Facile one-pot synthesis of 2-amino-1,3,4-oxadiazole tethered peptidomimetics by molecular-iodine-mediated cyclodeselenization

Article abstract of DOI:10.1039/c7nj02278f

Synthesis of 2-amino-1,3,4-oxadiazole tethered peptidomimetics is described by reaction of N^α-protected amino acid hydrazides with isoselenocyanato esters in one pot. The molecular-iodine-mediated cyclodeselenization of in situ generated seleno

Full text of DOI:10.1039/c7nj02278f

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ISSN 1144-0546
PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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A facile one-pot synthesis of 2-amino-1,3,4-oxadiazole tethered
peptidomimetics by molecular-iodine-mediated
cyclodeselenization
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
L. Santhosh, C. Srinivasulu, S. Durgamma, Girish Prabhu and Vommina. V. Sureshbabu*
Synthesis of 2-amino-1,3,4-oxadiazole tethered peptidomimetics through the reaction of Nα-protected amino acid
hydrazides with isoselenocyanato esters in one-pot is described. The molecular-iodine-mediated cyclodeselenization of in
situ generated selenosemicarbazide intermediates resulted in the facile formation of 2-amino-1,3,4-oxadiazoles under
mild conditions in excellent yields. The method employs environmentally benign iodine as the cyclizing agent and thereby
avoids the harsh conditions that are being employed in the existing routes.
in the development and biological evaluation of Phe-
Glymimetics of dermorphin (Tyr-D-Ala-Phe-Gly-Tyr-Pro-Ser-
NH2) and substance P (Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-
Introduction
Peptidomimetics is a thriving area of research with multitude
of applications in diverse fields. Especially peptidomimetics
based drug design has been at the forefront of pharma
research with increasing number of molecules in clinical trials
stage as well as foraying into the market.1 Molecular
combinations of peptides and heterocycles have been
investigated with the goal of blending the desirable properties
of peptides with those of heterocycles to obtain highly
bioactive and still metabolically stable and membrane-
permeable molecules. They possess properties that are
dictated by the chemical and physical properties of the
constituent heterocycle.
Leu-Met-NH2, SP).8 Results have shown that 1,3,4-oxadiazoles
as Phe-Glymimetics in dermorphin displayed high affinities for
the μ-receptor and retained their agonist activity. They have
also been utilized as bioisosteres of carboxamide moiety in
benzodiazepine
receptor
agonists,9
NK1
receptor
antagonists.10 Due to their potential to mimic the peptide turn
conformations, 1,3,4-oxadiazole peptidomimetics have been
considered as “universal peptidomimetics”.11,12
1,3,4-Oxadiazole derivatives are formidable class of
compounds with a broad spectrum of biological activities
including anti-inflammatory and anti-infective (Fig. 1a),2a
inhibition of tubulin polymerization (Fig. 1b),2b antibacterial
and antifungal (Fig. 1c),2c antitubercular (Fig. 1d),2d and other
activities.2e-k They also form constituents of agrochemicals
with insecticidal, herbicidal and fungicidal characteristics.3 In
particular, marketed antihypertensive agents such as
tiodazosin4 and nesapidil5 as well as antibiotics such as
furamizole6 contain the oxadiazole unit. Their peptidomimetic
ability has been explored in muscarinic receptor agonists7 and
Figure
oxadiazole derivatives
1 Selected representative examples of biologically active 2-amino-1,3,4-
However,
reports
on
1,3,4-oxadiazoles
bearing
Room No. 109, Peptide Research Laboratory,,Department of Studies in Chemistry,
Central College Campus, Dr. B. R. AmbedkarVeedhi, Bangalore
University,Bangalore 560 001, India.
E-mail: sureshbabuvommina@rediffmail.com,hariccb@gmail.com,
hariccb@hotmail.com.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
peptidomimetics are rather scant in the literature. This might
be due to the fact that most of the synthetic methods reported
in the literature for the construction of 2-amino-1,3,4-
oxadiazoles involve rather forcing conditions and/or elevated
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temperatures which are quite unsuitable for use with the charge density than anticipated based ViewoAnrticle tOhnelinier
amino acids and peptides having sensitive functionalities.
electronegativity. Hence, a larger dipoleDmOIo: 1m0.e10n3t9/aCn7dNJh0i2g2h78eFr
Most of the literature protocols for the synthesis of 2-amino- acidity for the amide proton in chalcogen substituted
1,3,4-oxadiazole derivatives involve mainly two routes. These congeners of peptides has been reported.18d Based on the
are cyclodehydration of semicarbazides13 using reagents like above
rationale,
we
hypothesized
that
the
POCl3, H2SO4, Burgess type reagents or cyclodesulfurization of selenosemicarbazide intermediate on account of high
thiosemicarbazides14 using toxic mercury or lead salts, polarizability of C=Se bond might have a greater tendency for
I2/NaOH, p-tosyl chloride, carbodiimides (DCC or EDC). C=Se bond activation and subsequent cyclodeselenization.
