A simple approach for the synthesis of new classes of dithiocarbamate-linked peptidomimetics

Article abstract of DOI:10.1016/j.tetlet.2009.09.172

An efficient protocol for the synthesis of a new series of dithiocarbamate-linked peptidomimetics is described. The in situ generated dithiocarbamic acid intermediate formed by the reaction of an amino acid ester and carbon disulfide in the presence of triethylamine was treated with N-protected amino alkyl iodide to afford title compounds 3a-g in good to moderate yields. The synthesis of N-Fmoc-protected tripeptidomimetics 4a-e containing two dithiocarbamate linkages is also described. The protocol was further extended to synthesize N,N′-orthogonally protected dithiocarbamate-linked dipeptidomimetics 7a-c as well. The mild reaction conditions and non-toxic reagents are the advantages of the present method.

Full text of DOI:10.1016/j.tetlet.2009.09.172

Tetrahedron Letters 50 (2009) 7062–7066
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple approach for the synthesis of new classes of dithiocarbamate-linked
peptidomimetics
*
Hosahalli P. Hemantha, Vommina V. Sureshbabu
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, 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:
An efficient protocol for the synthesis of a new series of dithiocarbamate-linked peptidomimetics is
described. The in situ generated dithiocarbamic acid intermediate formed by the reaction of an amino
acid ester and carbon disulfide in the presence of triethylamine was treated with N-protected amino alkyl
iodide to afford title compounds 3a–g in good to moderate yields. The synthesis of N-Fmoc-protected tri-
peptidomimetics 4a–e containing two dithiocarbamate linkages is also described. The protocol was fur-
ther extended to synthesize N,N0-orthogonally protected dithiocarbamate-linked dipeptidomimetics 7a–
c as well. The mild reaction conditions and non-toxic reagents are the advantages of the present method.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 3 August 2009
Revised 26 September 2009
Accepted 30 September 2009
Available online 2 October 2009
Keywords:
Peptidomimetics
Dithiocarbamate
Dithiocarbamic acid
Carbon disulfide
Natural peptides have been the potent source of lead com-
pounds in drug discovery albeit with limited utility due to their
poor pharmacokinetic properties, rapid metabolism and low bio-
availability.1,2 Hence a variety of peptide mimics are being devel-
oped to introduce drug-like character along with increased po-
tency, target specificity and longer duration of action. To this
end, several classes of peptidomimetics are tailored by replacing
the native amide bond with various other tethers and are biologi-
cally scrutinized.3 Our group has been involved in developing effi-
cient methods for the synthesis of peptidomimetics by inserting
non-native linkages such as urea,4 thiourea,5 retro-amide,6 carba-
mate7 and heterocycles.8 Recently, we turned our attention to-
wards another useful and biologically important functionality
namely dithiocarbamate.9 Reports in the literature demonstrate
that the dithiocarbamate containing molecules show antibacterial,
anthelmintic, anti-cancer, fungicidal and growth depressant prop-
erties.10,11 The utility of dithiocarbamate group as linkers in solid
phase organic synthesis12,13 and in certain photochemical applica-
tions14 is also well documented. The dithiocarbamate functionality
chelates heavy metals that make them versatile ligands,15 and are
applicable as NO scavengers. Furthermore, the functionalized
dithiocarbamates such as benzamide-based thiocarbamates have
been developed as HIV-I NCp7 inhibitors.16
and carbon disulfide (CS2) on electron-deficient alkene through Mi-
chael-type reaction in the presence of a base or solid alkaline
Al2O3.18 Ranu et al., recently described a one-pot three-component
condensation of an amine, CS2 and an activated alkene in an ionic
