Enzymatic Synthesis and Stereocomplex Formation of Chiral Polyester

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Enzymatic synthesis and stereocomplex formation of chiral polyester containing long-chain aliphatic alcohol backbone Bo Xia, Yu Zhang, Qiaoyan Zhu, Xianfu Lin, and Qi Wu Biomacromolecules, Just Accepted Manuscript • DOI: 10.1021/acs.biomac.9b00918 • Publication Date (Web): 19 Aug 2019 Downloaded from pubs.acs.org on August 20, 2019

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Biomacromolecules

1

Enzymatic synthesis and stereocomplex formation of

2

chiral polyester containing long-chain aliphatic

3

alcohol backbone

4

Bo Xia ‡, # Yu Zhang, †, # Qiaoyan Zhu, † Xianfu Lin, † Qi Wu *, †

5

† Department

6

‡ Jiyang

7

KEYWORDS: Enzymatic polymerization, Chiral polyesters, Stereocomplex

of Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of China;

College of Zhejiang A&F University, Zhuji 311800, People’s Republic of China;

8

9

ABSTRACT

10

Herein we demonstrated a novel lipase-catalyzed synthesis of isotactic D-/L-poly (aspartate-

11

octanediol) ester containing long chain alcohols backbone and discovered their stereocomplex

12

feature with an increased Tm for the first time. Simple design of monomer structures not only

13

overcomes the inherent selectivity limitation of enzyme used, but also achieves totally isotactic

14

polyester products. By crystallizing the mixed enantiopure isotactic polyesters in different

15

solvents, the formation of amorphous mixture, homocrystallites or stereocomplex crystallites were

16

observed, respectively. This study is expected to open up a new way to prepare various polyesters

ACS Paragon Plus Environment

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Biomacromolecules 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 26

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stereocomplex containing long-chain aliphatic alcohol backbone and a wide variety of functional

2

groups.

3

Introduction

4

Polymer stereocomplexation is the stereoselective interaction between two stereoisotactic

5

complementary polymers in the crystalline state, and it has become an attractive route to improve

6

thermal and mechanical properties of polymeric materials.1 To date, the most studied examples of

7

polymer stereocomplex are poly (methyl methacrylate) (PMMA) 2, 3 and poly (lactic acid) (PLA).

8

4, 5, 6

9

polylactide, melting temperature (Tm) of the stereocomplex increases about 50 oC and the

10

hydrolytic degradation rate can be reduced by more than 3 times. 7 These improved mechanical

11

and thermal properties associated with the polylactide stereocomplexation accelerate its

12

application in biological medicine field greatly. 8

Compared with the common homocrystallite (HC) composed of enantiopure D- or L-

13

Besides polylactide stereocomplex, CO2-based stereoisotactic polycarbonates are another

14

important type of stereocomplex developed in recent years, such as poly (limonene carbonate)s,

15

poly (propylene carbonate)s and poly (cyclopentene carbonate), which were synthesized through

16

steric selective copolymerization between CO2 and enantiopure- or meso-epoxides under the

17

catalysis of chiral complexes of cobalt (Co) or zinc (Zn). 9 Significant improvement in thermal

18

properties was observed for these stereoisotactic CO2-based polycarbonates. 9b-9c What’s more, as

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a pioneer in this field, Coates and coworkers first observed the formation of stereocomplex

20

between (S)- and (R)- poly (propylene succinate), which were synthesized via a cobalt complexes-

21

catalyzed alternating copolymerization of enantiopure propylene oxide and succinic anhydride. 10

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More recently, Wang and coworkers reported a new crystalline stereocomplex by mixing isotactic

23

(D)- and (L)-poly(mandelic acid) (PMA), an aryl analogue of poly(lactic acid) (PLA), which were


2

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Biomacromolecules

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prepared via ring-opening polymerization of manOCA monomer (O-carboxyanhydrides from

2

mandelic acid) mediated by a bifunctional single molecule organocatalysts.11 However, only very

3

limited classes of polymer stereocomplexes have been reported so far. And to the best of our

4

knowledge, no example of the formation of stereocomplex between enantiocomplementary

5

polyesters containing long-chain alcohols backbone has been reported. 12 Therefore, the discovery

6

of more novel polymer stereocomplexes is highly desirable.

