Biomacromolecules
Article
1
product was purified by column chromatography eluting with 50%
acetone/hexanes to give the product as a yellow oil in 85% yield. The
NMR of N-functionalization-D-amino acid diesters were the same as
N-functionalization-L-amino acid diesters.
N-Boc-D-α-octanediol-β-methyl-aspartate (D-11). H NMR (400
MHz, CDCl3) δ: 5.51−5.49 (m, 1H), 4.57−4.55 (m, 1 H), 4.17−4.11
(m, 2H), 3.69 (s, 3H), 3.66−3.63 (t, 2H, J = 12 Hz), 3.04−2.2.79 (m,
2H), 1.63−1.53 (m, 4H), 1.45 (s, 9H), 1.33−1.28 (m, 8H) ppm; 13C
NMR (100 MHz, CDCl3) δ: 171.16, 171.11, 155.43, 80.09, 65.9, 63.0,
52.0, 50.0, 36.7, 32.7, 29.2, 29.1, 28.4, 28.3, 26.7, 25.6 ppm.
Dimethyl N-Benzyl-L-aspartate (L-2). 1H NMR (400 MHz,
CDCl3) δ: 7.32−7.25 (m, 5H), 3.90−3.87 (d, 1H, J = 12.8), 3.74
(s, 3H), 3.72−3.68 (d, 1H, J = 24 Hz), 3.68 (s, 3H), 3.67−3.65 (m,
1H), 2.74−70 (m, 2H), 1.87 (brs, 1H) ppm. 13C NMR (100 MHz,
CDCl3) δ: 174.1,171.3, 139.5, 128.4, 128.3, 127.2, 56.9, 52.2, 52.0,
51.9, 38.0 ppm.
1
N-Boc-D-α-methyl-β-octanediol-aspartate (D-12). H NMR (400
MHz, CDCl3) δ: 5.55−5.53 (m, 1H), 4.58−4.56 (m, 1H), 4.10−4.07
(t, 2H, J = 12 Hz), 3.65−3.62 (t, 2H, J = 12 Hz), 2.98−2.79 (m, 2H),
1.63−1.55 (m, 4H), 1.45 (s, 9H), 1.37−1.33 (m, 8H) ppm; 13C NMR
(100 MHz, CDCl3) δ: 171.65, 171.06, 155.42, 80.17, 65.18, 62.89,
52.71, 49.93, 36.83, 32.66, 29.22, 29.10, 28.43, 28.28, 25.72, 25.61
ppm.
Enzymatic Polymerization of Diesters and Diols. Diols (0.2
mmol) and Novozym 435 (15%, wt of monomers) were added into
the solution of diesters (0.2 mmol) in 3.0 mL of toluene. Then, the
flask was replaced under a nitrogen atmosphere and the reaction
mixture was prepolymerized at 80 °C for 3 days. The mixture was
concentrated in vacuum to remove the solvent and then reacted in
vacuum for another 2 days (0.01 MPa). The obtained polymers were
dissolved in 1.0 mL of chloroform. Then, 5.0 mL of petroleum ether
(60−90 °C) was added slowly. After 10 min standing, the supernatant
was discarded, and this procedure was repeated with the residue for 3
times. The final obtained polymers were concentrated in vacuum.
The polymerization of D-11 and D-12 was under the same reaction
conditions (without the addition of diols) as the polymerization of
diesters and diols.
Dimethyl N-(Thiophen-2-ylmethyl)-L-aspartate (L-3). 1H NMR
(400 MHz, CDCl3) δ: 7.15−7.14 (m, 1H), 6.88−6.86 (m, 2H),
4.05−3.86 (m, 2H), 3.68 (s, 3H), 3.64−3.61 (d, 1H, J = 12 Hz), 3.62
(s, 3H), 2.68 (m, 2H), 2.21 (brs, 1H) ppm. 13C NMR (100 MHz,
CDCl3) δ: 173.9, 171.3, 143.3, 126.6, 125.2, 124.8, 56.3, 52.2, 51.9,
46.7, 38.0 ppm.
Synthesis of L-4 to L-9. Aspartic acid diester (1.0 equiv) was
dissolved in dichloromethane. Then, anhydride (1.1 equiv), DMAP
(10%, wt % of the ester), and tetraethylammonium (TEA) (2.0 equiv)
were added to this solution and stirred overnight at room temperature
(RT). After the reaction was complete as verified by thin-layer
chromatography (TLC) (petroleum ether/ethyl acetate = 3:1), the
mixture was washed with.0 M HCl and saturated NaHCO3 solution.
The obtained organic solution was dried over MgSO4 and
concentrated in vacuum to get the crude product. The crude product
was used for further polymerization without any purification.
