A convenient synthesis of 1,3,4-thiadiazole and 1,3,4-oxadiazole based peptidomimetics employing diacylhydrazines derived from amino acids

Article abstract of DOI:10.1016/j.tetlet.2010.09.122

Synthesis of novel orthogonally protected 1,3,4-thiadiazole and 1,3,4-oxadiazole tethered dipeptide mimetics is described. Both the heterocycles are prepared via a set of diacylhydrazines derived from amino acids. 1,3,4-Thiadiazoles are synthesized by deh

Full text of DOI:10.1016/j.tetlet.2010.09.122

Tetrahedron Letters 51 (2010) 6338–6341
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A convenient synthesis of 1,3,4-thiadiazole and 1,3,4-oxadiazole based
peptidomimetics employing diacylhydrazines derived from amino acids
⇑
G. Nagendra, Ravi S. Lamani, N. Narendra, 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 novel orthogonally protected 1,3,4-thiadiazole and 1,3,4-oxadiazole tethered dipeptide
mimetics is described. Both the heterocycles are prepared via a set of diacylhydrazines derived from
amino acids. 1,3,4-Thiadiazoles are synthesized by dehydrosulfurization using Lawesson’s reagent while
1,3,4-oxadiazoles are obtained by EDC mediated cyclodehydration.
Received 30 August 2010
Revised 23 September 2010
Accepted 25 September 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Peptidomimetics
Diacylhydrazine
Cyclization
Thiadiazole
Oxadiazole
The changes in conformation, polarity and metabolic stability
generated by structural modifications of peptide backbone have
prompted the synthesis of several new classes of peptide mimics,
which contain unnatural linkages as replacements for the native
peptide bonds. These molecules have shown enhanced potency,
specificity and oral bioavailability than the natural peptides and
are considered to be potential candidates in drug discovery.1 One
such important class of molecules is peptides substituted with het-
erocycles, also referred to as peptide heterocycles. The heterocyclic
unit in these molecules can introduce conformational constraints
to the structure that enhances the activity and alters the struc-
ture–activity-relationships.2 Thus several heterocycles such as
1,2,3- and 1,2,4-triazole,3 oxazole,4 thiazole, and tetrazole,5 have
been inserted en route to the design of new peptidomimetics. 2-Al-
kyl amino-1,3,4-oxadiazole based peptidomimetics have been de-
scribed earlier by our group.6 In view of the above and as a part
of our ongoing work on the synthesis of amino acids and peptide
derivatives containing heterocyclic units,7 we herein report the
facile synthesis of novel N,N0-orthogonally protected 1,3,4-thi-
adiazolo- and 1,3,4-oxadiazolo-substituted peptides. Substances
bearing these heterocycles have attracted significant interest in
medicinal and bio-organic chemistry. For example, thiadiazole
derivatives are known to be potent aminopeptidase inhibitors8
and metalloprotease inhibitors.9 Similarly, biologically relevant
entities containing the oxadiazole motif include HIV integrase
inhibitors and the angiogenesis inhibitors.10,11
Although numerous reports are available for the construction of
1,2,4-oxadiazole peptidomimetics,7a,12 the reports on the synthesis
of 1,3,4-oxadiazole and 1,3,4-thiadiazoles containing peptides are
rare. Recently Katritzky et al.,13 described a related class of com-
pounds which are amino acid derivatives containing 2-alkyl
amino-1,3,4-thiadiazole units. The synthesis consisted of coupling
N-protected amino acid hydrazides with alkyl isothiocyanates fol-
lowed by dehydration of the resulting thiosemicarbazides. Several
others have reported the synthesis of molecules containing a 1,3,4-
thiadiazole unit starting from alkyl and aryl diacylhydrazines.14
The standard method for the synthesis of 1,3,4-thiadiazoles
involves cyclization of N0-(acyl)thiohydrazide15a or thiosemicar-
bazides15b employing usually POCl3, PCl5, MsOH, or H2SO4 as dehy-
drating agents. The other important route is via the exchange of
the oxygen atom in 1,3,4-oxadiazole to sulfur using thiourea and
tetraphosphorus decasulfide.16 Following the former route, Katri-
a
tzky et al.,13 have used H2SO4 for the cyclization of N -Cbz pro-
tected amino acid derived thiosemicarbazides and have obtained
the thiadiazole products with concomitant removal of the Cbz-
group. We envisaged that the use of strong acidic conditions for
cyclization, apart from being harsh, is not suitable for amino acid
substrates when they bear acid sensitive protecting group(s). In
this regard, we sought a mild and effective route for the insertion
of 1,3,4-thiadiazole into peptides.