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On the other hand, developing more eco-friendly synthesis methods for polymer

8

stereocomplexes is another challenge because almost all polymer stereocomplexes reported to

9

date, except poly (mandelic acid) (PMA)

11,

were synthesized by using specific chiral metal-

10

complexes, which usually are expensive and complicated, and have some unadmired

11

environmental disadvantages. Enzymatic polymerization is a highly environmentally friendly

12

pathway with high chemo-, regio- and stereo-selectivity in polymer synthesis.13-14 Chiral polyesters

13

can be enzymatically synthesized by either the enantioselective polycondensation of diacids and

14

diols (or hydroxy acids), or ring-opening polymerization (ROP) of lactones. For the last decades,

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some significant advances of enzymatic synthesis of chiral polyesters have been achieved,

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however, there are still some problems to be solved. For example, the molecular weight of the

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produced chiral polyesters is usually low because there is a contradiction between molecular

18

weight and optical purity of products in the kinetic resolution polymerization of racemic

19

monomers.

20

configuration of the monomers, thus enantiocomplementary polyesters are difficult to be prepared.

21

16b, e

22

polyesters when using racemic diacids or diols with asymmetric terminals as monomers because

23

there are several possible connections of their monomers, such as tail-to-tail, head-to-head or head-

15b

15-16

Another problem is that lipases are usually highly selective towards one specific

Moreover, one of the biggest challenges is that it usually cannot provide isotactic chiral


3


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to-tail. Thus, these enantiopure polyesters are difficult to form stereocomplex. Therefore, we

2

proposed to exploit a new strategy for enzymatic synthesis of enantiocomplementary isotactic

3

polyesters with controlled molecular weights (up to 24 kDa) and long-chain alcohols backbones

4

and hope to discover their stereocomplexation features.

5

Herein, we reported a new class of chiral polyester stereocomplex of isotactic D- and L-poly

6

(aspartate-octanediol) ester containing long-chain aliphatic alcohol backbone and readily

7

commercially available amino acids, which was prepared via a facile and eco-friendly lipase-

8

catalyzed route (Scheme 1). By crystallizing the mixed enantiopure polyesters in different solvent,

9

we were able to obtain the amorphous mixture, homocrystallites or stereocomplexed crystallites,

10

respectively. Stereocomplex of stereoisotactic D- and L-poly (aspartate-octanediol) ester possesses

11

an increased Tm and a greater level of crystallinity. O HN

Cbz O

O

O HN

OH

OH

O

O

6

O

Cbz 6

O

L-2a

D-2a

CALB-catalyzed polycondensation O HN

Cbz

O HN O

O 6

O

Cbz

O

isotactic L-polyester

O

O

n

6

n

isotactic D-polyester Mixed

12

Amorphous mixture DCM/MeOH (1:2)

Stereocomplex DCM/MeOH (1:3)

Homocrystallites DCM or DCM/hexane (1:3)

13

Scheme 1. Lipase-catalyzed synthesis of enantiocomplementary isotactic polyesters with long-

14

chain alcohol backbone and their stereocomplex

15


4

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Biomacromolecules

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Experimental Section

2

Materials

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The L- or D- aspartic acid were purchased from Sigma-Aldrich. Immobilized Lipase B from

4

Candida antarctica (Novozym 435) was purchased from Sigma-Aldrich too. Toluene (99%) and

5

other reagents were purchased from Sinopharm Chemical Reagent Co. Ltd. Other regents and

6

compounds were purchased by J&K Scientific.

7

Methods

8

Nuclear Magnetic Resonance (NMR): 1H NMR and

13C

NMR spectra were recorded with

9

tetramethylsilane (TMS) as the internal standard using a Bruker AMX-400 MHz spectrometer

10

(Rheinstetten, Germany) using CDCl3 as solvents. 1H and 13C spectra were determined using the

11

standard pulse sequence provided by Bruker. The samples were analyzed at 25 oC. TMS (ppm: 0)

12

was used as the internal standard for NMR analysis.

13

Differential scanning calorimetry (DSC): Thermal analysis was carried out with a DSCQ1000

14

TA Instrument, with the calorimeter under nitrogen (30 mL/min) connected to a cryostat from the

15

same manufacturer. DSC experiments were prepared in crimped aluminum pans and standard

16

experiments were conducted with a heating rate of 10 ºC/min from -50 ºC to 100ºC.

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Gel Permeation Chromatography (GPC): Molecular weights of polyesters were measured by

18

GPC with a system equipped with a refractive-index detector (Waters 2414) and Waters Styragel

19

GPC columns (Massachusetts, USA). The GPC columns were standardized with narrow-dispersity

20

polystyrene in molecular weight ranging from 6×105 to 500. The mobile phase was THF at a flow

21

rate of 1.0 mL/min.


