A facile synthesis of N-Z/Boc-protected 1,3,4-oxadiazole-based peptidomimetics employing peptidyl thiosemicarbazides

Article abstract of DOI:10.1016/j.tetlet.2010.07.004

Synthesis of 1,3,4-oxadiazole containing peptidomimetics is described by a p-TsCl/pyridine-mediated cyclization of the corresponding dipeptidyl thiosemicarbazides, which are readily prepared by coupling N-protected amino acid hydrazides with amino acid-derived isothiocyanato esters. Further, the protocol has also been extended for the synthesis of orthogonally protected 1,3,4-oxadiazole tethered mimetics as well. The synthetic route is simple and mild conditions are used so that the chirality of the starting amino acids is retained.

Full text of DOI:10.1016/j.tetlet.2010.07.004

Tetrahedron Letters 51 (2010) 4705–4709
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Tetrahedron Letters
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A facile synthesis of N-Z/Boc-protected 1,3,4-oxadiazole-based
peptidomimetics employing peptidyl thiosemicarbazides
*
Ravi S. Lamani, G. Nagendra, 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:
Synthesis of 1,3,4-oxadiazole containing peptidomimetics is described by a p-TsCl/pyridine-mediated
cyclization of the corresponding dipeptidyl thiosemicarbazides, which are readily prepared by coupling
N-protected amino acid hydrazides with amino acid-derived isothiocyanato esters. Further, the protocol
has also been extended for the synthesis of orthogonally protected 1,3,4-oxadiazole tethered mimetics as
well. The synthetic route is simple and mild conditions are used so that the chirality of the starting amino
acids is retained.
Received 25 May 2010
Revised 26 June 2010
Accepted 1 July 2010
Available online 11 July 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
Peptidomimetics
Amino acid hydrazides
Peptidyl thiosemicarbazides
Cyclization
1,3,4-Oxadiazoles
1. Introduction
As a part of our continued interest in the synthesis of hetero-
cycles tethered peptidomimetics,17 we report herein the synthesis
Peptides are essential components of living organisms function-
ing as signal molecules such as hormones, neurotransmitters, and
neuromodulators. They exert an essential influence on basic bio-
logical functions including metabolism, reproduction, respiration,
and immune defense.1 However, their clinical applications have
been limited due to their rapid hydrolysis and low bioavailability.2
To circumvent some of these problems, peptide bonds are replaced
with a wide variety of structural functionalities such as retro-
amide, urea,3 peptoid,4 carbamate,5 sulfonamide,6 and heterocy-
cles,7 which contribute to the hydrolytic resistance and enhanced
bioavailability of the resulting peptidomimetics.
1,3,4-Oxadiazole is an important bioactive class of heterocycle
with a broad spectrum of pharmaceutical applications.8 In particu-
lar, marketed antihypertensive agents such as tiodazosin9 and
nesapidil10 as well as antibiotics such as furamizole11 contain the
oxadiazole nucleus. They have also been utilized as bioisosteres
of the carboxamide moiety in benzodiazepine receptor agonists,12
muscarinic receptor agonists,13 NK1 receptor antagonists,14 and in
the design of dipeptidomimetics15 as peptide building blocks. In
addition, 1,3,4-oxadiazoles are also useful intermediates in organic
synthesis, particularly as electron-deficient azadienes in the in-
verse electron demand Diels–Alder reactions.16
of 1,3,4-oxadiazole-derived peptidomimetics. Several approaches
have been reported to assemble 1,3,4-oxadiazole containing mole-
cules,18 in particular, 2-amino-1,3,4-oxadiazoles are prepared by
cyclization of the corresponding acyclic semicarbazide or thiosem-
icarbazide derivatives both in solution as well as in solid phase.
