An efficient one-pot access to trithiocarbonate-tethered peptidomimetics

Article abstract of DOI:10.1016/j.tetlet.2010.09.075

A simple protocol for the synthesis of a new class of trithiocarbonate- linked peptidomimetics and neoglycosylated amino acids is described. N-Protected amino alkyl thiols were treated with CS₂ in the presence of triethylamine (TEA) to generate trithiocarbonate salt, which upon reaction with appropriate halides afforded dipeptidomimetics in good yields. Further, the procedure was also extended for the synthesis of N,N′-orthogonally protected trithiocarbonate-linked dipeptidomimetics.

Full text of DOI:10.1016/j.tetlet.2010.09.075

Tetrahedron Letters 51 (2010) 6169–6173
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An efficient one-pot access to trithiocarbonate-tethered peptidomimetics
⇑
N. Narendra, H. S. Lalithamba, Vommina V. Sureshbabu
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B.R. Ambedkar Veedhi, Bangalore University,
Bangalore 560 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 July 2010
Revised 15 September 2010
Accepted 19 September 2010
Available online 24 September 2010
A simple protocol for the synthesis of a new class of trithiocarbonate-linked peptidomimetics and neo-
glycosylated amino acids is described. N-Protected amino alkyl thiols were treated with CS2 in the pres-
ence of triethylamine (TEA) to generate trithiocarbonate salt, which upon reaction with appropriate
halides afforded dipeptidomimetics in good yields. Further, the procedure was also extended for the syn-
thesis of N,N0-orthogonally protected trithiocarbonate-linked dipeptidomimetics.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Peptidomimetics
Amino alkyl thiols
Carbon disulfide
Trithiocarbonates
Peptides are attractive targets for drug discovery because of
their high affinity and specificity towards biological functions.
However, the poor in vivo stability, inadequate pharmacokinetic
properties and low bioavailability1 have generally limited their
broader utility. In this context, a variety of peptide mimics are
being developed by introducing a plethora of structural motifs as
replacement to the native peptide bond with the objective of
improving the activity of peptide based drugs.2 Our group previ-
ously had reported efficient methods for the synthesis of pepti-
domimetics containing unnatural linkages such as retro-amide,
urea, carbamate, heterocycles, and dithiocarbamate moieties as
peptide bond surrogates.3 In continuation of this work, we have
now focused our attention toward the synthesis of hitherto unre-
ported class of peptidomimetics containing trithiocarbonate
linkage.
Trithiocarbonate compounds possess a wide range of applica-
tions. For instance, they act as therapeutic agents such as inhibitors
of histone deacetylases (HDAC) in the treatment of cancer,4 and as
pesticides and insecticides.5 In organic synthesis, these compounds
are employed as reversible addition fragmentation chain-transfer
agents (RAFT) in radical polymerization6 and as key precursors
for the preparation of a number of compounds like trithiocarbon-
ate-S-oxides,7 thiols,8 olefins,9 thioacetates,10 and derivatives of
dicarbonyldithiocarboxylate.11 They have also been employed as
a protection for thiol functionality12 and as useful compounds in
the growing arsenal of nanotechnology in surface and colloidal
science.13
Earlier approaches for the synthesis of trithiocarbonates em-
ployed the reaction of thiols with chlorodithioformates14 or thio-
phosgene.15 Another method for their preparation includes the
dialkylation of trithiocarbonate anion with halides using a phase-
transfer catalyst or thermal assistance.16 Other alternative routes
for their synthesis include the reaction of sodium trithiocarbonates
with epoxides,17 reaction of metal xanthates with episulfides,18 or
the reaction of thiol with CS2 in the presence of KOH under phase
transfer catalyst to form potassium trithiocarbonate followed by
subsequent reaction with an alkyl halide.5 Wood et al. reported
the synthesis of symmetrical trithiocarbonates starting from pri-
mary thiols using 1,10-thiocarbonyldiimidazole (TCDI).6 Trithiocar-
bonates syntheses by S-arylation of potassium carbonotrithioates
with diaryliodonium salts were developed by Wang et al.19 They
have also been prepared by a one-pot reaction of alkyl halides with
CS2 in the presence of Cs2CO3,20 KF/Al2O3,21 or tetra-n-butylammo-
nium hydroxide (TBAH).22 It was recently described that symmet-
rical and unsymmetrical trithiocarbonates can be prepared from
CS2, thiol, and alkyl halide in the presence of TEA in water at room
temperature in one-pot.23 Chaturvedi et al. demonstrated a one-
pot, three component coupling of thiols with CS2 using Mitsunobu
reagent at room temperature.24
However, in spite of the wide spread importance of trithiocar-
bonates, their insertion into peptide back bone is yet to be
reported. The properties of trithiocarbonate linkage to act as pep-
tide bond surrogate and its biological and conformational conse-
quences have not been studied in detail yet. However in the
available reports, it has been shown that a trithiocarbonate group
in a-position to the carbonyl group (a subunit present in the title
⇑
Corresponding author. Tel.: +91 08 2296 1339; mobile: +91 09986312937.
