A facile one-pot synthesis of Nα-Z/Boc-protected S-linked 1,3,4-oxadiazole tethered peptidomimetics

Article abstract of DOI:10.1016/j.tetlet.2011.12.093

A new class of S-linked 1,3,4-oxadiazole-tethered N^α- protected peptidomimetics is designed and synthesized by a reaction of N ^α-Z/Boc-protected 1,3,4-oxadiazole-2-thiol with α-bromo ester derived from amino acid. The protocol has al

Full text of DOI:10.1016/j.tetlet.2011.12.093

Tetrahedron Letters 53 (2012) 1332–1336
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
a
A facile one-pot synthesis of N -Z/Boc-protected S-linked 1,3,4-oxadiazole
tethered peptidomimetics
⇑
Vommina V. Sureshbabu , B. Vasantha, G. Nagendra
#109, 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
a
Article history:
A new class of S-linked 1,3,4-oxadiazole-tethered N -protected peptidomimetics is designed and synthe-
a
Received 3 October 2011
Revised 21 December 2011
Accepted 23 December 2011
Available online 5 January 2012
sized by a reaction of N -Z/Boc-protected 1,3,4-oxadiazole-2-thiol with
a-bromo ester derived from
amino acid. The protocol has also been employed for the synthesis of glycosylated amino acids and
N,N0-orthogonally protected dipeptidomimetics bearing S-linked 1,3,4-oxadiazole mimetics as well. The
intermediate 5-alkyl amino-1,3,4-oxadiazole-2-thiols have been isolated as stable compounds. Further,
the chain extension at both N- and C-termini of N-protected S-linked 1,3,4-oxadiazole tethered dipepti-
domimetics was also demonstrated.
Keywords:
Oxadiazole-2-thiol
Peptidomimetics
Glycosylated amino acids
Ultrasonication
Ó 2012 Elsevier Ltd. All rights reserved.
Peptides are the important constituents of living organisms
possessing diverse biological functions. However, the poor meta-
bolic stability in vivo, low oral bioavailability, and hydrolysis by pro-
teases limited the application of some of the peptides as drug
candidates. Decoration of the peptide backbone with various
amide-surrogates such as urea, thiourea, carbamate, and heterocy-
cles have often been found to improve the biological potency of the
naturally occurring peptides, thus making them suitable candidates
for various applications.1 In particular, the insertion of heterocycles
such as tetrazole, triazole, thiazole, and isoxazoline in the place of
amide bond is of considerable interest in designing the peptidomi-
metics due to the added pharmacophoric values of those aromatic
nuclei.2 In this regard our group has reported several new classes
of peptidomimetics possessing heterocycles such as 1,3,4-oxadiaz-
ole, 1,3,4-thiadiazole, and 1,2,4-oxadiazole and Fmoc protected
amino alkyl S/Se-linked tetrazoles.3
Compounds possessing 1,3,4-oxadiazole moiety have gained
special interest in drug discovery.4 Some of them are known to ex-
ert anti-hypertensive, antibiotic, antiviral properties.5 This hetero-
cycle can also serve as a surrogate of amide and esters.6 In
particular, S-linked 1,3,4-oxadiazoles have been endowed with a
wide spectra of pharmacological activities such as antiviral,7 anti-
microbial,8 antitubercular,9 pesticidal,10 and anti HIV-1 activity of
adamantane derivatives11 (Fig. 1A) due to the presence of sulfur
adjacent to the heterocycle.
