A simple synthesis of imide-dipeptides

Article abstract of DOI:10.1055/s-0029-1217167

We report a simple approach to synthesize a new class of imide-dipeptides. This approach is mild, and the starting materials are the easily accessible amino acid derivatives. The imide-dipeptides were synthesized from the coupling of an amide and a 4-nitrophenyl activating ester of an amino acid. The acidic proton of the first amide was removed by 1 equivalent of n-butyl lithium to afford the corresponding amide anion which then reacted with the activating ester to give the desired imide derivatives. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217167

1506
LETTER
A Simple Synthesis of Imide-Dipeptides
A
S
imple Synthesi
a
s
of Imide-
m
D
ipeptides ei Ke,a,b Chuanlang Zhan,*a Xiao Li,a,b Alexander D. Q. Li,c Jiannian Yao*a
a
Beijing National Laboratory of Molecular Science (BNLMS), Laboratory of Photochemistry, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100190, P. R. of China
Fax +86(10)82616517; E-mail: clzhan@iccas.ac.cn; E-mail: jnyao@iccas.ac.cn
Graduate School, Chinese Academy of Sciences, Beijing 100039, P. R. of China
Department of Chemistry, Washington State University, Pullman, Washington 99164, USA
b
c
Received 2 February 2009
dinane might effectively oxidized secondary amides into
the corresponding imide derivatives.9 Xu showed that
ceric ammonium nitrate was able to promote oxidation of
oxazoles into imide derivatives.10 Fu and Zhao reported
Abstract: We report a simple approach to synthesize a new class of
imide-dipeptides. This approach is mild, and the starting materials
are the easily accessible amino acid derivatives. The imide-dipep-
tides were synthesized from the coupling of an amide and a 4-nitro-
phenyl activating ester of an amino acid. The acidic proton of the that copper complexes were capable of catalyzing the
first amide was removed by 1 equivalent of n-butyl lithium to afford
amidation of aldehydes by C–H activation, and thus imide
the corresponding amide anion which then reacted with the activat-
derivatives were synthesized from the coupling of alde-
ing ester to give the desired imide derivatives.
hydes and amide.11 Although these approaches have been
shown to be highly efficient for the synthesis of imide de-
Key words: imides, dipeptides, amino acids, amides, coupling
rivatives, especially aromatic imide derivatives, to our
best knowledge, there are no reports yet on the synthesis
Short peptides generally do not participate in specific H- of peptidomimetics bearing both natural amino acid resi-
bonding interactions and peptidyl chains possessing high dues and the imide moiety.
flexibility generally adopt random coil conformations in
solution. Incorporating rigid motifs into the peptidyl back-
bone is a general approach to produce linear b-strand mi-
metics,1 which may reduce the flexibility of the peptide
main chains. Since the finding of naturally occurring urea-
containing peptide backbone,2 the urea unit has been used
to develop a set of short peptidomimetics, which has been
found to adopt b-folding and form b-sheetlike assembly in
solution through the self-pairing H-bonds between C=O
and NH of the urea unit.3 Similarly, the imide unit also
provides complementary hydrogen-bonding building
blocks.4 However, peptidomimetics containing the imide
moiety are rarely reported, probably due to their difficult
synthetic accessability. We have been interested to devel-
op peptidomimetics containing the imide moiety and re-
ported herein a mild and straightforward route to the
synthesis of imide-dipeptides (Figure 1). The imide unit
appears in a large number of naturally occurring com-
pounds, for examples, uracil, thymine, and fumaramid-
mycin – an antibiotic isolated from a streptomycete
NR-7GG1.5
O
R1
R2
O
H
N
R3
O
N
N
O
H
H
O
O
1a: R1 = R2 = Me, R3 = t-Bu
1b: R1 = R2 = i-Bu, R3 = t-Bu
1c: R1 = R2 = Bn, R3 = t-Bu
1d: R1 = R2 = (CH2)4-NHCbz, R3 = t-Bu
1e: R1 = Bn, R2 = -(CH2)4-NHCbz, R3 = t-Bu .