Luthman17 and co-workers reported the synthesis of Phe-Gly
dipeptidomimetics containing 1,3,4-oxadiazole and 1,2,4-oxadiaz-
ole and Gly mimetics containing 1,3,4-oxadiazoles18 through
⇑
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.2010.09.122

G. Nagendra et al. / Tetrahedron Letters 51 (2010) 6338–6341
6339
R2
R1
cyclodehydration of diacylhydrazines derived from Boc-Phe-
NHNH2 and methyl malonyl chloride. Huryn and co-workers,19
synthesized S-linked 2,5-disubstituted oxadiazoles through
chemoselective alkylation of oxadiazolethiones obtained from
Boc-Trp-NHNH2. Synthesis of amino acid derived oxadiazoles via
the dehydrothiolative cyclization of thiosemicarbazide has also
been reported.20 The present report deals with the synthesis of
1,3,4-thiadiazole and oxadiazole based peptidomimetics through
S
NHPg2
Pg1HN
Pg1HN
(a)
75-90%
R1
O
N
N
H
N
NHPg2
4
Pg1HN
N
H
R2
R1
O
R2
O
(b)
70-92%
3
NHPg2
N
N
5
a facile route which involves N,N0-di-
a-aminoacyl hydrazines as
common precursors.
Scheme 2. Synthesis of 1,3,4-thiadiazoles 4 and 1,3,4-oxadiazoles 5. Reagents and
conditions: (a) LR, THF, reflux, 3 h, (b) EDC/TEA, DCM, reflux, 3 h.
The required diacylhydrazines were synthesized as follows. Ini-
tially, the N-Boc/Z-protected amino acids were converted to their
corresponding hydrazides 1 following the reported protocol.21 N-
Acylation of the latter with a second amino acid to furnish the dia-
cylhydrazine was achieved by the treatment with N-Boc/Z pro-
Table 2
List of 1,3,4-thiadiazoles 4/oxadiazoles 5 prepared
Entry
Mp (°C)
Yield (%)
Mass
tected
a-amino acid fluorides. Unlike amino acid chlorides, N-
Calcd
Obsd
urethane protected amino acid fluorides are excellent coupling re-
agents for both solution and solid phase synthesis. Their most
impressive application is in the synthesis of extremely hindered
dipeptides.22 The N-protected amino acid fluorides 2 used were
prepared through the reaction of protected amino acids with
Deoxo-fluor23 in the presence of N-methylmorpholine (NMM). In
a typical example, Fmoc-Ala-F was treated with Boc-Phe-NHNH2
in dry CH2Cl2 at room temperature for 30 min. The resulting pepti-
dyl diacylhydrazine 3b was isolated and purified (Scheme 1).24 The
list of N-protected diacylhydrazines prepared is summarized in Ta-
ble 1.
Lawesson and co-workers, have described the thionation of 1,2-
diacylhydrazines with 2,4-bis(4-methoxypheny1)-1,2,3,4-dithiadi-
phosphetane (Lawesson’s reagent, LR), followed by spontaneous
ring closure through dehydrosulfurization leading to the formation
of thiadiazole ring.25 Their study dealt mainly with the preparation
of dialkyl thiadiazoles. We sought to extend this route for the syn-
thesis of thiadiazole tethered N,N0-orthogonally protected dipepti-
domimetics 4 through the direct cyclization of diacylhydrazines
(without the requirement of a separate thionation step).
4a
5a
4b
5b
4c
5c
4d
5d
4e
5e
4f
128
83
82
73
94
81
90
86
76
80
95
91
83
81
96
88
83
71
79
88
90
94
651.2253
613.2662
593.2
555.2607
593.2198
577.2427
593.2
555.2641
467.1787
451.2
647.3
631.3
633.2
639.2583
586.2675
570.3
435.2
441.2
651.2257b
613.2668a
593.3d
Gum
131
123
148
Gum
113
148
Gum
197
56
152
141
78
Gum
145
126
Gum
93
555.2610a
593.2196b
577.2426b
593.2d
555.2646a
467.1792a
451.2c
647.8c
5f
631.2c
4g
5g
4h
5h
4i
5i
4j
5j
633.3c
639.2588b
586.2679b
570.8d
435.0c
441.3d
c
340.1
346.3357
340.8
346.3362b
a
b
c
HRMS [M+H+].
