Synthesis of a cyclen-functionalized α-amino acid and its incorporation into peptide sequence

Article abstract of DOI:10.1055/s-2005-861854

A cyclen-functionlized α-amino acid was obtained through embedding cyclen into the side chain of homoserine. The α-amino acid can be conveniently incorporated into peptide sequence to form new ligands, which have strong coordination ability for transition metal ions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-861854

888
PAPER
Synthesis of a Cyclen-Functionalized a-Amino Acid and its Incorporation into
Peptide Sequence
C
a
yclen-Functi
h
onalized
a
-A
a
mino
A
cidn-Yong Chen,a Yu Huang,a Guo-Lin Zhang,b Hua Cheng,a Chuan-Qin Xia,a Li-Jian Ma,a Hong Yu,a Xiao-Qi Yu*a
Department of Chemistry, Key Laboratory of Green Chemistry and Technology (Ministry of Education), Sichuan University,
Chengdu 610064, P. R. China
b
Chengdu Institute of Biology, The Chinese Academy of Sciences, Chengdu 610041, P. R. China
Fax +86(28)85415886; E-mail: schemorg@mail.sc.cninfo.net
Received 27 September 2004
ology applicable for designing a ligand-functionalized
peptides in the side chains, we report here the synthesis of
a cyclen-functionalized homoserine as a novel building
block, which was conveniently incorporated into peptide
sequence in high yield. The important building block is a
particularly interesting target because: 1) the cyclen-func-
tionalized peptides can be extended from N-terminal or C-
terminal to synthesize multi-functionalized peptides; and
2) the cyclen-functionalized peptides can form stable
complexes with different metal ions and that binding
might be so dominated by the cyclen cores that the substit-
uents would exert little effect.
Cyclen22 and L-homoserine23 were prepared as previously
reported. Selective monoalkylation of cyclen can be run
using two main strategies, i.e. direct alkylation of an ex-
cess of cyclen with the appropriate alkyl halide24 or selec-
tive N-functionalization followed by alkylation-
deprotection steps.25 In this paper the selective monoal-
kylation of cyclen was first chosen to synthesize the
aimed product 10 as described in Scheme 1. The amino
group of L-homoserine (3) was protected with Boc (tert-
butyloxycarbonyl) group and then the carboxyl group was
converted to benzyl ester 4. The hydroxyl group of N-Boc
homoserine benzyl ester 4 was activated with p-toluene-
sulfonyl chloride to give active compound 5, which was
conveniently converted to bromo compound 6 in 73%
yield by treatment with NaBr. Unfortunately, the coupling
of 6 and tri-Boc-protected cyclen 7 did not give the de-
sired product 10 due to the strong hindrance of 6, which
was facilely converted to the undesired product 8 in high
yield (Scheme 2). The methyl ester of 4-bromo-2-tert-bu-
tyloxycarbonylaminobutanoic acid was also chosen as a
starting material to synthesize 4-[tris(N-tert-butyloxycar-
bonyl)cylcen]-2-N-tert-butyloxycarbonylaminobutanoic
acid methyl ester, an analogue of compound 10, which
similarly afforded the desired product in poor yield be-
cause of the direct formation of lactone 8.
Abstract: A cyclen-functionlized a-amino acid was obtained
through embedding cyclen into the side chain of homoserine. The
a-amino acid can be conveniently incorporated into peptide se-
quence to form new ligands, which have strong coordination ability
for transition metal ions.
