DOI: 10.1002/chem.201402373
Full Paper
& Chiral Polymers
Organocatalyzed Step-Growth Polymerization through Desymmetrization of Cyclic Anhydrides: Synthesis of Chiral Polyesters Anthony Martin,[a] Frdric Robert,[a] Daniel Taton,[b] Henri Cramail,*[b] Jean-Marc Vincent,*[a] and Yannick Landais*[a]
Abstract: The polymerization of prochiral bis-anhydrides with diols catalyzed by a cinchona alkaloid was shown to provide chiral polyesters in good yields and with high levels of stereocontrol. The structures of the polyesters were determined by 1H and 13C NMR analyses, whereas their size was estimated by both size-exclusion chromatography (SEC) and MALDI-TOF mass spectrometry, which indicated that moderate degrees of polymerization were attained through this step-growth polymerization. The enantioselectivity of the process was evaluated by using chiral HPLC analysis of the
Introduction Many naturally occurring polymers including proteins or polysaccharides are chiral in essence, with their chirality being a key-component of their function of molecular recognition, binding, and catalytic activities. Chiral synthetic polymers are less common but are receiving increasing attention.[1] Chirality in polymers is of crucial importance in a wide range of applications, for instance as chiral stationary phases for separation of racemic compounds[2] or as precursors for self-assembled materials and in asymmetric catalysis.[3] They also exhibit valuable physical properties, including piezoelectric and nonlinear optical features depending on their two- or three-dimensional structures.[4] Optically active polymers bearing photosensitive groups should also be useful for information storage materials.[5] Many synthetic chiral polymers have been conceived to mimic some of the properties of natural polymers, which has motivated increasing interest in the synthesis of optically active polymeric materials. Whereas Nature often relies on the [a] Dr. A. Martin, Dr. F. Robert, Dr. J.-M. Vincent, Prof. Dr. Y. Landais Universit de Bordeaux, Institut des Sciences Molculaires (ISM) UMR-CNRS 5255, 351, Cours de la Libration 33405 Talence Cedex (France) E-mail: [email protected] [email protected] [b] Prof. Dr. D. Taton, Prof. Dr. H. Cramail Universit de Bordeaux, Laboratoire des Polymres Organiques (LCPO) UMR-CNRS 5629, 33600 Pessac (France) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402373. Chem. Eur. J. 2014, 20, 11946 – 11953
bis-lactones resulting from a controlled chemoselective degradation of the polyesters. The best stereocontrol was reached for oligomers formed from bis-anhydride and diol monomers bearing rigid aromatic spacers between the reactive functional groups. In this case, average enantioselectivities were comparable to those observed during ring-opening of simple anhydrides with similar alcohols. In contrast, the use of more flexible spacers between reactive entities generally led to lower levels of stereocontrol.
assembly of low or high molecular weight homochiral precursors to generate natural polymers, the introduction of chirality into synthetic polymer backbones is a challenging task.[6] This can be achieved either by resorting to optically active monomers,[6b, 7] or by polymerizing only one enantiomer of a racemic mixture in the so-called enantiomer-selective polymerization (kinetic resolution).[8] However, these two approaches suffer from a lack of available chiral monomers and also from the required use of highly specific metal-based or enzyme catalysts. Alternative routes to generate pseudoasymmetric centers in polymer main chains utilize readily available achiral (prochiral) monomers,[1, 9, 10] using the so-called asymmetric polymerization approach. Modern methods mainly rely on metal-catalyzed chain polymerization processes, starting from prochiral monomers. The Ziegler–Natta/metallocene olefin polymerizations are prototypical examples of asymmetric chain growth polymerization of prochiral monomers.[10] However, the resulting polymers are generally optically inactive. Asymmetric ring-opening polymerization (ROP) has also been described.[11] To access chiral polymers, we propose here another option that is not based on a chain growth polymerization but on an asymmetric and organocatalyzed step-growth polymerization method; that is, by repetitive elementary asymmetric reactions between prochiral monomers. This methodology is inspired by recent extensive studies that have focused on asymmetric synthesis in molecular chemistry.[12] A large number of highly efficient enantioselective reactions utilizing chiral catalysts and nonchiral (prochiral) reagents have indeed been developed. For the purpose of polymer synthesis, one can expect to transfer the chirality from the catalyst to the main chain, stepwise, by se-
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Full Paper lecting appropriate chiral catalysts and thus generate optically active polymers. Although some examples have been proposed, in particular by Itsuno and co-workers,[13] asymmetric polymerizations utilizing a step-growth approach have not been investigated in great detail. In addition, most asymmetric polymerizations based on either chain or step-growth mechanisms use metallic catalysts that are moisture- and/or air-sensitive and that are generally difficult to remove from the polymer. Moreover, the use of metal-based (Pd, Ti, Zr, etc.) catalysts also raise environmental concerns. An alternative route that we envisage here relies on environmentally benign strategies, that is, following organocatalyzed approaches. Whereas intense research is underway in the field of organocatalysis,[14] with ongoing applications to polymer synthesis,[15] to our knowledge the synthesis of chiral polymers following organocatalyzed pathways has not yet been explored. To fill this gap, we envisioned the development of such a polymerization by using an organocatalyzed reaction that has proven to be successful on monofunctional substrates. Organocatalyzed aldol and Mannich reactions were first designed because a wealth of data is available on these reactions.[14] However, our preliminary experiments in polyaldol reactions met with limited success, producing mixtures of polymers in which crotonization by-products were present to a large extent.[16] Moreover, to avoid diastereocontrol issues, the methodology was restricted to difunctional substrates generating a single stereocenter, thus limiting the scope of the polymerization. This led us to consider a more potent reaction that would circumvent the above limitations. Organocatalyzed ring-opening of anhydrides with alcohols appeared to be a reasonable choice because this process has been studied in detail on monofunctional precursors and is known to provide hemiesters in high yield (more than 90 %) and excellent enantioselectivities (more than 90– 95 %) within a few hours at room temperature.[17] The reaction is catalyzed by readily available small molecules obtained from the chiral pool, including cinchona alkaloids. Unlike polycondensation, this reaction does not generate any by-product, and constitutes an excellent illustration of an atom-economical process. The ring-opening of anhydrides also increases functional complexity, leading to ester and carboxylic acid functions that allow further elaboration of the polymeric backbone. The symmetrical nature of the precursors implies that a single stereogenic center is created upon enantioselective ring opening, avoiding the diastereoselectivity issues mentioned before. A wide range of precursors can then be designed, offering a larger reactivity pattern. Finally, the presence in the final polymer of functional groups having different reactivities allows a chemoselective degradation of the polymer, which will be useful to evaluate the enantioselectivity of each elementary step. Controlled degradation of polymers is also of concern for further recycling of polymer waste. The anhydride ring-opening process thus combines features that might be difficult to find in other efficient organocatalyzed reactions and make this reaction suitable for application in polymer synthesis. We report here the first preparation of optically active polyesters II, having pendant carboxylic acid functions, through desymmetrization of meso-bis-anhydrides I by cinchona-alkaloid Chem. Eur. J. 2014, 20, 11946 – 11953
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catalyzed alcoholysis with diols III (Figure 1).[17] A series of new oligomers was thus obtained, the structures of which were determined by 1H and 13C NMR, MALDI-TOF, and SEC analyses. The high level of enantioselectivity was evaluated after controlled depolymerization of II, involving chemoselective reduc-
Figure 1. Desymmetrizing polymerization of bis-anhydrides and depolymerization of the resulting polyester through a chemoselective reduction/lactonization sequence.
tion of the carboxylic acid function followed by lactonization, eventually forming the chiral bis-lactones IV. The influence of the flexibility of the carbon backbone between reacting functional groups (anhydrides and alcohols) was also investigated by varying the nature of the spacers in both monomers.
Results and Discussion Bis-anhydride precursors 4 a–c were prepared in a three-step sequence,[18] starting from bis-benzaldehydes 1 a–c, with 1 a and 1 b being available through O-alkylation of p-hydroxybenzaldehyde (see the Supporting Information).[19] The Knoevenagel condensation between 1 a–c and ethyl cyanoacetate led to the desired a-cyanoesters 2 a–c, which, after purification by crystallization, were treated with Meldrum’s acid to give tetracids 3 a–c. The latter compounds were purified by column chromatography over silica gel (CH2Cl2/MeOH/HCOOH, 95:5:0.5) (Scheme 1). The modest yield obtained during this step might be attributed to the loss of material during chromatography. Dehydration of 3 a–c using acetic anhydride finally afforded the target bis-anhydrides 4 a–c in satisfactory overall yield. Prior to the “desymmetrizing polymerization” of bis-anhydrides 4 a–c, model studies were carried out with mono-anhydride 5 to optimize the reaction conditions, including the nature of the alcohol (Scheme 2). It is worth mentioning that, in contrast to standard conditions used with monofunctional analogues, polymerization of 4 a–c requires a strict stoichiometry between the bis-anhydride and the diol to achieve the highest polymer molecular weight.[20] Therefore, anhydride 5
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Full Paper Table 1. Model reaction of monofunctional anhydride 5 with ROH (Scheme 2). Entry
ROH
Cat. 6 [%]
Additive ([equiv])
Yield [%][b]
ee [%][c]
1 2 3 4 5 6 7 8
MeOH nHexOH tBuCH2OH BnOH BnOH BnOH BnOH BnOH
10 10 10 10 30 10 10 30
– – – – – Pemp[a] (1) Pemp[a] (2) Pemp[a] (1)
63 61 21 64 66 68 72 75
84 78 52 85 89 73 62 81
[a] Pemp: pempidine or N-methyl-2,2,6,6-tetramethylpiperidine. [b] Isolated yield after 100 h stirring. [c] Measured by chiral HPLC analysis using a WHELK-O 2 column.
