Letter Cite This: ACS Macro Lett. 2019, 8, 1188−1193
pubs.acs.org/macroletters
Enantiocomplementary Chiral Polyhydroxyenoate: Chemoenzymatic Synthesis and Helical Structure Control Yu Zhang,† Bo Xia,‡ Yujing Hu,† Qiaoyan Zhu,† Xianfu Lin,*,† and Qi Wu*,† †
Department of Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of China Jiyang College of Zhejiang A&F University, Zhuji 311800, People’s Republic of China
‡
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S Supporting Information *
ABSTRACT: Here, we present the chemoenzymatic synthesis of two pairs of configuration-customized unsaturated chiral polyesters and discover that they are able to selfassemble into a helical superstructure. The chiral (R)- or (S)polyesters with a polar unsaturated main-chain and an apolar side chain were designed to be stereoregular and amphiphiliclike. The solvent polarity, stereoregularity, unsaturated bond in the backbone and the structure of side chains were found to be the key factors to affect the self-assembly performance of the chiral polyesters. As the solvent polarity increased, the nanostructures of stereoregular unsaturated polyesters transformed from spheres to helical fibers, while there was no such transformation for the racemic or saturated polyesters.
H
with excellent biocompatibility, low toxicity, and readily biodegradability, chiral polyester has rarely been applied in the field of helical structure.24,25 Considering its great potential, the discovery of more novel helical chiral polyesters is highly desired. Herein, we reported the chemoenzymatic synthesis of two pairs of configuration-customized unsaturated polyesters. With the stereoregular (R)- or (S)-configuration, the polyesters were able to form a one-handed helix at the molecular level. And due to the different solvophobic interactions between the polar main chain and apolar side chain of the polyesters, the selfassembly performance and the formed helical structure of the chiral polyesters were expected to be controlled. A chemoenzymatic synthesis method with high conversion and excellent chiral resolution efficiency was specially designed and successfully applied to the preparation of the target polyesters. As shown in Scheme 1, the process was initially implemented by the combination of enzymatic dynamic kinetic resolution (DKR) of homoallylic alcohols and olefin metathesis to provide the enantiopure ω-substituted unsaturated hydroxyvalerate. By employing the wild-type Candida antarctic lipase B (WT-CALB) and Shvo’s catalyst, the DKR of homoallylic alcohol 1a provided the (R)-configurational ester products (2a) with 99% conversion and 99% ee. Similarly, (S)2a can be obtained with 99% conversion and 99% ee under the cocatalysis of one engineered CALB mutant (W104 V/A281L/ A282 K)26,27 and Shvo’s catalyst (Figure S1). For 1b, DKR
elical morphologies are the most fundamental and fascinating biological architectures in nature that are established by the interplay among secondary interactions. Deoxyribonucleic acid (DNA), with a double-helical conformation, is a significant intermediate, storing and transferring genetic information in living systems. Inspired by the selfassembly of biopolymers, artificial polymers have been designed using these secondary interactions for self-assembly into nanoscale architectures,1 such as peptide nucleic acids (PNA),2 helicates,3−5 aromatic oligoamides,6,7 oligoresorcinols,8 and some specially designed polymers.9,10 The research on the preparation of the artificial helical polymers is of great significance and full of challenges. Chirality plays a crucial role in the formation and control of the helical superstructures. The one-handed helical structure in biological systems mostly relies on the homochirality of each component, such as the L-amino acids in the right-handed proteins. Artificial helical structure could be formed from optically active polymers possessing chiral centers in the backbone or side chain11,12 or be induced in foldamers13 by introducing a chiral residue at the pendant or chain end or using chiral additives.14−16 Noncovalent bonding interactions, such as hydrogen bonding and π−π aromatic stacking,17,18 have a significant impact on the construction of helical structures. Literature studies also revealed that the chemical structures of the polymers, such as the steric hindrance19 and unsaturation,20 may control the self-assembled nanostructures as twisted nanofibers, helices, or coils. In addition, solvophobic interactions between polymers and solvents may determine the polymer stack during the self-assembly process in some cases.21−23 However, as an important type of chiral polymer © XXXX American Chemical Society