Key words: cyclen, unnatural amino acid, metallopeptides
In recent years, there has been an enormous interest in the
synthesis of novel amino acids and peptides with unnatu-
ral side-chain functionalities due to their biological and
toxicological properties.1 Among the variety of unnatural
amino acids, ligand-functionlized a-amino acid that can
bind metal ions, are of special interest for their applica-
tions in the design of metalloproteins,2,3 metallopeptides4,5
and for the study of electron transfer in peptides.6 Cyclen
(1,4,7,10-tetraazacyclododecane) has strong coordination
ability towards a wide range of cations, including transi-
tion metal ions and lanthanide ions,7,8 and their complexes
have been widely used as MRI contrast agents,8,9 lumines-
cent probes,10,11 DNA recognition,12,13 DNA cleavers,14
enzyme mimics,15,16 and medicines for radioimmunother-
apy.17,18 Yet, cyclen-functionalized amino acids and pep-
tides with large affinity constants for transition metal ions
are apparently rare. Suh and co-workers reported that cy-
clen can be located into the N-terminal of amino acids and
demonstrated that their Cu(II) or Co(III) complexes can
be used as catalytic drugs to promote the selective cleav-
age of protein.19 Miltschitzky and Konig synthesized a
glutamic derivative with protected cyclen side chain func-
tionality.20 The cyclen was anchored on the O-terminal of
amino acids. Burger and Still found that the metal ion-
binding properties of peptide-substituted cyclens do in-
deed vary with the nature of the peptide sequences and
suggested that ionophore libraries having members capa-
ble of selectively binding many different ions are best
constructed around cores that have relatively poor intrin-
sic ion-binding selectivities.21 In all of the examples the
cyclen core, attached through a linker, can be located at
the terminus of a peptide, unlike the natural metalloen-
zymes where ligands for coordination with metal ions are
always in the sequence of peptides. To develop a method-
Alternatively, we turned our attention to the direct use of
cyclen to synthesize cyclen-functionalized amino acid. As
a general synthetic method, cyclen should be able to react
with different activated or non-activated alkyl bromides
due to its excellent nucleophilicity. In the traditional sta-
tistical method, a large excess amount of costly cyclen is
needed. Previously Li and Wong found that 2 equivalents
of tetraazamacrocycles versus alkylating agents is neces-
sary to maintain the high yield of mono N-alkylated prod-
SYNTHESIS 2005, No. 6, pp 0888–0892
x
x
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x
x
.2
0
0
5
Advanced online publication: 10.03.2005
DOI: 10.1055/s-2005-861854; Art ID: F13904SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Scheme 1
Scheme 2
Cyclen-Functionalized a-Amino Acid
889
O
O
PhCH2Br, Et3N
acetone reflux
(Boc)2O
HO
TsCl, Pyridine
HO
OH
O
CH2Cl2, 0 °C
NH2
Boc NH
3
4
O
O
NaBr
acetone reflux
TSO
Br
O
O
Boc NH
Boc NH
6
5
Boc
N
Boc
N
O
O
O
Br
Boc N
N H
+
Boc N
N
O
N
Boc
N
Boc NH
Boc NH
Boc
6
10
7
O
O
HN Boc
8
ucts.26 We have now found that 1.8 equivalents of cyclen By using DCC as coupling agent, in the presence of
(9) can be used for coupling with 6. Because the direct NMM, the protective cyclen-functionalized amino acid 11
coupling product was very difficult to purify, the alkyla- was facilely coupled with L-amino acid methyl ester hy-
tion of cyclen (9) with compound 6 followed by protec- drochloride to afford the desired product 12 in over 60%
tion with Boc group were employed and provided the yield. The saponification of 12 with aqueous 2 N sodium
desired compound 10 in 79% yield (Scheme 3). As a key hydroxide solution was monitored by TLC and followed
intermediate, fully N-Boc protected product 11 could be to remove the Boc group by HCl in acetone. The hydro-
obtained in 92% yield through the alkaline hydrolysis of chloride of compound 2 was eluted over a basic anion ex-
10.
change column to give the cyclen-functionalized
dipeptide 2 in high yield (Scheme 4). Preliminary results
indicate that the affinity of cyclen-functionalized dipep-
tide (as free base) towards transition metal ions such as
Zn2+ is not affected by its incorporation into peptide. The
synthesis of complexes of cyclen-functionalized dipeptide
and their catalytic feature for hydrolytic reaction is cur-
rently pursued in our laboratory.