HRMS [M+Na+].
ESI-MS [M+H+].
ESI-MS [M+Na+].
In a typical experiment, the diacylhydrazine 3b was refluxed
with LR in THF for 3 h which yielded the 1,3,4-thiadiazolo-dipeptide
4b. The same protocol was used to prepare several differentially pro-
tected 1,3,4-thiadiazolo-peptides 4a–j containing N,N0-orthogonal
amino protecting groups (Scheme 2, Table 2, Fig 1).26
The synthesis of oxadiazolo-peptides 5a–j was then under-
taken. 1,3,4-Oxadiazoles have been synthesized by several ap-
proaches, involving dehydrocyclization of diacylhydrazines and
d
X
X
CbzHN
NHBoc
CbzHN
N
N
N
N
X = S, 4i
X = O, 5i
X = S, 4j
X = O, 5j
Figure 1.
R1
R2
R1
O
H
N
H
N
DCM, rt
30 min
F
NHPg2
Pg1HN
NH2
Pg2HN
Pg1HN
N
H
R2
oxidation of acylhydrazones. In the former route regents such as
O
O
O
3
2
1
Et2OꢀBF3,27 hexamethyldisilazane,28 Tf2O,29 polyphosphoric acid,30
Pg1 = Boc or Z group
31
SOCl2. and POCl3 have been frequently used as dehydrating
Pg2 = Boc, Z or Fmoc group
Scheme 1. Synthesis of diacylhydrazines 3.
agents for cyclization. However, the use of these reagents is not al-
ways compatible with amino acid/peptides due to their ability to
Table 1
List of diacyl hydrazines 3 prepared
Compd
Pg1
Amino acid (R1)
Pg2
Amino acid (R2)
Mp (°C)
Yield (%)
3a
3b
3c
Boc
Boc
Boc
Gly
Phe
Phe
Fmoc
Fmoc
Fmoc
Glu(Bzl)
Ala
Gum
178
178
78
90
90
D-Ala
3d
3e
3f
3g
3h
Boc
Boc
Z
Z
Z
Ile
Ala
Phe
Val
Z
Z
Cys(Bzl)
Met
Leu
Phe
Ala
151
Gum
205
167
147
81
84
89
96
76
Fmoc
Fmoc
Boc
Lys(Boc)

6340
G. Nagendra et al. / Tetrahedron Letters 51 (2010) 6338–6341
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Chem. 1999, 42, 4331.
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19. Myers, M. C.; Shah, P. P.; Diamond, S. L.; Huryn, D. M.; Smith, A. B. Bioorg. Med.
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21. 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.
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1999, 64, 7048; (b) Singh, R. P.; Shreeve, J. M. Synthesis 2002, 2561.
24. Typical experimental procedure for the synthesis of diacylhydrazines 3.
To a solution of hydrazide 1 (10 mmol), in DCM (10 mL) was added a solution
of acid fluoride 2 (10 mmol) in DCM (5 mL) and the mixture was stirred at rt for
30 min or till the completion of the reaction (TLC analysis). The solvent was
evaporated under reduced pressure and the residue was extracted with EtOAc.
The organic layer was washed with citric acid (10%, 10 mL ꢁ 2), Na2CO3 (10%,
10 mL ꢁ 2), water (10 mL) and brine (10 mL) and finally dried over anhydrous
Na2SO4.
cause undesired reactions like cleavage of protecting groups. The
mild reagents generally used are carbodiimides,32 TsCl/pyridine33
,
trimethyl silylchloride34, and Burgess reagent.35 Therefore, we fo-
cused on employing ethyl-3-(3-dimethylaminoprophyl)carbodiim-
ide (EDC) as cyclodehydrating agent. EDC was particularly
attractive because of easy handling, simplicity associated to the
workup of the product, efficiency in terms of product yield and
the familiarity with its use in peptide and peptidomimetic(s) syn-
thesis. In a typical procedure, the reaction of the N-Boc, N0-Fmoc
protected diacylhydrazine 3b in dry CH2Cl2 was refluxed in the
presence of 1 equiv of EDC and 1.5 equiv of triethylamine (TEA)
for 3 h which resulted in the formation of 1,3,4-oxadiazole deriva-
tive 5b in almost quantitative yield. Extending the protocol further,
a series of Boc, Z and Fmoc-protected 1,3,4-oxadiazole containing
dipeptidomimetics 5a–j were prepared starting from the corre-
sponding diacylhydrazides (Scheme 2, Table 2, Fig. 1).36
Using the above protocols, the 1,3,4-thiadiazole/oxadiazole
moieties were also inserted between an orthogonally protected
sterically hindered dipeptide Z-Aib-CONHNHCO-Aib-Boc (Fig. 1,
4i and 5i). In another example Z-Ala-CONHNH2 was coupled to
C6H5COF and subsequently cyclized into 1,3,4-thiadiazole/oxadiaz-
ole derivative (Fig. 1, 4j and 5j).