Invariably harsh reaction conditions and long reaction hours Thus, though the electronegativities of sulfur and selenium are
have been employed in these protocols and also nearly identical, on bonding with iodine, a base can trigger a
stoichiometric amount of undesirable by-products from facile deselenization by deprotonation leading to
cyclization reagents are generated (Fig. 2). Recently, we carbodiimide intermediate. Thus formed carbodiimide can be
developed mild synthesis of 2-amino-1,3,4-oxadiazoles cyclized in situ by the intramolecular nucleophilic attack of
a
a
through the cyclodesulfurization of thiosemicarbazides amide oxygen of selenosemicarbazide to form the desired 2-
mediated by o-iodoxybenzoic acid (IBX) at room amino-1,3,4-oxadiazole.
temperature.15 IBX was also found to be efficient for the
Molecular iodine has played a pivotal role as a catalyst and
cyclization of selenosemicarbazide as well.15 The efficacy of stoichiometric reagent in many organic reactions,19 and it was
selenosemicarbazide moiety for the preparation of 2-amino- opted for deselenization because of its benignant nature,
1,3,4-oxadiazoles has also been demonstrated by Xie’s group selenophilicity and solubility in organic solvents. This way we
which involved heating of selenosemicarbazides in DMF for 3-4 can eliminate the harsh conditions that were frequently
h.16a It was observed that longer reaction time up to 24 h is employed for desulfurization in such organic transformations.
required for the cyclization of selenosemicarbazides at lower Similar desulfurization reactions using iodine20a and more
temperatures. Pieczonka et al. reported the imidazole linked 2- reactive IBX20b were rather inefficient in case of substrates
amino-1,3,4-oxadiazole derivatives from selenosemicarbazides with alkyl amine substituents attached to the thiocarbonyl
by refluxing them in DMF at 100 °C.16b However, both these carbon. This has been ascribed to lower pKa of alkyl amines
reports involved higher temperatures as well as the presence and a lesser acidity of NH protons attached to the thiocarbonyl
of aromatic or electron withdrawing groups (R1 & R2; Fig. 2) carbon. With our best interest in synthesis of heterocycle
which are deemed necessary for the efficient cyclization of tethered peptidomimetics using deselenizing chemistry
selenosemicarbazides to oxadiazoles. Recent literature reports employing molecular iodine,21 we herein report the synthesis
also suggest that synthesis of 2-amino-1,3,4-oxadiazole of 2-amino-1,3,4-oxadiazole tethered peptidomimetics.
derivatives required higher temperatures and longer reaction
durations.17 We reasoned that if cyclodeselenization can be
effected at low temperature under mild conditions, it can be
Results and discussion
efficiently utilized in peptidomimetic chemistry.
Initially, several Boc and Cbz-protected amino acids were
converted to the corresponding hydrazides by the reported
protocol.22 Isoselenocyanato esters
were prepared by a
1
2
protocol previously developed by us. The isoselenocyanato
esters have been efficiently utilized by our group for the
synthesis
selenoureas, and hydantoins.23 With both the substrates
in hand, the insertion of 2-amino-1,3,4-oxadiazole into the
peptide backbone was undertaken.
