A simple approach for the synthesis of thio-, dithio- and selenothiocarbamate-tethered peptidomimetics

Article abstract of DOI:10.1055/s-0031-1290683

A simple and efficient method is described for the synthesis of thio-, dithio- and selenothiocarbamate-linked peptidomimetics. The nucleophilic addition of enantiopure N^α-protected amino alkyl thiols to isocyanates, isothiocyanates or isoselenocyanates obtained from amino acid esters proceeds smoothly in the presence of catalytic amount of DMAP. The protocol was further extended for the synthesis of N,N-orthogonally protected thio-, dithio- and selenothiocarbamate-linked peptidomimetics. The reaction is mild, free from racemization, and the products were obtained in good yield. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290683

1516▌
LETTER
lAetteSr imple Approach for the Synthesis of Thio-, Dithio- and Selenothio-
carbamate-Tethered Peptidomimetics
Synthesis of Thio-, Dithio- and Selenothiocarbamate-Tethered Peptidomimetics
H. S. Lalithamba, T. M. Vishwanatha, M. Samarasimha Reddy, Vommina V. Sureshbabu*
#109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B. R. Ambedkar
Veedhi, Bangalore 560001, India
E-mail: hariccb@hotmail.com; E-mail: hariccb@gmail.com
Received: 23.02.2012; Accepted after revision: 09.04.2012
The compounds possessing thio-, dithio- or selenothiocar-
Abstract: A simple and efficient method is described for the syn-
bamate functionality have been known for their interest-
thesis of thio-, dithio- and selenothiocarbamate-linked peptidomi-
metics. The nucleophilic addition of enantiopure Nα-protected
ing anticancer, antibacterial and anthelmintic, fungicidal
and growth depressant properties.7,8 Dithiocarbamates
amino alkyl thiols to isocyanates, isothiocyanates or isoselenocya-
nates obtained from amino acid esters proceeds smoothly in the have been developed as HIV-I NCp7 inhibitors9 which are
also used as linkers in solid-phase organic synthesis.10
presence of catalytic amount of DMAP. The protocol was further
extended for the synthesis of N,N′-orthogonally protected thio-, di-
Thiocarbamates are mostly known for their use as com-
thio- and selenothiocarbamate-linked peptidomimetics. The reac-
mercial herbicides. Selenothiocarbamates are less men-
tion is mild, free from racemization, and the products were obtained
tioned in the literature, although considering the important
in good yield.
biomedical applications of organoselenium compounds,
Key words: peptidomimetics, isocyanates, isothiocyanates and
these compounds may exhibit interesting reactivities to-
isoselenocyanates, amino alkyl thiols, thiocarbamates, dithiocarba-
wards various inhibitors and in several other functional
mates, selenothiocarbamates
group transformations.11,12
Handful of reports are available on the preparation of S/Se
analogues of carbamates.13 Generally, nucleophilic addi-
Peptidomimetics are designed to circumvent some of the
tion of thiols to isocyanates, isothiocynates or isoseleno-
cyanates has been the frequently employed protocol for
the synthesis of title carabamates.14 Additionally, several
carbonylating agents (CDI or thio-CDI) were also used as
carbonyl/thiocarbonyl donors.15 Usually these reagents
were treated with amines and thiols or alcohols to afford
thiocarbamates or carbamates, respectively. Dithiocarba-
mates can also be prepared by the reaction of an amine
with thiophosgene or CS2.16 The only report available on
the preparation of selenothiocarbamates was from
Koketsu et al., through a reaction of N,N-dimethylseleno-
carbamoyl chloride with lithium alkylthiolate.17 We have
reported a new class of peptidomimetics containing the di-
thiocarbamate linkages at the peptide backbone.18 This
one-pot reaction involving carbon disulfide, amino alkyl
iodide and amino acid ester was accessed via in situ gen-
erated dithiocarbamic salt. However, the same chemistry
cannot be applied for the synthesis of thiocarbamates and
selenothiocarbamates which otherwise requires the use of
carbon monoxide or toxic carbon diselenide. With the in-
tension to develop a general protocol for the synthesis of
chalcogeno derivatives of carbamates at the peptide back-
bone, we herein describe a simple approach for the syn-
thesis of sulfur- and selenium-containing carbamate
peptidomimetics. The protocol involves the reaction of
stable N-protected amino alkyl thiol with optically pure
isocyanato-, isothiocyanato- and isoselenocyanato esters
in the presence of 4-(N,N-dimethylamino)pyridine
(DMAP). Extension of this protocol is also compatible for
the synthesis of N,N′-orthogonally protected thio-, dithio-
and selenothiocarbamate-linked dipeptidomimetics.
