One-pot synthesis of orthogonally protected dipeptide selenazoles employing Nα-amino selenocarboxamides and α-bromomethyl ketones

Article abstract of DOI:10.1016/j.tetlet.2014.10.085

A simple and efficient protocol for the synthesis of selenazole containing dipeptidomimetics using N^α-amino selenocarboxamides and α-bromomethyl ketones is described. All the compounds made were isolated in good yields and fully characterized.

Full text of DOI:10.1016/j.tetlet.2014.10.085

Tetrahedron Letters 55 (2014) 6831–6835
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Tetrahedron Letters
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One-pot synthesis of orthogonally protected dipeptide
a
selenazoles employing N -amino selenocarboxamides
and a-bromomethyl ketones
Chilakapati Madhu a, Nageswara Rao Panguluri a, N. Narendra b, V. Panduranga a,
Vommina V. Sureshbabu a,
⇑
a #109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B.R. Ambedkar Veedhi, Bangalore 560 001, India
b Department of Chemistry, Government Science College, Tumkur University, B.H. Road, Tumkur 572 103, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple and efficient protocol for the synthesis of selenazole containing dipeptidomimetics using
a
Received 30 May 2014
Revised 13 October 2014
Accepted 14 October 2014
Available online 22 October 2014
N -amino selenocarboxamides and
a
-bromomethyl ketones is described. All the compounds made were
isolated in good yields and fully characterized.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Amino nitrile
Phosphorus pentaselenide
a
N -Amino selenocarboxamide
a-Bromomethyl ketone
Selenazole
Selenium is an essential trace element for higher organisms and
nide.11b Geisler et al., reported an efficient protocol for the
synthesis of selenocarboxamides from the corresponding nitriles
using phosphorous pentaselenide12 (P2Se5). P2Se5 is a more reliable
reagent because of its ease of preparation, less toxic than NaSeH
or H2Se, and moreover the ability of P2Se5 circumvents the addition
of NEt3/pyridine10 and borontrifluoride diethyletherate.11b This
prompted us to opt for P2Se5 toward the synthesis of selenocarbox-
the enzymes which contain selenium such as glutathione peroxi-
dase (GPX), 5-deiodase type-1 play an important role in human
physiology.1 In recent years organoselenium derivatives have
shown marked biological and enzyme inhibitory activities.2,3
Notably, selenazole derivatives are one of the significant groups
of organoselenium compounds due to their pharmacological rele-
vance and are of interest in the field of material science.4 Molecules
containing this functional group possess strong inhibitory activity
against inducible nitric oxide synthase.5 The prominent examples
are selenazofurin, a potent known antiviral agent, 2-piperidinosel-
enazole and 4-phenyl-2-piperidinoselenazole, which exhibit
superoxide anion-scavenging activity.6
a
amides from the corresponding N -protected amino nitriles (Fig. 1).
Recently our group has reported the synthesis of selenoxopep-
tides,13 Nb-protected amino alkyl isoselenocyanate,14 selenourea,15
selenohydantoin,16 selenocarbamate, and selenazole containing
peptidomimetics.17 The utility of both carboxamides, as well as
a
thiocarboxamide derived from N -protected amino acids18 as
Selenocarboxamides are
a
class of reactive intermediates,
building blocks for the construction of oxazole/thiazole peptidom-
imetics has been well documented.19 In continuation of our inter-
est on organoselenium compounds, herein we report the one-pot
synthesis of orthogonally protected selenazole dipeptidomimetics
similar to their oxygen and sulfur analogs. They are important
precursors for the synthesis of biologically active heterocycles like
1,3-selenazoles7 and 1,3-selenazines.8 The reported methods for
the synthesis of selenocarboxamides include the reaction of nitrile
with hydrogen selenide9 (H2Se), sodium hydrogen selenide10
a
employing N -Fmoc/Boc/Z protected amino selenocarboxamides
and
a-bromomethyl ketone which involves the following retro-
(NaSeH), monoselenophosphate11a
, and bis(trimethylsilyl)sele-
synthetic pathway (Fig. 2).
a
Initially, the preparation of N -protected amino nitrile was
a
undertaken. N -Protected amino acid was converted to the corre-
⇑
Corresponding author. Tel.: +91 80 22961339/8147757961.