liquid.19 Villa and co-workers, synthesized bis(dithiocarbamate)
derivatives of glycerol through a multi-step process and have dem-
onstrated their antifungal activity.20 A similar chemistry was fol-
lowed by Rafin and co-workers21 for the synthesis of
dithiocarbamate derivatives of carbohydrate conjugates. A three-
component reaction employing Cs2CO3, tetrabutylammonium io-
dide (TBAI) and CS2 for a reaction between an amine and a substi-
tuted halide was reported by Jung and co-workers22 Strong bases
such as anhydrous potassium phosphate have also been used for
the reaction of an amine and CS2 with electrophilic alkenes to ob-
tain corresponding dithiocarbamate compounds.23 While a one-
pot synthesis of dithiocarbamates starting from corresponding
alcohols using Mitsunobu reagent was developed by Chaturvedi
and Ray,24 benzotriazole-assisted synthesis of dithiocarbamates
by a reaction of S-nucleophiles with thiocarbonylbenzotriazoles
was developed by Katritzky’s group.25 Saidi and co-workers have
described a straightforward catalyst-free one-pot synthesis of
dithiocarbamates under solvent-free conditions.26,27 The same
group has also demonstrated a Michael-type reaction between an
Earlier approaches for the synthesis of dithiocarbamate esters
employed the reaction of an amine with expensive and toxic re-
agents such as thiophosgene and its derivatives.17 Synthesis of
substituted dithiocarbamates is carried out by a reaction of amine
amine, CS2 with a
,b-unsaturated compounds in water.28 Dithiocar-
bamate preparation by a reaction between an epoxide, amine and
CS2 in one-pot fashion is also known.29
A thorough literature survey revealed that the dithiocarbamate-
linked peptidomimetics are yet to be reported. In correlation with
other non-amide tethers such as ureas and carbamates, incorpora-
tion of dithiocarbamate into peptide backbone may result in
* Corresponding author. Tel.: +91 08 2296 1339/09986312937.
E-mail address: sureshbabuvommina@rediffmail.com (V.V. Sureshbabu).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.172

H. P. Hemantha, V. V. Sureshbabu / Tetrahedron Letters 50 (2009) 7062–7066
7063
R1
R2
H
N
R1
CS2, TEA
COOX
THF, 0 °C-rt
S
COOX
Pg-HN
I
H2N
R2
+
Pg-HN
S
2
3a-g
1
Pg= Fmoc or Z group; X= Methyl or Ethyl moiety
Scheme 1. Synthesis of dithiocarbamates 3a–g.
interesting class of molecules. Similar to the strategy described
earlier by Salvatore et al.,22 we, in the present Letter report a sim-
ple synthesis of dithiocarbamate-linked peptidomimetics by a
reaction of CS2 with suitably chosen amino acid derived amine
and halide components in the presence of triethylamine (TEA).
The reaction between carbon disulfide and an N-nucleophile in-
volves addition of CS2 to NH bonds. It results in dithiocarbamate
salt that can be transformed into various intermediates and prod-
ucts such as isothiocyanates. Recently, we reported the preparation
of N-protected amino alkyl isothiocyanates employing CS2 and
TEA.5 During this study, it was envisaged that the intermediate
dithiocarbamic acid salts react with electron-deficient carbon cen-
tres such as alkyl halides to afford respective class of dithiocarba-
mate compounds. This chemistry was explored to prepare new
classes of peptidomimetics and the results are discussed here.
Our first target was a dipeptidomimetic of the type 3. This was
accomplished by a reaction of an amino acid ester, CS2, TEA and
N-protected amino alkyl iodide. The iodo intermediates used in
the present studies were prepared by following a reported proto-
col.30 Briefly, an N-protected amino acid was reduced into corre-
sponding aminol and the hydroxy group was subjected to
Mitsunobu reaction using PPh3, imidazole and iodine to afford cor-
responding N-protected amino alkyl iodide 1. In a typical reaction,
the preparation of compounds 3 involved first treatment of a
Table 1
List of dithiocarbamate tethered peptidomimetics 3
Compd No.