Boc
N
N
N
Boc
H
N
O
(Boc)2O
Et3N
6
Boc N
H N
N H
O
CH3CN
reflux
N
H
9
Boc NH
10
NaOH
In conclusion, a cyclen-functionalized amino acid as a
new ligand with strong binding ability for metal ions has
been synthesized. Our results indicate that the functional-
ized a-amino acid as a novel building block can be incor-
porated into peptide sequence conveniently.
Boc
N
N
N
Boc
O
Boc N
OH
Boc NH
11
ESI-MS and HRMS spectral data were recorded on Finnigan
LCQDECA and Bruker Daltonics Bio TOF mass spectrometer respec-
tively. IR spectra were recorded on FT-IR 16PC spectrometer. 1H
NMR spectra were measured on a Varian INOVA-400 spectrometer
and chemical shifts in ppm are reported relative to internal Me4Si
(CDCl3) or 3-(trimethylsilyl)propionic-2,2,3,3-d4 acid sodium salt
(D2O). 13C NMR spectra were measured on a Bruker Avance 600
Scheme 3
As outlined in Scheme 4, compound 11 can be conve-
niently converted to cyclen-functionalized amino acid 1 in
91% yield by deprotection of Boc group with 47% HBr,
which can be used as an important building block for the spectrometer. Polarimetric analyses were determined on a WZZ-2B
automatic polarimeter. Melting points were determined by using a
synthesis of multi-functionalized organic compounds or
micro-melting point apparatus without any corrections. All chemi-
complexes.
Synthesis 2005, No. 6, 888–892 © Thieme Stuttgart · New York

890
S.-Y. Chen et al.
PAPER
Boc
N
N
N
Boc
R
Boc
N
N
N
Boc
R
O
O
L-NH2CHCOOCH3⋅HCl
OCH3
Boc N
Boc N
N
OH
NMM, DCC, HOBt
H
O
Boc NH
Boc NH
12 a R=H
11
b R=CH3
(1) NaOH
(1) HBr,ethanol
(2) HCl,acetone
(2) ion-exchange rsin
(3) ion-exchage resin
H
N
H
N
R
O
O
H N
N
OH
H N
N
OH
N
H
N
H
N
H
NH2
O
NH2
1
a R=H
2
b R=CH3
Scheme 4
cals and reagents were obtained commercially and used without fur-
ther purification. Petroleum ether used had bp 60–90 °C.
ESI-MS: m/z = 371.3 (M).
4-[Tris(N-tert-butyloxycarbonyl)cyclen]-2-N-tert-butyloxycar-
bonylaminobutanoic Acid Benzyl Ester (10)
N-tert-Butyloxycarbonyl-L-homoserine Benzyl Ester (4)
To a stirred solution of L-homoserine (3; 11.9 g, 100 mmol) in H2O
(100 mL) was added dioxane (50 mL), solid NaHCO3 (8.4 g, 200
mmol) and di-tert-butyl dicarbonate (26 g, 120 mmol). After stir-
ring for 20 h at r.t., the solution was neutralized with aq sat. citric
acid, and concentrated to 60 mL in vacuo. The mixture was acidi-
fied with aq 10% citric acid, and extracted with EtOAc (4 × 20 mL).
The EtOAc extracts were combined and dried (Na2SO4). Then the
solvent was evaporated in vacuo. To the residue in acetone (100
mL) was added Et3N (12.3 mL, 100 mmol) and benzyl bromide
(20.5 g, 120 mmol). After refluxing for 5 h, the solvents were evap-
orated and the residue was dissolved in EtOAc (100 mL). The
EtOAc layer was washed with 0.5 N HCl, and dried (Na2SO4). After
evaporating the solvent, petroleum ether was added and shaken
well. The mixture was stored overnight in a refrigerator, filtered and
washed with petroleum ether to give a white solid; yield: 21.6 g
(70%, based on the amount of homoserine); mp 58–59 °C.
