Enzymatic synthesis of functional polyesters

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 P-BL, the enantioselec-tivity was low; an enantioselective polymerization of P-BL occurred by using thermophilic lipase to give (R)-enriched PHB with 20-37% enantiomeric excess

The enantioselectivity was greatly improved by the copolymerization with 7- or 13-membered non-substituted lactone using lipase CA catalyst (Scheme 8); the ee value reached ca. 70% in the copolymerization of P-BL with DDL.97 It is to be noted that in the case of lipase CA catalyst, the (S)-isomer was preferentially reacted to give the (S)-enriched optically active copolymer. The lipase CA-catalyzed copolymerization of 8-caprolactone (6-membered) with DDL enan-tioselectively proceeded, yielding the (R)-enriched optically active polyester with ee of 76%.

Optically active polyesters were synthesized by lipase CA-catalyzed ring-opening polymerization of racemic 4-methyl or ethyl-e-caprolactone. The (S)-isomer was enantioselectively polymerized to produce the polyester with >95% ee.98 Quantitative reactivity of 4-substituted e-caprolactone using lipase CA as catalyst was analyzed.99 The polymerization rate decreased by a factor of 2 upon the introduction of a methyl substitutent at the 4-position. Furthermore, 4-ethyl-e-caprolactone polymerized five times slower than the 4-methyl-e-caprolactone. This reactivity difference is strongly related to the enan-tioselectivity. Interestingly, lipase CA displayed S-selectivity for 4-methyl or ethyl-e-caprolactone, and the enantioselectivity was changed to the (R)-enantiomer in the case of 4-propyl-e-caprolactone.

Lipase BC induced the enantioselective polymerization of 3-methyl-4-oxa-6-hexanolide (MOHEL).16 The initial reaction rate of the S-isomer was seven times

Racemic monomer o.

Racemic monomer

(S)-enriched

(R)-enriched (unreacted)

(S)-enriched

(R)-enriched (unreacted)

ro2cch2ch—chch2co2r 1 2m trans (r=ch2cci3) Lipase

Scheme 9

larger than that of the R-isomer, indicating that the enantioselective polymerization of MOHEL took place through lipase catalysis. (S)-MOHEL was also polymerized by lipase PF, whereas no polymerization of the R-isomer took place with lipase PF.

PPL catalyzed an enantioselective polymerization of bis(2,2,2-trichloroethyl) trans-3,4-epoxyadipate with 1,4-butanediol in diethyl ether to give a highly optically active polyester (Scheme 9).100 The molar ratio of the diester to the diol was adjusted to 2:1 to produce the (-) polymer with enantiomeric purity of >96%. The polymerization of racemic bis(2-chloroethyl) 2,5-dibromoadipate with excess of 1,6-hexanediol using lipase A catalyst produced optically active trimer and pentamer.101 The polycondensation of 1,4-cyclohexanedimethanol with fumarate esters using PPL catalyst afforded moderate diastereoselectivity for the cis/trans monocondensate and markedly increased diastereoselectivity for the dicondensate product.102

An optically active oligoester was enantioselectively prepared from racemic 10-hydroxyundecanoic acid using lipase CR catalyst.103 The resulting oligomer was enriched in the (S)-enantiomer to a level of 60% ee and the residual monomer was recovered with a 33% ee favoring the antipode. Lactic acid was converted to the corresponding oligomer with DP up to 9 by lipase CA catalyst.104 HPLC analysis showed that the (R)-enantiomer possessed higher enzymatic reactivity. Optically active oligomers (DP < 6) were also synthesized from racemic e-substituted-e-hydroxy esters using PPL catalyst.105 The enantioselectivity increased as a function of bulkiness of the monomer substituent. The enzymatic copolymerization of the racemic hydroxyacid esters with methyl 6-hydroxyhexanoate produced the optically active polyesters with molecular weight higher than 1 x 103. Enzymatic enantioselective oligomerization of a symmetrical hydroxy diester, dimethyl p-hydroxyglutarate, produced a chiral oligomer (dimer or trimer) with 30-37% ee.106 Polyols such as glycerol and sugars were enzymatically regioselectively polymerized with dicarboxylic acid derivatives to form soluble polyesters. The lipase-catalyzed polycondensation of glycerol and divinyl esters produced polyesters having a secondary hydroxy group in the main chain.107 NMR analysis of the polymer obtained from divinyl sebacate and glycerol using lipase CA

Lipase

-CH3CHO

Scheme 10

catalyst at 60°C in bulk showed that 1,3-diglyceride was a main unit and that a small amount of the branching unit (triglyceride) was contained.108 The regios-electivity of the acylation between primary and secondary hydroxy groups was 74:26. In the polymerization at 45°C, the regioselectivity was perfectly controlled to give a linear polymer consisting exclusively of 1,3-glyceride units (Scheme 10).

