Synthesis of triazole cages containing C3-symmetric α-cyclic tripeptide scaffold

Article abstract of DOI:10.1016/j.tetlet.2014.02.089

Two water-soluble C₃-symmetric 1,2,3-triazole cages containing α-cyclic tripeptide were efficiently synthesized. The key steps include a click reaction to incorporate l-glutamic or l-aspartic acids to a tripodal linker and a unique one-pot cyclotrimerization.

Full text of DOI:10.1016/j.tetlet.2014.02.089

Tetrahedron Letters 55 (2014) 2274–2276
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of triazole cages containing C -symmetric
a
-cyclic
3
tripeptide scaffold
⇑
Subrata Chakraborty, Dar-Fu Tai
Department of Chemistry, National Dong Hwa University, Hualien, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Two water-soluble C -symmetric 1,2,3-triazole cages containing
synthesized. The key steps include a click reaction to incorporate
tripodal linker and a unique one-pot cyclotrimerization.
a
L
-cyclic tripeptide were efficiently
-glutamic or -aspartic acids to a
3
Received 30 November 2013
Revised 26 January 2014
Accepted 24 February 2014
Available online 3 March 2014
L
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
C
3
-Symmetric cage
Cyclic tripeptide
-Amino acids
,2,3-Triazole
Water-soluble
a
1
Cyclic peptides are important biomolecules,1 because of their
state, it stays in crown14 form that helps cyclic tripeptides to act
as unique receptors.
broad-ranging biological applications. Its rigid peptide backbone
2
reduces the entropic penalty to help it act as a biological receptor.
We constructed two new C
3
-symmetric cages (1 and 2) that
The presence of optically pure amino acids allows cyclic peptides
contain either -glutamyl or -aspartyl cyclic tripeptide scaffolds
L
L
to form a chiral scaffold. Among them, C
3
-symmetrical systems
with a unique nine-member backbone structure. Synthesis was
achieved via a tripodal compound, which controlled its self-assem-
bly and cyclooligomerization during cyclization.
have wide applications in several areas, such as molecular recep-
3
4
5
tors, dendrimers, organometallic ligands, and asymmetric catal-
6
ysis. The synthesis of cage like macromolecular structures with
We took Boc-
block to construct cage 1. The
with methyl group by reacting with dimethyl sulfate in the pres-
ence of potassium carbonate in acetone to give Boc- -glutamyl-
(OMe)- -benzyl ester 4. Liberation of carboxylic acid in side chain
L-glutamic acid
c-benzyl ester 3 as a building
well defined 3D sizes and shapes derived from constrained cyclic
a-acid of compound 3 was protected
7
8
peptide scaffolds is a promising research topic. The 3D geometri-
cal constraints produced by the cage molecules make them extre-
mely useful in the field of supramolecular chemistry.9 Cyclic
hexapeptides are in general, relatively flexible compared to cyclic
tripeptide; to make the backbone rigid, heterocyclic rings were
L
a-
c
of 4 with Pd/C-catalyzed hydrogenolysis, followed by coupling
0
with propargylamine in the presence of N,N -dicyclohexylcarbodi-
7
a,b
usually incorporated.
imide (DCC), hydroxybenzotriazol (HOBt), and triethylamine (TEA)
in dichloromethane resulted in a propargylamine modified com-
pound 6 with a 90% yield. Alternatively, compound 5 can be
All reported cyclic peptide cages were synthesized from natu-
rally occurring thiazole- and oxazole-containing cyclic hexapep-
tide alkaloids as scaffolds (derived from serine, threonine, and
cysteine amino acids).1 Positively-charged triazolium cages are
directly prepared from Boc-L-glutamic acid enzymatically with a
0
15
90% yield (Scheme 1).
1
1
known for sensing halides, fluorides, chlorides, and oxoanions.
We choose tris 2-azidoethyl amine 9 as tripodal linker instead
1
2
Triazole cage with
a-cyclic tripeptide is remained unreported be-
of tris-carboxylic acid to avoid the formation of diastereomer
1
6
cause synthetic difficulties of cyclic nine-member ring synthesis.
Cyclic tripeptides are the most rigid member of the cyclic peptide
family and require all cis amide bonds13 to synthesize it. In cyclic
cages. Tris 2-azidoethyl amine 9 was prepared from tris 2-chloro-
1
7
18
ethyl amine hydrochloride 8 using reported procedure (see
Supporting information).
Side chain Boc-L-glutamyl-a(OMe) propargyl amide 6 was at-
1
9
tached with tripodal linker 9 via click reaction. Mixing lutidine,
N,N-diisopropylethylamine (DIPEA), and Cu(I) iodide in degassed
acetonitrile gave glutamyl-tripodal methyl ester 10 with a 90%
⇑
Corresponding author. Tel.: +886 38633579; fax: +886 38633570.
E-mail address: dftai@mail.ndhu.edu.tw (D.-F. Tai).
http://dx.doi.org/10.1016/j.tetlet.2014.02.089
040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
0