problems associated with several natural peptides like sta-
bility against proteolysis and poor bioavailability.1 Cer-
tain other properties such as receptor selectivity or
potency can be substantially improved.2 Hence mimics
have enormous potential in drug discovery. Therefore,
several studies have been carried out over the years to
ameliorate the disadvantages of peptide characteristics
and thus generate viable pharmaceutical therapies that
have focused on the creation of unnatural carbamate-
linked peptide mimetics. The carbamate-tethered peptide
oligomers have been synthesized by Cho and Liskamp
groups.3 They play a major role in various applications in-
cluding medicine, agrochemicals, polymers and drugs.4
They are also present in several natural products. Impor-
tantly they serve as potential inhibitors of serine, thrombin
and HIV proteases.5 The amide bond isosteres and/or
modification of the native peptide backbone containing
sulfur or selenium have been the subject of interest. In-
deed, several sulfur-possessing peptidomimetics were de-
signed which show their increased bioavailability and in
vivo stability of a peptide without significantly reducing
the biological activity of the oxygen counterpart. Conse-
quently, the oxygen of the carbamate may be replaced
with sulfur or selenium leading to new mimetics which
may find use as drug candidates for pharmaceutical chem-
istry, e.g., in developing the treatment of infectious dis-
eases and for several protease inhibitors.6
SYNLETT 2012, 23, 1516–1522
Advanced online publication: 25.05.2012
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6
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1
4
1
4
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DOI: 10.1055/s-0031-1290683; Art ID: ST-2012-D163-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Thio-, Dithio- and Selenothiocarbamate-Tethered Peptidomimetics
1517
Over the course of many years, our group and others have
registered a series of detailed synthetic approaches for
various unnatural amino acids and showed their viability
in the construction of novel peptidomimetics. Thus, enan-
tiopure isocyano esters and Nα-urethane-protected amino
alkyl isocyanates, isothiocyanates and isoselenocyanates
have been prepared (Figure 1) and effectively used as sub-
strates to synthesize isonitriles,19 ureas,20 thioureas21 and
selenoureido peptidomimetics.22 We now focused our in-
terest on the application of isocyanates, isothiocyanates
and isoselenocyanates in the synthesis of respective car-
bamates.
Table 1 Optimization of the Reaction Conditions for the Synthesis
of 5a
Entry Base catalyst
Temp (ºC) Time
Yield (%)
1
2
3
4
5
6
none
25
65
35
50
25
25
5 h
3 h
68
72
75
79
92
80
none
NMM (0.5 equiv)
Et3N (0.5 equiv)
DMAP (0.2 equiv)
DBU (0.3 equiv)
2 h
2 h
30 min
50 min
R
SH
R1
PGHN
SH
PGHN
R1
R
R
1
H
DMAP
N
C
X
S
N
COOMe
+
X
C
N
COOY
PGHN
PGHN
CH2Cl2, Ar
r.t.
R2
O
R2
X = O, S, Se; Y = Me, Et, Bn; PG = Fmoc, Boc, Z group
5a–c: X = O
5d–f: X = S
5g–i: X = Se
X
C
N
COOMe
Figure 1 Substrate used for the present work
2: X = O
3: X = S
4: X = Se
PG = Fmoc or Z group
The retrosynthetic analysis of the title sulfur- or selenium-
bearing carbamates reveals that the most feasible path to
synthesize them is the reaction between N-protected ami-
no alkyl thiols with isocyanato derivatives. The required
N-protected amino alkyl thiols 1 were made through re-
ported procedures. Briefly, N-protected amino alkyl io-
dides were prepared under Mitsunobu condition, which
were then treated with thiourea followed by mild hydroly-
sis with Na2S2O5.23 To prepare dipeptidomimetics of the
type 5a–c (Scheme 1), reaction of methyl isocyano valin-
ate 2a with equimolar amount of N-Fmoc-Ala-ψ-
[CH2SH] 1a without using any base was carried out in
CH2Cl2. Interestingly, thiocarbamate 5a was obtained in
68% yield when the reaction was stirred at room temper-
ature for five hours (Table 1, entry 1) and in 72% yield
when the reaction was performed at 65 ºC for three hours
(Table 1, entry 2).
Scheme 1 Synthesis of N- and C-terminal protected thio-, dithio- and
selenothiocarbamate-linked peptidomimetics
up followed by column chromatographic purification
yielded the pure N-protected thiocarbamate-linked dipep-
tidomimetics 5a–c (Table 2). We then undertook the
synthesis of dithiocarbamates 5d–f. Interestingly, isothio-
cyanato esters 3 were also effectively reacted with thiols
1 in the presence of DMAP. However, the reaction rate
was slightly lower and hence longer duration of time was
required to obtain good yield of the products 5d–f (Table
2). The reactions were complete in about 50 minutes as
monitored by TLC. Further, the reaction of thiols with
isoselenocyanates derived from amino acid esters was
found to be more or less similar to that of the former iso-
thiocyanates (Table 2, 5g–i).
The method is also useful for the synthesis of N,N′-
orthogonally protected carbamate derivatives 7. N-Ure-
thane-protected amino alkyl isocynato derivatives were
synthesized by following published protocols.14,16,17 The
thiols 1 reacted smoothly with the N-protected amino al-
kyl isocyanate, isothiocyanate and isoselenocyanate 6 in
the presence of 0.2 equivalent of DMAP to provide the de-
sired carbamates 7 (Scheme 2, Table 3).
In order to increase the reaction rate as well as yield, ad-
dition of catalytic amount of a base was explored. Our tri-
al experiment employing 0.2 equivalent of DMAP led to
good yield of 5a at room temperature in 30 minutes (Table
1, entry 5). In contrast, screening of other bases, NMM,
Et3N and DBU (Table 1, entries 3, 4 and 6), did not lead
to an improvement in the yield (Table 1).