1f: R1 = i-Bu, R2 = Bn, R3 = Bn
Figure 1 Chemical structures of the synthesized imide-dipeptides 1
R4
O
R5
NH2
n-BuLi
H
R4
N
R5
(1.1 equiv)
+
O
O
NO2
THF, –76 °C
O
O
2
3
4
Scheme 1 Synthesis of imide derivatives
In general, acylation of aromatic amide by using large ex-
cess of acyl chloride or anhydride produces stable aromat-
ic imide derivatives.6,7 Recently, we have successfully
synthesized a set of pyridine-imide oligomers by acyla-
tion of pyridine-carboxamide with pyridinoyl chloride.8
Alternatively, several recent reports demonstrated the
synthesis of imide derivatives using a catalysis approach.
Nicolaou and Mathison reported that Dess–Martin perio-
In this letter, we selected an easily accessible amide and
4-nitrophenyl activating ester to synthesize imide deriva-
tives (Scheme 1) and the imide-dipeptides (Scheme 2).
We supposed that the acidic proton of the first amide
might be efficiently removed by using n-butyl lithium at
–76 °C to afford a nucleophilic intermediate – a lithium
anion of amide, which may then react with the activating
ester to give the desired imide derivatives. Here, we se-
lected the 4-nitrophenyl group as an activating ester
group.12
SYNLETT 2009, No. 9, pp 1506–1510
x
x.
x
x.
2
0
0
9
Advanced online publication: 13.05.2009
DOI: 10.1055/s-0029-1217167; Art ID: W01509ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
A Simple Synthesis of Imide-Dipeptides
1507
This hypothesis was first proved by the successful synthe- was necessary to increase the product yield, as indicated
sis of diacetamide (Table 1, entry 1, product 4a) from ac- by TLC analysis. As a comparison, although acetyl chlo-
etamide and 4-nitrophenyl acetyl ester in a yield of 75%. ride was expected to react with the amide anion, but a sim-
Reaction of acetamide and 4-nitrophenyl N-Boc-L-alanine ilar reaction by replacing the 4-nitrophenyl acetyl ester
ester yielded product 4b (entry 2), revealing that the N- with acetyl chloride gave a low yield of the product 4a,
Boc-carbamate group was inert and stable under this reac- typically <40%. The yield was found to be far lower for a
tion condition. Entry 3 further demonstrated that the reaction between the N-Boc-L-alanine amide and the
amide proton preferred to react with n-BuLi, while the N- acetyl chloride, typically about 10%, suggesting that 4-
Boc-carbamate proton (NH) was inert and stable, and thus nitrophenyl group was a better activating group than acyl
the N-Boc-carbamate group may be incorporated into any chloride for this approach.
one of the substrates – the activating ester or amide for this
reaction. It seemed that further heating for another 3 hours
Table 1 Synthesis of Different Imide Derivatives
Entry
1
Substrate A
Substrate B
Product
Yield (%)a
75
O
O
NH2
O
diacetamide 4a
NO2
H
Boc
N
NH2
O
Boc
N
O
2
70
N
H
H
O
O
O
NO2
4b
4b
O
Boc
N
NH2
NH2
3
73
56
O
H
NO2
O
Boc
O
O
4b
1a
1b
Boc
N
H
N
H
O
O
O
O
NO2
5
6
68
65
Boc
Boc
NH2
N
H
N
H
NO2
1c
Boc
O
Boc
NH2
N
H
N
H
O
O
NO2
Cbz
Cbz
HN
HN
7
1d
54
Boc
O
Boc
NH2
N
H
N
H
O
O
NO2
Synlett 2009, No. 9, 1506–1510 © Thieme Stuttgart · New York

1508
D. Ke et al.
LETTER
Table 1 Synthesis of Different Imide Derivatives (continued)
Entry
Substrate A
Substrate B
Product
Yield (%)a
Cbz
HN
8
1e
68
Boc
N
NH2
Boc
N
O
H
O
H
O
NO2
9
1f
1f
56
60
Boc
NH2
Cbz
Boc
O
O
N
H
N
H
O
O
O
NO2
10
N
H
Cbz
NH2
N
H
NO2
O
a Isolated yields.
b A typical procedure for synthesis of 4-nitrophenyl N-Boc-L-alanine ester and N-Boc-L-alanine amide, please see ref. 14.