S. Chakraborty, D.-F. Tai / Tetrahedron Letters 55 (2014) 2274–2276
2275
HO
O
MeO
O
O
O
a
N
N
Boc
Boc
N
N
H
OBn
94%
N
H
OBn
n
N
N
N
n
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N3
N3
N
3
, n = 2
4, n = 2
N3
9
1
3, n = 1
14, n = 1
a
b
HN
O
NH
HN
O
NH
90%
87%
HN
HN
O
HN
O
O
O
MeO
O
O
b
95%
OMe
O
HN
OH
O
HN
Boc
N
H
N
OMe
HN
O
OH
HN
OH
H
OMe
HN
O
O
16
O
HO
O
O
MeO
O
O
MeO
O
c
O
d
Boc
Boc
Boc
18
19
N
H
OH
55~90%
N
H
OH
N
H
N
H
n
n
91%
n
7
, n = 2
5, n = 2
6, n = 2
1
7, n = 1
15, n = 1
16, n = 1
Scheme 1. Reagents and conditions: (a) dimethyl sulfate, K
2 3
CO , acetone; (b) Pd/C,
N
N
H
2
, MeOH; (c) DCC, HOBt, TEA, propargylamine, 0 °C ꢀ rt; (d) Papain, pH 4.2, MeOH.
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
d
c
yield. Three
a-methyl esters on tripodal 10 were removed by
NH
HN
O
51%
HN
O
HN
NH
O
O
saponification in 1 N NaOH/methanol (1:1), followed by coupling
with pentafluorophenol, which led to form a glutamyl-tripodal
activated ester 12. This tripodal 12 was treated with TFA to effect
the cleavage of Boc group and was, then, subjected to macrocycli-
zation in pyridine at high dilution (2 mM) to provide water-soluble
cyclotriglutamyl cage 120 with a 40% yield (Scheme 2). An attempt
was made to directly cyclize fully deprotected tripodal amino acids
by PyBOP and DIPEA in DMF at high dilution. However, it ended up
with cyclooligomer as the major product. Formation of monomeric
compound was confirmed from mass spectrometry. The NMR
spectroscopic data for 1 were consistent with those expected for
O
HN
O
O
HN
Opfp
O
H
Opfp
HN
N
Opfp
HN
O
HN
O
O
NH
O
2
0
2
Scheme 3. Reagents and conditions: (a) lutidine, DIPEA, CuI, acetonitrile; (b) 1 N
NaOH/MeOH; (c) DCC, pentafluorophenol, DCM; (d) (i) TFA/DCM (1:1), 0 °C, (ii)
pyridine, high dilution, rt.
construction of cyclic tripeptide cage. As previously noted, we
modified the aspartic acid side chain. The side chain propargyl-
3
C -symmetric cyclotriglutamyl cage. Two singlet peaks at d 2.89
1
amine modified Boc-
yield from Boc- -aspartic acid-
tion, followed by removal of
L
-Asp(OMe) 16 was synthesized with a 91%
-(OBn) 13 via -methyl esterifica-
-benzyl ester and coupling with
and d 4.16 were observed in H NMR spectrum for the correspond-
ing two –CH groups of tripodal linker. NMR signals were also ob-
served for -protons (d 4.21–4.24) within the cyclotripeptide ring
L
c
a
2
c
a
13
propargylamine by DCC in dichloromethane (Scheme 1).
Modified aspartic acid 16 was attached with a tripodal linker 9
3:1 ratio) via click reaction to obtain aspartyl-tripodal methyl es-
and –CH protons (d 7.34–7.56) of triazole rings. C spectrum
showed only one set of carbon peaks and directly supported the
formation of a C -symmetric cage.
3
(
ter 18 with a 90% yield. Methyl esters were removed by basic
hydrolysis and followed by esterification with pentafluorophenol
gave aspartyl-tripodal activated ester 20. It was further treated
with TFA to remove the Boc protecting group and subjected to
cyclization in pyridine at high dilution to obtain water-soluble
After successful synthesis of cyclotriglutamyl cage, we at-
tempted to synthesize cyclotriaspartyl cage and extend our study
to know the effect of a shortened side chain amino acid on the
2
1
cyclotriaspartyl cage 2 with a 51% yield (Scheme 3). An 11% in-
crease in yield indicates that chain length may play a vital role in
cyclization step. Tripodal with longer chain lengths is probably
more flexible at reducing the chances of cyclization. As a result, a
short chain length tripodal will convert more to the corresponding
cage. Mass spectroscopy also confirmed the formation of the de-
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N3
N3
N3
a
b
9
HN
O
HN
O
NH
NH
9
2%
HN
82%
HN
O
O
O
O
MeO
O
OMe
O
OH
O
3
sired monomer. Furthermore, C -symmetric structure of 2 was
H
N
HN
HN
Boc
1
N
H
confirmed by H NMR spectra which showed two triplet peaks at
d 2.85, d 4.10 for tripodal linker and one singlet peak at d 7.49
for triazole ring. The presence of only one set of carbon peaks in
OMe
HN
HN
OH
HN
HN
O
O
OMe
O
OH
6
O
O
10
11
1
3
C NMR supports the presence of symmetry.
Two novel cryptand like cages 1 and 2 based with a-cyclic tri-
peptide scaffold were synthesized in good yields. This is the first
synthesis of cages that contain nine-member cyclic tripeptide ring.
We synthesized cyclic scaffold and cages simultaneously via con-
trolled assembly using a tertiary nitrogen linker. This cyclization
technique can be used to overcome synthetic barriers for the
formation of rigid 9-member cyclic tripeptides with polar side
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
HN
O
d
c
NH
HN
NH
HN
O
O
40%
O
HN
O
1
1c
Opfp
O
O
chain. Applications for water-soluble triazole hosts
to be used
HN
O
H
N
as a potential 3D carrier to enhance dissolution rate for poor
water-soluble guests are currently in progress.
Opfp
HN
HN
O
Opfp
HN
O
O
NH
O
12
1
Acknowledgement
Scheme 2. Reagents and conditions: (a) lutidine, DIPEA, CuI, acetonitrile; (b) 1 N
NaOH/MeOH; (c) DCC, pentafluorophenol, DCM; (d) (i) TFA/DCM (1:1), 0 °C, (ii)
pyridine, high dilution, rt.
The present work is partially supported by a Grant from the
National Science Council of Taiwan.

