Cascade Synthesis of Chiral Block Copolymers Combining Lipase

Jul 21, 2004 - The enantioselective polymerization of methyl-substituted ε-caprolactones using Novozym 435 as the catalyst was investigated. All subs...
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Biomacromolecules 2004, 5, 1862-1868

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Cascade Synthesis of Chiral Block Copolymers Combining Lipase Catalyzed Ring Opening Polymerization and Atom Transfer Radical Polymerization Joris Peeters,† Anja R. A. Palmans,*,† Martijn Veld,† Freek Scheijen,† Andreas Heise,‡ and E. W. Meijer*,† Laboratory of Macromolecular and Organic Chemistry, Eindhoven University of Technology, P.O. Box 513, 5600 MB Eindhoven, The Netherlands, and DSM Research, P.O. Box 18, 6160 MD Geleen, The Netherlands Received April 6, 2004; Revised Manuscript Received June 9, 2004

The enantioselective polymerization of methyl-substituted -caprolactones using Novozym 435 as the catalyst was investigated. All substituted monomers could be polymerized except 6-methyl--caprolactone (6-MeCL), which failed to propagate after ring opening. Interestingly, an odd-even effect in the enantiopreference of differently substituted monomers was observed. The combination of 4-methyl--caprolactone with Novozym 435 showed good enantioselectivity also in bulk polymerization and resulted in enantiomerically enriched P((S)-4-MeCL) (eep up to 0.88). Subsequently, a novel initiator combining a primary alcohol to initiate the ring opening polymerization and a tertiary bromide to initiate atom transfer controlled radical polymerization (ATRP) was synthesized, and showed high initiator efficiencies (>90%) in the ring opening polymerization of 4-methyl--caprolactone in bulk. In addition, the enantioselectivity was retained (E ) 11). By using Ni(PPh3)2Br2 as the ATRP catalyst, Novozym 435 could be effectively inhibited at the desired conversion of 4-methyl--caprolactone, thus ensuring a high enantiomeric excess in the polymer backbone. At the same time, Ni(PPh3)2Br2 catalyzed the ATRP of methyl methacrylate resulting in the formation of P((S)-4-MeCLb-MMA) block copolymers. By this combination of two inherently different polymerization reactions, chiral P((S)-4-MeCL-b-MMA) block copolymers can be conveniently obtained in one pot without intermediate workup. 1. Introduction In recent years, enzymatic polymerizations have been evaluated as a new methodology for polymer synthesis.1 Enzymes are an attractive alternative to conventional chemical polymerization catalysts because of their selectivity, ability to operate under mild conditions, recyclability, and biocompatibility. The lipase B of Candida antarctica (CALB), for example, is recognized widely as a versatile catalyst for enzymatic polymerizations.1-3 Recently, the scope of lipase catalysis in polymer chemistry has been further widened by the preparation of block copolymers and hyperbranched polymers.4,5 The potential of lipases to perform reactions in a highly enantioselective way is well exploited in industry for the synthesis of, e.g., pharmaceutical intermediates.6 In contrast, their potential for enantioselective polymerizations has received considerably less attention despite promising findings.7 The enantioselectivity of CALB makes this lipase the ideal catalyst for evaluation in enantioselective (ring opening) polymerizations.2 This may lead to enantiomerically enriched polymers with interesting properties starting from racemic mixtures. * Corresponding authors. E-mail: [email protected]; A.R.A.Palmans@ tue.nl. † Eindhoven University of Technology. ‡ DSM Research.

Our aim is to extend our recently reported concept of the combination of lipase catalyzed ring opening polymerization (ROP) and atom transfer controlled radical polymerization (ATRP) to synthesize chiral block copolymers in a one-pot approach.4 Therefore, we have focused on the enantioselective ring opening polymerization (ROP) of methyl-substituted -caprolactones. It was recently found that CALB shows promising enantioselectivity in the ROP of 4-substituted -caprolactones leading to enantiomerically enriched polyesters.7a In the first part of the paper, we report on the regio- and stereoselectivity of CALB in ROP of substituted -caprolactones and the optimization of reaction conditions in order to achieve high enantiomeric ratios. In the second part, 4-methyl--caprolactone is used in a one-pot reaction combining enantioselective ROP and ATRP to procure chiral block copolymers (Scheme 1). The combination of two different, consecutively proceeding polymerization reactions without intermediate workup can be referred to as cascade polymerization in analogy to cascade conversions in organic synthesis.8 2. Materials and Methods 2.1. Materials. All chemicals were purchased from Aldrich and used without further purification unless other-