Dithiocarbamate
½
a2D5ꢀ c 1, CHCl3
Yield (%)
HRMS obsd/calcd
H
N
S
S
COOMe
Ph
3a
ꢁ44.6
ꢁ52.7
ꢁ38.1
ꢁ110.1
ꢁ19.8
+17.5
+9.0
72
585.1831
(585.1858)
Fmoc-HN
S
S
H
N
COOMe
Fmoc-HN
FmocN
3b
3c
3d
3e
3f
74
65
68
70
69
62
523.1698
(523.1701)
H
S
N
COOMe
S
567.1429
(567.1422)
S
H
665.1583
(665.1578)
S
N
COOMe
FmocNH
S
S
Ph
Ph
H
469.1222
(469.1232)
S
S
N
COOEt
ZNH
S
Ph
H
N
483.1394
(483.1388)
COOMe
O
ZNH
S
S
H
3g
670.2380
(670.2385)
N
FmocNH
N
H
COOMe
S
Ph

7064
H. P. Hemantha, V. V. Sureshbabu / Tetrahedron Letters 50 (2009) 7062–7066
R1
R3
S
R2
H
N
H
N
1. DEA/CH2Cl2
S
COOMe
S
Fmoc-HN
Fmoc-HN
S
N
H
COOMe
2. CS2, TEA, 1
S
R2
S
R1
THF, 0 °C, rt
4a-e
3
Comp. R1
No.
R2
R3
Yield
(%)
[ ]25
D
c
1,
CHCl3
4a
4b
4c
4d
4e
CH(CH3)2 CH2C6H5
CH3
-78.7
58
61
55
60
53
CH3
H
CH2CH(CH3)2 CH2C6H5
-32.0
(CH2)2SCH3
(CH2)2SCH3
CH(CH3)2
+11.8
-(CH2)3-
CH3
CH2CH(CH3)2 -85.2
CH2CH(CH3)2 CH(CH3)CH2
CH3
-74.6
Scheme 2. Synthesis of dithiocarbamate-linked tripeptidomimetics through N-terminal elongation.
R1
H
R2
N
S
Pg1-NH
NHPg2
1
R1
R1
S
7a-c
H
N
CS2, TEA
NH2
S
HNEt3
Pg1-NH
Pg1-NH
THF, 0 °C-rt
Br
COOY
R1
5
6
S
H
N
S
COOY
Pg1-NH
Dithiocarbamic acid salt
Pg= Fmoc, Boc, Z
6a: Y= Me
6b: Y= Et
S
8a-c
Scheme 3.
Table 2
Dithiocarbamate-linked dipeptidomimetics 7, 8
Compd No.
Dithiocarbamates
½
a2D5ꢀ c 1, CHCl3
Yield (%)
HRMS obsd (calcd)
Ph
H
N
7a
ꢁ46.8
72
670.2757
(670.2749)
S
BocNH
HNFmoc
HNFmoc
S
H
N
S
7b
7c
8a
8b
8c
ꢁ19.3
ꢁ12.7
+29.7
+33.5
ꢁ8.2
68
65
62
67
70
614.2119
(614.2123)
ZNH
S
H
614.2133
(614.2123)
N
S
FmocNH
HNZ
S
Ph
H
N
421.1230
(421.1232)
S
COOMe
BocNH
S
H
N
S
COOEt
481.1220
(481.1232)
FmocNH
ZNH
S
H
421.1229
(421.1232)
N
S
COOMe
S

H. P. Hemantha, V. V. Sureshbabu / Tetrahedron Letters 50 (2009) 7062–7066
7065
5. Sureshbabu, V. V.; Naik, S. A.; Hemantha, H. P.; Narendra, N.; Das, U.; Row, T. N.
G. J. Org. Chem. 2009, 74, 5260–5266.
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7. Sureshbabu, V. V.; Sudarshan, N. S.; Venkataramanarao, R. Int. J. Pept. Res. Ther.
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8. (a) Sureshbabu, V. V.; Venkataramanarao, R.; Naik, S. A.; Chennakrishnareddy,
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chilled solution of HClꢂH–Phe–OMe in dry THF with TEA and CS2.