E-mail addresses: narendrachem@gmail.com (N. Narendra), sureshbabuvommi-
na@rediffmail.com, hariccb@hotmail.com, hariccb@gmail.com (V.V. Sureshbabu).
sponding carboxamide via its mixed anhydride and then treated
with aqueous ammonia. The resulting amide was subjected with
http://dx.doi.org/10.1016/j.tetlet.2014.10.085
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

6832
C. Madhu et al. / Tetrahedron Letters 55 (2014) 6831–6835
Se
P
Se
Se
P
Se
Se
P2Se5
Figure 1. Structure of P2Se5.
R1
R1
R1
R2
NHPG2
R2
N
NH
N
PG1HN
PG1HN
PG1HN
O
NHPG2
Se
Se
Se
NHPG2
OH
R2
O
R1
NH2
Br
NHPG2
PG1HN
Se
R2
Figure 2. Retro-synthetic analysis of orthogonally protected selenazole dipeptidomimetics.
trifluoroacetic anhydride (TFAA)/pyridine (py) at 0 °C in THF to
obtain the nitrile (Scheme 1). Later, elemental Se was heated with
red phosphorus under electric Bunsen burner till the mixture
became glassy black purple solid indicating the formation of
P2Se5. Then it was cooled to rt and powdered thoroughly.
In the next step, the synthesis of N -protected amino seleno-
carboxamide 2 was carried out (Scheme 1). In a typical procedure
Fmoc-Lue-w[CN] (1.0 equiv) 1b was dissolved in EtOH and freshly
prepared P2Se5 (2.0 equiv) was added. The reaction mixture was
heated to reflux and then a few drops of water were added to gen-
erate H2Se, which reacts with nitrile 1b for the formation of the
corresponding selenocarboxamide 2b. After completion of the
reaction, the reaction mixture was filtered and washed with EtOH
model systems with well defined secondary structures. Peptides
containing thiazole subunits are characterized by reduction of
multi drug resistance of certain types of lymphoblasts, antifungal,
antibacterial, antimicrobial, and antitubercular activities.21 The
structure of fascinating selenazole resembles with oxazole/thiazole.
Different protocols have been reported for the synthesis of selenaz-
oles by using selenoamide22 or selenourea23 as the starting mate-
rial. Selenoureas are inconvenient due to their high cost and low
stability to air and light. In particular Zhang et al., have synthesized
selenazole containing cyclic peptides (QZ59Se-SSS and QZ59Se-
RRR) for crystallization with p-glycoprotein (pgp) but this protocol
is limited to the preparation of Boc-amino selenocarboxamides.24
Thus, the limited applicability with the available literature
prompted us to prepare orthogonally protected dipeptide selenaz-
a
to obtain Fmoc-Leu-w[C(@Se)NH2] 2b. The crude residue was puri-
a
fied by column chromatography and the isolated pure compound
2b was characterized by Mass, 1H, 13C and 77Se NMR spectroscopy.
The 77Se NMR shows a characteristic single peak at around d 529.9
for the selenocarbonyl group. The adoptability and efficacy of the
protocol were further demonstrated by synthesizing a series of
oles from the corresponding N -amino selenocarboxamides.
a
In the next part of our study, the synthesis of N -urethane
orthogonally protected selenazole linked dipeptidomimetics
was carried out (Scheme 2). In a typical procedure, Fmoc-Leu-
w
[C(@Se)NH2] (2b) was refluxed with Boc-Phe-w
[C(@O)CH2Br]25
a
N -Fmoc/Boc/Cbz selenocarboxamides 2 from the corresponding
(3b) in acetone to obtain selenazole linked dipeptidomimetic 4b.
