Tert-butyl Glycidyl Ether Research Articles

Functional Poly(ester-alt-sulfide)s Synthesized by Organo-Catalyzed Anionic Ring-Opening Alternating Copolymerization of Oxiranes and γ-Thiobutyrolactones

The copolymerization of tert-butyl glycidyl ether (tBuGE), allyl glycidyl ether (AGE), ethoxyethyl glycidyl ether (EEGE) and 1,2-epoxybutane (BO) with γ-thiobutyrolactone was investigated using benzyl alcohol–phosphazene bases as initiating systems. The prepared copolymers display perfect (poly(ester-alt-sulfide)) alternating structures for all epoxide monomers as evidenced by 1H, 13C, and 2D NMR and MALDI–TOF mass spectrometry. A marked influence of the reaction temperature on the occurrence of transesterification side reactions has been evidenced. In particular, at elevated temperature, transesterification reactions led to the formation of alternating macrocycles. The choice of the phosphazene base (tBuP4, tBuP2, or tBuP1) has a strong impact on the system reactivity and on the control of the polymerization. The use of tBuP1 led to very slow polymerization rates. The polymerization is much faster in the presence of tBuP2 even at low temperature. The use of tBuP4 shows an intermediate polymerization rate and enabled a good polymerization control at moderate temperatures. Finally, the synthesis of well-defined polyether-block-poly(ester-alt-sulfide) and the polymerization of a challenging substituted γ-thiolactone were proven to be feasible.

Enantioselective terpolymerization of racemic and meso-epoxides with anhydrides for preparation of chiral polyesters

The preparation of stereochemistry- and sequence-defined polymers, in which different monomer units are arranged in an ordered fashion just like biopolymers, is of great interest and has been a long-standing goal for chemists due to the expectation of unique macroscopic properties. Here, we describe the enantioselective terpolymerization of racemic terminal epoxides, meso-epoxides, and anhydrides mediated by the privileged chiral dinuclear Al(III) catalyst system, to afford optically active polyester terpolymers with either gradient or random distribution as determined by the epoxides employed during their preparation. The enantioselective terpolymerization of racemic tert-butyl glycidyl ether (rac-TBGE) and cyclopentene oxide with phthalic anhydride (PA) or naphthyl anhydride (NA) gives novel gradient polyesters, in which the crystallization behavior varies continuously along the main chain, due to the decrement of one ester component and the increment of the other occurring sequentially from one chain end to the other. In contrast, the enantioselective terpolymerization of rac-TBGE and meso-epoxide (cyclohexene oxide, 3,4-epoxytetrahydrofuran, or 1,4-dihydronaphthalene oxide) with an anhydride (PA or NA) provided chiral statistical terpolyesters with the random distribution of two kinds of ester units, resulting in a material possessing a mixed glass transition temperature. The present study therefore provides a convenient route to chiral polyesters bearing a range of physical and degradability properties.

Self-assembled dual-drug loaded core-shell nanoparticles based on metal-free fully alternating polyester for cancer theranostics

Recent research has been directed to the use of biocompatible and biodegradable metal-free fully alternating polyester nanomaterial in drug delivery application. The practice of triethyl borane (Et3B)/Bis(triphenylphosphoranylidene)ammonium chloride (PPNCl) Lewis pair as non-metallic catalyst was carried out to synthesize alternating copolymer of commercially available tert-butyl glycidyl ether (tBGE) and phthalic anhydride (PA) (poly(tBGE-alt-PA) copolymer) of low Mnvia nearly controlled ring-opening copolymerization (ROCOP) reaction. This biocompatible, hemocompatible, and biodegradable copolymer was used in the fabrication of different nanodrug formulations (NDFs) loaded with doxorubicin (DOX), curcumin (CUR) and their combination. Transmission electron microscope (TEM) imaging showed the spherical shape and core-shell internal structure for all NDFs with an average particle diameter ranging between 200 and 250 nm. X-ray diffraction (XRD) analysis displayed the amorphous nature of both DOX and CUR after their entrapment into the copolymer matrix. Differential scanning colorimetry (DSC) analysis presented no potential chemical interactions between the drug and copolymer. The cellular drug uptake study showed the increased uptake for all NDFs compared to free drug and exhibited higher DOX and CUR accumulation in dual-drug loaded nanoparticles treated pancreatic cancer (MIA PaCa-2) cells. The in vitro drug release kinetic study displayed the slow sustained drug release behavior with anomalous transport for both DOX and CUR in a defined physiological environment. Further, the anti-tumor efficacy of all NDFs was examined on several different cancer cell lines and maximum cytotoxicity was observed in MIA PaCa-2 cells with low inhibitory concentration (IC50) values. These NDFs inhibited the proliferation of MIA PaCa-2 cells due to cell cycle arrest in G2/M phase. In result, MIA PaCa-2 cells underwent apoptosis with significant changes in mitochondrial membrane potential and increased reactive oxygen species (ROS) level. In future, this study will open several novel insights related to the use of such biocompatible and biodegradable metal-free polyesters in targeted drug delivery, tissue engineering and other biomedical applications.