Earlier reports on the synthesis of S-linked oxadiazolyl compounds
include the cyclization of substituted hydrazinecarbodithionic acid to
thiol followed by S-alkylation. Andrushko et al., reported the synthesis
of 5-substituted 2-aroylmethylthio-1,3,4-oxadiazoles (Fig. 1B) by the
reaction of the corresponding thiones with a
-halo ketones.12 Vainilavi-
cius group employed the reaction of 5-pyrimidyl substituted thiones
with various electrophiles in the presence of triethylamine (TEA)
under reflux to obtain the corresponding S-linked oxadiazole.13
Indium tribromide catalyzed reaction of an organic halide to 5-(3,4,
5-trimethoxyphenyl)-1,3,4-oxadiazole-2-thiol also affords the corre-
sponding S-linked oxadiazoles.14 Bhandari et al., synthesized novel
S-substituted phenacyl-1,3,4-oxadiazoles through the S-alkylation of
the corresponding phenacyl-1,3,4-oxadiazole-2-thiol with substituted
acetophenone in the presence of pyridine and screened for anti-
inflammatory, analgesic, and ulcerogenic activity (Fig. 1C).15 Zarudnit-
skii and colleagues reported the synthesis of S-linked 1,3,4-oxadiazole
via the coupling of 2-aryl-5-trimethylsilyl-1,3,4-oxadiazoles with 2-
nitrobenzenesulfenyl chloride in Et2O which took 9 days at rt.16 Most
of the synthetic methods available for the construction of 1,3,4-oxadi-
azoles molecules involve forcing reaction conditions like high temper-
ature, use of strong base which are not compatible with amino acid
chemistry. In view of the increasing demand for the novel class of pep-
tidomimetics in drug discovery and with the understanding of the sig-
nificance of S-linked 1,3,4-oxadiazole moiety, a protocol has been
designed for incorporating this group into the peptide backbone. It in-
volves the reaction of hitherto unreported class of N-protected amino
acid derived 5-alkyl amino-1,3,4-oxadiazole-2-thiols with
a-bromo
esters. The aforesaid precursors, viz 5-substituted-1,3,4-oxadiazole-
2-thiols are generally prepared by the reaction of hydrazides with car-
bon disulfide in the presence of ethanolic KOH under reflux.17 The
⇑
Corresponding author. Tel.: +91 80 2296 1339/09986312937.
E-mail addresses: hariccb@hotmail.com, sureshbabuvommina@rediffmail.com,
hariccb@gmail.com (V.V. Sureshbabu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.093

V. V. Sureshbabu et al. / Tetrahedron Letters 53 (2012) 1332–1336
1333
R2
N
N
R
R
R3
S
O
O
N
N
N
N
NH
S
S
O
Cl
Cl
O
O
R1
A
B
C
Figure 1. Representative examples of biologically active S-linked 1,3,4-oxadiazole tethered molecules.
reaction of aromatic hydrazides with thiophosgene in the presence of
R1
Hunig’s base affords respective 1,3,4-oxadiazole-2-thiones (which are
NHNH2
tautomers of the corresponding thiols).18
PgHN
PgHN
O
R1
In the first stage of this study, the preparation of 1,3,4-oxadiaz-
ole-2-thiols from N-protected amino acid was undertaken. In a
typical experiment, Z-Phe-NHNH2 1c, prepared by the reaction of
hydrazine hydrate on the corresponding methyl ester19 was
refluxed along with CS2 in the presence of N-methyl morpholine
(NMM) in ethanol. The reaction was found to be complete in 4 h
as monitored by TLC analysis (Scheme 1). Evaporation of the sol-
vent followed by a simple work-up afforded the corresponding
5-alkyl amino-1,3,4-oxadiazole-2-thiol 2c in a 75% yield. The pro-
tocol was repeated with a few other amino acids successfully to
confirm its generality and the corresponding 5-substituted oxadi-
azole-2-thiols were isolated (Scheme 1, Table 1, 2a–2e). 25The 1H
NMR and chiral HPLC studies carried out on specimen examples
of oxadiazole-2-thiol confirmed that they were chemically homo-
geneous and thus the reaction is free from racemization.20 On
1
O
R2
O
CS2, NMM
S
PgHN
RO
OX
OX
, EtOH
R2
N
N
Br
3
5a-5h
O
R1
X = Me or Et
O
SH
, NMM
O
N
N
RO
2
R1
O
RO
RO
RO
RO
O
S
NHPg
OR
OR
Br
N
N
4
5i-5k
R = Ac, Bz
Scheme 2. Synthesis of S-linked 1,3,4-oxadiazoles 5a–5k.
the other hand, a-bromo esters 3 were prepared via diazotization
of the amino acids followed by esterification using SOCl2 in
foul smelling 5-substituted oxadiazole-2-thiol derivatives. Indeed,
an ultrasound-mediated one-pot protocol was designed and dem-
onstrated which reduced the reaction time; and also increased the
efficacy of the overall reaction. Typically, a mixture of Z-Phe-NHNH2
1c, CS2 and NMM were initially exposed to ultrasonic waves for
20 min. After confirming the formation of the corresponding oxadi-
azole-2-thiol derivative (TLC analysis), the reaction mixture was
charged with an equivalent of Br-Phe-COOMe and NMM and the
exposure to ultrasonic waves was continued. S-alkylation was com-
plete in the next 15 min (TLC) to afford 5c in a 92% yield after simple
work-up and purification. Encouraged by the above result, several
examples of 1,3,4-oxadiazole containing dipeptide mimics (Scheme
2, Table 2, 5a–5h) were prepared and consistent yield and purities
were recorded in all cases.
