Simple and effective preparation of amino sulfonylureas from amino acids: application to the synthesis of amino sulfonylurea-containing peptidomimetics

Article abstract of DOI:10.1016/j.tetlet.2008.04.047

Several amino sulfonylureas have been synthesized, starting from amino acids. The synthetic procedure is simple affording high yields of products under mild conditions. Furthermore, it is shown that these compounds can be incorporated into a peptide sequence.

Full text of DOI:10.1016/j.tetlet.2008.04.047

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3943–3945
Simple and effective preparation of amino sulfonylureas
from amino acids: application to the synthesis of amino
sulfonylurea-containing peptidomimetics
ˇ
Roman Sink, Anamarija Zega *
Faculty of Pharmacy, University of Ljubljana, Asˇkercˇeva 7, 1000 Ljubljana, Slovenia
Received 17 October 2007; revised 31 March 2008; accepted 8 April 2008
Available online 11 April 2008
Dedicated to Professor Slavko Pecˇar on the occasion of his 60th birthday
Abstract
Several amino sulfonylureas have been synthesized, starting from amino acids. The synthetic procedure is simple affording high yields
of products under mild conditions. Furthermore, it is shown that these compounds can be incorporated into a peptide sequence.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Amino sulfonylurea; Peptidomimetic; Amino acid
Peptide backbone modification has developed into a
powerful tool to introduce desired structural motifs and
to enhance biological properties in peptidomimetics. Bio-
isosteric replacement of a peptide bond with various surro-
gates is a widespread strategy for improving the biological
activity, physicochemical properties, and the stability of
peptides.1–3 In the past, a wide variety of modified peptides
have been developed (e.g., azapeptides, depsipeptides, retro
and retro-inverso peptides, phosphapeptides, ureidopep-
tides, and peptidosulfonamides).4,5 By combining these
classes of peptidomimetics, the diversity of compounds
can be increased enormously to yield ‘hybrid’ peptidomi-
metics, which might be very useful for the development
of lead compounds from peptides. The urea linkage is
one of the most common types of peptide bond surrogate
to be introduced into a peptide sequence.6 On the other
hand, peptidosulfonamides have been recognized as inter-
esting building blocks for preparing peptidomimetics, espe-
cially transition state enzyme inhibitors, since sulfonamides
possess a tetrahedral geometry similar to the tetrahedral
intermediate formed in the process of amide bond cleavage
and formation.7
In this context and as a part of our research on enzyme
inhibitors, we have investigated the incorporation of amino
sulfonylurea, which can be considered as a hybrid of a sul-
fonamide and a urea peptidomimetic, into a peptide back-
bone (Fig. 1).
Nonpeptidic amino sulfonylureas had been recognized
previously as building blocks in hypoglycemic agents,
ACAT inhibitors, and herbicides.8 This scaffold possesses
an acidic proton on the nitrogen atom situated between
the carbonyl and sulfonyl groups that, in solution, can
form salts which can be alkylated, and thus contributes
the additional possibility for the introduction of diversity
into this linkage.9 In thisLetter, the synthesis of amino sulf-
R4
O
O
O
R2
O
R4
H
N
R1
H
N
R1
H
N
R3
H
N
H
N
N
H
N
H
N
H
N
S
O
R3
H
O
O
O O
*
Fig. 1. Peptide backbone and a ‘hybrid’ amino sulfonylurea-containing
peptide.
Corresponding author. Tel.: +386 1 476 9673; fax: +386 1 425 8031.
E-mail address: anamarija.zega@ffa.uni-lj.si (A. Zega).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.047

