Novel synthesis method of ester free trimethylene carbonate derivatives

Article abstract of DOI:10.1016/j.tetlet.2018.12.002

Ester free poly(trimethylene carbonate) (PTMC) derivatives show biocompatibility and biodegradability and do not generate any acidic compounds after decomposition. Their syntheses methods are limited however, hampering their material application. Herein, we established a novel synthesis route of ester free trimethylene carbonate (TMC) derivatives. The novel synthesis route was described using six aldehydes and one ketone as starting compounds. The key reaction is the selective deprotection from two protected hydroxyl groups in the cyclic acetal structure by diisobutylaluminium hydride. This novel synthesis route means that it is possible to convert aldehyde group to ether groups in the side chain of TMC. Conventionally, only a substituent derived from a primary alcohol was introduced into the side chain. We therefore succeeded in decreasing the number of reaction steps from five to three, compared with the conventional route. Furthermore, the development of a novel synthesis route enabled the introduction of substituents derived from secondary alcohols, anticipating the creation of further types of ester free TMC derivatives.

Full text of DOI:10.1016/j.tetlet.2018.12.002

Accepted Manuscript
Novel synthesis method of ester free trimethylene carbonate derivatives
Hiroaki Nobuoka, Hiroharu Ajiro
PII:
S0040-4039(18)31434-5
https://doi.org/10.1016/j.tetlet.2018.12.002
TETL 50465
DOI:
Reference:
Tetrahedron Letters
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29 October 2018
21 November 2018
2 December 2018
Please cite this article as: Nobuoka, H., Ajiro, H., Novel synthesis method of ester free trimethylene carbonate
derivatives, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.12.002
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Hiroaki Nobuoka and Hiroharu Ajiro