Enhancing the anti-cancer therapeutic efficacy by optimizing molecular weight of metal-free fully alternating semi-aromatic polyester as nano-drug carriers

The molecular weight of a polymer always influences the outcome of any drug delivery system. In this milieu, understanding the effect of molecular weight of polymer in designing an effective drug delivery system has caught a significant attention. Here, in this study, we have systematically examined the effects of molecular weights of metal-free fully alternating semi-aromatic polyester made up of commercially available tert-butyl glycidyl ether (tBGE) and phthalic anhydride (PA) monomers (poly(tBGE-alt-PA) copolymer) to design an efficient drug delivery system for cancer therapy. The molecular weights of such polyester greatly influenced the encapsulation efficiency, drug loading capacity, in vitro drug release profile and intracellular drug uptake of different nano-drug carriers, which finally determined its drug delivery efficiency. The anti-tumor therapeutic efficacy of all nano-drug carriers was tested on MIA PaCa-2 cells and maximum cytotoxicity was exhibited in case of poly(tBGE-alt-PA)-DOX nanoparticles of Mn = 9.2 kDa with low IC50 value. These results were further corroborated with colony forming unit data, where maximum inhibition in MIA PaCa-2 cell proliferation was also found in case of low molecular weight DOX nanoparticles. Hence, we proved that poly(tBGE-alt-PA) copolymer of Mn = 9.2 kDa can be used further in the broader applications of drug delivery.

Metal-free Lewis pair catalyst synergy for fully alternating copolymerization of norbornene anhydride and epoxides: Biocompatible tests for derived polymers

Synthesis of high molecular weight alternating copolymers from epoxides and norbornene anhydride via metal-free catalyst remains a challenge in aliphatic biodegradable polyester synthesis. Metal-free Lewis pair catalyst system, consisting of Lewis acid B(C2H5)3 (triethylborane) and a Lewis base DMAP (4-dimethylaminopyridine); TBD (1, 5, 7-triazabicyclo[4.4.0]dec-5-ene) and DBU (1,8 diazabicyclo[5.4.0]undec-7-ene) as a cooperative catalyst system for fully alternating polyesters synthesis is described here. By using these simple systems we have obtained, high molecular weight (Mn = 2–31.5 kDa) polyesters with narrow molecular weight distributions (MWD’s = 1.948–1.069) via ring-opening alternating copolymerisation (ROAC) of various epoxides (e.g. CHO, cyclohexene oxide; PO, propylene oxide; tBGE, tert-butyl glycidyl ether and PGE, phenyl glycidyl ether) with cis-5 norbornene-endo 2, 3 dicarboxylic anhydride (NB). Furthermore, we demonstrated that these polyesters are biocompatible in nature when tested on human embryonic kidney cells (HEK-293) showing more than 80% cell viability in 72 h and can be used for different biological applications such as drug delivery, tissue engineering or anti-microbial polymeric coatings on biomedical devices. The use of these green functional polyesters for biological studies was realized for the first time by a metal-free Lewis pair approach.

Core-Shell-Corona Micelles from a Polyether-Based Triblock Terpolymer: Investigation of the pH-Dependent Micellar Structure.