We then examined the synthesis of other imide-dipeptides In summary, a new set of imide-dipeptides were success-
(Scheme 2). Entry 4 shows that reaction of N-Boc-L- fully synthesized from a mild and straightforward ap-
alanine amide, which had been treated by using 1 equiva- proach by using easily accessible amide and 4-nitrophenyl
lent n-BuLi, and 4-nitrophenyl N-Boc-L-alanine ester14 activating ester of an amino acid as starting materials. In
resulted in the imide-dipeptide 1a13 in a yield of 56%. En- this approach, n-butyl lithium was used to remove the
tries 5–7 indicated that this approach may be a straightfor- acidic proton of the amide at –76 °C to generate the lithi-
ward route to synthesize N-Boc-protected imide- um anion of the amide, which then directly reacted with
dipeptides of different amino acids, and entry 7 also re- the 4-nitrophenyl activating ester to afford the desired
vealed that the Cbz-N proton was inert and stable under imide-dipeptides.
this reaction conditions. Entry 8 showed the synthesis of
an N-Boc-protected imide-dipeptide 1e containing two
different amino acid residues. Entries 9 and 10 suggested
that our approach may be used to synthesize N-Boc- and
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
N-Cbz-protected, asymmetrical imide-dipetides contain-
ing two different amino acid residues.
Acknowledgment
We thank NSFC (Nos. 20872145, 20733006), the Chinese Acade-
my of Sciences, the National Research Fund for Fundamental Key
Project 973 (2006CB806200, 2007CB936401), and the CAS/
SAFEA International Partnership Program for Creative Research
Teams.
R1
R
O
N
H
O
NO2
5
R1
R2
H
N
+
R
R'
N
N
References and Notes
R2
H
H
O
O
(1) (a) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.;
Moore, J. S. Chem. Rev. 2001, 101, 3893. (b)Venkatraman,
J.; Shankaramma, S. C.; Balaram, P. Chem. Rev. 2001, 101,
3131. (c) Loughlin, W. A.; Tyndall, J. D. A.; Glenn, M. P.;
Fairlie, D. P. Chem. Rev. 2004, 104, 6085. (d) Hughes,
R. M.; Waters, M. L. Curr. Opin. Struct. Biol. 2006, 16, 514.
(2) Stefanelli, S.; Cavaletti, L.; Sarubbi, E.; Ragg, E.; Colombo,
L.; Selva, E. J. Antibiot. 1995, 48, 332.
R'
NH2
1
N
H
O
6
R
1 = Rala, Rleu, Rphe, Rlys
R2 = Rala, Rleu, Rphe, Rlys
R = Boc or Cbz
R' = Boc or Cbz
Scheme 2 Synthesis of the imide-dipeptides
Synlett 2009, No. 9, 1506–1510 © Thieme Stuttgart · New York

LETTER
A Simple Synthesis of Imide-Dipeptides
1509
(3) (a) Zhao, X.; Chang, Y.-L.; Fowler, F. W.; Lauher, J. W.
J. Am. Chem. Soc. 1990, 112, 6627. (b) Cbang, Y.-L.;West,
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Andrews, D. M.; Bamborough, P.; Carey, S. J.; Johnson,
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Stewart, A. J.; Skarzynski, T. Org. Lett. 2003, 5, 4627.
(h) Walther, T.; Arndt, H.-D.; Waldmann, H. Org. Lett.
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(4) (a) Rochon, F. D.; Kong, P. C.; Melanson, R. Inorg. Chem.
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Chem. Soc. 1991, 113, 2586. (c) Reutzel, S. M.; Etter, M. C.