The reaction was found to be complete within 30 min, as observed
by TLC analysis. It was also evident by the disappearance of bromo-
methyl ketone peak at around 1735 cmÀ1 in the IR spectrum. The
isolated crude selenazole dipeptidomimetic 4b was purified
through column chromatography (hexane/EtOAc 9:1%) and
characterized by NMR and mass spectrometry. The generality of
nitriles 1 (Table 1).
Heterocyclic amino acids such as oxazoles and thiazoles are sub-
structures comprising numerous macrolactam natural products
having biological activities including cytotoxicity, p-glycoprotein
pump inhibition, and metal binding properties.20 Oxazole contain-
ing amino acids are suitable building blocks for the preparation of
R1
1.NMM, ECF
THF,-15 °C
R1
R1
THF,0 °C
OH
NH2
PGHN
PGHN
PGHN
CN
2. aq NH3
TFAA, Pyridine
O
O
R1
R1
P2Se5, EtOH/H2O
reflux, 3-4 h
NH2
PGHN
PGHN
CN
Se
1
2
PG= Fmoc, Boc or Cbz group
R1= amino acid side chain
a
Scheme 1. Synthesis of N -protected amino selenocarboxamides.

C. Madhu et al. / Tetrahedron Letters 55 (2014) 6831–6835
6833
Table 1
a
List of N -protected amino selenocarboxamides 2
Entry
Nitrile 1
Selenocarboxamide 2
Yield (%)
88
HRMS Obsd. (Calcd)*
a
473.0744 (473.0735)
NH2
FmocHN
FmocHN
CN
CN
Se
b
c
82
78
439.0901 (439.1012)
531.0799 (531.0682)
NH2
FmocHN
FmocHN
BzlOOC
Se
BzlOOC
NH2
FmocHN
FmocHN
CN
Se
NH2
d
e
68
79
275.0275 (275.0315)
303.0588 (303.0617)
BocHN
BocHN
CN
CN
Se
NH2
BocHN
BocHN
Se
NHCbz
NHCbz
NH2
f
64
466.1221 (466.0982)
BocHN
CN
BocHN
Se
NH2
g
78
88
309.0118 (309.0109)
294.9962 (294.1084)
CbzHN
CbzHN
CbzHN
CN
CN
Se
NH2
CbzHN
h
Se
BzlS
BzlS
NH2
i
73
69
431.0308 (431.0314)
335.0275 (335.0186)
CbzHN
CbzHN
CN
Se
NH2
j
CbzN
CbzN
CN
Se
*
[M+Na]+.
R1
R1
O
NHPG2
Acetone
NH2
R2
PG1HN
Br
+
N
PG1HN
reflux, 30 min
R2
Se
NHPG2
Se
2
3
4
Scheme 2. Synthesis of orthogonally protected dipeptide selenazoles.
the protocol was demonstrated for the synthesis of a series of
orthogonally protected dipeptide selenazoles (Table 2).
These observations inferred that the present protocol was free
from racemization.
Using chiral HPLC, the racemization study of the prepared dia-
stereomeric dipeptide selenazoles 4d and 4d⁄ were analyzed. They
showed peaks at Rt = 13.53 min (4d) and Rt = 18.42 min (4d⁄),
respectively. Also intentionally prepared equimolar mixture of 4d
and 4d⁄ showed distinct peaks at Rt = 13.62 and Rt = 18.60 min.
In conclusion we have developed a simple protocol for the syn-
thesis of selenazole linked N-orthogonally protected dipeptidomi-
a
metics by the condensation of N -amino selenocarboxamides
a
with
a
-bromomethyl ketones. Various N -protected selenocarbox-
amides have also been synthesized.

