Ring-opening polymerization lipase

Various cyclic esters have been subjected to hpase-catalyzed ring-opening polymerization. Lipase catalyzed the ring-opening polymerization of 4- to 17-membered non-substituted lactones.In 1993, it was first demonstrated that medium-size lactones, 8-valerolactone (8-VL, six-membered) and e-caprolactone (e-CL, seven-membered), were polymerized by lipases derived from Candida cylindracea, Burkholderia cepacia (lipase BC), Pseudomonas fluorescens (lipase PF), and porcine pancreas (PPL). °... 

In polyester synthesis via ring-opening polymerizations, metal catalysts are often used. For medical applications of polyesters, however, there has been concern about harmful effects of the metallic residues. Enzymatic synthesis of a metal-free polyester was demonstrated by the polymerization of l,4-dioxan-2-one using Candida antarctica lipase (lipase CA). Under appropriate reaction conditions, the high molecular weight polymer (molecular weight = 4.1 x 10" ) was obtained. 

Lipase catalysis is often used for enantioselective production of chiral compounds. Lipase induced the enantioselective ring-opening polymerization of racemic lactones. In the lipase-catalyzed polymerization of racemic (3-BL, the enantioselec-tivity was low an enantioselective polymerization of (3-BL occurred by using thermophilic lipase to give (/ )-enriched PHB with 20-37% enantiomeric excess (ee). ... 

Optically active polyesters were synthesized by lipase CA-catalyzed ring-opening polymerization of racemic 4-methyl or ethyl-e-caprolactone. The (5 )-isomer was enantioselectively polymerized to produce the polyester with >95% ee. Quantitative reactivity of 4-substituted e-caprolactone using lipase CA as catalyst was analyzed. The polymerization rate decreased by a factor of 2 upon the introduction of a methyl substitutent at the 4-position. Furthermore, 4-ethyl-8-caprolactone polymerized five times slower than the 4-methyl-8-caprolactone. This reactivity difference is strongly related to the enantioselectivity. Interestingly, lipase CA displayed 5 -selectivity for 4-methyl or ethyl-8-caprolactone, and the enantioselectivity was changed to the (f )-enantiomer in the case of 4-propyl-8-caprolactone. 

Reactive polyesters were enzymatically synthesized. Lipase catalysis chemoselecfively induced the ring-opening polymerization of a lactone having exo-methylene group to produce a polyester having the reactive exo-methylene group in the main chain (Scheme 16). This is in contrast to the anionic... 

Lipase-Catalyzed Ring-Opening Polymerization of Cyclic Monomers... 

Polyester syntheses have been achieved by enzymatic ring-opening polymerization of lactide and lactones with various ring-sizes. Here, we focus not only on these cyclic esters but also other cyclic monomers for lipase-catalyzed ringopening polymerizations. Figure 8 summarizes cyclic monomers for providing polyesters via lipase catalysis. 

Ring-opening polymerization of racemic a-methyl-/J-propiolactone using lipase PC catalyst proceeded enantioselectively to produce an optically active (S)-enriched polymer [68]. The highest ee value of the polymer was 0.50. NMR analysis of the product showed that the stereoselectivity during the propagation resulted from the catalyst enantiomorphic-site control. 

Lipase catalyzed the ring-opening polymerization of medium-size lactones, d-valerolactone (<5-VL, six-membered) and -caprolactone (c-CL, seven-mem-bered). Lipases CC, PF and PPL showed high catalytic activity for the polymerization of <5-VL [74,75]. The molecular weight of the polymer obtained in bulk at 60 °C was relatively low (less than 2000). 

Ring-opening polymerization of a-methyl-substituted medium-size lactones, a-methyl-y-valerolactone and a-methyl-c-caprolactone, proceeded by using lipase CA catalyst in bulk [82]. As to (R)- and (S)-3-methyl-4-oxa-6-hexa-nolides (MOHELs), lipase PC induced the polymerization of both isomers. The apparent initial rate of the S-isomer was seven times larger than that of the R-isomer, indicating that the enantioselective polymerization of MOHEL took place through lipase catalysis [83]. 

Enzyme activity for the polymerization of lactones was improved by the immobilization on Celite [93]. Immobilized lipase PF adsorbed on a Celite showed much higher catalytic activity than that before the immobilization. The catalytic activity was further enhanced by the addition of a sugar or poly(ethylene glycol) in the immobilization. Surfactant-coated lipase efficiently polymerized the ring-opening polymerization of lactones in organic solvents [94]. 

An alcohol could initiate the ring-opening polymerization of lactones by lipase catalyst ( initiator method ). In the lipase CA-catalyzed polymerization of DDL using 2-hydroxyethyl methacrylate as initiator, the methacryloyl group was quantitatively introduced at the polymer terminal, yielding the methacryl-type polyester macromonomer [98]. This methodology was expanded to synthesis of co-alkenyl- and alkynyl-type macromonomers by using 5-hexen-l-ol and 5-hexyn-l-ol as initiator. 