Scheme 1. Synthesis of the bis-anhydride precursors 4 a–c.
Scheme 2. Desymmetrization of monofunctional anhydride model 5.
was treated with a series of alcohols ROH (1 equiv) in the presence of catalyst 6 in THF at room temperature. The choice of catalyst 6 was dictated by the seminal work of Song et al.,[21] who reported high enantioselectivity during alcoholysis of glutaric anhydrides. This bifunctional catalyst was shown to carry out dual activation of the alcohol and the anhydride, explaining its high reactivity even with less-strained anhydrides such as 5. Studies on the conversion of 5 as a function of time, in the presence of various alcohols ROH (see the Supporting Information), indicated an alcohol reactivity in the following order: MeOH > BnOH > nHexOH > tBuCH2OH, which is in line with their respective pKa. These results are in good agreement with Song’s transition state model,[21] suggesting a basic activation of the alcohol by the quinuclidine nitrogen of 6. Yields and enantioselectivities of hemiesters 7 a–d are summarized in Table 1. MeOH afforded satisfactory results (entry 1), with 7 a formed in 84 % ee. The latter was then converted into amide 8 a by coupling with an optically pure naphthylmethyl amine. The configuration of 8 a was determined by X-ray diffraction studies, thus establishing an R-configuration for hemiChem. Eur. J. 2014, 20, 11946 – 11953
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esters 7 a–d, which is consistent with Song’s report.[21] Use of a longer linear alkyl chain as in nHexOH led to a slightly reduced enantioselectivity (entry 2). Increasing the steric bulk b to the alcohol function resulted in low yield and loss of stereocontrol (entry 3). The use of benzylic alcohol led to yields and enantioselectivities that were similar to those obtained with MeOH (entry 4). Increasing the catalyst loading slightly improved the enantioselectivity (entry 5). Interestingly, addition of pempidine[17i, 22] notably increased the reaction rate, with more than 90 % conversion after 5 h, compared with approximately 55 % conversion without pempidine (Table 1, entries 5 vs. 8, see the Supporting Information for kinetic studies). However, whereas addition of pempidine led to an increase in the yield, a slight decrease in the enantioselectivity was observed (entries 5 vs. 8 and 6 vs. 7), suggesting that this electron-rich amine likely traps the generated carboxylic acid proton, but also deactivates the bifunctional catalyst 6 through interaction with the acidic NH function. Overall, these results suggest that benzylic and linear diols such as 9 a–c are appropriate candidates for the reaction with bis-anhydrides 4 a–c (Scheme 3). The optimized conditions thus include the use of 10 mol % catalyst 6 in THF at a concentration of 0.1 m, at 25 8C. Linear diol 9 a and benzylic diols 9 b and 9 c were thus reacted with 4 a–c in the presence of organocatalyst 6, leading to polyesters 10 a–i (Scheme 3). Bis-anhydrides were not completely soluble at the early stage of the reaction at 25 8C, but solubilized in the course of the polymerization. Consumption of 4 a and diol 9 b as a function of time was monitored by 1H NMR spectroscopic analysis (see the Supporting Information), indicating a conversion of 90 % after seven days. It is believed that the reaction could not reach completion because of the presence of CO2H functions generated upon anhydride ring opening, which likely sequester the bifunctional catalyst. Polyester characteristics, with respect to molar mass and molar mass distribution, were obtained from both SEC and MALDI-TOF mass spectrometry analysis (Table 2). These data demonstrate that the organocatalyzed polymerization of bis-anhydrides 4 a–c in the presence of diols 9 a–c provides oligoesters 10 a–i with degree of polymerization (DP) up to 14. The formation of oligomers was also confirmed through 1H and 13C NMR spectroscopic analysis (see the Supporting Information). In particu-
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Scheme 3. Synthesis of polyesters 10 a–i by desymmetrizing step-growth polymerization of bis-anhydrides 4 a–c with diols 9 a–c.
Table 2. Step-growth polymerization of bis-anhydrides 4 a–c in the presence of alcohols 9 a–c mediated by organocatalyst 6 (Scheme 2). Entry
10
Cat 6 [%]
Pemp [equiv]
nmax lin.[a]
nmax cycl.[b]
Mn[c]
Mw[c]
D[d]
1 2 3 4 5 6 7 8 9 10 11 12
10 a 10 a 10 b 10 b 10 c 10 c 10 d 10 e 10 f 10 g 10 h 10 i
10 30 10 30 10 30 10 10 10 10 10 10
– 1 – 1 – 1 – – – – – –
9 14 11 10 10 9 6 8 8 9 8 11
0 5 7 6 4 5 2 4 4 6 4 3
2600 3000 4850 8900 1300 1750 1050 1300 950 400 450 950
3450 4900 9600 19200 2000 2550 1600 2050 1950 500 600 1250
1.33 1.63 1.98 2.16 1.54 1.46 1.53 1.58 2.05 1.25 1.33 1.31
[a] Length of the linear oligomers determined by MS MALDI-TOF analysis. [b] Length of the cyclic oligomers determined by MS MALDI-TOF analysis. [c] Molar mass in g mol1 of the oligomers estimated through SEC analysis; DMF as eluent with PS standards. [d] Dispersity (Mw/Mn) of the oligomers estimated through SEC analysis; DMF as eluent with PS standards.
lar, 1H NMR analysis showed that the CO2H functions generated upon anhydride ring opening did not react with alcohol functions of diols 9 a–c under the reaction conditions, indicating the absence of cross-linking, as also supported by the fact that polyesters 10 a–i remained soluble in organic solvents. Slightly longer chains were obtained when higher catalyst loading and pempidine were employed (entries 2, 4 and 6), the highest molecular weights being reached with benzenedimethanol (entry 4). The more flexible bis-anhydride 4 a led consistently to the highest molecular weights, whereas the more rigid 4 c Chem. Eur. J. 2014, 20, 11946 – 11953
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only afforded oligomers 10 g–i (entries 10–12), likely due to their lower solubility in the reaction medium. As a representative example, the MALDI-TOF spectrum of 10 g (Figure 2) shows the presence of both cyclic and linear oligomers, with the longest linear chain having a total molecular weight of 3570 g mol1, corresponding to DP = 9 (the MALDI-TOF mass fragments of 10 a–i are given in the Supporting Information). Several populations of peaks can be observed corresponding to different oligomers and adducts. As illustrated by the expansion in the region between m/z 1080 and 1405, sodium and potassium adducts of cyclic trimers are clearly observed. Populations of peaks are separated by m/z equal to 392.1 mass units, which corresponds to the molar mass of one hemi-ester unit. The main fragments have m/z values that are in perfect agreement with the molar mass of sodium-complexed cyclic oligomers. For instance, the peak observed at m/z 1199.2 corresponds to the structure (C20H24O8)3,Na + , that is, a sodium-complexed cyclic oligomer made of three repeating units derived from 4 c and 9 a. Linear oligomers in which the glutaric anhydride terminal chain ends have been hydrolyzed during the work-up and/or by ionization during the MALDI-TOF analysis, are also observed. This conclusion was verified by the presence of chain-ends with four acidic functions (m/z 1145.1 and 1161.1 for Na and K adducts, respectively), a diacid and an alcohol (m/z 1217.2, Na and 1233.1 for K) and finally two alcohol functions (m/z 1289.2, Na and 1305.2 for K). Similar trends were found with other oligomers 10 a–f and 10 h–i (see the Supporting Information). For example, the peak observed at m/z 1217.2 corresponds to the structure H(C20H24O8)3OH,Na + . Other oligomers possessing different chain ends, such as alcohol and hydrolyzed glutaric anhydride, are also observed. The peak observed at m/z 1289.2 corresponds to the structure HO(CH2)4(C20H24O8)3OH, Na + . The optical purity of polymer 10 a–i was then evaluated and the enantioselectivity of the process was examined in detail. The generation of several stereogenic centers during the stepgrowth polymerization using an external source of chirality (e.g., catalyst 6) leads to some questions regarding the propagation of chirality within the growing polymer chain. Desymmetrization of a glutaric anhydride unit provides a single stereogenic center, which is initially controlled by catalyst 6, the only source of chirality in the medium. However, as the polymerization progresses, the polymer chain itself becomes chiral, thus adding in the medium a second source of chirality, which may impact on the overall stereoselectivity of the process by introducing potent double stereodifferentiation.[23] We anticipated that the introduction of spacers with a range of flexibilities between the two anhydride units in precursors 4 a–c might influence the topicity at the two newly created stereocenters within this bis-anhydride unit. To gain an insight into the stereoselectivity of the process, we first developed a chemoselective and straightforward degradation of the polyester chain into smaller building blocks, the enantiomeric excess of which could be determined by using chiral HPLC analysis. It was reasoned that the chemoselective reduction of the acidic function of the poly-hemi-esters 10 a–i would generate poly(hydroxyester) compounds.[24] Cyclization of the latter
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Figure 2. Expansion of the MALDI-TOF mass spectrum of polyester 10 g (see the Supporting Information for the complete spectrum).