E-mail addresses: sureshbabuvommina@rediffmail.com, hariccb@gmail.com,
trithiocarbonate-linked petidomimetics) constitutes a new head
group for HDAC inhibitors.4,25a In this case, the trithiocarbonate
hariccb@hotmail.com (V.V. Sureshbabu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.075

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N. Narendra et al. / Tetrahedron Letters 51 (2010) 6169–6173
moiety is
a
substitution to the well-known benzamide and
92–94% yield.27 Similarly Paladino et al. have observed that during
hydroxamate groups in HDAC inhibitors. Besides, the trithiocar-
bonate ion itself has shown to mimic the sulfonamide and urea
(moieties frequently used as peptide bond surrogates) binding to
the carboxy anhydrase enzyme.25b Regarding the conformation of
the dialkyl trithiocarbonates, it has been shown through low tem-
perature 1H NMR studies that in case of dimethyl trithiocarbonate,
the E,Z and E,E conformations are present in 0.52:0.48 ratio.25c
X-ray crystallographic studies of monoalkyl trithiocarbonates and
several organometallic compounds containing trithiocarbonate
ligands have been carried out.25d With the rapid progress made
in the area of peptidomimetics, synthetic studies on such novel
compounds would result in interesting molecules with biological
advantages. This Letter describes a simple synthesis of trithiocar-
bonate-linked peptidomimetics employing a reaction between
CS2, a N-protected amino alkyl thiol and an amino acid derived al-
kyl halide in the presence of TEA. According to established mecha-
nism, the thiol and CS2 react initially in the presence of TEA to
generate a triethylamine salt of corresponding trithiocarbonate,
which then react with alkyl halide to furnish the trithicarbonate
compound.5
Our primary targets were dipeptidomimetics of the type 4
(Scheme 1 and Table 1) which were accessed by employing a
N-protected amino alkyl thiol, CS2, TEA and bromomethyl ester.
The Fmoc/Z-protected amino alkyl thiols 1 were prepared accord-
ing to the protocol recently reported by us. Briefly, the N-protected
amino acids were converted to respective alkyl iodides via the
established procedure and then refluxed with thiourea in acetone
to yield isothiouronium salt. This intermediate was hydrolyzed
with aqueous sodium pyrosulfite to afford corresponding thiol.26
the coupling of a-bromo acids with thiols, inversion of configura-
tion at the bromo derivative occurs to a large extent.29 On this
basis, it is reasonable to understand that in the present study, in
the dipeptidomimetics 4c–g synthesized starting from
esters, the chiral carbon to ester group will be of D-configuration
due to inversion during the reaction. The HPLC of crude samples of
4e and 4f prepared through reacting Fmoc-Phe- [CH2–SH] with
the bromo esters obtained from - and -Ala, respectively revealed
L-a-bromo
a
w
L
D
the presence of diastereomers in 93:7 and 94:6 ratio respectively.
Further, the 1:1 mixture of 4e and 4f had two well separated peaks
at Rt values corresponding to each isomer.30 The major isomers in
the crude samples correspond to the products resulting from
inversion.
In the next stage, the chain extension of the dipeptidomimetic 4
on N-terminus was undertaken. Starting with 4a, the amine was
deprotected using 60% diethylamine (DEA) in dry CH2Cl2 and the
resulting free amino dipeptidomimetic was coupled with an
N-protected amino acid 5 via the mixed anhydride method to
obtain trithiocarbonate bearing tripeptidomimetic 6 (Scheme 2).
