Protected Glycidol Research Articles

Controlled “one-pot” block copolymerization of β-butyrolactone and oxiranes via quantitative active centers transformation

The synthesis of block copolymers of oxiranes and β-butyrolactone based on a method of sequential monomer addition was developed. The anionic controlled polymerization of protected glycidol - ethoxyethyl glycidyl ether (EEGE) and β-butyrolactone (BBL) was used. By quantitatively transforming the hydroxyl groups at the ends of the polyoxirane chains to the carboxylate centers, a one-pot synthesis was possible without further purification of the intermediates. The main part of the study was directed toward verifying the degree of precision of the transformation step and copolymer synthesis and clarifying the role of hydroxyl groups potentially present during the polymerization of BBL. It was also found that the presence of a small excess of anhydride during the transformation reaction did not affect the subsequent synthesis steps. The use of a macroinitiator in the form of poly(ethylene glycol) allowed us to obtain well-defined block copolymers of oxiranes and BBL of di-, tri- and pentablock structures.

The evolution of a stereoselective synthesis of the C1-C16 fragment of bryostatins.

The development of a synthesis of the C1-C16 fragment of bryostatins in which the key step is a stereoselective oxy-Michael reaction used to assemble the cis-2,6-disubstituted tetrahydropyran with the exocyclic alkene already installed, is described. Following early work using Stille reactions to prepare precursors for oxy-Michael reactions, a more efficient route was devised based on a ketophosphonate-aldehyde condensation to prepare the key dienone. Synthesis of the aldehyde required for the ketophosphonate condensation involved the highly stereoselective addition of a diorganocuprate derived from allylmagnesium bromide and copper(i) iodide to the methyl 5-hydroxyhex-2-ynoate prepared by ring-opening of a protected glycidol using lithiated methyl propiolate. Ester reduction, selective alcohol protection and oxidative cleavage of the terminal double bond gave the required aldehyde. The ketophosphonate was prepared in 13 steps from (R)-pantolactone using a synthesis based on a chelation controlled aldol condensation and an anti-selective reduction of a 3-hydroxyketone. Following the ketophosphonate-aldehyde reaction, selective deprotection followed by treatment with base effected the oxy-Michael reaction that gave the cis-2,6-disubstituted tetrahydropyran via thermodynamic control. Subsequent functional group manipulation led to the synthesis of a hydroxy ester that corresponded to the C1-C16 fragment of the bryostatins in 23 steps from (R)-pantolactone. The synthesis was repeated using slightly different protecting groups for a study of a ring-closing metathesis approach to the bryostatins.

Beyond poly(ethylene glycol): linear polyglycerol as a multifunctional polyether for biomedical and pharmaceutical applications.

Polyglycerols (sometimes also called "polyglycidols") represent a class of highly biocompatible and multihydroxy-functional polymers that may be considered as a multifunctional analogue of poly(ethylene glycol) (PEG). Various architectures based on a polyglycerol scaffold are feasible depending on the monomer employed. While polymerization of glycidol leads to hyperbranched polyglycerols, the precisely defined linear analogue is obtained by using suitably protected glycidol as a monomer, followed by removal of the protective group in a postpolymerization step. This review summarizes the properties and synthetic approaches toward linear polyglycerols (linPG), which are at present mainly based on the application of ethoxyethyl glycidyl ether (EEGE) as an acetal-protected glycidol derivative. Particular emphasis is placed on the manifold functionalization strategies including, e.g., the synthesis of end-functional linPGs or multiheterofunctional modifications at the polyether backbone. Potential applications like bioconjugation and utilization as a component in degradable biomaterials or for diagnostics, in which polyglycerol acts as a promising PEG substitute are discussed. In the last section, the important role of linear polyglycerol as a macroinitiator or as a highly hydrophilic segment in block co- or terpolymers is highlighted.

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.