MeOH/EtOH.21
In the next step, the assembly of S-linked 1,3,4-oxadiazole-teth-
ered peptidomimetics was carried out. In a typical reaction, Z-Phe-
w
[(C2N2O)SH] 2c was stirred with L-Br-Phe-COOMe in the presence
of NMM in ethanol under reflux. After the completion of the reaction
(TLC; 5 h), a simple work-up followed by column chromatography
afforded the desired S-alkylated oxadiazole 5c in a 75% yield.
At this stage, we envisioned that the development of a one-pot
protocol to arrive at the title compounds starting from the corre-
sponding hydrazides will be more beneficial. This would aid the
synthesis of a series of compounds in short time and in lesser steps
together with the added advantage of circumventing the isolation of
Thiolysis of chiral
SN2 mechanism, thus leading to the inversion of configuration at
the carbon
to bromo group.22 To examine this, a pair of epimeric
dipeptidomimetics were synthesized by reacting Z-Val- [(C2N2O)
SH] 2b with - and -Br-Ala-COOMe in separate experiments. The
a-bromo ester is known to proceed through
R1
R1
CS2, NMM
O
NHNH2
SH
PgHN
PgHN
a
, 4 h
EtOH
N
N
O
w
L
D
1
2
alanyl methyl protons of these samples resonated as distinct dou-
blets (at d 1.28 and 1.30 ppm for 5b and at d 1.32 and 1.34 ppm
for 5b⁄) suggesting the presence of single epimer in each sample
which would be the possibility in case of complete inversion. How-
ever, chiral HPLC analyses of the epimer displayed two peaks at Rt
12.85 and 16.26 in the ratio 98:2 and 1:99, respectively, major peak
in each compound is due to the inversion of configuration.
In recent years, the synthesis of glycosylated heterocycles has
gained interest due to their application as biological inhibitors.
Kur’yanov23 and El-sayed24 had reported the synthesis of glycosyl
thio-oxadiazole via the reaction of 5-substituted-1,3,4-oxadiazole-
Pg = Z, Boc group
R1 = CH3, CH(CH3)2, CH2C6H5, C6H5, (CH2)4NHZ
a
Scheme 1. Synthesis of N -Boc/Z-protected 1,3,4-oxadiazole-2-thiols 2.
Table 1
List of Z/Boc-protected 5-alkyl amino-1,3,4-oxadiazole-2-thiols 2 prepared
Entry
Pg
R1
Yield (%)
HR-MS [M+Na]+ calcd/obsd
2a
2b
2c
2d
2e
Z
Z
Z
CH3
70
68
75
67
65
302.0575/302.33a
330.0888/330.0880
378.0888/378.0881
308.1069/308.1066b
459.1678/459.1685
CH(CH3)2
CH2C6H5
C6H5
2-thiol with
a-
D-glucopyranosyl chloride (under phase transfer
Boc
Boc
catalyst) or 2,3,4,6-tetra-O-acetyl-a-D-galacto/glucopyranosyl bro-
(CH2)4NHZ
mide. Likewise, the synthesis of glycosylated peptidomimetics has
also drawn much attention. Owing to the importance of neoglyco-
peptides and thio heterocycles, the present protocol was extended
a
ESI-MS.