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Leroux, N.; Zeegers-Huyskens, T. J. Chem. Soc., Faraday
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(5) (a) Maruyama, H. B.; Suhara, Y.; Suzuki-Watanabe, J.;
Maeshima, Y.; Shimizu, N.; Ogura-Hamada, M.; Fujimoto,
H.; Takano, K. J. Antibiot. 1975, 28, 636. (b) Suhara, Y.;
Maruyama, H. B.; Kotoh, Y.; Miyasaka, Y.; Yokose, K.;
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(13) A Typical Procedure to Synthesize the Imide-dipeptides
The amide (1.1 mmol) of an N-Boc-L-amino acid was
dissolved in distilled THF (10 mL). Then, n-BuLi (1.1 equiv,
1.5 mM in hexane) was added at –76 °C. One hour later, the
reaction mixture was injected into 4-nitrophenyl N-Boc-L-
amino acid ester (1.0 mmol) in distilled THF (10 mL) and
stirred overnight at r.t. The mixture was then refluxed for
another 3 h. After removal of solvents, the residue was
applied to chromatography to yield desired imide-dipeptides
as a white solid.
54.0, 40.7, 28.4, 24.9, 23.3, 21.5 ppm. ESI-MS: m/z = 443,
466 [+ Na+].
Imide-dipeptide (1c)
After removal of solvents, the residue was applied to
chromatography by using PE–EtOAc (5:1) as eluents to
yield 1c as a white solid (290 mg, 0.65 mmol, 65%, Rf = 0.2).
1H NMR (400 MHz, CDCl3): d = 9.13 (s, 1 H, imide NH),
7.19–7.16 (m, 6 H, phenyl H, 3J = 6.0 Hz), 7.01–7.00 (d, 4
H, phenyl H, 3J = 6.4 Hz), 4.94 (d, 2 H, carbamate NH, 3J =
8.0 Hz), 4.57 (q, 2 H, a-protons, 3J = 8.2 Hz), 3.01 (d, 4 H,
BnCH2, 3J = 6.0 Hz), 1.45 (s, 18 H, Boc H) ppm. 13C NMR
(100 MHz, CDCl3): d = 174.0, 156.0, 139.5, 128.7, 127.6,
126.2, 80.6, 54.5, 37.8, 28.4 ppm. ESI-MS: m/z = 511, 534
[+ Na+].
Imide-dipeptide (1d)
After removal of solvents, the residue was applied to
chromatography by using PE–EtOAc (3:1) as eluents to
yield 1d as a white solid (400 mg, 0.54 mmol, 54%, Rf = 0.2).
1H NMR (400 MHz, CDCl3): d = 8.96 (s, 1 H, imide NH),
7.35–7.26 (m, 10 H, phenyl H, 3J = 6.0 Hz), 5.15 (s, 2 H, Cbz
NH), 5.06 (s, 4 H, BnCH2), 4.95 (s, 2 H, carbamate NH),
4.30 (m, 2 H, a-protons, 3J = 8.0 Hz), 3.11 (m, 4 H, CH2,
3J = 6.0 Hz), 1.79 (br s, 2 H, CH2), 1.65 (m, 2 H, CH2, 3J =
7.9 Hz), 1.47–1.32 (m, 8 H, CH2, 3J = 7.4 Hz), 1.45 (s, 18 H,
Boc H) ppm. 13C NMR (100 MHz, CDCl3): d = 173.9, 156.0,
141.1, 128.6, 128.2, 80.6, 66.6, 53.4, 41.0, 32.0, 29.4, 28.4,
22.5 ppm. ESI-MS: m/z = 741, 764 [+ Na+].
Imide-dipeptide (1e)
After removal of solvents, the residue was applied to
chromatography by using PE–EtOAc (4:1) as eluents to
yield 1e as a white solid (430 mg, 0.68 mmol, 68%, Rf = 0.2).