The polymerization of divinyl sebacate with 1,2,4-butanetriol or 1,2,6-hexanetriol at 60° C produced the polymer containing the branched unit. In the polymerization at lower temperature, the regioselectivity was perfectly controlled to give the linear polymer consisting of exclusively a, w-disubstituted unit.109 The lipase origin and feed ratio of monomers greatly affected the microstructure of the polymer. The lipase MM-catalyzed polymerization of divinyl sebacate and glycerol produced a linear polymer consisting of 1,2- and 1,3-disubstituted units, whereas the 1,3-disubstituted and trisubstituted units were observed in the polymer obtained using lipase PC catalyst. Interestingly, the highly branched polyester with branching factor >0.7 was formed by the lipase CA-catalyzed reaction of poly(azelaic anhydride) and triols such as glycerol.

As a possible application of glycerol-based polyesters, new crosslinkable polyesters were synthesized by lipase CA-catalyzed polymerization of divinyl sebacate and glycerol in the presence of unsaturated higher fatty acids derived from renewable plant oils (Scheme 11).110,111 The polymerization under reduced pressure improved the polymer yield and molecular weight. The curing of the polymer obtained using linoleic or linolenic acid proceeded by cobalt naphthenate catalyst or thermal treatment to give a crosslinked transparent film. Biodegrad-ability of the obtained film was evaluated by biochemical oxygen demand (BOD) measurement in an activated sludge. The degradation gradually took place and the biodegradability reached 45% after 42 days, indicating the good biodegradability of this crosslinked film.

Epoxide-containing polyesters were enzymatically synthesized via two routes using unsaturated fatty acids as starting substrate (Scheme 11).112 Lipase catalysis was used for both polycondensation and epoxidation of unsaturated fatty acid group. One route was synthesis of aliphatic polyesters containing an

Scheme 11

unsaturated group in the side chain from divinyl sebacate, glycerol, and the unsaturated fatty acids, followed by an epoxidation of the unsaturated fatty acid moiety in the side chain of the resulting polymer. In another route, epoxidized fatty acids were prepared from the unsaturated fatty acids and hydrogen peroxide in the presence of lipase catalyst, and subsequently the epoxidized fatty acids were polymerized with divinyl sebacate and glycerol. The polymer structure was confirmed by NMR and IR, and for both routes, the high epoxidized ratio was achieved. Curing of the resulting polymers proceeded thermally, yielding transparent polymeric films with high gloss surface. Pencil scratch hardness of the present film improved, compared with that of the cured film obtained from the polyester having an unsaturated fatty acid in the side chain. The obtained film showed good biodegradability, evaluated by BOD measurement in an activated sludge.

For regioselective acylation of sugars, proteases were often used as catalyst.1 Polyesters having a sugar moiety in the main chain were synthesized via the protease catalysis. In the polycondensation of sucrose with bis(2,2,2-trifluoroethyl) adipate catalyzed by an alkaline protease from Bacillus sp. showing an esterase activity, the regioselective acylation of sucrose at the 6 and 1'-positions was claimed to yield the sucrose-containing polyester (Scheme 12).113 The reaction proceeded slowly; the molecular weight reached larger than 1 x 104 after 7 days.114

Scheme 12

Two-step synthesis of sugar-containing polyesters by lipase CA catalyst was reported (Scheme 13).115 Lipase CA catalyzed the condensation of sucrose with an excess of divinyl adipate to produce sucrose 6,6' -O-divinyl adipate, which was reacted with a,w-alkylene diols by the same catalyst, yielding polyesters containing a sucrose unit in the main chain. This method conveniently affords

Upase - CH3CHO

oh oh oh

Scheme 14

the sugar-containing polyesters with relatively high molecular weight. Similarly, a trehalose-containing polyester was obtained from trehalose 6,6'-O-divinyl adipate through the catalysis of lipase CA.