To explore the scope of the present methodology, various
side chain functionalized N-Fmoc/Z-amino alkyl thiols
and isocyano esters were employed. In all the cases reac-
tions were clean with excellent yields in less duration of
time. The completion of the reaction was monitored
through TLC as well as IR analysis of the reaction mixture
at regular intervals (the disappearance of distinct IR peak
for isocyanate at 2196 cm–1 and appearance of a new peak
at 1814 cm–1 corresponding to the thiocarbamate). After
the complete consumption of the reactants, a simple work-
R1
SH
PG1HN
R1
R2
H
1
S
N
DMAP
PG2HN
NHPG2
+
CH2Cl2, Ar
r.t.
R2
X
PG1 = Fmoc, Z group
PG2 = Fmoc, Z, Boc: X = O, S
PG2 = Boc, Z: X = O, S, Se
X
C
N
NHPG2
Scheme 2 Synthesis of N,N′-orthogonally protected thio-, dithio- and
selenothiocarbamate-linked dipeptidomimetics
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1516–1522

1518
H. S. Lalithamba et al.
LETTER
It has been observed that isocyanates were found to be ing the synthesis of dithio- and selenothiocarbamates even
more reactive with thiols compared to isothiocynates or after the reaction mixture being stirred for about five
isoselenocynates. Some of the thiocarbamates have been hours at room temperature, about 5% of isothiocynates or
isolated as pure compounds by recrystallization after the isoselenocynates remained unreacted. As a result, the di-
workup or by triturating with diethyl ether. However, dur-
Table 2 List of Thio-, Dithio- and Selenothiocarbamate-Linked Dipeptidomimetics 5
Product 5
[α]D25 (c = 1, CHCl3)
Yield (%)
92
HRMS [M + Na]+ found (calcd)
–35.4
493.1775
(493.1773)
H
N
S
COOMe
FmocHN
O
5a
Ph
–27.9
90
529.1770
(529.1773)
H
S
S
N
COOMe
Ph
ZHN
O
5b
–33.2
–43.6
–51.9
–38.9
89
91
90a
88
541.1805
(541.1807)
H
N
COOMe
SBn
ZHN
O
5c
H
N
615.1595
(615.1599)
S
COOMe
FmocHN
S
COOBn
COOMe
5d
H
N
523.1705
(523.1701)
S
FmocHN
S
5e
481.1261
(481.1265)
H
S
N
COOMe
NHZ
S
SMe
5f
H
N
–42.5
–33.9
85
90
605.0984
(605.0989)
S
S
COOMe
FmocHN
Se
Ph
5g
691.1352
(691.1357)
H
N
COOMe
COOBn
FmocHN
5h
Se
Ph
–29.9
89
559.1149
(559.1146)
H
S
N
COOMe
ZHN
Se
5i
a See ref. 18.
Synlett 2012, 23, 1516–1522
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Thio-, Dithio- and Selenothiocarbamate-Tethered Peptidomimetics
1519
Table 3 List of N,N′-Orthogonally Protected S- and Se-Possessing Carbamate-Linked Dipeptidomimetics 7
Product 7
[α]D25 (c = 1, CHCl3)
Yield (%)
HRMS [M + Na]+ found (calcd)
H
N
612.2505
(612.2508)
S
S
–19.3
88
FmocHN
NHZ
NHZ
O
O
7a
ZHN
4
H
N
761.2980
(761.2985)
FmocHN
–23.7
–29.5
90
86
7b
H
598.2350
(598.2352)
S
N
ZHN
NHFmoc
O
7c
Ph
H
N
670.2745
(670.2749)
S
–46.9
–20.6
89a
FmocHN
NHBoc
S
7d
H
704.2595
(704.2593)
S
N
91
ZHN
NHFmoc
S
7e
H
614.2126
(614.2123)
S
N
–27.8
–43.4
–20.9
–19.2
90a
87
85
87
FmocHN
NHZ
S
7f
H
S
N
540.1416
(540.1411)
NHZ
NHBoc
Se
7g
H
N
642.1886
(642.1881)
S
FmocHN
NHBoc
Se
7h
Ph
H
N
S
738.1884
(738.1881)
FmocHN
NHZ
Se
7i
a See ref. 18.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1516–1522

1520
H. S. Lalithamba et al.
LETTER
thio- and selenothiocarbamate derivatives have been iso- In conclusion, new classes of both N- and C-terminal-pro-
lated through column chromatographic purification.
tected as well as N,N′-orthogonally protected thio-, di-
thio- and selenothiocarbamate-linked peptidomimetics
have been synthesized by reacting N-protected amino al-
kyl thiols with amino acid derived isocyanate, isothiocya-
nate and isoselenocyanates.24 Catalytic amount of DMAP
facilitates the rapid reaction and high yield of the prod-
ucts.
Both 13C NMR as well as 77Se NMR were utilized to con-
firm the products. A 13C NMR signal corresponding to the
carbonyl carbon of the carbamate (OCONH) was reported
to resonate in the region δ = 155–157 ppm.3 As expected,
compared to carbamates a downfield shift at around δ =
161–165 ppm was observed in 13C NMR signal pertaining
to the carbonyl group of thiocarbamate (SCONH). Simi-
larly, due to more delocalized electrons on sulfur, the thio-
carbonyl group of dithiocarbamates (SCSNH) appeared
further downfield in the range δ = 195–200 ppm.