To a solution of cyclen (9; 3.1 g, 18 mmol) in anhyd MeCN (40 mL)
was added 6 (3.73 g, 10 mmol) in anhy MeCN (50 mL) dropwise
during 4 h at 85 °C under N2. The mixture was then refluxed for 3
h. Et3N (10 mL) was added at r.t., followed by di-tert-butyl dicar-
bonate (14.9 g, 68 mmol). The solution was stirred for another 10 h
at r.t. The solvents were removed in vacuo to give a yellow oil
which was chromatographed on silica gel (EtOAc–petroleum
ether, 1:5) to give an amorphous solid; yield: 5.3 g (79%, based on
the amount of 6); [a]D20 –4.8 (c = 0.5, MeOH).
IR (KBr): 3434, 3076, 2976, 1694, 1464, 1416, 1366, 1166 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.33 (s, 5 H, C6H5), 5.61 (s, 1 H,
NH), 5.23-5.08 (dd, 2 H, J = 12.0, 12.4 Hz, CH2Ph), 4.23 (s, 1 H,
CaH), 3.47–3.25 (m, 12 H, CH2-cyclen), 2.58–2.49 [m, 6 H,
CH2N(CH2)CH2], 1.95–1.89 (m, 2 H, CbH2), 1.44–1.41 (m, 36 H,
CH3-Boc).
13C NMR (600 MHz, CDCl3): d = 172.2, 156.0, 155.6, 155.2, 135.4,
128.6, 128.4, 79.8, 79.7, 79.5, 79.3, 67.0, 54.8, 53.8, 52.3, 50.1,
48.4, 48.0, 47.7, 47.3, 28.6, 28.4, 28.3, 27.5.
ESI-MS: m/z = 344.2 (M + Cl).
N-tert-Butyloxycarbonyl-O-tosyl-L-homoserine Benzyl Ester
(5)
HRMS-ESI: m/z calcd for C39H66N5O10 [MH]+: 764.4804; found:
To a solution of N-Boc-L-homoserine benzyl ester (4; 9.27 g, 30
mmol) in anhyd CH2Cl2 (60 mL) was added p-toluenesulfonyl chlo-
ride (8.6 g, 45 mmol), followed by anhyd pyridine (10 mL) and the
mixture was stirred overnight at 0 °C. The CH2Cl2 layer was
washed with aq citric acid, dried (Na2SO4) and evaporated to give a
yellow oil which was chromatographed (EtOAc–petroleum
ether, 1: 3) to give a white solid; yield: 11.1 g (80%); mp 86–88 °C.
764.4763.
4-[Tris(N-tert-butyloxycarbonyl)cyclen]-2-N-tert-butyloxycar-
bonylaminobutanoic Acid (11)
To 10 (3.36 g, 5.0 mmol) in MeOH (20 mL), was added NaOH (2
N, 10 mL). The solution was stirred for 1 h at r.t., acidified with cit-
ric acid, and extracted with EtOAc (3 × 20 mL). The EtOAc layer
was dried (Na2SO4) and the solvent was removed in vacuo to give
an amorphous solid; yield: 3.09 g (92%); [a]D20 +4.6 (c = 0.5,
MeOH).
ESI-MS: m/z = 498.4 (M + Cl).
4-Bromo-2-butyloxycarbonylaminobutanoic Acid 6
IR (KBr): 3054, 2964, 1684, 1286 cm–1.
To 5 (9.3 g, 20 mmol) in acetone (100 mL ) was added NaBr (10.3
g, 100 mmol) and refluxed for 10 h under N2. After filtration, the
solvent was evaporated in vacuo to give a yellow oil. The crude
product was chromatographed (EtOAc–petroleum ether, 1: 3) to
give a colorless oil, which solidified overnight in a refrigerator;
yield: 5.4 g (73%); mp 50–52 °C (Lit.27 mp 53 °C).
1H NMR (400 MHz, CDCl3): d = 7.31 (s, 5 H, C6H5), 5.19 (m, 2 H,
CH2Ph), 5.11 (s, 1 H, NH), 4.47 (s, 1 H, CaH), 3.41 (t, 2 H, J = 8.3
Hz, CH2Br), 2.43 (m, 1 H, CbH2), 2.23 (m, 1 H, CbH2), 1.44 (s, 9 H,
CH3-Boc).
