Method for a convenient and efficient synthesis of amino acid acrylic monomers with zwitterionic structure

Article abstract of DOI:10.1080/00397910500212932

Ampholyte monomers with zwitterionic moiety derived from α-amino acid, that is, L-lysine and L-serine, were obtained using a method in which their copper complexes could be produced in simple steps. The N-acryloylation of L-lysine and L-serine was carried out by reaction between their copper complexes and acryloyl chloride. Specifically, the removal of copper from the copper complex of acryloyl amino acid through the use of 8-hydroxyquinoline as an organic chelate precipitant increased the yield of the ampholyte monomers with zwitterionic moiety. These syntheses were easily carried out in a three-step procedure. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1080/00397910500212932

This article was downloaded by: [University of Memphis]
On: 12 September 2012, At: 01:17
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Method for a Convenient and
Efficient Synthesis of Amino
Acid Acrylic Monomers with
Zwitterionic Structure
b
a
b
Shoji Nagaoka , Atsuomi Shundo , Takao Satoh
,
d
c
d
Kazuhiko Nagira , Ryoich Kishi , Katsuhiko Ueno
d
b
,
a
Kokoro Iio & Hirotaka Ihara
Kumamoto Industrial Research Institute,
Kumamoto, Japan
b
Department of Applied Chemistry and
Biochemistry, Faculty of Engineering, Kumamoto
University, Kumamoto, Japan
c
Dojindo Laboratories, Kumamoto, Japan
d
National Institute of Advanced Industrial Science
and Technology, Ibaraki, Japan
Version of record first published: 18 Aug 2006.
To cite this article: Shoji Nagaoka, Atsuomi Shundo, Takao Satoh, Kazuhiko
Nagira, Ryoich Kishi, Katsuhiko Ueno, Kokoro Iio & Hirotaka Ihara (2005): Method
for a Convenient and Efficient Synthesis of Amino Acid Acrylic Monomers with
Zwitterionic Structure, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 35:19, 2529-2534
To link to this article: http://dx.doi.org/10.1080/00397910500212932

PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

w
Synthetic Communications , 35: 2529–2534, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910500212932
Method for a Convenient and Efficient
Synthesis of Amino Acid Acrylic Monomers
with Zwitterionic Structure
Shoji Nagaoka
Kumamoto Industrial Research Institute, Kumamoto, Japan
Atsuomi Shundo and Takao Satoh
Department of Applied Chemistry and Biochemistry, Faculty of
Engineering, Kumamoto University, Kumamoto, Japan
Kazuhiko Nagira
Dojindo Laboratories, Kumamoto, Japan
Ryoich Kishi, Katsuhiko Ueno, and Kokoro Iio
National Institute of Advanced Industrial Science and Technology,
Ibaraki, Japan
Hirotaka Ihara
Department of Applied Chemistry and Biochemistry, Faculty of
Engineering, Kumamoto University, Kumamoto, Japan
Abstract: Ampholyte monomers with zwitterionic moiety derived from a-amino acid,
that is, L-lysine and L-serine, were obtained using a method in which their copper
complexes could be produced in simple steps. The N-acryloylation of L-lysine and
L-serine was carried out by reaction between their copper complexes and acryloyl
chloride. Specifically, the removal of copper from the copper complex of acryloyl
amino acid through the use of 8-hydroxyquinoline as an organic chelate precipitant
Received in Japan March 18, 2005
Address correspondence to Shoji Nagaoka, Kumamoto Industrial Research
Institute, Higashimachi, Kumamoto 862-0901, Japan. Tel.: þ81-96-365-5172;
Fax: þ81-96-365-5172; E-mail: nagaoka@kmt-iri.go.jp
2
529

