Synthesis of a new series of dithiocarbamate-linked peptidomimetics and their application in Ugi reactions

Article abstract of DOI:10.1039/c3ra44552f

Novel peptidomimetics containing dithiocarbamate groups were synthesized via the Ugi reaction. Also, dithiocarbamates of natural amino acids were prepared and were used successfully in Ugi reactions to prepare novel peptidomimetics bearing amino acid and dithiocarbamate groups in a single structure. In addition the prepared dithiocarbamates based on amino acids are converted to the corresponding amides.

Full text of DOI:10.1039/c3ra44552f

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Synthesis of a new series of dithiocarbamate-linked peptidomimetics and
their applications in Ugi reaction
HN
S
HN
O
N
O
N
O
O
N
S
S
N
O
H
NH
N
S
O
C
H
CH3
H
S
N
S
Bu
Azim Ziyaei Halimehjani,* Mohammad Amin Ranjbari and Hamed Pasha Zanussi

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ARTICLE TYPE
Synthesis of a new series of dithiocarbamate-linked peptidomimetics and
their application in Ugi reaction
Azim Ziyaei Halimehjani,* Mohammad Amin Ranjbari and Hamed Pasha Zanussi
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Novel peptidomimetics containing the dithiocarbamate groups were synthesized via the Ugi reaction.
Also, dithiocarbamates of natural amino acids were prepared and were used successfully in Ugi reaction
to prepare novel peptidomimetics bearing amino acid and dithiocarbamate groups in single structure. In
addition the prepared dithiocarbamates based on amino acids are converted to the corresponding amides.
fragmentation chain transfer (RAFT) polymerizations,15 and in
10 Peptidomimetics are biologically important class of artificial
small molecules. The term “peptidomimetics” include the
modification of amino acid side chains, the introduction of
constraints to fix the location of different parts of the molecule,1
the development of templates that induce or stabilize secondary
15 structures of short chains,2 the creation of scaffolds that direct
sideꢀchain elements to specific locations, and the modification of
the peptide backbone. Peptidomimetics are designed to
circumvent some of the problems associated with several natural
peptides like stability against proteolysis and poor
20 bioavailability.3 Certain other properties such as receptor
selectivity or potency can be substantially improved. Hence a
variety of peptide mimics are being developed to introduce drugꢀ
like character along with increased potency, target specificity and
longer duration of action. To this end, several classes of
25 peptidomimetics are tailored by replacing the native amide bond
with various other tethers and are biologically scrutinized.4
Peptidomimetics by inserting nonꢀnative linkages such as urea,5
thiourea,6 retroꢀamide,7 carbamate,8 nucleic bases9, steroids10and
heterocycles11 have been reported extensively.
molecular electronic devices.16 Moreover, due to their biological
45 activities as antihistaminic,17antibacterial,18and anticancer19agents
and their vital role in agriculture as pesticides and fungicides,20
development of convenient synthetic method for these
compounds is important. Also due to coordination ability through
sulfur atoms the dithiocarbamates have received much attention
50 as ligand in recent years.21Owing to their strong metalꢀbinding
capacity, they can also act as enzyme inhibitors, such as
indoleamine 2,3ꢀdioxygenase (IDO), which plays an important
role in tumor growth.22 Many proteins have cysteine and
methionine residues and hence dithiocarbamate derivatives of αꢀ
55 amino acids may be valid models for the study of the
coordination of proteins to metal ions.23 In addition,
dithiocarbamates have been developed as HIVꢀI NCp7
inhibitors.24 Furthermore, in recent years several natural and
unnatural amino acids containing dithiocarbamate side chains
60 were synthesized and used in the construction of novel
peptidomimetics.25
In continuation of our interest on the chemistry of
dithiocarbamates,26 herein we report a novel and efficient method
for the synthesis of new peptidomimetics containing
65 dithiocarbamate group via Ugi fourꢀcomponent (4CRs) reaction.
Initially, we focused our attempt on the synthesis of a starting
material containing the dithiocarbamate group suitable for Ugi
reaction. For this purpose, a series of dithiocarbamates containing
carboxylic acid were synthesized via oneꢀpot threeꢀcomponent
70 reaction of an amine, CS2 and chloroacetic acid or
chloropropionic acid as outline in Scheme 1.
30
Among the methods for the multicomponent synthesis of
peptides or amino acids, the Ugi reaction, is without any doubt
the most widely exploited.12 This powerful reaction involves a
oneꢀpot condensation of an amine, a carbonyl compound, a
carboxylic acid, and an isocyanide to provide a substituted
35 peptideꢀlike product. Various modifications of the classical Ugiꢀ
4CR have been introduced. Those involved the varying of one of
the components or the introduction of new functional groups
leading to the synthesis of new derivatives of αꢀamino acyl amide
derivatives with novel biological activities.
<<Insert Scheme 1>>
Then, Ugi fourꢀcomponent coupling reaction between
40
Dithiocarbamates are valuable compounds due to their use as
versatile synthetic intermediates,13 linkers in solid phase organic
synthesis,14 radical chain transfer agents in the reversible addition
an amine, an aldehyde,
a
carboxylic acid containing
75 dithiocarbamate group, and an isocyanide were used for
preparation of novel peptidiomimetics containing the
dithiocarbamate group. (Scheme 2) The reaction proceeded quite
This journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