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C. Madhu et al. / Tetrahedron Letters 55 (2014) 6831–6835
Table 2
List of orthogonally protected selenazole dipeptidomimetics prepared
N
N
CbzHN
N
FmocHN
BocHN
Se
NHBoc
Se
NHBoc
Se
4c, yield 81%
NHCbz
4b, yield 78%
4a, yield 82%
N
FmocHN
N
N
FmocHN
Se
CbzHN
NHBoc
Se
NHBoc
Se
NHFmoc
4d, yield 75%
4e, yield 79%
4f, yield 83%
Tetrahedron Lett. 2012, 53, 377; (c) Pozdnev, V. F. Tetrahedron Lett. 1995, 36,
7115; (d) Sureshbabu, V. V.; Nagendra, G.; Venkataramanarao, R. Ultrason.
Sonochem. 2008, 15, 92.
Acknowledgments
We thank the Board of Research in Nuclear Sciences (BRNS),
Mumbai (No. 2011/37C/35/BRNS) for the financial assistance. Mad-
hu is thankful to UGC for SRF fellowship.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.10.
085.
22. (a) Geisler, K.; Künzler, A.; Below, H.; Bulka, E.; Pfeiffer, W. D.; Langer, P.
Synthesis 2004, 97; (b) Koketsu, M.; Takenaka, Y.; Ishihara, H. Synthesis 2001,
731; (c) Zhang, P. F.; Chen, Z. C. Synthesis 2000, 1219; (d) Shafiee, A.; Shafaati,
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Synthesis 1979, 66.
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Cell. Biochem. 2009, 99, 807; (b) Choi, S. Y.; Jo, Y. O.; Koketsu, M.; Ishihara, H.;
Kim, S. H.; Kim, S. Y. J. Korean Soc. App. Biol. Chem. 2009, 52, 371; (c) Nam, K. N.;
Koketsu, M.; Lee, E. H. Eur. J. Pharmacol. 2008, 589, 53.
5. (a) Ueda, S.; Terauchi, H.; Suzuki, K.; Yano, A.; Matsumoto, M.; Kubo, T.; Minato,
H.; Arai, Y.; Tsuji, J.; Watanabe, N. Bioorg. Med. Chem. Lett. 2005, 15, 136; (b)
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Kim, C. K. Biol. Pharm. Bull. 2003, 26, 1657.
6. (a) Goldstein, B. M.; Kennedy, S. D.; Hennen, W. J. J. Am. Chem. Soc. 1990, 112,
8265; (b) Sekiguchi, A.; Nishina, A.; Kimura, H.; Fukumoto, R. H.; Kanoh, K.;
Ishihara, H.; Koketsu, M. Chem. Pharm. Bull. 2005, 53, 1439.
7. (a) Larsen, R.; Shinkai, I. In Comprehensive Heterocyclic Chemistry II; Elsevier
Science: Oxford, 1996; Vol. 3, Chapter 8; (b) Koketsu, M.; Nada, F.; Ishihara, H.
Synthesis 2002, 195; (c) Wirth, T. Organo Selenium Chemistry Modern
Developments in Organic Synthesis; Springer: Berlin, 2000; (d) Geisler, K.;
Pfeiffer, W. D.; Muller, C.; Nobst, E.; Bulka, E.; Langer, P. Synthesis 2003, 1215.
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Sommen, G. L.; Linden, A.; Heimgartner, H. Helv. Chim. Acta 2007, 90, 472.
9. (a) Dell, C. P.; Moody, C. J. In Comprehensive Organic Functional Group
Transformation; Elsevier: Oxford, 1995; Vol. 5, p 565; (b) Ogawa, A.; Miyake,
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Further reading
26. (a) General procedure for the preparation of P2Se5
Red phosphorus was washed with anhydrous ether (10 mL) then dried. It
(10 mmol) was taken into glass vial and greyish elemental selenium powder
(25 mmol) was added. The resulting mixture was heated under electric
Bunsen until it turned to glassy black-purple solid and then cooled to rt and
grained.
(b) General procedure for the synthesis of N -protected amino selenocarboxamides
2a–j.