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Tetrahedron Letters
journal homepage: www.elsevier.com
Novel synthesis method of ester free trimethylene carbonate derivatives
Hiroaki Nobuokaa and Hiroharu Ajiroa,b
aDivision of Materials Science, Nara Institute of Science and Technology, 8916-5, Takayama-cho, Ikoma, Nara 630-0192, Japan
bInstitute for Research Initiatives, Nara Institute of Science and Technology, 8916-5, Takayama-cho, Ikoma, Nara 630-0192, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Ester free poly(trimethylene carbonate) (PTMC) derivatives show biocompatibility and
biodegradability and do not generate any acidic compounds after decomposition. Their syntheses
methods are limited however, hampering their material application. Herein, we established a
novel synthesis route of ester free trimethylene carbonate (TMC) derivatives. The novel
synthesis route was described using six aldehydes and one ketone as starting compounds. The
key reaction is the selective deprotection from two protected hydroxyl groups in the cyclic acetal
structure by diisobutylaluminium hydride. This novel synthesis route means that it is possible to
convert aldehyde group to ether groups in the side chain of TMC. Conventionally, only a
substituent derived from a primary alcohol was introduced into the side chain. We therefore
succeeded in decreasing the number of reaction steps from five to three, compared with the
conventional route. Furthermore, the development of a novel synthesis route enabled the
introduction of substituents derived from secondary alcohols, anticipating the creation of further
types of ester free TMC derivatives.
Available online
Keywords:
Trimethylene Carbonate
Ester free
Biodegradable
Biomaterial
2018 Elsevier Ltd. All rights reserved.
Introduction
modification of the substrate,16 and application to biodegradable
hydrogels incorporating antibodies.17
Recently, the aging society has become a world-wide problem,
making the development of various medical materials such as
scaffolds for tissue engineering an urgent issue.1,2 In particular,
biodegradable materials have attracted attention for medical
application.3 The biodegradable property of materials used in
medical implant devices allows them to degrade gradually in the
body. Therefore, there is no need to perform further surgery after
implantation, which helps to reduce the mental and physical
burden on the patient.4
However, most of the currently known PTMC derivatives
have a structure with an ester bond in the side chain.18-21 In this
case, acidic compounds are generated upon decomposition. As a
result, we believe that this feature of ester free PTMC weakens
the polymer main chain. Thus, we were motivated to develop
ester free PTMC derivatives with functional groups at the side
chain. In fact, there are some examples available for the
syntheses of TMC derivatives. This is a technique of introducing
a substituent by ether linkage into the side chain of TMC. For
example, there is a synthesis method using Candida antarctica
lipase B22 and another method using a four-membered ring as an
intermediate.23 However, the structures and methods are limited
to the specific compounds.
Poly(lactic acid) (PLA) is well-known as a biodegradable
medical material. PLA has attracted attention because it can be
synthesized from renewable plant resources, but it is sometimes
difficult to use in biomedical applications due to its hardness and
brittleness.5,6 It has also been pointed out that it changes pH in
the body and is thought to be a source of inflammation,7,8 since it
generates acidic compounds after decomposition. On the other
hand, poly(trimethylene carbonate) (PTMC) obtained by
polymerization of trimethylene carbonate (TMC) which is a six-
Previously, we have also reported on ester free TMC
derivatives, resulting in functional polymers with ether linkages
in the side chain. Firstly, we have reported on thermoresponsive
ester free PTMC derivatives bearing oligoethylene glycol (OEG)
in the side chain.24 Secondly, photoresponsive PTMC derivative
coumarin derivatives have been synthesized.25 The analysis of the
degradation behaviors of PTMC derivatives with OEG in the side
chain26 and the formation of nanoparticles by amphiphilic
copolymer with PLA and PTMC derivatives have also been
reported.27 Since they do not generate any acidic compounds at
the time of disassembling, treatment could be carried out without
membered ring carbonate is also widely known as
a
biocompatible and biodegradable compound.9-13 Flexibility is one
of the properties of PTMC.14 Furthermore, it is possible to design
the TMC derivatives by introducing substituents into the side
chain in order to add functionality. Many potential applications
have been reported such as DNA delivery systems for gene
therapy15, suppression of platelet adhesion by surface
 Corresponding author. Tel.: +81-743-72-5508; fax: +81-743-72-5509; e-mail: ajiro@ms.naist.jp