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Page 6 of 26

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Circular Dichroism (CD): CD spectra were recorded on a JASCO J-815 spectrometer. The light

2

path length of the quartz cell used was 10 mm. The concentration was about 0.01 mg/mL, and the

3

solvent was acetonitrile.

4

X-ray Diffraction (XRD): XRD patterns were recorded with a PANalytical X’Pert PRO powder

5

diffractometer using Cu Kα radiation (λ= 0.1541 nm). The working voltage was 40 kV and the

6

working current was 40 mA. The patterns were collected with a 2θ range from 3◦ to 50◦at a step of

7

0.0501◦.

8 9 10

All geometry optimizations were carried out using the semi-empirical GFN2-xTB method17. Graphical representations of molecular structures were drawn using PyMOL.99rc6 program18. Synthesis of N-Cbz- Asp diester

11

2.0 mL Thionyl chloride was added into a solution of N-Cbz Asp (5.0 g) in 50 mL MeOH. Then

12

the reaction mixture was refluxed overnight and concentrated in vacuum. The obtained crude

13

product was used for next polymerization without any purification.

14

Dimethyl L-N-Cbz-aspartate, L-1: 1H-NMR (400 MHz, CDCl3) δ: 7.26 (m, 5H, -phenyl), 5.05

15

(s, 2H, -CH2-phenyl), 4.57 (m, 1H, -CH-NH-), 3.69 (s, 3H, β-OCH3), 3.61 (s, 3H, α-OCH3), 2.88

16

(m, -CH2-COOMe) ppm. 13C-NMR (100 MHz, CDCl3) δ: 171.4, 171.2, 155.9, 136.1, 128.6, 128.3,

17

128.1, 67.2, 52.9, 52.1, 50.3, 36.5 ppm. The NMR spectra of Dimethyl D-N-Cbz-aspartate, D-1

18

was as same as L-1.

19

Synthesis of D- and L-N-Cbz-α-octanediol-β-methyl-aspartate

20

A solution of D- or L- N-Cbz-β-methyl-aspartate (0.1 mmol) in 50 mL DCM was added 1, 8-

21

octanediol (0.15 mmol), DMAP (0.01 mmol) and DCC (0.1 mmol). Then the reaction mixture was

22

stirred overnight at R.T. and TLC was used to monitor the reaction progress. After the reaction

23

completed, the mixture was washed with 5% NaHCO3 and 5% citric acid. The organic phase was


6

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Biomacromolecules

1

dried over anhydrous MgSO4 and concentrated in vacuum. The residue was purified with column

2

chromatography (petrol ether/EtOAc=3:1).

3

N-Cbz-D-α-octanediol-β-methyl-aspartate, D-2a: 1H-NMR (400 MHz, CDCl3) δ: 7.37-7.32 (m,

4

5H, -phenyl), 5.81-5.79 (m, 1H, -NH-Cbz), 5.12 (s, 2H, -CH2-phenyl), 4.64-4.61 (m, 1H, -CH-

5

NH-), 4.17-4.13 (m, 2H, -CH2-O-CO-), 3.68 (s, 3H, -OCH3), 3.65-3.61 (m, 2H, -CH2-OH), 3.06-

6

2.83 (m, 2H, -CH2-COOMe), 1.62-1.47 (m, 4H, -OCO-CH2-CH2-(CH2)4-CH2-CH2-OH), 1.32-

7

1.26 (m, 8H, -OCO-CH2-CH2-(CH2)4-CH2-CH2-OH) ppm; 13C-NMR (100 MHz, CDCl3) δ: 171.3,

8

170.7, 156.0, 136.1, 128.6, 128.2, 128.1, 67.1, 66.0, 63.0, 52.1, 50.4, 36.5, 32.7, 29.2, 29.0, 28.4,

9

25.6 ppm.

10

N-Cbz-L-α-octanediol-β-methyl-aspartate, L-2a: 1H-NMR (400 MHz, CDCl3) δ: 7.37-7.32 (m,

11

5H, -phenyl), 5.81-5.79 (m, 1H, -NH-Cbz), 5.12 (s, 2H, -CH2-phenyl), 4.64-4.61 (m, 1H, -CH-

12

NH-), 4.17-4.13 (m, 2H, -CH2-O-CO-), 3.68 (s, 3H, -OCH3), 3.65-3.61 (m, 2H, -CH2-OH), 3.06-

13

2.83 (m, 2H, -CH2-COOMe), 1.62-1.47 (m, 4H, -OCO-CH2-CH2-(CH2)4-CH2-CH2-OH), 1.32-

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1.26 (m, 8H, -OCO-CH2-CH2-(CH2)4-CH2-CH2-OH) ppm; 13C-NMR (100 MHz, CDCl3) δ: 171.3,

15

170.7, 156.0, 136.1, 128.6, 128.2, 128.1, 67.1, 66.0, 63.0, 52.1, 50.4, 36.5, 32.7, 29.2, 29.0, 28.4,

16

25.6 ppm.