10.1021/bm049794q CCC: $27.50 © 2004 American Chemical Society Published on Web 07/21/2004

Cascade Synthesis of Chiral Block Copolymers

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Scheme 1. Cascade Approach to a Chiral Block Copolymer Combining Enantioselective ROP of 4-Methyl--caprolactone and ATRP of Methyl Methacrylate

wise noted. Benzyl alcohol and substituted -caprolactones were freshly distilled from CaH2 under reduced pressure and stored over 4 Å molecular sieves. Methyl methacrylate (MMA) was washed with a 1 M NaOH solution, dried over MgSO4, and distilled. Toluene was freshly distilled from sodium and tetrahydrofuran (THF) from molecular sieves. All other solvents used in polymerization reactions were stored over activated molecular sieves. Novozym 435 was purchased from Novozymes A/S and stored over P2O5 in a desiccator. 2.2 Analytical Methods. All reactions were followed by chiral gas chromatography (GC) with a Shimadzu 6C-17A GC equipped with an flame ionization detector (FID) employing a Chrompack Chirasil-DEX CB (DF ) 0.12) column. Injection and detection temperatures were set at 300 and 325 °C, respectively. Separations were done under isocratic conditions with the column temperature set at 125 °C; in all cases baseline separation of the enantiomers/ regioisomers was achieved. The internal standard method, taking the polymerization solvent as the internal standard, was used to determine the lactone conversion and enantiomeric excess (eem) in the unreacted monomer; all samples were measured in triplo using a Shimadzu AOC-20i autosampler. The eem was calculated as follows: eem ) (R S)/(R + S), where R and S represent the surfaces of the GC peaks of the R- and S-enantiomers, respectively. The GC data were used to calculate the enantiomeric excess in the polymer (eep) as described in the literature.7b The enantiomeric ratio (E ratio)9 which in terms of conversion (c) and eem is expressed as E ) ln[(1 - c)(1 - eem)]/ln[(1 - c)(1 + eem)], was fitted using Origin 6.0 employing the nonlinear curve fit option and rewriting the formula to c ) 1 - [(1 eem)/(1 + eem)E](1/E-1). The initial rate constants (ki) were derived from the slope of the ln(1 - c) versus time plot assuming first-order kinetics. 1H and 13C NMR spectra were taken with a Varian Mercury Vx 400 or 300 spectrometer (400 or 300 MHz) in CDCl3 with the delay time (d1) set at 10 s. For the polymerization of 4-MeCL in bulk, the conversion, c, was determined from 1H NMR spectra by comparing the intensity of the CH2CdO peak at 2.65 ppm (Iδ)2.65) of the monomer to the intensity of the CH2CdO peak at 2.30 ppm of the polymer (Iδ)2.30) so c ) (Iδ)2.30)/ [(Iδ)2.30) + (Iδ)2.65)]. Initiator 1 conversions were calculated as c ) (Iδ)5.10)/[(Iδ)5.10) + (Iδ)4.75)] and the degree of polymerization in P(4-MeCL), DP, was calculated as DP )