Recently there has been a surge in the interest in the synthesis
of neoglycosylated amino acids in which the native linkage be-
tween the carbohydrate and amino acid segments is replaced with
unnatural ones. This is because of the finding that glycosylation of
peptides increases the absorption of poorly bio-available peptides
by increasing their membrane permeability.31a With our interest
in such class of molecules, the present protocol was extended to
prepare a set of trithiocarbonate-linked neoglycosylated amino
acids as well. Toward this end, a reaction between N-protected
amino alkyl thiol and sugar bromide was undertaken. Starting with
On the other hand,
a
-bromo esters 2 were prepared through diaz-
D-galactose, the required 2,3,4,6-tetra-O-acetyl-b-D-glucopyranosyl
otization of the corresponding amino acid in the presence of KBr
bromide 3 was prepared employing well established procedure.31b
Further, a solution of 1 was reacted with 3 in the presence of CS2
and TEA to yield trithiocarbonate-linked N-protected amino alkyl
glycosides (4i–k). All the products were isolated as pure samples
and characterized by 1H NMR, 13C NMR and mass analyses.
Finally, the current protocol was extended to synthesize N,
N0-orthogonally protected trithiocarbonate-linked dipeptidomi-
metics by replacing the bromomethyl ester in the above men-
tioned protocol with N-protected amino alkyl halides. Starting
with an N-protected amino alkyl thiol 1, the triethylamine salt
of corresponding trithiocarbonate intermediate 7 was generated
via the reaction with CS2 in presence of TEA which without isola-
tion was treated with N-protected amino alkyl iodide 8 to yield
trithiocarbonate-linked orthogonally protected dipeptidomimetics
9a–g (Scheme 3 and Table 2) in excellent yield. The reaction was
complete in about 6 h. All the compounds were isolated after a
simple work-up as yellow colored compounds and fully
characterized.32
followed by esterification using CH3OH and SOCl2.27
Having the amino acid derived halide and thiol components in
hand, we next proceeded toward the synthesis of title molecules.
In a typical experiment, Fmoc-Phe-w[CH2–SH] in THF was treated
with CS2 and TEA, followed by the addition of a solution of
BrCH(CH2C6H5)COOMe in CH2Cl2. The reaction was complete in
about 5 h, as monitored by TLC. A simple work-up followed by col-
umn chromatography yielded pure N-protected trithiocarbonate-
linked dipepetidomimetic 4c in 80% yield (Scheme 1).28 The
generality of this protocol was demonstrated by synthesizing a ser-
ies of dipeptidomimetics (4a–h) in good yield and purity, employ-
ing several Fmoc/Z-amino alkyl thiols and bromomethyl esters.
It is well known that the thiolysis/alcoholysis of chiral a-bromo
alkyl esters proceed through SN2 mechanism leading to the inver-
sion of configuration at the asymmetric carbon. Yang et al. during
their work on
a-aminoxy esters that involved a reaction between
bromo ester and Cbz-NHOH obtained the inverted product in
R1
R2
CS2,TEA
THF, rt
S
S
COOX
PgHN
Br
COOX
R1
S
R2
2
SH
4a-4h
AcO
PgHN
OAc
O
+
AcO
1
OAc
OAc
R1
CS2,TEA
THF, rt
Br
AcO
O
S
S
AcO
3
FmocHN
OAc
S
4i-4k
Pg = Fmoc or Z group,
X= Methyl or Ethyl group
Scheme 1. Synthesis of trithiocarbonates 4a–k.

N. Narendra et al. / Tetrahedron Letters 51 (2010) 6169–6173
6171
Table 1
List of trithiocarbonate tethered peptidomimetics 4
½ ꢀ (c 1, CHCl3)
a 2D5
Compd No.