17

Preparation of regio-random L-poly (N-Cbz-Asp-octanediol) ester

18

CAL B (45 mg, 15% wt of diester) were added into the solution of diols (0.2 mmol) and diesters

19

(0.2 mmol) in 3.0 mL toluene. Then the flask was replaced with nitrogen and the reaction mixture

20

was pre-polymerized at 80 oC for 3 days. The mixture was concentrated in vacuum to remove the

21

solvent and then reacted in vacuum for another 2 days (0.01 MPa). The obtained polymers were

22

dissolved in 1.0 mL chloroform (EtOAc). Then 5.0 mL MeOH (60-90 oC) was added slowly. After


7


Page 8 of 26

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10 minutes’ standing, the supernatant was discarded and the residue was treated with this

2

procedure for 3 times. The final obtained polymers were concentrated in vacuum.

3

Regio-random L-poly (N-Cbz-Asp-octanediol) ester, L-poly-1a, 1H-NMR (400 MHz, CDCl3), δ:

4

7.29-7.19 (m, 5H, -phenyl), 5.73-5.71 (d, 1H, J=8 Hz, -NH-Cbz), 5.04 (s, 2H, -CH2-phenyl), 4.55-

5

4.53 (m, 1H, -CH-NH-), 4.06-3.97 (m, 4H, -OCO-CH2-CH2-(CH2)4-CH2-CH2-OCO-), 3.68 (s,

6

0.02 H, CH3O-), 2.91-2.78 (m, 2H, -CH2-COOMe), 1.58-1.52 (m, 4H, -OCO-CH2-CH2-(CH2)4-

7

CH2-CH2-OCO-), 1.22 (s, 8 H, -OCO-CH2-CH2-(CH2)4-CH2-CH2-OCO-) ppm. 13C-NMR (100

8

MHz, CDCl3) δ: 169.96, 169.73, 154.94, 135.16, 127.51, 127.18, 127.04, 66.04, 64.90, 64.15,

9

49.44, 35.64, 28.04, 28.01, 27.43, 27.36, 24.74, 24.64 ppm.

10

Preparation of isotactic D- and L- poly (N-Cbz-Asp-octanediol) ester

11

CAL B (47 mg, 15%, wt% of monomer) were added into the solution of diester monomer (0.2

12

mmol) in 3.0 mL toluene. Then the flask was replaced with nitrogen and the reaction mixture was

13

pre-polymerized at 80 oC for 3 days. The mixture was concentrated in vacuum to remove the

14

solvent and then reacted in vacuum for another 2 days (0.01 MPa). The obtained polymers were

15

dissolved in 1.0 mL chloroform. Then 5 mL petrol ether (60-90 oC) was added slowly. After 10

16

minutes’ standing, the supernatant was discarded, and the residue was treated with this procedure

17

for 3 times. The final obtained polymers were concentrated in vacuum.

18

Isotactic D-poly (N-Cbz-Asp-octanediol) ester, D-poly-2a, 1H-NMR (400 MHz, CDCl3), δ: 7.29-

19

7.19 (m, 5H, -phenyl), 5.73-5.71 (d, 1H, J=8 Hz, -NH-), 5.04 (s, 2H, -CH2-phenyl), 4.55-4.53 (m,

20

1H, -CH-NH-), 4.06-3.97 (m, 4H, -OCO-CH2-CH2-(CH2)4-CH2-CH2-OCO-), 3.68 (s, 0.06 H,

21

CH3O-), 2.91-2.78 (m, 2H, -CH2-COOMe), 1.58-1.52 (m, 4H, -OCO-CH2-CH2-(CH2)4-CH2-

22

CH2-OCO-), 1.22 (s, 8H, -OCO-CH2-CH2-(CH2)4-CH2-CH2-OCO-) ppm.

13C-NMR

(100 MHz,


8

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Biomacromolecules

1

CDCl3) δ: 170.89, 170.77, 155.97, 136.19, 128.54, 128.21, 128.07, 67.07, 65.93, 65.18, 50.47,

2

36.67, 29.09, 29.05, 28.46, 28.39, 25.78, 25.67 ppm.