(Iδ)2.30)/(Iδ)3.75). The mole percentage of the water initiated chain was determined by comparing the intensities of the benzyl end group at 5.10 ppm and the alcohol end group at 3.75 ppm as follows: mole percentage of water initiated chains ) 1 - [(Iδ)5.10)/(Iδ)3.75)]. Gel permeation chromatography (GPC) was carried out on a Waters 712 WISP HPLC system with a Waters 410 differential refractometer detector and a PL gel guard precolumn (5 mm, 50 × 7.5 mm) followed by two PL gel mixed-C columns (10 mm, 300 × 7.5 mm, Polymer Laboratories), using THF as the eluent. All molecular weights were relative to polystyrene standards. 2.3. Monomer and Initiator Synthesis and Characterization. Baeyer-Villiger oxidations were performed as described previously.10 The peaks in the GC traces were assigned by comparison with literature data.7a,10b 4-Methyl--caprolactone. Yield ) 70%. bp ) 64-65 °C/0.56 Torr. 1H NMR (CDCl3): δ 4.25 (m, 2H, CH2OCdO); 2.65 (m, 2H, CH2CdO); 2.00-1.15 (4× m, 5H, CH and CH2); 1.02 (d, 3H, CH3).13C NMR (CDCl3): δ 176.0 (CdO); 68.0; 37.2; 35.1; 33.1; 30.7; 22.1. GC retention time: (S)-4-MeCL ) 9.6 min; (R)-4-MeCL ) 9.9 min. 6-Methyl--caprolactone Contaminated with 5% 2-Methyl-caprolactone. Yield ) 76%. bp ) 58-60 °C/0.6 Torr. 1H NMR (CDCl3): δ 4.45 (q, 1H, CHOCdO); 2.60 (m, 2H, CH2CdO); 1.90-1.40 (2× m, 6H, CH2); 1.30 (d, 3H, CH3). 13 C NMR (CDCl3): δ 175.4 (CdO); 76.60; 36.0; 34.8; 28.0; 22.7; 22.4. GC retention time: (S)-6-MeCL ) 6.5 min; 2-MeCL ) 7.0 min; (R)-6-MeCL ) 7.3 min. 3/5-Methyl--caprolactone. Yield ) 76%. bp ) 61 °C/0.6 Torr. 1H NMR (CDCl3): δ 4.30-3.70 (2× m, 4H, CH2OCdO); 2.50 (m, 4H, CH2CdO); 1.90-1.30 (m, 10H, CH and CH2); 0.95(d, 3H, CH3); 0.85 (d, 3H, CH3). 13C NMR (CDCl3): 175.7, 174.8 (CdO); 73.7, 69.0 (C-ipso); 41.6; 36.8; 36.5; 34.1; 33.6; 29.0; 27.5; 22.0; 21.3; 17.4. GC retention time: (S)-3-MeCL ) 8.1 min; (R)-3-MeCL ) 8.3 min; (R)-5-MeCL ) 8.7 min; (S)-5-MeCL ) 9.0 min. Initiator 1. To a two-neck round-bottom flask were added 1,4-benzenedimethanol (5.0 g, 36.1 mmol), freshly distilled triethylamine (3.7 g, 36.1 mmol), and dry THF (150 mL). The solution was cooled with an ice bath. Then, 2-bromoisobutyryl bromide (8.3 g, 36.1 mmol) in 40 mL of dry THF was slowly added via a dropping funnel. After the addition was complete, the mixture was stirred 1 h at room temperature. The salts were filtered off, and the filtrate was

