Synthesis of glucosamine derivative with double caffeic acid moieties at N– and 6-O-positions for developments of natural based materials

Article abstract of DOI:10.1016/j.molstruc.2020.127689

Glucosamine derivatives with double caffeic acid moieties were synthesized for developments of natural based materials. Caffeic acids were introduced to glucosamine derivatives through the synthesis roots as protection and de-protection reactions. Firstly, the silyl groups and tert-butoxycarbonyl groups were selected for the protection of each hydroxyl group and amino group. The designed glucosamine derivative showed reactivity of the double bonds, which was confirmed by UV spectra. Photoresponsivity was observed both in solution and heterogeneous suspension. The oligomerization was also confirmed in water suspension. The solubility and thermal stability were changed after the UV irradiation. This results show the potential of great progress a natural based material development.

Full text of DOI:10.1016/j.molstruc.2020.127689

Journal of Molecular Structure 1206 (2020) 127689
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Synthesis of glucosamine derivative with double caffeic acid moieties
at Ne and 6-O-positions for developments of natural based materials
, b, *
Kenta Yamatani a, Ryo Kawatani a, Hiroharu Ajiro a
a Division of Materials Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Takayama-cho 8916-5, Ikoma, Nara,
630-0192, Japan
b Institute for Research Initiatives, Nara Institute of Science and Technology, Takayama-cho 8916-5, Ikoma, Nara, 630-0192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Glucosamine derivatives with double caffeic acid moieties were synthesized for developments of natural
based materials. Caffeic acids were introduced to glucosamine derivatives through the synthesis roots as
protection and de-protection reactions. Firstly, the silyl groups and tert-butoxycarbonyl groups were
selected for the protection of each hydroxyl group and amino group. The designed glucosamine deriv-
ative showed reactivity of the double bonds, which was confirmed by UV spectra. Photoresponsivity was
observed both in solution and heterogeneous suspension. The oligomerization was also confirmed in
water suspension. The solubility and thermal stability were changed after the UV irradiation. This results
show the potential of great progress a natural based material development.
Received 25 November 2019
Received in revised form
31 December 2019
Accepted 3 January 2020
Available online 6 January 2020
Keywords:
Glucosamine
Photosensitive
Caffeic acid
© 2020 Elsevier B.V. All rights reserved.
1. Introduction
specifically focusing on selective introductions of functional com-
pounds, probably syntheses of glucosamine derivatives are too
Developments of materials using natural based polymers were
imperative chemistry in order to contribute the solution of the
depletion of natural energy source. Among them, chitosan de-
rivatives were any one of keenly anticipated polymers for natural
based materials which were produced from crab and shrimp shells
and many kind of biomaterials using them were reported, such as,
nanofibers [1,2], gels [3], particles [4e6], coagulated drug [7,8] and
anti-oxidant agent [9]. However, almost chitosan derivatives show
poor solubility in every solvents which behavior prevents the
further developments of various applications.
On the other hand, the glucosamine is monomer of chitosan
which is also produced at enough to industrial scale from natural
sources. Solubilities of glucosamine derivatives were improved
compared with chitosan derivatives because of low molecular
compounds. Therefore, developments of natural based materials
using glucosamine derivatives could be expanded for various ap-
plications, such as coagulated drug [10], antitumor drug [11],
adjuvant drug [12] and gelator [13]. The main contents of these
research were usually syntheses of glucosamine derivatives
difficult to achieve the evaluation of various applications easily.
Therefore, the researches of glucosamine derivatives are not known
so much due to longways synthesis roots derived from protection
groups [12e15]. However, it is important to solve the problem of
natural energy source, by the usages of bio-based materials which
are developed by photo-polymerization.
Similarly, caffeic acid is natural compound, which is one of
cinnamic acid derivatives and also a photo-polymerizable mono-
mer which is conjugated into the synthetic polymers in our pre-
vious work, thermal stabilities of poly(lactic acid) are improved
about 100 ꢀC by introduction of cinnamic acid derivatives [16,17].