of
selenoureidopeptides,
unsymmetrical
1
and
2
In a typical experiment, a solution of Cbz-Ala-CONHNH2 1a in
THF was treated with SeCN-Val-OMe 2a at room temperature
(Table 1). The reaction mixture was stirred for 1-2 h until the
TLC showed complete disappearance of the reactants (1a and
2a). The in situ generated selenosemicarbazide was then
treated with triethylamine (TEA) (2 equiv.) followed by the
addition of molecular iodine (1 equiv.) portion-wise over a
period of 5 min. The precipitation of reddish brown selenium
powder was observed. TLC analysis after 30 min indicated that
the incomplete reaction of intermediate (as small amount of
selenosemicarbazide remained unreacted) and formation of
small amount of few unidentified side products along with
good yield of the desired compound (Table 1, entry a). Since
deselenization with I2 and Et3N being slightly exothermic, it is
expected to show these undesired results. The studies on
Figure 2 Literature protocols and present protocol for the preparation of 2-amino-
1,3,4-oxadiazole derivatives
Substitution of the carbonyl oxygen in a molecule with
progressively heavier atoms viz. S or Se reportedly changes its
physicochemical properties substantially.18 Due to the larger
polarizabilities of heavier chalcogens, they accommodate more
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reaction with respect to the solvent, temperature and molar Higher equivalents of iodine and TEA did not improve the
View Article Online
DOI: 10.1039/C7NJ02278F
equivalents of iodine and TEA were then carried out. output of the reaction (Table 1, entries i and j), whereas lesser
Importantly no product was observed in the absence of equivalent of TEA led to a decrease in the yield of the product
molecular iodine with TEA alone (Table 1, entry b). Also, yields (Table 1, entry k).
were negligible under reflux conditions and when the reaction Though screening revealed THF to be a suitable solvent,
o
was sonicated in THF at 50 C for 1 h (Table 1, entry c and d). further improvement were desired to avoid aforementioned
The solvent influence on the reaction was also studied; during undesired results. Mild reaction condition was then
which only aprotic solvents were preferred as it is well known maintained by carrying out reaction of deselenization of
o
that protic solvents react with I2 to form iodides and selenosemicarbazide at 0 C (Table 1, entry l). Gratifyingly, the
hypoiodites,19funavailing stoichiometric I2 as a deselenizing reaction was completed within 15 min and there was only a
agent. Screening of various solvents such as dichloromethane formation of expected product (by TLC analysis). The
(CH2Cl2), acetonitrile (CH3CN), ethyl acetate (EtOAc) and N, N- precipitated selenium powder was filtered off. The desired 2-
dimethylformamide (DMF) revealed THF to be the best solvent amino-1,3,4-oxadiazole 4a was isolated in 92% yield after
(Table 1, entries e-h) and it can be from the complete solubility simple aqueous work up followed by column chromatography
of Nα-protected amino acid hydrazides in it.
on silica gel.
Table 1 Optimization of conditions for the synthesis of 2-amino-1,3,4-oxadiazole
tethered peptidomimetics 4a
The optimized protocol was then generalized to reaction of
different Nα-Boc/Cbz-protected amino acid hydrazides
with
isoselenocyanato esters
to obtain Nα-Boc/Cbz-protected 2-
amino-1,3,4-oxadiazole bearing dipeptidomimetics (Table 2,
1
2
4
entries 4a-j). In all the cases clean reaction was observed and
the products were obtained in good yields.
The structures of the peptidyl 2-amino-1,3,4-oxadiazoles
4
1
were confirmed by H NMR, 13C NMR and mass spectrometric
analyses.
Entry
Solvent
Molar ratio
I2:TEA
Temp.
(OC)
Time
(min)
Yield (%)b
a
b
c
THF
THF
THF
1:2
0:2
0:2
rt
30
86
--
rt
60
reflux
120
nd
d
e
THF
0:2
1:2
50c
rt
60
45
nd
80
Scheme
peptidomimetics 4
1 Synthesis of Boc/Cbz-protected 2-amino-1,3,4-oxadiazole tethered
CH2Cl2
Though the present reaction conditions were mild, the
f
CH3CN
EtOAc
1:2
1:2
rt
rt
60
78
70
possibility of racemization was studied in the case of two
epimeric 1,3,4-oxadiazoles Cbz-Phe-ψ-[C2N2O]-NH-L-Ala-OMe
4g and Cbz-Phe-ψ-[C2N2O]-NH-D-Ala-OMe 4g*. The analytical
RP-HPLC profiles of oxadiazoles 4g and its epimer 4g* showed
distinct retention times of Rt 19.557 and 18.544 min
respectively, thus confirming the absence of racemization.
g
120
h
i
DMF
THF
THF
1:2
1:3
rt
rt
rt
120
30
65
86
84
j
1.2:2
30
k
l
THF
THF
1:1.5
1:2
rt
60
15
65
92
0 0C
aReactions were monitored by TLC. bIsolated yield after column chromatography.
c sonication. nd = not determined
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one-pot, to supplement the proposed reactionVimeweAcrthicalenOisnlmine,
selenosemicarbazide (3e) was isolated and characterized by
Table 2 Synthesis of 2-amino-1,3,4-oxadiazole tethered peptidomimetics
DOI: 10.1039/C7NJ02278F
Mass and NMR studies, which gave a conclusive evidence of in
situ formed selenosemicarbazide.