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evaporated in vacuo. Then 1 M HCl (125 mL) was added and the mixture was extracted with dichloromethane (3 × 50 mL). The combined organic layers were extracted with water (200 mL), saturated Na2CO3 (200 mL), and saturated NaCl (200 mL), dried with MgSO4, filtrated, and evaporated in vacuo to yield the crude product. This crude product was purified using column chromatography (SiO2 and CH2Cl2 as the eluent) yielding pure 1 as a clear oil. Yield ) 41%. 1H NMR (CDCl3) δ ) 1.70 (t, 1H, OH); 1.95 (s, 6H, CH3); 4.75 (d, 2H, CH2OH); 5.15 (s, 2H, CH2OCdO); 7.40 (s, 4H, CH-Ar). 13C-MR (CDCl3): 172.0 (CdO); aromatic carbons: 141.2, 134.6, 128.1, 127.2; aliphatic carbons: 67.4, 64.6, 55.8 (C-ipso), 30.8 (CH3). Anal. Calcd for C12H15O3Br (287.15): C, 50.19%; H, 5.27%. Found: C, 50.12%; H, 5.32%. 2.4. General Procedure for the Polymerization of Methyl-Substituted E-Caprolactones. Novozym 435 (stored over P2O5, 200 mg), benzyl alcohol (34 mg, 0.31 mmol), the appropriate MeCL (2.00 g, 15.62 mmol), and the appropriate amount of solvent were weighed into a dried Schlenk tube. All polymerizations were conducted under Ar atmosphere at 45 °C, and the kinetics were followed by taking samples via a syringe at regular intervals and analyzing the samples by chiral GC. The polymerizations were stopped by adding dichloromethane and removing the enzyme by filtration. The polymers were purified by precipitation in heptane. All polymers were obtained as clear oils. 2.5. General Procedure for the Synthesis of Enantiomerically Enriched P(4-MeCL-b-PMMA). Novozym 435 (100 mg) was weighed in an oven-dried Schlenck tube. Then, the tube was provided with a stirring bar and rubber septum and put overnight in a vacuum oven at 50 °C together with some P2O5. The vacuum was released by filling the oven with nitrogen, and some molecular sieves were added to the tube. The reaction tube was then filled with argon, and the stock solution of 4-MeCL/initiator 1 in a 50/1 ratio (1.05 g) was added through the septum. The reaction was stirred for 7 h at 45 °C, and then a sample was taken for 1H NMR, GC, and GPC. Then, toluene (1 mL) and MMA (1.99 g, 19.90 mmol) were added through the septum. The septum was removed and under argon flushing Ni(PPh3)2Br2 (0.118 g, 0.16 mmol: equimolar amount to initiator 1) was added, after which the tube was directly capped with a new septum. To remove most of the oxygen, four freeze-pumpthaw cycles were performed. The reaction mixture was stirred for 18 h at 80 °C. A crude sample was taken for 1H NMR, GC, and GPC, which was first filtered over Al2O3 to remove the Ni catalyst. Finally, the crude product was dissolved in dichloromethane and filtered over Al2O3 followed by precipitation in heptane, affording the block copolymer as a white powder (isolated yield ) 50-60%). 1 H NMR (CDCl3): δ: 7.40 (m, H-Ar); 5.15 (s, Ar-CH2OC(dO)C(CH3)2); 5.10 (s, Ar-CH2O(CdO)CH2); 4.10-4.20 (m, CH2OCdO); 3.75 (t, CH2OH); 3.65 (s, CH3O-); 2.25-2.40 (m, CH2COO); 2.00 (s, -(CH3)2C); 1.70-2.00 (m, CH2CH2O); 1.85 (s, CH2(CdO)(CH3)); 1.40-1.70 (m, CH2CH2CdO); 1.20-1.45 (m, CH(CH3)); 1.00 (d, (CH3)CH); 0.90 (s, (CH3)C). Hydrolysis of the P(4-MeCL) block was performed according to a literature procedure.11

Peeters et al.

3. Results and Discussion 3.1. Monomer and Initiator Synthesis. All methylsubstituted -caprolactones were prepared from their corresponding cyclohexanones by Baeyer-Villiger oxidations using m-chloroperbenzoic acid.10 The oxidation of 4-methylcyclohexanone afforded pure 4-methyl--caprolactone (4MeCL), whereas the oxidation of 2-methylcyclohexanone afforded 6-methyl--caprolactone (6-MeCL) with a 2-methyl-caprolactone (2-MeCL) impurity (4-5%). The oxidation of 3-methylcyclohexanone resulted in a 1:1 mixture of 3-methyl--caprolactone (3-MeCL) and 5-methyl--caprolactone (5-MeCL). The monomers, 6-MeCL, 4-MeCL, and the 1/1 mixture of 3- and 5-MeCL, were purified by vacuum distillation from CaH2. Initiator 1 (Scheme 1) combines a primary hydroxy group for initiating ROP with a tertiary bromide for ATRP and was obtained in one step by reacting 1,4-benzenedimethanol with an equimolar amount of 2-bromoisobutyryl bromide. The resulting statistical mixture was purified using column chromatography affording pure 1 as a clear oil in 41% yield. 3.2. Synthesis of Enantiomerically Enriched Polyesters. To assess which methyl-substituted lactone is most appropriate for obtaining well-defined enantiomerically enriched block copolymers, we investigated the selectivity and polymerization kinetics of Novozym 435 as a function of the position of the methyl group. The monomers 4-MeCL, 3/5-MeCL, and 6-MeCL were polymerized in 1,2,3,4tetramethylbenzene (TMB) at 45 °C under argon at 40 M. Benzyl alcoholsserving as a model for initiator 1swas used as an initiator in a 1:50 molar ratio to the monomer. Commercially available Novozym 435, i.e., CALB immobilized on macroporous resin beads, was used as enzymatic catalyst (10% w/w with respect to the monomer). The conversion of the monomer and enantiomeric excess in the nonreacted monomer (eem) were followed as a function of time with chiral GC using the solvent TMB as the internal standard. In these experiments, TMB was selected over toluene as the solvent since its high boiling point renders the GC method more accurate. For all polymerizations, the conversion of each enantiomer was plotted versus the reaction time. As an example, the result of the ROP of 4-MeCL is given in Figure 1a. As expected for an enzyme-catalyzed reaction, an almost quantitative consumption of (S)-4-MeCL is observed within 180 min while (R)-4-MeCL only starts reacting after most of the S-enantiomer is consumed. From the unreacted monomer remaining in the mixture, eem was determined and plotted against the conversion (Figure 1b). By fitting these data according to the method of Cheng et al.,9 an enantiomeric ratio (E ratio) of 93 ( 27 was determined. Table 1 summarizes the end conversion and the initial rate constants (ki) of the faster reacting enantiomers of all methylsubstituted -caprolactones. The E ratio was determined for 3-, 4-, and 5-MeCL, and the enantiomeric excess in the polymer backbone (eep) was calculated for 4-MeCL. CALB shows S-selectivity for all methyl-substituted -caprolactones except for 5-MeCL, where R-selectivity is observed. A closer look at the three-dimensional structure