3

Isotactic L-poly (N-Cbz-Asp-octanediol) ester, L-poly-2a, 1H-NMR (400 MHz, CDCl3), δ: 7.36-

4

7.31 (m, 5H, -phenyl), 5.80-5.78 (d, 1H, J=8 Hz, -NH-), 5.12 (s, 2H, -CH2-phenyl), 4.63-4.61 (m,

5

1H, -CH-NH-), 4.15-4.05 (m, 4H, -OCO-CH2-CH2-(CH2)4-CH2-CH2-OCO-), 3.68 (s, 0.06 H,

6

CH3O-), 2.87-2.83 (m, 2H, -CH2-COOMe), 1.61-1.59 (m, 4H, -OCO-CH2-CH2-(CH2)4-CH2-

7

CH2-OCO-), 1.29 (s, 8H, -OCO-CH2-CH2-(CH2)4-CH2-CH2-OCO-) ppm.

8

CDCl3) δ: 170.88, 170.76, 155.97, 136.17, 128.53, 128.20, 128.06, 67.06, 65.92, 65.17, 50.46,

9

36.66, 29.08, 29.03, 28.45, 28.38, 25.76, 15.66 ppm.

10

13C-NMR

(100 MHz,

Results and Discussion

11

Considering the high commercial availability of D- and L-aspartic acid (Asp), and the

12

convenience for introducing functional groups into the -NH2 of Asp, we selected D-/L-Asp as an

13

alternative of racemic diacids for preparing chiral polyesters. Candida antarctica lipase B (CALB,

14

Novozym 435) was used as the catalyst due to its high stereo- and regioselectivity, and wide

15

applications

16

polymerization.14,19,20 We selected dimethyl N-Cbz-aspartate (N-Cbz-Asp (OMe)2) as an Asp

17

monomer to avoid the formation of polyamide by protecting -NH2 group with -Cbz.21 In order to

18

test the selectivity of Novozym 435 towards L- and D-Asp monomers, we compared the

19

polymerization results of D- and L-N-Cbz-Asp (OMe)2 (D-1 and L-1) and 1, 8-octanediol as shown

20

in Table 1 (entry 1, 2) and Scheme 2. The polycondensation of L-1 successfully provided L-

21

poly(N-Cbz-Asp-octanediol)) ester (L-poly-1a) with a molecular weight of 24.2 kDa (Mn) and

22

76% yield, while the polycondensation of D-1 was unsuccessful (entry 1 vs. 2, Table 1). The

23

structure of the targeting polyester was confirmed by NMR (Figure S4-6). These results indicated

in

various

organic

transformations

including

kinetic

resolution

and


9


Page 10 of 26

1

that Novozym 435 had higher preference for L-monomer than D-monomer in polymerization. It

2

was also confirmed by the Novozym 435-catalyzed transesterification resolution between 1-

3

octanol and D- or L-Asp monomers (D-/L-N-Cbz-Asp (OMe)2) (results were listed in Figure S11).

4

Novozym 435 presented high L-configuration stereoselectivity, and the ee value of obtained

5

dioctyl N-Cbz- aspartate reached up to 97%.

6 7

Table 1. CALB-catalyzed Polycondensation for the Synthesis of Regio-random or Isotactic

8

Polyesters

entry monomer

9

a

Mn c (kDa)

polymer

Mw c (kDa)

PDI c

DP d

yield (%)

1a

D-1 + octanediol

Regio-random Dpoly-1a

1.4

1.4

-e

5

4

2a

L-1 + octanediol

Regio-random Lpoly-1a

24.2

39.5

1.64

141

76

3b

D-2a

Isotactic D-poly2a

12.0

21.7

1.81

78

72

4b

L-2a

Isotactic L-poly2a

12.3

19.4

1.57

69

70

Reaction conditions: 0.1 mmol diester (D-1 or L-1), 0.1 mmol diol, pre-polymerization at 80 oC for 3 days,

10

then polymerization in vacuum for 2 days.

