Macrocyclic peptoids by selective s-acylation of cysteine esters

Article abstract of DOI:10.1055/s-0032-1318148

Optimized selective S-acylations of cysteine esters gave intermediates for the synthesis of macrocyclic peptoids by a benzotriazole-based method. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1318148

PAPER
▌767
paper
Macrocyclic Peptoids by Selective S-Acylation of Cysteine Esters
Macrocyclic Peptoids
Mohamed A. Ibrahim,a,b,c Siva S. Panda,a Linda Nhon,a Ahmed Hamed,a Said A. El-Feky,b Alan R. Katritzky*a,d
a
Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, FL 32611-7200, USA
b
Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt
c
Department of Organic Chemistry, College of Pharmacy, Misr University for Science and Technology, P.O. Box 77, Al-Motamayez District,
6th of October City, Egypt
d
Chemistry Department, King Abdulaziz University, Jeddah 21589, Saudi Arabia
Fax +1(352)3929199; E-mail: katritzky@chem.ufl.edu
Received: 02.11.2012; Accepted after revision: 10.01.2013
bridges,11,12 ring-closing olefin metathesis,13 click chem-
istry,14–16 and several other approaches.11,17–19
Abstract: Optimized selective S-acylations of cysteine esters gave
intermediates for the synthesis of macrocyclic peptoids by a benzo-
triazole-based method.
The importance of S-acylcysteines in various applications
justifies the development of a mild and efficient method
for the selective S-acylation of cysteine esters. In a previ-
ous communication,2 we reported a preferential selective
S-acylation (over N-acylation) of free cysteine with N-ac-
ylbenzotriazoles. Here, we report the selective S-acyla-
tion of cysteine esters under optimized conditions, the
synthesis of macrocyclic peptoids by using the benzotri-
azole method, and the use of S-acylated cysteine esters as
active intermediates.
Key words: acylations, amino acids, macrocycles, heterocycles
Cysteine residues are common components of natural
products such as insulin.1 S-Acylated cysteines are poten-
tially useful as intermediates for the synthesis of oxytocin-
like peptides2 or proteins through native chemical liga-
tion. Cysteine β-thioesters are S-acyl isopeptides that can
be converted into natural peptides through S-to-N intra-
molecular acyl-migration reactions.
Many reports describe the synthesis of cyclic peptides, but
few include the use of functional groups in the side chain
of the amino acid cysteine to build the ring. We succeeded
in optimizing the reaction conditions for S-acylation of
cysteine derivatives 7a–j to give the corresponding thio
esters 8a–h, and we used the acylated derivatives 8b, 8c,
and 8e as active intermediates for the synthesis of macro-
cyclic peptoids.
There are several previous reports on selective S-acyla-
tion reactions of cysteine esters. For example, Zervas and
co-workers S-acylated cysteine esters in 52% overall
yield through the reaction of an acyl chloride with a cys-
teine residue, followed by esterification;1 Hedrick and co-
workers synthesized S-acylcysteine esters through the re-
action of an excess of an acyl chloride with ethyl cystein-
ate hydrochloride under vigorous conditions, followed by
removal of residual acyl chloride by evaporation;3 and
Clark and co-workers selectively S-acylated α-cysteine
amides with an acyl chloride in trifluoroacetic acid.4
First, we synthesized the N-acylbenzotriazoles 3a–e by
our previously reported method (Scheme 1).20,21
O
In drug discovery, cyclic peptides and cyclic peptidomi-
metics are of interest as protein-binding molecules, be-
cause they have a greater conformational rigidity than
their linear counterparts.5 Small proteins frequently con-
tain intermolecular side-chain constraints, often in the
form of disulfide bonds between cysteine residues. Such
disulfide bridges stabilize three-dimensional structures in
otherwise flexible systems. Cyclotides6,7 are small pro-
teins that contain cysteine knot motifs that can be engi-
neered to form β-hairpins.8 Cyclization of oligopeptides
can enhance their resistance to proteases9 and improve
their cell permeability.10 Chemical strategies that have
been employed to develop novel covalent intermolecular
constraints include the formation of lactam or lactone
N
N
R
N
SOCl2, CH2Cl2
20 °C, 2 h
N
N
RCOOH
+
N
H
1a–e
2
3a–e
R = Ph, 4-MeOC6H4, 4-O2NC6H4, 1-naphthyl
Scheme 1 Synthesis of N-acylbenzotriazoles 3a–e
We then prepared the bisbenzotriazoles 5a–f in 52–85%
yield by treatment of the corresponding dicarboxylic acid
with eight equivalents of 1H-1,2,3-benzotriazole and 2.2
equivalents of thionyl chloride in tetrahydrofuran at 20 °C
for two hours (Table 1).