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DOI: 10.1039/C3RA44552F
smoothly with good to excellent yields by employing methanol as
solvent at room temperature. The results are summarized in Table
Recently we have shown that dithiocarbamates are suitable
building blocks for synthesis of thioureas.28 For this purpose,
1. Carboxylic acids containing dithiocarbamate group 1a-g were 55 reaction of dithiocarbamates 5c-e with aromatic amines such as
used successfully in this reaction. Also different isocyanides such
as cyclohexyl isocyanide and βꢀnaphthylisocyanide were used
with high yields. Toluenesulphonylmethyl isocyanide was also
used without suitable results. In addition, aromatic amines and
aniline, 4ꢀchloroaniline, 3,4ꢀdichloroaniline, 4ꢀmethylaniline and
1ꢀnaphthylamine was carried out in solventꢀfree condition at 100
°C as outline in Scheme 5. Amides 7a-h were obtained with
excellent yields as the only product and no thiourea 8 was
5
aromatic aldehydes were used successfully in this process. 60 obtained. The results are summarized in Table 3. The proposed
Aliphatic amines and aldehydes gave low yield of products
10 compare to the aromatic ones.
mechanism for synthesis of the amide products is outlined in
Scheme 6. The amide bond formation was promoted by
dithiocarbamate group via formation of thiazolꢀ5(4H)ꢀone as
intermediate and subsequent addition of aniline to this
65 intermediate. This reaction is not possible with 5a-b.
<<Insert Scheme 2>>
<<Insert Table 1>>
<<Insert Scheme 5>>
<<Insert Scheme 6>>
Also bisdithiocarbamate containing carboxylic acid based on
piperazine 3 is synthesized and used in Ugi reaction to provide
15 polyfunctional 1,4ꢀdisubstituted piperazine 4 as a symmetrical
bivalent compound. (Scheme 3)
<<Insert Table 3>>
<<Insert Scheme 3>>
In conclusion, we have presented an efficient procedure for the
70 synthesis
of
novel
peptidomimetics
containing
the
dithiocarbamate groups via Ugi four components reaction. Also
we have shown that dithiocarbamates prepared with natural
amino acids can be simply used in Ugi reaction as acid surrogate
for synthesis of peptidomimetics bearing amino acids and
75 dithiocarbamate group in single structure. In addition the
prepared dithiocarbamate based on amino acids are converted to
the corresponding amides without using any catalyst and harsh
conditions. It is notable that dithiocarbamates are wellꢀknown
group for protection of the amino group of amino acids.29 So by
80 simple deprotection, the amino group can be furnished in the
structure of Ugi adducts for further constructions and
applications.
In continue, natural αꢀamino acids such as glycine, dlꢀalanine,
and Sꢀproline were used as amine surrogate for synthesis of
20 dithiocarbamates 5a-e as shown in Scheme 4. By using two
equimolar of sodium hydroxide as promoter, good to excellent
yields of product 5a-e were obtained. Primary alkyl halides such
as benzyl chloride and butyl bromide were used successfully in
this process. Only the dithiocarbamic acid ester was obtained and
25 no ester of carboxylic acid was observed. The results are
summarized in Scheme 4. To the best of our knowledge it is the
first report on the synthesis of dithiocarbamates from amino acids
without any protection. In the case of Sꢀproline no epimerization
was observed.
Acknowledgment
30
<<Insert Scheme 4>>
We are grateful to the Faculty of Chemistry of Kharazmi
85 University for supporting this work.
The prepared dithiocarbamic acid esters of amino acids 5a-e
have been successfully used in the Ugi reaction to produce new