ˇ
R. Sink, A. Zega / Tetrahedron Letters 49 (2008) 3943–3945
3944
R
HOOC NH2
1a-1e
a
R
R
O
O O
S
H
R
MeOOC NH3Cl-
2a-2e
c
b
MeOOC NH2
MeOOC
N
H
N
Cl
4a-4e
c
3a-3e
d
R
O
R
O
R
O
O O
S
H
O O
S
H
O O
S
H
e
d
R2
R2
MeOOC
N
H
N
Cl
HOOC
N
H
N
N
H
MeOOC
N
H
N
N
H
6a-6q
3a-3e
5a-5q
Scheme 1. Reagents and conditions. (a) MeOH, SOCl2, 0 °C; (b) CH2Cl2, 0 °C, then washing with 0.5 M NaOH; (c) chlorosulfonyl isocyanate, CH2Cl2,
À15 °C, 1 h; (d) R2NH2, dioxane, triethylamine, 5 °C, then rt 6–12 h; (e) NaOH/dioxane/water, 0 °C, 3 h.
Table 1
onylurea-based peptidomimetics, starting from various
amino acids, using mild conditions and affording high
R and R2 in synthesized compounds 6a–q and the overall yields
yields, is reported (Scheme 1).
R
O
O
O
S
R2
Amino acids were used as starting compounds. First,
conversion of the amino acid carboxyl group to a methyl
ester using methanol and thionyl chloride (95–98% yields)
was performed. For the next step, the reaction between
the amino group and the isocyanate group of chlorosulfon-
yl isocyanate, different synthetic approaches have been
described.8–13 However, in our hands, for the reaction
between the amino group of a protected amino acid and
the isocyanate group of chlorosulfonyl isocyanate, these
procedures gave yields that were too low, and not repro-
ducible enough to be used in the early steps of complex syn-
theses of enzyme inhibitors.
MeOOC
N
H
N
N
H
H
6a-6q
R
R2
Overall yield (%)
6a
6b
6c
6d
6e
6f
H
H
H
H
Benzyl
Phenyl
Cyclopentyl
Benzothiazol-2-yl
Thiazol-2-yl
Benzyl
Phenyl
Cyclopentyl
Benzyl
Phenyl
Cyclopentyl
Benzyl
Phenyl
Cyclopentyl
Benzyl
Phenyl
Cyclopentyl
80
82
79
63
57
83
77
80
79
76
86
73
72
81
83
76
76
H
CH3
CH3
CH3
6g
6h
6i
CH2CH2COOH
CH2CH2COOH
CH2CH2COOH
CH2Ph
6j
We therefore sought an improved synthetic route that
would be generally applicable to the preparation of amino
sulfonylurea-based peptidomimetics.
6k
6l
6m
6n
6o
6p
6q
CH2Ph
CH2Ph
CH(CH3)2
CH(CH3)2
CH(CH3)2
The reaction of the amino group of the protected amino
acid with chlorosulfonyl isocyanate was performed with
and without the conversion of the hydrochloride salt of
the amine to the free primary amino group, however, there
was no significant difference in yields. The reaction was
optimized with respect to solvent, reaction time and tem-
perature. Given the reaction type and solubility problems,
it was not surprising that only a few solvents were found to
be appropriate, however, the use of dichloromethane at
low temperature led to high yields of the desired products
(Table 1).14
Isolation of the chlorosulfonylurea derivatives turned
out to be very difficult because these compounds are very
O
O O
S
ClSO2NCO
CH2Cl2, rt., 4 h
MeOOC NH3Cl-
MeOOC
N
H
N
N
H
COOMe
H
If the temperature was raised, or the reaction time was
prolonged, the predominant product 3r shown in Scheme
2 was obtained and characterized.15
3r
2a
Scheme 2. An undesired product of the synthesis.