Treatment of the L-cysteine ester hydrochlorides 6a and
6b with the N-acylbenzotriazoles 3a–e at 20 °C in aque-
ous tetrahydrofuran for three hours gave the correspond-
ing S-acylcysteine esters 7a–j exclusively in 50–73%
yield (Table 2).
SYNTHESIS 2013, 45, 0767–0772
Advanced online publication: 21.02.2013
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DOI: 10.1055/s-0032-1318148; Art ID: SS-2012-M0856-OP
© Georg Thieme Verlag Stuttgart · New York

768
M. A. Ibrahim et al.
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Table 1 Preparation of N-Acylbisbenzotriazoles 5a–f
Similarly, treatment of L-cysteine ester hydrochlorides 6a
and 6b with the N-acylbisbenzotriazoles 5a–f in aqueous
tetrahydrofuran at room temperature for three hours gave
the corresponding S-acylcysteines 8a–h exclusively in
59–92% yields (Table 3).
N
O
O
N
N
N
N
N
N
H
COOH
N
N
HOOC
Z
2
Z
4a–f
SOCl2, CH2Cl2
20 °C, 2 h
Table 3 Selective S-Acylation of Cysteine Ester Hydrochlorides 6a
and 6b with N-Acylbisbenzotriazoles 5a–f
5a–f
Product
Z
Yield (%)
52
Mp ( °C)
O
O
SH
N
N
N
N
Z
N
N
5a
189–19022
OR
+
+
Cl– H3N
O
6a,b
5a–f
THF–H2O (9.5:0.5)
O
20 °C, 3 h
O
5b
5c
70
68
183–185
200–202
+
+
Cl– H3N
NH3 Cl–
S
S
Z
RO
O
O
OR
8a–h
NO2
O
Product
Z
R
Yield (%) Mp ( °C)
5d
5e
60
85
142–14422
151–15322
S
8a
Me
Me
70
61
163–164
165–167
5f
72
100–10122
8b
8c
Table 2 Selective S-Acylation of Cysteine Ester Hydrochlorides 6a
and 6b with N-Acylbenzotriazoles 3a–e
Me
66
219–220
O
SH
R2O
NO2
THF–H2O
(9.5:0.5)
N
O
R1
N
N
OR2
S
O
+
O
– H3N
8d
8e
Me
Et
65
70
oil
R1
+ Cl
20 °C, 3 h
+
NH3Cl–
O
6a,b
7a–j
3a–e
203–204
Product
R1
R2
Yield (%) Mp (°C)
7a
7b
7c
7d
7e
7f
Ph
Me
Me
Me
Me
Me
Et
50
52
51
61
66
71
54
57
68
73
oil4
8f
Et
59
190–192
4-Tol
oil
4-MeOC6H4
4-O2NC6H4
1-naphthyl
Ph
177–79
182–184
176–178
oil23
8g
8h
Et
Et
92
72
218–220
oil
NO2
O
7g
7h
7i
4-Tol
Et
110–112
175–177
oil
4-MeOC6H4
4-O2NC6H4
1-naphthyl
Et
Compounds 5a and 5f were treated with cysteine ester hy-
drochlorides 8b, 8c, and 8e in the presence of four equiv-
alents of triethylamine in N,N-dimethylformamide with
microwave irradiation at 50 °C and 50 W power for 20
minutes to give the novel macrocyclic peptoids 9a–d (64–
72%) (Table 4). In this reaction sequence, compounds 8b,
Et
7j
Et
oil
Synthesis 2013, 45, 767–772
© Georg Thieme Verlag Stuttgart · New York

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Macrocyclic Peptoids
769
ternal standard) or 75 MHz for 13C NMR. Elemental analyses were
performed on a Carlo Erba-EA1108 instrument.
Table 4 Preparation of Macrocyclic Peptoids 9a–d
Z2
O
O
All microwave-assisted reactions were carried out with a single-
mode-cavity Discover Microwave Synthesizer (CEM Corp., Mat-
thews, NC). The reaction mixtures were transferred into a 10-mL
glass pressure microwave tube equipped with a magnetic stirrer bar.