Acknowledgment
The authors thank the Board of Research in Nuclear Sciences, the
Department of Atomic Energy (grant No. 2011/37/C/35/BRNS),
Govt. of India for financial support. H.S.L. thanks the Siddaganga
Institute of Technology, Tumkur for a research leave.
Table 4 Racemization Studies
Ph
H
S
N
COOMe
References
*
PGHN
(1) (a) Conradi, R. A.; Hilgers, A. R.; Ho, N. F. H.; Burton, P.
S. Pharm. Res. 1992, 9, 435. (b) Pseudo-Peptides in Drug
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R. M. J. Angew. Chem., Int. Ed. Engl. 1994, 33, 633.
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Bioorg. Med. Chem. Lett. 1999, 7, 1171. (b) Warrass, R.;
Walden, P.; Wiesmuller, K.-H.; Jung, G. Lett. Pept. Sci.
1998, 5, 125.
X
X = O, S, Se
Product
[α]D25 (c = 0.1 CHCl3)
HPLCa tR
D
L
D
L
thiocarbamate
+16.6
+32.2
+ 5.8
–25.3
– 8.5
–16.9
12.1
14.3
16.9
12.6
14.0
17.1
dithiocarbamate
selenothiocarbamate
a HPLC particulars: Agilent 1100 series having G1311A VWD at λ =
254 nm, flow rate: 0.50 mL/min, Column: Agilent Eclipse XDB-C18,
pore size 5 μm, diameter × length = 4.6 × 150 mm; gradient elution:
H2O–MeCN–TFA (30:70:0.1); 0.5 mL/min.
On the other hand, selenothiocarbamates (SCSeNH) can
be identified by both 13C NMR and 77Se NMR. In 13C
NMR spectrum, the carbonyl group of selenothiocarba-
mates showed a single resonance in the region at around δ
= 200–206 ppm which was found to be downfield com-
pared to thiocarbamates. Additionally, 77Se NMR analysis
of the selenothiocarbamates was also carried out to find
the nature of the selenium nucleus attached to carbon.
Thus, a sharp signal resonance in the range δ = 323–353
ppm was detected for selenothiocarbamates which is in
agreement with the reported values.17
(5) Wang, X.; Huq, I.; Rana, T. M. J. Am. Chem. Soc. 1997, 119,
6444.
(6) (a) Sharma, A. K.; Sharma, A.; Desai, D.; Madhunapantula,
S. V.; Huh, S. J.; Robertson, G. P.; Amin, S. J. Med. Chem.
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S.; Taimoory, S.; Abtin, E. Asian J. Biochem Pharma. Res.
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J. Med. Chem. 2006, 49, 1648. (e) Elgemeie, G. H.; Sayed,
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C.; Li, R. Bioorg. Med. Chem. Lett. 2006, 16, 4214.
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Y.-P.; Jiang, Y.-Y.; Liu, S.-Y.; Ding, G.-Y.; Li, R.-T.
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Compounds: Their Chemistry and Biology; Wiley: New
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Selenium in Natural Products Synthesis; CIS Inc:
Philadelphia, 1984, Chap. 3.
To investigate the stereospecificity of the peptide carba-
mate analogues synthesized through the present protocol,
we undertook the synthesis of three sets of model com-
pounds by the reaction of Nα-Fmoc-Phe-ψ-[CH2SH] with
isocyanato esters (2, 3 and 4) derived from L- and D-Ala-
OMe (Table 4). The resulting crude products were sub-
1
1
mitted to HPLC and H NMR analysis. In each case H
NMR of the particular epimer contained a single distinct
methyl group doublet; also the HPLC chromatograms and
optical rotations for the particular epimer had separate and
distinct values. Thus the above study inferred that com-
pounds prepared in this communication retain their opti-
cal integrity.
(9) Goel, A.; Mazur, S. J.; Fattah, R. J.; Hartman, T. L.; Turpin,
J. A.; Huang, M.; Rice, W. G.; Appella, E.; Inman, J. K.
Bioorg. Med. Chem. Lett. 2002, 12, 767.
Synlett 2012, 23, 1516–1522
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Thio-, Dithio- and Selenothiocarbamate-Tethered Peptidomimetics
1521
(10) (a) Morf, P.; Raimondi, F.; Nothofer, H.-G.; Schnyder, B.;
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3.60 (s, 3 H), 3.91 (m, 1 H), 4.28 (m, 1 H), 4.20 (t, 1 H, J =
4.6 Hz), 5.01 (d, 2 H, J = 5.1 Hz), 5.16 (br, 2 H), 7.22–7.77
(m, 8 H). 13C NMR (100 MHz, CDCl3): δ = 19.6, 20.1, 30.9,
37.4, 45.7, 47.1, 51.9, 58.3, 66.6, 126.8, 127.3, 128.2, 128.9,
141.4, 143.2, 155.7, 164.5, 171.8. HRMS: m/z [M + Na]+
calcd for C25H30N2O5S: 493.1773; found: 493.1775.
Compound 5b: 1H NMR (300 MHz, CDCl3): δ = 2.70–3.02
(m, 2 H), 3.21–3.30 (m, 4 H), 3.62 (s, 3 H), 4.20 (m, 1 H),
4.83 (m, 1 H), 5.16 (br, 2 H), 5.32 (s, 2 H), 7.19–7.25 (m, 15
H). 13C NMR (100 MHz, CDCl3): δ = 34.1, 36.2, 43.3, 52.3,
53.1, 56.5, 64.3, 126.1, 126.3, 126.8, 127.0, 127.2, 127.4,
127.8, 128.2, 129.0, 138.1, 139.0, 140.1, 155.2, 164.2,
171.7. HRMS: m/z [M + Na]+ calcd for C28H30N2O5S:
529.1773; found: 529.1770.