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R. Sink, A. Zega / Tetrahedron Letters 49 (2008) 3943–3945
3945
10. El-Sherbeny, M. A.; Youssef, K. M.; Mahran, M. A. Sci. Pharm.
2003, 71, 195–209; Jons, T.; Wittscheiber, D.; Beyer, A.; Meier, C.;
Brune, A.; Thomzig, A.; Ahnert-Hilger, G.; Veh, R. W. J. Cell. Sci.
2006, 119, 3087–3097.
Ph
O
O
O
S
HOOC
N
H
COOH
N
N
H
H
11. Picard, J. A.; O’Brien, P. M.; Sliskovic, D. R.; Anderson, M. K.;
Bousley, R. F.; Hamelehle, K. L.; Krause, B. R.; Stanfield, R. L. J.
Med. Chem. 1996, 39, 1243–1252.
Fig. 2. Amino sulfonylurea-linked pseudodipeptide.
unstable in the presence of moisture. Therefore it was
decided in the next step, the reaction between the chloro-
sulfonylurea and an amine or amino acid in the presence
of triethylamine,16 to use the crude product, after vacuum
filtration.
Finally, saponification of the methyl ester was carried
out to obtain the free carboxylic group.17
The products were fully characterized by IR, MS, and
1H NMR spectroscopy.15–17
In order to test the general applicability of this almost
one-pot procedure, a series of compounds 6a–q were syn-
thesized from various amino acids 1a–e. Products 6a–q
and the total yields of the synthesis are listed in Table 1.
The procedure can be used with different amino acid esters
and aliphatic or aromatic amines, since the yields were sat-
isfactory regardless of the type of amino acid or amine
used.
Finally, the applicability of the reported protocol for the
insertion of an amino sulfonylurea linkage into a peptide
backbone was demonstrated. The amino sulfonylurea-
linked pseudodipeptide presented in Figure 2 was synthe-
sized as shown in Scheme 1 in 73% yield.
In conclusion, a convenient route for the synthesis of
interesting novel peptidomimetic building blocks is pre-
sented for the preparation of amino sulfonylurea-based
peptidomimetics. The applicability was illustrated by incor-
porating an amino sulfonylurea moiety into a small
peptide.
12. McManus, J. M.; McLamore, W. M.; Laubach, G. D. GB Patent
990860, 1965; Chem. Abstr. 1965, 43840.
13. Riebel, H. J.; Gesing, E. R. F.;. Muller, K. H.; Findeisen, K.; Santel,
H. J.; Lurssen, K.; Schmidt, R. R. Eur. Pat. Appl. PCT/EP1993/
001227, 1993; Chem. Abstr. 1994, 164238.
14. Typical procedure for compound 3e: Methyl 2-amino-3-methyl
butanoate (1.5 mmol; 200 mg) or methyl 2-amino-3-methyl butanoate
hydrochloride (1.5 mmol; 250 mg) was dissolved or suspended in dry
dichloromethane (25 ml), cooled to À15 °C, then chlorosulfonyl
isocyanate (1.55 mmol; 0.13 ml) was added dropwise. The reaction
mixture was stirred at À15 °C for 1 h, then 40 ml of hexane was added
and warmed to room temperature. The crude product, methyl 2-(3-
(chlorosulfonyl)ureido)-3-methylbutanoate (390 mg; 96% yield) (3e)
was isolated by vacuum filtration, and then used immediately in the
next step.
15. Characterization of compound 3r: Methyl 2-{[({[(2-methoxy-2-oxo-
ethyl)amino]carbonyl}amino)sulfonyl]amino}acetate: white solid;
mp: 114–115 °C; IR (KBr, cmÀ1): 3389, 3294, 2961, 2917, 2364,
1752, 1676, 1534, 1485, 1436, 1373, 1345, 1246, 1216, 1171, 1121,
1062, 985, 898, 603; 1H NMR (DMSO-d6, 300 MHz): d (ppm) = 3.64
(6H), 3.80–3.85 (m, 4H), 6.60 (t, 1H, J = 5.7 Hz), 7.97 (t, 1H, J = 6
Hz), 10.26 (s, 1H); MS (ESI) m/z: 316 (MH+); HRMS calcd for
C7H14N3O7S m/z: (MH+) 284.0552, found 284.0554.
16. Typical procedure and selected data for compound 5l: Benzylamine
(1 mmol; 0.1 ml) was dissolved in dry dioxane (15 ml), cooled to 5 °C,
then triethylamine was added (3 mmol; 0.4 ml) followed by slow
dropwise addition of methyl 2-(3-(chlorosulfonyl)ureido)-3-phenyl-
propanoate (1 mmol; 320 mg). The mixture was allowed to warm to
room temperature and stirred for 8 h. On completion of the reaction,
the reaction mixture was poured into 1 M hydrochloric acid (20 ml),
cooled to 0 °C and extracted with ethyl acetate (3 Â 10 ml), then dried
(Na2SO4) and concentrated in vacuo to afford methyl 2-(3-(N-
benzylsulfamoyl)ureido)-3-phenylpropanoate as
a solid product
(347 mg; 89% yield). Mp: 85–87 °C; IR (KBr, cmÀ1): 3343, 3064,
2887, 1739, 1663, 1557, 1454, 1334, 1217, 1047, 915, 739, 697; 1H
NMR (DMSO-d6, 300 MHz): d (ppm) = 2.97–3.04 (m, 2H), 3.65 (s,
3H), 4.04 (m, 2H), 4.44–4.50 (m, 1H), 6.52 (d, 1H, J = 7.2 Hz), 7.18–
7.34 (m, 10H), 7.98 (t, 1H, J = 6.3 Hz), 10.01 (s, 1H); MS (ESI) m/z:
392 (MH+); HRMS calcd for C18H22N3O5S m/z: (MH+) 392.1280,
found 392.1276.
Acknowledgments
This work was supported financially by the European
Union FP6 Integrated Project EUR INTAFAR (Project
No. FP6CT-2004-512138) and Ministry of Education,
Science and Sport of the Republic of Slovenia.
17. A typical procedure and selected data for compound 6f: Methyl 2-(3-
(N-benzylsulfamoyl)ureido)propanoate (5f) (0.5 mmol; 157 mg) was
dissolved in dioxane/water (5 ml), cooled to 0 °C, then 1 M NaOH
(2 ml) was added and the reaction mixture stirred for 3 h. On
completion of the reaction, the mixture was allowed to warm to room
temperature and dioxane was removed under reduced pressure. The
solution was washed with ethyl acetate (3 Â 10 ml), then acidified to
pH 2 with 2 M HCl and extracted with ethyl acetate (3 Â 10 ml). The
combined organic layers were dried (Na2SO4) and concentrated in
vacuo to afford 2-(3-(N-benzylsulfamoyl)ureido)propanoic acid as a
solid product (143 mg; 95% yield). Mp: 103–106 °C; IR (KBr, cmÀ1):
3368, 3105, 2922, 1721, 1657, 1557, 1480, 1346, 1261, 1164, 1059, 906,
References and notes
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700; 1H NMR (DMSO-d6, 300 MHz):
d (ppm) = 1.27 (d, 3H,
J = 7.2 Hz), 4.11 (dd, 2H, J1 = 6.0 Hz, J2 = 3.9 Hz), 4.15–4.17 (m,
1H), 6.53 (d, 1H, J = 7.2 Hz), 7.31–7.33 (m, 5H), 8.02 (t, 1H,
J = 6.3 Hz), 9.91 (s, 1H), 12.8 (s, 1H); MS (ESI) m/z: 302 (MH+);
HRMS calcd for C11H16N3O5S m/z: (MH+) 302.0743, found
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