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Cascade Synthesis of Chiral Block Copolymers

Figure 2. Structures of the faster reacting enantiomers in Novozym 435 catalyzed ROP of the respective monomer mixtures.

Figure 1. (a) Monomer conversion during ROP of racemic 4-MeCL initiated by benzyl alcohol as a function of time; T ) 45 °C and benzyl alcohol/4-MeCL ratio ) 1/50: (b) (S)-4MeCL; (O) (R)-4MeCL. (b) Development of eem as a function of conversion; the dotted line represents the calculated development of eem as a function of conversion taking E ) 93. Table 1. Results of the Lipase Catalyzed ROP of Methyl-Substituted -Caprolactones at 45 °C faster reacting enantiomer monomer

configuration

ki (1/h)

conversion (%)

eep (%)

E

6-MeCL 5-MeCLc 4-MeCL 3-MeCLc

6S 5R 4S 3S

200fold molar excess with respect to the lipase, which results in less than 0.5% of Ni consumption. 3.4. Cascade Synthesis of Chiral Block Copolymers. For the cascade polymerization, we employ a bifunctional initiator that allows the synthesis of block copolymers without further transformation of the polymer end groups.18 Both polymerizations are conducted consecutively in one pot. Due to the absence of an intermediate workup step, impurities caused by side reactions in the first polymerization step cannot be removed prior to the second polymerization. To realize a high block copolymer yield, it is therefore important to minimize all side reactions that could result in the formation of homopolymers or other side products. In the ATRP step, the formation of homopolymers can only be caused by initiator not attached to a P(4-MeCL) chain. A high initiator efficiency approaching quantitative incorporation of the initiator is thus an essential requirement in the first step of the synthesis, i.e., the lipase catalyzed ROP. The formation of P(4-MeCL) homopolymer, on the other hand, can be caused by water acting as the acylating agent in the initiation of CL or in a transesterification reaction, respectively.19 This process is competitive to the initiation by the bifunctional initiator and produces PCL without active ATRP end groups but with carboxylic acid end groups. The frequency of this side reaction can be minimized by a low initial water concentration in the reaction mixture and a fast initiation kinetic of the bifunctional initiator. In a parallel study, we investigated the influence of the reaction conditions, e.g., the drying conditions and the initiator design, on the block copolymer yield. The detailed results of that study will be reported elsewhere; however, the optimized conditions are applied in the present study. Among others, initiator 1 demonstrates an initiator efficiency > 95% in the lipase catalyzed ROP of -caprolactone, validating the suitability of 1 for the preparation of block copolymers.20 In analogy to that result, we carefully evaluated the kinetics of 1 and 4-MeCL (ratio initiator/monomer ) 1/50) under the conditions of block copolymer synthesis, i.e., in bulk at 45 °C. As is evident from Figure 4, 1 is consumed fast and shows an initiator conversion exceeding 90% at a 4-MeCL conversion of about 20%. Moreover, the enanti-