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Fukuta, Y.; Ishihara, H. J. Org. Chem. 2002, 67, 1008.
(f) Azizi, N.; Aryanasab, F.; Saidi, M. R. Org. Lett. 2006, 8,
5275. (g) Watkins, B. E.; Rapoport, H. J. Org. Chem. 1982,
47, 4471.
(14) (a) Yamaguchi, T.; Harada, N.; Ozaki, K.; Hayashi, M.;
Arakawa, H.; Hashiyama, T. Tetrahedron 1999, 55, 1005.
(b) McCarthy, W. C.; Foss, L. E. J. Org. Chem. 1977, 42,
1508. (c) Vermeulen, M.; Zwanenburg, B.; Chittenden,
G. J. F.; Verhagen, H. Eur. J. Med. Chem. 2003, 38, 729.
(15) Wood, M. R.; Duncalf, D. J.; Rannard, S. P.; Perrier, S. Org.
Lett. 2006, 8, 553; and references cited therein.
(16) (a) Walter, W.; Bode, K. D. Angew. Chem., Int. Ed. Engl.
1967, 6, 281. (b) Garin, J.; Melandz, E.; Merchain, F. L.;
Tejero, T.; Urid, S.; Ayestaron, J. Synthesis 1991, 147.
(c) Xia, S.; Wang, X.; Ge, Z.-M.; Cheng, T.-M.; Li, R.-T.
Tetrahedron 2009, 65, 1005. (d) Ranu, B. C.; Saha, A.;
Banerjee, S. Eur. J. Org. Chem. 2008, 519. (e) Len, C.;
Boulogne-Merlot, A.-S.; Postel, D.; Ronco, G.; Villa, P.
J. Agric. Food Chem. 1996, 44, 2856.
(17) (a) Koketsu, M.; Fukuta, Y.; Ishihara, H. J. Org. Chem.
2002, 67, 1008. (b) Koketsu, M.; Otsuka, T.; Ishihara, H.
Phosphorus, Sulfur Silicon Relat. Elem. 2004, 178, 443.
(18) Hemantha, H. P.; Sureshbabu, V. V. Tetrahedron Lett. 2009,
50, 7062.
Compound 5c: 1H NMR (300 MHz, CDCl3): δ = 0.94 (t, 3 H,
J = 6.0 Hz), 1.02 (d, 3 H, J = 5.7 Hz), 1.22 (m, 2 H), 2.24 (m,
1 H), 2.92–3.24 (m, 4 H), 3.61 (s, 3 H), 3.75 (m, 2 H), 3.78
(m, 1 H), 4.81 (m, 1 H), 5.18 (br, 2 H), 5.32 (s, 2 H), 7.18–
7.20 (m, 10 H). 13C NMR (100 MHz, CDCl3): δ = 12.1, 15.0,
24.1, 32.2, 33.3, 39.0, 40.0, 52.1, 53.9, 55.7, 65.4, 126.4,
127.2, 128.1, 128.3, 128.5, 128.9, 137.4, 141.3, 155.8,
165.2, 171.8. HRMS: m/z [M + Na]+ calcd for
C26H34N2O5S2: 541.1807; found: 541.1805.
Compound 5d: 1H NMR (300 MHz, CDCl3): δ = 2.20–2.30
(m, 4 H), 3.13 (d, 2 H, J = 5.2 Hz), 3.43–3.60 (m, 3 H), 3.63
(s, 3 H), 4.20 (t, 1 H, J = 3.5 Hz), 4.91 (d, 2 H, J = 5.8 Hz),
5.15 (br, 2 H), 5.21 (s, 2 H), 7.19–7.72 (m, 13 H). 13C NMR
(100 MHz, CDCl3): δ = 25.2, 28.3, 37.4, 40.6, 47.2, 51.8,
55.2, 68.1, 68.9, 126.2, 126.9, 127.5, 128.0, 128.4, 128.6,
129.0, 141.2, 143.2, 157.0, 171.1, 173.2, 196.2. HRMS:
m/z [M + Na]+ calcd for C31H32N2O6S2: 615.1599; found:
615.1595.
Compound 5e: 1H NMR (300 MHz, CDCl3): δ = 0.90 (d, 6
H, J = 6.3 Hz), 1.25 (d, 3 H, J = 5.8 Hz), 1.70–1.75 (m, 3 H),
2.12–3.20 (m, 2 H), 3.63 (s, 3 H), 3.66 (m, 1 H), 3.85 (m, 1
H), 4.28 (t, 1 H, J = 4.8 Hz), 4.91 (d, 2 H, J = 6.7 Hz), 5.15
(br, 2 H), 7.26–7.78 (m, 8 H). 13C NMR (100 MHz, CDCl3):
δ = 18.5, 19.6, 20.7, 40.5, 43.8, 47.0, 47.5, 50.9, 52.4, 66.0,
126.7, 127.5, 128.0, 128.6, 141.4, 143.2, 154.7, 173.2,
195.7. HRMS: m/z [M + Na]+ calcd for C26H32N2O4S2:
523.1701; found: 523.1705.
