Ionic liquid incorporated polystyrene resin for solid-phase peptide synthesis

Article abstract of DOI:10.1016/j.tetlet.2011.01.067

Ionic liquid (IL) resins with an ionic liquid environment on solid support were prepared by immobilizing ionic liquid spacers on polystyrene (PS) resin. The properties of IL resins were dramatically changed as the anions of IL were exchanged. The performa

Full text of DOI:10.1016/j.tetlet.2011.01.067

Tetrahedron Letters 52 (2011) 1459–1461
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Tetrahedron Letters
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Ionic liquid incorporated polystyrene resin for solid-phase peptide synthesis
a
a
b
c
a
a,b,
⇑
Hong-Jun Cho , Sang-Myung Lee , Sungwon Jung , Tae-Kyung Lee , Hyo-Jin Yoon , Yoon-Sik Lee
a
School of Chemical and Biological Engineering, Seoul National University, Seoul 151-744, Republic of Korea
Department of Nano Science and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Suwon 443-270, Republic of Korea
Department of Chemistry, University of Texas at Dallas, Richardson, TX 75080, USA
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Ionic liquid (IL) resins with an ionic liquid environment on solid support were prepared by immobilizing
ionic liquid spacers on polystyrene (PS) resin. The properties of IL resins were dramatically changed as the
anions of IL were exchanged. The performance of IL resins for solid-phase peptide synthesis (SPPS) was
evaluated by measuring coupling kinetics of the first amino acid and synthesizing several peptides on
IL resins.
Received 9 November 2010
Revised 5 January 2011
Accepted 17 January 2011
Available online 21 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Ionic liquid
Anion exchange
Ionic liquid resin
Solid-phase peptide synthesis (SPPS)
Polystyrene (PS) resin is one of the most commonly used poly-
mer supports in solid-phase peptide synthesis (SPPS). It has high
controllable environments when ILs are used as a soluble support
or as reaction media. Therefore, introducing versatile IL groups to
PS resin may address weaknesses in the PS resin and enhance
the efficiency of in coupling reactions.
1
mechanical and chemical stability, as well as good swelling proper-
ties in various solvents. However, PS resin presents some problems
because of the hydrophobic matrix, which causes difficulties in the
diffusion of reagents and aggregation of growing peptides sus-
Immobilization of imidazole groups on a solid support is one
way of introducing an IL environment on a PS resin. Previously,
ILs have been immobilized on solid supports, such as silica parti-
2
,3
pended on resin. For these reasons, polymer backbones com-
posed of polyamide or polyethylene glycol (PEG) were introduced
9
10
cles and PS resin, to develop heterogeneous catalysts. However,
to the best of our knowledge, there has been no report on the appli-
cation of IL conjugation to SPPS. Herein, we report the preparation
of imidazolium IL coupled resins, which are designed to allow var-
iable IL environments with improved performance in SPPS.
The loading method of the imidazolium group on a polymer
2
,4
to provide a hydrophilic environment on polymer supports. Fur-
thermore, ethylene glycol units have been used as cross linkers to
increase the flexibility of the polymer matrix.3 Since hydrophilic
polymer supports are fully solvated by polar solvents and compat-
ible with peptides on resin, they can afford high yield and purity of
peptide in SPPS. Previously, we developed core–shell type resins to
,5
support is well known with respect to heterogeneous metals or
6
9,10
circumvent the problems caused by the hydrophobic matrix.
Lewis acid catalysts.
However, imidazolium IL resin for solid-
Core–shell type resins can minimize the influence of hydrophobic
environments on the resin due to their distinctive structures. De-
spite many efforts, the controversy over the interaction of polymer
matrix, peptide chain and solvent is continuing with heated
discussions.
phase peptide synthesis requires an extra amine/hydroxy group,
from which linkers or amino acids are elongated. Thus, 1-(3-ami-
nopropyl)imidazole (API) was chosen as an imidazolium precursor
and a linker for SPPS. Before introducing the imidazolium group on
chloromethyl PS resin, the free amine group was protected by Boc
group to obtain Boc-API (1) in 79% yield (Scheme 1). Then, CMPS
resin was treated with an excess amount of compound 1. The
Recently, as part of an effort to synthesize peptides more effi-
7
8
ciently, IL was introduced as a solvent and a soluble support. In
peptide synthesis, coupling reagents and amino acid derivatives
can be effectively dissolved in IL and stabilized for selective reac-
existence of imidazolium in the IL resin was verified by FT–IR
À1
(carbamate band: 1699 cm
, quaternary imidazolium band:
7
À1
tions. In addition, an attractive feature of ILs is that its polarity
1162 cm , Suppl. Fig. 1). The loading level of theimidazolium
group on IL resin (3A) was determined to be 1.2 mmol/g by mea-
suring nitrogen contents and Fmoc titration after coupling Fmoc-
OSu. To obtain imidazolium IL resins which have different anions
and solubility can be easily modulated by changing the anion spe-
cies. This unique characteristic feature facilitates the generation of
À
À
À
À
(
BF , OTf , PF and TFSI ), the IL resin (3A) was treated with an ex-
⇑
Corresponding author. Tel: +82 2 880 7073; fax: +82 2 876 9625.
E-mail addresses: yslee@snu.ac.kr, cho0122@snu.ac.kr (Y.-S. Lee).
4 6
À
À
À
-
2
cess amount of NaBF , NaOTf , NaPF , or LiTFSI in DMF/H O (1:1,
4
6
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.01.067