Trithiocarbonate
Yield (%)
79
HRMS
obsd/calcd
S
S
S
S
COOMe
COOEt
484.0690
(484.0687)
4a
12.5
22.0
FmocHN
S
S
526.1150
(526.1156)
4b
4c
83
80
FmocHN
Ph
650.1467
(650.1469)
S
S
COOMe
27.0
FmocHN
S
Ph
S
S
COOMe
662.1508
(662.1503)
4d
4e
17.0
13.9
88
81
FmocHN
Ph
S
S
Ph
574.1159
(574.1156)
S
S
S
COOMe
FmocHN
Ph
S
574.1158
(574.1156)
S
COOMe
4f
23.6
80
FmocHN
S
S
S
COOMe
S
305.9850
(305.9853)
ZHN
4g
4h
13.6
8.2
81
82
S
Ph
322.0133
(322.0132)
S
S
COOMe
ZHN
S
AcO
O
OAc
OAc
742.1420
(742.1426)
4i
4j
22.3
28.1
76
79
S
S
FmocHN
FmocHN
OAc
S
AcO
O
OAc
OAc
770.1731
(770.1739)
S
S
OAc
S
S
AcO
O
OAc
OAc
784.1890
(784.1896)
4k
19.2
75
S
FmocHN
OAc
S
S
i) DEA, CH2Cl2
H
N
S
S
COOMe
FmocHN
S
S
COOMe
FmocHN
S
O
5
FmocHN COOH
ii)
6
4a
NMM, ECF,
THF
Scheme 2. Synthesis of trithiocarbanate-linked tripeptidomimetic 6 through N-terminal elongation.
In summary, we have demonstrated a facile and efficient method
for the synthesis of a new class of trithiocarbonate-linked pepti-
domimetics. The reaction is rapid, high yielding, and free from toxic
reagents. All the compounds were isolated and fully characterized.

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N. Narendra et al. / Tetrahedron Letters 51 (2010) 6169–6173
NHPg2
I
R1
R2
R1
8
R2
R1
S
S
CS2,TEA
THF, rt
Pg1HN
NHPg2
+
S
S-
HN Et3
Pg1HN
SH
Pg1HN
S
S
9a-9g
1
7
Triethylamine salt of N-protected
alkyl trithiocarbonate
Pg1 = Pg2 = Fmoc or Z group
Scheme 3. Synthesis of trithiocarbonate-linked orthogonally protected dipeptidomimetics.
Table 2
List of trithiocarbonate-linked orthogonally protected dipeptidomimetics 9
½ ꢀ (c 1, CHCl3)
a 2D5
Compd No.
Trithiocarbonate
Yield (%)
HRMS
obsd/calcd
Ph
571.1647
(571.1649)
9a
13.5
16.1
82
79
S
S
S
S
FmocHN
NHZ
S
S
515.1027
(515.1023)
9b
FmocHN
NHZ
NHZ
523.1646
(523.1649)
9c
9d
9e
18.9
24.0
21.7
84
76
78
S
S
S
S
FmocHN
FmocHN
S
S
S
541.1216
(541.1214)
NHZ
495.1332
(495.1336)
S
S
ZHN
NHFmoc
S
521.1490
(521.1493)
9f
15.4
14.5
80
77
S
S
S
S
NFmoc
ZHN
Ph
S
S
515.1020
(515.1023)
9g
ZHN
NHFmoc
3. Hemantha, H. P.; Sureshbabu, V. V. Tetrahedron Lett. 2009, 50, 7062–7066. and
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Acknowledgments
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Authors thank the University Grants Commission (Grant No. 37-
79/2009), Govt. of India, New Delhi for the financial assistance. HSL
thanks Siddaganga Institute of Technology, Tumkur for a research
leave.
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Felix, A., Moroder, L., Toniolo, C., Eds.Georg Thieme; Stuttgart: Germany, 2003;
Vol. E22c,. and references cited therein (b) Boeijen, A.; van Ameijde, J.; Liskamp,
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2003, 44, 315–317.
30. Samples 4e and 4f eluted at Rt values 22.6 and 23.9 min, respectively, while the
equimolar mixture of these diastereomers had two distinct peaks at Rt 22.7 and
23.8 min. (HPLC particulars: Agilent 1100 series having G1311A VWD at
k = 254 nm, flow 0.50 mL/min, Column: Agilent Eclipse XDB-C18, pore size
18. Creighton, A. M.; Owen, L. N. J. Chem. Soc. 1960, 1024–1029.
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24. Chaturvedi, D.; Chaturvedi, A. K.; Mishra, N.; Mishra, V. Tetrahedron Lett. 2008,
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31. (a) Salvador, L. A.; Elofsson, M.; Kihlberg, J. Tetrahedron Lett. 1995, 51, 5643–
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32. Spectral data for selected compounds: Compound 4b: 1H NMR (400 MHz, CDCl3):
d 0.95 (d, 6H, J = 6.0 Hz), 1.25 (t, 3H, J = 5.2 Hz), 1.88 (m, 1H), 3.62 (d, 2H,
J = 4.7 Hz), 3.81 (m, 1H), 4.13–4.46 (m, 7H), 4.81 (br, 1H), 7.29–7.76 (m, 8H);
13C NMR (100 MHz, CDCl3): d 14.0, 18.1, 32.2, 38.7, 40.0, 47.3, 55.6, 62.0, 66.6,
119.9, 125.0, 127.0, 127.6, 141.3, 143.8, 156.0, 167.1, 170.4.