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Cascade Synthesis of Chiral Block Copolymers Table 2. Characteristics of the Polymers Obtained in a ROP/ ATRP Cascade Approach of 4-MeCL and MMAa conversion (%) reaction (S)-4- (R)-4entry time (h) MeCL MeCL MMA A1 7 77 9 A2 25 79 9 97 A3 A4 B1 B2 B3 B4

7 25

86 89

10 11

Mnb ini 1 eep (g/mol) PDb DPc 90 0.80 3 200 1.8 26 0.79 10 900 1.3 d 10 100 1.4 e 6 700 1.5 94

97

d e

0.80

3 500 17 300 17 300 13 300

2.1 1.5 1.5 1.5

25

a Entries A and B refer to an initiator 1/4-MeCL/MMA Ratio of 1/50/64 and 1/50/128, respectively. b Determined by GPC relative to polystyrene standards. c Determined by 1H NMR end group analysis. d Precipitated polymer. e Hydrolyzed polymer.

oselectivity during the polymerization of 4-MeCL is retained (E ) 11). After 7 h, the conversion of (S)- and (R)-4-MeCL were 86 and 10%, respectively, resulting in an eep of 0.84. These results suggest that initiator 1 can be employed in the one-pot cascade synthesis of block copolymers in high yield and high enantioselectivity combining enzymatic polymerization and ATRP. For the cascade polymerization, all starting materials were carefully dried and kept under inert atmosphere. The synthesis of block copolymers was carried out following a one-pot, two-step procedure without intermediate workup. First a mixture of 1 and 4-MeCL was reacted to about 50% total monomer conversion in 7 h. Subsequently, oxygen was removed from the reaction medium by several consecutive freeze-pump-thaw cycles. The ATRP was initiated by adding MMA and Ni(PPh3)2Br2 and raising the reaction temperature to 80 °C (Scheme 1). For the block copolymers, we targeted two different block length ratios as determined by the molar ratios of monomers to initiator (1/4-MeCL/ MMA) of 1/50/64 and 1/50/128 (Table 2). Considering that only (S)-4-MeCL is expected to react, this would lead to block copolymers with average molecular weights for the P(4-MeCL)/PMMA blocks of 3200/6400 and 3200/12 800, respectively. The monomer conversion of the one-pot reaction was followed by chiral GC and 1H NMR conducted on samples withdrawn from the reaction vessel. Analysis of the obtained data confirm the high selectivity of the enzyme for the (S)-4MeCL resulting in an eep of around 0.80 in the homopolymer and polyester block of the block copolymers (see Table 2, entries A1 and A2). After addition of Ni(PPh3)2Br2, no additional conversion of the lactone enantiomers was detected. On the other hand, an immediate conversion of MMA was observed by 1H NMR (see entries A2 and B2). This confirms that Ni(PPh3)2Br2 not only remains active as an inhibitor but also acts as an ATRP catalyst under the applied conditions. Further analysis of the 1 H NMR spectra of the crude P(4-MeCL) samples withdrawn from the reaction mixture prior to the initiation of the ATRP (entries A1 and B1) revealed that the mole percentage of water initiated chains was less than 5% and the degree of polymerization (DP) of the polyester block was 26 and 25, respectively. In both cascade polymerizations an almost

Figure 5. (a) GPC traces of unprecipitated P(4-MeCL) [trace A, entry A1 (see Table 2)] and P(4-MeCL-b-MMA) (trace B, entry A2). (b) GPC traces of the precipitated block copolymer obtained in a one-pot reaction before (trace B, entry A3) and after (trace C, entry A4) hydrolysis of the polyester block.