The tube was closed with a silicon septum, and the mixture was sub-
jected to microwave irradiation (Discover mode; run time: 60 s;
PowerMax-cooling mode).
S
O
O
S
Cl–
Cl–
Z1
+
N
N
N
N
O
O
+
+
H3N
NH3
N
N
5a,f
OR
OR
8b,c,e
MW (50 °C, 50 W)
20 min
DMF, Et3N
Bis-1H-benzotriazoles 5a–f; General Procedure
The compounds were synthesized by using our established proce-
dure.22
Z2
O
O
(5-Methylbenzene-1,3-diyl)bis(1H-benzotriazol-1-ylmeth-
anone) (5b)
R
HN
O
O
NH
O
O
R
White microcrystals; yield: 0.150 g (70%); mp 183–185 °C.
1H NMR (300 MHz, CDCl3): δ = 8.82 (br s, 1 H), 8.38 (d, J = 8.4
Hz, 2 H), 8.31 (br s, 2 H), 8.14 (d, J = 8.4 Hz, 2 H), 7.71 (t, J = 7.7
Hz, 2 H), 7.54 (t, J = 7.8 Hz, 2 H), 2.60 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 165.9, 146.0, 139.2, 136.9, 132.5,
132.4, 132.1, 130.8, 126.8, 120.5, 115.0, 21.7.
S
S
Z1
O
O
9a–d
Product Z1
Z2
R
Yield Mp
Anal. Calcd for C21H14N6O2: C, 65.96; H, 3.69; N, 21.98. Found: C,
65.64; H, 3.66; N, 21.96.
(%)
( °C)
(5-Nitrobenzene-1,3-diyl)bis(1H-benzotriazol-1-ylmethanone)
(5c)
9a
9b
Et
Et
64
oil
oil
White microcrystals; yield: 0.170 g (68%); mp 200–202 °C.
1H NMR (300 MHz, CDCl3): δ = 9.41–9.40 (m, 1 H), 9.38 (d, J =
1.5 Hz, 2 H), 8.44 (d, J = 8.1 Hz, 2 H), 8.22 (d, J = 8.4 Hz, 2 H),
7.80 (t, J = 7.7 Hz, 2 H), 7.63 (t, J = 7.7 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 163.7, 146.1, 139.8, 133.9, 132.1,
132.0, 131.5, 130.6, 127.4, 120.9, 115.0.
70
72
Anal. Calcd for C20H11N7O4: C, 58.11; H, 2.68; N, 23.72. Found: C,
58.08; H, 2.36; N, 23.60.
9c
Me
Me
oil
oil
Alkyl S-Aroyl-L-cysteinates 7a–j; General Procedure
A solution of the cysteine ester hydrochloride 6a or 6b (0.843
mmol) in H2O (0.5 mL) was added to a soln of the N-acylbenzotri-
azole derivative 3a–e (0.843 mmol) in THF (10 mL), and the het-
erogeneous mixture was stirred at r.t. for 3 h. The solid was then
collected by filtration, washed with Et2O (3 × 30 mL), and dried in
a desiccator under vacuum.
9d
67
NO2
Methyl S-(4-Methylbenzoyl)-L-cysteinate Hydrochloride (7b)
Colorless oil; yield: 0.128 g (52%).
8c, and 8e underwent S- to N-acyl migration in the pres-
ence of triethylamine,2 which reacted further with 5a and
5f in situ to give the desired macrocyclic peptoids 9a–d.
Examples of similar S- to N-acyl rearrangements have
been previously observed.24
1H NMR (300 MHz, CD3OD): δ = 7.82 (d, J = 8.4 Hz, 2 H), 7.28 (d,
J = 8.1 Hz, 2 H), 4.37 (t, J = 5.4 Hz, 1 H), 3.80 (s, 3 H), 3.68 (dd,
J = 14.7, 4.8 Hz, 1 H), 3.52 (dd, J = 15.0, 6.3 Hz, 1 H), 2.36 (s, 3 H).
13C NMR (75 MHz, CD3OD): δ = 191.3, 169.3, 147.0, 134.9, 130.8,
128.8, 54.3, 54.2, 29.4, 21.8.
HRMS: m/z [M – HCl + Na]+ calcd for C12H15NNaO3S: 276.0665;
found: 276.0665.
In summary, we have developed a method for selectively
synthesizing S-acylcysteine esters in good yields by using
N-acylbenzotriazoles and N-acylbisbenzotriazoles. The
bis-S-acylcysteine esters were used as precursors for the
synthesis of macrocyclic peptoids.