When thiosemicarbazides are used as oxadiazole precursors, a
variety of reagents have been employed for their cyclization
including I2/NaOH,19 carbodiimide,20 tosyl chloride (p-TsCl),21
and stoichiometric mercury salts.22 Selective activation of the
sulfur moiety followed by cyclization has also been achieved by
coupling reagents such as dicyclohexylcarbodiimide (DCC),23
1-ethyl-3-(3-dimethylaminoprophyl)carbodiimide (EDC),24 and
highly reactive alkylating agents such as methyl iodide25 and ethyl
bromoacetate.26
Though 1,2,4-oxadiazole bearing peptidomimetics are known in
the literature,17,18,27 the corresponding 1,3,4-oxadiazoles are
scanty. Luthman and co-workers,15 employed 1,3,4-oxadiazole to
synthesize enantiomerically pure Boc-Phe-Gly dipeptidomimetic
with a methylene spacer ( Fig. 1 A). For this, initially Boc-L-Phe
hydrazide was treated with methyl malonyl chloride in the pres-
ence of SOCl2/pyridine to afford 1,2,3,4-oxathiadiazole S-oxide
intermediate which on thermal elimination of sulfur dioxide
yielded the target mimetic. They also reported several Xaa-Gly
mimetics containing 1,3,4-oxadiazoles (Fig. 1 B).28 Batey and co-
workers,29 described a one-pot procedure for the synthesis of
1,3,4-oxadiazoles from Boc-protected amino acid hydrazides and
arylisothiocyanates in the presence of HgCl2 (Fig. 1 C). Kudelko
* Corresponding author. Tel.: +91 08 2296 1339/09986312937.
E-mail addresses: sureshbabuvommina@rediffmail.com, hariccb@gmail.com,
hariccb@hotmail.com (V.V. Sureshbabu).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.004

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R. S. Lamani et al. / Tetrahedron Letters 51 (2010) 4705–4709
R1
O
R3
H
N
OH
R1
H2N
N
H
O
R2
O
n
Native Peptide
H
N
COOEt
R6
R5
O
O
O
R4
BocHN
BocHN
Ac/BocHN
O
N
H
COOEt
N N
N N
N N
N N
A
B
C
D
R1 = R2 = R3 = amino acid side chain
R4 = Ac/Boc or H-Xaa
R5 = H, Me,Br, NO2 etc.,
R6 = H, Me, Et, Ph
R1
O
H
N
O
X
O
Z/BocHN
R2
N N
X = Me, Bn
4
Figure 1.
and Zielinski30 group reported the synthesis of 2-aminomethyl-
were prepared by the reaction of N-protected amino acid-derived
hydrazides and isothiocyanato esters. Initially, several N-Boc/Z-
protected amino acids were converted to the corresponding hydra-
zides 1 following the literature procedure.31 The isothiocyanates 2
derived from amino acid esters are well known entities in peptide
chemistry.32 We have recently reported the synthesis of Nb-ure-
thane-protected amino alkyl isothiocyanates and demonstrated
their utility in the synthesis of dithioureidopeptides.33 Following
the similar protocol, in the current study, isothiocyanato esters
were prepared by treating the amino acid esters with CS2 and
triethylamine (TEA) in THF at 0 °C for 20 min and subsequent
decomposition of the in situ generated dithiocarbamic acid salt
with p-TsCl at the same temperature.34 In the next step, the reac-
tion of 1 with the isothiocyanato esters 2 in THF afforded the cor-
responding Boc/Z-peptidyl thiosemicarbazides 3 (Scheme 1, Table
a
a
1,3,4-oxadiazoles from N -Ac and N -Boc-protected phenylglycine
hydrazide and triethyl orthoesters under reflux in acetic acid (Fig. 1
D). To the best of our knowledge, 1,3,4-oxadiazole bearing dipepti-
domimetics of the type 4 are yet to be reported. This letter
describes the facile synthesis of 1,3,4-oxadiazole linked peptidom-
imetics via the corresponding thiosemicarbazides which possess
both amino and carboxy functionalities, which can be employed
for the elongation of the peptide chain or to increase the molecular
diversity.
2. Results and discussion
In the present work, the precursor, peptidyl thiosemicarbazides
which themselves are hitherto unreported class of intermediates,
R2
R1
S
R2
R1
H
N
THF
rt
H
N
O
O
SCN
X
PgHN
O
N
H
N
H
X
PgHN
NH2
O
O
O
O
1
2
3
R1
H
N
p-TsCl, Py
O
X
PgHN
O
THF, , 3 h
R2
N N
4
Scheme 1. Synthesis of oxadiazoles 4.