11

polymerization at 80 oC for 3 days, then polymerization in vacuum for 2 days. c The Mn, Mw and PDI were

12

determined by GPC using THF as solvent. d DP refer to average degree of polymerization. e Not detected.

b

Reaction conditions: 0.1 mmol monomers (D-2a or L-2a), pre-

13 14

Concerning the failed polycondensation between D-1 and octanediol, we believe that steric

15

hindrance of D-Asp diester is perhaps the main reason. There are three acyl groups in D-1 (α-, β-

16

and N-acyl) (Scheme 2). The N-acyl group cannot react with diols because of the lower

17

nucleophilicity of hydroxyl group than amino group, and also the bulky benzyl group in -Cbz


10

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Biomacromolecules

1

which prevents from binding into the active site of CALB. Only α- and β-acyl can participate in

2

the polycondensation with diols. The steric hindrance and non-preferential selectivity limitation of

3

the α-acyl in D-Asp diesters would be much larger than that of β-acyl due to its’ shorter distance

4

to the chiral center. Transesterification between α-acyl and hydroxyls was probably unfavorable,

5

thus hindering the chain propagation.

6 7

Scheme 2. CALB-catalyzed Polycondensation of D-/L-N-Cbz Asp Diesters and Octanediol

8

In order to remove the selectivity limitation of Novozym 435 for the slow reacting D-Asp

9

diesters, and to obtain the D- poly (N-Cbz-Asp-octanediol) ester, we designed N-Cbz-D-α-

10

octanediol-β-methyl-aspartate (D-2a, Scheme 1) as a starting monomer by hiding the chiral center

11

and unfavorable α-acyl in D-1. Interestingly, CALB-catalyzed polycondensation of D-2a

12

successfully provided the targeting D-configurational polyester (D-poly-2a) with a molecular

13

weight of 12.0 kDa (Mn) and 72% yield (entry 3, Table 1). In order to prove the efficiency of this

14

strategy, polycondensation of N-Cbz-L-α-octanediol-β-methyl-aspartate (L-2a) was tested, and a

15

good result was also obtained (entry 4, Table 1). It was consistent with our prediction that the

16

hided chiral center of D-2a was far away from the terminal reacting group, and then a successful

17

polycondensation can be achieved. This successful demonstration also offers a new option for

18

overcoming the selectivity limitation of enzymes through facile and simple substrate engineering,


11

Biomacromolecules

1

rather than protein engineering which is generally used to solve these types of problem, while is

2

relative difficult for chemists. 22 Another more important advantage of this novel synthetic strategy

3

is that the prepared chiral polyesters are totally isotactic, however lipase-catalyzed

4

polycondensation of the common N-Cbz-Asp diester and diols monomers only provided regio-

5

random polyesters (Scheme 2). Circular dichroism (CD) spectroscopy was applied to investigate

6

the conformation and chiroptical properties of obtained chiral polyesters. As shown in Figure 1,

7

it clearly showed that the L-poly-1a, L-poly-2a and D-poly-2a, respectively, produce vertically

8

8 mirrored negative and positive CD signals at 225 nm. 6

L-poly-2a D-poly-2a L-poly-1a

4

CD (mdeg)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 12 of 26

2

0

-2

-4 200

9

250

300

Wavelength (nm)

350

10

Figure 1. CD spectra of enantiopure regio-random and isotactic poly (N-Cbz-Asp-octanediol) ester

11

Neither regio-random L-poly-1a itself nor the mixture of regio-random L-poly-1a and isotactic

12

D-poly-2a showed any crystallinity. Interestingly, the DSC of both isotactic D-poly-2a and L-

13

poly-2a showed obvious crystallinity in the first heat (Figure 2A and 2C). For D-poly-2a, a Tm

14

around 49 oC and a ΔH value of 12.2 J/g were observed along with a glass transition temperature

15

(Tg) of −6 °C. Tm, ΔH and Tg values of L-poly-2a were 56 oC, 23.8 J/g, and -3.0 oC respectively.

16

Figure 2B and 2D showed that both D-poly-2a and L-poly-2a parent polymers do slowly

17

crystallize from the melt. After about 24 days, crystallinity of D-poly-2a was first observed with


12

Page 13 of 26

1

a slightly low Tm and ΔH value (46 oC, 8.5 J/g). And, the crystallization process of L-poly-2a was

2

a little slower than its D-stereoisomer, with crystallinity first appearing after about 36 days. It is a

3

reason why no Tm was seen on the 2nd heat. A

B

1st heat O HN

Cbz O

6

O

O

3 days

Exo up (W/g)

Exo up (W/g)

2nd heat

1 days

12 days 24 days

n

D-poly-2a

-40

-20

0 20 40 Temperature (oC)

4

60

-40

C

-20

D

60

Cbz O O

12 days

Eco up(W/g)

Exo Up(W/g)

40

3 days

1st heat O HN

0 20 Temperature (oC)