Cinnamic acid derivatives were utilized for the creation of a bio-
plastic [18,19] prepared by photo-polymerization [20,21]. In addi-
tion, caffeic acid include catechol unit in the chemical structure
which are expected for adhesive materials [22e25] and anti-
oxidant agent, although there are few data available concerning
the modification of glucosamine with caffeic acid derivatives [26].
In this study, we designed and synthesized the glucosamine
derivatives bearing double caffeic acid moieties, which are selec-
tively modified at the N- and 6-O- positions for developments of
natural based materials, in order to produce a series of multiple
introductions of polyphenol moieties into the monosaccharide.
Then, the synthesized glucosamine derivatives were oligomerized
by UV irradiation. It is noteworthy that the compound includes the
* Corresponding author. Division of Materials Science, Graduate School of Science
and Technology, Nara Institute of Science and Technology, Takayama-cho 8916-5,
Ikoma, Nara, 630-0192, Japan.
E-mail address: ajiro@ms.naist.jp (H. Ajiro).
https://doi.org/10.1016/j.molstruc.2020.127689
0022-2860/© 2020 Elsevier B.V. All rights reserved.

2
K. Yamatani et al. / Journal of Molecular Structure 1206 (2020) 127689
multiple interactive moieties and the regulated conformation. The
multiple interaction moieties, such as hydroxyl, amide, polyphenol,
double bond, and aromatic groups, would allow the combination of
various molecules, as well as selective interaction due to the
regulated conformation. In addition, the obtained oligomers were
analyzed by FT-IR, UV spectrometer and MALDI-TOF MS to confirm
the dimerization reaction of double bond derived from caffeic acids.
2.1.1.3. Synthesis of 1,3,4-tri-O-benzyl-6-O-tert-butyldiphenylsilyl-2-
N-tert-butoxy carbonyl-D-glucosamine (4). To a solution of 6-O-tert-
Butyldiphenylsilyl-2-N-tert-butoxycarbonyl-D-glucosamine
(3)
(6.60 g, 12.8 mmol) and NaH 60% in oil (1.69 g, 42.1 mmol) in dry
DMF (25 mL) was stirred at room temperature for 1 h under the
nitrogen atmosphere in 300 mL 2-neck eggplant shaped flask. TBAI
(0.480 g, 1.28 mmol) and BnBr (5.0 mL, 42.1 mmol) were added to
the solution in the ice bath. The mixture was stirred for 18 h. After
completion of the reaction, the residual BnBr was quenched with
H2O. The solution was extracted with hexane, ethyl acetate and
H2O. The organic layer was dried over Na2SO4 and evaporated. The
crude was purified by silica gel column chromatography with
hexane/ethyl acetate (9:1) to give compound 4 as yellow oil (6.90 g,
8.76 mmol, 69%).
2. Experimental sections
2.1. Materials and analytical apparatus
Sodium methoxide (CH3ONa), di-tert-butyl dicarbonate, Caffeic
acid, N,N-Diisopropylethylamine (DIPEA), Benzyl bromide (BnBr),
Sodium hydride (NaH), triethylamine, Glucosamine, Tetrabuty-
lammonium iodine (TBAI), Butyl(chloro)dimethylsilane), Dime-
thyltin dichloride (Me2SnCl2), trifluoroacetic acid were purchased
from Tokyo Chemical Industry Co. Ltd (Japan). tert-Butyl(chloro)
diphenylsilane (TBDPSCl) and imidazole were purchased from
Aldrich Co. Ltd (USA).
1H NMR 400 MHz (DMSO‑d6):
d (ppm) 7.73e7.62 (m, 3H),
7.47e7.10 (m, 22H), 4.84 (m, 2H), 4.74e4.54 (m, 3H), 4.45 (d,
J ¼ 8.0 Hz, 1H), 3.96e3.87 (m, 3H), 3.68e3.61 (m, 3H), 3.53 (m, 1H),
1.41 (s, 9H), 1.00 (s, 9H); Rf: 0.38 (Hexane: EtOAc ¼ 4 : 1 (v:v)).