Table 1
List of dipeptidyl thiosemicarbazides 3 prepared
Entry
Hydrazide 1
Amino acid
Isothiocyanate 2
Time (h)
Mp (°C)
Yield (%)
Mass calcd/obsd
Pg
3a
3b
3c
3d
3e
3f
Boc
Boc
Boc
Boc
Z
Ala
Phe
Pro
Asp(Bzl)
Phe
Leu-OMe
Val-OMe
Lys(Z)-OMe
Phg-OMe
Ala-OMe
2.0
0.5
1.0
2.0
0.5
0.5
Gum
68
Gum
72
108
112
75
68
64
74
88
82
413.2/413.1a
475.1991/475.1996b
566.2/566.5c
567.1889/567.1883b
459.1702/459.1708d
459.1702/459.1707d
Z
Phe
D
-Ala-OMe
3g
3h
3i
Z
Z
Z
Z
Leu
Met
Val
Cys(Bzl)
Ala-OMe
Val-OMe
Phe-OMe
Benzyl
1.0
1.5
1.0
0.5
Gum
69
140
139
80
76
69
92
447.1678/447.1686b
471.2/471.0c
487.2/487.1c
3j
531.1501/531.1508b
a
b
c
ESI-MS [M+Na+].
HRMS [M+Na+].
ESI-MS [M+H+].
HRMS [M+H+].
d

R. S. Lamani et al. / Tetrahedron Letters 51 (2010) 4705–4709
4707
1). The reaction proceeded smoothly at room temperature and the
chromatographic purification yielded analytically pure peptidyl
thiosemicarbazides in good yields.35
In the next step, the cyclization reaction of the thiosemicarbaz-
ides 3 was undertaken. Various aforementioned reagents like DCC,
p-TsCl, and HgCl2 were explored for cyclodesulfurisation. However,
during the optimization of reaction conditions, p-TsCl/pyridine21
was found to be attractive in terms of furnishing good yield and
mild reaction condition. In a typical procedure, Boc-Phe-NH-NH-
CS-Val-OMe 3b on treating with 1.5 equiv of p-TsCl and 2.5 equiv
of pyridine in THF under reflux for 3 h resulted in the formation
of 1,3,4-oxadiazole derivative 4b which was isolated by a simple
work-up followed by column chromatography in good yield36
(Scheme 1, Table 2). Extending this protocol, a series of Boc and
Table 2
List of oxadiazoles 4
Entry
Compound
Mp (° C)
Yield (%)
80
Mass calcd/obsd
357.2/357.6a
O
O
H
N
O
BocHN
O
O
4a
Gum
N N
441.2114/441.2118b
532.3/532.2a
H
N
4b
4c
78
74
73
O
BocHN
BocN
N N
O
H
O
N
Gum
O
N N
NHCbz
O
BzlO
O
H
N
O
4d
4e
Gum
171
68
84
533.2012/533.2017b
447.1644/447.1649b
BocHN
O
N N
O
H
N
O
ZHN
ZHN
O
N N
O
425.2/425.2a
H
N
4f
178
175
76
71
O
O
N N
O
H
4g
413.1801/413.1798b
O
N
ZHN
S
O
N N
O
O
H
N
4h
120
68
459.1678/459.1684b
O
ZHN
ZHN
O
O
N N
H
N
O
4i
4j
175
101
78
85
475.1957/475.1962b
475.2/475.0a
N
N
BzlS
ZHN
H
N
O
N N
ESI-MS [M+H+].
HRMS [M+Na+].
a
b

4708
R. S. Lamani et al. / Tetrahedron Letters 51 (2010) 4705–4709
R1
H
S
R1
NHPg2
H
N
THF, rt
N
NHPg2
SCN
Pg1HN
N
H
N
H
Pg1HN
NH2
R2
R2
O
O
1
5
R1
R2
H
N
p
-TsCl, Py
O
Pg1HN
NHPg2
THF, , 4 h
N
N
6
Scheme 2. Synthesis of orthogonally protected 1,3,4-oxadiazoles 6.
3. Sureshbabu, V. V.; Patil, B. S.; Venkataramanarao, R. J. Org. Chem. 2006, 71,
7697.