2
Tetrahedron Letters
changing the pH in the body. However, the starting compound
for their monomer is limited to the primary alcohol, as well as
requiring many synthesis steps, usually five. This could therefore
be one of the reasons why there are not so many ester free TMC
derivatives.14
In this study, we have developed a novel synthesis route to
make ester free TMC derivatives, using more common materials.
The novel synthesis route introduces the aldehyde compound as
the starting material and converts it to the TMC side chain by
ether bond. The key reaction uses diisobutylaluminium hydride
(DIBAL) which is a reducing agent.28 By using DIBAL, it is
possible to cut off only one side of the acetal structure.29-32
Several compounds were synthesized to confirm the usefulness
of the novel synthesis route.
Results and discussion
The novel synthesis method differs from the conventional
method in the number of reaction steps. In the conventional
synthesis method, two hydroxyl groups are protected and the
remaining hydroxyl group and the sulfonyl protected substituent
are coupled. Then, deprotection of two hydroxyl groups is carried
out, and the TMC derivative is synthesized by the carbonation
reaction. Hence, there are five reaction steps.10 Also, since it is
the SN2 reaction, a steric effect is caused, and it has been a
problem that only limited substituents can be introduced.
Therefore, in order to synthesize the ester free type TMC
derivative more easily, it was proposed to directly introduce the
compound used for protecting the hydroxyl group into the side
chain. In the novel synthesis method, however, two hydroxyl
groups are protected with the substituent to be introduced and
only one side of the cyclic acetal structure is deprotected using
DIBAL (Scheme 1). Using this method, it was possible to
synthesize a diol into which a substituent, which is a precursor of
the TMC derivative, was introduced after protecting the hydroxyl
group. Thereafter, the carbonation reaction was carried out, and a
TMC derivative was synthesized by three-step reaction using a
novel synthesis method. This method was applied to six
aldehydes and one ketone to successfully synthesize eight TMC
derivatives.
Figure 1. 1H NMR spectra of compound 1 (a), 2 (b) and 3 (c)
(500 MHz, CDCl3).
Figure 2. FT-IR spectra of compound 1 (a), 2 (b) and 3 (c).
cm-1 in compound 3 was observed, the formation of the TMC
derivative was confirmed (Figures 2b and 2c).
A series of synthesized TMC derivatives are shown in Table
1. Eight TMC derivatives were synthesized, seven derivatives are
novel compounds (Table 2, entries 2-8). All currently known
ester free type TMC derivatives are liquid, while compounds 12,
18, 21 and 24 are solid TMC derivatives. Compounds 3, 18 and
21 in which no substituent was attached to the aromatic ring were
obtained with relatively high yield. However, compounds 6, 9, 12
and 24 with substituents attached to the aromatic ring were
obtained at relatively low yield. This result suggests that when
DIBAL reduces the acetal structure, the deprotection reaction is
inhibited by steric bulkiness. It is also suggested that the
electronic effect of the substituent is affected. The yield of each
intermediate compound is shown in Table 1. Diol compounds 2,
14, 17 and 20 in which no substituent was attached to the
aromatic ring were obtained with relatively high yield. Compared
with the compounds 2, 14, 17, and 20, the diol compounds 5 and
23 having an electron donating substituent on an aromatic ring
have a lower yield. In particular, the diol compound 8 and 11
having an electron withdrawing substituent have the lowest yield.
Therefore, selective deprotection by DIBAL was determined to
be affected by steric and electronic effects. Compound 15 had a
low yield in the acetal reaction, so that the overall yield was low.
This is due to side reactions occurring during the acetal reaction,
resulting in a decrease in yield.
Scheme 1. Novel synthesis of ester free type trimethylene carbonate
derivatives.
Figure 1 shows 1H NMR spectra when benzaldehyde was used
as the starting material. Since the peak of the methylene proton at
5.44 ppm in compound 1 shifted to the low magnetic field of 4.52
ppm in compound 2 by the deprotection reaction by DIBAL,
formation of the diol compound 2 was confirmed (Figures 1a and
1b). Also, since the peak of the hydroxyl group of 2.37 ppm in
compound 2 disappeared and the peak of the methylene proton at
3.58 to 3.74 ppm shifted to a high magnetic field of 4.07 to 4.38
ppm in compound 3, the formation of the TMC derivative was
confirmed (Figures 1b and 1c).
Figure 2 shows FT-IR spectra when benzaldehyde was used as
a starting material. Since the peak of the hydroxyl group at 3,485
cm-1 in compound 1 was changed to 3,271 cm-1 in compound 2,
formation of the diol compound 2 was confirmed (Figures 2a and
2b). Also, since the peak of the hydroxyl group at 3,271 cm-1 in
compound 2 disappeared and the peak of the carbonate at 1,746
Comparisons of compounds 3, 9 and 12 showed almost no
change in Tg and T10. Compounds 3 and 9 were liquid and 12 was