Synthesis of 1,3,4-Tri-O-benzyl-2-N-tert-butoxycarbonyl- -
D
glucosamine (5) To
butyldiphenylsilyl-2-N-tert-butoxycarbonyl-
a
solution of 1,3,4-Tri-O-benzyl-6-O-tert-
-glucosamine (4)
D
1H NMR was measured with JEOL JNM-ECM 400 (JEOL Ltd.
Japan). FT-IR spectra were measured by the Spectrum 100 FT-IR and
IRAffinity-1S ATR (Shimadzu Corporation, Japan). ESI-MASS was
measured by JEOL AccuTOF, JMS-T100LC (JEOL Ltd., Japan). DART-
MASS was measured by JEOL JMS-Q1000TD (JEOL Ltd., Japan).
MALDI-TOF-MS was measured by Bruker Autoflex II (Bruker Dal-
tonics K.K., Japan). UV spectra were monitored by UV-2600 (Shi-
madzu Corporation, Japan). TGA was analyzed by TGA-50
(Shimadzu Corporation Japan). DSC was analyzed by DSC-60 Plus
and TAC/L system (Shimadzu Corporation, Japan). UV light was
irradiated by SUPERCURE-352S (SAN-EI Electric Co. Ltd., Japan).
(6.90 g, 8.76 mmol) and 1 M TBAF/THF (17.5 mL, 17.5 mmol) in dry
THF (8.7 mL) was stirred at room temperature for 24 h under the
nitrogen atmosphere in 300 mL 2-neck eggplant shaped flask. After
completion of the reaction, the solution was extracted with ethyl
acetate and H2O. The organic layer was dried over Na2SO4 and
evaporated. The crude was purified by silica gel column chroma-
tography with hexane/ethyl acetate (2:1) to give compound 5 as
colorless crystal (1.88 g, 3.42 mmol, 39%).
1H NMR 400 MHz (CDCl3):
d (ppm) 7.38e7.27 (m, 15H),
4.89e4.47 (m, 7H), 3.96e3.32 (m, 6H), 1.44 (s, 9H); Rf: 0.38 (Hex-
ane: EtOAc ¼ 1 : 1 (v:v)).
2.1.1. Syntheses
2.1.1.4. Synthesis of 1,3,4-tri-O-benzyl-
tion of 1,3,4-Tri-O-benzyl-2-N-tert-butoxycarbonyl-
D
-glucosamine (6). To a solu-
-glucosamine
D
2.1.1.1. Synthesis of 2-N-tert-butoxycarbonyl-D-glucosamine (2).
(5) (1.88 g, 3.42 mmol) and trifluoroacetic acid (2.60 mL,
34.0 mmol) in CH2Cl2 (7.0 mL) was stirred at room temperature for
1 h in 200 mL eggplant shaped flask. After completion of the re-
action, the residual trifluoroacetic acid was quenched with NaHCO3
aq. The solution was extracted with CH2Cl2 and H2O. The organic
layer was dried over Na2SO4 and evaporated. The crude was puri-
fied by silica gel column chromatography with hexane/ethyl ace-
tate/TEA (1:1:0.2) to give compound 6 as colorless crystal (1.45 g,
3.23 mmol, 94%).
To
a
solution of D-(þ)-Glucosamine hydrochloride (30.8 g,
143 mmol) and CH3ONa (8.53 g, 158 mmol) in CH3OH (400 mL) was
stirred at room temperature for 1 h in 1 L egg plant shaped flask.
After dissolving, di-tert-butyl dicarbonate (34 mL, 171 mmol) and
triethylamine (20 mL, 143 mmol) were added to the solution. The
mixture was stirred at room temperature for 6 h. The solvent was
concentrated and the residue was recrystallized to give compound
2 as white solid (35.5 g, 127 mmol, 89%).