1H NMR (400 MHz, CDCl3, 10 mM): d = 9.09 (s, 1 H, imide
NH), 7.29–7.13 (m, 10 H, phenyl H), 5.22 (s, 1 H, Cbz NH),
5.06 (m, 1 H, carbamate NH, overlapping, 3J = 7.2 Hz), 5.03
(s, 2 H, BnCH2), 4.91 (s, 1 H, carbamate NH), 4.73 and 4.67
(br s, 1 H, a-protons), 4.46 (br s, 1 H, a-protons), 3.11 (s, 2
H, CH2), 3.11 (br s, 1 H, BnCH2, overlapping), 2.85 (br s, 1
H, BnCH2), 1.74 (br s, 2 H, CH2), 1.47 (m, 4 H, CH2, 3J = 6.4
Hz), 1.29 and 1.20 (s, 18 H, Boc H) ppm.13C NMR (100
MHz, CDCl3): d = 172.7, 171.9, 156.7, 155.9, 155.4, 136.5,
135.8, 129.4, 128.6, 128.5, 128.1, 127.1, 80.4, 66.7, 56.3,
55.1, 40.1, 37.5, 31.0, 29.2, 28.3, 22.4 ppm. ESI-MS: m/z =
626, 749 [+ Na+].
Imide-dipeptide (1f)
After removal of solvents, the residue was applied to
chromatography by using PE–EtOAc (5:1) as eluents to
yield 1f as a white solid (290 mg and 310 mg, 0.56 mmol and
0.60 mmol, 56% and 60%, Rf = 0.2). 1H NMR (400 MHz,
CDCl3): d = 8.89–8.82 (d, 1 H, imide NH), 7.35–7.17 (m, 10
H, phenyl H), 5.29 (s, 1 H, Cbz NH), 5.05 (s, 2 H, BnCH2),
5.00 (d, 1 H, carbamate NH, 3J = 8.4 Hz), 5.00 (m, 1 H, a-
protons, overlapping), 4.57 (m, 1 H, a-protons, 3J = 8.2 Hz),
3.11 (m, 1 H, BnCH2), 2.85 (m, 1 H, BnCH2), 1.74–1.60 (m,
2 H, b-H of Leu, 3J = 5–7 Hz), 1.47–1.40 (m, 1 H, g-H of
Leu, 3J = 4.8 Hz), 1.45 (s, 9 H, Boc H), 0.98–0.88 (q, 6 H,
d-H of Leu, 3J = 6.5, 5.2 Hz) ppm. 13C NMR (100 MHz,
CDCl3): d = 174.0, 173.3, 156.2, 156.0, 141.1, 140.3, 129.5,
128.7, 128.6, 128.5, 128.2, 127.1, 80.6, 66.0, 54.9, 54.0,
40.7, 37.8, 28.4, 24.9, 23.3, 22.2 ppm. ESI-MS: m/z = 511,
534 [+ Na+].
Imide-dipeptide (1a)
After removal of solvents, the residue was applied to
chromatography by using PE–EtOAc (4:1) as eluents to
yield 1a as a white solid (200 mg, 0.56 mmol, 56%, Rf = 0.2).
1H NMR (400 MHz, CDCl3, 16.7 mM): d = 9.21 (s, 1 H,
imide NH), 5.02 (d, 2 H, carbamate NH, 3J = 6.7 Hz), 4.57–
4.52 (m, 2 H, a-proton, 3JHNa= 8.0 Hz), 1.45 (s, 18 H, Boc
H), 1.27 (t, 6 H, b-H of Ala, 3J = 6.8 Hz) ppm. 13C NMR (100
MHz, CDCl3): d = 171.9, 154.5, 98.6, 79.6, 27.2, 16.5 ppm.
ESI-MS: m/z = 359, 382 [+ Na+].
Imide-dipeptide (1b)
After removal of solvents, the residue was applied to
chromatography by using PE–EtOAc (3:1) as eluents to
yield 1b as a white solid (300 mg, 0.68 mmol, 68%, Rf = 0.2).
1H NMR (400 MHz, CDCl3, 10 mM): d = 9.02 (s, 1 H, imide
NH), 4.89 (d, 2 H, carbamate NH, 3J = 7.7 Hz), 4.57 (br s, 2
H, a-protons), 1.74–1.60 (m, 4 H, b-H of Leu, 3J = 5–7 Hz),
1.47–1.40 (m, 2 H, g-H of Leu, 3J = 4.8 Hz), 1.45 (s, 18 H,
Boc H), 0.98–0.94 (q, 12 H, d-H of Leu, 3J = 6.5, 5.2 Hz)
ppm. 13C NMR (100 MHz, CDCl3): d = 173.3, 156.0, 80.6,
(14) Typical Procedure for the Synthesis of 4-Nitrophenyl N-
Boc-L-alanine Ester and N-Boc-L-alanine Amide
N-Boc-L-alanine Acid
L-Alanine (4.5g, 50 mmol) and KOH (3.8 g, 55 mmol) were
dissolved in a mixture of H2O (200 mL) and THF (20 mL).