1
460
H.-J. Cho et al. / Tetrahedron Letters 52 (2011) 1459–1461
a
b
a
N
N
NH
2
(Boc)
2
O
N
N
NH Boc
1
Cl-
Cl-
b
c
Cl
N
N
N
NH Boc
N
N
NH
2
2
3A
Cl-
X-
N
-
-
a
X = BF (3B)
4
N
NH2
N
NH2
-
OTf (3C)
PF6 (3D)
TFSI (3E)
-
-
3
B-E
Scheme 1. Reagents and conditions: (a) synthesis of 1-[(N-tert-butoxycarbonyl)aminopropyl]-3-(3-triethoxysilylpropyl)imidazolium(1) and preparation of IL resin (3A): (a)
NaHCO in H O and THF, rt, 4 h; (b) compound 1, NMP, 80 °C, 24 h; (c) TFA, DCM, rt, 2 h, and (b) process of anion exchange of IL resin: (a) NaBF , NaOTf, NaPF , LiTFSI in H O/
DMF(1:1, v/v).
3
2
4
6
2
v/v) (Scheme 1b). The anions of imidazolium on the resin were eas-
ily identified by energy dispersive X-ray spectroscopy (EDS) (Suppl.
Fig. 2). Traces of chloride ions in 3B–E resins and fluoride ions in 3A
resin were observed, but a majority of original anions were mostly
changed in each resin.
Finally, we applied imidazolium IL resins to SPPS to evaluate
their synthetic performance. As a model pentapeptide, Leu-
enkephalin (H-YGGFL-NH ) was synthesized using Fmoc/t-Bu
2
chemistry after anchoring Fmoc Rink amide linker on the IL resins
and AMPS resin, respectively. Then, the peptide was cleaved and
analyzed by HPLC and MALDI-TOF mass spectroscopy (Suppl.
Figs. 3 and 4). Leu-enkephalin was recovered quantitatively in high
purity (93–95% purity, Table 1) on IL resins (3B–3E). We found that
3A resin showed relatively low yield (82%) and low purity (87%)
The swelling property of resins is the primary criterion for esti-
mating solvent compatibility, which affects diffusion of the re-
agents into the resin and ultimately the synthetic efficiency in
SPPS. When the swelling properties were compared in various sol-
vents, there were considerable differences in each solvent depend-
ing on the anions (Suppl. Table 1). In general, IL resins with
hydrophilic anions had a tendency to swell in polar solvents, while
they were not completely compatible in less polar organic solvents
such as DCM, THF, and hexane. It has been known that a polymer-
supported ionic liquid system swells considerably in polar aprotic
solvents such as DMF and DMSO and its swelling property can be
À
due to the intrinsic property of IL[Cl ]. However, IL resins generally
exhibited better synthetic performance than AMPS resin (Table 1)
1
3
and solution-phase synthesis in which ionic liquid was used as a
soluble support (overall yield: 50%, purity: 90%). As a result of
synthesis of Leu-enkephalin, we can conclude that the synthesis
of peptide on IL resins is more efficient than on AMPS resin or
in ionic liquid, although the synthetic performance of IL resins
can not be precisely compared with an easy sequence to be
synthesized.
1
1
controlled by anion. In our cases, IL resins (3B–E) also swelled
well in polar aprotic solvents (NMP and DMF), and especially 3E re-
sin displayed the highest swelling property in NMP. Because TFSI
To further investigate the clear differences on the effect of an-
À
À
À
14
anion is the most hydrophobic among other anions (Cl , BF , OTf
ions and the IL environment in SPPS, Jung-Redemann 10-mer
4
À
and PF ), the ionic liquid with TFSI anion generates amphiphilic
2
(JR 10-mer, H-WFTTLISTIM-NH ), which was known as one of the
6
environment in polymer matrix which is presumably highly com-
patible with NMP or DMF.
most difficult sequence to be synthesized, was synthesized on IL
resins using Fmoc/t-Bu chemistry. JR 10-mer is a suitable peptide
model for examining the efficiency of solid support in SPPS.15
Peptide synthesis showed that JR-10mer was obtained in higher
purities from IL resins (3A–E) than from AMPS resin (Table 1). In
To evaluate IL environment effects on peptide synthesis, the
coupling reaction kinetics of the first amino acid most affected
by polymer matrix on the resins was measured in NMP. Fmoc-
His(Trt)-OH and Fmoc-Phe-OH, which were known to have poor
and good loading yield, respectively,1 were selected as model cou-
pling amino acids. During the time course of the reaction, small
portions of the resin were withdrawn from the reaction mixture
and the coupling kinetics was examined by Fmoc titration. As
shown in the line graph (Fig. 1a), coupling kinetics of Fmoc-
His(Trt)-OH exhibited similar trends on IL resins and on AMPS
resin except for3A resin. Because of difficulty in coupling Fmoc-
His(Trt)-OH on most of the polymer supports, the environmental
change of IL resins gave little influence on coupling kinetics. In
the case of 3A resin, the low swelling property might contribute
to low coupling kinetics. However, in the Fmoc-Phe-OH coupling
À
particular, the best resin for SPPS was IL[TFSI ] resin (3E, 57%
2
purity). The performance of IL resins appeared to depend on the
swelling properties, especially loading of the first amino acid on
the resin. However, despite having a similar swelling property to
3D resin, AMPS resin exhibited the lowest performance in SPPS.
These results are attributed to not only the swelling property of
resins but also to the IL spacer group which can furnish the
growing peptide with an adequate ionic environment within the
polymer matrix and may inhibit the peptide on the resin from
self-aggregation. Based on this, we demonstrated that the IL spacer
could create an ideal environment for efficient SPPS.
In conclusion, we have prepared IL resins by introducing amine
functionalized an imidazolium group to a PS resin. By changing the
(Fig. 1b), the yield and coupling kinetics on IL resins were propor-
À
À
À
À
À
tional to swelling property. In particular, 3D and 3E resins had
anions (Cl , BF , OTf , PF and TFSI ) of the IL, IL resins revealed
4 6
much better coupling efficiency than the AMPS resin. Therefore,
different properties based on the characteristics of each IL spacer
IL resins with TFSI or PF
6
anion and NMP as a solvent give the opti-
group. For example, the swelling properties of IL resins were dra-
À
mal condition for coupling of the first amino acid in SPPS. Based on
these results, we confirmed that the initial coupling kinetics was
mostly affected by swelling properties originated from the IL
environments.
matically changed in different solvents. In particular, IL[PF ] and
6
À
IL[TFSI ] resins swelled the most in NMP and performed well in
initial loading of amino acids. They also achieved higher purity in
solid-phase peptide synthesis than AMPS resin.