quantitative conversion of MMA was achieved after 18 h of ATRP (entries A2 and B2). From the crude samples taken after each step, i.e., after 7 h (before Ni(PPh3)2Br2 addition) and after 25 h (before precipitation), the average molecular weights and polydispersities (PD) were determined by GPC. Although based on polystyrene standards, the achieved molecular weights are in good agreement with the expected values as calculated from the monomer ratios (Table 2). The resulting block copolymers were isolated by precipitation in heptane and obtained as white powders in 50-70% isolated yield.21 The 1H NMR spectra of the precipitated block copolymers show signals characteristic for PMMA and P(4-MeCL). More importantly, the singlet attributed to Ar-CH2-OH of 1 at δ ) 4.75 ppm now appears at δ ) 5.10 ppm. This is the expected shift for a benzylic ester, indicative that all initiator moieties in the precipitated sample are indeed linked to P(4-MeCL). Further evidence of the block copolymer structure was provided by the GPC analysis of the unprecipitated polymers before and after ATRP. As an example, the GPC traces of P(4-MeCL) macroinitiator and P(4-MeCLb-MMA) are given in Figure 5a (Table 2, entries A1 and

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A2). The traces of both polymers are well separated with an increase of the molecular weight from 3200 g/mol (entry A1) to 10 900 g/mol after the second step (entry A2) with concomitant decrease of the polydispersity from 1.8. to 1.4. Moreover, comparison of both GPC traces provides no evidence of unreacted P(4-MeCL) macroinitiator in the block copolymer GPC trace. This can be rationalized by the almost quantitative incorporation of 1 into the P(4-MeCL); i.e., ATRP exclusively occurs from the polyester macroinitiator. Analogous results are obtained when the molecular weight of the PMMA block was doubled (entry B). Finally, the polyester blocks of both block copolymers were hydrolyzed employing a literature procedure which resulted in the PMMA homopolymer with MW of 6700 g/mol and PD of 1.4 (entry A4) and 13 300 g/mol and 1.5 (entry B4), respectively.11 As an example, the GPC traces before and after degradation of the polyester block are shown in Figure 5b (entries A3 and A4). A clear shift is observed from 10 100 g/mol to 6700 g/mol after hydrolysis, providing additional evidence for the block copolymer structure. 4. Conclusions A series of enantiomerically enriched polyesters was prepared by lipase catalyzed ROP of methyl-substituted -caprolactones using Novozym 435 as the catalyst. Interestingly, an odd-even effect in the enantioselectivity of differently substituted monomers was observed. The combination of 4-MeCL with Novozym 435 showed a good enantioselectivity and resulted in enantiomerically enriched poly(S)-4-MeCL (eep up to 0.88). We subsequently designed and synthesized a novel initiator combining an ROP and ATRP initiating moiety. This initiator showed high initiator efficiencies (>90%) in the ROP of 4-MeCL while retaining the enantioselectivity (E ) 11). Interestingly, Ni(PPh3)2Br2 proved to be an efficient inhibitor for CALB activity. This inhibition was exploited to stop CALB activity at the desired (S)-4-MeCL conversion (ensuring a high eep), and at the same time, Ni(PPh3)2Br2 catalyzed the ATRP of MMA. Based on the evidence presented, (i) high initiator 1 efficiency, (ii) low mole percentage of water initiated chains, (iii) eep of around 0.80, and (iv) well-separated traces of P(4-MeCL), P(4-MeCL-bMMA), and PMMA after hydrolysis, we conclude that welldefined, enantiomerically enriched block copolymers are indeed obtained via a cascade polymerization combining enantioselective lipase catalyzed ROP with ATRP. This combination of two inherently different polymerization reactions affords a novel and accessible route to chiral block copolymers in a one-pot approach and without intermediate workup. Acknowledgment. The authors thank Joost van Dongen and Wieb Kingma for help with GC and GPC, the Junior

Peeters et al.