This was followed by the addition of a solution of N-Fmoc-Val-
W
[CH2–I]. The reaction was complete in about an hour as adjudged
by TLC. A simple work-up followed by column chromatography
yielded pure N-protected dithiocarbamate-linked dipeptidomi-
metic 3a in 72% yield (Scheme 1).31 The generality of this reaction
was demonstrated with a series of N-Fmoc/Z-amino alkyl iodides
and amino acid esters to afford the corresponding dipeptidomi-
metics 3b–g in good to moderate yields (Table 1). The products
were found to be analytically pure and the protocol was racemiza-
tion free as evident by HPLC and NMR analyses.32
In the subsequent study, the chain elongation of dipeptidomi-
metics 3 on N-terminal was undertaken to synthesize tripeptidom-
imetics containing two dithiocarbamate linkages in the backbone.
Starting with 3a, the amine was deprotected using 50% diethyl-
amine (DEA) in CH2Cl2 and the resulting amino-free dipeptidomi-
10. Hou, X.; Ge, Z.; Wang, T.; Guo, W.; Cui, J.; Cheng, T.; Lai, C.; Li, R. Bioorg. Med.
Chem. Lett. 2006, 16, 4214–4219.
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Simon, H. J. Agric. Food. Chem. 1997, 45, 3–6; (b) Ronconi, L.; Marzano, C.;
Zanello, P.; Corsini, M.; Miolo, G.; Macca, C.; Trevisan, A.; Fregona, D. J. Med.
Chem. 2006, 49, 1648–1657; (c) Cao, S.-L.; Feng, Y.-P.; Jiang, Y.-Y.; Liu, S.-Y.;
Ding, G.-Y.; Li, R.-T. Bioorg. Med. Chem. Lett. 2005, 15, 1915–1917.
12. (a) Morf, P.; Raimondi, F.; Nothofer, H.-G.; Schnyder, B.; Yasuda, A.; Wessels, J.
M.; Jung, T. A. Langmuir 2006, 22, 658–663; (b) Bongar, B. P.; Sadavarte, V. S.;
Uppalla, L. S. J. Chem. Res. 2004, 9, 450–451.
13. Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.;
Wiley: Interscience, New York, 1999. pp 484–486.
14. Plyusnin, V. F.; Grivin, V. P.; Larionov, S. V. Coord. Chem. Rev. 1997, 159, 121–
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15. (a) Hidaka, S.; Funakoshi, T.; Shimada, H.; Tsuroka, M.; Kojima, S. J. Appl. Toxicol.
1995, 15, 267–273; (b) Fujii, S.; Yoshimura, T. Coord. Chem. Rev. 2000, 198, 89–
99.
16. 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, 767–770.
17. (a) Walter, W.; Bode, K. D. Angew. Chem., Int. Ed. Engl. 1967, 6, 281–293; (b)
Garin, J.; Melandz, E.; Merchain, F. L.; Tejero, T.; Urid, S.; Ayestaron, J. Synthesis
1991, 147–157.
18. Xia, S.; Wang, X.; Ge, Z.-M.; Cheng, T.-M.; Li, R.-T. Tetrahedron 2009, 65, 1005–
1009.
19. Ranu, B. C.; Saha, A.; Banerjee, S. Eur. J. Org. Chem. 2008, 519–523.
20. Len, C.; Boulogne-Merlot, A.-S.; Postel, D.; Ronco, G.; Villa, P. J. Agric. Food Chem.
1996, 44, 2856–2858.