1H NMR 400 MHz, D2O):
d (ppm) 5.17 (d, 0.75H), 4.66 (d, 0.25H),
1H NMR 500 MHz (CDCl3):
d (ppm) 7.37e7.27 (m, 15H), 4.97 (d,
3.98e3.25 (m, 6H), 1.42 (s, 9H); Rf: 0.60 (CH2Cl2: CH3OH ¼ 7 : 3
J ¼ 10.5 Hz, 1H), 4.86 (t, J ¼ 11.5 Hz, 2H), 4.73e4.61 (m, 3H), 4.37 (d,
J ¼ 8.0 Hz,1H), 3.89 (d, J ¼ 11.5 Hz,1H), 3.75 (d, J ¼ 12.0 Hz, 1H), 3.63
(t, J ¼ 9.5 Hz, 1H), 3.47 (t, J ¼ 9.25 Hz, 1H), 3.42e3.39 (m, 1H), 2.90
(dd, J ¼ 8.0, 10.0 Hz, 1H); Rf: 0.13 (Hexane: EtOAc: NEt3 ¼ 1 : 2: 0.1
(v:v:v)).
(v:v)).
2.1.1.2. Synthesis of 6-O-tert-butyldiphenylsilyl-2-N-tert-butox-
ycarbonyl-D-glucosamine (3). To
a solution of 2-N-tert-butox-
ycarbonyl- -glucosamine (2) (21.5 g, 77.0 mmol) and imidazole
D
(4.18 g, 61.4 mmol) in dry DMF (250 mL) was stirred at room
temperature for 1 h under the nitrogen atmosphere in 500 mL 2-
neck eggplant shaped flask. After dissolving, TBDPSCl (14 mL,
54.0 mmol) in dry THF (50 mL) were added to the solution in the ice
bath. The mixture was stirred for 18 h. After completion of the re-
action, the residual TBDPSCl was quenched with H2O. The solution
was extracted with hexane, ethyl acetate and H2O. The organic layer
was dried over Na2SO4 and evaporated. The crude was purified by
silica gel column chromatography with hexane/ethyl acetate (1:1)
to give compound 3 as colorless crystal (25.9 g, 50.0 mmol, 81%).
2.1.1.5. Synthesis of (E)-3-(3,4-bis((tert-Butyldimethylsilyl)oxy)caffeic
acid (8). To a solution of caffeic acid (1.51 g, 8.38 mmol) and
imidazole (2.55 mL, 37.4 mmol) and TBSCl (tert-butyl(chloro)
dimethylsilane) (5.66 g, 37.4 mmol) in dry DMF (16.0 mL) was
stirred at room temperature for 20 h under the nitrogen atmo-
sphere in 300 mL 2-neck eggplant shaped flask. After completion of
the reaction, the reaction was quenched with H2O. The solution was
extracted with ethyl acetate and H2O. The organic layer was dried
over Na2SO4 and evaporated. The crude was purified by silica gel
column chromatography with hexane/ethyl acetate (1:1) and vac-
uum at 100 ꢀC to give compound 8 as pale yellow crystal (3.05 g,
7.47 mmol, 90%).
1H NMR 400 MHz (CDCl3):
d (ppm) 7.70e7.64 (m, 4H), 7.47e7.36
(m, 6H), 5.19 (s, 1H), 3.91e3.84 (m, 2H), 3.76e3.62 (m, 2H), 3.08 (s,
1H), 2.96 (s, 1H), 1.45 (s, 9H), 1.05 (s, 9H); Rf: 0.25 (Hexane:
EtOAc ¼ 1 : 1 (v:v)).
1H NMR 400 MHz (CDCl3):
(m, 1H), 6.83 (d, J ¼ 8.8 Hz, 2H), 6.25 (d, J ¼ 16.0 Hz, 1H), 1.00 (s,
d
(ppm) 7.67 (d, J ¼ 16.0 Hz, 1H), 7.05

K. Yamatani et al. / Journal of Molecular Structure 1206 (2020) 127689
3
18H), 0.22 (s, 12H); Rf: 0.45 (Hexane: EtOAc ¼ 2 : 1 (v:v)).
