Synthese und Charakterisierung von bioabbaubaren Polymeren auf der Basis von Polydepsipeptiden

The thesis deals with the synthesis and characterization of bioresorbable polymers based on polydepsipeptides. Four different types of polydepsipeptide-polyether block copolymers were synthesized via ring-opening polymerization of morpholine-2,5-dione derivatives. The dependence of the macroscopic properties of the block copolymers on their structure is discussed. A new method for the synthesis of polydepsipeptides, i.e. the enzyme-catalyzed ring-opening polymerization of morpholine-2,5-dione derivatives, is presented. Synthesis and characterization of new block copolymers based on polydepsipeptides ABA block copolymers with polydepsipeptides (A) and poly(ethylene oxide) ( = 6000, PEO, B) blocks were synthesized via ring-opening polymerization of 3(S)-sec-butyl-morpholine-2,5-dione or 3(S)-isobutyl-morpholine-2,5-dione in the presence of hydroxytelechelic poly(ethylene oxide) with stannous octoate as a catalyst. of the resulting copolymers increases with increasing amount of morpholine-2,5-dione derivatives. No racemization of the isoleucine or leucine residue takes place during both homopolymerization and polymerization of morpholine-2,5-dione derivatives in the presence of PEO and Sn(oct)2. The melting temperature of the poly(Glc-Leu) segments in poly(Glc-Leu)-PEO-poly(Glc-Leu) block copolymers increases with increasing length of the poly(Glc-Leu) blocks. The poly(Glc-Leu) block crystallizes first upon cooling from the melt. This leads to imperfect crystallization or no crystallization of the PEO block. The melting temperature of the PEO block is lower than that of the homopolymer, and the crystallinity of the PEO block decreases with increasing length of the polydepsipeptide blocks in both triblock copolymers. Static contact angle measurement with water clearly reveal that the hydrophilicity of the resulting copolymers increases greatly with increasing PEO content in the copolymers. Four different types of polydepsipeptide-polyether block copolymers were synthesized via ring-opening polymerization of 3(S)-sec-butyl-morpholine-2,5-dione or 3(S)-isobutyl-morpholine-2,5-dione in the presence of poly(ethylene oxide) with one, two, three and four terminal OH-groups with stannous octoate as a catalyst, i.e., an AB block copolymer, an ABA block copolymer, an (A)2B star shaped block copolymer and an (A)2B(A)2 star shaped block copolymer, respectively, where A is a polydepsipeptide and B a PEO block. The molar ratio of depsipeptide to PEO was varied to obtain copolymers with different weight fractions of polydepsipeptide blocks ranging from 47 to 97.5 wt%. The crystallinity of the PEO block decreases in the following order: AB > (A)2B > ABA > (A)2B(A)2. The static contact angle q with water decreases with increasing PEO content in the block copolymers. Polydepsipeptides with protected functional groups were obtained by ring-opening copolymerization of DLLA with morpholine-2,5-dione derivatives having protected functional substituents. The copolymerization was carried out in the bulk at 140°C in the presence of Sn(oct)2 as a catalyst. Polyester amides with pendant carboxylic acid groups were prepared by catalytic hydrogenation of the protected copolymers. Copolymers with a PEO8000 center block and two arms of random lactide/depsipeptides copolymers were synthesized and characterized. Increasing proportion of PEO results in a decrease in molecular weight of the block copolymer and higher crystallinity in PEO block. The block copolymers having a high fraction of PEO (> 40%) are brittle. The block copolymers based on depsipeptides, DLLA and PEO have much higher elongation at break and lower Young's modulus than the corresponding block copolymers based on depsipeptides, LLA and PEO. The mechanical properties are mainly influenced by the crystallinity of copolymer blocks, when the block copolymers were prepared from the same depsipeptide and with the same molar ratio, but different lactide, i.e., DLLA or LLA. Hydrolytic degradation of block copolymers based on polydepsipeptides In vitro degradation experiments reveal that the block copolymers based on depsipeptides, DLLA and PEO lose their weight faster than the block copolymers based on depsipeptides, LLA and PEO. The weight loss rates depend on the weight fraction of PEO in the block copolymers and the starting molecular weight. The molecular weight decreases quickly, while the molecular weight distribution increases up to a polydispersity from 1.63 to 4.29 with increasing degradation time. CaH2 as a co-initiator for the ring-opening polymerization of Cyclo(Glc-Val) Block copolymers with poly(Glc-Val) and PEO6000 blocks were synthesized