Ring-opened 4-hydroxy-δ-valerolactone subunit as a key structural fragment of polyesters that degrade without acid formation

Article abstract of DOI:10.1016/j.mencom.2018.11.022

Random copolymers of ?-caprolactone with O-benzyl-protected 4-hydroxy- or 2,4-dihydroxy-δ-valerolactone after hydrogenation form γ-hydroxy functionalized polyesters that degrade via the cyclization to γ-butyrolactone fragments without carboxylic acid formation.

Full text of DOI:10.1016/j.mencom.2018.11.022

Mendeleev
Communications
Mendeleev Commun., 2018, 28, 629–631
Ring-opened 4-hydroxy-δ-valerolactone subunit as a key structural
fragment of polyesters that degrade without acid formation
Ilya E. Nifant’ev,*a,b Andrey V. Shlyakhtin,a Vladimir V. Bagrov,a Roman N. Ezhov,a
Boris A. Lozhkin,a Andrei V. Churakovc and Pavel V. Ivchenkoa,b
a Department of Chemistry, M. V. Lomonosov Moscow State University, 119991 Moscow,
Russian Federation. E-mail: inif@org.chem.msu.ru
b A. V. Topchiev Institute of Petrochemical Synthesis, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
c N. S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences,
119991 Moscow, Russian Federation
DOI: 10.1016/j.mencom.2018.11.022
Comonomers
New way of biodegradation without acid formation
O
O
O
obtained in 6 stages
from D-xylose
P
BnO
O
Random copolymers of ε-caprolactone with O-benzyl-protected
4-hydroxy- or 2,4-dihydroxy-δ-valerolactone after hydrogena-
tion form γ-hydroxy functionalized polyesters that degrade
via the cyclization to γ-butyrolactone fragments without
carboxylic acid formation.
O
O
O
+
P
OH
X
O
O
OBn
O
X
P
O
HO
O
P
P
O
CL
O
obtained in 8 stages
from L-glutamic acid
OBn
= poly( CL)
X = H, OH
The control of the degradation rate and the release of degradation
products are essential aspects in the design of synthetic polymers
for biomedical use. Adjusting the degradation rate is necessary
to tailor material for a specific application.1–4 Despite the absence
of toxicity, degradation products from aliphatic polyesters may
cause an inflammatory response at the implantation site due to
the formation of acids that generally have a negligible effect on
the surrounding tissue.5–7 In addition, a pH decrease induced by
a large amount of acidic degradation products might cause a
toxic response if the degradation occurs at an anatomical site
with limited body fluid flow.8,9 Acidic degradation products may
also influence the stability and hydrolysis rate of pH-sensitive
drugs used for drug delivery applications.10 The design of polymers
that degrage without acid formation represents a significant
way for the development of biomedical materials with enhanced
biocompatibility.11,12
hydrolytic biodegradation of the polyester backbone leads to the
formation of cardoxylic acid fragments (Scheme 1, route 1).
Ring-opening polymerization (ROP) of cyclic esters is mainly
used in the synthesis of polyesters. Ring-opening with a formation
of polyester polymer chain is energetically favorable for strained
β-propiolactone, and for lactones with six-membered (δ-valero-
lactone), seven-membered (ε-caprolactone, εCL) and extended
cycles; five-membered γ-butyrolactone (γBL) is thermodynami-
cally stable.20 Recently we demonstrated the tendency of organic
compounds containing the HO(CH2)3C(O) fragment to form
γBL cycle in the presence of efficient ROP catalysts such as
1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD).21
We hypothesized that the high stability of γBL can be effectively
used in the design of polyesters, which are able to decompose by
non-traditional reaction mechanism with a formation of γBL cycles
(see Scheme 1, route 2) thus retaining the medium acidity. To test
this assumption, we synthesized cyclic esters, 4-benzyloxy-δ-valero-
lactones 1a,b from available starting compounds, l-glutamic acid
and d-xylose, respectively (Schemes 2 and 3, detailed descrip-
tion of experiments is given in Online Supplementary Materials).
Then, we performed the copolymerization of lactones 1a,b with
εCL, prepared the deprotected copolymers containing OH groups,
and proved the feasibility of the route 2 (see Scheme 1) for the
degradation of polyesters. Note that the application of benzyl
protective groups for ROP monomers was demonstrated earlier
through the example of 3-benzyloxytrimethylene carbonate.22,23
Lactones 1a,b were enantiopure. As shown previously,24
diazotization at the first stage of the synthesis of 1a is stereo-
specific, the configuration of asymmetric carbon atom at sub-
sequent stages remains unchanged. The first stages of the synthesis
of 1b also do not affect the configuration of the chiral centers of
the molecule. We should also note the high stereoselectivity of
hydrogenation at the last stage of the synthesis of 1b (more
than 90% by NMR, see Online Supplementary Materials). The
Polylactones represent an important group of biopolymers.
Their hydrophilicity and biodegradability are controlled by monomer
type,1,6,13,14 as well as by introducing poly(ethylene glycol)15,16
or poly(ethylene phosphate)17–19 blocks. However, traditional
route 1
O
O
Nu
P
+
P
HO
H2O
P
O
P
OH
O
O
route 2
Nu
P
H2O
O
O
P
OH
O
O
+
P
P
HO
O
O
Scheme 1
© 2018 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 629 –