[M+H]+.
b

1334
V. V. Sureshbabu et al. / Tetrahedron Letters 53 (2012) 1332–1336
Table 2
List of S-linked oxadiazoles 5 prepared
Entry
Compound
Time (min)
35
Yield (%)
HR-MS [M+Na]+ calcd/obsd
464.1256/464.1259
O
O
S
ZHN
OMe
5a
90
88
N
N
Ph
O
O
S
S
5b
5c
40
35
416.1256/416.1248
540.1569/540.1575
ZHN
ZHN
OMe
N
Ph
N
O
O
92
86
OMe
N
N
Ph
O
450.2063/450.2068a
O
5d
35
S
S
ZHN
OEt
N
S
N
O
5e
5f
40
42
38
85
83
81
434.0820/434.0825
621.2359/621.2360
492.1029/492.1025b
O
ZHN
OMe
N
N
NHZ
O
4
O
S
S
BocHN
OMe
N
N
N
Ph
O
Ph
O
BocHN
OMe
5g
N
2
S
SBn
O
O
S
N
BocHN
AcO
OMe
5h
45
82
518.1759/51.1761
N
N
O
AcO
AcO
O
S
5i
36
42
35
78
74
76
660.18/660.21c
NHZ
OAc
N
COOBn
NHBoc
AcO
O
AcO
AcO
O
S
S
5j
710.2231/710.2235
846.2309/846.2315
OAc
N
N
BzO
O
BzO
BzO
O
5k
NHBoc
OBz
N
N
a
b
c
[M+H]+.
[M+K]+.
ESI-MS.
to prepare a few S-linked 1,3,4-oxadiazole tethered glycosylated
amino acid derivatives. 26The required 2,3,4,6-tetra-O-acetyl-
glucopyranosyl bromide was prepared starting from -glucose
In the next step, the chain elongation of dipeptidomimetics 5
was undertaken at N- as well as C- termini to construct tri and tet-
rapeptidomimetics. Toward this end, 5c was subjected to LiOH
mediated hydrolysis and to the resulting free carboxy group,
valinyl methyl ester was coupled via the conventional 1-ethyl-3-
(3-dimethylaminopropyl)carbodiimide (EDC)/1-hydroxy benzotri-
azole (HOBt) activation method. The resulting tripeptidomimetic
6a was isolated in an 85% yield. In the next step, the N-terminal
extension of this tripeptidomimetic was undertaken. First, it was
subjected to catalytic hydrogenation (10% Pd–C/H2) to remove
the Z-group and the resulting free amino product was coupled to
a-D-
D
according to the literature procedure.27 Then, a solution of 5-substi-
tuted-1,3,4-oxadiazole-2-thiol prepared by the reaction of the cor-
responding hydrazide with CS2 and NMM under ultrasonication
was reacted with sugar bromide in the presence of NMM to yield
the corresponding S-linked oxadiazole bearing glycosylated amino
acid conjugate (Scheme 2, Table 2, 5i–5k).28 All the compounds pre-
pared were isolated via column chromatography (30% EtOAc in n-
hexane) and characterized.

V. V. Sureshbabu et al. / Tetrahedron Letters 53 (2012) 1332–1336
R1
1335
O
R3
R1
O
O
1N LiOH
O
S
OMe
S
PgHN
N
H
PgHN
OMe
EDC/HOBt
R2
O
N
N
N
R2
N
H-CH(R3)-OMe
6a:Pg = Z; R1= CH2C6H5; R2 = CH2C6H5; R3 = CH(CH3)2 (85%)
5
6b: Pg = Boc; R1 = (CH2)4NHZ; R2 = CH2C6H5; R3 = CH3 (83%)
R3
O
R1
O
Pd-C/H2 for 6a
O
TFA:DCM (1:1) for 6b
PgHN
S
OMe
N
H
N
H
EDC/HOBt
R4
R2
O
N
N
Pg-CH(R4)-OH
7a: Pg = Fmoc; R4 = CH3 (82%)
7b: Pg = Z; R4 = CH(CH3)2 (79%)
Scheme 3. Synthesis of tri and tetrapeptidomimetics.
the reaction of CS2 and NMM under sonication (TLC, 20 min) which
without isolation was treated with orthogonally protected amino al-
kyl iodide in the presence of NMM to yield 8a–8e within 15 min
(Scheme 4, Table 3). The orthogonal protection renders the selective
chain extension of these peptidomimetics.
In summary, a simple one-pot protocol for the preparation of
new class of S-linked 1,3,4-oxadiazolyl dipeptidomimetics and
neoglycosylated amino acids is described. The protocol involves a
reaction of N-protected amino acid derived hydrazide with CS2
and NMM generating the corresponding oxadiazole-2-thiol fol-
1. CS2, NMM
R1
R2
R1
, EtOH
R2
O
S
NHPg1
NHNH2
PgHN
PgHN
2.