2.1.1.6. Synthesis of 2,6-di-O,N-(E)-3,4-bis(tert-butyldimethylsily-
was prepared so as to be 65
m
M CH3OH in quartz cell. The solution
was treated with nitrogen bubbling. While stirring, the solution
was irradiated with UV light using UV irradiation machine (Hg
loxy)caffeoyl-1,3,4-tri-O-benzyl- -glucosamine (10). To a solution of
D
lump, l
> 280 nm, 56 mW/cm2) in the iced bath under the nitrogen
(E)-3-(3,4-bis((tert-utyldimethylsilyl)oxy)caffeic acid (8) (0.767 g,
1.88 mmol) and 1 M SOCl2/CH2Cl2 (7.5 mL, 7.50 mmol) in dry CH2Cl2
(1.8 mL) was stirred and reflux for 15 h under the nitrogen atmo-
sphere in 100 mL 2-neck eggplant shaped flask. After completion of
the reaction, the solution was concentrated to obtain acid chloride
atmosphere to occur the [2 þ 2] photocyclization. The irradiation
condition (irradiated area: 3 cm2, distance to the source of UV light:
5 cm) was fixed. The solution of UVeVis spectra were measured at
0, 10, 20, 30 s, 1, 2, 3, 5, 10, 20, 30, 60, 120, 180 and 240 min.
Photo reactivity of 2,6-Di-O,N-(E)-caffeoyl-1,3,4-tri-O-benzyl-
D
-
(9).To a solution of 1,3,4-Tri-O-benzyl- -glucosamine (6) (0.352 g,
D
glucosamine (11) in H2O
0.783 mmol) and Me2SnCl2 (0.0188 g, 0.0783 mmol) and DIPEA
(N,N-Diisopropylethylamine) (0.55 mL, 3.13 mmol) in dry THF
(1.0 mL) was stirred under the nitrogen atmosphere in 50 mL 2-
neck eggplant shaped flask. Acid chloride (9) in dry THF (1.5 mL)
was added to the solution at room temperature and the solution
was stirred for 24 h. After completion of the reaction, the solution
was extracted with ethyl acetate and H2O. The organic layer was
dried over Na2SO4 and evaporated. The crude was purified by silica
gel column chromatography with hexane/ethyl acetate (1:1) to give
compound 10 as pale yellow crystal (0.535 g, 4.35 mmol, 55%).
2,6-Di-O,N-(E)-caffeoyl-1,3,4-tri-O-benzyl- -glucosamine (11)
D
was prepared so as to be 1.0 mM aqueous solution in screw bial. The
solution was treated with nitrogen bubbling. While stirring, the
solution was irradiated with UV light using UV irradiation machine
(Hg lump,
l
> 280 nm, 56 mW/cm2) in the iced bath under the
nitrogen atmosphere to occur the [2 þ 2] photocyclization. The
irradiation condition (distance to the source of UV light: 5 cm) was
fixed. The solution was irradiated by UV light for 4 h. After irradi-
ation, the mixture was washed with CH3OH and acetone. The sol-
uble part (0.009 g, 12%) and insoluble part (0.068 g, 88%) were
collected respectively.
1H NMR 400 MHz (CDCl3):
d
(ppm) 7.59 (d, J ¼ 16.0 Hz, 1H), 7.47
(d, J ¼ 15.6 Hz, 1H), 7.37e7.27 (m, 15H), 7.02e6.96 (m, 4H), 6.82 (d,
J ¼ 8.0 Hz, 2H), 6.26 (d, J ¼ 16.0 Hz,1H), 5.93 (d, J ¼ 15.6 Hz,1H), 5.38
(d, J ¼ 10.0 Hz, 1H), 4.97e4.59 (m, 6H), 4.51e4.45 (m, 3H), 4.36 (m,
1H), 3.97 (m 1H), 3.85e3.74 (m, 2H), 1.00 (s, 36H), 0.22 (s, 24H).