Here, lipase-catalyzed ring-opening polymerization of cyclic compounds giving polymers other than polyesters is described. l,3-Dioxan-2-one, six-membered cyclic carbonate, was polymerized in the presence of lipase catalysts (Fig. 13)... 

S)-Isopropylmorpholine-2,5-dione, six-membered depsipeptide, was polymerized by lipase PC and PPL catalysts [112]. High temperature (100°C or 130°C) was required for the polymerization, yielding biodegradable poly(de-psipeptide). During the polymerization, the racemization of the valine residue took place. Demonstrated was PPL-catalyzed ring-opening polymerization of ethylene isopropyl phosphate, five-membered cyclic phosphate [113]. 

Uyama H, Kobayashi S (1993) Enzymatic ring-opening polymerization of lactones catalyzed by lipase. Chem Lett 1149-1150... 

Feng Y, Kniifermann J, Klee D, Hdcker H (1999) Lipase-catalyzed ring-opening polymerization of 3(S)-isopropylmorpholine-2,5-dione. Macromol Chem Phys 200 1506-1514... 

Enantioselective Ring-Opening Polymerizations of Substituted Lactones Using Lipases... 

Ring-opening polymerization of several l,3-dioxan-2-ones using a series of lipases has also been reported and these studies have been reviewed . 

Conventional ring-opening polymerization of cyclic anhydrides, carbonates, lactones, and lactides require extremely pure monomers and anhydrous conditions as well as metallic catalysts, which must be completely removed before use, particularly for medical applications. To avoid these difficult restrictions, an enzymatic polymerization may be one of the more feasible methods to obtain the polyesters. This method was first reported by two independent groups (Kobayashi [152] and Gutman [153]) who showed that lipases, enzymes capable of catalyzing the hydrolysis of fatty acid esters, can polymerize various medium-sized lactones. 

The aliphatic poly(ether lactonejs are a group of synthetic polymers with high elasticity and high tissue absorptivity [293]. The ether function in the polymer backbone adds flexibility to the ester chain. Ring-opening polymerization of l,4-dioxan-2-one yields an elastic polymer, polydioxanone, with a tensile strength similar to that of human tissue [294]. Polydioxanone has been successfully used to prepare monofilament sutures, with a flexibility superior to that of PGA sutures [294]. Recently, the lipase-catalyzed polymerization of polydioxanone was demonstrated [295]. 

In another solvent-free process with the same lipase as above, trimethylene carbonate underwent an almost quantitative ring-opening polymerization in 120 h at 70 °C to form poly(trimethylene carbonate) [18]. No decarboxylation was detected (Scheme 4). w-Pentadecalactone was likewise polymerized with lipases in the absence of a solvent to form polyesters of high molecular weight [19]. 

Poly(s-caprolactone) Poly(e-caprolactone) is a semicrystalline polymer synthesized by anionic, cationic, free-radical, or ring-opening polymerization [94]. It is available in a range of molecular weights and degrades by bulk hydrolysis autocatalyzed by the carboxylic acid end groups. The presence of enzymes such as protease, amylase, and pancreatic lipase accelerates polymer degradation [95], The various methods of preparation of poly(e-caprolactone) nanoparticles include emulsion polymerization, interfacial deposition, emulsion-solvent evaporation, desolvation, and dialysis. These methods and various applications are extensively reviewed [94],... 

Lipase Transesterification and direct esterification (inch polyester synthesis) Ring-opening polymerization of 8-caprolactone Hydrolysis alcoholysis acetylation Higher stability of enzyme greater activity catalyst recyclable sometimes higher enantio- and regio-selectivity compared with VOCs... 

As for the enzymatic ring-opening polymerization of e-CL, various commercially available lipases have been tested as a catalyst. Several crude lipases (PPL, lipases CR, PC, and Pseudomonas fluorescens lipase (lipase PF)) induced the polymerization however, a... 

Lipase-catalyzed ring-opening polymerization of nine-membered lactone, 8-octanolide (OL), has been reported.165 Lipases CA and PC showed the high catalytic activity for the polymerization. Racemic fluorinated lactones with a ring size from 10 to 14 were enantioselectively polymerized by lipase CA catalyst to give optically active polyesters.166... 

Besides cyclic esters and carbonates, six-membered cyclic depsipeptides and a five-membered cyclic phosphate were subjected to lipase-catalyzed ring-opening polymerizations, yielding poly (ester amide)s190 and polyphosphate,191 respectively. High temperatures (100—130 °C) were required for the polymerization of the former monomers. 

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