metic was reacted with CS2, TEA and N-Fmoc-Ala-w[CH2–I] 1 to
afford N-Fmoc-tripeptidomimetic 4a possessing two dithiocarba-
mate groups (Scheme 2). Employing this protocol, four more
dithiocarbamate-linked tripeptidomimetics 4b–e were prepared
and isolated successfully that were adequately characterized.33
Finally, the protocol was further explored to describe two other
types of dithiocarbamate-linked peptidomimetics starting from N-
protected amino acid derived vicinal diamines 5. The required N-
protected amino alkyl amines 5 were synthesized using known
protocol. N-Fmoc amino alkyl amines34 were prepared by reducing
the corresponding alkyl azides under catalytic hydrogenation,
while N-Boc and N-Z-amino alkyl amines were synthesized by
LiAlH4-mediated reduction of their nitriles.5 Then a reaction of 5
with CS2 in the presence of TEA gave the corresponding dithiocar-
bamic acid intermediate which without isolation, was treated with
either N-protected amino alkyl iodide 1 or bromo acetic acid ester
6 to afford dithiocarbamate-linked orthogonally protected dipepti-
domimetics 7a–c and simple dipeptidomimetics 8a–c, respectively
(Scheme 3, Table 2). All the compounds were isolated after a sim-
ple work-up as gummy solids and fully characterized using mass
and NMR spectroscopic techniques.
21. Rafin, C.; Veignie, E.; Sancholle, M. J. Agric. Food Chem. 2000, 48, 5283–5287.
22. Salvatore, R. N.; Sahab, S.; Jung, K. W. Tetrahedron Lett. 2001, 42, 2055–2058.
23. Guo, B.; Ge, Z.; Cheng, T.; Li, R. Synth. Commun. 2001, 31, 3021–3025.
24. Chaturvedi, D.; Ray, S. Tetrahedron Lett. 2006, 47, 1307–1309.
25. Katritzky, A. R.; Witek, R. M.; Rodriguez-Garcia, V.; Mohapatra, P. P.; Rogers, J.
W.; Cusido, J.; Abdel-Fattah, A. A. A.; Steel, P. J. J. Org. Chem. 2005, 70, 7866–
7881.
26. Azizi, N.; Aryanasab, F.; Saidi, M. R. Org. Lett. 2006, 8, 5275–5277.
27. Halimehjani, A. Z.; Maleki, H.; Saidi, M. R. Tetrahedron Lett. 2009, 50, 2747–
2749.
28. Azizi, N.; Aryanasab, F.; Torkiyan, L.; Ziyaei, A.; Saidi, M. R. J. Org. Chem. 2006,
71, 3634–3635.
In conclusion, we report a simple and mild protocol for the syn-
thesis of a new class of dithiocarbamate-linked peptidomimetics
using CS2, TEA and corresponding amines and appropriate halides.
The reaction is fast, high yielding and is devoid of the use of toxic
reagents. The protocol is racemization free and all the synthesized
compounds were isolated and well characterized.
29. Azizi, N.; Pourhasan, B.; Aryanasab, F.; Saidi, M. R. Synlett 2007, 8, 1239–1242.
30. Mondal, S.; Fan, E. Synlett 2006, 306–308.
31. Typical procedure for the synthesis of dithiocarbamate-linked dipeptidomimetic
3a: To a chilled solution of HClꢂH–Phe–OMe (3 mmol) and TEA (8 mmol) in dry
THF (15 mL) was added CS2 (6 mmol). After 10 min, a solution of N-Fmoc-Val-
w
[CH2–I] (4 mmol) in THF was added slowly and the reaction mixture was
allowed to warm to rt gradually and stirred for two hours. After completion of
the reaction (TLC), it was evaporated under vacuum and the crude was
partitioned between ethyl acetate (15 mL) and water. 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 (10–15%) as
eluent.
Acknowledgements
We thank the Department of Science and Technology (DST),
Government of India (Grant No. SR/S1/OC-26/2008) and the Coun-
cil of Scientific and Industrial Research (CSIR), New Delhi for finan-
cial support.