Finally, the possibility of racemization during the synthesis of
title thiadiazoles and oxadiazoles was studied by determination
of the chiral purity of the samples of 4b, 5b, 4c, and 5c prepared
via the present protocol by means of 1H NMR and HPLC analy-
ses.37,38 The studies revealed that the tested samples were opti-
cally homogenous, and further the described protocol is free
from racemization.
In conclusion, the current protocol is a simple and straightfor-
ward route for the insertion of 1,3,4-thiadiazolo- and 1,3,4-
oxadiazolo-units into peptides. The synthesis makes use of amino
acid substituted diacylhydrazines as common intermediate which
on treatment with Lawesson’s reagent and EDC furnishes the thi-
adiazolyl and oxadiazolyl compounds, respectively. The proce-
dures give good yields and good purities with no detectable
enantiomerization.
The solvent was removed under reduced pressure and the resulting crude
compound was purified by column chromatography. Spectroscopic data for 3b:
1H NMR (CDCl3, 300 MHz,) d 1.41 (s, 9H), 1.46 (d, J = 5.8 Hz, 3H), 3.00–3.04 (m,
1H), 3.12–3.16 (m, 1H), 4.20 (t, J = 6.2 Hz, 1H), 4.39–4.43 (m, 3H), 4.82 (t,
J = 6.2 Hz, 1H), 6.30 (br, 1H), 7.03–7.64 (m, 13H), 8.76 (br, 1H); 13C NMR
(CDCl3,75 MHz) d 16.2, 28.7, 33.2, 42.8, 48.3, 53.4, 64.6, 79.8, 126.1, 126.7,
127.6, 128.0, 128.1, 128.5, 128.9, 137.6, 140.3, 143.1, 155.3, 155.8, 169.2,
170.1; HRMS calcd for C32H36N4O6 m/z 595.2533 [M+Na+], found 595.2537
[M+Na+].
Acknowledgments
25. Rasmussen, P. B.; Pedersen, U.; Thomsen, I.; Yde, B.; Lawesson, S. O. Bull. Soc.
Chim. Fr. 1998, 1, 62.
This research was supported by the University Grants Commis-
sion [UGC, Grant No. F. No. 37-79/2009 (SR)] Govt. of India and
R.S.L. thanks University Grants Commission, New Delhi, India for
the award of Dr. D. S. Kothari Postdoctoral Fellowship. We also
thank Mr. Girish Prabhu, Dept. of Chemistry, Bangalore University
for useful assistance in preparing this manuscript.
26. Typical experimental procedure for the synthesis of 1,3,4-thiadiazoles 4.
To a solution of diacylhydrazine 3 (10 mmol) in THF, Lawesson’s reagent
(2.85 g, 15 mmol) was added and the solution was refluxed for 3 h. After
completion of the reaction (monitored by TLC), the reaction mixture was
filtered and the solvent was removed in vacuo. The resulting crude compound
was purified by column chromatography (EtOAc/n-hexane, 2:8) to afford
analytically pure product. Spectroscopic data for 4i: 1H NMR (CDCl3, 300 MHz,)
d 1.40 (s, 9H), 1.55 (s, 12H), 5.08 (s, 2H), 6.18 (br, 1H), 6.78 (br, 1H), 7.08–7.19
(m, 5H); 13C NMR (CDCl3, 75 MHz) d 28.1, 28.5, 48.6, 55.9, 64.6, 80.2, 127.2,
127.4, 127.9, 135.5, 155.6, 155.8, 167.9, 169.5; ESI-MS calcd for C21H30N4O4S
m/z 435.2 [M+H+], found 435.0 [M+H+].