To a solution of N -protected amino nitrile (10 mmol) in EtOH (10 mL),
freshly prepared glassy black powdered P2Se5 (20 mmol) was added. The
reaction mixture was refluxed followed by the addition of a few drops of
water. After complete consumption of the starting material (TLC analysis; 3–
4 h), the reaction mixture was filtered. The solvent was removed in vacuo and
the crude residue was purified by column chromatography (hexane/EtOAc
8:2%).
(c) General procedure for the synthesis of orthogonally protected dipeptide
selenazoles 4a–f
To a solution of N -protected amino selenocarboxamide (10 mmol) in dry
acetone (10 mL), N -protected amino acid derived bromomethylketone
a
a
a
a
(10 mmol) was added. The reaction mixture was refluxed for about 30 min.
After completion of the reaction, the solvent was removed in vacuo and the
crude residue was purified by column chromatography (hexane/EtOAc 9:1%)
to obtain the pure dipeptide selenazole in good yield.
14. Chennakrishna Reddy, G.; Nagendra, G.; Hemantha, H. P.; Das, Ushati; Guru
Row, T. N.; Sureshbabu, V. V. Tetrahedron 2010, 66, 6718.
15. Sureshbabu, V. V.; Vasantha, B.; Madhu, C. Indian J. Chem. 2013, 52B, 895.
16. Hemantha, H. P.; Sureshbabu, V. V. J. Pept. Sci. 2010, 16, 644.
17. Lalithamba, H. S.; Narendra, N.; Naik, S. A.; Sureshbabu, V. V. ARKIVOC 2010, xi,
77.
27. Characterization data for selected compounds
Compound 2a: 1H NMR (300 MHz, DMSO-d6): d 2.91 (d, 2H, J = 6.8 Hz), 3.94 (t,
1H, J = 5.4 Hz), 4.36 (t, 1H, J = 4.8 Hz), 4.59 (d, 2H, J = 4.8 Hz), 6.12 (br, 1H),
7.12–7.55 (m, 13H), 9.83 (br s, 1H), 10.26 (br s, 1H); 13C NMR (75 MHz, DMSO-
d6): d 40.1, 48.3, 51.7, 66.9, 122.6, 125.2, 126.2, 127.7, 128.0, 128.3, 128.7,
139.3, 141.0, 143.5, 152.4, 196.1; 77Se NMR (75 MHz, DMSO-d6): d 490.5;
HRMS (m/z) calcd for: C24H22N2O2SeNa 473.0744; found: 473.0735 [M+Na]+.
Compound 2f: 1H NMR (300 MHz, DMSO-d6): d 1.22–1.25 (m, 2H), 1.37 (s, 9H),
18. (a) Cava, M. P.; Levinson, M. I. Tetrahedron 1985, 41, 5061; (b) Nuijens, T.; Piva,
E.; Kruijtzer, J. A. W.; Rijkers, D. T. S.; Liskamp, R. M. J.; Quaedflieg, P. J. L. M.

C. Madhu et al. / Tetrahedron Letters 55 (2014) 6831–6835
6835
1.38–1.41 (m, 2H), 1.50–1.53 (m, 2H), 2.85 (t, 2H, J = 4.8 Hz), 3.72 (t, 1H,
J = 4.2 Hz), 5.18 (s, 2H), 6.88 (br, 1H), 7.10 (br, 1H), 7.12–7.16 (m, 5H), 9.56 (br
s, 1H), 9.92 (br s, 1H); 13C NMR (75 MHz, CDCl3): 21.9, 27.9, 31.2, 33.5, 40.8,
50.3, 66.1, 78.5, 127.2, 127.6, 129.8, 140.9, 151.9, 153.3, 197.1; 77Se NMR
(75 MHz, CDCl3): d 517.1; HRMS (m/z) calcd for: C19H29N3O4SeNa 466.1221;
found: 466.0982 [M+Na]+.