Aqueous Solution Properties of Polyglycidol-Based Analogues of Pluronic Copolymers. Influence of the Poly(propylene oxide) Block Molar Mass

With the present contribution we complement the picture of the behavior in aqueous solution of the entire family of LGP copolymers. The latter are considered analogues of the Pluronic copolymers in which the flanking poly(ethylene oxide) (PEO) blocks are substituted by linear polyglycidol (PG). PG is structurally similar to PEO and differs in that each monomer unit bears a hydroxymethylene group. So far two series of LGP copolymers, that is LGP60 and LGP130, based on poly(propylene oxide) (PPO) of molar masses 2000 and 4000, respectively, and PG contents ranging from 10 to 84 wt % have been studied. In particular, in the present paper we report on the synthesis and aqueous solution properties of a novel series of LGP copolymers that are close in composition to the Pluronic copolymers of the lowest molar mass of the central block of PPO, L31−P38. Seven copolymers based on PPO of molar mass of 1000 and PG content ranging from 30 to 90 wt % were prepared by applying the same two-step procedure employed for the synthesis of the LGP60 and LGP130 copolymers. The copolymers were prepared by means of anionic polymerization of ethoxyethyl glycidyl ether (protected glycidol) followed by cleavage of the protective groups. The aqueous solution properties were thoroughly investigated by a variety of methods, e.g., dye solubilization for determination of the critical micellization concentrations, turbidimetry, light scattering, small-angle neutron scattering, and rheology. A number of parameters were extracted from the experimental data and compared to those of the related copolymers from the LGP60 and LGP130 series to assess the influence of the molar mass of the central block of PPO.

Synthesis, characterization and properties of functional star and dendritic block copolymers of ethylene oxide and glycidol with oligoglycidol branching units

Well-defined, four-arm star block copolymers of ethylene oxide and glycidol were prepared via controlled anionic polymerization using protected glycidol. The length of the poly(ethylene oxide) block was varied from DP = 10 to 50, while the length of the short polyglycidol block remained nearly constant, at DP = 4–6. Star block copolymers with hydroxyl groups at the ends of the arms after conversion to the corresponding alkoxides were used as multifunctional macroinitiators for the sequential polymerization of ethylene oxide and protected glycidol. After deprotection, the branched block copolymers of ethylene oxide and glycidol had narrow molar mass distributions and multiple hydroxyl groups (up to 200) at the peripheries. The structure and functionality were determined using size exclusion chromatography with a light scattering detector and nuclear magnetic resonance spectroscopy. The thermal properties of the synthesized copolymers were also investigated, as well as the hydrophilic dye uptake to the hydrophobic phase containing copolymers.

Synthesis and degradation of biomedical materials based on linear and star shaped polyglycidols

AbstractLinear and star shaped polyglycidols (synonym with polyglycerols) are prepared in a controlled ring opening polymerization of protected glycidols. Beside the molar mass and the polydispersity, the architecture of the polyglycidols is controlled by using mono‐ and multifunctional mono‐ and polydispers initiators. Copolymers of dissimilarly protected glycidols as well as copolymers with nonfunctional oxiranes were prepared by means of anionic polymerization while copolymers of protected glycidol with tetrahydrofuran were prepared by means of cationic polymerization. Polyethers with functional groups in the side chains (functional polyethers) with special emphasis on polyglycidols (containing hydroxymethyl groups in the side chains) were used to prepare multifunctional polymers and (hetero)grafted polymer brushes via chemical and enzyme catalyzed reaction. The potential of poly(glycidol‐graft‐ε‐caprolactone)‐co‐glycidol) prepared via enzyme catalyzed grafting of polyglycidols using ε‐caprolactone as a monomer and Lipase B from Candida antarctica as a catalyst is presented. Finally, comparative degradation studies of densely and loosely grafted polyglycidols are presented and discussed. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3209–3231, 2009

Synthesis of Polyglycidol-Based Analogues to Pluronic L121−F127 Copolymers. Self-Assembly, Thermodynamics, Turbidimetric, and Rheological Studies