Mendeleev Commun., 2018, 28, 629–631
O
O
O
O
OR
OR
O
v
i
iii
viii
OR2
O
O
Me2N
O
HO
OH
O
O
OR1
NH2
OBn
R = H
R = Et (80%)
R = H (40%)
R = THP (95%)
R1 = H, R2 = THP (95%)
R1 = Bn, R2 = THP (90%)
R1 = Bn, R2 = H (90%)
iv
ii
vi
vii
1a (70%)
Scheme 2 Reagents and conditions: i, NaNO2, H2SO4; ii, EtOH, TsOH; iii, NaBH2, EtOH; iv, THP, CH2Cl2; v, Me2NH, H2O; vi, BnBr, NaH, THF;
vii, TsOH, MeOH; viii, TsOH, C6H6, reflux.
OH
OR2
O
C(15)
R1O
R1O
C(16)
C(17)
HO
HO
BnO
BnO
O
O
O
C(14)
C(13)
iv
i
O(1)
C(1)
C(12)
C(11)
C(4)
OH
OR1
OBn
70%
O(2)
O(11)
71% (3 steps)
C(5)
C(3)
R1 = H, R2 = Me
R1 = Bn, R2 = Me
R1 = Bn, R2 = H
C(2)
ii
O(21)
C(21)
C(27)
iii
C(26)
C(25)
O
O
C(22)
BnO
BnO
vi
C(23)
O
O
v
C(24)
OBn
95%
OBn
Figure 1 Molecular structure of 2,4-dibenzyloxy-δ-valerolactone 1b (50%
thermal ellipsoid probability). Selected bond lengths (Å): C(1)–O(1) 1.192(2),
C(1)–O(2) 1.349(2), C(1)–C(5) 1.512(2), C(2)–O(2) 1.442(2), C(2)–C(3)
1.503(2), C(3)–C(4) 1.533(2), C(4)–C(5) 1.5200(19).
1b (77%)
Scheme 3 Reagents and conditions: i, SOCl2, MeOH, reflux; ii, NaH,
BnBr, THF, DMF; iii, H2SO4, H2O, 1,4-dioxane, AcOH, reflux; iv; I2,
K2CO3, CH2Cl2; v, TBD, 130°C; vi, H2, PtO2, AcOEt.
Table 1 Synthesis and characteristics of the products of copolymerization of
εCL with monomers 1a,b and corresponding products of hydrogenation.a
molecular structure of 1b was confirmed by X-ray diffraction
analysis (Figure 1).†
Copolymers
Copolymers
Con-
t/h version
(%)
Monomer εCL
3a,b
4a,b
Run
(equiv.) (equiv. )
In copolymerization of 1a,b with εCL (Scheme 4) we used
single-component catalyst [(BHT)Mg(m-OBn)(THF)]2 2 that
demonstrated high activity in polymerization of lactones.25–27
Reactionswerecarriedoutintoluene/THF. Polymercharacteristics
are given in Table 1.
Narrow molecular weight distribution curves (SEC) and
sufficient agreement between MnNMR and MnSEC values confirm
the ‘living’ character of copolymerization. Copolymers 3a,b
(see Scheme 4) were hydrogenated to eliminate benzyl protective
Mnth b MnNMR MnSEC c ÐM MnSEC c ÐM
c
c
1d 1a (5)
45
95
95
6
1
1
1
1
99
96
92
98
95
6280 7500 9100 1.43 8600 1.55
11980 14800 18200 1.58 15500 1.64
12510 24100 23600 1.52 17900 1.61
12440 20900 28500 1.64 16100 1.70
13500 22500 26500 1.56 18000 1.68
2
3
4
5
1a (5)
1b (5)
1a (10) 90
1b (10) 90
aReaction conditions: 0°C, 2 m (total) monomer solutions in THF/toluene.
th
bCalculated by formula Mn = MBnOH + [εCL]/[2]·MεCL + [monomer]/
[2]·Mmonomer, where M are corresponding molecular weights. cSEC data,
THF as an eluent, PS standard. dData of the preliminary experiment, 1 m
(total) monomer solution in THF/toluene.
But
Me
O
Bn
O
But
O
O
O
Mg
Mg
But
O
O
CL (10–20 equiv.)
+
O
Bn
Me
But
R1
OR2
O
R1
2 (cat.)
O
H
O
R2O
O
O
n O
O
m
O
3a R1 = H, R2 = Bn
BnO
3a,b
4a,b
1a R1 = H
H2/Pd
3b R1 = OBn, R2 = Bn
4a R1 = R2 = H
1b R1 = OBn
R
4b R1 = OH, R2 = H
H+ or Nu
H2O
O
+
O
O
H
O
H
O
O
HO
n
O
m
R = H, OH
Scheme 4
†
Crystallographic data for 1b: C19H20O4, M = 312.35, monoclinic, space
with I > 2s(I); wR2 = 0.1100 for all data; GOF = 1.050, largest diff.
electron density, peak/hole: 0.166/–0.164 eÅ–3.
CCDC 1845789 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk.
group P21, a = 11.153(4), b = 5.579(2), c = 13.192(3) Å, b= 92.63(2)°,
V = 820.0(5) Å3, Z = 2, dcalc = 1.265 g cm–3, F(000) = 332, l(CuKa) =
= 1.54178 Å, T = 295 K, 3.35° £ q £ 75.03°, 6462 reflections measured,
3351 independent reflections (Rint = 0.020), R1 = 0.0401 for 3186 reflections
– 630 –

Mendeleev Commun., 2018, 28, 629–631
This work was supported by the Russian Science Foundation
1b + n εCL
(a)
(grant no. 16-13-10344, in part of copolymer design and synthesis)
and partially supported by the TIPS RAS State Plan (experimental
study of polymer characteristics).
ROP
O
O
d
c
f1
f2
R
b
O
O
b
c
n
O
O
d
f
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2018.11.022.
Ph
O
Ph
4.9 4.7 4.5 4.3 4.1 3.9
d/ppm
H2/cat.
c
O
c
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b
b
R
O
O
n
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‡
For details of synthetic experiments and NMR spectra of copolymers,
see Online Supplementary Materials.
Received: 4th June 2018; Com. 18/5599
– 631 –