peptidomimetics containing the natural amino acids and
dithiocarbamate group 6a-n.The results are summarized in Table
Notes and references
Faculty of Chemistry, Kharazmi University (former Tarbiat Moallem
University), 49 Mofateh St.,Tehran, Iran. Tel.: +98(21)88848949, Fax:
+98(21)88820992. Eꢀmail: ziyaei@khu.ac.ir
35 2. As shown in Table 2, electron–donating and –withdrawing
groups on the aldehyde component do not affect the reaction
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yield with R configuration on newly created stereogenic center
50 which was confirmed by NOE analyses. Structure of all products
was fully characterized using 1H and 13C NMR, CHN analyses.
90
† Electronic Supplementary Information (ESI) available: [Full
experimental details, characterization data, copy of 1H and 13C NMR
spectra for all compounds]. See DOI: 10.1039/b000000x/
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DOI: 10.1039/C3RA44552F
S
R
R
1. NaOH(2 eq), MeOH
OH
COOH
S
DMF
OH
Cl
R
CS2
n
NH
COOH
PhCH2Cl
CS2
N
S
N
S
n
N
2. HCl (2M)
O
r.t., 18h
H
R
O
1
Ph
5
n=1 or 2
yield (%)a
55
Amino acid
product
5a
amine
alkyl halide
Yield (%)a
n
product
Sꢀproline
benzyl chloride
butyl bromide
95
81
70
90
diethyamine
pyrrolidine
piperidine
1a
1
Sꢀproline
5b
1
2
1b
1c
benzyl chloride
benzyl chloride
70
68
dlꢀalanine
5c
Glycine
5d
1d
1e
1
2
60
60
Glycine
butyl bromide
5e
83
morpholine
azepane
a Isolated yield.
65
52
1
1
1f
1g
25
a isolated yield.
Scheme 4 Synthesis of novel peptidomimetics containing
dithiocarbamate group
Scheme1 Synthesis of dithiocarbamates
30
5
S
OH
S
N
N
NH2
10
H
H
OH
O
solventꢀfree
100 o
8
S
N
H
C
O
S
H
S
N
NH2
N
H
N
O
S
N
5d
H
N
S
O
HO
O
N
2
CH3OH
O
7
rt
S
S
CHO
Scheme 5 Amide bond formation promoted by dithiocarbamate
CN
35
group
Scheme 2 Synthesis of Ugi adduct containing the
dithiocarbamate group
15
40
O
S
O
S
OH
S
NHPh
S
S
H2NꢀPh
N
N
NH2
HN
CHO
ꢀH2O
H
S
NC
S
R
R
R
S
O
HN
O
N
S
O
N
O
DMSO/MeOH
50 o
N
S
N
S
HO
OH
S
N
S
N
O
NH
S
C
O
S
3
Scheme 6 Proposed mechanism for amide bond formation
4
NH2
CHO
NC
45
20
Scheme 3 Synthesis of bisUgi adduct based on piperazine
50
4
| Journal Name, [year], [vol], 00–00
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DOI: 10.1039/C3RA44552F
Table 3 Diversity in the synthesis of amides 7 with the reaction
Table 1 Diversity in the synthesis of Ugi adducts containing
dithiocarbamate groupa
of amino acid based dithiocarbamates with aromatic amines
S
S
NO2
H
N
H
N
O
S
N
S
N
N
H
H
H
O
O
O
O
N
O
H
N
Cl
N
N
N
7a(87%)
7b(85%)
N
NH
NH
O
S
O
S
O
N
S
Cl
S
O
S
S
S
S
H
N
H
N
S
S
Cl
N
O
N
S
N
S
N
H
O
H
O
CH3
2a (76%)
2b (85%)
2c (75%)
2d (69%)
7d(80%)
7c(90%)
O
O
O
S
CH3
S
CH3
H
H
N
N
N
N
H
O
H
O
N
N
O
NH
S
S
N
S
N
N
S
H
O
O
H
O
N
O
Cl
NH
O
S
S
S
7e(75%)
7f(78%)
S
S
S
N
N
S
N
H
N
N
S
N
H
2f (75%)
2g (77%)
2h (56%)
2e (70%)
O
7g(70%)
a Isolated yield
a Isolated yield.
10
5
Table 2 Diversity in the synthesis of novel peptidomimetics
containing natural amino acids and dithiocarbamate groups a
OCH3
O
O
O
O
O
NO2
O
N
N
H
N
H
H
N
N
N
H
N
HN
HN
N
HN
HN
O
S
S
S
S
O
S
S
S
S
CH3
Bu
Bu
6d (51%)
6a (71%)
6b (50%)
6c (75%)
CH3
CH3
O
O
S
S
OH
N
O
O
N
O
N
O
NH
HN
NH
HN
NH
NH
HN
O
S
N
H
S
N
S
Bu
S
S
O
S
Br
6f (60%)
6h (60%)
6e (80%)
6g (40%)
O
CH3
O
H3C
H3C
N
HN
N
Cl
S
H
N
C
N
H
O
O
N
CH3
NH
HN
NH
O
H
O
HN
S
N
S
S
S
O
C
S
H
CH3
H
S
S
S
N
Bu
6l (45%)
6i (85%)
6j (45%)
6k (33%)
H3CO
Br
CH3
S
N
S
N
CH3
NH
CH3
NH
NH
NH
O
S
O
S
S
S
6m (40%)
6n (42%)
a Isolated yield.
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Journal Name, [year], [vol], 00–00 | 5