Methyl S-(4-Methoxybenzoyl)-L-cysteinate Hydrochloride (7c)
White microcrystals; yield: 0.133 g (51%); mp 177–179 °C.
1H NMR (300 MHz, CD3OD): δ = 7.87 (d, J = 9.0 Hz, 2 H), 6.94 (d,
J = 9.0 Hz, 2 H), 4.34 (t, J = 5.4 Hz, 1 H), 3.78 (s, 3 H), 3.76 (s, 3
H), 3.63 (dd, J = 14.9, 4.7 Hz, 1 H), 3.48 (dd, J = 14.9, 6.5 Hz, 1 H).
13C NMR (75 MHz, CD3OD): δ = 190.0, 169.3, 166.3, 131.0, 130.1,
115.3, 56.4, 54.3, 54.2, 29.4.
HRMS: m/z [M – HCl + Na]+ calcd for C12H15NNaO4S: 292.0614;
found: 292.0623.
Commercial reagents were purchased from Sigma-Aldrich and
were used without purification. Solvents were purified by distilla-
tion. Melting points were determined on a capillary melting-point
apparatus equipped with a digital thermometer. NMR spectra were
recorded in CDCl3, or CD3OD on Mercury or Gemini NMR spec-
trometers operating at 300 MHz for 1H NMR (with TMS as an in-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 767–772

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M. A. Ibrahim et al.
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Methyl S-(4-Nitrobenzoyl)-L-cysteinate Hydrochloride (7d)
White microcrystals; yield: 0.165 g (61%); mp 182–184 °C.
HRMS: m/z [M – HCl + Na]+ calcd for C16H17NNaO3S: 326.0821;
found: 326.0812.
1H NMR (300 MHz, CD3OD): δ = 8.39 (d, J = 9.0 Hz, 2 H), 8.22 (d,
J = 9.0 Hz, 2 H), 4.52 (t, J = 5.6 Hz, 1 H), 3.89 (s, 3 H), 3.81 (dd,
J = 13.3, 8.6 Hz, 1 H), 3.69 (dd, J = 15.0, 6.3 Hz, 1 H).
13C NMR (75 MHz, CD3OD): δ = 190.9, 169.1, 152.5, 141.9, 129.9,
125.3, 54.3, 54.1, 29.9.
HRMS: m/z [M – HCl + H]+ calcd for C11H13N2O5S: 285.0545;
found: 285.0545.
Dialkyl S,S′-Arylene- and S,S′-Alkylenebis-L-cysteinates 8a–h;
General Procedure
A soln of cysteine ester hydrochloride 6a or 6b (0.542 mmol) in
H2O (0.5 mL) was added to a soln of a bisbenzotriazole derivative
5a–f (0.271 mmol) in THF (10 mL), and the heterogeneous mixture
was at r.t. for 3 h. The solid collected by filtration, washed with
Et2O (3 × 30 mL), and dried in a desiccator under vacuum.
Dimethyl (2S,2′S)-3,3′-[Benzene-1,2-diylbis(carbonylsulfanedi-
yl)]bis(2-aminopropanoate) Dihydrochloride (8a)
Methyl S-2-Naphthoyl-L-cysteinate Hydrochloride (7e)
White microcrystals; yield: 0.180 g (66%); mp 176–178 °C.
White microcrystals; yield: 0.180 g (70%); mp 163–164 °C.
1H NMR (300 MHz, CD3OD): δ = 8.46 (d, J = 8.1 Hz, 1 H), 8.14 (d,
J = 7.2 Hz, 1 H), 8.08 (d, J = 8.1 Hz, 1 H), 7.90 (d, J = 8.1 Hz, 1 H),
7.60–7.49 (m, 3 H), 4.51 (t, J = 5.6 Hz, 1 H), 3.84 (s, 3 H), 3.80–
3.64 (m, 2 H).
13C NMR (75 MHz, CD3OD): δ = 193.5, 169.3, 135.3, 135.1, 130.3,
129.9, 129.7, 129.4, 128.0, 126.2, 126.0, 125.8, 54.0, 31.0, 30.5.