Core-shell-corona micelles featuring a pH-responsive shell have been characterized in dilute aqueous solution at different pH values (4-8) by using dynamic light scattering (DLS), field-flow fractionation coupled with multiangle light scattering detector (FFF-MALS), steady-state fluorescence, small-angle X-ray scattering (SAXS), and cryogenic transmission electron microscopy (cryo-TEM). The micelles are formed by self-assembly of a polyether-based triblock terpolymer consisting of a hydrophobic poly( tert-butyl glycidyl ether) block (P tBGE), a pH-responsive modified poly(allyl glycidyl ether) segment (PAGECOOH), and a neutral hydrophilic poly(ethylene oxide) block (PEO). Because of the side-chain carboxylic acids in the middle block, the micellar structure and size depends on the solution pH. Hereby, we show that an increase in pH induces a decrease in the aggregation number ( Nagg). In addition, the combination of the above measurements revealed an unexpected morphological change from spherical to ellipsoidal micelles by increasing pH.

Ring-opening copolymerization of maleic anhydride or L-Lactide with tert-butyl glycidyl ether by using efficient Ti and Zr benzoxazole-substituted 8-Hydroxyquinolinate catalysts

Ring-opening polymerization (ROP) of maleic anhydride (MA) or L-Lactide (L-LA) with tert-butyl glycidyl ether (tBGE) were carried out in the presence of Ti and Zr complexes of benzoxazole substituted 8-hydroxyquinoline ligands (1a-3a and 1b-3b), delivering nearly alternative P(tBGE-co-MA) and block-like P(tBGE)-b-PLLA co-polymers with high molecular weight (Mn) and narrow to broad molecular weight distributions (Mw/Mn). The molecular structures of the Ti and Zr complexes (1a and 3b) were confirmed by single-crystal X-ray diffraction analysis. The Zr complex 3b exhibited superior reactivity and produced copolymers within one hour at 80 °C in dry toluene (Mn,GPC = 14–40 Kg mol-1 and Mw/Mn = 1.19–1.55). In case of P(tBGE-co-MA) copolymer synthesis, the polymer arm with tBGE fraction was building faster (82–100 unit%) compared to MA (52–99 unit%). In contrast, incorporation of L-LA was higher (82–99 unit%) compared to tBGE insertion (20–60 unit%) in P(tBGE)-b-PLLA copolymer synthesis.

Polyglycerol Surfmers and Surfactants for Direct and Inverse Miniemulsion.

Poly(ethylene glycol)-based surfactants are a prominent example for nonionic surfactants. Poly(glycerol) (PG) is discussed as a polyfunctional alternative, however, it is not yet used to stabilize miniemulsions. The anionic polymerization of glycidyl ethers is used to prepare surfactants for direct or inverse emulsions and ambident surfactants by adjusting the copolymer composition. Orthogonal-protected poly(glycerol) block copolymers, using ethoxyethyl glycidyl ether and allyl glycidyl ether (AGE) or tert-butyl glycidyl ether (tBuGE), are synthesized. After cleavage of the acetal groups, these all-polyglycerol surfactants (PG-b-PtBuGE) or multifunctional surfmers (PG-b-PAGE), are used in direct and inverse miniemulsion polymerizations. Polystyrene nanoparticles are obtained by free-radical miniemulsion polymerization, in which the allyl-functionalized copolymers act as surfmer. In inverse miniemulsion, hydroxyethyl starch nanocarriers are synthesized with PG-b-PAGE as surfmer, transferred into aqueous PG-b-PtBuGE solution, and functionalized by thiol-ene addition. The PG-b-PtBuGE with equal block length ratio is used as a surfactant for direct and inverse miniemulsions. With the PG being covalently bound to the nanocarriers, a desorption during protein adsorption does not occur. It is believed that these surfactants are promising alternatives to conventional surfactants with additional functionality.

Functional PEG building blocks via copolymerization of ethylene carbonate and tert-butyl glycidyl ether

Functional poly(ethylene glycol) building blocks were synthesized with ethylene carbonate as a new source for ethylene oxide repeating units.

Small but powerful: co-assembly of polyether-based triblock terpolymers into sub-30 nm micelles and synergistic effects on cellular interactions.