32. Note: To confirm the optical purity of the synthesized dithiocarbamates, a
model study was carried out as follows: Two epimeric dithiocarbamate
compounds were prepared by coupling N-Fmoc-Phe-w[CH2–I] with (R)- and
(S)-1-phenylethylamines separately. The 1H NMR spectra of methyl group of
these two compounds contained distinct doublets at d values 1.35, 1.37 and
1.38, 1.40 ppm, respectively, indicating the absence of racemization during the
course of the reaction. Also, the HPLC profiles of the samples of these two
epimers had peak at Rt values 16.4 and 17.1, respectively, while the equimolar
mixture of these epimers prepared by reacting racemic phenylethylamine with
References and notes
1. Sewald, N.; Jakubke, H. D. In Peptides: Chemistry and Biology; Wiley-VCH, 2002.
2. (a) Conradi, R. A.; Hilgers, A. R.; Ho, N. F. H.; Burton, P. S. Pharm. Res. 1992, 9,
435–439; (b)Pseudo-Peptides in Drug Discovery; Nielsen, P. E., Ed.; Wiley-VCH:
Germany, 2004; (c)Peptides: Chemistry and Biology; Sewald, N., Jakubke, H.-D.,
Eds.; Wiley-VCH: Weinheim, Germany, 2002. p 354.
3. (a) Vagner, J.; Qu, H.; Hruby, V. J. Curr. Opin. Chem. Biol. 2008, 12, 292–296; (b)
Nowick, J. S. Org. Biomol. Chem. 2006, 4, 3869–3885; (c)Synthesis of Peptides and
Peptidomimetics (Houben-Weyl); Goodman, M., Felix, A., Moroder, L., Toniolo, C.,
Eds.; Georg Thieme: Stuttgart, Germany, 2003; Vol. E22c,. and references cited
therein (d) Cho, C. Y.; Moran, E. J.; Cherry, S. R.; Stephans, J. C.; Fodor, S. P. A.;
Adams, C. L.; Sundaram, A.; Jacobs, J. W.; Schultz, P. G. Science 1993, 261, 1303–
1305; (e) Boeijen, A.; van Ameijde, J.; Liskamp, R. M. J. J. Org. Chem. 2001, 66,
8454–8462.
Fmoc-Phe-w[CH2–I] had two distinct peaks at Rt values 16.5 and 17.1 min. This
confirmed that the samples of the epimers were optically pure.
33. Spectral data for selected compounds: Compound 3b: 1H NMR (300 MHz, CDCl3):
d 0.94 (d, 6H, J = 6.3 Hz), 1.30 (d, 3H, J = 5.8 Hz), 1.72–1.74 (m, 3H), 2.04 (m,
2H), 3.73 (s, 3H), 3.77 (m, 1H), 3.80 (m, 1H), 4.20 (t, 1H, J = 4.8 Hz), 4.39 (d, 2H,
J = 6.7 Hz), 5.15 (br, 1H), 5.16 (br, 1H), 7.29–7.76 (m, 8H) ppm; 13C NMR
(100 MHz, CDCl3): d 18.2, 19.9, 20.3, 23.4, 28.1, 40.1, 43.3, 47.5, 50.7, 52.5, 65.2,
126.6, 127.2, 127.9, 128.1, 141.2, 143.7, 154.6, 173.0, 195.3 ppm; IR: 1741,
1696, 1119 cmꢁ1
.
Compound 3c: 1H NMR (300 MHz, CDCl3): d 1.71 (m, 2H), 1.92 (m, 2H), 2.03 (s,
3H), 2.55 (m, 4H), 2.83 (d, 2H, J = 5.5 Hz), 3.72 (t, 2H, J = 7.1 Hz), 3.76 (s, 3H),
4.13 (t, 1H, J = 4.8 Hz), 4.23 (d, 2H, J = 6.2 Hz), 4.42 (m, 2H), 5.29 (br, 1H), 7.31–
7.77 (m, 8H) ppm; 13C NMR (100 MHz, CDCl3): d 16.3, 21.4, 26.4, 29.2, 30.7,
33.7, 46.3, 47.5, 49.8, 50.9, 55.6, 65.4, 127.2, 127.7, 128.4, 128.7, 140.0, 141.3,
4. (a) Patil, B. S.; Vasanthakumar, G. R.; Sureshbabu, V. V. J. Org. Chem. 2003, 68,
7274–7280; (b) Sureshbabu, V. V.; Patil, B. S.; Ramanarao, R. V. J. Org. Chem.