ESI-MS ¼ [MþNa]þ ¼ 1253.69; FT-IR: 2929, 2858, 1712, 1508,
1286, 1251, 1165, 1124, 904, 837, 779, 694 cmꢁ1; Rf: 0.23 (Hexane:
EtOAc ¼ 4 : 1 (v:v)).
3. Results and discussion
Initially, we had planned to synthesize the target compound
directly without protecting groups, however, it was very difficult to
confirm whether the product was target compound or not by thin
layer chromatography (TLC). So, the protective groups were utilized
for the N-position and 6-O-position as shown in Scheme 1.
Considering the introduction of functional groups at N- and 6-O-
positions with different reactivities from the other positions, it was
necessary to protect the rest of 2-O-, 3-O-, and 4-O- hydroxyl po-
sitions at first. So, the careful selection of protecting groups for 2-O-
, 3-O-, and 4-O- hydroxyl positions was required to keep the other
protecting groups stable at N- and 6-hydroxyl positions under their
deprotection reaction at 2-O-, 3-O-, and 4-O- hydroxyl positions.
We selected the Boc group which could be removed under acidic
conditions for the protection of the amino group at the N-position,
and we selected the silyl group for the selective protection of the
primary alcohol at the 6-O-position. Next, the protection of the
three hydroxyl groups was attempted as shown in Scheme 2.
Actually, the compound 4 could not be obtained under some
conditions, although the reason was unclear. For example, the
proton at the N-position also reacted under an excessive amount of
NaH (6 eq). No reaction was confirmed under the milder alkaline
condition, such as the triethylamine and the potassium carbonate
at room temperature. Furthermore, some reactions could not pro-
ceed because of the poor reactivity after protections and the failure
of the selective deprotections. Thus, we pursue the different
pathway to synthesize the target compound. That was the reason
why we synthesized 6 through the synthesis roots in Scheme 2 and
the following Scheme 3.
Using compound 4, selective deprotection of TBDPS was ach-
ieved in THF at room temperature. Successively, the deprotection of
the Boc group proceeded under an acidic condition with 10eq. of
the trifluoro acetic acid at room temperature. Although compound
6 is a reported compound elsewhere [12], it is noteworthy that the
total steps of the synthesis decreased with the higher yield. In order
to conjugate with compound 6, the caffeic acid derivative 9 was
synthesized by the following reaction as shown in Scheme 4, using
the N-position and 6-O-position of compound 6.
Two aromatic hydroxyl groups were protected by the t-butyl-
dimethylsilyl group, then the tionyl chloride was treated with
compound 8, in order to react with the amide or the primary
alcohol of compound 6. The obtained compound 9 was directly
2.1.1.7. Synthesis of 2,6-di-O,N-(E)-caffeoyl-1,3,4-tri-O-benzyl-
glucosamine (11). To solution of 2,6-Di-O,N-(E)-3,4-bis(tert-
butyldimethylsilyloxy)caffeoyl-1,3,4-tri-O- benzyl- -glucosamine
D-
a
D
(10) (0.807 g, 0.656 mmol) and TBAF (3.2 mL, 3.15 mmol) in dry THF
(0.60 mL) was stirred at room temperature for 3 h under the ni-
trogen atmosphere in 50 mL 2-neck eggplant shaped flask. The
solution was extracted with CH2Cl2 and H2O. The organic layer was
dried over Na2SO4 and evaporated. The crude was purified by silica
gel column chromatography with CH2Cl2/CH3OH (9:1) to give
compound 11 as brown crystal (0.406 g, 0.525 mmol, 80%).
1H NMR 400 MHz (DMSO‑d6):
d (ppm) 9.64 (s, 1H), 9.41 (s, 1H),
9.18 (s, 2H), 8.31 (d, J ¼ 9.2 Hz, 1H), 7.51 (s, 1H), 7.40e7.19 (m, 15H),
7.07e6.85 (m, 4H), 6.74 (d, J ¼ 8.0 Hz, 2H), 6.53 (d, J ¼ 15.6 Hz, 1H),
6.35 (d, J ¼ 15.6 Hz, 1H), 5.28 (s, 1H), 4.83e4.57 (m, 6H), 4.51 (m,
1H), 4.38 (m, 1H), 4.30e4.15 (m, 2H), 3.92e3.81 (m, 2H), 3.63 (t,
1H).