2530
S. Nagaoka et al.
increased the yield of the ampholyte monomers with zwitterionic moiety. These
syntheses were easily carried out in a three-step procedure.
Keywords: Amino acid copper complex, 8-hydroxyquinoline, zwitterionic monomer
The hydrogel structure formed on the surface of zwitterionic amino acid
moiety, for example, O-methacryloyl L-serine and 1-methacryloyl L-lysine,
[
1–3]
is a suitable biocompatible material.
Sugiyama et al. reported that copoly-
mers containing the zwitterionic L-serine moiety greatly inhibit the aggrega-
tion of platelet-rich plasma (PRP). The zwitterionic monomer was prepared
through a complex three-step procedure involving the esterification of the
hydroxyl group in N-t-butoxycarbonyl L-serine using methacryloyl chloride,
followed by laborious treatment with trifluoroacetic acid as a deblocking
[
4]
reagent, which resulted in 25% yield. We have sought a convenient and
efficient synthetic method without need for the organic blocking reagent
and deblocking reagent, which are highly acidic substances, in order to
increase the yield of the zwitterionic monomer derived from L-serine.
We noticed the reaction between the amino acid copper complex and
acryloyl chloride. Morawetz et al. have obtained a zwitterionic monomer con-
taining the L-lysine side chain group using the following procedures: (1) they
synthesized the methacryloyl L-lysine copper complex and (2) they passed
hydrogen sulfide through a suspension of the copper complex in an aqueous
methanol solution to remove copper from the copper complex. However,
[
5]
the resulting yield was only 1%.
In an attempt to create a convenient and efficient collection method
without using hydrogen sulfide, we developed the following simple
procedure: (1) the acryloylation of a-amino acid copper complexes (i.e.,
L-lysine copper complexes, Scheme 1, or L-serine copper complexes,
Scheme 2), and (2) the extraction of copper from their copper complexes
[6]
using 8-hydroxyquinoline as an organic chelate precipitant.
Stirring L-lysine hydrochloride with basic cupric carbonate in water at
9
08C gave the copper complex 1 of L-lysine. After KOH aqueous solution
and acetone were added to the aqueous solution of the copper complex of
L-lysine, acryloyl chloride and KOH aqueous solution were added in four
doses at 38C. The precipitates of N-acrylamide cupric complex 2 of
L-lysine were obtained in a 78% yield by filtrating and washing successively
with water, methanol, and ether.
In addition, O-acryloyl L-serine copper complex 5 was produced by the
esterification of the hydroxyl group of L-serine copper complex 4 by the
same procedure as used in the synthesis of 2. The yield was 50%.
The acryloyl copper complexes of the respective amino acids were then
dispersed in water and the chloroform solution of 8-hydroxyquinoline was
added. After shaking in a separation funnel, a green precipitate was produced

Amino Acid Acrylic Monomers
2531
Scheme 1.
in the chloroform layer, and this was removed by filtration. The product in
water was recrystallized from teterahydrofuran. The yield of the 1-acryloyl
L-lysine (LysAAm) 3 monomer estimated from L-lysine as the starting
material was 74%. It is clear that the yield of 3 was much higher than that
[
5]
reported by Morawetz et al.
In addition, d-acryloyl L-ornitine (OrnAAm) could be produced by the
same procedure used for the synthesis of 3 in good yields.
However, the 50% yield of 5 estimated from the amount of L-serine was
lower than that of the copper complex of basic amino acids, L-lysine and
Scheme 2.

