oligosaccharide structure. Highly efficient enrichment of N-glycoproteins/N-glycopeptides with >95% conversion rate is achieved within 1 h, which is eight times faster than using solid/insoluble hydrazide enrichment materials. Mass spectrometry analysis achieves low femtomolar identification sensitivity and obtained 1317 N-glycopeptides corresponding to 458 N-glycoproteins in mouse brain, which is more than twice the amount obtained after enrichment using commercial solid/insoluble materials. These results demonstrate the capability of this "smart" polymer system to combine stimuli-responsive and target-enrichment moieties to achieve improved identification of key biological and disease related biomolecules.

Designing Phase Selectively Soluble Polymer-Supports for Dimethylaminopyridine and Phosphine-Ligated Pd(0) Catalysts

Soluble poly(4-alkylstyrene) containing 4-methyl-, 4-tert-butyl, 4-dodecyl-, and 4-octadecylstyrene were formed either with monomers containing dyes-, ligands, or catalysts or with 5–10 mol% of 4-chloromethylstyrene and studied as supports for ligands or catalysts. Studies with dye-labeled polymers showed that polymers containing longer alkyl groups alone or at ca. 10 mol% loading are highly soluble in heptane can be used to separate and recycle organo- and transition metal catalysts.

Use of an isotactic-propylene/hexene copolymer as a new, versatile, soluble support

The use of isotactic-poly(propylene-co-hexene) (iPPH) as new polymeric scaffold for synthesis as well as a phase-selective, soluble polymer support for homogeneous catalysis is described. It was possible to functionalize olefin-terminated iPPH using standard organic transformations. Each derivative could be isolated and purified using typical precipitations into a minimum amount of polar solvent, negating the need for wasteful work up and chromatographic procedures. Furthermore, it was demonstrated that an iPPH-supported DMAP could serve as a recoverable, recyclable catalyst. Published 2013. J. Polym. Sci., Part A: Polym. Chem. 2014, 52, 600–605

Diastereoselective Synthesis of Bridged Polycyclic Alkaloids via Tandem Acylation/Intramolecular Diels–Alder Reaction

A mild and efficient stereoselective synthesis of hexacyclic indole alkaloids with a tetrahydro-β-carboline motif has been developed by utilizing the Pictet-Spengler reaction and tandem N-acylation followed by intramolecular Diels-Alder cyclization. Initially, a diene unit was installed in the tetrahedron β-carboline skeleton through Pictet-Spengler cyclization of the corresponding aldehyde with tryptophan ester. The dienophile moiety was introduced by N-acylation of tetrahydro-β-carboline. Successive, in situ, [4 + 2] intramolecular Diels-Alder cycloaddition of the activated dienophile and conjugated diene containing intermediate furnished bridged polycyclic heterocycles with high diastereoselectivity. Formation of four new rings, five new covalent bonds, and five new chiral centers with excellent stereoselectivity is the key feature of this strategy. The diastereoselective formation of product was attributed to intramolecular chirality transfer through a chiral amino acid. The stereoselective outcome of this tandem reaction was confirmed by X-ray crystallographic studies. The developed synthetic strategy was also explored on a soluble polymer support to incorporate the advantage of rapid synthesis and a high-throughput workup process toward the development of a green synthetic protocol for polycyclic alkaloids.

Use of triazole-ring formation to attach a Ru/TsDPEN complex for asymmetric transfer hydrogenation to a soluble polymer

The cycloaddition of a chiral ligand containing a terminal alkyne to a soluble polymer containing an azide provides a convenient means for the attachment of an asymmetric transfer hydrogenation catalyst to a soluble polymer support. Using these ligands in complexes with Ru(II), gave good results in terms of conversion and enantioselectivity (up to 95% ee) in ketone reduction reactions.

Pd-catalysed amination on a soluble polymer support: arylation of anilines with PEG-supported aryl halides

PEG supported aryl halides were found to serve as substrates for the Pd-catalysed N-arylation of several substituted anilines and alkyl amines under solventless conditions. Moreover, the Pd2dba3/XPhos catalyst system enabled the coupling reactions to take place smoothly with excellent yields under a low catalyst loading (1 mol% Pd and 3 mol% ligand).

Poly(4-dodecylstyrene) as a phase-selectively soluble polymer support in homogeneous catalysis

4-Dodecylstyrene was copolymerized with 4–15 mol% of styrene monomers containing functional groups to synthesize polystyrene-like, alkane phase-selectively soluble polymer supports. Comparison studies of substituted polystyrenes containing dansyl groups showed that dodecyl groups significantly increase the phase selective solubility of a dodecyl-substituted polystyrene analog in the heptane phase of a heptane–acetonitrile mixture versus the phase selective solubility of poly(4-tert-butylstyrene) in this same solvent mixture. Coupling of a 4-dimethylaminopyridine (DMAP) derivative to poly(4-dodecylstyrene) (C12PS) formed a (C12PS)-supported DMAP organocatalyst. This C12PS-bound DMAP catalyst had activity like that of other polymer-supported DMAP catalysts and was fully recyclable in a variety of acylation reactions. Catalyst recycling was effected using a biphasic liquid–liquid separation step after a monophasic reaction. By using a C12PS-supported DMAP catalyst that contained dansyl groups, we were able to show that the C12PS-bound DMAP organocatalyst could be recycled as many as 20 times with catalyst leaching that was as low as 0.002% of the starting catalyst per cycle.

Liquid phase organic synthesis of 3,5-disubstituted 1,3,5-thiadiazinane-2-thione derivatives on polyethylene glycol (PEG) support

An efficient liquid-phase synthesis of 3,5-disubstituted 1,3,5-thiadiazinane-2-thione derivatives (THTT) is described using soluble polymer support polyethylene glycol (PEG) 5000 via one-pot condensation of PEG-bound free amino acid or PEG-bound tripeptide, a dithiocarbamate and formaldehyde under mild conditions. This procedure affords the target compounds in good yields and high purity with a facile work-up procedure. This synthetic approach has also allowed the efficient preparation of new compounds endowed with two THTT rings linked through the N-3 nitrogen atoms. The structures of all synthesized compounds were unequivocally established by standard spectroscopic techniques.