would degrade the polymer into both the starting diol and a chiral bis-lactone, the optical purity of which would be easy to determine by standard HPLC analysis. Model studies were carried out by using hemi-ester 11 a–c issued from the organocatalyzed alcoholysis of bis-anhydride 4 a (Scheme 4). The ring opening was carried out by using alcohols that mimic those used during the polymerization, including MeOH, nBuOH, and BnOH. The selective reduction of the acid function of 11 a–c was carried out through NaBH4-mediated reduction of the corresponding mixed anhydrides formed in situ.[25] The resulting bis-hydroxy esters were then cyclized by using a catalytic amount of guanidine 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(TBD),[26] leading to bis-lactone 12 a in a reasonable and reproducible overall yield. Rather good levels of enantio- and diastereocontrol were obtained, irrespective of the nature of the alcohols (Table 3).
Table 3. Enantioselective synthesis of bis-lactone 12 a from hemiesters 11 a–c (Scheme 4). Entry
R’OH
11
Yield 12 [%][a]
RR/SS[b]
(RR+SS)/meso[b]
ee[c]
1 2 3
MeOH nBuOH BnOH
11 a 11 b 11 c
35 35 57
99:1 98:2 99:1
82:18 79:21 83:17
81 76 81
[a] Isolated yields over three steps. [b] Ratio determined by chiral HPLC analysis using a Chiralpak IA column. [c] Average enantiomeric excess calculated through Equation (1).
Scheme 4. Synthesis of the chiral bis-lactone 12 a. Chem. Eur. J. 2014, 20, 11946 – 11953
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The three stereoisomers of 12 a were readily separated by using chiral HPLC. As expected for racemic 12 a, three peaks in a 1:2:1 ratio, corresponding to the RR/meso/SS isomers, were observed. According to the results obtained with model anhydride 5, it was assumed that the major bis-lactone isomer of 12 a had the R,R configuration, which was confirmed by X-ray diffraction studies of a crystalline sample of 12 a (Scheme 4). An average enantiomeric excess was also extracted from HPLC traces, using Equation (1), with R as the area corresponding to the R,R enantiomer (Eq. (1) is derived in detail in the Supporting Information). This ee provides an estimation of the average enantioselectivity of the process (enantioselectivity at each stereogenic center) and allows for a comparison with the enantioselectivity observed for the monofunctional anhydride 5. As an 11950
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Full Paper example, the chromatogram of 12 a obtained from bis-hemiester 11 b (entry 2, Table 3) showed three peaks with area 77.75:20.78:1.47 for the R,R, R,S/S,R and S,S isomers, respectively. According to Equation (1), the average enantioselectivity for each stereogenic center in 12 a was thus estimated to be around 76 % (entry 2). Interestingly, average enantioselectivities in Table 3 are closely related to those observed for hemiesters 7 obtained from ring opening of anhydride 5 with the same alcohols (Table 1), indicating that the rather flexible spacer (e.g., (CH2)5) has little influence on the enantioselectivity of the process with anhydride 4 a. pffiffiffi e:e: ¼ 2 R 1
ð1Þ
The sequence developed for hemiesters 11 a–c was then applied to polyesters 10 a–i (Table 4), although the yields of the degradation sequence were generally lower. Overall, average enantioselectivities were slightly lower than those observed for the ring opening of simple anhydride 5 (Table 1), except for polymers detailed in entries 3, 8, and 11, for which the selectivities were in the same range (80–90 %). It is worth noting that, whereas pempidine increased molar masses during polymerization (Table 2, entries 2, 4, and 6), it also provided oligomers with lower stereoselectivities (Table 4, entries 2, 4, and 6). The nature of the diol was shown to influence the level of stereocontrol, with the amount of meso-bis-lactone increasing with the flexibility of the diol spacer (Table 4, entries 1 vs. 3 or 10 vs. 11 and 7 vs. 8), with the best results being obtained with
Table 4. Enantioselective synthesis of bis-lactone 12 a–c from polyesters 10 a–i.
benzenedimethanol 9 b (Table 4, entries 3, 8, and 11). The best stereocontrol was thus observed with the more rigid oligomer 10 h having aromatic spacers on both monomers 4 c and diol 9 b (entry 11). Increasing the rigidity of the polymer chain (on both monomers) thus leads to enantioselectivities in the range of those observed for ring opening of anhydride 5 with similar alcohols (compare for instance Table 1, entry 4 and Table 4, entry 11). Spectroscopic studies performed on 10 h using vibrational circular dichroism (VCD) associated with ab initio calculations[27] were not conclusive with respect to the occurrence of a secondary structure of the polymer chain (such as an helix), which might influence the control of the stereochemistry during polymerization. A more rigid monomer backbone may also maintain a distance between the reactive anhydrides and pendant CO2H functions, thus favoring chain growth and limiting chain folding, which might interfere with the enantioselective process. This would explain the higher selectivity with oligomer 10 h compared with more flexible analogues such as 10 g (entry 10). It should be added that the putative influence on the enantioselectivity of the spacer group between both anhydride moieties is measurable by examining in detail the RR/meso/SS ratio of the racemic bis-lactone 12 a–c resulting from reactions using the quinuclidine as an achiral catalyst (see the Supporting Information). Whereas racemic 12 a and 12 b originating, respectively, from bis-anhydrides 4 a and 4 b (having flexible spacers) exhibit perfect 1:2:1 RR/meso/SS ratio [in good agreement with Equation (1)], the more rigid analogue 12 c arising from 4 c exhibits a 1:1.6:1 RR/meso/SS ratio.[28] This clearly indicates that in flexible systems 12 a and 12 b, the chiral information on one stereogenic center is not transferred to the second during polymerization. Stereogenic centers thus behave as if they were in isolated molecules. When flexibility decreases, as in 12 c (or when more rigid alcohols are added), then some chiral information may be transferred from one stereogenic center to the second through the rigid backbone, leading for instance to a reduced amount of the meso isomer.[29]
Conclusion Entry
10
12
Yield 12 [%][a]
RR/SS[b]
(RR+SS)/meso[b]
ee [%][e]
1 2 3 4 5 6 7 8 9 10 11 12
10 a 10 a[c] 10 b 10 b[c] 10 c 10 c[c] 10 d 10 e 10 f 10 g 10 h 10 i
12 a 12 a 12 a 12 a 12 a 12 a 12 b 12 b 12 b 12 c 12 c 12 c
29 12 18 34 11 35 7 16 11 11 7 9
95:5 92:2 99:1 97:3 97:3 90:10 91:9 99:1 n.d.[d] 94:6 99:1 99:1
71:29 67:33 81:19 76:24 76:24 64:36 69:31 82:18 n.d. 66:34 92:8 78:22
65 60 79 72 72 52 59 80 – 57 92 77
[a] Isolated yields over three steps. [b] Ratio determined by chiral HPLC analysis using a Chiralpak IA column. [c] The synthesis of oligomers 10 a– c was carried out by using 6 (30 mol %) and pempidine (1 equiv; see Table 2). [d] Not determined. [e] Average enantiomeric excess calculated by using Equation (1).
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We have reported here the first example of step-growth desymmetrizing polymerization between symmetrical bis-anhydrides and diols triggered by a homochiral organocatalyst. These polymerizations proceed with high levels of stereocontrol, and desymmetrization of the bis-anhydrides occurs through transfer of the chirality from the cinchona-type catalyst to the growing polymer chain. The rigidity of the monomer backbone was found to be critical to access high levels of enantiocontrol during the polymerization. The polymerization rate slowed down owing to the poor solubility of the monomers, and to the formation of polar carboxylic acid functions, which likely deactivate the catalyst through protonation. The use of an achiral base such as pempidine[17i] was found to increase the reaction kinetics and the molar mass of the final polymer, albeit at the expense of stereoselectivity. The level of stereocontrol was evaluated by conducting a straightforward and controlled degradation of the polymer, leading to enantio11951
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Full Paper merically enriched bis-lactones. Although modest degrees of polymerization have been obtained, these preliminary results open new avenues in organocatalyzed polymerization. More reactive organocatalysts are expected to become available, which will be able to deliver higher molecular weights while maintaining high levels of enantiocontrol. Finally, it is anticipated that such asymmetric polymerizations using newly designed organocatalysts will be of high general significance and should certainly be extended to many more elementary reactions.