Table 3
List of orthogonally protected oxadiazoles 6
4. Simon, R. J.; Kania, R. S.; Zuckermann, R. N.; Huebner, V. D.; Jewell, D. A.;
Banville, S.; Ng, S.; Wang, S.; Rosenberg, S.; Marlowe, C. K.; Spellmeyer, D. C.;
Tan, R.; Frankel, A. D.; Santi, D. V.; Cohen, F. E.; Bartlett, P. A. Proc. Natl. Acad. Sci.
U.S.A. 1992, 89, 9367.
5. Cho, C. Y.; Moran, E. J.; Cherry, S. R.; Stephans, J. C.; Fodor, S. P.; Adams, C. L.;
Sundaram, A.; Jacobs, J. W.; Schultz, P. G. Science 1993, 261, 1303.
6. Moree, W. J.; Van der Marel, G. A.; Liskamp, R. J. J. Org. Chem. 1995, 60, 5157.
7. Videnov, G.; Kaiser, D.; Kempter, C.; Jung, G. Angew. Chem., Int. Ed. 1996, 35,
1503.
8. (a) Rostom, S. A. F.; Shalaby, M. A.; El-Demellawy, M. A. Eur. J. Med. Chem. 2003,
38, 959; (b) Holla, B. S.; Gonsalves, R.; Shenoy, S. Eur. J. Med. Chem. 2000, 35,
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9. Vardan, S.; Smulyan, H.; Mookherjee, S.; Eich, R. Clin. Pharm. Ther. 1983, 34, 290.
10. Schlecker, R.; Thieme, P. C. Tetrahedron 1988, 44, 3289.
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12. Tully, W. R.; Gardner, C. R.; Gillespie, R. J.; Westwood, R. J. Med. Chem. 1991, 34,
2060.
Entry
Hydrazide 1
Isothiocyanate 5
Yield (%)
6a
6b
6c
Boc-Ala
Boc-Leu
Z-Phe
Z-Val
Z-Phe
Boc-Val
72
69
74
Z-protected 1,3,4-oxadiazole containing dipeptidomimetics 4a–j
were prepared. All the synthesized dipeptidyl 1,3,4-oxadiazole
derivatives were characterized by 1H NMR, 13C NMR, and mass
spectroscopic analyses. Also the course of the reaction was found
to be recemization free as was evident by both 1H NMR37 and HPLC
studies.38
The present approach was then extended to prepare the orthog-
13. Orlek, B. S.; Blaney, F. E.; Brown, F.; Clark, M. S. G.; Hadley, M. S.; Hatcher, J.;
Riley, G. J.; Rosenberg, H. E.; Wadsworth, H. J.; Wyman, P. J. Med. Chem. 1991,
34, 2726.
14. Ladduwahetty, T.; Baker, R.; Cascieri, M. A.; Chambers, M. S.; Haworth, K.;
Keown, L. E.; MacIntyre, D. E.; Metzger, J. M.; Owen, S.; Rycroft, W.; Sadowski,
S.; Seward, E. M.; Shepheard, S. L.; Swain, C. J.; Tattersall, F. D.; Watt, A. P.;
Williamson, D. W.; Hargreaves, R. J. J. Med. Chem. 1996, 39, 2907.
15. Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.; Terenius, L.; Luthman, K. J. Med.
Chem. 1999, 42, 4331.
16. (a) Ishikawa, H.; Elliott, G. I.; Velcicky, J.; Choi, Y.; Boger, D. L. J. Am. Chem. Soc.
2006, 128, 10596; (b) Elliott, G. I.; Fuchs, J. R.; Blagg, B. S. J.; Ishikawa, H.; Tao,
H.; Yuan, Z.-Q.; Boger, D. L. J. Am. Chem. Soc. 2006, 128, 10589.
17. (a) Sureshbabu, V. V.; Hemantha, H. P.; Naik, S. A. Tetrahedron Lett. 2008, 49,
5133; (b) Sureshbabu, V. V.; Venkataramanarao, R.; Naik, S. A.;
Chennakrishnareddy, G. Tetrahedron Lett. 2007, 48, 7038; (c) Narendra, N.;
Vishwanatha, T. M.; Sudarshan, N. S.; Sureshbabu, V. V. Protein Pept. Lett. 2009,
16, 1029.