1 day

2nd heat

6

O

24 days 36 days

n

L-poly-2a -40

-20

5


60

-40

-20

F

E

Exo up (W/g)

Sample 2 (Precipitated in DCM/hexane) Sample 3 (Precipitated in DCM/MeOH)

-40

-20

0 20 40 Temperature(oC)

20

40

60

DCM/MeOH=1:3

L-poly-2a + D-poly-2a DCM/MeOH=1:5 DCM/MeOH=1:7

L-poly-2a + D-poly-2a

6

0

Temperature (oC)

DCM/MeOH=1:2

Sample 1 (Evaporated in DCM)

Exo up(W/g)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

60

-40

-20


60


13


Page 14 of 26

1

Figure 2. DSC of (A) isotactic D-poly-2a, (B) crystallization of isotactic D-poly-2a over time,

2

(C) isotactic L-poly-2a, (D) crystallization of isotactic L-poly-2a, (E) isotactic D-poly-2a and L-

3

poly-2a mixture prepared by different methods, (F) isotactic D-poly-2a and L-poly-2a mixture

4

crystallized in DCM/MeOH with different ratio.

5

To test the formation of stereocomplex, three samples were prepared with different methods,

6

and each sample consisted of equal amount of D-poly-2a and L-poly-2a. Thermal properties of

7

these samples were analyzed by DSC and the data were compared with their parent polyesters

8

(Figure 2E). No stereocomplexation was observed in the DSC test of sample 1 and 2. For these

9

two samples, a same Tm around 51 oC was observed. The Tm of sample 1 and 2 is very close to

10

their parent polyesters (49 oC, D-poly-2a; 56 oC, L-poly-2a), indicating the formation of

11

homocrystallites. The increased Tm of sample 3 (67 °C with a ΔH value of 23.9 J/g) showed the

12

formation of stereocomplex. Compared with its parent polyesters, the Tm of stereocomplex

13

increased about 20 oC. The influence of solvents on the stereocomplex formation might be

14

attributed to the solubility difference of D- or L-poly-2a in different mixed solvents. When n-

15

hexane was added to the DCM solution of D-poly-2a and L-poly-2a, the precipitate formed much

16

faster than when MeOH was added. We believe that the rapid precipitation would disturb

17

stereocomplexation between D-poly-2a and L-poly-2a. Therefore, the stereocomplex probably

18

only formed in the mixed solvent of DCM/MeOH with a suitable ratio.

19

According to the above test, stereocomplex formed only in a specific DCM/MeOH mixed

20

solvent. Thus, the ratio of DCM/MeOH (1:2, 1:3, 1:5 and 1:7) was further investigated (Figure

21

2F). For the sample prepared from the 1:2 DCM/MeOH solvent, no crystallization melting peak

22

but a low Tg (-11.7 oC) was observed. Interestingly, polyester mixture precipitated in 1:5

23

DCM/MeOH solvent formed a polymorph which contained a homo-crystallite with a Tm of 50 oC


14

Page 15 of 26

1

and a stereocomplex with a Tm of 62 oC. However, as the coexistence of both homocrystallites and

2

stereocomplex, Tm of stereocomplex was 5.0 oC lower than the pure stereocomplex (67 oC vs 62

3

oC).

4

homocrystallites were observed with a Tm around 51 oC and a ΔH value of 43.1 J/g.

With the increase of methanol content to 1:7, stereo-complexation disappeared and only

5

Powder X-ray diffraction (XRD) was also used to confirm the formation of stereocomplex

6

(Figure 3). The presence of different crystalline diffraction peaks in comparison with the

7

diffraction profiles of its parent polymers demonstrated the successful stereocomplexation. The

8

polymer stereocomplex shows four large peaks at 18.1o, 19.3o, 21.9o and 23.2o, and one small

9

shoulder at 21.0o. In contrast, both D-poly-2a and L-poly-2a show small crystalline diffraction

10

signals at 19.8 o and 21.9o. The degree of crystallinity of stereocomplex was calculated through the

11

multipeak fitting method, and the results are shown in Figure S12. An approximation of the

12

amorphous region of the polymers can be subtracted from an approximation of the crystalline peak

13

area. The stereocomplex shows a crystallinity of 85%, while the crystallinity of D-poly-2a and L-

14

poly-2a was 63% and 71%, respectively. 6000 5000

Intensity (cps)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

A 4000

B

3000

C

2000 1000 10

15

15

20

25

30

35

2 Theta (degree)


15


Page 16 of 26

1

Figure 3. Powder XRD profiles: (A) stereocomplex. (B) isotactic L-poly-2a. (C) isotactic D-poly-

2

2a.