2006, 71, 7697–7705.
155.7, 172.4, 194.2 ppm; IR: 1747, 1712, 1125 cmꢁ1
.

7066
H. P. Hemantha, V. V. Sureshbabu / Tetrahedron Letters 50 (2009) 7062–7066
Compound 3f: 1H NMR (300 MHz, CDCl3): d 1.29 (s, 6H), 2.36 (d, 2H, J = 7.1 Hz),
Compound 7a: 1H NMR (300 MHz, CDCl3): d 0.93 (d, 6H, J = 5.2 Hz), 1.25 (s, 9H),
1.77 (m, 3H), 2.48–2.53 (m, 4H), 2.61 (d, 2H, J = 4.9 Hz), 3.48 (m, 1H), 3.51 (m,
1H), 4.06 (t, 1H, J = 4.2 Hz), 4.31 (d, 2H, J = 7.7 Hz), 6.47 (br, 2H), 7.11–7.82 (m,
13H) ppm; 13C NMR (100 MHz, CDCl3): d 19.7, 23.1, 27.3, 38.7, 39.8, 41.5, 46.7,
47.7, 48.9, 51.3, 65.2, 81.2, 127.3, 127.5, 127.6, 128.2, 128.4, 128.9, 129.1,
3.61 (s, 3H), 3.71 (d, 2H, J = 6.6 Hz), 3.82 (m, 1H), 5.11 (s, 2H), 5.62 (br, 2H),
7.11- 7.62 (m, 10H) ppm; 13C NMR (100 MHz, CDCl3): d 22.3, 39.6, 43.1, 51.3,
52.2, 60.1, 66.2, 127.1, 127.4, 127.6, 128.3, 128.8, 129.1, 140.1, 140.7, 154.3,
172.4, 192.3 ppm IR: 1738, 1693, 1179 cmꢁ1
.
Compound 4b: 1H NMR (300 MHz, CDCl3): d 1.25 (d, 3H, J = 6.2 Hz), 1.28 (d, 3H,
J = 5.8 Hz), 2.48 (d, 2H, J = 5.7 Hz), 2.51–2.67 (m, 4H), 3.58 (s, 3H), 3.71–3.92
(m, 3H), 4.17–4.32 (m, 3H), 5.92 (br, 1H), 6.11 (br, 2H), 7.25–7.79 (m, 13H)
ppm; 13C NMR (100 MHz, CDCl3): d 17.1, 17.4, 31.2, 32.5, 35.4, 40.7, 45.6, 48.6,
49.8, 52.1, 68.8, 126.6, 127.3, 127.5, 128.0, 128.3, 128.6, 129.1, 139.6, 140.7,
142.3, 160.2, 173.4, 192.5, 193.2 ppm; ESI-MS calcd for C33H37N3NaO4S4:
141.6, 142.2, 143.4, 155.7, 156.3, 194.2 ppm; IR: 1712, 1696, 1059 cmꢁ1
.
Compound 8c: 1H NMR (300 MHz, CDCl3): d 1.01 (d, 6H, J = 5.8 Hz), 1.62 (m,
2H), 1.77 (m, 1H), 2.61 (m, 2H), 3.41 (m, 1H), 3.42 (s, 3H), 3.65 (s, 2H), 5.07 (s,
2H), 6.37 (br, 2H), 6.92–7.34 (m, 5H) ppm; 13C NMR (100 MHz, CDCl3) d: 19.6,
22.8, 37.2, 41.7, 43.4, 51.2, 53.1, 63.4, 127.3, 127.7, 128.6, 140.8, 154.6, 166.8,
191.5 ppm; IR: 1734, 1689, 1147 cmꢁ1
.
690.15, found: 690.20 [M+Na]; IR: 1752, 1708, 1085, 1101 cmꢁ1
.
34. Boeijen, A.; van Ameijde, J.; Liskamp, R. M. J. J. Org. Chem. 2001, 66, 8454–8462.