We introduce a versatile ABC triblock terpoly- mer platform based on poly(ethylene oxide)-block-poly(allyl glycidyl ether)-block-poly(tert-butyl glycidyl ether) (PEO-b-PAGE-b-PtBGE) and subsequent functionalization of the PAGE segment with thiogalactose (hydroxyl), cysteamine (amino), and 2-mercaptopropionic acid (carboxy) by thiol-ene chemistry. These materials are used to prepare core-shell-corona micelles with a PtBGE core, a PAGE shell, and a PEO corona and sizes below 30 nm in aqueous media. We investigate the influence of different functional groups on micelle formation and cellular uptake. Moreover, co-assembly of differently functionalized materials allows to create micelles with a mixed shell and adjustable charge and, in that way, important characteristics such as cell uptake or cytotoxicity can be controlled. Furthermore, we demonstrate that even the uptake mechanism depends on the substitution pattern of the underlying triblock terpolymer.

Polyglycidol-Based Prepolymers to Tune the Nanostructure of Microgels

The use of prepolymers for microgel synthesis via miniemulsification allows predefining the chemical functionality and the nanostructure of microgels. We report on tailor-made polyglycidol-based prepolymers using three protected glycidol monomers (allyl glycidyl ether, AGE; ethoxy ethyl glycidyl ether, EEGE; and tert-butyl glycidyl ether, tBGE). AGE with its pendant double bonds serves as site for cross-linking or functionalization, whereas the EEGE and tBGE building blocks represent precursors for hydroxyl functionalities. Following the prepolymer approach, we design statistical and block copolymers to control the nanostructure of the microgel. Cross-linking of the prepolymers is achieved in miniemulsions under UV irradiation in a thiol–ene click type reaction addressing the allyl groups with 2,2′-(ethylenedioxy)diethanethiol. Analysis with cryo-TEM reveals that microgels derived from poly(glycidol)-block-poly(AGE) show larger hydrophobic domains than microgels derived from statistical copolymers. Additionally, the cross-linking of pH responsive tBGE/AGE prepolymers with different microstructures leads to microgels with nanostructures differing in local charge distributions.

Regioselective epoxide ring opening mediated by iron oxide-pillared clay

Iron oxide pillared clays (FeOx-pillared clays) such as FeOx-pillared hectorite and FeOx-pillared bentonite were synthesized by the intercalation of iron (III) chloride into clay interlayers and calcined at 300°C. The synthesized catalysts were utilized for styrene oxide ring opening by methanol, comparing with raw clays and Fe2O3. FeOx-pillared bentonite efficiently catalyzed the ring-opening of epoxides to produce β-alkoxyalcohols in excellent yields under extremely mild reaction conditions. The quantitative yield of 2-methoxy-2-phenylethanol was obtained using 30wt% FeOx-pillared bentonite to styrene oxide at 70°C for 10min. The optimized condition was applied to the ring opening of different epoxides such as 1-dodecene oxide, cyclohexene oxide, butyl glycidyl ether, tert-butyl glycidyl ether and α-pinene oxide to furnish the desired products in moderate to excellent yields.

Understanding and tuning the self-assembly of polyether-based triblock terpolymers in aqueous solution

The synthesis and self-assembly of well-defined poly(ethylene oxide)-block-poly(allyl glycidyl ether)-block-poly(tert-butyl glycidyl ether) (PEO-b-PAGE-b-PtBGE) triblock terpolymers with varying block lengths of PAGE and PtBGE are reported. The materials were synthesized using sequential living anionic ring-opening polymerization (AROP). The middle block, PAGE, was further modified by post-polymerization addition of 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranose via thiol–ene chemistry, resulting in PEO-b-PAGEGal-b-PtBGE. Self-assembly of the terpolymers in aqueous media resulted in the predominant formation of core–shell–corona architectures and the aggregates featured a PtBGE core, a PAGE shell, and a PEO corona. The structures were investigated using dynamic light scattering (DLS) and cryogenic transmission electron microscopy (cryo-TEM) measurements. In addition, the presence of a PEO corona rendered the formed micellar structures thermo-responsive, as demonstrated using turbidimetry. Depending on the ratio of hydrophilic to hydrophobic segments and on the thermal history of the samples, several micellar morphologies could be identified, including spheres of different size, worm-like structures, and vesicles. More important, both reversible and irreversible structural rearrangements could be identified during the heating–cooling cycles.