I
N
N
O
NHPg1
8a-8e
Pg1 = Fmoc, Z or Boc group
,
NMM
Scheme 4. Synthesis of orthogonally protected S-linked oxadiazole tethered
dipeptidomimetics 8a–8e.
lowed by S-alkylation with a-bromo ester or sugar-1-bromide un-
der ultrasonication. The protocol is extended for the synthesis of
orthogonally protected oxadiazolyl dipeptidomimetics as well. In
addition, the N- as well as C-terminal extension of N -Z/Boc-pro-
tected S-linked 1,3,4-oxadiazole tethered peptidomimetics is also
demonstrated.
Fmoc-Ala-OH employing EDC/HOBt to obtain tetrapeptidomimetic
7a in an 82% yield. In another set of experiments, dipeptidomimet-
ic 5f was hydrolyzed and coupled with Ala-OMe to obtain tripepti-
domimetic 6b and later extended at N-terminus by Boc cleavage
(TFA/DCM, 1:1) followed by coupling reaction with Z-Val to afford
tetrapeptidomimetic 7b in a 79% yield (Scheme 3).
a
Acknowledgements
In the final part of the study, N,N0-orthogonally protected oxadiaz-
ole linked dipeptidomimetics were synthesized. A similar protocol
We thank the University Grants Commission, New Delhi [UGC,
Grant No. F. No. 37–79/2009 (SR)] Govt. of India for financial assis-
tance. BV thanks the University Grants Commission, New Delhi, In-
dia for the award of UGC-RFSMS fellowship.
described above was executed wherein, the
a-bromo ester was
replaced with N-protected-b-amino alkyl iodides. In brief, starting
with N-protected hydrazides, the intermediate 2 was generated via
Table 3
List of S-linked oxadiazole containing orthogonally protected dipeptidomimetics 6 synthesized
Entry
Compound
Time (min)
Yield (%)
79
HR-MS [M+Na]+ calcd/obsd
657.2148/657.2137
Ph
O
8a
25
S
S
ZHN
NHFmoc
S
N
N
2
547.20/547a
O
8b
8c
8d
30
30
40
89
71
85
ZHN
NHBoc
N
N
SBn
Ph
O
765.2181/765.2175
579.1889/579.1885
S
ZHN
NHFmoc
NHZ
N
N
COOBn
O
S
BocHN
N
N
N
Ph
8e
35
87
555.2641/555.2649b
O
S
BocHN
NHZ
N
a
ESI-MS.
[M+H]+.
b

1336
V. V. Sureshbabu et al. / Tetrahedron Letters 53 (2012) 1332–1336
22. Paladino, J.; Thurieau, C.; Morris, A. D.; Kucharczyk, N.; Rouissi, N.; Regoli, D.;
References and notes
Fauchere, J.-L. Int. J. Peptide Protein Res. 1993, 42, 284–293.
23. Kur’yanov, V. O.; Kotlar, S. A.; Priskoka, U. S.; Chupakhina, T. A.; Chirva, V. Y.
Russ. J. Bioorg. Chem. 2006, 32, 468–471.
24. (a) El-Sayed, W. A.; Fathi, N. M.; Gad, W. A.; El-Ashry, E. S. H. J. Carbohydr. Chem.
2008, 27, 357–372; (b) Ashry, E. S. H. E.; Tamany, E. S. H. E.; Aly, M. R. E.; Boraei,
T. A. Synlett 2010, 2247–2250.
1. (a) Patil, B. S.; Vasanthakumar, G. R.; Sureshbabu, V. V. J. Org. Chem. 2003, 68,
7274–7280; (b) Sureshbabu, V. V.; Naik, S. A.; Hemantha, H. P.; Narendra, N.;
Das, U.; Row, T. N. G. J. Org. Chem. 2009, 74, 5260–5266; (c) Videnov, G.; Kaiser,
D.; Kempter, C.; Jung, G. Angew. Chem. Int. Ed. 1996, 35, 1503–1505; (d) Gellman,
S. H. Acc. Chem. Res. 1998, 31, 173–180; (e) Emmons, T. K.; Murali, R.; Greene, M.
I. Curr. Opin. Biotech. 1997, 8, 435–441; (f) Sewald, N.; Jakubke, H. –D. Peptides:
Chemistry and Biology; Wiley-VCH: Weinheim, Germany, 2002.
