Synthesis of N-substituted cyclic triglycines and their response to metal ions

Article abstract of DOI:10.1016/j.tetlet.2003.10.214

N,N′,N″-Trisubstituted-cyclo-triglycines were synthesized. The major conformation of these compounds has C₃ symmetry, and the carbonyl groups and substituents on the nitrogen are inclined in the same direction. Their response to various metal ions was estimated by constructing ion-selective electrodes. Two of them responded selectively to Ca²⁺ over other cations, demonstrating that N,N′,N″-trisubstituted-cyclo- triglycines provide a new scaffold to act as host molecules.

Full text of DOI:10.1016/j.tetlet.2003.10.214

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1091–1094
Synthesis of N-substituted cyclic triglycines and their response to
metal ions
Hideaki Hioki,a,* Hiroyuki Kinami,a Atsushi Yoshida,a Aoi Kojima,a Mitsuaki Kodama,a
Shigeru Takaoka,a Keisuke Uedab and Takashi Katsub
aFaculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, Tokushima 770-8514, Japan
bFaculty of Pharmaceutical Sciences, Okayama University, Tsushima, Okayama 700-8530, Japan
Received 3 October 2003; revised 27 October 2003; accepted 31 October 2003
Abstract—N,N0,N00-Trisubstituted-cyclo-triglycines were synthesized. The major conformation of these compounds has C3 sym-
metry, and the carbonyl groups and substituents on the nitrogen are inclined in the same direction. Their response to various metal
ions was estimated by constructing ion-selective electrodes. Two of them responded selectively to Ca2þ over other cations,
demonstrating that N,N0,N00-trisubstituted-cyclo-triglycines provide a new scaffold to act as host molecules.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Cyclic peptides are attractive candidates for artificial
O
O
1) 1 M NaOH / MeOH
receptors because they have a rigid peptide backbone
that forms a cavity and provides binding sites suitable
for guest molecules. The conformations of N-methylated
cyclic glycine oligomers have been investigated over the
past two decades.1–5 NMR measurements indicate that
di, tri, and tetramers have a rigid conformation, but
pentamers or larger have multiple major conforma-
tions.1;2 We focused on the cyclic trimer, which has a C3
symmetry conformation (crown conformation) eluci-
dated by NMR1;2 and X-ray crystallography studies.3
The N-methyl groups in the cyclic trimers are inclined
in the same direction and the mutual distance between
the carbonyl groups was comparable to the distance of
phenolic oxygen in calix[4]arene. Thus, we hypothesized
that N-substituted cyclic triglycines could act as host
molecules. In this communication, we describe the syn-
thesis of some N-substituted cyclic triglycines and esti-
mate their response to various metal ions by
constructing ion-selective electrodes.6–9
EtO
Boc
N
N
Boc
N
N
EtO
N
2) N-allylglycine ethylester
O
O
O
EDC, CH2Cl2
87 %
3
2
Cl
Cl
O
1) TFA, CH2Cl2
O
N
Boc
1) 1 M NaOH / MeOH
N
N
2) 2,4,5-trichlorophenol
EDC, CH2Cl2
O
O
2) Py, DMF
100 ˚C
Cl
91 %
11 %
4
COOH
O
N
O
N
RuCl3, NaIO4
MeCN, H2O
N
O
HOOC
N
O
O
O
N
N
COOH
79 %
5
1
Scheme 1. Synthesis of N,N0,N00-trisubstituted-cyclo-triglycine.
the ester group in 2 was hydrolyzed and coupled with
Boc-protected N-allylglycine ethylester to afford 3.
Following TitlesteadÕs procedure,2 the ethyl ester in 3
was converted to 2,4,5-trichlorophenol ester 4. The
activated ester 4 was slowly added to the mixture of
pyridine and dimethylformamide using a syringe pump
under diluted conditions. The cyclic tripeptide 1 was
isolated in 11% yield along with 22% of N,N0-diallyldi-
ketopiperazine (cyclic dimer). A substantial amount of
cyclic hexamer was detected in the crude product by
We chose N,N0,N00-triallyl-cyclo-triglycine 1 as a scaffold
for the various functionalized host molecules. The
scaffold 1 was prepared by simple condensation (shown
in Scheme 1). Starting from Boc-protected dipeptide 2,10
Keywords: Cyclic peptide; Ionophore; Ion-selective electrode.
* Corresponding author. Tel.: +81-88-622-9611x5413; fax: +81-88-655-
3051; e-mail: hioki@ph.bunri-u.ac.jp
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.214