3

In order to make the formation of stereocomplex of D-poly-2a and L-poly-2a much clearer, a

4

preliminary structure model containing chains of opposite chirality was constructed and optimized

5

using the semi-empirical GFN2-xTB method17 that has shown to be particularly suitable and

6

accurate to highly efficient geometry optimization of very large molecules (Figure 4). The

7

minimum energy packing model implied that it probably benefited from some formed H-bonds

8

between the amino groups of Asp and carbonyls of Asp or Cbz in the enantiomeric polyester

9

chains, as well as pi-pi interactions between benzene rings (Figure 4A). Crystallization of the

10

stereocomplex of D-poly-2a and L-poly-2a might be driven by the tight interdigitation of the

11

backbone and side chains of enantiocomplementary polyesters belonging to adjacent layers,

12

similar as a “steric zipper” described by Coates and coworkers (Figure 4B).9d, 23

13 14

Figure 4. Minimum energy packing model for enantiomeric polyester chains. A, side view, B,

15

front view. D-poly-2a is indicated as ball and stick in black and L-poly-2a as stick in green. Cbz

16

groups is indicated as lines in grey. Oxygen and nitrogen atoms are indicated in red and blue,

17

respectively.


16

Page 17 of 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Biomacromolecules

1 2

Conclusions

3

In this work, we reported a novel lipase-catalyzed synthesis of isotactic D- and L-poly (aspartate-

4

octanediol) ester containing long chain diols and readily commercially available amino acids and

5

discovered the first example of a crystalline stereocomplex in this area. By designing a N-Cbz-α-

6

octanediol-β-methyl-aspartate as the starting monomer to hide the chiral center and create a ‘non-

7

chiral’ condensation environment artificially for enzymatic polymerization, isotactic D- and L-

8

poly (N-Cbz-Asp-octanediol) ester could be prepared under the catalysis of CALB. Generally

9

speaking, it is difficult to prepare the similar isotactic polyesters with high molecular weight and

10

optical purity by conventional catalysts, considering the eco-friendly reaction conditions and strict

11

demand of the residual metal ion.24 The stereocomplex formation between isotactic D- and L- poly

12

(N-Cbz-Asp-octanediol) ester was confirmed by DSC and XRD. The influence of solvent

13

compositions on the formation of stereocomplex was observed. The formation of stereocomplex

14

in-creased the crystallinity and their Tm about 20 oC. Based on the highly commercial availability

15

of amino acid and aliphatic diols, a series of biocompatible polyester stereocomplexes with

16

controlled stereoregularity and improved physical and chemical properties could be synthesized in

17

the future via eco-friendly enzymatic polymerizations.

18 19

ASSOCIATED CONTENT

20

Supporting Information

21

(Experimental procedures, characterization data and spectra of all new compounds. This material

22

is available free of charge via the Internet at http://pubs.acs.org.)


17


1

AUTHOR INFORMATION

2

Corresponding Author

3

* E-mail for Q. W.: [email protected]

4

ORCID

5

Qi Wu: 0000-0001-9386-8068

6

Bo Xia: 0000-0002-7791-2636

7

Author Contributions

8

# These

9

Funding Sources

Page 18 of 26

authors contributed equally to this work

10

Financial support from the National Natural Science Foundation of China (21574113), and

11

Natural Science Foundation of Zhejiang province, China (LY19B020014, LY17B040002) is

12

gratefully acknowledged.

13

Notes

14

The authors declare no competing financial interests.

15

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(23) Auriemma, F., De Rosa, C., Di Caprio, M. R., Di Girolamo, R., Coates, G. W.

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Crystallization of Alternating Limonene Oxide/Carbon Dioxide Copolymers: Determination of

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the Crystal Structure of Stereocomplex Poly (limonene carbonate). Macromolecules 2015, 48,

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2534-2550.

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(24) Anantharaj, S., Jayakannan, M. Amyloid-Like Hierarchical Helical Fibrils and

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Conformational

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Biomacromolecules 2015, 16, 1009−1020.

Reversibility

in

Functional

Polyesters

Based

on

L-Amino

Acids.

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Enzymatic synthesis and stereocomplex formation of chiral polyester containing long-chain aliphatic alcohol backbone Bo Xia ‡, # Yu Zhang, †, # Qiaoyan Zhu, † Xianfu Lin, † 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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Enzymatic Synthesis and Stereocomplex Formation of Chiral Polyester

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