Diethyl N-Propionyl-L-aspartate (L-4). 1H NMR (400 MHz,
CDCl3), δ: 6.64−6.62 (m, 1H), 4.74−4.72 (m, 1H), 40.9−4.01 (m,
4H), 2.85−2.69 (m, 2H), 2.16−2.14 (m, 2H), 1.16−1.01 (m, 9H)
ppm; 13C NMR (100 MHz, CDCl3), δ: 172.67, 170.04, 169.93, 60.73,
59.94, 52.59, 47.51, 35.40, 28.35, 13.10, 13.05, 8.62 ppm.
Dimethyl N-Hexanoyl-L-aspartate (L-5). 1H NMR (400 MHz,
CDCl3), δ: 6.51−6.49 (brs, 1H), 4.90−4.86 (m, 1H), 3.77 (s, 3H),
3.70 (s, 3H), 3.07−3.01 (dd, 1H, J = 4 Hz), 2.89−2.85 (dd, 1H, J = 4
Hz), 2.25−2.21 (m, 2H), 1.66−1.62 (m, 2H), 1.32−1.31 (m, 4H),
0.91−0.88 (t, 3H, J = 12 Hz) ppm; 13C NMR (100 MHz, CDCl3), δ:
172.9, 171.7, 171.3, 52.8, 52.0, 48.3, 36.4, 36.1, 31.3, 25.2, 22.4, 13.9
ppm.
Poly(N-Cbz-L-asp-(1,8-octanediol)) Ester, Poly(L-1a). SEC data:
Mw = 39.5 × 103 g/mol, Đ = 1.64; H NMR (400 MHz, CDCl3), δ:
1
7.29−7.19 (m, 5H), 5.73−5.71 (d, 1H, J = 8 Hz), 5.04 (s, 2H), 4.55−
4.53 (m, 1H), 4.06−3.97 (m, 4H), 2.91−2.78 (m, 2H), 1.58−1.52
(m, 4H), 1.22 (s, 8H) ppm.
Poly(N-Cbz-L-asp-(1,4-butanediol)) Ester, Poly(L-1c). SEC data:
Mw = 9.8 × 103 g/mol, Đ = 1.29; H NMR (400 MHz, CDCl3), δ:
1
7.34−7.30 (m, 5H), 5.84 (s, 1H), 5.11 (s, 2H), 4.63−4.61 (m, 1H),
4.15−4.07 (m, 4H), 3.01−2.81 (m, 2H), 1.65 (s, 4H) ppm.
Poly(N-Cbz-L-asp-(1,6-hexanediol)) Ester, Poly(L-1d). SEC data:
Mw = 12.8 × 103 g/mol, Đ = 1.29; H NMR (400 MHz, CDCl3), δ:
1
1
Diethyl N-(2,2,2-Trifluoroacetyl)-L-aspartate (L-6). H NMR (400
7.36−7.31 (m, 5H), 5.82 (s, 1 H), 5.12 (s, 2 H), 4.63−4.61 (m, 1H),
4.14−4.04 (m, 4H), 3.03−2.81 (m, 2H), 1.61−1.59 (m, 4H), 1.33−
1.26 (m, 4H).
Poly(N-Cbz-L-asp-(1,12-dodecanediol)) Ester, Poly(L-1e). SEC
data: Mw = 16.9 × 103 g/mol, Đ = 1.45; 1H NMR (400 MHz,
CDCl3), δ: 7.37−7.32 (m, 5H), 5.79−5.77 (m, 1H), 5.12 (s, 2H),
4.63−4.61 (m, 1H), 4.14−4.04 (m, 4H), 1.62−1.58 (m, 4H), 1.28−
1.28 (m, 16H).
MHz, CDCl3) δ: 7.37−7.36 (brs, 1H), 4.76−4.72 (m, 1H), 4.21−
4.17 (m, 2H), 4.13−4.08 (m, 2H), 3.07−2.79 (m, 2H), 1.24−1.18
(m, 6H) ppm; 13C NMR (100 MHz, CDCl3) δ: 169.6, 168.0, 156.1,
155.7, 116.0, 113.1, 61.6, 60.5, 47.9, 34.4, 13.0, 12.9 ppm.
Dimethyl N-Isobutyryl-L-aspartate (L-7). 1H NMR (400 MHz,
CDCl3), δ: 6.51−6.49 (brs, 1H), 4.89−4.84 (m, 1H), 3.77 (s, 3H),
3.70 (s, 3H), 3.06−2.88 (dd, 1H, J = 4 Hz), 2.88−2.83 (dd, 1H, J = 4
Hz), 2.44−2.39 (m, 1H), 1.19−1.15 (t, 6H, J = 16 Hz) ppm; 13C
NMR (100 MHz, CDCl3), δ: 176.7, 171.7, 171.4, 52.8, 52.0, 48.2,
36.1, 35.4, 19.4, 19.3 ppm.