1092
H. Hioki et al. / Tetrahedron Letters 45 (2004) 1091–1094
O
C (40)
HNR1R2
DMT-MM
COOH
O
NR1R2
O
O
N
O
N
O
HOOC
O
N
O
O (6)
N
EtOH / H2O
R2R1N
N
COOH
N
NR1R2
C (23)
O
C (31)
C (15)
5
6
C (17)
NR1R2
N(C10H21
compound
yield
20
C (7)
)
2
6a
O (8)
C (10)
N (1)
N (27)
O
C (25)
N (12)
C (13)
6b
6c
N
N
14
OBn
O
C (34)
C (39)
23
36
N
Ot-Bu
OBn
C (33)
2
O (16)
C (30)
N
6d
6e
2
C (36)
C (38)
Figure 1. X-ray structure of 1.
n-Pr
N
12
OBn
Scheme 2. Condensation of 5 with secondary amines.
mass spectroscopy, but the hexamer was not isolated.
1
The H and 13C NMR spectra of 1 indicate that the
utility as a scaffold for the ionophores. Many attempts
to obtain the amides 6 using common dehydrating re-
agents such as EDC14 or PyBOP15 failed, due to the
insolubility of 5 in aprotic solvent. The expected product
was isolated when DMT-MM16 was used as a dehy-
drating reagent, which can be used in protic solvent
(Scheme 2). The compound 7, having N-benzyloxyethyl
groups, was synthesized in the same manner as above
(Scheme 3).
major conformation was the expected crown form along
with some boat form (6%; crown to boat ratio 16:1) in
CDCl3. The crown to boat ratio depends on the solvent
(52:1 in DMSO-d6 and 38:1 in D2O11). X-ray crystal-
lography of 1 indicates the crown form12 (Fig. 1), which
is almost identical to the conformation simulated by the
conformational analysis using MacroModel software.13
The double bonds in 1 were oxidatively cleaved to afford
the tricarboxylic acid 5. The conformation of 5 had the
crown form, and the boat form of 5 could not be de-
tected by NMR analysis in D2O. Finally, some sec-
ondary amines were condensed to explore their potential
The potentiometric ion-selectivity coefficients of the
electrodes17 based on these synthetic compounds are
shown in Figure 2. The selectivity coefficients against
EtO
Boc
OBn
EtO
H2N
N
NH
Boc2O
EtO
O
Br
O
Et3N, CH2Cl2
Et3N, CH2Cl2
O
OBn
OBn
100 %
10
9
54 %
8
OBn
O
1) 1 M NaOH, MeOH
1) 1 M NaOH, MeOH
O
N
Boc
EtO
N
2) 9 Et3N, CH2Cl2
2) 9, Et3N, CH2Cl2
94 %
83 %
OBn
11
OBn
OBn
O
Cl
Cl
O
EtO
N
Boc
1) 1 M NaOH / MeOH
O
Boc
N
N
N
N
N
O
O
O
O
2) 2,4,5-trichlorophenol
EDC, CH2Cl2
Cl
OBn
OBn
OBn
OBn
58 %
12
13
OBn
N
1) TFA, CH2Cl2
O
N
BnO
N
O
O
2) Py, DMF
100 ˚C
OBn
11 %
7
Scheme 3. Synthesis of N,N0,N00-tribenzyloxyethyl-cyclo-triglycine.