18. Jakopin, Z.; Dolenc, M. S. Curr. Org. Chem. 2008, 12, 850.
19. Rai, K. M. L.; Linganna, N. Farmaco 2000, 55, 389.
20. (a) Coppo, F. T.; Evans, K. A.; Graybill, T. L.; Burton, G. Tetrahedron Lett. 2004, 45,
3257; (b) Baxendale, I. R.; Ley, S. V.; Martinelli, M. Tetrahedron 2005, 61, 5323.
21. Dolman, S. J.; Gosselin, F.; O’Shea, P. D.; Davies, I. W. J. Org. Chem. 2006, 71,
9548.
22. Wang, X.; Li, Z.; Wei, B.; Yang, J. Synth. Commun. 2002, 32, 1097.
23. (a) Ahmed, M. M.; Aboulwafa, O. M.; Kader, O. Monatsh. Chem. 1989, 120, 571;
(b) Aboulwafa, O. M.; Omar, A.; Mohsen, M. E. Sulfur Lett. 1992, 14, 181.
24. Severinsen, R.; Kilbrun, J. P.; Lau, J. F. Tetrahedron 2005, 61, 5565.
25. Fulop, F.; Semega, E.; Dombi, G.; Bernath, G. J. Heterocycl. Chem. 1990, 27, 951.
26. Kucukguzel, S. G.; Oruc, E. E.; Rollas, S.; Sahin, F.; Ozbek, A. Eur. J. Med. Chem.
2002, 37, 197.
onally protected oxadiazoles
6 as well (Scheme 2). In this
approach, both the starting materials, that is, hydrazides and iso-
thiocyanates were prepared through the carboxy modification of
N-protected amino acid. Orthogonality of the N-protecting group
of participating reactants was maintained so as to enable selective
chain extension. For this, Boc/Z-protected amino alkyl isothiocya-
nates were prepared from the corresponding vicinal diamines,32
purified, and subsequently coupled with Z/Boc-amino acid hydra-
zides 1 in THF to obtain the key thiosemicarbazide intermediates
which upon desulfurative cyclization with p-TsCl/pyridine under
reflux conditions furnished the oxadiazoles 6 in good yields.39
The crude 1,3,4-oxadiazoles were purified through column chro-
matography and were fully characterized (Table 3). HPLC analysis
carried out on these derivatives proved that all the products are
free from racemization.37
In conclusion, a simple and convenient method for the synthesis
of 1,3,4-oxadiazole-linked dipeptidomimetics from corresponding
peptidyl thiosemicarbazides has been described. The protocol has
also been extended to prepare few N,N0-orthogonally protected
dipeptidomimetics. All the products were found to be chemically
homogeneous as analyzed by spectroscopic techniques. These
dipeptidomimetics can be utilized for the preparation of 1,3,4-oxa-
diazole containing oligopeptidomimetics through N- and C-termi-
nal chain extensions.
27. Pace, A.; Pierro, P. Org. Biomol. Chem. 2009, 7, 4337.
28. Borg, S.; Estenne-Bouhtou, G.; Luthman, K.; Csoeregh, I.; Hesselink, W.;
Hacksell, U. J. Org. Chem. 1995, 60, 3112.
Acknowledgments
29. Gavrilyuk, J. I.; Lough, A. J.; Batey, R. A. Tetrahedron Lett. 2008, 49, 4746.
30. Kudelko, A.; Zielinski, W. Tetrahedron 2009, 65, 1200.
31. (a) Gillessen, D.; Schnabel, E.; Meinhofer, J. Justus Liebigs Ann. Chem. 1963, 667,
164; (b) Strachan, R. G.; Paleveda, W. J.; Nutt, R. F.; Vitali, R. A.; Veber, D. F.;
Dickinson, M. J.; Grasky, V.; Deak, J. E.; Walton, E.; Jenkins, S. R.; Holly, F. W.;
Hirschmann, R. J. Am. Chem. Soc. 1969, 91, 503; (c) Guttmann, S.; Boissonnas, R.