3
Table 1. The yield of each intermediate compound.
Compound
1
Product
Yield (%)
Compound
9
Product
Yield (%)
Compound
17
Product
Yield (%)
O
OH OH
O
O
O
O
O
89
44
62
O
OH
F
F
OH OH
O
O
O
O
F
O
O
O
2
3
75
67
10
11
72
31
18
19
76
97
OH
O
O
OH OH
O
O
O
O
F
O
O
O
F
OH
O
OH OH
O
O
O
O
O
O
F
O
O
4
34
12
73
20
71
F
OH
O
OH OH
O
O
O
O
O
O
O
O
OH
5
6
54
70
13
14
7
21
22
75
69
OH
O
O
OH OH
O
O
O
O
O
O
O
O
O
O
O
64
O
O
O
OH OH
F
O
O
O
O
O
O
O
7
8
87
15
16
82
23
24
43
65
O
O
OH
OH OH
O
O
O
O
O
O
O
O
5
73
F
OH
O
O
solid. It was thought that this was due to the fact that
benzaldehyde and 4-fluorobenzaldehyde were liquid and 2,4-
difluorobenzaldehyde was solid. Likewise, compound 15 was a
liquid because 1-naphthaldehyde was a liquid, and compound 18
became a solid because benzophenone was a solid. Although
vanillin was a solid, compound 6 became a liquid. This is due to
the fact that the ethylchloroformate reacted with the hydroxyl
group of the aromatic ring, and the intermolecular bond via the
hydroxyl group disappeared. In compounds 21 and 24, the
product became a solid despite the fact that benzaldehyde and p-
anisaldehyde were liquid. As a result, if the starting material is a
liquid even if it has a rigid structure, the possibility of
solidification should be considered. Compared with compounds
18 and 21 having no substituent on the aromatic ring, the Tg and
Tm of compound 18 using ketone as a starting material was higher
than that of compound 21 in which the aldehyde was used as a
starting material. It is derived from the side chain structure.
Compound 18 is in a form in which a secondary alcohol is
introduced into the side chain, and compound 21 is in a form in
which a primary alcohol is introduced. Therefore, because
compound 21 could move relatively freely compared with
compound 18, it was considered that there was a difference in
thermal properties.
Conclusion
In conclusion, we succeeded in developing a novel synthesis
route for ester free TMC derivatives. By developing this novel
synthesis route, it became possible to introduce a substituent in
the side chain in the form of an ether bond using aldehyde or
ketone as a starting substance. This made it possible to introduce
a substituent derived from a secondary alcohol into the side
chain. In addition, compared with the conventional synthesis
method, it was possible to reduce the number of reaction steps
from five to three, enabling time and cost reductions.
It was suggested that the state of the TMC derivative could be
controlled by the selection of starting material and structure.
Thermal analysis showed that T10 was more than 200 ℃ in all
TMC derivatives. This makes it possible to conduct dry heat
sterilization allowing it to be used as a medical material. This
novel synthesis method opens the possibility of a wide range of
new ester free type TMC derivatives.
Supporting Information
Experimental details; Figures S1−S48 (1H NMR and FT-IR).

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Tetrahedron Letters
Table 2. Ester free type trimethylene carbonate derivatives were synthesized.
aldehyde or
Entry
1
Product
appearance
Tg a (℃)
Tm a (℃)
T10 b (℃)
Yield (%)
ketone
O
O
(3)
O
O
O
H
Liquid
-50
-
239
45
O
O
H
(6)
O
O
O
O
O
O
2
3
Liquid
Liquid
-24
-50
-
-
291
252
13
3
HO
O
O
O
O
H
(9)
O
O
F
O
F
O
F
O
(12)
O
O
H
F
F
4
5
Solid
-51
-22
85
240
276
16
4
O
F
O
O
(15)
O
O
O
H
Liquid
-
O
O
(18)
O
O
6
7
8
Solid
Solid
Solid
-7
75
53
76
279
288
257
34
52
19
O
O
O
O (21)
O
H
O
O
-33
-39
O
O
(24)
O
O
O
O
H
O
O
O
aDetermined by DSC. bDetermined by TGA. T10 is the temperature which 10% of the weight loss.
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6
Tetrahedron
・Novel synthesis method is shown for ester free
trimethylene carbonate derivatives.
・Six aldehydes and one ketone compounds
converted to monomers
・It requires only three steps.
・The selective deprotection by
diisobutylaluminium hydride is key reaction.
・This method would provide variety of functional
biodegradable polymers.