2. (a)Yu,K. L.; Johnson, R. L. J. Org. Chem. 1987, 52, 2051–2059; (b) Tam, A.; Arnold, U.;
Soellner, M. B.; Raines, R. T. J. Am. Chem. Soc. 2007, 129, 12670–12671; (c)You, S. L.;
Kelly, J. W. TetrahedronLett.2005, 46, 2567–2570;(d)Kim,B. H.;Chung, Y.J.;Keum,
G.; Kim, J.; Kim, K. Tetrahedron Lett. 1992, 33, 6811–6814.
3. (a) Lamani, R. S.; Nagendra, G.; Sureshbabu, V. V. Tetrahedron Lett. 2010, 51,
4705–4709; (b) Nagendra, G.; Lamani, R. S.; Narendra, N.; Sureshbabu, V. V.
Tetrahedron Lett. 2010, 51, 6338–6341; (c) Sureshbabu, V. V.; Vasantha, B.;
Hemantha, H. P. Synthesis 2011, 1447–1455.
4. (a) Rostom, S. A. F.; Shalaby, M. A.; El-Demellawy, M. A. Eur. J. Med. Chem. 2003,
38, 959–974; (b) Holla, B. S.; Gonsalves, R.; Shenoy, S. Eur. J. Med. Chem. 2000,
35, 267–271.
5. (a) Schlecker, R.; Thieme, P. C. Tetrahedron 1988, 44, 3289; (b) Ogata, M.; Atobe,
H.; Kushida, H.; Yamamoto, K. J. Antibiot. 1971, 24, 443; (c) Kohara, Y.; Imamiya,
E.; Kubo, K.; Wada, T.; Inada, Y.; Naka, T. Bioorg. Med. Chem. Lett. 1995, 5, 1903.
6. (a) Andersen, K. E.; Lundt, B. F.; Jorgensen, A. S.; Braestrup, C. Eur. J. Med. Chem.
1996, 31, 417; (b) Jakopin, Z.; Roskar, R.; Delenc, M. S. Tetrahedron Lett. 2007,
48, 1465.
7. El-Essawy, F. A.; Khattab, A. F.; Abdel-Rahman, A.-H. Monatsh. Chem. 2007, 138,
777–785.
8. Zareef, M.; Iqbal, R.; Mirza, B.; Khan, K. M.; Manan, A.; Asim, F.; Khan, S. W.
Arkivoc 2008, 2, 141–152.
9. Pancechowska-Ksepko, D.; Foks, H.; Landowska, E.; Janowiec, M.; Zwolska
-Kwiek, Z. Acta. Pol. Pharm. 1986, 43, 116–121.
10. Dutta, M. M.; Kataky, J. C. S. J. Indian Chem. Soc. 1992, 69, 107–112.
11. El-Emam, A. A.; Al-Deeb, O. A.; Al-Omar, M.; Lehmann, J. Bioorg. Med. Chem.
2004, 12, 5107–5113.
12. Andrushko, A. P.; Demchenko, A. M.; Krasovskii, A. N.; Rusanov, E. B.; Chernega,
A. N.; Lozinskii, M. O. Russ. J. Gen. Chem. 2001, 71, 1754–1758.
13. Smicius, R.; Jakubkiene, V.; Burbuliene, M. M.; Vainilavicius, P. Monatsh. Chem.
2002, 133, 173–181.
14. Chen, C.-J.; Song, B.-A.; Yang, S.; Xu, G.-F.; Bhadury, P. S.; Jin, L.-H.; Hu, D.-Y.; Li,
Q.-Z.; Lu, F.; Xue, W.; Lu, P.; Chen, Z. Bioorg. Med. Chem. 2007, 15, 3981–3989.