A. Helv. Chim. Acta 1960, 43, 200.
32. Nowick et al., reported the synthesis of peptidyl isothiocyanates employing
modified Schotten–Baumann conditions under biphasic system by treating
peptide esters with thiophosgene. See: Nowick, J. S.; Holmes, D. L.; Noronha, G.;
Smith, E. M.; Nguyen, T. M.; Huang, S. J. Org. Chem. 1996, 61, 3929.
33. Sureshbabu, V. V.; Naik, S. A.; Hemantha, H. P.; Narendra, N.; Das, U.; Row, T. N.
G. J. Org. Chem. 2009, 74, 5260.
This research was supported by the Council of Scientific and
Industrial Research (Grant No. 01(2323)/09/EMR-II), Govt. of India
and R.S.L. thanks University Grants Commission, New Delhi, India
for the award of Dr. D. S. Kothari Postdoctoral Fellowship.
References and notes
1. Fletcher, M. D.; Campbell, M. Chem. Rev. 1998, 98, 763.
2. (a) Davis, S. S. In Perspectives in Medicinal Chemistry; Testa, B., Kyburz, E., Fuhrer,
W., Giger, R., Eds.; Verlag Helvetica Chimica Acta: Basel, 1993; pp 533–544; (b)
Hummel, G.; Reineke, U.; Reimer, U. Mol. BioSyst. 2006, 2, 499.
34. General procedure for the synthesis of isothiocyanato amino acid ester 2: To a
solution of amino acid ester salt (10 mmol) in CH2Cl2 was added CS2 (0.66 mL,
11 mmol) followed by TEA (5.58 mL, 40 mmol) at 0 °C, and stirred for 30 min at

R. S. Lamani et al. / Tetrahedron Letters 51 (2010) 4705–4709
4709
the same temperature and then for 30 min at room temperature. The reaction
mixture was again cooled to 0 °C and p-TsCl (2.48 g, 13 mmol) was added. The
stirring was continued for 3 h or until the completion of the reaction (TLC
analysis). An excess of DCM (5 mL ꢀ 2) was added and the organic layer was
washed twice with 10% citric acid solution (15 mL), followed by water
(10 mL ꢀ 2) and brine (10 mL ꢀ 2). It was then dried over anhydrous sodium
sulfate and concentrated under reduced pressure. The resulting crude product
was subjected to column chromatography (10% EtOAc in hexane) to afford the
product as pure one.
J = 4.8 Hz, 1H), 3.71 (s, 3H), 3.97–4.04 (m, 1H), 5.21 (br, 1H), 7.03–7.18 (m, 5H);
13C NMR (CDCl3, 75 MHz) d 18.52, 28.31, 33.67, 47.5, 49.55, 52.30, 63.38, 79.11,
126.26, 127.44, 127.80, 128.83, 130.88, 136.42, 155.36, 170.62, 171.51, 171.60;
HRMS calcd for C21H30N4O5 m/z 441.2114 [M+Na+], found 441.2118 [M+Na+].
37. Two epimeric thiosemicarbazides Z-Phe-
w-[CONHNHCSNH]-L-Ala-OMe 3e and
Z-Phe- -[CONHNHCSNH]-
w
D
-Ala-OMe 3f were prepared. In the 1H NMR
spectrum, the alanyl methyl group of 3e appeared as doublet at 1.40 and
1.42 ppm, while 3f had distinct doublets at 1.43 and 1.45 ppm confirming the
presence of single epimer in each sample. In a similar way, the oxadiazole
35. General procedure for the synthesis of thiosemicarbazide 3: To a solution of
samples Z-Phe-
were studied and in this case also the alanyl methyl group was observed as
distinct doublets at 1.39 and 1.41; 1.41, and 1.43, respectively, thus
w-[C2N2O]-L-Ala-OMe, 4e and Z-Phe-w-[C2N2O]-D-Ala-OMe, 4f
hydrazide
1 (10 mmol) in THF (10 mL) was added the isothiocyanate 2
(10 mmol), and the reaction mixture was stirred at room temperature till the
completion of the reaction (TLC analysis). The solvent was removed under
reduced pressure and the crude compound was purified by column
chromatography (20% EtOAc in hexane). Data for compound 3e: yield 88%; Rf
0.20 (4:6 EtOAc/n-hexane); 1H NMR (CDCl3, 300 MHz) d 1.43 (d, J = 6.8 Hz, 3H),
3.08–3.14 (m, 1H), 3.33–3.39 (m, 1H), 3.72 (s, 3H), 4.12–4.18 (m, 1H), 4.22 (t,
J = 7.2 Hz, 1H), 4.97 (br, 1H), 5.07 (s, 2H), 5.97 (br, 1H), 7.20–7.33 (m, 10H), 8.85
(br, 1H), 9.52 (br, 1H); 13C NMR (CDCl3, 75 MHz) d 16.35, 37.79, 54.19, 54.31,
60.37, 67.11, 127.81, 127.70, 127.97, 128.35, 128.49, 128.57, 128.63, 129.11,
129.34, 129.42, 133.56, 135.85, 156.48, 170.82, 171.71, 181.13; HRMS calcd for
d
confirming the absence of racemization.