27. Tandon, V. K.; Chhor, R. B. Synth. Commun. 2001, 31, 1727.
28. Cauliez, P.; Rigo, B.; Fasseur, D.; Couturier, D. J. Heterocycl. Chem. 1996, 33,
1073.
29. Liras, S.; Allen, M. P.; Segelstein, B. E. Synth. Commun. 2000, 30, 437.
30. Holla, B. S.; Gonsalves, R.; Shenoy, S. Eur. J. Med. Chem. 2000, 35, 267.
31. Dost, J.; Heschel, M.; Stein, J. J. Prakt. Chem. 1985, 327, 109.
32. Chekler, E. L. P.; Elokdah, H. M.; Butera, J. Tetrahedron Lett. 2008, 49, 6709.
33. Dolman, S. J.; Gosselin, F.; O’Shea, P. D.; Davies, I. W. J. Org. Chem. 2006, 71,
9548.
References and notes
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1997, 53, 12789.
3. (a) Angell, Y. L.; Burgess, K. Chem. Soc. Rev. 2007, 36, 1674; (b) Demange, L.;
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(c) Bartlett, P. A.; Acher, F. Bull. Soc. Chim. Fr. 1986, 771.
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36. Typical experimental procedure for the synthesis of 1,3,4-oxadiazoles 5.
To a solution of diacylhydrazide 3 (10 mmol) in DCM, EDC (1.91 g, 10 mmol)
and TEA (2.09 mL, 15 mmol) were added and the reaction mixture was refluxed
for 3 h (monitored by TLC). The solvent was removed in vacuo and the crude
was dissolved in EtOAc (10 mL ꢁ 2) and it was washed successively with citric
acid (10%, 10 mL ꢁ 2), Na2CO3 (5%, 10 mL), water (2 ꢁ 10 mL) and brine
(10 mL) and dried over anhydrous Na2SO4. The solvent was removed under
vacuum and purified by column chromatography (EtOAc/n-hexane, 2:8) to
afford pure oxadiazole.
Spectroscopic data for 5e: 1H NMR (CDCl3, 300 MHz) d 1.39 (s, 9H), 1.46 (d,

G. Nagendra et al. / Tetrahedron Letters 51 (2010) 6338–6341
6341
J = 6.0 Hz, 3H), 2.01 (s, 3H), 2.28 (m, 2H), 2.39 (m, 2H), 4.61 (m, 1H), 4.98 (m,
1H), 5.10 (s, 2H), 6.33 (br, 1H), 7.05–7.17 (m, 5H), 8.35 (br, 1H); 13C NMR
(CDCl3, 75 MHz) d 15.2, 17.2, 28.7, 29.0, 33.7, 48.3, 51.0, 64.1, 79.9, 126.8,
127.3, 128.2, 139.8, 154.9, 155.8, 166.8, 169.7; ESI-MS calcd for C21H30N4O5S
m/z 451.2 [M+H+], found 451.2 [M+H+].
d 1.30 and 1.34 for 4b and at d 1.28 and 1.32 for 4c, at d 1.31 and 1.35 for 5b
and at d 1.28 and 1.32 for 5c supporting their enantiopurity.
38. The enantiopurity of each of the above compounds was further supported by
the HPLC analysis by using column: Agilent Eclipse XDB-C18 (flow rate 0.5 mL/
min; eluting with 0.1% TFA water–acetonitrile; 30–100% in 30 min).
37. 1H NMR analysis of samples 3b and 3c revealed that methyl group appeared as
doublet at d 1.29 and 1.33 ppm for 3b and at d 1.30 and 1.34 ppm for 3c,
Diacylhydrazines 3b and 3c showed single peak with retention time at 12.48
and 12.06 min, respectively. Similarly in the case of 1,3,4-thiadiazole
derivatives, single retention time at 9.55 min for 4b and at 9.43 min for 4c
were observed, whereas the corresponding enantiopure 1,3,4-oxadiazoles 5b
and 5c showed single retention times at 11.73, 11.67 min, respectively.
respectively. Similarly, the 1H NMR of samples of thiadiazoles Boc-Phe-
w-
[C2N2S]-Ala-Fmoc 4b, 4c and oxadiazoles Boc-Phe-w-[C2N2O]-Ala-Fmoc 5b, 5c
were studied. The alanyl methyl groups were resonated as distinct doublets at