We first demonstrated that lipase CA produced the reduced sugar-containing polyesters regioselectively from divinyl sebacate and sorbitol, in which sorbitol was exclusively acylated at the 1 and 6-positions (Scheme 14).116 Mannitol and meso-erythritol were also regioselectively polymerized with divinyl sebacate. The enzymatic formation of the high molecular weight sorbitol-containing polyester was confirmed by combinatorial approach.80

The lipase CA-catalyzed polycondensation of adipic acid and sorbitol also took place in bulk.117 In the polymerization at 90°C, the molecular weight reached 1 x 104; however, the regioselectivity decreased (85%), probably due to the high temperature and/or the bulk condition. These data suggest that the divinyl ester is a suitable monomer for regioselective synthesis of sugar-containing polymers. The copolymerization of adipic acid, sorbitol, and 1,8-octanediol enhanced the molecular weight of the sugar-containing polyesters. The melting and crystallization temperatures as well as the melting enthalpy decreased with increasing sorbitol content.118 This is attributed to the polyol units along the polyester chain which disrupt crystallinity. The biocompatibility of the sugar-containing polyester from adipic acid, sorbitol, and 1,8-octanediol was examined by using a mouse fibroblast 3T3 cell line in vitro.119

Polyester-sugar or polyester-polysaccharide conjugates were regioselec-tively synthesized via enzyme catalysis. Lipase CA-catalyzed polymerization of e-CL in the presence of alkyl glucopyranosides produced polyesters bearing a sugar at the polymer terminal (Scheme 15).120121 In the initiation step, the primary hydroxy group of the glucopyranoside was regioselectively acylated. Polysaccha-rides also initiated the lipase-catalyzed polymerization of e-CL.122 The enzymatic graft polymerization of e-CL on hydroxyethyl cellulose produced cellulose-graft-poly(e-CL) with degree of substitution from 0.10 to 0.32.

Reactive polyesters were enzymatically synthesized. Lipase catalysis chemoselectively 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).123 124 This is in contrast to the anionic

polymerization; the vinyl polymerization of this monomer took place by a conventional anionic initiator or catalyst.

Terminal-functionalized polymers such as macromonomers and telechelics are very important as prepolymer for construction of functional materials. Singlestep functionalization of polymer terminal was achieved via lipase catalysis. Alcohols could initiate the ring-opening polymerization of lactones by lipase catalyst. The lipase CA-catalyzed polymerization of DDL in the presence of 2-hydroxyethyl methacrylate gave the methacryl-type polyester macromonomer, in which 2-hydroxyethyl methacrylate acted as initiator to introduce the methacryloyl group quantitatively at the polymer terminal ("initiator method").125 This methodology was expanded to the synthesis of w-alkenyl- and alkynyl-type macromonomers by using 5-hexen-1-ol and 5-hexyn-1-ol as initiator, respectively.

A methacryl-type polyester macromonomer was synthesized by lipase PF-catalyzed polymerization of DDL using vinyl methacrylate as terminator ("terminator method"), in which the vinyl ester terminator was present from the beginning of the reaction (Scheme 17).126 In using divinyl sebacate as terminator, the telechelic polyester having a carboxylic acid group at both ends was obtained.127 Various non-protected thiol compounds were used as initiator or terminator for the thiol end-functionalization of poly(e-CL).128

Long-chain unsaturated a,w-dicarboxylic acid methyl esters and their epox-idized derivatives were polymerized with 1,3-propanediol or 1,4-butanediol in the presence of lipase CA catalyst to produce reactive polyesters.129 The molecular weight of the polymer from 1,4-butanediol was higher than that from

Scheme 17

1,3-propanediol. All the resulting polymers possessed melting point in the range from 23 to 75°C.