Researchers Institute for supplying monomers/initiator, and the NRSC-C for financial support. References and Notes (1) (a) Gross, R. A.; Kumar, A.; Kalra, B. Chem. ReV. 2001, 101, 2097. (b) Kobayashi, S.; Uyama, H.; Kimura, S. Chem. ReV. 2001, 101, 3793. (2) Anderson, E. M.; Larsson, K. M.; Kirk, O. Biocatal. Biotransform. 1998, 16, 181. (3) Binns, F.; Harffey, P.; Roberts, S. M.; Taylor, A. J. Chem. Soc., Perkin Trans. 1 1999, 2671. (4) Meyer, U.; Palmans, A. R. A.; Loontjens, T.; Heise, A. Macromolecules 2002, 35, 2873. (5) Skaria, S.; Smet, M.; Frey, H. Macromol. Rapid Commun. 2002, 23, 292. (6) (a) Schmid, A.; Dordick, J. S.; Hauer, B.; Kiener, A.; Wubbolts, M.; Witholt, B. Nature 2001, 409, 258. (b) Schulze, B.; Wubbolts, M. G. Curr. Opin. Biotechnol. 1999, 10, 609. (7) (a) Al-Azemi, T. F.; Kondaveti, L.; Bisht, K. S. Macromolecules 2002, 35, 3380. (b) Svirkin, Y. Y.; Xu, J.; Gross, R. A.; Kaplan, D. L.; Swift, G. Macromolecules 1996, 29, 4591. (c) Kuellmer, K.; Kikuchi, H.; Uyama, H.; Kobayashi, S. Macromol. Rapid Commun.1998, 19, 127. (d) Kikuchi, H.; Uyama, H.; Kobayashi, S. Macromolecules 2000, 33, 8971. (e) Wallace, J. S.; Morrow, C. J. J. Polym. Sci., Part A: Polym. Chem. 1989, 27, 2553. (f) Xie, W.; Li, J.; Chen, D.; Wang, P. G. Macromolecules 1997, 30, 6997. (g) Runge, M.; O’Hagan, D.; Haufe, G. J. Polym. Sci., Part A: Polym. Chem 2000, 38, 2004. (8) Bruggink, A.; Schoevaart, R.; Kieboom, T. Org. Process Res. DeV. 2003, 7, 622. (9) Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982, 104, 7294. (10) (a) Trollsås, M.; Lee, V. Y.; Mecerreyes, D.; Lo¨wenhielm, P.; Mo¨ller, M.; Miller, R. D.; Hedrick, J. L. Macromolecules 2000, 33, 4619. (b) Shioji, K.; Matsuo, A.; Okuma, K.; Nakamura, K.; Ohno, A. Tetrahedron Lett. 2000, 41, 8799. (11) Mecerreyes, D.; Moineau, G.; Dubois, P.; Je´roˆme, R.; Hedrick, J. L.; Hawker, C. J.; Malmstro¨m, E. E.; Trollsås, M. Angew. Chem., Int. Ed. 1998, 37, 1274. (12) Hedenstro¨m, E.; Nguyen, B.-V.; Silks, L. A. Tetrahedron: Asymmetry 2002, 13, 835. (13) (a) Rotticci, D.; Haeffner, F.; Orrenius, C.; Norin, T.; Hult, K. J. Mol. Catal. B: Enzymatic 1998, 5, 267. (b) Orrenius, C.; Haeffner, F.; Rotticci, D.; Ohrner, N.; Norin, T.; Hult, K. Biocatal. Biotransform. 1998, 16, 1. (14) (a) Rotticci, D.; Norin, T.; Hult, K. Org. Lett. 2000, 2, 1373. (b) Pepin, P.; Lortie, R. Biotechnol. Bioeng. 2001, 75, 559. (c) Carrea, G. Trends Biotechnol. 1995, 13, 63. (d) Ottosson, J.; Fransson, L.; King, J. W.; Hult, K. Biochim. Biophys. Acta 2002, 1594, 325. (15) Faber, K. Biotransformations in organic chemistry, 3rd ed.; SpringerVerlag: Berlin, 1997. (16) Kondaveti, L.; Al-Azemi, T. F.; Bisht, K. S. Tetrahedron: Asymmetry 2002, 13, 129. (17) Heise, A.; Peeters, J.; Meyer, U.; van Gemert, G.; Palmans, A. R. A. Polym. Prepr. (Am. Chem. Soc., DiV. Polym. Chem.) 2002, 43, 40. (18) Hawker, C. J.; Hedrick, J. L.; Malmstro¨m, E. E.; Trollsås, M.; Mecerreyes, D.; Moineau, G.; Dubois, P.; Je´roˆme, R. Macromolecules 1998, 31, 213. (19) Panova, A. A.; Kaplan, D. A. Biotechnol. Bioeng. 2003, 84, 103. (20) de Geus, M.; Hermans, T. M.; Wolffs, M.; Palmans, A. R. A.; Heise, A.; Koning, C. Manuscript in preparation. (21) These relative low isolated yields are explained by taking several samples during the polymerization and the filtering of the crude block copolymer over Al2O3 to remove the Ni catalyst.

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