Compound 4c: 1H NMR (400 MHz, CDCl3): d 2.89–2.98 (m, 1H), 3.09 (m, 1H),
3.10–3.25 (m, 4H), 3.61 (s, 3H), 4.15 (m, 2H), 4.35 (d, 2H, J = 4.0 Hz), 4.48 (t, 1H,
J = 6.4 Hz), 5.04 (br, 1H), 7.17–7.75 (m, 18H); 13C NMR (100 MHz, CDCl3): d
37.5, 40.1, 40.5, 47.2, 52.3, 52.7, 53.4, 71.2, 125.6, 126.9, 127.0, 127.1, 127.6,
128.4, 128.5, 128.6, 129.0, 129.3, 136.7, 139.2, 141.3, 143.8, 155.5, 170.2, 174.5.
Compound 6: 1H NMR (400 MHz, CDCl3,): d 0.95 (d, 6H, J = 4.6 Hz), 1.10 (d, 3H,
J = 6.2 Hz), 2.91 (m, 1H), 3.24 (d, 2H, J = 4.2 Hz), 3.91 (s. 3H), 4.0 (s, 2H), 4.23 (m,
1H), 4.30 (m, 1H), 4.41 (t, 1H, J = 4.32 Hz), 4.72 (d, 2H, J = 5.2 Hz), 5.03 (br, 2H),
7.15–74 (m, 8H); 13C NMR (100 MHz,CDCl3): d 17.4, 20.1, 32.1, 39.9, 40.2, 45.5,
48.2, 51.2, 61.9, 67.7, 126.8, 127.9, 128.4, 128.9, 140.1, 143.6, 156.1, 169.2,
170.3, 175.2.
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28. Typical procedure for the synthesis of trithiocarbonate-linked dipeptidomimetics
4c: To a solution of N-Fmoc-Phe
(3 mL) was added TEA (3.75 mmol). After 20 min,
w
[CH2–SH] (2.5 mmol) in THF (5 mL) and CS2
solution of
a
BrCH(CH2C6H5)COOMe (2.5 mmol) in CH2Cl2 was added and the reaction
mixture was continued to stir for 5 h. After completion of the reaction (TLC), it
was evaporated under vacuum and the crude was taken into ethyl acetate
(15 mL). The organic layer was washed with citric acid solution (10%, 10 mL),
water and brine. After drying over sodium sulfate, the organic phase was
concentrated and the crude was purified through column chromatography
using EtOAc in hexane as eluent.
Compound 9e: 1H NMR (400 MHz, CDCl3): d 0.85–0.86 (m, 6H), 1.10–1.17 (m,
5H), 1.42 (m, 1H), 3.25 (m, 1H), 3.38 (m. 1H), 3.60 (d, 2H, J = 4.4 Hz), 3.77 (d,
2H, J = 4.5 Hz), 4.2 (t, 1H, J = 6.3 Hz), 4.31 (d, 2H, J = 5.6 Hz), 4.99 (s, 2H), 7.28–
7.42 (m, 10H), 7.65–7.68 (m, 2H), 7.86–7.88 (m, 3H); 13C NMR (100 MHz,
CDCl3): d 11.2, 14.8, 20.2, 24.9, 39.9, 40.1, 45.7, 46.7, 47.3, 53.6, 65.0, 65.2,
120.0, 121.2, 124.3, 125.0, 126.9, 127.6, 128.2, 140.7, 141.2, 144.0, 155.8, 170.5.
29. Paladino, J.; Thurieau, C.; Morris, A. D.; Kucharczyk, N.; Rouissi, N.; Regoli, D.;
Fauchere, J.-L. Int. J. Pept. Protein Res. 1993, 42, 284–293.