15. Bhandari, S. V.; Bothara, K. G.; Raut, M. K.; Patil, A. A.; Sarkate, A. P.; Mokale, V.
J. Bioorg. Med. Chem. 2008, 16, 1822–1831.
16. Zarudnitskii, E. V.; Pervak, I. I.; Merkulov, A. S.; Yurchenko, A. A.; Tolmachev, A.
A. Tetrahedron 2008, 64, 10431–10442.
17. Zarghi, A.; Hamedi, S.; Tootooni, F.; Amni, B.; Sharifi, B.; Faizi, M.; Tabatabai, S.
A.; Shafiee, A. Sci. Pharm. 2008, 76, 185–201.
18. Kramer, J. B.; Boschelli, D. A.; Connor, D. T.; Kostlan, C. R.; Kuipers, P. J.;
Kennedy, J. A.; Wright, C. D.; Bornemeier, D. A.; Dyer, R. D. Bioorg. Med. Chem.
Lett. 1993, 3, 2827–2830.
19. 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, 503–505.
25. General procedure: Z/Boc-protected-1,3,4-oxadiazole-2-thiols (2). A mixture of
hydrazide 1 (10 mmol), CS2 (0.7 mL, 12 mmol) and NMM (1.3 mL, 12 mmol) in
ethanol (10 mL) was heated under reflux for 4 h. After completion of the
reaction (TLC), the solvent was evaporated in vacuo after which it was acidified
with 10% citric acid solution and the residue was diluted with EtOAc, washed
with water (2 ꢀ 10 mL), brine (10 mL) and dried over anhydrous Na2SO4. The
solvent was removed in vacuo and recrystallised using THF:n-hexane to obtain
the product as analytically pure one.
Compound 2e: yield: 65%; 1H NMR (DMSO-d6, 400 MHz) d 1.11–1.27 (m, 4H),
1.36 (s, 9H), 1.71 (m, 2H), 2.96 (m, 2H), 4.55 (br, 1H), 4.98 (s, 2H), 7.21 (m, 1H),
7.28–7.36 (m, 5H), 7.51 (d, J = 5.4 Hz, 1H), 14.38 (br s, 1H); 13C NMR (DMSO-d6,
100 MHz) d 22.5, 27.1, 28.9, 35.3, 39.8, 48.5, 65.5, 76.7, 125.1, 126.5, 127.7,
139.1, 156.8, 157.5, 162.5, 167.5; HR-MS calcd for C20H28N4O5S m/z 459.1678
[M+Na]+, found 459.1685.
26. General
procedure:
Z/Boc-protected-S-linked-1,3,4-oxadiazole
tethered
mimetics (5 and 8). To
a
solution of hydrazide (10 mmol) in ethanol
1
(10 mL) were added CS2 (0.7 mL, 12 mmol) and NMM (1.3 mL, 12 mmol) and
subjected to ultrasonication. After complete consumption of starting material
(TLC, 20 min) NMM was added (1.3 mL, 12 mmol) followed by halogen
derivative (12 mmol) and sonication was continued for another 20 min. The
solvent was removed in vacuo and the resulting crude product was subjected
to column chromatography (20% EtOAc in n-hexane) to obtain the analytically
pure product.
Compound 5c: yield: 92%; 1H NMR (DMSO-d6, 400 MHz) d 3.22–3.35 (m, 4H),
3.65 (s, 3H), 4.50 (m, 1H), 5.03 (m, 1H), 5.29 (s, 2H), 5.42 (m, 1H), 7.07–7.25 (m,
15H); 13C NMR (DMSO-d6, 100 MHz) d 39.3, 48.8, 50.8, 52.8, 53.4, 67.2, 127.1,
127.3, 127.8, 128.2, 128.4, 128.5, 128.7, 129.1, 129.2, 134.9, 135.9, 136.1, 155.4,
162.9, 167.2, 170.1; HR-MS calcd for C28H27N3O5S m/z 540.1569 [M+Na]+,
found 540.1575.
Compound 5h: yield: 82%; 1H NMR (DMSO-d6, 400 MHz) d 1.12 (d, J = 5.2 Hz,
6H), 1.27 (s, 9H), 1.82 (m, 1H), 2.11 (m, 2H), 3.15 (d, J = 5.8 Hz, 2H), 3.65 (s, 3H),
3.72 (s, 2H), 4.23 (m, 1H), 5.13 (m, 1H), 6.95 (m, 1H), 7.12 (m, 5H); 13C NMR
(DMSO-d6, 100 MHz) d 21.5, 25.8, 27.8, 35.1, 38.5, 40.1, 41.8, 52.6, 53.9, 75.3,
125.6, 127.1, 128.5, 138.5, 155.8, 162.8, 167.9, 171.5; HR-MS calcd for
C
23H33N3O5S2 m/z 518.1759 [M+Na]+, found 518.1761.