2532
S. Nagaoka et al.
L-ornitine. This phenomenon is caused by L-serine’s neutrality as an amino
acid. However, the yield of O-acryloyl L-serine 6 obtained by the extraction
of copper using 8-hydroxyquinoline is estimated to be 92%, based on the
amount of its copper complex. The yield of 6 estimated from the amount of
L-serine is 46%. It is clear that the yield of 6 was higher than that reported
[
4]
by Sugiyama et al.
We developed a simpler method for the synthesis of ampholyte
monomers with a high yield starting from basic amino acids, L-lysine and
L-ornithine, and even starting with a neutral amino acid such as L-serine.
These syntheses were easily carried out using a three-step procedure. The
yield of the ampholyte monomers with zwitterionic moiety could be easily
increased by extracting the copper from the acryloyl amino acid copper
complexes using the 8-hydroxyquinoline–chloroform solution.
EXPERIMENTAL
General
1
H NMR spectra were recorded with a JEOL GX-400 spectrometer. IR spectra
were measured as KBr disks with diffuse reflectance infrared Fourier-
transform (DRIFT) spectroscopy (JASCO FT/IR-700).
1-Acryloyl L-Lysine Copper Complex 2
L-Lysine hydrochloride (100 g, 548 mmol) was dissolved in water (1200 ml)
at 908C. Basic cupric carbonate (66.6 g, 301 mmol) was added slowly to the
solution and stirred for 10 min. After cooling and filtering the insoluble
residue, 580 ml of acetone was added. After 274 ml of 2.0 M KOH aqueous
solution were added into solution of the copper complex of the L-lysine,
acryloyl chloride (13.8 ml, 171 mmol) and 77 ml of 2.0 M KOH aqueous
solution was added every 5 min at 38C. This procedure was repeated four
times. After stirring for 12 h, the precipitates of the acrylamide cupric
complex of the L-lysine were filtrated and washed successively with water,
methanol, and ether. The yield was 98.7 g (78%). Their structure was
2
1
confirmed by their IR spectra. IR (cm ): 3100–3400, nN-H (amide, amine);
880–2960, nC-H; 1660, nC 55 O (amide I); 1620, dN-H (amide II); 670, dN-H
amide V). Elemental analysis (%) calcd. for C H N O Cu: C, 46.80; H,
2
(
1
8 30 4 6
6
.55; N, 12.13. Found: C, 45.00; H, 6.52; N, 11.81.
1-Acryloyl L-Lysine (LysAAm) 3
The solid of 2 (21.0 g, 45.5 mmol) was dispersed in water (300 ml), and a
chloroform solution (300 ml) of 8-quinolinol (7.91 g, 54.5 mmol) was added.

Amino Acid Acrylic Monomers
2533
After shaking for 12 h in a separation funnel, a green precipitate in the chloro-
form layer was produced, and this was removed by filtering. Three extractions
with chloroform were performed to remove traces of 8-hydroxy quinoline.
The water layer was concentrated to 50 ml after the removal of 8-hydroxy-
quinoline. The white precipitate was recrystallized from teterahydrofuran. The
1
yield was 17.1 g (94%). The structure was confirmed by its H NMR and IR
1
spectra. The H NMR spectrum of the monomer was measured in D O. H
1
2
NMR (D O, d ppm): 1.42 (m, 2H, CH ), 1.60 (m, 2H, CH ), 1.86 (m, 2H,
2
2
2
CH ), 3.26 (t, 2H, CH ), 3.73 (t, 2H, CH ), 5.75 (d, 1H, CH 55 CH[trans]),
2
2
2
2
2
1
6.18 (d, 1H, CH 55 CH[cis]), 6.21 (dd, 1H, CH 55 CH). IR (cm ): 3350,
2 2
nN-H (amide); 2880–2960, nC-H; 2200–3200, nN-H (NH ); 2000–2222,
þ
3
þ
dN-H (NH ); 1660, n
3
(amide I); 1620, dN-H (amide II); 670, dN-H (amide
C 55 O
V). Elemental analysis (%) calcd. for C H N O : C, 53.22; H, 7.72; N,
9
16 2 3
1
3.80. Found: C, 53.98; H, 8.05; N, 13.99.
d-Acryloyl L-Ornithine (OrnAAm)
d-Acryloyl L-ornithine copper complex was produced from L-ornithine
hydrochloride (100 g, 594 mmol) using the same procedure as that for
L-lysine. The yield was 91.0 g (71%). The structure was confirmed by IR
2
1
spectra. IR (cm ): 3100–3400, nN-H (amide, amine); 2880–2960, nC-H
660, nC 55 O (amide I); 1620, dN-H (amide II); 670, dN-H (amide V).
Elemental analysis (%) calcd. for C H N O Cu: C, 44.29; H, 6.04; N,
;
1
1
6 26 4 6
1
2.91. Found: C, 42.35; H, 6.15; N, 12.78.
In addition, L-OrnAAm was produced from d-Acryloyl L-ornithine
copper complex (32.1 g, 74.1 mmol) using the same procedure as that for
the synthesis of L-lysAAm. The yield was 25.2 g (92%). The structure was
1
confirmed by its H NMR and IR spectra. The H NMR spectrum of the
1
1
monomer was measured in D O. H NMR (D O, d ppm): 1.63 (m, 2H,
2
2
CH ), 1.88 (m, 2H, CH ), 3.30 (t, 2H, CH ), 3.74 (t, 2H, CH ), 5.76 (d, 1H,
2
2
2
2
CH 55 CH[trans]), 6.19 (d, 1H, CH 55 CH[cis]), 6.21 (dd, 1H, CH 55 CH).
2
2
2
2
IR (cm ): 3350, nN-H (amide); 2880–2960, nC-H; 2200–3200, nN-H (NH );
1
þ
3
þ
2 (amide I); 1620, dN-H (amide II); 670,
C 55 O
dN-H (amide V). Elemental analysis (%) calcd. for C H N O : C, 51.60; H,
000–2222, dN-H (NH ); 1660, n
3
8
14 2 3
7
.58; N, 15. 04. Found: C, 51.14; H, 7.33; N, 15.04.
O-Acryloyl L-Serine Copper Complex 5
L-Serine (5.0 g, 47.6 mmol) was dissolved in water (50 ml) at 908C. Basic
cupric carbonate (5.90 g, 26.2 mmol) was added slowly to the solution and
stirred for 10 min. After filtering the insoluble residue, washing with hot
water (30ml), and cooling, acetone (10 ml) was added. After 27.1ml of 2.0 M
KOH aqueous solution were added into the solution of the copper complex