Unsaturated ester oligomers were synthesized by lipase-catalyzed polymerization of diesters of fumaric acid and 1,4-butanediol.130 Isomerization of the double bond did not occur to give all-trans oligomers showing crystallinity, whereas the industrial unsaturated polyester having a mixture of cis and trans double bonds is amorphous.131 The enzymatic polymerization of bis(2-chloroethyl) fumarate with xylylene glycol produced the unsaturated oligoester containing aromaticity in its backbone.132

Chemoenzymatic synthesis of alkyds (oil-based polyester resins) was demonstrated.133 PPL-catalyzed transesterification of triglycerides with an excess of 1,4-cyclohexanedimethanol mainly produced 2-monoglycerides, followed by thermal polymerization with phthalic anhydride to give the alkyd resins with molecular weight of several thousands. The reaction of the enzymatically obtained alcoholysis product with toluene diisocyanate produced the alkyd-urethane.

The enzymatic polymerization of 12-hydroxydodecanoic acid in the presence of 11-methacryloylaminoundecanoic acid conveniently produced the methacrylamide-type polyester macromonomer.134 135 Lipases CA and CC were active for the macromonomer synthesis. Enzymatic selective monosubstitution of a hydroxy-functional dendrimer was demonstrated.136 Lipase CA-catalyzed polymerization of e-CL in the presence of the first generation dendrimer gave the poly(e-CL)-monosubstituted dendrimer.

Poly(ethylene glycol) (PEG)-containing polyesters were synthesized via lipase catalysis.137 The lipase CA-catalyzed polymerization of dimethyl 5-hydroxyisophthalate, a,w-alkylene glycol, and PEG having a hydroxy group at both ends gave the PEG-containing polyesters. The chemoenzymatic synthesis of amphiphilic polyesters was examined by the lipase CA-catalyzed polymerization of dimethyl 5-hydroxyisophthalate and PEG, followed by the coupling with alkyl bromide.138 The supramolecular organization of the resulting polymeric nanomi-celles in an aqueous medium was confirmed by NMR and light scattering. In vivo studies by encapsulating anti-inflammatory agents in the polymeric nanomicelles and by applying topically resulted in significant reduction in inflammation. The reduction ratio in inflammation using the polymeric nanomicelles was about 60%.

A novel chemoenzymatic route to polyester polyurethanes was developed without employing highly toxic isocyanate intermediates.139 First, diurethane diols were prepared from cyclic carbonates and primary diamines, which were subsequently polymerized with dicarboxylic acids and glycols by using lipase CA as catalyst, yielding the polyurethanes under mild reaction conditions.

Fluorinated polyesters were synthesized by the enzymatic polymerization of divinyl adipate with fluorinated diols. Lipase CA was effective in producing the fluorinated polyesters.140 The highest molecular weight (5.2 x 103) was achieved by the polymerization using 3,3,4,4,5,5,6,6-octafluorooctan-1,8-diol in bulk. A silicon oligomer was synthesized by the polycondensation of diethoxydimethylsilane using lipid-coated lipase from Rhizopus delemar as catalyst in isooctane containing a small amount of water.141 The polymerization is proposed to be initiated at the OH head group of the coating lipid.

Block copolymers were synthesized by a combination of lipase-catalyzed polymerization and atom transfer radical polymerization (ATRP).142'143 At first, the polymerization of 10-hydroxydecanoic acid was carried out by using lipase CA as catalyst. The terminal hydroxy group was modified by the reaction with a-bromopropionyl bromide, followed by ATRP of styrene using CuCl/2,2'-bipyridine as catalyst system to give the polyester-polystyrene block copolymer. Trichloromethyl-terminated poly(e-CL), which was synthesized by lipase CA-catalyzed polymerization with 2,2,2-trichloroethanol initiator, was used as initiator for ATRP of styrene.

Enzyme catalysts are useful for polymer recycling. We first proposed a new concept of chemical recycling of polymers using lipase catalyst.144 Aliphatic polyesters were subjected to hydrolytic degradation by lipase catalyst in organic solvents. The lipase CA-catalyzed degradation of poly(e-CL) with molecular weight 4 x 104 readily took place in toluene at 60°C to give oligomers with molecular weight less than 500. The degradation behavior catalyzed by lipase was quite different than an acid-catalyzed degradation (random bond cleavage of polymer). After the removal of the solvent from the reaction mixture, the residual oligomer was polymerized in the presence of the same catalyst of lipase. These data provide a basic concept that the degradation-polymerization could be controlled by

Scheme 18

Scheme 18

the presence or absence of the solvent, providing a new methodology of plastics recycling (Scheme 18).

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