H. Hioki et al. / Tetrahedron Letters 45 (2004) 1091–1094
1093
Figure 2. Selectivity coefficients of electrodes.
various inorganic cations were compared. For compar-
ison, we examined the selectivity coefficients of the
electrode based on an ion exchanger, potassium tetra-
kis(p-chlorophenyl)borate (KTpClPB), which responds
to inorganic cations based on their lipophilic proper-
ties.6;9 In contrast to KTpClPB-based electrode, the
electrodes made from 6d and 6e responded more
strongly to Ca2þ compared to other cations, including
alkali metal ions such as Naþ and Kþ. The di-
decylcarbamoylmethyl derivative 6a had less affinity for
Ca2þ. These results indicate that some of the benzylic
oxygens of 6d and 6e preferentially provide a coordi-
nating site for Ca2þ. In particular, the electrode using 6d
had high affinity for Ca2þ, enhancing the ion selectivity
of Ca2þ against Kþ. Based on the molecular modeling of
6e, one or two benzylic oxygens are outside of the cavity
in some rotational isomers of amide linkage, which
might result in the lower Ca2þ/Kþ selectivity of 6e.
Compounds 6c and 6b had much worse selectivity for
Ca2þ, probably due to the presence of several coordi-
nation sites, resulting in low recognition of specific metal
cations. The calibration graphs for Ca2þ are shown in
Figure 3.18 The slope and the detection limit of the
electrode using 6d were 28 mV/decade and 1 · 10ꢀ5 mol/
L, respectively, performing the best among the various
compounds examined in the present study. However, the
sensitivity and the selectivity of the present electrode
could not exceed those of Ca2þ-selective electrodes so far
developed.7
Figure 3. Calibration plots for Ca2þ
.
In summary, we synthesized some N,N0,N00-tricarba-
moyloxy triglycines. Compounds 6d and 6e had high
affinity for Ca2þ, demonstrating that the N,N0,N00-tri-
substituted triglycines provide a new scaffold to act as
host molecules. A combinatorial approach to discover
better host molecules using this scaffold is under inves-
tigation.
Acknowledgements
We are grateful to Prof. Munetaka Kunishima for the
special gift of DMT-MM16 for the dehydrating reagent
in aqueous media.

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H. Hioki et al. / Tetrahedron Letters 45 (2004) 1091–1094
15. PyBOP: 1H-Benzotriazol-1-yloxytripyrrolidinophospho-
References and notes
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17. Sensor membranes of the electrodes were prepared as
reported previously,6–9 by incorporating 1 mg ionophore,
50 mol % KTpClPB relative to the ionophore, 60 lL
o-nitrophenyl octyl ether (NPOE), and 30 mg poly(vinyl
chloride). A sensor membrane based on an ion exchanger
alone was composed of 0.5 mg KTpClPB, 60 lL NPOE,
and 30 mg poly(vinyl chloride). The selectivity coefficients
of the electrodes were determined using a separate
solution method6;8 with the respective chloride salts at
0.1 M, except for Pb2þ, for which we used the acetate salt.
To cross-check the values of the selectivity coefficients, we
measured the coefficients for 6d against several metal
cations using a matched potential method6;9 (Mg2þ )2.7;
Sr2þ )0.6; Ba2þ )0.3; Naþ )2.7; Kþ )2.0). These values
were similar to those obtained using the separate solution
method. With the matched potential method, we used a
fixed concentration (1.0 ꢁ 10ꢀ4 M) of CaCl2 as the back-
ground. The selectivity coefficients were calculated from
the concentration of the interfering ions that induced the
same amount of potential change as that induced by
increasing the concentration of CaCl2 to 2.0 · 10ꢀ4 M.
This measurement was performed in the presence of
0.1 M Tris–HCl (pH 7) to maintain a constant ionic
strength.
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11. Kraemer et al.4 reported a similar phenomenon. They
described that polar solvent stabilized the dipole moment
of the crown form.
12. Crystallographic data (excluding structure factors) for 1
have been deposited with the Cambridge Crystallographic
Data Centre as supplementary publication no. CCDC-
220730. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/conts/retrieving.html (or from the
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033; e-mail: deposit@ccdc.cam.ac.uk).
13. A Monte Carlo conformational search employing the
AMBER force field included with MacroModel software
(v. 6.0).
18. Measurements were performed at room temperature
(approximately 25 ꢁC) in 0.1 M Tris–HCl (pH 7) to adjust
the ionic strength of the solution.
14. EDC: N-(3-Dimethylaminopropyl)-N0-ethylcarbodiimide
hydrochloride.