1H NMR (300 MHz, CD3OD): δ = 8.43 (s, 1 H), 8.21 (d, J = 7.8 Hz,
2 H), 7.68 (t, J = 8.0 Hz, 1 H), 4.44 (t, J = 5.4 Hz, 2 H), 3.80 (s, 6
H), 3.75 (dd, J = 14.9, 4.7 Hz, 2 H), 3.61 (dd, J = 14.9, 6.2 Hz, 2 H).
13C NMR (75 MHz, CD3OD): δ = 191.1, 169.2, 138.1, 133.9, 131.3,
127.0, 54.3, 54.1, 29.7.
Anal. Calcd for C16H22Cl2N2O6S2·H2O: C, 39.11; H, 4.92; N, 5.70.
Found: C, 39.33; H, 4.75; N, 5.13.
HRMS: m/z [M – HCl + H]+ calcd for C15H16NO3S: 290.0845;
found: 290.0846.
Dimethyl (2S,2′S)-3,3′-[5-Methylbenzene-1,2-diylbis(carbonyl-
sulfanediyl)]bis(2-aminopropanoate) Dihydrochloride (8b)
White microcrystals; yield: 0.161 g (61%); mp 165–167 °C.
1H NMR (300 MHz, CD3OD): δ = 8.24 (br s, 1 H), 8.02 (br s, 2 H),
4.43 (t, J = 5.4 Hz, 2 H), 3.81 (s, 6 H), 3.74 (dd, J = 15.0, 4.8 Hz, 2
H), 3.60 (dd, J = 15.0, 6.0 Hz, 2 H), 2.44 (s, 3 H).
Ethyl S-(4-Methylbenzoyl)-L-cysteinate Hydrochloride (7g)
White microcrystals; yield: 0.139 g (54%); mp 110–112 °C.
1H NMR (300 MHz, CD3OD): δ = 7.90 (d, J = 8.7 Hz, 2 H), 7.36 (d,
J = 7.8 Hz, 2 H), 4.45 (t, J = 5.4 Hz, 1 H), 4.32 (q, J = 7.1 Hz, 2 H),
3.76 (dd, J = 14.9, 4.7 Hz, 1 H), 3.63 (dd, J = 15.0, 6.0 Hz, 1 H),
2.43 (s, 3 H), 1.33 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CD3OD): δ = 191.2, 168.8, 146.9, 135.0, 130.8,
128.8, 64.3, 54.3, 29.4, 21.8, 14.5.
13C NMR (75 MHz, CD3OD): δ = 199.6, 177.7, 150.5, 146.6, 142.7,
132.9, 62.8, 62.6, 38.2, 29.8.
Anal. Calcd for C17H24Cl2N2O6S2: C, 41.89; H, 4.96; N, 5.75.
Found: C, 42.05; H, 4.84; N, 5.81.
Anal. Calcd for C13H18ClNO3S·H2O: C, 48.52; H, 6.26; N, 4.35.
Found: C, 49.10; H, 6.01; N, 4.87.
Dimethyl (2S,2′S)-3,3′-[5-Nitrobenzene-1,2-diylbis(carbonyl-
sulfanediyl)]bis(2-aminopropanoate) Dihydrochloride (8c)
White microcrystals; yield: 0.175 g (66%); mp 219–220 °C.
1H NMR (300 MHz, CD3OD): δ = 8.86 (d, J = 1.5 Hz, 2 H), 8.69 (t,
J = 1.5 Hz, 1 H), 4.47 (t, J = 5.4 Hz, 2 H), 3.84–3.76 (m, 8 H), 3.65
(dd, J = 15.0, 6.3 Hz, 2 H).
Ethyl S-(4-Methoxybenzoyl)-L-cysteinate Hydrochloride (7h)
White microcrystals; yield: 0.155 g (57%); mp 175–177 °C.
1H NMR (300 MHz, CD3OD): δ = 7.97 (d, J = 9.0 Hz, 2 H), 7.05 (d,
J = 9.0 Hz, 2 H), 4.43 (t, J = 6.3 Hz, 1 H), 4.31 (q, J = 6.8 Hz, 2 H),
3.89 (s, 3 H), 3.73 (dd, J = 14.9, 5.0 Hz, 1 H), 3.59 (dd, J = 14.9, 6.2
Hz, 1 H), 1.35 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CD3OD): δ = 189.8, 168.7, 166.1, 130.9, 130.0,
115.3, 64.1, 55.9, 29.4, 25.3, 14.6.
13C NMR (75 MHz, CD3OD): δ = 189.7, 169.0, 150.3, 139.4, 131.9,
127.5, 54.4, 54.0, 30.1.