The fifth paper of a series, which is focused on polyglycidol-based analogues to Pluronic copolymers, describes the synthesis of another group of eight well-defined polyglycidol−poly(propylene oxide)−polyglycidol (PG−PPO−PG) block copolymers with PG contents varying from 10 to 80 wt % and fixed molecular weight of the middle PPO block of 4000. In composition these copolymers are closest to the Pluronic copolymers of the highest molecular weight of PPO, L121−F127. The copolymers were prepared by means of anionic polymerization of ethoxyethyl glycidyl ether (protected glycidol) followed by cleavage of the protective groups. In aqueous solutions the copolymers were found to self-associate above a certain critical concentration (CMC). The CMC variations with temperature and PG content as well as the thermodynamic parameters of the self-assembly were compared to those of the corresponding Pluronic copolymers and related PG-based copolymers studied earlier. The turbidity measurements carried out in the temperature range from −10 to 60 °C revealed four types of transmittance vs temperature curve patterns depending on PG content. Formation of qualitatively different self-assembled structures was suggested to explain the different curve patterns. Dilute and concentrated aqueous solutions were investigated by means of rheology. Shear thinning was observed for all copolymers even in the dilute (0.5−2.0 wt %) limit which imparts high magnitudes of the zero shear viscosity. The mechanical properties of the high concentrated solutions (33 wt %) were studied by frequency-dependent oscillatory experiments. The solutions of all copolymers invariably behaved as fluids and elastic gels at low (15 °C) and elevated (60 °C) temperatures, respectively.

Poly(glycidol)-Based Analogues to Pluronic Block Copolymers. Synthesis and Aqueous Solution Properties

Eight well-defined poly(glycidol)−poly(propylene oxide)−poly(glycidol) (PG−PPO−PG) block copolymers with PG contents from 20 to 84 wt % and fixed molecular weight of the middle PPO block of 2000 were prepared. The copolymers are considered as analogues to the commercially available Pluronic, poly(ethylene oxide)−poly(propylene oxide)−poly(ethylene oxide) (PEO−PPO−PEO), block copolymers in which the PEO blocks are substituted by blocks of linear PG. They were prepared by means of anionic polymerization of ethoxyethyl glycidyl ether (protected glycidol) followed by cleavage of the protective groups. The resulting products bear hydroxyl groups in each repeating glycidol unit. In aqueous solution all studied copolymers were found to self-associate above a certain critical concentration (cmc), which depends on the PG content and temperature. The cmc values were found to decrease with increasing temperature and decreasing the content of the hydrophilic component less strongly than those of the corresponding Pluronic copolymers. According to the thermodynamic data, the substitution of the PEO blocks by blocks of linear PG reduces the enthalpic barrier to aggregation. The latter is entropically less favored compared to that of the Pluronics. The turbidity measurements reveal three types of transmittance vs temperature curve patterns. Two of them have been observed for some Pluronic copolymers. The third type, characterized by an increase of transmittance with increasing temperature, is exhibited only by the copolymers of higher (above 50 wt %) PG content. This behavior as well as other findings that deviate from the expectations can be understood with the well-documented in the present study fact that the interactions of the constituent blocks with water change with temperature in opposite manners.

Ring-Opening Polymerization of ε-Caprolactone by Means of Mono- and Multifunctional Initiators: Comparison of Chemical and Enzymatic Catalysis

Protected polyglycidols with a linear or star-shaped architecture were obtained via anionic ring-opening polymerization of protected glycidol in diglyme with potassium as counterion. Removal of the protecting groups lead to polyglycidols, which were used as multifunctional macroinitiators for the chemically and enzymatically catalyzed ring-opening polymerization of e-caprolactone. For the chemically catalyzed polymerization zinc(II) 2-ethylhexanoate was used, while Novozyme 435 (Lipase B from Candida antarctica immobilized on a macroporous resin) was used for the enzymatically catalyzed polymerization. To determine the characteristics of the two differently catalyzed polymerizations, monofunctional macroinitiators based on poly(ethylene glycol) were applied. The main difference observed was the initiator efficiency, which was explained by the different polymerization mechanism. By using multifunctional macroinitiators the difference in the initiation efficiency lead to different polymer architectures. For...