Then, di-tert-butyl-dicarbonate (13.0 g, 55 mmol) was
added. The resultant solution was allowed to react at 50 °C
Synlett 2009, No. 9, 1506–1510 © Thieme Stuttgart · New York

1510
D. Ke et al.
LETTER
for 2–3 h and at r.t. overnight. Then, 1 M HCl (55 mL) was
added dropwise to adjust pH value of the solution to about 5.
The solution was extracted with EtOAc (3 × 200 mL) and
CH2Cl2 (3 × 200 mL), respectively. The organic phases were
mixed and dried with anhyd Na2SO4. The reaction afforded
N-Boc-L-alanine acid as an oil-like solid (9 g, 47 mmol,
95%). 1H NMR (400 MHz, CDCl3): d = 10.66 (br s, 1 H, acid
H), 5.08 (s, 1 H, carbamate H), 4.35 (s, 1 H, a-proton), 1.53
(d, 3 H, CH3, 3J = 7.6 Hz), 1.45 (s, 9 H, Boc H) ppm. ESI-
MS: 188 [– H+], 189, 211 [– H+ and + Na+], 227 [– H+ and
+ K+].
light yellow solid (2.6 g, 8.4 mmol, 85%, Rf = 0.2). 1H NMR
(400 MHz, CDCl3): d = 8.30 (d, 2 H, phenyl H, 3J = 9.0 Hz),
7.32 (d, 2 H, phenyl H, 3J = 9.0 Hz), 5.11 (s, 1 H, carbamate
H), 4.54 (t, 1 H, a-proton, 3J = 7.1, 6.5 Hz), 1.58 (d, 3 H,
CH3, 3J = 7.4 Hz), 1.47 (s, 9 H, Boc H). 13C NMR (100 MHz,
CDCl3): d = 171.4, 155.3, 155.2, 145.6, 125.4, 122.4, 80.5,
49.7, 28.4, 18.1. ESI-MS: m/z = 333 [+ Na+].
N-tert-Butoxycarbonyl-L-alanine Amide
4-Nitrophenyl N-Boc-L-alanine ester (2.40 g, 7.7 mmol) was
dissolved in MeCN (30 mL) and bubbled by NH3 flow for
4–5 h. After removal of MeCN, the reacted residue was
purified with chromatography using PE–CH2Cl2–EtOAc
(1:1:1) as eluents to afford N-tert-butoxycarbonyl-L-alanine
amide as white solid (1.4 g, 7.4 mmol, 96%, Rf = 0.1). 1H
NMR (400 MHz, CDCl3): d = 6.04 (s, 1 H, amide H), 5.32
(s, 1 H, amide H), 4.89 (s, 1 H, carbamate H), 4.10 (s, 1 H,
a-proton), 1.36 (s, 9 H, Boc H), 1.30 (d, 3 H, CH3, 3J = 7.2)
ppm. 13C NMR (100 MHz, CDCl3): d = 171.7, 155.5, 80.3,
49.9, 28.3, 18.2 ppm. ESI-MS: m/z = 211 [+ Na+], 227 [+ K+].
4-Nitrophenyl N-Boc-L-alanine Ester
N-Boc-L-alanine acid (1.9 g, 10 mmol), 4-nitrophenol (1.7 g,
12 mmol), and DCC (2.8 g, 12 mmol) were mixed with
CH2Cl2 (100 mL). After stirred overnight at r.t., the
precipitate was filtered out, and the solvents of the filtration
were removed. The resultant residue was applied to flash
chromatography with PE–CH2Cl2–EtOAc (10:2:1) as
eluents to afford 4-nitrophenyl N-Boc-L-alanine ester as a
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