Experimental Section All experimental details can be found in the Supporting Information. The material includes compound characterization and copies of spectra of new compounds.
Typical procedure for the asymmetric polymerization (10) Compound 9 a (35 mL, 0.416 mmol) and 6 (25 mg, 0.042 mmol) were added to a solution of 4 a (200 mg, 0.416 mmol) in THF (4,2 mL) under argon (balloon). The reaction mixture was then stirred vigorously for 7 days at 25 8C. The resulting homogeneous solution was quenched with HCl (1 m, 10 mL), stirred for 10 min, and extracted with CH2Cl2/THF (7:3, 3 20 mL). The organic layer was washed with HCl (1 m, 3 10 mL), evaporated, and dried under vacuum at 60 8C for 12 h to afford 10 a (236 mg) as a yellow foam. 1 H and 13C NMR, MALDI-TOF and SEC data are available in the Supporting Information.
Typical procedure for the controlled degradation of polymer leading to bis-lactone (12) NMM (151 mL, 1.373 mmol) and EtOCOCl (131 mL, 1.373 mmol) were added to a solution of 10 a (236 mg) in THF at 15 8C under argon (balloon). The reaction mixture was then stirred vigorously for 1 h. The precipitated N-methylmorpholine hydrochloride salt was removed by filtration and washed with THF (5 mL). The filtrate was cooled to 0 8C and NaBH4 (71 mg, 1.872 mmol) was added, followed by the dropwise addition of water (1.4 mL). The reaction mixture was stirred at 0 8C for 0.5 h and the resulting solution was quenched with saturated aqueous NH4Cl (10 mL), stirred for 10 min, and extracted with CH2Cl2 (3 20 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and evaporated to afford the crude reduced polymer as a yellowish viscous oil. TBD (6 mg, 0.042 mmol) was added to a solution of the crude reduced polymer in THF (9 mL) and the reaction mixture was stirred vigorously for 15 h at 25 8C. The resulting solution was concentrated to 1 mL and water (6 mL) was added. The resulting solution was extracted with CH2Cl2 (3 20 mL) and the organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and evaporated. The crude was purified by column chromatography over silica gel (petroleum ether/EtOAc, 1:1) to afford the desired bis-lactone 12 a (55 mg, 29 %) as a white solid; m.p. 128– 129 8C; 1H NMR (600 MHz, CDCl3) d = 7.16–7.12 (m, 4 H), 6.92–6.89 (m, 4 H), 4.51 (dt, J = 11.5, 4.4 Hz, 2 H), 4.40 (td, J = 11.0, 3.7 Hz, 2 H), 4.00 (t, J = 6.4 Hz, 4 H), 3.24–3.18 (m, 2 H), 2.91 (ddd, J = 17.6, 5.9, 1.7 Hz, 2 H), 2.62 (dd, J = 17.6, 10.6 Hz, 2 H), 2.20–2.14 (m, 2 H), 2.02 (m, 2 H), 1.92–1.85 (m, 4 H), 1.71–1.64 ppm (m, 2 H); 13C NMR (151 MHz, CDCl3) d = 170.90, 158.24, 134.91, 127.53, 114.98, 68.75, 67.92, 37.86, 36.76, 30.62, 29.12, 22.85; IR (ATR): n˜ = 2944, 1732, 1513, 1264, 1246, 1234 cm1; HRMS (ESI): m/z calcd. for C77H32O6Na: Chem. Eur. J. 2014, 20, 11946 – 11953
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475.2091 [M+Na] + ; found: 475.2096; The isomer ratio was determined by HPLC analysis using a chiral stationary phase. Chiral HPLC (Chiralpak IA column, 275 nm, RT, eluent: nhexane/CH2Cl2 30:70, flow rate = 1.0 mL min1): Rt = 10.5 (RR), 12.0 (meso), 13.2 (SS) min.
X-ray crystallography data CCDC-987870 (8 a) and -987871 (12 a) contain the crystallographic data for this paper (see the Supporting Information). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements We thank the CNRS, MNERT, Rgion Aquitaine and ANR (Chirpol, grant No. 09-BLAN-0178–02) for financial support. We gratefully acknowledge M. Berlande for chiral HPLC measurements, Dr. B. Kaufmann (IECB, University of Bordeaux), and A. Lacoudre (ISM, University of Bordeaux) for X-ray diffraction studies, N. Guidolin (LCPO, University of Bordeaux) for SEC measurements, and Dr. T. Buffeteau and Dr. D. Cavagnat (ISM, University of Bordeaux) for VCD experiments. Keywords: anhydrides enantioselectivity · polymerization
· desymmetrization organocatalysis · polyesters
· ·
[1] For reviews on asymmetric polymerization, see : a) Polymeric Chiral Catalyst Design and Chiral Polymer Synthesis, 1edst ed(Ed.: S. Itsuno), Wiley, Hoboken, 2011; b) P. Pino, Fortschr. Hochpolymer. Forsch. 1965, 4, 393; c) Y. Okamoto, T. Nakano, Chem. Rev. 1994, 94, 349; d) S. Itsuno, Md. Masud Parvez, N. Haraguchi, Polym. Chem. 2011, 2, 1942; e) E. Yashima, K. Maeda, H. Lida, Y. Furusho, K. Nagai, Chem. Rev. 2009, 109, 6102. [2] a) Y. Okamoto, CHEMTECH 1987, 144; b) Y. Okamoto, S. Honda, I. Okamoto, H. Yuki, S. Murata, R. Noyori, H. Takaya, J. Am. Chem. Soc. 1981, 103, 6971; c) C. Yamamoto, Y. Okamoto, Bull. Chem. Soc. Jpn. 2004, 77, 227; d) Y. Okamoto, E. Yashima, Angew. Chem. 1998, 110, 1072; Angew. Chem. Int. Ed. 1998, 37, 1020; e) T. Kubota, C. Yamamoto, Y. Okamoto, J. Am. Chem. Soc. 2000, 122, 4056; f) G. Blaschke, W. Brçker, W. Fraenkel, Angew. Chem. 1986, 98, 808; Angew. Chem. Int. Ed. Engl. 1986, 25, 830. [3] a) S. Akabori, S. Sakurai, Y. Izumi, Y. Fujii, Nature 1956, 178, 323; b) E. Peggion, M. Terbojevich, A. Cosani, C. Colombini, J. Am. Chem. Soc. 1966, 88, 3630; c) S. Juli, J. Masana, J. C. Vega, Angew. Chem. 1980, 92, 968; Angew. Chem. Int. Ed. Engl. 1980, 19, 929; d) E. R. Jarvo, S. J. Miller, Tetrahedron 2002, 58, 2481; e) L. Canali, J. K. Karjalainen, D. C. Sherrington, O. Hormi, Chem. Commun. 1997, 123; f) H.-B. Yu, Q.-S. Hu, L. Pu, Tetrahedron Lett. 2000, 41, 1681; g) E. A. C. Davie, S. M. Mennen, Y. Xu, S. J. Miller, Chem. Rev. 2007, 107, 5759; h) R.-M. Ho, Y.-W. Chiang, S.-C. Lin, C.-K. Chen, Prog. Polym. Sci. 2011, 36, 376. [4] a) M. Sawano, K. Tahara, Y. Orita, M. Nakayama, Y. Tajitsu, Polym. Int. 2010, 59, 365; b) K. Hiraoka, P. Stein, H. Finkelman, Macromol. Chem. Phys. 2004, 205, 48; c) J. H. Wendorff, Angew. Chem. 1991, 103, 416; Angew. Chem. Int. Ed. Engl. 1991, 30, 405; d) J. S. Moore, S. I. Stupp, J. Am. Chem. Soc. 1992, 114, 3429. [5] a) A. Y. Bobrovsky, V. P. Shibaev, Adv. Funct. Mater. 2002, 12, 367; b) L. Andruzzi, A. Altomare, F. Ciardelli, R. Solaro, S. Hvilsted, P. S. Ramanujam, Macromolecules 1999, 32, 448. [6] a) G. W. Coates, in Comprehensive Asymmetric Catalysis, Vol. 3 (Eds, : E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer, Berlin, 1999, Chapter 36, p. 1329; b) L. Pu, Acta Polymerica 1997, 48, 116. [7] a) F. Ciardelli, E. Benedetti, O. Pieroni, Die Makromol. Chem. 1967, 103, 1; b) M. Lemaire, D. Delabouglise, R. Garreau, A. Guy, J. Roncali, J. Chem. Soc. Chem. Commun. 1988, 658; c) R. L. Elsenbaumer, H. Eckhardt, Z.