High molecular arborescent polyoxyethylene with hydroxyl containing shell

Arborescent polyoxyethylene of high molar mass (2×10 5 g/mol) and narrow molar mass distribution was synthesized in a three-stage process. In the first stage a triblock copolymer of ethylene oxide (central block, DP ca. 90) and 2,3-epoxypropanol-1 (short flanking blocks, DP ca. 5) was synthesized. The potassium alcoholate derived from this copolymer was used to initiate the polymerization of ethylene oxide and the subsequent addition of protected glycidol (1-etoxyethyl glycidyl ether). After deprotection the short polyglycidol blocks were used as branching units for the next generation. Repeated step by step process leads to the ‘pom-pom like’ branched polyoxyethylene macromolecules enriched with the reactive hydroxyl groups in the outer shell. The branched structure of the obtained polymers was evidenced by the size exclusion chromatography and NMR spectroscopy.

Stereocontrolled synthesis of 3-(trans-2-aminocyclopropyl)alanine, a key component of belactosin A.

Herein we report a concise synthesis of 3-(trans-2-aminocyclopropyl)alanine, a component of belactosin A, using asymmetric alkylation of a glycine enolate in the presence of chiral phase-transfer catalysts to control the configuration at C2. Reaction of protected glycidol with triethyl phosphonoacetate (Wadsworth-Emmons cyclopropanation) is used for enantiospecific preparation of an intermediate cyclopropanecarboxylate that is converted to a cyclopropylamine via Curtius rearrangement. [reaction: see text]

Convenient Synthesis of Monoprotected 1,2-Diols

Abstract Reaction of the protected glycidol derivatives (1A-C) with a wide variety of Grignard reagents (2a-h) in the presence of catalytic amount of CuCN provided the corresponding monoprotected diol derivatives (3) in a highly regioselective manner.

Synthesis of chiral and racemic functional polymers from glycidol and thioglycidol

AbstractRacemic and optically active protected glycidols (as 1‐ethoxyethyl ethers) are readily polymerized with anionic initiators (e.g., CsOH). Polymers with molecular weights up to 30 000 are obtained without cleavage of the protective group. Oligomers (degree of polymerization [DPn] 5 to 10) are prepared using an aluminium complex derived from a Schiff's base. The protected thioglycidol (synthesized from the protected glycidol) leads to very high‐molecular‐weight polymers (150 000–320 000) using anionic or anionic coordinated initiators. Copolymers of protected glycidol with ethylene oxide are obtained with KOH as initiator. Regeneration of hydroxyl groups in polymers is carried out with acidic cleavage. Treatment of protected polyglycidol with formic acid leads first to the formate of polyglycidol. Then, after saponification, pure polyglycidol is obtained. The use of aqueous hydrochloric acid leads directly to the free polymer.

Versatile methods for the synthesis of mixed-acid 1,2-diacylglycerols

Two methods for synthesizing mixed-acid 1,2-diacylglycerols starting from 2,3-epoxy-1-propanol (glycidol) or 3-chloro-1,2-propanediol have been described. This first method involves fatty acid addition to a protected glycidol derivative and solid-state isomerization. The second approach exploits the specificity of the trityl group for primary alcohols and the nucleophilic replacement of chlorine by a carboxylate ion in an aprotic solvent. The second method proves to be more general: with 3-chloro-1- O-trityl-1,2-propanediol as an intermediate compound apparently all types of mixed-acid, saturated and unsaturated, chiral and racemic 1,2-diacylglycerols can be prepared in good yields. In the first method tritylglycidol is a good starting compound. The use of this method, however, is restricted because only the 2-position of glycerol can be occupied with an unsaturated fatty acid. For de-blocking protected 1,2-diacylglycerols, the trityl group and other protecting groups were exchanged for the trifluoroacetyl group, which group could then be removed without any detectable acyl migration (< 1%). To this end, the 1,2-diacyl-3-trifluoroacetyl-glycerols were dissolved at room temperature in methanol containing pyridine, whereby the trifluoroacetyl group was split off, giving the 1,2-diacylglycerol.