Compound 5i: Yield: 78%; 1H NMR (DMSO-d6, 400 MHz) d 0.89 (d, J = 5.2 Hz,
6H), 1.98 (s, 12H), 2.78 (m, 1H), 4.12 (d, J = 5.4 Hz, 2H), 4.51 (m, 1H), 4.65 (d,
J = 5.2 Hz, 1H), 4.71 (m, 1H), 4.81 (m, 1H), 4.98 (d, J = 10.2 Hz, 1H), 5.01 (m, 1H),
5.30 (s, 2H), 6.99 (br, 1H), 7.10–7.16 (m, 5H); 13C NMR (DMSO-d6, 100 MHz) d
16.9, 20.8, 32.3, 51.5, 59.9, 65.2, 66.1, 68.5, 75.8, 81.3, 126.5, 127.2, 128.5,
139.8, 156.1, 162.2, 167.5, 171.1; ESI-MS calcd for C28H35N3O12S m/z 660.18
[M+Na]+, found 660.21.
Compound 8a: yield: 79%; 1H NMR (DMSO-d6, 400 MHz) d 1.21 (d, J = 5.2 Hz,
3H), 2.71 (d, J = 5.4 Hz, 2H), 3.35 (d, J = 6.4 Hz, 2H), 4.21 (t, J = 4.6 Hz, 1H), 4.55
(d, J = 5.8 Hz, 2H), 4.71 (m, 1H), 4.98 (m, 1H), 5.35 (s, 2H), 5.65 (m, 2H),
7.12–7.73 (m, 18H); 13C NMR (DMSO-d6, 100 MHz) d 19.8, 36.5, 41.3, 47.5,
48.3, 51.8, 65.1, 65.6, 125.1,125.4,125.8, 126.5, 126.8, 127.1, 127.5, 128.0,
128.5, 129.0, 138.5, 139.5, 141.0, 143.5, 156.5, 155.8, 162.5, 167.9; HR-MS
calcd for C36H34N4O5S m/z 657.2148 [M+Na]+, found 657.2137.
20. The absence racemization during the course of the reaction was verified
through the 1H NMR and chiral HPLC (chiralpak IC 250 ꢀ 4.6 mm.
5 lL)
analyses of the enantiomeric oxadiazole-2-thiols Z-Ala-w[(C2N2O)SH] 2a and
27. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel’s Textbook of
Practical Organic Chemistry, 5th ed.; Addison Wesley Longman Limited, 1989.
28. (a) Gamblin, D. P.; Garnier, P.; van Kasteren, S.; Oldham, N. J.; Fairbanks, A. J.;
Davis, B. G. Angew. Chem. Int. Ed. 2004, 43, 828–833; (b) Beldi, R.; Atta, K. F.;
Aboul-Ela, S.; Ashry, E. S. H. E. J. Heterocycl. Chem. 2011, 48, 50–56; (c) Attia, A. M.
E. Tetrahedron 2002, 58, 1399–1405; (d) Miyachi, A.; Miyazaki, A.; Shingu, Y.;
Matsuda, K.; Dohi, H.; Nishida, Y. Carbohydr. Res. 2009, 344, 36–43; (e) Gueyrard,
D.; IOri, R.; Tatibouet, A.; Rollin, P. Eur. J. Org. Chem. 2010, 3657–3664.
Z-D-Ala-w
[(C2N2O)SH] 2a⁄ prepared via the present protocol. In the 1H NMR
spectrum alanyl methyl groups were resonated as distinct doublets at d 1.24
and 1.28 for 2a and at d 1.28 and 1.32 for 2a⁄ supporting their optical purity.
This was further confirmed by the HPLC profiles of 2a and 2a⁄ which showed
the presence of single peak at Rt 14.45 and 17.12 min respectively.
21. Yang, D.; Li, B.; Ng, F.-F.; Yan, Y.-L.; Qu, J.; Wu, Y.-D. J. Org. Chem. 2001, 66,
7303–7312.