(19) Sureshbabu, V. V.; Narendra, N.; Nagendra, G. J. Org.
Chem. 2009, 74, 153.
Compound 5f: 1H NMR (300 MHz, CDCl3): δ = 0.95 (d, 6
H, J = 5.2 Hz), 2.15 (s, 3 H), 2.23–2.47 (m, 5 H), 2.95 (d, 2
H, J = 5.8 Hz), 3.45 (m, 1 H), 3.62 (s, 3 H), 3.86 (m, 1 H),
5.17 (br, 2 H), 5.22 (s, 2 H), 7.19–7.22 (m, 5 H). 13C NMR
(100 MHz, CDCl3): δ = 16.2, 17.3, 17.5, 29.0, 31.1, 33.2,
36.5, 52.1, 56.2, 58.4, 65.4, 126.1, 127.6, 128.3, 142.1,
155.7, 171.2, 197.0. HRMS: m/z [M + Na]+ calcd for
C20H30N2O4S3: 481.1265; found: 481.1261.
(20) (a) Patil, B. S.; Vasanthakumar, G. R.; Sureshbabu, V. V.
J. Org. Chem. 2003, 68, 7274. (b) Sureshbabu, V. V.; Patil,
B. S.; Ramanarao, R. V. J. Org. Chem. 2006, 71, 7697.
(21) Sureshbabu, V. V.; Naik, S. A.; Hemantha, H. P.; Narendra,
N.; Das, U.; Guru Row, T. N. J. Org. Chem. 2009, 74, 5260.
(22) (a) Hemantha, H. P.; Sureshbabu, V. V. J. Pept. Sci. 2010,
16, 644. (b) Chennakrishnareddy, G.; Nagendra, G.;
Hemantha, H. P.; Das, U.; Guru Row, T. N.; Sureshbabu,
V. V. Tetrahedron 2010, 66, 6718.
Compound 5g: 1H NMR (300 MHz, CDCl3): δ = 1.33 (d, 3
H, J = 4.6 Hz), 2.96–3.02 (m, 2 H), 3.04–3.31 (m, 2 H), 3.50
(s, 3 H), 3.81 (m, 1 H), 4.10 (m, 1 H), 4.12 (t, 1 H, J = 4.9
Hz), 4.99 (d, 2 H, J = 6.4 Hz), 5.22 (br, 2 H), 7.12–7.81 (m,
13 H). 13C NMR (100 MHz, CDCl3): δ = 19.1, 36.2, 37.1,
47.2, 48.2, 52.0, 58.7, 67.2, 125.1, 126.7, 127.5, 127.9,
128.0, 128.2, 128.6, 139.0, 141.1, 143.4, 155.7, 171.2,
205.7. 77Se NMR (76 MHz, Me2Se–CDCl3): δ = 322.0.
HRMS: m/z [M + Na]+ calcd for C29H30N2O4SSe: 605.0989;
found: 605.0984.
(23) Sureshbabu, V. V.; Vishwanatha, T. M.; Vasantha, B.
Synlett 2010, 1037.
(24) General Procedure for the Synthesis of Thio-, Dithio-
and Selenothiocarbamate-Linked Peptidomimetics: To a
solution of PgNH-CHR-ψ-[CH2SH] (10.0 mmol) in anhyd
CH2Cl2 (10.0 mL), isocyanato derivatives (10.0 mmol) and
DMAP (0.2 equiv) were added. The reaction mixture was
stirred for 30–50 min at r.t. After the completion of the
reaction (TLC), the organic layer was washed with H2O (10
mL), brine (10 mL) and dried over Na2SO4. The organic
phase was evaporated under vacuo and the crude was
recrystallized (Et2O–THF) or purified through column
chromatography using EtOAc–n-hexane (20:80) as eluent.
Spectral data for compounds:
Compound 5h: 1H NMR (300 MHz, CDCl3): δ = 0.95 (d, 6
H, J = 5.6 Hz), 2.30 (m, 1 H), 2.73–2.95 (m, 2 H), 2.98–3.21
(m, 2 H), 3.61 (s, 3 H), 3.80 (m, 1 H), 4.10 (m, 1 H), 4.21 (t,
1 H, J = 4.2 Hz), 4.80 (d, 2 H, J = 6.4 Hz), 5.21 (br, 2 H),
5.30 (s, 2 H), 7.12–7.81 (m, 13 H). 13C NMR (100 MHz,
CDCl3): δ = 17.2, 17.4, 32.9, 34.3, 37.4, 47.2, 51.8, 52.1,
58.3, 67.1, 69.2, 125.3, 126.2, 127.2, 127.3, 128.0, 128.3,
128.6, 141.3, 142.1, 143.7, 155.1, 171.2, 173.2, 203.4. 77Se
Compound 5a: 1H NMR (300 MHz, CDCl3): δ = 0.98 (d, 6
H, J = 6.1 Hz), 1.59 (d, 3 H, J = 5.5 Hz), 2.90–3.11 (m, 3 H),
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1516–1522

1522
H. S. Lalithamba et al.
LETTER
NMR (76 MHz, Me2Se–CDCl3): δ = 322.0. HRMS: m/z
[M + Na]+ calcd for C33H36N2O6SSe: 691.1357; found:
691.1352.