2534
S. Nagaoka et al.
of L-serine, acryloyl chloride (4.8 ml, 59.5 mmol) in acetone (30 ml) was
added over 5 min. After stirring for 12 h, the precipitate of the acryloyl
cupric complex of the obtained serine was filtrated and washed successively
with water, methanol, and ether. The yield was 50% (4.83 g). The structure
2
1
was confirmed by their IR spectra. IR (cm ): 3160–3320, nN-H (amine);
880–2960, nC-H; 1725, nC 55 O (ester). Elemental analysis (%) calcd. for
C H N O Cu: C, 37.95; H, 4.25; N, 7.38. Found: C, 37.34; H, 4.33; N, 7.22.
2
1
2 16 2 8
O-Acryloyl L-Serine (SerAE) 6
In addition, L-SerAE was produced from 5 (4.83 g, 12.7 mmol) using the same
method as that used for L-LysAAm. The yield was 92% (3.79 g). The structure
1
was confirmed by its H NMR and IR spectra. The H NMR spectrum of the
1
1
monomer was measured in D O. H NMR (D O, d ppm): 4.11 (m, 2H, CH ),
2
2
2
4
.58 (t, 2H, CH ), 6.03 (d, 1H, CH 55 CH[trans]), 6.21 (dd, 1H, CH 55 CH),
2 2 2
2
1
þ
6
.44 (d, 1H, CH 55 CH[cis]). IR (cm ): 2200–3200, nN-H(NH ); 2880–
2
3
2960, nC-H; 1725, nC 55 O (ester). Elemental analysis (%) calcd. for C H NO :
6 9 4
C, 45.28; H, 5.7; N, 8.80. Found: C, 43.65; H, 5.56; N, 8.71.
ACKNOWLEDGMENT
The authors are grateful to Kazumi Nakayama of Dojindo Laboratories for her
capable assistance.
REFERENCES
1
2
3
4
. Shiraishi, K.; Ohnishi, T.; Sugiyama, K.; Okada, K.; Matsuo, O. Chem. Lett. 1997,
63–864.
. Shiraishi, K.; Ohnishi, T.; Sugiyama, K. Macromol. Chem. Phys. 1998, 199,
023–2028.
. Shiraishi, K.; Miura, K.; Asami, G.; Kohta, M.; Sugiyama, K. Kobunshi Ronbunshu
003, 60, 30–37.
. Sugiyama, K.; Shiraishi, K.; Ohnishi, T. (Meth)acrylic serine ester, its production,
copolymer and biocompatible material. Jpn. Patent 251209, September 22, 1998.
. Morawetz, H.; Sammak, E. J. Phys. Chem. 1957, 61, 1357–1359.
8
2
2
5
6
. Hill, C. H.; Tai, H.; Underwood, A. L.; Day, R. A. Anal. Chem. 1956, 1688–1689.