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Received: February 26, 2014 Revised: May 22, 2014 Published online on July 30, 2014
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& Chiral Polymers
Organocatalyzed Step-Growth Polymerization through Desymmetrization of Cyclic Anhydrides: Synthesis of Chiral Polyesters Anthony Martin,[a] Frdric Robert,[a] Daniel Taton,[b] Henri Cramail,*[b] Jean-Marc Vincent,*[a] and Yannick Landais*[a]
Abstract: The polymerization of prochiral bis-anhydrides with diols catalyzed by a cinchona alkaloid was shown to provide chiral polyesters in good yields and with high levels of stereocontrol. The structures of the polyesters were determined by 1H and 13C NMR analyses, whereas their size was estimated by both size-exclusion chromatography (SEC) and MALDI-TOF mass spectrometry, which indicated that moderate degrees of polymerization were attained through this step-growth polymerization. The enantioselectivity of the process was evaluated by using chiral HPLC analysis of the
Introduction Many naturally occurring polymers including proteins or polysaccharides are chiral in essence, with their chirality being a key-component of their function of molecular recognition, binding, and catalytic activities. Chiral synthetic polymers are less common but are receiving increasing attention.[1] Chirality in polymers is of crucial importance in a wide range of applications, for instance as chiral stationary phases for separation of racemic compounds[2] or as precursors for self-assembled materials and in asymmetric catalysis.[3] They also exhibit valuable physical properties, including piezoelectric and nonlinear optical features depending on their two- or three-dimensional structures.[4] Optically active polymers bearing photosensitive groups should also be useful for information storage materials.[5] Many synthetic chiral polymers have been conceived to mimic some of the properties of natural polymers, which has motivated increasing interest in the synthesis of optically active polymeric materials. Whereas Nature often relies on the [a] Dr. A. Martin, Dr. F. Robert, Dr. J.-M. Vincent, Prof. Dr. Y. Landais Universit de Bordeaux, Institut des Sciences Molculaires (ISM) UMR-CNRS 5255, 351, Cours de la Libration 33405 Talence Cedex (France) E-mail: [email protected] [email protected] [b] Prof. Dr. D. Taton, Prof. Dr. H. Cramail Universit de Bordeaux, Laboratoire des Polymres Organiques (LCPO) UMR-CNRS 5629, 33600 Pessac (France) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201402373. Chem. Eur. J. 2014, 20, 11946 – 11953
bis-lactones resulting from a controlled chemoselective degradation of the polyesters. The best stereocontrol was reached for oligomers formed from bis-anhydride and diol monomers bearing rigid aromatic spacers between the reactive functional groups. In this case, average enantioselectivities were comparable to those observed during ring-opening of simple anhydrides with similar alcohols. In contrast, the use of more flexible spacers between reactive entities generally led to lower levels of stereocontrol.
assembly of low or high molecular weight homochiral precursors to generate natural polymers, the introduction of chirality into synthetic polymer backbones is a challenging task.[6] This can be achieved either by resorting to optically active monomers,[6b, 7] or by polymerizing only one enantiomer of a racemic mixture in the so-called enantiomer-selective polymerization (kinetic resolution).[8] However, these two approaches suffer from a lack of available chiral monomers and also from the required use of highly specific metal-based or enzyme catalysts. Alternative routes to generate pseudoasymmetric centers in polymer main chains utilize readily available achiral (prochiral) monomers,[1, 9, 10] using the so-called asymmetric polymerization approach. Modern methods mainly rely on metal-catalyzed chain polymerization processes, starting from prochiral monomers. The Ziegler–Natta/metallocene olefin polymerizations are prototypical examples of asymmetric chain growth polymerization of prochiral monomers.[10] However, the resulting polymers are generally optically inactive. Asymmetric ring-opening polymerization (ROP) has also been described.[11] To access chiral polymers, we propose here another option that is not based on a chain growth polymerization but on an asymmetric and organocatalyzed step-growth polymerization method; that is, by repetitive elementary asymmetric reactions between prochiral monomers. This methodology is inspired by recent extensive studies that have focused on asymmetric synthesis in molecular chemistry.[12] A large number of highly efficient enantioselective reactions utilizing chiral catalysts and nonchiral (prochiral) reagents have indeed been developed. For the purpose of polymer synthesis, one can expect to transfer the chirality from the catalyst to the main chain, stepwise, by se-
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Full Paper lecting appropriate chiral catalysts and thus generate optically active polymers. Although some examples have been proposed, in particular by Itsuno and co-workers,[13] asymmetric polymerizations utilizing a step-growth approach have not been investigated in great detail. In addition, most asymmetric polymerizations based on either chain or step-growth mechanisms use metallic catalysts that are moisture- and/or air-sensitive and that are generally difficult to remove from the polymer. Moreover, the use of metal-based (Pd, Ti, Zr, etc.) catalysts also raise environmental concerns. An alternative route that we envisage here relies on environmentally benign strategies, that is, following organocatalyzed approaches. Whereas intense research is underway in the field of organocatalysis,[14] with ongoing applications to polymer synthesis,[15] to our knowledge the synthesis of chiral polymers following organocatalyzed pathways has not yet been explored. To fill this gap, we envisioned the development of such a polymerization by using an organocatalyzed reaction that has proven to be successful on monofunctional substrates. Organocatalyzed aldol and Mannich reactions were first designed because a wealth of data is available on these reactions.[14] However, our preliminary experiments in polyaldol reactions met with limited success, producing mixtures of polymers in which crotonization by-products were present to a large extent.[16] Moreover, to avoid diastereocontrol issues, the methodology was restricted to difunctional substrates generating a single stereocenter, thus limiting the scope of the polymerization. This led us to consider a more potent reaction that would circumvent the above limitations. Organocatalyzed ring-opening of anhydrides with alcohols appeared to be a reasonable choice because this process has been studied in detail on monofunctional precursors and is known to provide hemiesters in high yield (more than 90 %) and excellent enantioselectivities (more than 90– 95 %) within a few hours at room temperature.[17] The reaction is catalyzed by readily available small molecules obtained from the chiral pool, including cinchona alkaloids. Unlike polycondensation, this reaction does not generate any by-product, and constitutes an excellent illustration of an atom-economical process. The ring-opening of anhydrides also increases functional complexity, leading to ester and carboxylic acid functions that allow further elaboration of the polymeric backbone. The symmetrical nature of the precursors implies that a single stereogenic center is created upon enantioselective ring opening, avoiding the diastereoselectivity issues mentioned before. A wide range of precursors can then be designed, offering a larger reactivity pattern. Finally, the presence in the final polymer of functional groups having different reactivities allows a chemoselective degradation of the polymer, which will be useful to evaluate the enantioselectivity of each elementary step. Controlled degradation of polymers is also of concern for further recycling of polymer waste. The anhydride ring-opening process thus combines features that might be difficult to find in other efficient organocatalyzed reactions and make this reaction suitable for application in polymer synthesis. We report here the first preparation of optically active polyesters II, having pendant carboxylic acid functions, through desymmetrization of meso-bis-anhydrides I by cinchona-alkaloid Chem. Eur. J. 2014, 20, 11946 – 11953
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catalyzed alcoholysis with diols III (Figure 1).[17] A series of new oligomers was thus obtained, the structures of which were determined by 1H and 13C NMR, MALDI-TOF, and SEC analyses. The high level of enantioselectivity was evaluated after controlled depolymerization of II, involving chemoselective reduc-
Figure 1. Desymmetrizing polymerization of bis-anhydrides and depolymerization of the resulting polyester through a chemoselective reduction/lactonization sequence.
tion of the carboxylic acid function followed by lactonization, eventually forming the chiral bis-lactones IV. The influence of the flexibility of the carbon backbone between reacting functional groups (anhydrides and alcohols) was also investigated by varying the nature of the spacers in both monomers.
Results and Discussion Bis-anhydride precursors 4 a–c were prepared in a three-step sequence,[18] starting from bis-benzaldehydes 1 a–c, with 1 a and 1 b being available through O-alkylation of p-hydroxybenzaldehyde (see the Supporting Information).[19] The Knoevenagel condensation between 1 a–c and ethyl cyanoacetate led to the desired a-cyanoesters 2 a–c, which, after purification by crystallization, were treated with Meldrum’s acid to give tetracids 3 a–c. The latter compounds were purified by column chromatography over silica gel (CH2Cl2/MeOH/HCOOH, 95:5:0.5) (Scheme 1). The modest yield obtained during this step might be attributed to the loss of material during chromatography. Dehydration of 3 a–c using acetic anhydride finally afforded the target bis-anhydrides 4 a–c in satisfactory overall yield. Prior to the “desymmetrizing polymerization” of bis-anhydrides 4 a–c, model studies were carried out with mono-anhydride 5 to optimize the reaction conditions, including the nature of the alcohol (Scheme 2). It is worth mentioning that, in contrast to standard conditions used with monofunctional analogues, polymerization of 4 a–c requires a strict stoichiometry between the bis-anhydride and the diol to achieve the highest polymer molecular weight.[20] Therefore, anhydride 5
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Full Paper Table 1. Model reaction of monofunctional anhydride 5 with ROH (Scheme 2). Entry
ROH
Cat. 6 [%]
Additive ([equiv])
Yield [%][b]
ee [%][c]
1 2 3 4 5 6 7 8
MeOH nHexOH tBuCH2OH BnOH BnOH BnOH BnOH BnOH
10 10 10 10 30 10 10 30
– – – – – Pemp[a] (1) Pemp[a] (2) Pemp[a] (1)
63 61 21 64 66 68 72 75
84 78 52 85 89 73 62 81
[a] Pemp: pempidine or N-methyl-2,2,6,6-tetramethylpiperidine. [b] Isolated yield after 100 h stirring. [c] Measured by chiral HPLC analysis using a WHELK-O 2 column.