2
276
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2
1
8 (c 0.1, MeOH); 1H NMR: (D
20. Data for 1: ½
2.00–2.01 (m, 2H), 2.28 (t, 6H, J = 8.08 Hz), 2.35–2.45 (m, 2H), 2.89 (s, 6H), 4.16
(s, 6H), 4.21–4.24 (m, 3H), 4.32 (s, 2H), 4.38 (s, 4H), 7.34–7.56 (m, 3H); 13
NMR: (D O, 100 MHz) 25.1, 29.2, 34.4, 48.4, 53.1, 57.0, 123.8, 144.2, 174.7,
a
ꢁ
2
O, 400 MHz) 1.87–1.92 (m, 2H),
D
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(
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182.2. IR (KBr) 3410, 2956, 2108, 1678, 1550, 1436, 1390, 1253, 1152, 1120,
ꢂ1
[M+H]+
8
9
.
.
1059, 770, 667 cm
;
HRMS (ESI): m/z calcd. for
C
30
H
43
N
16
O
6
3
723.3547; found 723.3622.
21
); 1H NMR: (D
O, 400 MHz) 2.45 (dd, 3H,
3 2
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21. Data for 2: ½
J = 5.53 Hz, J = 18.29 Hz), 2.85 (t, 6H, J = 6.24 Hz), 3.03 (q, 3H), 3.87 (q, 3H), 4.10
(t, 6H, J = 5.78 Hz), 4.65 (s, 6H), 7.49 (s, 3H); 13C NMR: (D
O, 100 MHz) 33.4,
aꢁ
ꢂ11 (c 0.1, CHCl
D
2
(
d) Wang, F.; Zhang, J.; Ding, X.; Dong, S.; Liu, M.; Zheng, B.; Li, S.; Wu, L.; Yu, Y.;
36.6, 48.6, 49.8, 53.2, 124.4, 141.7, 177.5, 180.9; IR (KBr) 3429, 2926, 2854,
ꢂ1
Gibson, H. W.; Huang, F. Angew. Chem., Int. Ed. 2010, 49, 1090–1094; (e) Zhang,
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Gibson, H. W. J. Am. Chem. Soc. 2011, 133, 2836–2839.
1707, 1666, 1546, 1434, 1406, 1338, 1226, 1170, 1057, 617, 579 cm ; HRMS
+
(ESI): m/z calcd. for C27
H
37
N
16
O
6
[M+H] 681.3076; found 681.3125.