Received: July 10, 2019 Accepted: August 26, 2019
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DOI: 10.1021/acsmacrolett.9b00527 ACS Macro Lett. 2019, 8, 1188−1193
Letter
ACS Macro Letters Scheme 1. Chemoenzymatic Synthesis of Helical Chiral Polyesters
the self-assembly of chiral polyesters was first investigated employing (S)-poly-3a as the model. In a polar solvent (DCM), the polyester was soluble, and a flake structure was formed after solvent evaporation (Figure S15a), while adding an apolar solvent (hexane) to the DCM solution caused polyesters to aggregate to form a random precipitate (Figure S15b). The difference in the morphology of the polyester implied that solvent polarity could partly influence the stacking of the macromolecule. Thus, we decided to regulate the selfassembly of the polyesters by changing the solvent polarity. Employing a mixture of DCM and hexane, the solvent polarity could be controlled by tuning the ratio of polar and apolar solvents. Various compositions of the mixed solvents (DCM/ hexane 1:10, 1:4, 1:1) and concentrations of the polyester (0.2, 0.5, 1 mg in 1 mL DCM) were employed to investigate the influence of solvent on the self-assembly performance. Experimentally, the polyesters were first dissolved in DCM to certain concentrations, and different amounts of hexane were added subsequently. Nanostructures produced under different conditions were shown in Figure 1. The nanostructure evolution from microsphere to helical fiber was observed with the increase of the DCM ratio. In solvent with a composition of DCM/hexane = 1/10, the polyester selfassembled into microspheres. When the solvent ratio of DCM/ hexane turned to 1:4, the fiber structure came into view along with microspheres, and when the solvent ratio further increased to 1:1, only a distinct helical nanostructure was observed. For the polyester, when polarity was taken into consideration, the main-chain containing an ester group was the polar segment, and the aliphatic or aromatic side chain was the apolar segment. According to the solvophobic interactions, we proposed that solvent polarity was the internal influence factor to the formation of the helical structure. Thus, the mixed solvent (DCM/hexane = 1:10) with a weak polarity would cause the folding and aggregation of polymer chains due to the large polarity gap between the backbone of the polyester and the solvent, and no helical nanostructure was observed but microspheres. Mixed solvent with relatively stronger polarity, on the other hand, would help the stretching of the backbone
under the catalysis of WT-CALB and W104 V/A281L/A282 K mutant provided enantiocomplementary 2b products with 92% ee (99% conv.) and 96% ee (99% conv.), respectively (Figure S2). Chiral polyester with side chains of an aromatic (poly(5hydroxy-5-phenyl-2-pentenoic acid) ester, poly-3a) and an aliphatic (poly(5-hydroxy-5-heptyl-2-pentenoic acid) ester, poly-3b) were subsequently synthesized using the corresponding monomers through chemical polycondensation (Table 1; Table 1. Polycondensation of ω-Substituted Hydroxyvaleratea and Information Summarizing the Resulting Polyesters
entry
monomer
configuration
Mnb (KDa)
Đb
yield (%)
1 2 3 4 5 6
3a 3a 3a 3b 3b 3b
racRSracSR-
3.5 3.8 4.6 5.5 5.5 4.9
1.21 1.24 1.15 1.12 1.12 1.15
50 60 56 46 52 38
a
Reaction conditions: 1.0 mmol monomer in 1.0 mL of anhydrous toluene was added to 0.1 mmol Ti(OiPr)4, and prepolymerization took place for 4 h at 120 °C, followed by polymerization in a vacuum for 12 h. bMn and PDI were determined by GPC using THF as solvent.