ESI-MS ¼ [MþNa]þ ¼ 796.27; FT-IR: 3294, 2954, 2927, 1693,
1597, 1514, 1273, 1157, 1112, 1016, 977, 696 cmꢁ1; Rf: 0.53 (CH2Cl2:
CH3OH ¼ 9 : 1 (v:v)).
2.1.2. Photo reactivity
Photo reactivity of 2,6-Di-O,N-(E)-3,4-bis(tert-butyldimethylsi-
lyloxy)caffeoyl-1,3,4-tri-O-benzyl-
2,6-Di-O,N-(E)-3,4-bis(tert-butyldimethylsilyloxy)caffeoyl-
1,3,4-tri-O-benzyl- -glucosamine (10) was prepared so as to be
45 M CH3OH in quartz cell. The solution was treated with nitrogen
bubbling. While stirring, the solution was irradiated by UV light
using UV irradiation machine (Hg lump,
> 280 nm, 56 mW/cm2)
D-glucosamine (10) in CH3OH
D
m
l
in the iced bath under the nitrogen atmosphere to occur the [2 þ 2]
photocyclization. The irradiation condition (irradiated area: 3 cm2,
distance to the source of UV light: 5 cm) was fixed. The UVeVis
spectra of solution was measured at 0, 10, 20, 30 s, 1, 2, 3, 5, 10,
20, 30, 60, 120, 180 and 240 min.
Photo reactivity of 2,6-Di-O,N-(E)-caffeoyl-1,3,4-tri-O-benzyl-
glucosamine (11) in CH3OH
D-
2,6-Di-O,N-(E)-caffeoyl-1,3,4-tri-O-benzyl- -glucosamine (11)
D

4
K. Yamatani et al. / Journal of Molecular Structure 1206 (2020) 127689
Scheme 1. Synthesis of compound 3.
Scheme 2. Synthesis of compound 4.
Scheme 3. Synthesis of compound 6.
Scheme 4. Synthesis of compound 9.
combined with the compound 6 as shown in Scheme 5.
As a result, the monomer of the photo-polymerization was
successfully synthesized, using the glucosamine as a core moiety,
accompanied by double caffeic acid moieties. During the reaction,
the protecting groups played important roles in the aspects of both
solubility and selectivity (see Fig. 1). After the successful synthesis
of compounds 10 and 11, their characteristics were examined. At
first, the photo-reactivity of the double bonds was investigated in
The condensation reaction of glucosamine and caffeic acid was
depicted in Scheme 5 [27]. DIPEA was employed for trapping the
acid which was generated in the reaction, and Me2SnCl2 was uti-
lized for the acceleration of the reaction as an acid. Then, com-
pound 10 was successfully obtained. Generally, the protection of
the aromatic hydroxyl groups was easier than aliphatic hydroxyl
groups when TBDPS groups was used. Then the deprotection re-
action of aromatic hydroxyl groups were also proceeded effectively,
resulting in compound 11. The catechol groups were confirmed by
1H NMR in DMSO‑d6, as well as the confirmation of hydroxyl groups
methanol (Fig. 2). Compound 10 was irradiated by UV light at 45 mM
after nitrogen bubbling, and the UVevis adsorption spectra were
monitored. The peak top at 317 nm decreased after the irradiation
as shown in Fig. 2a, indicating that the photo-generated radical was
consumed. The same tendency as compound 10 was confirmed for
by FT-IR spectrometer at around 3000 cmꢁ1
.
Scheme 5. Synthesis of 10 and 11.

K. Yamatani et al. / Journal of Molecular Structure 1206 (2020) 127689
5
Fig. 1. Chemical structure of the glucosamine derivative with symmetric caffeic acid moieties at the N- and 6-O-positions in this study.