Scheme 1. Synthesis of the bis-anhydride precursors 4 a–c.
Scheme 2. Desymmetrization of monofunctional anhydride model 5.
was treated with a series of alcohols ROH (1 equiv) in the presence of catalyst 6 in THF at room temperature. The choice of catalyst 6 was dictated by the seminal work of Song et al.,[21] who reported high enantioselectivity during alcoholysis of glutaric anhydrides. This bifunctional catalyst was shown to carry out dual activation of the alcohol and the anhydride, explaining its high reactivity even with less-strained anhydrides such as 5. Studies on the conversion of 5 as a function of time, in the presence of various alcohols ROH (see the Supporting Information), indicated an alcohol reactivity in the following order: MeOH > BnOH > nHexOH > tBuCH2OH, which is in line with their respective pKa. These results are in good agreement with Song’s transition state model,[21] suggesting a basic activation of the alcohol by the quinuclidine nitrogen of 6. Yields and enantioselectivities of hemiesters 7 a–d are summarized in Table 1. MeOH afforded satisfactory results (entry 1), with 7 a formed in 84 % ee. The latter was then converted into amide 8 a by coupling with an optically pure naphthylmethyl amine. The configuration of 8 a was determined by X-ray diffraction studies, thus establishing an R-configuration for hemiChem. Eur. J. 2014, 20, 11946 – 11953
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esters 7 a–d, which is consistent with Song’s report.[21] Use of a longer linear alkyl chain as in nHexOH led to a slightly reduced enantioselectivity (entry 2). Increasing the steric bulk b to the alcohol function resulted in low yield and loss of stereocontrol (entry 3). The use of benzylic alcohol led to yields and enantioselectivities that were similar to those obtained with MeOH (entry 4). Increasing the catalyst loading slightly improved the enantioselectivity (entry 5). Interestingly, addition of pempidine[17i, 22] notably increased the reaction rate, with more than 90 % conversion after 5 h, compared with approximately 55 % conversion without pempidine (Table 1, entries 5 vs. 8, see the Supporting Information for kinetic studies). However, whereas addition of pempidine led to an increase in the yield, a slight decrease in the enantioselectivity was observed (entries 5 vs. 8 and 6 vs. 7), suggesting that this electron-rich amine likely traps the generated carboxylic acid proton, but also deactivates the bifunctional catalyst 6 through interaction with the acidic NH function. Overall, these results suggest that benzylic and linear diols such as 9 a–c are appropriate candidates for the reaction with bis-anhydrides 4 a–c (Scheme 3). The optimized conditions thus include the use of 10 mol % catalyst 6 in THF at a concentration of 0.1 m, at 25 8C. Linear diol 9 a and benzylic diols 9 b and 9 c were thus reacted with 4 a–c in the presence of organocatalyst 6, leading to polyesters 10 a–i (Scheme 3). Bis-anhydrides were not completely soluble at the early stage of the reaction at 25 8C, but solubilized in the course of the polymerization. Consumption of 4 a and diol 9 b as a function of time was monitored by 1H NMR spectroscopic analysis (see the Supporting Information), indicating a conversion of 90 % after seven days. It is believed that the reaction could not reach completion because of the presence of CO2H functions generated upon anhydride ring opening, which likely sequester the bifunctional catalyst. Polyester characteristics, with respect to molar mass and molar mass distribution, were obtained from both SEC and MALDI-TOF mass spectrometry analysis (Table 2). These data demonstrate that the organocatalyzed polymerization of bis-anhydrides 4 a–c in the presence of diols 9 a–c provides oligoesters 10 a–i with degree of polymerization (DP) up to 14. The formation of oligomers was also confirmed through 1H and 13C NMR spectroscopic analysis (see the Supporting Information). In particu-
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Scheme 3. Synthesis of polyesters 10 a–i by desymmetrizing step-growth polymerization of bis-anhydrides 4 a–c with diols 9 a–c.
Table 2. Step-growth polymerization of bis-anhydrides 4 a–c in the presence of alcohols 9 a–c mediated by organocatalyst 6 (Scheme 2). Entry
10
Cat 6 [%]
Pemp [equiv]
nmax lin.[a]
nmax cycl.[b]
Mn[c]
Mw[c]
D[d]
1 2 3 4 5 6 7 8 9 10 11 12
10 a 10 a 10 b 10 b 10 c 10 c 10 d 10 e 10 f 10 g 10 h 10 i
10 30 10 30 10 30 10 10 10 10 10 10
– 1 – 1 – 1 – – – – – –
9 14 11 10 10 9 6 8 8 9 8 11
0 5 7 6 4 5 2 4 4 6 4 3
2600 3000 4850 8900 1300 1750 1050 1300 950 400 450 950
3450 4900 9600 19200 2000 2550 1600 2050 1950 500 600 1250
1.33 1.63 1.98 2.16 1.54 1.46 1.53 1.58 2.05 1.25 1.33 1.31
[a] Length of the linear oligomers determined by MS MALDI-TOF analysis. [b] Length of the cyclic oligomers determined by MS MALDI-TOF analysis. [c] Molar mass in g mol1 of the oligomers estimated through SEC analysis; DMF as eluent with PS standards. [d] Dispersity (Mw/Mn) of the oligomers estimated through SEC analysis; DMF as eluent with PS standards.
lar, 1H NMR analysis showed that the CO2H functions generated upon anhydride ring opening did not react with alcohol functions of diols 9 a–c under the reaction conditions, indicating the absence of cross-linking, as also supported by the fact that polyesters 10 a–i remained soluble in organic solvents. Slightly longer chains were obtained when higher catalyst loading and pempidine were employed (entries 2, 4 and 6), the highest molecular weights being reached with benzenedimethanol (entry 4). The more flexible bis-anhydride 4 a led consistently to the highest molecular weights, whereas the more rigid 4 c Chem. Eur. J. 2014, 20, 11946 – 11953
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only afforded oligomers 10 g–i (entries 10–12), likely due to their lower solubility in the reaction medium. As a representative example, the MALDI-TOF spectrum of 10 g (Figure 2) shows the presence of both cyclic and linear oligomers, with the longest linear chain having a total molecular weight of 3570 g mol1, corresponding to DP = 9 (the MALDI-TOF mass fragments of 10 a–i are given in the Supporting Information). Several populations of peaks can be observed corresponding to different oligomers and adducts. As illustrated by the expansion in the region between m/z 1080 and 1405, sodium and potassium adducts of cyclic trimers are clearly observed. Populations of peaks are separated by m/z equal to 392.1 mass units, which corresponds to the molar mass of one hemi-ester unit. The main fragments have m/z values that are in perfect agreement with the molar mass of sodium-complexed cyclic oligomers. For instance, the peak observed at m/z 1199.2 corresponds to the structure (C20H24O8)3,Na + , that is, a sodium-complexed cyclic oligomer made of three repeating units derived from 4 c and 9 a. Linear oligomers in which the glutaric anhydride terminal chain ends have been hydrolyzed during the work-up and/or by ionization during the MALDI-TOF analysis, are also observed. This conclusion was verified by the presence of chain-ends with four acidic functions (m/z 1145.1 and 1161.1 for Na and K adducts, respectively), a diacid and an alcohol (m/z 1217.2, Na and 1233.1 for K) and finally two alcohol functions (m/z 1289.2, Na and 1305.2 for K). Similar trends were found with other oligomers 10 a–f and 10 h–i (see the Supporting Information). For example, the peak observed at m/z 1217.2 corresponds to the structure H(C20H24O8)3OH,Na + . Other oligomers possessing different chain ends, such as alcohol and hydrolyzed glutaric anhydride, are also observed. The peak observed at m/z 1289.2 corresponds to the structure HO(CH2)4(C20H24O8)3OH, Na + . The optical purity of polymer 10 a–i was then evaluated and the enantioselectivity of the process was examined in detail. The generation of several stereogenic centers during the stepgrowth polymerization using an external source of chirality (e.g., catalyst 6) leads to some questions regarding the propagation of chirality within the growing polymer chain. Desymmetrization of a glutaric anhydride unit provides a single stereogenic center, which is initially controlled by catalyst 6, the only source of chirality in the medium. However, as the polymerization progresses, the polymer chain itself becomes chiral, thus adding in the medium a second source of chirality, which may impact on the overall stereoselectivity of the process by introducing potent double stereodifferentiation.[23] We anticipated that the introduction of spacers with a range of flexibilities between the two anhydride units in precursors 4 a–c might influence the topicity at the two newly created stereocenters within this bis-anhydride unit. To gain an insight into the stereoselectivity of the process, we first developed a chemoselective and straightforward degradation of the polyester chain into smaller building blocks, the enantiomeric excess of which could be determined by using chiral HPLC analysis. It was reasoned that the chemoselective reduction of the acidic function of the poly-hemi-esters 10 a–i would generate poly(hydroxyester) compounds.[24] Cyclization of the latter
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Figure 2. Expansion of the MALDI-TOF mass spectrum of polyester 10 g (see the Supporting Information for the complete spectrum).