H.-J. Cho et al. / Tetrahedron Letters 52 (2011) 1459–1461
1461
Figure 1. Coupling kinetics of Fmoc-His(Trt)-OH (a) and Fmoc-Phe-OH (b) on IL resins.
Table 1
2. Bayer, E. Angew. Chem., Int. Ed. 1991, 30, 113–129.
Purity of peptides (Leu-enkephalin and JR 10-mer) using IL resins and AMPS resin
3. Wang, Y.; Zhang, G.; Yan, H.; Fan, Y.; Shi, Z.; Lu, Y.; Sun, Q.; Jiang, W.; Zheng, Y.;
Li, S.; Liu, Z. Tetrahedron 2006, 62, 4948–4953.
4. Atherton, E.; Clive, D. L. J.; Sheppard, R. C. J. Am. Chem. Soc. 1975, 97, 6584–
Resin
Leu-enkephalin (%)
JR 10-mer (%)
6
585.
À
3
3
3
3
3
A (Cl )
87
95
93
94
94
86
42
48
43
51
57
33
5
6.
.
Moss, J. A.; Dickerson, T. J.; Janda, K. D. Tetrahedron Lett. 2002, 43, 37–40.
(a) Kim, H.; Cho, J. K.; Chung, W. J.; Lee, Y. S. Org. Lett. 2004, 6, 3273–3276; (b)
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7135–7138; (c) Lee, T. K.; Cho, J. H.; Ryoo, S. J.; Lee, Y. S. J. Pept. Sci. 2007, 13,
655–661.
À
B (BF4
)
À
C (OTf )
À
D (PF6
)
À
E (TFSI )
AMPS resin
7. Vallette, H.; Ferron, L.; Coquerel, G.; Gaumont, A. C.; Plaquevent, J. C.
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Acknowledgments
9
(a) Mehnert, C. P.; Cook, R. A.; Dispenziere, N. C.; Afeworki, M. J. Am. Chem. Soc.
This work has been supported by the Seoul Fellowship and the
WCU (World Class University) program through the Korea Science
and Engineering Foundation funded by the Ministry of Education,
Science and Technology (Grant No. R32-2008-000-10213-0).
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Supplementary data
1
4
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.01.067.
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