Na]+ calcd for C36H45N3O4S2: 670.2749; found: 670.2745.
Compound 7e: 1H NMR (300 MHz, CDCl3): δ = 0.99 (d, 6
H, J = 5.6 Hz), 1.40 (m, 2 H), 1.80 (m, 1 H), 2.74–3.10 (m,
6 H), 3.80 (m, 1 H), 4.19 (m, 1 H), 4.35 (t, 1 H, J = 4.2 Hz),
4.87 (d, 2 H, J = 6.7 Hz), 5.33 (s, 2 H), 5.82 (br, 3 H), 7.23–
7.81 (m, 18 H). 13C NMR (100 MHz, CDCl3): δ = 22.1, 23.1,
23.3, 39.4, 41.9, 42.3, 47.0, 47.8, 49.5, 55.5, 65.1, 67.4,
126.5, 126.8, 127.1, 127.5, 127.9, 128.2, 128.5, 128.7,
129.5, 139.2, 141.2, 143.3, 155.2, 155.8, 198.4. HRMS:
m/z [M + Na]+ calcd for C39H43N3O4S2: 704.2593; found:
704.2595.
Compound 5i: 1H NMR (300 MHz, CDCl3): δ = 0.94 (t, 3 H,
J = 5.8 Hz), 1.01 (d, 3 H, J = 6.1 Hz), 1.37 (m, 2 H), 2.51 (m,
1 H), 2.60–2.81 (m, 2 H), 2.94–3.23 (m, 2 H), 3.41 (m, 1 H),
3.59 (s, 3 H), 4.21 (m, 1 H), 5.19 (br, 2 H), 5.29 (s, 2 H),
7.12–7.20 (m, 10 H). 13C NMR (100 MHz, CDCl3): δ = 12.2,
15.2, 36.2, 37.1, 42.2, 51.2, 55.3, 58.9, 66.3, 125.4, 126.5,
127.4, 128.0, 128.3, 128.7, 139.1, 141.4, 155.2, 171.3,
202.4. 77Se NMR (76 MHz, Me2Se–CDCl3): δ = 322.0.
HRMS: m/z [M + Na]+ calcd for C25H32N2O4SSe: 559.1146;
found: 559.1149.
Compound 7f: 1H NMR (300 MHz, CDCl3): δ = 0.91 (t, 3 H,
J = 5.6 Hz), 1.08 (d, 3 H, J = 5.1 Hz), 1.32 (m, 2 H), 2.23 (m,
1 H), 2.81–3.32 (m, 6 H), 3.80 (m, 1 H), 4.37 (t, 1 H, J = 5.2
Hz), 4.99 (d, 2 H, J = 6.7 Hz), 5.30 (s, 2 H), 5.82 (br, 3 H),
7.20–7.78 (m, 13 H). 13C NMR (100 MHz, CDCl3): δ = 12.2,
16.1, 25.5, 35.3, 40.2, 41.0, 43.2, 47.1, 54.2, 66.1, 68.4,
126.6, 127.4, 127.8, 128.5, 128.7, 129.0, 129.5, 141.0,
141.5, 144.3, 155.6, 156.0, 198.4. HRMS: m/z [M + Na]+
calcd for C32H37N3O4S2: 614.2123; found: 614.2126.
Compound 7g: 1H NMR (300 MHz, CDCl3): δ = 0.97 (d, 6
H, J = 5.4 Hz), 1.31 (d, 3 H, J = 5.8 Hz), 1.12 (s, 9 H), 2.40
(m, 1 H), 2.74–2.99 (m, 2 H), 3.04–3.22 (m, 2 H), 3.81–4.01
(m, 2 H), 5.01 (s, 2 H), 6.02 (br, 3 H), 7.10–7.26 (m, 5 H).
13C NMR (100 MHz, CDCl3): δ = 17.2, 19.2, 29.0, 31.2,
39.1, 47.2, 48.2, 59.1, 65.2, 79.2, 127.5, 127.8, 128.2, 141.2,
155.7, 204.2. 77Se NMR (76 MHz, Me2Se–CDCl3): δ =
320.0. HRMS: m/z [M + Na]+ calcd for C22H35N3O4SSe:
540.1411; found: 540.1416.
Compound 7a: 1H NMR (300 MHz, CDCl3): δ = 0.97 (d, 6
H, J = 6.0 Hz), 1.31 (d, 3 H, J = 5.4 Hz), 1.43 (m, 2 H), 1.76
(m, 1 H), 2.90–3.21 (m, 2 H), 3.01–3.35 (m, 2 H), 4.01–4.21
(m, 2 H), 4.25 (t, 1 H, J = 4.0 Hz), 5.01 (d, 2 H, J = 7.2 Hz),
5.31 (s, 2 H), 5.88 (br, 3 H), 7.19–7.82 (m, 13 H). 13C NMR
(100 MHz, CDCl3): δ = 20.2, 22.1, 23.4, 37.5, 42.2, 45.2,
47.0, 47.8, 48.9, 65.2, 67.2, 127.2, 127.4, 127.8, 128.1,
128.5, 128.8, 129.4, 141.2, 141.5, 143.1, 155.7, 163.1.
HRMS: m/z [M + Na]+ calcd for C33H39N3O5S: 612.2508;
found: 612.2505.