Anal. Calcd for C16H21Cl2N3O8S2·HCl: C, 34.64; H, 4.00; N, 7.57.
Found: C, 35.07; H, 3.51; N, 7.46.
HRMS: m/z [M – HCl + Na]+ calcd for C13H17NNaO4S: 306.0770;
found: 306.0763.
Methyl (4S,14S)-4,14-Diamino-3,7,11-trioxo-2,9-dioxa-6,12-di-
thiapentadecan-15-oate Dihydrochloride (8d)
Colorless oil; yield: 0.156 g (65%).
1H NMR (300 MHz, CD3OD): δ = 4.40 (d, J = 1.5 Hz, 4 H), 4.34 (t,
J = 5.6 Hz, 2 H), 3.79 (s, 6 H), 3.54 (dd, J = 14.9, 4.7 Hz, 2 H), 3.39
(dd, J = 14.7, 6.3 Hz, 2 H).
13C NMR (75 MHz, CD3OD): δ = 199.6, 169.2, 77.4, 54.2, 54.1,
28.4.
HRMS: m/z [M – 2HCl + Na]+ calcd for C12H20N2NaO7S2:
391.0604; found: 391.0610.
Ethyl S-(4-Nitrobenzoyl)-L-cysteinate Hydrochloride(7i)
Colorless oil; yield: 0.192 g (68%).
1H NMR (300 MHz, CD3OD): δ = 8.39 (d, J = 9.0 Hz, 2 H), 8.22 (d,
J = 9.0 Hz, 2 H), 4.51 (t, J = 5.6 Hz, 1 H), 4.34 (q, J = 7.2 Hz, 2 H),
3.84 (dd, J = 15.0, 4.8 Hz, 1 H), 3.70 (dd, J = 15.0, 6.2 Hz, 1 H),
1.35 (t, J = 7.1 Hz, 3 H).
13C NMR (75 MHz, CD3OD): δ = 190.8, 168.6, 152.5, 141.9, 129.9,
125.3, 64.4, 54.1, 29.9, 14.5.
HRMS: m/z [M – HCl + Na]+ calcd for C12H14N2NaO5S: 321.0516;
found: 321.0526.
Diethyl (2S,2′S)-3,3′-[Benzene-1,2-diylbis(carbonylsulfanedi-
yl)]bis(2-aminopropanoate) Dihydrochloride (8e)
White microcrystals; yield: 0.190 g (70%); mp 203–204 °C.
Ethyl S-2-Naphthoyl-L-cysteinate Hydrochloride (7j)
Colorless oil; yield: 0.210 g (73%).
1H NMR (300 MHz, CD3OD): δ = 8.51 (d, J = 8.1 Hz, 1 H), 8.18 (d,
J = 7.2 Hz, 1 H), 8.12 (d, J = 8.1 Hz, 1 H), 7.94 (d, J = 8.4 Hz, 1 H),
7.66–7.53 (m, 3 H), 4.53 (t, J = 5.6 Hz, 1 H), 4.33 (q, J = 7.0 Hz, 2
H), 3.82 (dd, J = 15.0, 5.1 Hz, 1 H), 3.72 (dd, J = 14.9, 5.9 Hz, 1 H),
1.33 (t, J = 7.2 Hz, 3 H).
1H NMR (300 MHz, CD3OD): δ = 8.42–8.39 (m, 1 H), 8.21–8.16
(m, 2 H), 7.65 (t, J = 7.8 Hz, 1 H), 4.40 (t, J = 5.4 Hz, 2 H), 4.23 (q,
J = 7.1 Hz, 4 H), 3.72 (dd, J = 14.9, 4.7 Hz, 2 H), 3.60 (dd, J = 15.0,
6.0 Hz, 2 H), 1.23 (t, J = 7.1 Hz, 6 H).
13C NMR (75 MHz, CD3OD): δ = 190.9, 168.6, 138.1, 133.8, 131.3,
126.9, 64.3, 54.1, 29.7, 14.5.
13C NMR (75 MHz, CD3OD): δ = 193.4, 168.8, 135.3, 135.1, 130.3,
129.9, 129.7, 129.4, 128.0, 126.0, 125.8, 64.3, 54.0, 30.4, 14.5.
Synthesis 2013, 45, 767–772
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PAPER
Macrocyclic Peptoids
771
Anal. Calcd for C18H26Cl2N2O6S2·HCl: C, 40.19; H, 5.06; N, 5.21.