see Supporting Information for experimental details). Structures of chiral polyesters were confirmed by 1H NMR (Figures S3−S8), and their molecular weight was determined by GPC (Figures S9−S14). Results in Table 1 clearly implied that the polyesters with a racemic, (R)- or (S)-configuration and with phenyl or heptyl side chains were synthesized successfully. The morphology and self-assembled nanostructure of the chiral polyester aggregates were observed using a scanning electron microscope (SEM). The impact of solvent polarity on 1189
DOI: 10.1021/acsmacrolett.9b00527 ACS Macro Lett. 2019, 8, 1188−1193
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ACS Macro Letters
Figure 1. SEM images of (S)-poly-3a precipitated in DCM/hexane of 1:10, 1:4, and 1:1 at concentrations of 0.2, 0.5, and 1.0 mg/mL.
and induce the formation of more ordered assemblies of the helical nanostructure. In order to confirm the influence of polarity, methanol was employed as the poor solvent with a polarity even stronger than DCM. Due to the high polarity of the solvent mixed by DCM and methanol, the apolar side chain substituent of the polyester gathered, and the polymer chain folded into a random coil. Consistent with the expectation, polyesters only self-assembled into microspheres in solvents with different methanol contents (Figure S16). The concentration of the polyester was found to be another important condition influencing the nanostructure. The polyester dissolved in the DCM/hexane (1/10) mixed solvent with different concentrations was found to be assembled into microspheres with different diameters. With the increase of the concentration of the polyester, the diameter of the microspheres changed from 300 nm (0.2 mg/mL) to 500 nm (0.5 mg/mL) and 800 nm (1 mg/mL; Figure S17). Similar patterns were observed when the polyester assembled to helical fibers; the width broadened as the concentration increased. Finally, the optimal conditions for the formation of a perfect helical fiber structure were the following: the solvent ratio of DCM/ hexane = 1/1 at a concentration of 0.5 mg/mL. Under the above optimal conditions, the helical structure can be formed from all stereoregular polyesters ((R)- and (S)poly-3a, (R)- and (S)-poly-3b, Figure 2a−d). However, racpoly-3a can form nanospheres with a diameter ranging from 100 to 400 nm, and only random precipitates can be observed in the case of rac-poly-3b (Figure 2e,f). XRD analysis was applied for further characterization (Figure S19). The helical structure presented different diffraction peaks in comparison with the nanospheres of poly-3a, with peaks at 7.7°, 17.3°, 20.2°, 21.4°, and 21.9°. Thus, the optical purity and structural composition of the polyesters were proved to have significant influences on the helical structure. Polyesters with different substituents in the side chain, such as phenyl and heptyl, also presented some notable distinction on the self-assembly result. For microspheres formed in the mixed solvent of DCM/hexane (1:10), comparatively, the microspheres of poly-3a (Figure 3, left) had a smoother surface than those of poly-3b (Figure 3, right). It might be attributed
Figure 2. SEM images of (a) (R)-poly-3a, (b) (S)-poly-3a, (c) (R)poly-3b, (d) (S)-poly-3b, (e) rac-poly-3a, and (f) rac-poly-3b in the mixed solvent of DCM/hexane (1:1) at a concentration of 0.5 mg/ mL.
Figure 3. SEM of (a) (R)-poly-3a and (b) (R)-poly-3b precipitated in DCM/hexane (1:10).
to the “π−π” stacking interaction28 of phenyl in poly-3a. This interaction of aromatic side chain made sphere more pyknotic 1190
DOI: 10.1021/acsmacrolett.9b00527 ACS Macro Lett. 2019, 8, 1188−1193
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ACS Macro Letters
urations. As shown, both (R)- and (S)-poly-3b had a much higher melting temperature (Tm = 64 °C) and ΔH value (37 J/ g), almost 20 °C or 32 J/g higher than that of rac-poly-3b (Tm = 44°C, ΔH = 4 J/g). Poly-3a showed a similar tendency (Figure S21), where the Tm of (R)-poly-3a was 84 °C, 20 °C higher than that of rac-poly-3a. The increase of Tm should be attributed to the higher regularity of the chiral polyesters than that of the racemic ones. Circular dichroism (CD) spectroscopy was applied to investigate the conformation and chiral optical properties of these polymers. The far-UV (