Scheme 2 Plausible mechanism for the formation of 2-amino-1,3,4-oxadiazole 4 from
selenosemicarbazide 3
Conclusions
In summary, synthesis of Nα-Cbz/Boc-protected 2-amino-1,3,4-
oxadiazole tethered peptidomimetics by molecular iodine
mediated cyclodeselenization of in situ generated peptidyl
selenosemicarbazides in one-pot is developed. The present
method is mild and effective than the previously reported
methods (from semicarbazides or thiosemicarbazides) in the
literature and uses environmentally benign iodine as the
cyclization reagent. Other advantages of the method include
high product yields, mild reaction conditions and short
reaction time. The precipitation of elemental selenium and
formation of triethylammonium iodide largely simplifies the
purification procedure and the concern on precipitated
selenium can be diminished by reusing it for the preparation of
isoselenocyanato esters. We expect that the mild synthetic
route described here should increase the utility of this
amide/ester bioisostere in the synthesis of pseudopeptides for
the molecular recognition studies and in drug development.
Isolated yields are given in the parenthesis
A plausible mechanism has been proposed based on our
results and literature precedents15,18,21 (Scheme 2). Initially the
nucleophilic attack of Se on the molecular iodine will form the
Experimental section
All chemicals were used as obtained from Sigma Aldrich
Company, USA. All the solvents were dried and purified using
recommended procedures in the literature whenever
necessary. High resolution mass spectra were recorded on a
Micromass Q-TOF micromass spectrometer using electron
spray ionization mode.1H NMR and 13C NMR spectra were
intermediate
leads to the carbodiimide intermediate
A
. Then TEA assisted deselenization (path a)
. The subsequent
B
cyclization involving the nucleophilic attack of carbonyl oxygen
onto the carbodimide results in 2-amino-1,3,4-oxadiazole.
However, a second pathway b involving cyclization via direct
nucleophilic attack of carbonyl oxygen assisted by TEA cannot
be ruled out. It is noteworthy to mention that the mechanism
was also derived from the stoichiometric amount of TEA and I2
added for the cyclization via deselenization. In the reaction, 1
equiv. of I2 and 2 equiv. of TEA were consumed for the
formation of 2-amino-1,3,4-oxadiazole from its corresponding
selenosemicarbazide, the same stoichiometric amounts are
reflected in the proposed mechanism. Though our protocol is
recorded on
a Bruker AMX 400 MHz and 100 MHz
spectrometer, respectively. Melting points were determined in
an open capillary and are uncorrected. TLC experiments were
done using MERCK TLC aluminum sheets (silica gel 60 F254)
and chromatograms were visualized by exposing in iodine
chamber and in UV-lamp. Column chromatography was
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4
5
6
7
S. Vardan, H. Smulyan, S. Mookherjee and R. Eich, Clin.
performed on silica gel (100-200 mesh) using ethyl acetate and
hexane mixture as eluent.
View Article Online
Pharm. Ther., 1983, 34, 290-296.
DOI: 10.1039/C7NJ02278F
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General procedure
Synthesis of 2-amino-1, 3, 4-oxadiazole peptidomimetics 4;
To a solution of N-protected amino acid hydrazide
mmol) in THF (8 mL) was added a solution of isoselenocyanato
ester (1.0 mmol) and the reaction mixture was stirred for 1-2
1 (1.0
8
2
h at room temperature till the complete conversion of starting
O
materials (TLC analysis). Then the mixture is cooled to 0 C and
then TEA (2.0 mmol) was added followed by addition of iodine
(1.0 mmol) portion-wise over 5 min. Stirring was continued for
15 min and during the reaction precipitation of reddish brown
selenium powder was observed. After the reaction was
completed (monitored by TLC), the selenium powder was
filtered off and washed with THF (10 mL). The combined
filtrate was concentrated under vacuum and the residue was
diluted with EtOAc and washed with Sat. Na2S2O3, 10% citric
acid, 5% Na2CO3, brine solution and finally dried over Na2SO4,
and solvent was evaporated under reduced pressure, the
resulting crude product was purified by column
chromatography on silica gel (n-hexane-EtOAc = 7:3).
9
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Acknowledgements
We sincerely thank the Department of Science and Technology
(DST), Govt. of India for the financial support.
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