Compound 7b: 1H NMR (300 MHz, CDCl3): δ = 1.21 (d,
3 H, J = 6.6 Hz), 1.25–1.60 (m, 6 H), 2.90–3.20 (m, 4 H),
3.25–3.45 (m, 2 H), 3.75 (m, 1 H), 5.01 (m, 1 H), 4.23 (t, 1
H, J = 4.5 Hz), 5.21 (d, 2 H, J = 6.1 Hz), 5.32 (s, 4 H), 5.81
(br, 4 H), 7.16–7.79 (m, 18 H). 13C NMR (100 MHz, CDCl3):
δ = 17.7, 22.4, 29.2, 33.8, 35.0, 47.1, 47.4, 49.2, 49.4, 49.8,
67.4, 68.2, 68.5, 126.1, 126.3, 126.9, 127.2, 127.4, 127.7,
128.2, 128.6, 128.9, 129.4, 141.1, 141.4, 141.8, 143.4,
155.3, 155.7, 156.2, 167.5. HRMS: m/z [M + Na]+ calcd for
C41H46N4O7S: 761.2985; found: 761.2980.
Compound 7h: 1H NMR (300 MHz, CDCl3): δ = 0.95 (t, 3
H, J = 5.5 Hz), 0.99 (d, 3 H, J = 5.6 Hz), 1.10 (s, 9 H), 1.25
(m, 2 H), 1.32 (d, 3 H, J = 5.2 Hz), 2.12–3.32 (m, 5 H), 3.90
(m, 2 H), 4.30 (t, 1 H, J = 4.2 Hz), 4.92 (d, 2 H, J = 5.5 Hz),
5.69 (br, 3 H), 7.21–7.76 (m, 8 H). 13C NMR (100 MHz,
CDCl3): δ = 11.0, 14.3, 18.8, 26.5, 28.6, 32.1, 40.2, 48.1,
49.1, 52.3, 57.5, 68.2, 80.4, 126.0, 127.1, 127.8, 128.3,
141.3, 143.7, 155.1, 155.7, 202.3. 77Se NMR (76 MHz,
Me2Se–CDCl3): δ = 320.0. HRMS: m/z [M + Na]+ calcd for
C30H41N3O4SSe: 642.1881; found: 642.1884.
Compound 7c: 1H NMR (300 MHz, CDCl3): δ = 1.02 (d, 6
H, J = 5.2 Hz), 1.49 (m, 2 H), 1.81 (m, 1 H), 3.01–3.32 (m,
4 H), 3.69 (m, 2 H), 4.32 (m, 1 H), 4.31 (t, 1 H, J = 5.2 Hz),
4.83 (d, 2 H, J = 6.2 Hz), 5.32 (s, 2 H), 5.80 (br, 3 H), 7.19–
7.81 (m, 13 H). 13C NMR (100 MHz, CDCl3): δ = 22.1, 22.4,
23.3, 32.5, 39.0, 41.7, 46.3, 47.2, 47.5, 64.2, 68.2, 126.2,
127.6, 127.3, 128.2, 128.7, 128.9, 129.4, 141.3, 141.8,
143.5, 155.2, 156.3, 169.1. HRMS: m/z [M + Na]+ calcd for
C32H37N3O5S: 598.2352; found: 598.2350.
Compound 7i: 1H NMR (300 MHz, CDCl3): δ = 0.98 (d, 6 H,
J = 6.5 Hz), 2.40 (m, 1 H), 2.60–3.22 (m, 6 H), 3.87 (m, 1
H), 4.30 (m, 1 H), 4.33 (t, 1 H, J = 4.3 Hz), 4.92 (d, 2 H, J =
6.6 Hz), 5.33 (s, 2 H), 5.99 (br, 3 H), 7.21–7.76 (m, 18 H).
13C NMR (100 MHz, CDCl3): δ = 16.9, 32.8, 34.5, 40.9,
47.5, 49.6, 53.2, 59.9, 64.3, 68.4, 126.3, 126.8, 126.9, 127.0,
127.3, 127.9, 128.1, 128.3, 128.7, 129.0, 139.2, 140.3,
141.3, 143.9, 155.2, 155.9, 201.5. 77Se NMR (76 MHz,
Me2Se–CDCl3): δ = 320.0. HRMS: m/z [M + Na]+ calcd for
C38H41N3O4SSe: 738.1881; found: 738.1884.
Compound 7d: 1H NMR (300 MHz, CDCl3): δ = 0.95 (d, 6
H, J = 5.6 Hz), 1.20 (s, 9 H), 1.72 (m, 3 H), 2.40–2.49 (m, 4
H), 2.51 (d, 2 H, J = 4.9 Hz), 3.48 (m, 1 H), 3.99 (m, 1 H),
4.22 (t, 1 H, J = 4.2 Hz), 4.91 (d, 2 H, J = 6.7 Hz), 5.92 (br,
3 H), 7.21–7.78 (m, 13 H). 13C NMR (100 MHz, CDCl3):
δ = 20.1, 22.9, 27.7, 38.4, 40.1, 41.6, 46.9, 47.8, 49.1, 51.5,
65.7, 82.3, 127.5, 127.8, 127.9, 128.2, 128.6, 128.9, 129.5,
141.7, 142.3, 143.4, 155.6, 156.3, 194.5. HRMS: m/z [M +
Synlett 2012, 23, 1516–1522
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