Fig. 3. FT-IR spectra zoom of compound 11 before (a) and after (b) UV irradiation.
bond decreased on the FT-IR spectra after the UV irradiation (Fig. 3).
This change has been reported for the dimerization of caffeic acid
[28]. This result indicated the decrease of the double bond. At the
same time, a new peak appeared at 1750 cmꢁ1 unexpectedly, which
was assigned as a benzoquinone group, suggesting that the cross-
linking had occurred.
Fig. 4 shows the MALDI-TOF/MS of compound 11 after UV irra-
diation. Since the molecular weight of compound 11 was 773.26 g/
mol, the oligomer peaks were confirmed at dimer, trimer, tetramer,
and pentamer. This result demonstrates that the obtained com-
pound 11 is photosensitive to form the oligomers.
Finally, the physical properties of compound 11 were analyzed.
It was soluble in most of the common organic solvents, such as
methanol, ethanol, isopropanol, acetone, diethyl ether, and ethyl
acetate, whereas it was not soluble in water, dichloromethane, and
hexane. However, it could not be dissolved in any of the above-
mentioned solvents after UV irradiation. The DSC analysis of com-
pound 11 after UV irradiation showed no glass transition
temperature and melting points, while the degradation tempera-
ture was 291 ꢀC at the 10% weight loss temperature. These results
suggest that the solubility and thermal stability were improved
after UV irradiation. Since the oligomer was composed of the six
membered ring of glucosamine and aromatic groups of cinnamic
acid derivatives, the high rigid and strong heat resistant polymer
materials are expected. Currently, the further medication were
underway, which might lead to the high performance polymer
materials that can be controlled by photo-responsive functionality.
Fig. 2. UVevis spectra of compound 10 (45
mM) (a) and compound 11 (65 mM) (b) in
methanol UV irradiation ( > 280 nm) with each elapsed time.
l
compound 11 at 65 mM as shown in Fig. 2b. The peak top at 328 nm
similarly decreased. However, compound 11 showed a complete
decrease of the peak intensity of the double bonds. This results
probably based on the different bulkiness between 10 and 11,
supported by the molecular simulation (Supporting Information,
Figs. S13 and S14). The change of UV spectral pattern at the double
bond was also confirmed in THF as a solvent. As a model of
glucosamine materials for film formation, the aggregated behavior
of the compound was also investigated. 77.3 mg (0.1 mmol) of
compound 11 was suspended in 100 mL of ion exchanged water,
and then irradiated with UV light. After the UV irradiation, 9 mg
(12%) of the methanol soluble part and 68 mg (88%) of the methanol
insoluble part were recovered. The insoluble part was analyzed by
FT-IR and MALDI-TOF/MS. The FT-IR spectra of the samples before
and after UV irradiation are compared in Fig. 3.
4. Conclusion
We designed and synthesized a glucosamine derivative bearing
double caffeic acid moieties for developments of natural based
materials. The properly selected protection and deprotection
The peak intensity of the stretching and twisting of the double

6
K. Yamatani et al. / Journal of Molecular Structure 1206 (2020) 127689
Fig. 4. MALDI-TOF-MS of insoluble part of the compound 11.
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reactions of each the hydroxyl group and the amino group led to the
successful synthesis of compound 10 and 11. Their synthesis roots
contribute to the trim of syntheses steps and the improvement of a
final yield. In addition, synthesized glucosamine derivatives were
polymerized by UV irradiation and obtained oligomers were
investigated by FT-IR, UV spectrometer and MALDI-TOF-MS. These
results indicated that dimerization reactions of double bond at
caffeic acid were occurred and their reactivity were inferenced by
the structural bulkiness. Furthermore, the solubility and thermal
stability were improved after the UV irradiation. The insights from
the present study should contribute to developments of natural
based materials using glucosamine derivatives.
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Acknowledgments
The authors are grateful to Ms. Y. Nishikawa for the measure-
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