Development of a Scalable Synthesis of (S)-3-Fluoromethyl-γ-butyrolactone, Building Block for Carmegliptin’s Lactam Moiety

Several new routes are reported for the synthesis of (S)-3-fluoromethyl-γ-butyrolactone. An asymmetric hydrogenation-based synthesis was chosen as the enabling route to produce the lactone on a 10-kg scale. A superior stereoselective route starting from (S)-tert-butyl glycidyl ether which afforded the desired lactone in three steps with ∼50% overall yield was finally selected for further development and production.

Synthesis and Thermal Properties of Well-Defined Amphiphilic Block Copolymers Based on Polyglycidol

A series of amphiphilic block copolymers functionalized with three different alkyl side chains (alkyl chain length = C12, C14, and C16) were synthesized and analyzed via NMR spectroscopy, gel permeation chromatography (GPC), and differential scanning calorimetry (DSC). The block copolymers were obtained in a four-step synthesis. In the first step ethoxy ethyl glycidyl ether (EEGE) and tert-butyl glycidyl ether (tBuGE) were sequentially polymerized via an anionic mechanism. In the next step, the acetal protection groups of EEGE repeating units were selectively removed and the hydroxyl groups obtained were reacted with alkyl isocyanates. Finally, the tert-butyl ether protection groups were removed. All steps of the synthesis were controlled via 1H NMR spectroscopy, GPC, and DSC analyses. All block polymers showed three thermal transitions regardless of the chain length of the isocyanate used: a glass transition characteristic for the polyglycidol backbone and two endothermic peaks, associated with melting of the aliphatic side chains and subsequent breakdown of the hydrogen bonds due to the urethane groups. This thermal behavior suggests that diblock copolymers self-assemble into microdomains whose stability (existence) can be tuned with temperature.

Synthesis of Linear High Molar Mass Glycidol-Based Polymers by Monomer-Activated Anionic Polymerization

Linear polyglycidols of high molar masses were prepared by the monomer-activated anionic polymerization of the corresponding protected monomers, ethoxyethyl glycidyl ether and tert-butyl glycidyl ether, using a system composed of tetraoctylammonium bromide as initiator and triisobutylaluminum as monomer activator. The aluminic compound was used in 1.5−5-fold excess compared to the initiator. Linear poly(ethoxyethyl glycidyl ether) and poly(tert-butyl glycidyl ether), with narrow chain dispersity and controlled high molar masses, up to 85 000 g/mol, were prepared at 0 °C in a few hours. Deprotection of hydroxyl functions by acidic treatment of the polymers was shown to proceed quantitatively and cleanly affording the corresponding linear polyglycerol and validating the use of these protecting groups. The copolymerization of protected glycidols with propylene oxide and butene oxide was also investigated with the goal to broaden the scope of this synthetic approach to various polyethers and copolyethers.

Cloning of an epoxide hydrolase-encoding gene from Aspergillus niger M200, overexpression in E. coli, and modification of activity and enantioselectivity of the enzyme by protein engineering

The gene encoding an epoxide hydrolase from Aspergillus niger M200 has been cloned and its sequence determined. The gene is interrupted by seven introns, one exon being only nine nucleotides long. The non-coding 5′- and 3′-regions of the mRNA are composed of 47 and 76 nucleotides, respectively. Overexpression of the fungal epoxide hydrolase in E. coli TOP10 has led to a 15-fold increase in specific activity (compared to the wild-type strain). Saturation mutagenesis at codon 217 resulted in the discovery of nine enzyme variants showing in several cases profound differences in activity and enantioselectivity towards various epoxides when compared to the data of the wild-type enzyme. The site 217 is located at the entrance of the tunnel that provides the substrate with access to the active site. The exchange of Ala at this position for Cys has led to a doubled enantioselectivity ( E-value of 5.0) towards benzyl glycidyl ether. The same substitution resulted in a threefold-enhanced activity of the enzyme towards allyl glycidyl ether and styrene oxide without affecting enantioselectivity. The variant A217L showed an enhanced enantioselectivity towards tert-butyl glycidyl ether reaching an E-value of 100 (from 60 for the wild-type enzyme). Replacement of A217 by Val has led to higher activity towards allyl glycidyl ether by a factor of six. The substitutions Ala → Glu and Ala → Gln increased the enantioselectivity towards allyl glycidyl ether and styrene oxide by over 50% to E-values of 10 and 16, respectively. The study underlines that single amino acid exchanges in the substrate tunnel region can lead to significant improvements in enantioselectivity and activity of the epoxide hydrolase from A. niger M200.