would degrade the polymer into both the starting diol and a chiral bis-lactone, the optical purity of which would be easy to determine by standard HPLC analysis. Model studies were carried out by using hemi-ester 11 a–c issued from the organocatalyzed alcoholysis of bis-anhydride 4 a (Scheme 4). The ring opening was carried out by using alcohols that mimic those used during the polymerization, including MeOH, nBuOH, and BnOH. The selective reduction of the acid function of 11 a–c was carried out through NaBH4-mediated reduction of the corresponding mixed anhydrides formed in situ.[25] The resulting bis-hydroxy esters were then cyclized by using a catalytic amount of guanidine 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(TBD),[26] leading to bis-lactone 12 a in a reasonable and reproducible overall yield. Rather good levels of enantio- and diastereocontrol were obtained, irrespective of the nature of the alcohols (Table 3).
Table 3. Enantioselective synthesis of bis-lactone 12 a from hemiesters 11 a–c (Scheme 4). Entry
R’OH
11
Yield 12 [%][a]
RR/SS[b]
(RR+SS)/meso[b]
ee[c]
1 2 3
MeOH nBuOH BnOH
11 a 11 b 11 c
35 35 57
99:1 98:2 99:1
82:18 79:21 83:17
81 76 81
[a] Isolated yields over three steps. [b] Ratio determined by chiral HPLC analysis using a Chiralpak IA column. [c] Average enantiomeric excess calculated through Equation (1).
Scheme 4. Synthesis of the chiral bis-lactone 12 a. Chem. Eur. J. 2014, 20, 11946 – 11953
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The three stereoisomers of 12 a were readily separated by using chiral HPLC. As expected for racemic 12 a, three peaks in a 1:2:1 ratio, corresponding to the RR/meso/SS isomers, were observed. According to the results obtained with model anhydride 5, it was assumed that the major bis-lactone isomer of 12 a had the R,R configuration, which was confirmed by X-ray diffraction studies of a crystalline sample of 12 a (Scheme 4). An average enantiomeric excess was also extracted from HPLC traces, using Equation (1), with R as the area corresponding to the R,R enantiomer (Eq. (1) is derived in detail in the Supporting Information). This ee provides an estimation of the average enantioselectivity of the process (enantioselectivity at each stereogenic center) and allows for a comparison with the enantioselectivity observed for the monofunctional anhydride 5. As an 11950
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Full Paper example, the chromatogram of 12 a obtained from bis-hemiester 11 b (entry 2, Table 3) showed three peaks with area 77.75:20.78:1.47 for the R,R, R,S/S,R and S,S isomers, respectively. According to Equation (1), the average enantioselectivity for each stereogenic center in 12 a was thus estimated to be around 76 % (entry 2). Interestingly, average enantioselectivities in Table 3 are closely related to those observed for hemiesters 7 obtained from ring opening of anhydride 5 with the same alcohols (Table 1), indicating that the rather flexible spacer (e.g., (CH2)5) has little influence on the enantioselectivity of the process with anhydride 4 a. pffiffiffi e:e: ¼ 2 R 1
ð1Þ
The sequence developed for hemiesters 11 a–c was then applied to polyesters 10 a–i (Table 4), although the yields of the degradation sequence were generally lower. Overall, average enantioselectivities were slightly lower than those observed for the ring opening of simple anhydride 5 (Table 1), except for polymers detailed in entries 3, 8, and 11, for which the selectivities were in the same range (80–90 %). It is worth noting that, whereas pempidine increased molar masses during polymerization (Table 2, entries 2, 4, and 6), it also provided oligomers with lower stereoselectivities (Table 4, entries 2, 4, and 6). The nature of the diol was shown to influence the level of stereocontrol, with the amount of meso-bis-lactone increasing with the flexibility of the diol spacer (Table 4, entries 1 vs. 3 or 10 vs. 11 and 7 vs. 8), with the best results being obtained with
Table 4. Enantioselective synthesis of bis-lactone 12 a–c from polyesters 10 a–i.
benzenedimethanol 9 b (Table 4, entries 3, 8, and 11). The best stereocontrol was thus observed with the more rigid oligomer 10 h having aromatic spacers on both monomers 4 c and diol 9 b (entry 11). Increasing the rigidity of the polymer chain (on both monomers) thus leads to enantioselectivities in the range of those observed for ring opening of anhydride 5 with similar alcohols (compare for instance Table 1, entry 4 and Table 4, entry 11). Spectroscopic studies performed on 10 h using vibrational circular dichroism (VCD) associated with ab initio calculations[27] were not conclusive with respect to the occurrence of a secondary structure of the polymer chain (such as an helix), which might influence the control of the stereochemistry during polymerization. A more rigid monomer backbone may also maintain a distance between the reactive anhydrides and pendant CO2H functions, thus favoring chain growth and limiting chain folding, which might interfere with the enantioselective process. This would explain the higher selectivity with oligomer 10 h compared with more flexible analogues such as 10 g (entry 10). It should be added that the putative influence on the enantioselectivity of the spacer group between both anhydride moieties is measurable by examining in detail the RR/meso/SS ratio of the racemic bis-lactone 12 a–c resulting from reactions using the quinuclidine as an achiral catalyst (see the Supporting Information). Whereas racemic 12 a and 12 b originating, respectively, from bis-anhydrides 4 a and 4 b (having flexible spacers) exhibit perfect 1:2:1 RR/meso/SS ratio [in good agreement with Equation (1)], the more rigid analogue 12 c arising from 4 c exhibits a 1:1.6:1 RR/meso/SS ratio.[28] This clearly indicates that in flexible systems 12 a and 12 b, the chiral information on one stereogenic center is not transferred to the second during polymerization. Stereogenic centers thus behave as if they were in isolated molecules. When flexibility decreases, as in 12 c (or when more rigid alcohols are added), then some chiral information may be transferred from one stereogenic center to the second through the rigid backbone, leading for instance to a reduced amount of the meso isomer.[29]
Conclusion Entry
10
12
Yield 12 [%][a]
RR/SS[b]
(RR+SS)/meso[b]
ee [%][e]
1 2 3 4 5 6 7 8 9 10 11 12
10 a 10 a[c] 10 b 10 b[c] 10 c 10 c[c] 10 d 10 e 10 f 10 g 10 h 10 i
12 a 12 a 12 a 12 a 12 a 12 a 12 b 12 b 12 b 12 c 12 c 12 c
29 12 18 34 11 35 7 16 11 11 7 9
95:5 92:2 99:1 97:3 97:3 90:10 91:9 99:1 n.d.[d] 94:6 99:1 99:1
71:29 67:33 81:19 76:24 76:24 64:36 69:31 82:18 n.d. 66:34 92:8 78:22
65 60 79 72 72 52 59 80 – 57 92 77
[a] Isolated yields over three steps. [b] Ratio determined by chiral HPLC analysis using a Chiralpak IA column. [c] The synthesis of oligomers 10 a– c was carried out by using 6 (30 mol %) and pempidine (1 equiv; see Table 2). [d] Not determined. [e] Average enantiomeric excess calculated by using Equation (1).
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We have reported here the first example of step-growth desymmetrizing polymerization between symmetrical bis-anhydrides and diols triggered by a homochiral organocatalyst. These polymerizations proceed with high levels of stereocontrol, and desymmetrization of the bis-anhydrides occurs through transfer of the chirality from the cinchona-type catalyst to the growing polymer chain. The rigidity of the monomer backbone was found to be critical to access high levels of enantiocontrol during the polymerization. The polymerization rate slowed down owing to the poor solubility of the monomers, and to the formation of polar carboxylic acid functions, which likely deactivate the catalyst through protonation. The use of an achiral base such as pempidine[17i] was found to increase the reaction kinetics and the molar mass of the final polymer, albeit at the expense of stereoselectivity. The level of stereocontrol was evaluated by conducting a straightforward and controlled degradation of the polymer, leading to enantio11951
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Full Paper merically enriched bis-lactones. Although modest degrees of polymerization have been obtained, these preliminary results open new avenues in organocatalyzed polymerization. More reactive organocatalysts are expected to become available, which will be able to deliver higher molecular weights while maintaining high levels of enantiocontrol. Finally, it is anticipated that such asymmetric polymerizations using newly designed organocatalysts will be of high general significance and should certainly be extended to many more elementary reactions.