Compound 4b: 1H NMR (300 MHz, CDCl3): d 1.10 (d, 6H, J = 7.4 Hz), 1.35 (s,
9H), 1.67–1.93 (m, 3H), 2.63 (d, 2H, J = 5.6 Hz), 3.41 (t, 1H, J = 4.8 Hz), 4.16 (t,
1H, J = 5.2 Hz), 4.41 (t, 1H, J = 7.0 Hz), 4.68 (d, 2H, J = 7.0 Hz), 5.17 (s, 1H), 6.15
(br, 1H), 6.92 (br, 1H), 7.13–7.78 (m, 13H); 13C NMR (75 MHz, CDCl3): 23.5,
24.7, 29.1, 35.2, 38.7 41.1, 47.4, 55.2, 67.7, 80.4, 115.9, 126.1, 126.6, 127.7,
128.1, 128.5, 128.7, 129.2, 138.8, 141.5, 143.2, 151.5, 156.3, 157.2, 175.4; 77Se
Compound 2i: 1H NMR (300 MHz, DMSO-d6): d 2.72 (d, 2H, J = 6.6 Hz), 3.61 (s,
2H), 3.81 (t, 1H, J = 3.8 Hz), 5.37 (s, 2H), 7.05 (br, 1H), 7.12–7.19 (m, 10H), 9.88
(br s, 1H), 10.07 (br s, 1H); 13C NMR (75 MHz, DMSO-d6): 35.5, 39.5, 53.2, 65.9,
127.2, 127.6, 127.9, 128.2, 128.6, 128.8, 137.2, 141.3, 152.2, 196.7; 77Se NMR
NMR (75 MHz, CDCl3): d 681.7; HRMS (m/z) calcd for: C36H41N3O4SeNa
682.2160; found: 682.2195 [M+Na]+.
Compound 4e: 1H NMR (300 MHz, CDCl3): d 1.34 (d, 3H, J = 7.2 Hz), 2.51 (d, 2H,
J = 6.8 Hz), 3.85 (t, 1H, J = 4.6 Hz),), 4.32 (t, 1H, J = 6.2 Hz), 4.42–4.47 (m, 1H),
4.78 (d, 2H, J = 6.2 Hz), 5.12 (s, 1H), 5.28 (s, 2H), 6.31 (br, 1H), 6.92 (br, 1H),
7.15–7.71 (m, 18H); 13C NMR (75 MHz, CDCl3): 17.6, 35.4, 45.1, 47.3, 54.0,
65.7, 68.2, 110.9, 126.4, 126.8, 127.3, 127.6, 127.8, 128.3, 128.5, 128.7, 128.9,
129.2, 139.2, 140.8, 141.5, 143.2, 152.1, 156.2, 157.5, 171.8; 77Se NMR
(75 MHz, CDCl3): d 681.1; HRMS (m/z) calcd for: C36H33N3O4SeNa 674.1534;
found: 674.1527 [M+Na]+.
(75 MHz, DMSO-d6):
d 497.8; HRMS (m/z) calcd for: C18H20N2O2SSeNa
431.0308; found: 431.0314 [M+Na]+.
Compound 4a: 1H NMR (300 MHz, CDCl3): d 0.95 (d, 6H, J = 6.2 Hz), 1.17 (d, 6H,
J = 6.4 Hz), 1.38 (s, 9H), 1.52–1.57 (m, 2H), 1.71–1.74 (m, 1H), 2.33–2.37 (m,
1H), 3.25 (d, 1H, J = 6.8 Hz), 4.21 (t, 1H, J = 5.2 Hz), 5.15 (s, 1H), 5.31 (s, 2H),
5.75 (br, 1H), 6.62 (br, 1H), 7.15–7.19 (m, 5H); 13C NMR (75 MHz, CDCl3): 17.8,
21.2, 24.5, 29.3, 32.7, 41.4, 49.8, 56.9, 65.7, 81.1, 114.5, 127.1, 127.6, 128.5,
141.4, 149.8, 155.7, 156.5, 174.5; 77Se NMR (75 MHz, CDCl3): d 656.3; HRMS
(m/z) calcd for: C25H37N3O4SeNa 546.1847; found: 546.1884 [M+Na]+.