Polyglycidols with Two Orthogonal Protective Groups: Preparation, Selective Deprotection, and Functionalization

Anionic ring-opening polymerization and copolymerization of allyl glycidyl ether (AGE), tert-butyl glycidyl ether (tBuGE), and ethoxyethyl glycidyl ether (EEGE) was performed using potassium 3-phenyl-1-propanol as initiator. The polymers poly(AGE), poly(tBuGE), poly(EEGE) as well as poly(AGE-co-tBuGE), poly(AGE-co-EEGE), and poly(EEGE-co-tBuGE) were obtained with controlled degree of polymerization, narrow molecular weight distribution and a predetermined ratio of repeating units. First-order kinetics with respect to the glycidyl monomers were found for homo- and copolymerization. The removal of protection groups from the homopolymers was achieved using trifluoroacetic acid for poly(tBuGE), aqueous hydrochloric acid for poly(EEGE), and a palladium catalyst for poly(AGE); in all cases a linear poly(glycidyl ether) (poly(GE), 1) was obtained. The following conversions were achieved by selective removal of only one protection group: using aqueous hydrochloric acid, poly(AGE-co-EEGE) was converted to poly(AG...

Dielectric Study of Dynamic Heterogeneity in Miscible Blends of Polyethers and Poly(vinylethylene)

Dynamic heterogeneity in miscible blends was investigated by the use of dielectric relaxation spectroscopy for blends composed of poly(vinylethylene) (PVE) and various polyethers, i.e., poly(butylene oxide) (PBO), poly(isopropyl glycidyl ether) (PiPGE), poly(n-butyl glycidyl ether) (PnBGE), and poly(tert-butyl glycidyl ether) (PtBGE). All polyethers are type AB polymers and exhibit both the dielectric normal- and segmental-mode relaxations, but PVE exhibits only the segmental relaxation. The data indicate that the loss curves for the segmental relaxation of PVE/PBO blends are bimodal in the range of PBO content less than 0.25. Since the dielectric relaxation strength of PBO is much higher than that of PVE, unimodal loss curves are seen at high PBO content. The effective glass transition temperatures for the fast and slow modes estimated with the Lodge−McLeish model agree fairly well with the temperatures at which segmental relaxation times become ca. 100 s. The ratio of the relaxation times for the normal...

Purification and characterisation of a novel enantioselective epoxide hydrolase from Aspergillus niger M200

Purification of a novel enantioselective epoxide hydrolase from Aspergillus niger M200 has been achieved using ammonium sulphate precipitation, ionic exchange, hydrophobic interaction, and size-exclusion chromatography, in conjunction with two additional chromatographic steps employing hydroxylapatite, and Mimetic Green. The enzyme was purified 186-fold with a yield of 15%. The apparent molecular mass of the enzyme was determined to be 77 kDa under native conditions and 40 kDa under denaturing conditions, implying a dimeric structure of the native enzyme. The isoelectric point of the enzyme was estimated to be 4.0 by isoelectric focusing electrophoresis. The enzyme has a broad substrate specificity with highest specificities towards tert-butyl glycidyl ether, para-nitrostyrene oxide, benzyl glycidyl ether, and styrene oxide. Enantiomeric ratios of 30 to more than 100 were determined for the hydrolysis reactions of 4 epoxidic substrates using the purified enzyme at a reaction temperature of 10 °C. Product inhibition studies suggest that the enzyme is able to differentiate to a high degree between the ( R)-diol and ( S)-diol product of the hydrolysis reaction with tert-butyl glycidyl ether as the substrate. The highest activity of the enzyme was at 42 °C and a pH of 6.8. Six peptide sequences, which were obtained by cleavage of the purified enzyme with trypsin and mass spectrometry analysis of the tryptic peptides, show high similarity with corresponding sequences originated from the epoxide hydrolase from Aspergillus niger LCP 521.