Poly(N-Bn-L-asp-(1,8-octanediol)) Ester, Poly(L-2a). SEC data: Mw
= 12.1 × 103 g/mol, Đ = 1.49; 1H NMR (400 MHz, CDCl3), δ: 7.24−
7.23 (m, 5H), 4.13−3.97 (m, 4H), 3.82−3.79 (d, 2H, J = 12), 3.66−
3.63 (d, 2H, J = 12), 3.60−3.57 (m, 1H), 2.69−2.55 (m, 2H), 1.56−
153 (m, 4H), 1.25−1.22 (m, 8H) ppm.
Dimethyl N-Pivaloyl-L-aspartate (L-8). 1H NMR (400 MHz,
CDCl3) δ: 6.73−6.71 (brs, 1H), 4.86−4.52 (m, 1 H), 3.77 (s, 3H),
3.70 (s, 3H), 3.06−3.00 (dd, 1H, J = 4 Hz), 2.87−2.82 (dd, 1H, J = 4
Hz), 1.22 (s, 9H); 13C NMR (100 MHz, CDCl3) δ: 178.3, 171.7,
171.5, 52.8, 52.0, 48.4, 38.7, 35.9, 27.3, 26.5 ppm.
Poly(N-Thiophene-2-ylmethyl-L-Asp-(1,8-octanediol)) Ester,
Poly(L-3a). SEC data: Mw = 11.4 × 103 g/mol, Đ = 1.52; H NMR
1
Dimethyl N-(Tert-butoxycarbonyl)-L-aspartate (L-9). 1H NMR
(400 MHz, CDCl3) δ: 5.45−5.43 (brs, 1H), 4.52−4.50 (m, 1H), 3.69
(s, 3H), 3.63 (s, 3H), 2.97−2.92 (dd, 1H, J = 4 Hz), 2.78−2.73 (dd,
1H, J = 4 Hz), 1.38 (s, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ:
170.5, 155.8, 154.4, 51.7, 32.9, 27.3, 27.0, 24.6, 23.9 ppm.
(400 MHz, CDCl3), δ: 7.20−7.19 (m, 1H), 6.93−6.91 (m, 2H),
4.14−3.92 (m, 6H), 3.69−3.62 (m, 1H), 2.77−2.64 (m, 2H), 1.63−
1.60 (m, 4H), 1.31−1.25 (m, 8H) ppm.
Poly(N-Boc-L-asp-(1,8-octanediol)) Ester, Poly(L-9a). SEC data:
Mw = 14.7 × 103 g/mol, Đ = 1.62; H NMR (400 MHz, CDCl3), δ:
1
Synthesis of D-11 to D-12.2 1,8-Octane-diol (15 mmol),
dimethylaminopyridine (DMAP, 1.0 mmol), and dicyclohexylcarbo-
diimide (DCC, 10 mmol) were added into a solution of 20 mL of
dichloromethane containing N-Boc-D-β-methyl-aspartate (10 mmol)
or N-Boc-D-α-methyl-aspartate (10 mmol). Then, the reaction
mixture was stirred overnight at 40 °C and TLC (petroleum ether/
ethyl acetate = 3:1) was used to monitor the reaction progress. After
the reaction completed, the mixture was washed with 5% NaHCO3
and 5% citric acid. The organic phase was dried over MgSO4 and
concentrated in vacuum. The residue was purified with column
chromatography (petroleum ether/ethyl acetate = 5:1).
5.50−5.48 (d, 1H, J = 8 Hz), 4.56−4.51 (m, 1H), 4.14−4.05 (m, 4H),
3.00−2.77 (m, 2H), 1.62−1.58 (m, 4H), 1.44 (s, 9H), 1.30−1.24 (s,
8H) ppm.
Poly(N-Cbz-L-glu-(1,8-octanediol)) Ester, Poly(L-10a). SEC data:
Mw = 19.3 × 103 g/mol, Đ = 1.44; H NMR (400 MHz, CDCl3), δ:
1
7.35−7.32 (m, 5H), 5.48 (brs, 1H), 5.09 (s, 2H), 4.41−4.36 (m, 1H),
4.14−4.02 (m, 4H), 2.42−2.36 (m, 2H), 2.23−1.93 (m, 2H), 1.68−
1.57 (m, 4H), 1.30 (s, 8H) ppm.
Poly(N-Boc-D-asp-(1,8-octanediol)) Ester, Poly(D-9a). SEC data:
Mw = 23.1 × 103 g/mol, Đ = 2.09; H NMR (400 MHz, CDCl3), δ:
1
5.50−5.48 (d, 1H, J = 8 Hz), 4.56−4.51 (m, 1H), 4.14−4.05 (m, 4H),
920
Biomacromolecules 2021, 22, 918−926