38. HPLC particulars: Agilent 1100 series having G1311A VWD at k = 254 nm, flow
0.5 mL/min, Column: Agilent Eclipse XDB-C18, pore size-5
lm, diameter ꢀ
length = 4.6 ꢀ 150 mm; Method: gradient 0.1% TFA water–acetonitrile;
acetonitrile 30–100% in 30 min. HPLC profile of thiosemicarbazide, 3e and its
epimer, 3f had peaks at Rt values of 14.98 and 15.02 min, respectively.
Similarly, the oxadiazole samples 4e and its epimer 4f appeared at Rt 19.68 and
18.56 min, respectively. Thus from the above observations it is evident that the
dipeptide derivatives are optically pure and free from racemization. Similarly
for the compound 6a, the Rt value is 12.28 min and for its epimer prepared
C
22H26N4O5S m/z 459.1702 [M+H+], found 459.1708 [M+H+].
36. General procedure for the synthesis of oxadiazoles 4: To
a
solution of
from Boc-D-Ala is 12.06 min.
thiosemicarbazide 3 (10 mmol) in THF (10 mL), p-TsCl (2.85 g, 15 mmol) and
pyridine (2 mL, 25 mmol) were added and it was refluxed for 3 h. The solvent
was removed in vacuo and the crude was dissolved in EtOAc and it was washed
successively with 10% citric acid (10 mL ꢀ 2), 5% Na2CO3 (10 mL), water
(2 ꢀ 10 mL), brine (10 mL), and dried over anhydrous sodium sulfate. The
solvent was removed under vacuum and purified by column chromatography
(20% EtOAc in hexane) to afford analytically pure product. Data for compound
4b: yield 74%; Rf 0.33 (4:6 EtOAc/n-hexane); 1H NMR (CDCl3, 300 MHz) d 0.98
(d, J = 5.2 Hz, 6H), 1.36 (s, 9H), 2.18–2.24 (m, 1H), 2.83–2.89 (m, 2H), 3.36 (d,
39. Compound 6a: yield 72%; Rf 0.35 (4:6 EtOAc/n-hexane); 1H NMR (CDCl3,
300 MHz) d 0.98 (d, J = 6.2 Hz, 6H), 1.38 (s, 9H), 1.28 (d, J = 4.8 Hz, 3H), 2.32–
2.38 (m, 1H), 3.28–3.34 (m, 1H), 3.48–3.54 (m, 1H), 3.83–3.88 (m, 1H), 4.60–
4.65 (m, 1H), 4.90 (br, 1H), 5.06 (s, 2H), 5.61 (br, 1H), 7.03–7.24 (m, 5H), 8.81
(br, 1H); 13C NMR (CDCl3, 75 MHz) d 15.11, 19.17, 29.21, 30.74, 45.67, 47.70,
53.82, 66.39, 80.02, 127.03, 127.87, 128.14, 128.49, 129.49, 135.87, 153.12,
156.34, 169.66, 171.28; HRMS calcd for C22H33N5O5 m/z 470.2379 [M+Na+],
found 470.2383 [M+Na+].