1H NMR (400 MHz, CDCl3): d = 5.85 (s, 1 H, NH), 4.05 (s, 1 H,
CaH), 3.50–3.37 (m, 12 H, CH2-cyclen), 2.91–2.87 [m, 6 H,
CH2N(CH2)CH2], 2.03–1.96 (m, 2 H, CbH2), 1.51–1.43 (m, 36 H,
CH3-Boc).
13C NMR (600 MHz, CDCl3): d = 174.3, 156.1, 155.8, 80.4, 80.0,
79.6, 49.8, 48.7, 48.4, 48.2, 28.5, 28.4, 28.3, 27.6.
HRMS: m/z calcd for C32H60N5O10 [MH]+: 674.4335; found:
674.4334.
Synthesis 2005, No. 6, 888–892 © Thieme Stuttgart · New York

PAPER
Cyclen-Functionalized a-Amino Acid
Compounds 2a,b; General Procedure
891
Dipeptides 12a,b; General Procedure
Aminoacid methyl ester hydrochloride (1.0 mmol), 1-hydroxyben-
zotriazole monohydrate (0.15 g, 1.0 mmol), 11 (0.67 g, 1 mmol) and
N-methylmorpholine (0.13 mL, 1.2 mmol) were dissolved in anhyd
THF (20 mL). The mixture was stirred and cooled in an ice-water
bath while 1,3-dicyclohexylcarbodiimide (0.23 g, 1.1 mmol) was
added. The mixture was stirred for 1 h at 0 °C and overnight at r.t.
The N,N¢-dicyclohexylurea was removed by filtration and the sol-
vents were evaporated in vacuo. The crude product was dissolved in
EtOAc (30 mL), and washed with aq 10% citric acid (3 × 10 mL),
aq sat. NaHCO3 (3 × 10 mL) and H2O (2 × 10 mL). The organic
phase was dried (Na2SO4), filtered, and evaporated to dryness in
vacuo to give an amorphous solid.
To a solution of 12 (0.4 mmol) in MeOH (2 mL) was added aq 2 N
NaOH (1 mL). After stirring for 1 h at r.t., the solution was acidified
with aq 10% citric acid, and extracted with EtOAc (3 × 10 mL). The
combined organic phases were washed with H2O (10 mL) and brine
(2 × 15 mL), and dried (Na2SO4). The solvent was removed in vacuo
to give an amorphous solid. The solid was dissolved in acetone (10
mL) and HCl was bubbled through this solution. After stirring for 2
h at r.t., the white solid formed was filtered, and washed with ace-
tone to give the hydrochloride of compound 2. The above hydro-
chloride was dissolved in H2O (1.5 mL) and eluted over a basic
anion exchange column. The solution was evaporated to dryness
under reduced pressure to give compound 2 as a white solid.
12a
2a
Yield: 0.47 g (64%).
Yield: 0.11 g (83%); mp 221–225 °C.
IR (KBr): 3326, 2930, 1684 cm–1.
IR (KBr): 3422, 2930, 1679 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.04 (s, 1 H, NH), 5.78 (s, 1 H,
NH-Boc), 4.10 (s, 1 H, CaH), 4.03 (d, 2 H, J = 4.8 Hz,
NHCH2COOCH3), 3.74 (s, 3 H, COOCH3), 3.55–3.36 (m, 12 H,
CH2-cyclen), 2.67 [s, 6 H, CH2N(CH2)CH2], 2.01–1.98 (m, 1 H,
CbH2), 1.83–1.80 (m, 1 H, CbH2), 1.46–1.44 (m, 36 H, CH3-Boc).
13C NMR (600 MHz, CDCl3): d = 172.1, 170.0, 156.1, 155.9, 155.2,
80.0, 79.7, 79.5, 79.3, 55.5, 54.7, 53.2, 50.2, 48.8, 47.5, 47.2, 41.1,
28.6, 28.5, 28.3, 27.0.