Experimental Section All experimental details can be found in the Supporting Information. The material includes compound characterization and copies of spectra of new compounds.
Typical procedure for the asymmetric polymerization (10) Compound 9 a (35 mL, 0.416 mmol) and 6 (25 mg, 0.042 mmol) were added to a solution of 4 a (200 mg, 0.416 mmol) in THF (4,2 mL) under argon (balloon). The reaction mixture was then stirred vigorously for 7 days at 25 8C. The resulting homogeneous solution was quenched with HCl (1 m, 10 mL), stirred for 10 min, and extracted with CH2Cl2/THF (7:3, 3 20 mL). The organic layer was washed with HCl (1 m, 3 10 mL), evaporated, and dried under vacuum at 60 8C for 12 h to afford 10 a (236 mg) as a yellow foam. 1 H and 13C NMR, MALDI-TOF and SEC data are available in the Supporting Information.
Typical procedure for the controlled degradation of polymer leading to bis-lactone (12) NMM (151 mL, 1.373 mmol) and EtOCOCl (131 mL, 1.373 mmol) were added to a solution of 10 a (236 mg) in THF at 15 8C under argon (balloon). The reaction mixture was then stirred vigorously for 1 h. The precipitated N-methylmorpholine hydrochloride salt was removed by filtration and washed with THF (5 mL). The filtrate was cooled to 0 8C and NaBH4 (71 mg, 1.872 mmol) was added, followed by the dropwise addition of water (1.4 mL). The reaction mixture was stirred at 0 8C for 0.5 h and the resulting solution was quenched with saturated aqueous NH4Cl (10 mL), stirred for 10 min, and extracted with CH2Cl2 (3 20 mL). The combined extracts were washed with brine (10 mL), dried over Na2SO4, filtered, and evaporated to afford the crude reduced polymer as a yellowish viscous oil. TBD (6 mg, 0.042 mmol) was added to a solution of the crude reduced polymer in THF (9 mL) and the reaction mixture was stirred vigorously for 15 h at 25 8C. The resulting solution was concentrated to 1 mL and water (6 mL) was added. The resulting solution was extracted with CH2Cl2 (3 20 mL) and the organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and evaporated. The crude was purified by column chromatography over silica gel (petroleum ether/EtOAc, 1:1) to afford the desired bis-lactone 12 a (55 mg, 29 %) as a white solid; m.p. 128– 129 8C; 1H NMR (600 MHz, CDCl3) d = 7.16–7.12 (m, 4 H), 6.92–6.89 (m, 4 H), 4.51 (dt, J = 11.5, 4.4 Hz, 2 H), 4.40 (td, J = 11.0, 3.7 Hz, 2 H), 4.00 (t, J = 6.4 Hz, 4 H), 3.24–3.18 (m, 2 H), 2.91 (ddd, J = 17.6, 5.9, 1.7 Hz, 2 H), 2.62 (dd, J = 17.6, 10.6 Hz, 2 H), 2.20–2.14 (m, 2 H), 2.02 (m, 2 H), 1.92–1.85 (m, 4 H), 1.71–1.64 ppm (m, 2 H); 13C NMR (151 MHz, CDCl3) d = 170.90, 158.24, 134.91, 127.53, 114.98, 68.75, 67.92, 37.86, 36.76, 30.62, 29.12, 22.85; IR (ATR): n˜ = 2944, 1732, 1513, 1264, 1246, 1234 cm1; HRMS (ESI): m/z calcd. for C77H32O6Na: Chem. Eur. J. 2014, 20, 11946 – 11953
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475.2091 [M+Na] + ; found: 475.2096; The isomer ratio was determined by HPLC analysis using a chiral stationary phase. Chiral HPLC (Chiralpak IA column, 275 nm, RT, eluent: nhexane/CH2Cl2 30:70, flow rate = 1.0 mL min1): Rt = 10.5 (RR), 12.0 (meso), 13.2 (SS) min.
X-ray crystallography data CCDC-987870 (8 a) and -987871 (12 a) contain the crystallographic data for this paper (see the Supporting Information). These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements We thank the CNRS, MNERT, Rgion Aquitaine and ANR (Chirpol, grant No. 09-BLAN-0178–02) for financial support. We gratefully acknowledge M. Berlande for chiral HPLC measurements, Dr. B. Kaufmann (IECB, University of Bordeaux), and A. Lacoudre (ISM, University of Bordeaux) for X-ray diffraction studies, N. Guidolin (LCPO, University of Bordeaux) for SEC measurements, and Dr. T. Buffeteau and Dr. D. Cavagnat (ISM, University of Bordeaux) for VCD experiments. Keywords: anhydrides enantioselectivity · polymerization
· desymmetrization organocatalysis · polyesters
· ·
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2011, 40, 5564; for pioneering studies on the asymmetric ring opening of anhydrides by using cinchona alkaloids, see: d) M. Shimizu, K. Matsukawa, T. Fujisawa, Bull. Chem. Soc. Jap. 1993, 66, 2128; e) J. Hiratake, Y. Yamamoto, J. I. Oda, J. Chem. Soc. Chem. Commun. 1985, 1717; f) R. A. Aitken, J. Gopal, J. A. Hirst, J. Chem. Soc. Chem. Commun. 1988, 632; g) R. A. Aitken, J. Gopal, Tetrahedron: Asymmetry 1990, 1, 517; h) C. Bolm, A. Gerlach, C. L. Dinter, Synlett 1999, 195; i) C. Bolm, I. Schiffers, C. L. Dinter, A. Gerlach, J. Org. Chem. 2000, 65, 6984; for recent studies on the origin of the enantioselectivity in anhydride ring-opening reactions mediated by cinchona alkaloids, see: H. Yang, W. Wong, J. Am. Chem. Soc. 2013, 135, 5808. T. Teshirogi, J. Polym. Sci. Part A 1989, 27, 653. D. Ribera, A. Mantecn, A. Serra, J. Polym. Sci. Part A 2002, 40, 4344. Alcoholysis of anhydrides catalyzed by cinchona alkaloids generally requires an excess of alcohol to lead to efficient ring opening.[16] S. H. Oh, H. S. Rho, J. W. Lee, J. E. Lee, S. H. Youk, J. Chin, C. E. Song, Angew. Chem. 2008, 120, 7990; Angew. Chem. Int. Ed. 2008, 47, 7872. N-Methyl-2,2,6,6-tetramethylpiperidine (pempidine) is a basic, but poorly nucleophilic amine, introduced by Bolm and co-workers,[17i] which accelerates ring opening by favoring the regeneration of the cinchona alkaloid. For a discussion on double stereodifferentiation, see: E. L. Eliel, S. H. Wilen, L. N. Mander, Stereochemistry of Organic Compounds, Wiley, New York, 1994, p. 965. A. Fryszkowska, M. Komar, D. Koszelewski, R. Ostaszewski, Tetrahedron: Asymmetry 2005, 16, 2475. Y. Koseki, H. Yamada, T. Usuki, Tetrahedron: Asymmetry 2011, 22, 580. K. Fukushima, O. Coulembier, J. M. Lecuyer, H. A. Almegren, A. M. Alabdulrahman, F. D. Alsewailem, M. A. McNeil, P. Dubois, R. M. Waymouth, H. W. Horn, J. E. Rice, J. L. Hedrick, J. Polym. Sci. Part A 2011, 49, 1273. a) L. Ducasse, F. Castet, A. Fritsch, I. Huc, T. Buffeteau, J. Phys. Chem. A 2007, 111, 5092; b) T. Buffeteau, L. Ducasse, L. Poniman, N. Delsuc, I. Huc, Chem. Commun. 2006, 2714; c) T. B. Freedman, X. Cao, R. K. Dukorand, L. A. Nafie, Chirality 2003, 15, 743; d) T. Buffeteau, L. Ducasse, A. Brizard, I. Huc, R. Oda, J. Phys. Chem. A 2004, 108, 4080. In this case, Equation (1) is no longer valid because the expression was established based on the premise that the chirality at each stereogenic center was controlled by the organocatalyst independently from other sources of chirality, see: F. Lagasse, M. Tsukamoto, C. J. Welch, H. B. Kagan, J. Am. Chem. Soc. 2003, 125, 7490. For recent reports on remote asymmetric induction and the communication of stereochemical information through helical structures, see: a) L. Byrne, J. Sol , T. Boddaert, T. Marcelli, R. W. Adams, G. A. Morris, J. Clayden, Angew. Chem. Int. Ed. 2014, 53, 151; b) J. Clayden, A. Lund, L. Vallverdu, M. Helliwell, Nature 2004, 431, 966.
Received: February 26, 2014 Revised: May 22, 2014 Published online on July 30, 2014
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