Found: C, 39.92; H, 4.90; N, 6.03.
1H NMR (300 MHz, CDCl3): δ = 8.00 (dd, J = 7.8 Hz, 1.5 Hz, 2 H),
7.74 (br s, 1 H), 7.50 (t, J = 7.7 Hz, 1 H), 7.03 (d, J = 7.2 Hz, 2 H),
4.96–4.89 (m, 2 H), 4.26–4.18 (m, 4 H), 3.54 (dd, J = 14.6, 4.1 Hz,
2 H), 3.43 (dd, J = 14.4, 6.3 Hz, 2 H), 2.74 (d, J = 15.0 Hz, 2 H),
2.68 (d, J = 15.3 Hz, 2 H), 1.28 (t, J = 7.1 Hz, 6 H), 0.99 (s, 6 H).
13C NMR (75 MHz, CDCl3): δ = 198.7, 170.2, 167.1, 134.5, 131.7,
129.5, 123.5, 62.3, 53.2, 52.2, 35.0, 30.4, 28.9, 14.3.
Diethyl (2S,2′S)-3,3′-[5-Methylbenzene-1,2-diylbis(carbonyl-
sulfanediyl)]bis(2-aminopropanoate) Dihydrochloride (8f)
White microcrystals; yield: 0.165 g (59%); mp 190–192 °C.
1H NMR (300 MHz, CD3OD): δ = 8.20 (s, 1 H), 7.98 (s, 2 H), 4.40
(t, J = 5.7 Hz, 2 H), 4.22 (q, J = 7.1 Hz, 4 H), 3.72 (dd, J = 15.0, 4.8
Hz, 2 H), 3.60 (dd, J = 14.9, 6.2 Hz, 2 H), 2.41 (s, 3 H), 1.23 (t, J =
7.1 Hz, 6 H).
HRMS: m/z [M + H]+ calcd for C25H33N2O8S2: 553.1673; found:
553.1651.
13C NMR (75 MHz, CD3OD): δ = 190.9, 168.6, 142.0, 138.0, 134.2,
124.4, 64.3, 54.1, 29.7, 21.4, 14.5.
Dimethyl (5S,15S)-10-Methyl-2,7,13,18-tetraoxo-3,17-dithia-
6,14-diazatricyclo[17.3.1.18,12]tetracosa-1(23),8(24),9,11,19,21-
hexaene-5,15-dicarboxylate (9c)
Anal. Calcd for C19H28Cl2N2O6S2: C, 44.27; H, 5.47; N, 5.43.
Found: C, 44.67; H, 5.44; N, 5.52.
Colorless oil; yield: 0.156 g (72%).
1H NMR (300 MHz, CDCl3): δ = 8.36 (t, J = 1.8 Hz, 1 H), 7.95 (dd,
J = 8.4 Hz, 1.8 Hz, 2 H), 7.71–7.68 (m, 3 H), 7.49 (t, J = 7.7 Hz, 1
H), 6.85 (d, J = 8.7 Hz, 2 H), 5.28–5.20 (m, 2 H), 3.87–3.83 (m, 2
H), 3.81 (s, 6 H), 3.41 (dd, J = 14.3 Hz, 8.6 Hz, 2 H), 2.38 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 191.7, 170.8, 166.9, 139.6, 137.9,
134.5, 131.7, 131.3, 129.7, 128.6, 123.5, 53.3, 51.9, 31.7, 21.4.
Diethyl (2S,2′S)-3,3′-[5-Nitrobenzene-1,2-diylbis(carbonylsul-
fanediyl)]bis(2-aminopropanoate) Dihydrochloride (8g)
White microcrystals; yield: 0.237 g (92%); mp 218–220 °C.
1H NMR (300 MHz, CD3OD): δ = 8.90 (br s, 2 H), 8.73 (br s, 1 H),
4.48 (t, J = 5.4 Hz, 2 H), 4.28 (q, J = 7.2 Hz, 4 H), 3.83 (dd, J = 14.9,
4.7 Hz, 2 H), 3.69 (dd, J = 15.0, 6.3 Hz, 2 H), 1.28 (t, J = 7.2 Hz, 6
H).
HRMS: m/z [M + H]+ calcd for C25H25N2O8S2: 545.1047; found:
545.1033.
13C NMR (75 MHz, CD3OD): δ = 189.7, 168.6, 150.3, 139.5, 131.9,
127.5, 64.5, 54.0, 30.1, 14.5.