1H NMR (400 MHz, D2O): d = 3.99 (d, 1 H, J = 4.0 Hz, CaH), 3.81
(d, 2 H, J = 16.0 Hz, CH2-Gly), 2.69–3.16 (m, 18 H, CH2), 2.16–
2.10 (m, 1 H, CbH2), 2.06–1.99 (m, 1 H, CbH2).
13C NMR (600 MHz, D2O): d = 176.5, 173.1, 54.4, 51.6, 51.5, 51.2,
44.8, 44.4, 44.2, 43.7, 43.3, 42.5, 42.1, 28.3.
HRMS: m/z calcd for C14H31N6O3 [MH]+: 331.2452; found:
331.2467.
HRMS: m/z calcd for C35H65N6O11 [MH]+: 745.4706; found:
2b
745.4697.
Yield: 0.10 g (73%); mp 203–208 °C.
IR (KBr): 3422, 2970, 1704 cm–1.
12b
1H NMR (400 MHz, D2O): d = 4.25–4.20 (m, 1 H, CaH), 4.06–4.03
(m, 1 H, CaH), 3.21 (s, 8 H, CH2-cyclen), 3.10–2.76 (m, 10 H, CH2),
2.18–2.12 (m, 2 H, CbH2), 1.41 (d, 3 H, J = 8.2 Hz, CH3).
Yield: 0.57 g (75%).
IR (KBr): 3332, 2976, 1690 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.08–6.90 (s, 1 H, NH), 5.80–5.70
(s, 1 H, NH-Boc), 4.60–4.52 (m, 1 H, CaH), 4.15–4.06 (m, 1 H,
CaH), 3.73 (s, 3 H, COOCH3), 3.53–3.34 (m, 12 H, CH2-cyclen),
2.65 [s, 6 H, CH2N(CH2)CH2], 1.99–1.97 (m, 1 H, CbH2), 1.77–1.71
(m, 1 H, CbH2), 1.46–1.44 (m, 36 H, CH3-Boc), 1.26 (t, 3 H, J = 8.0
Hz, CH3CaH).
13C NMR (600 MHz, D2O): d = 179.5, 168.2, 51.7, 51.4, 51.3, 47.5,
47.0, 44.3, 42.9, 42.0, 41.5, 25.2, 25.0.
HRMS: m/z calcd for C15H33N6O3 [MH]+: 345.2609; found:
345.2626.
13C NMR (600 MHz, CDCl3): d = 173.0, 171.4, 156.1, 155.9, 155.2,
79.8, 79.7, 79.5, 79.2, 55.8, 54.9, 53.3, 52.9, 52.3, 50.2, 49.0, 48.5,
48.0, 47.7, 47.5, 28.6, 28.4, 28.3, 27.0, 18.0.
HRMS: m/z calcd for C36H67N6O11 [MH]+: 759.4862; found:
759.4862.
Acknowledgment
This work was financially supported by the National Natural Sci-
ence Foundation of China (20132020, 20372051), the Teaching and
Research Award Program for Outstanding Young Teachers in Hig-
her Education Institutions of MOE, Specialized Research Fund for
the Doctoral Program of Higher Education, and Scientific Fund of
Sichuan Province for Outstanding Young Scientist.
(2S)-2-Amino-4-(1,4,7,10-tetraazacyclododecan-1-yl)butanoic
Acid (1)
To a solution of 11 (0.67 g, 1.0 mmol) in EtOH (2 mL) was added
47% HBr (3 mL). After stirring at 0 °C for 4 h, the white solid
formed was filtered, and washed with absolute EtOH to give the hy-
drobromide of 1. The above hydrobromide was dissolved in H2O
(1.5 mL) and eluted over a basic anion exchange column. The solu-
tion was evaporated to dryness under reduced pressure to give 1 as
a white solid; yield: 0.23 g (84%); mp 165–170 °C; [a]D20 +13.3
(c = 0.6, MeOH).
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296.2064.
Synthesis 2005, No. 6, 888–892 © Thieme Stuttgart · New York

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S.-Y. Chen et al.
PAPER
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