via the ring-opening polymerization of 3(S)-isopropyl-morpholine-2,5-dione in the presence of PEO with CaH2 as a co-initiator at 140°C for 24 h or 96 h. of the resulting copolymers increases with increasing 3(S)-isopropyl-morpholine-2,5-dione content in the feed and reaction time. According to 1H NMR analysis, racemization of valine residue takes place during the polymerization. About 40% of 3(S)-isopropyl-morpholine-2,5-dione is racemized in 96 h at 140°C during polymerization, while about 12% is racemized in 24 h. The glass transition temperature of the poly(Glc-Val) segments in the triblock copolymers is about 74°C. The melting temperature of the PEO block upon first heating is lower than that of the homopolymer, and disappears with increasing length of the poly(Glc-Val) blocks. Enzyme-catalyzed ring-opening polymerization of morpholine-2,5-diones The enzymatic ring-opening polymerization of 6-membered cyclic depsipeptides, 3(S)-isopropyl-morpholine-2,5-dione, 3(R)-isopropyl-morpholine-2,5-dione, 3(R,S)-isopropyl-morpholine-2,5-dione, (3S, 6R,S)-3-isopropyl-6-methyl-morpholine-2,5-dione, 3(S)-isobutyl-morpholine-2,5-dione, 3(S)-sec-butyl-morpholine-2,5-dione, 6(S)-methyl-morpholine-2,5-dione and 6(R,S)-methyl-morpholine-2,5-dione in the bulk, was investigated by using the lipase PPL as a catalyst. In the absence of the enzyme, the monomers were recovered, indicating that the present polymerization proceeds through enzymatic catalysis. During the polymerization of morpholine-2,5-diones racemization of both the amino acid and the S-lactic acid moiety takes place. Enzymatic polymerization produces polydepsipeptides with a carboxylic acid group at one end and a hydroxyl group at the other one. Selected commercial lipases were screened as catalysts for the polymerization of 3(S)-isopropyl-morpholine-2,5-dione at 100°C in bulk. Polymerizations catalyzed with lipases PPL, PS and CR result in conversions of about 50%, and in molecular weights ranging from 3500 to 17500. Lipase PPL was selected for further studies. The apparent rate of polymerization increases with PPL concentration. When the PPL concentration is 5 wt% and 10 wt% with respect to the monomer, a conversion of about 70% is reached after 5 d and 7 d, respectively, while for PPL concentrations of 1 wt% and 0.5 wt% the conversion is less than 15% even after 11 d. High concentrations of PPL (10 wt%) result in high values (< 4 d); with decreasing concentration of PPL poly(Glc-Val) of lower molecular weight is obtained. The highest molecular weight poly(Glc-Val), = 30000 resulted from a polymerization conducted at 130°C. Increasing polymerization time (and conversion) leads for high PPL concentration (10 wt%) first to an increase in and later to a decrease. The general trends observed by variation of the polymerization temperature are the following: (i) increasing monomer conversion and with increasing reaction temperature from 100 to 130°C,.(ii) increasing reaction temperature leads to a bimodal molecular weight distribution. Water is an important factor that controls not only the conversion but also the molecular weight. With increasing water content, enhanced polymerization rates are achieved while the molecular weight of poly(Glc-Val) decreases. Polymerizations of 6(S)-methyl-morpholine-2,5-dione catalyzed with 10 wt% lipases PPL, PC and CR result in conversions of about 75% in 3 d, and in molecular weights ranging from 8200 to 12100. MJ showed lower catalytic activity for the polymerization. The apparent rate of polymerization increases with increasing PPL concentration when the temperature is 100°C. When the PPL concentration is 5 wt% and 10 wt% with respect to the monomer, a conversion of about 70% is reached after 6 d and 1 d, respectively, while for PPL concentration of 1 wt% the conversion is less than 20% even after 6 d. High concentrations of PPL (10 wt%) result in high values (< 3 d); with lower concentration of PPL poly(Lac-Gly) of lower molecular weight is obtained. The reaction temperature (100 - 130°C) affects monomer conversion and slightly. The effect of water on the conversion and the molecular weight is similar to that in the ring-opening polymerization of 3(S)-isopropyl-morpholine-2,5-dione in the presence of PPL. The lipase-catalyzed ring-opening polymerization of 3(S)-sec-butyl-morpholine-2,5-dione was also studied in detail. Copolymerization of 3(S)-isopropyl-morpholine-2,5-dione and D,L-lactide was carried out in the presence of PPL as a catalyst at 100°C for 168 h. Copolymers of various compositions were obtained. The enzymatic polymerization of DLLA and 3(S)-isopropyl-morpholine-2,5-dione produces copolymers with a carboxylic acid group at one end and a hydroxyl group at the other end