Dimethyl (5S,15S)-10-Nitro-2,7,13,18-tetraoxo-3,17-dithia-
6,14-diazatricyclo[17.3.1.18,12]tetracosa-1(23),8(24),9,11,19,21-
hexaene-5,15-dicarboxylate (9d)
Anal. Calcd for C18H25Cl2N3O8S2·HCl: C, 37.09; H, 4.50; N, 7.21.
Found: C, 37.07; H, 4.05; N, 7.47.
Colorless oil; yield: 0.155 g (67%).
Ethyl (5S,15S)-5,15-Diamino-4,8,12-trioxo-3,10-dioxa-7,13-di-
thiahexadecan-16-oate Dihydrochloride (8h)
Colorless oil; yield: 0.185 g (72%).
1H NMR (300 MHz, CD3OD): δ = 4.41 (d, J = 2.1 Hz, 4 H), 4.34 (t,
J = 5.4 Hz, 2 H), 4.26 (q, J = 7.1 Hz, 4 H), 3.56 (dd, J = 15.0, 4.5
Hz, 2 H), 3.42 (dd, J = 14.9, 6.2 Hz, 2 H), 1.28 (t, J = 7.2 Hz, 6 H).
13C NMR (75 MHz, CD3OD): δ = 199.5, 168.7, 77.4, 64.3, 54.8,
28.4, 14.5.
HRMS: m/z [M – 2HCl + Na]+ calcd for C14H24N2NaO7S2:
1H NMR (300 MHz, CDCl3): δ = 8.77 (d, J = 1.5 Hz, 2 H), 8.35 (t,
J = 1.7 Hz, 1 H), 8.27 (t, J = 1.4 Hz, 1 H), 7.99 (dd, J = 7.7, 1.7 Hz,
2 H), 7.52 (t, J = 7.8 Hz, 1 H), 7.30 (d, J = 8.7 Hz, 2 H), 5.34–5.28
(m, 2 H), 3.99–3.90 (m, 2 H), 3.86 (s, 6 H), 3.41 (dd, J = 14.3 Hz,
8.6 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 191.7, 170.4, 164.7, 148.8, 137.7,
136.3, 131.9, 131.8, 129.9, 128.5, 125.3, 53.5, 52.3, 31.6.
HRMS: m/z [M + Na]+ calcd for C24H21N3NaO10S2: 598.0561;
found: 598.0572.
419.0917; found: 419.0919.
Acknowledgement
Macrocycles 9a–d; General Procedure
A mixture of the N-acylbenzotriazole derivative 5a or 5g (0.399
mmol), S-acylated cysteine ester dihydrochloride 8b, 8c, or 8e
(0.399 mmol), and Et3N (1.596 mmol) in DMF (5 mL) was irradiat-
ed in a microwave oven at 50 °C and 20 W for 20 min. The soln was
poured onto crushed ice and the mixture was extracted with EtOAc
(3 × 50 mL). The organic layers were combined, washed with sat.
aq Na2CO3, dried (Na2SO4), filtered, and concentrated. The residue
was purified by column chromatography.
We thank Dr. C. D. Hall for useful suggestions and for checking the
English. We also thank Dr. Kiran Bajaj for her help in the early sta-
ges of this project, and we are grateful to the University of Florida,
The Kenan Foundation, and the King Abdulaziz University, Jeddah,
Saudi Arabia for providing financial support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
Diethyl (5S,15S)-2,7,13,18-Tetraoxo-3,17-dithia-6,14-diazatri-
cyclo[17.3.1.18,12]tetracosa-1(23),8(24),9,11,19,21-hexaene-5,15-
dicarboxylate (9a)
Colorless oil; yield: 0.143 g (64%).
References
1H NMR (300 MHz, CDCl3): δ = 8.40 (t, J = 1.7 Hz, 1 H), 8.02–7.90
(m, 5 H), 7.57–7.47 (m, 2 H), 6.84 (d, J = 8.7 Hz, 2 H), 5.29–5.21
(m, 2 H), 4.29 (q, J = 7.2 Hz, 4 H), 3.90 (dd, J = 14.1, 4.2 Hz, 2 H),
3.40 (dd, J = 14.1, 8.7 Hz, 2 H), 1.35 (t, J = 7.2 Hz, 6 H).
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© Georg Thieme Verlag Stuttgart · New York
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Synthesis 2013, 45, 767–772
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