A simple protocol for the synthesis of triazole-linked cyclic glycopeptidomimetics: A sequential Ugi-MCR and azide-alkyne cycloaddition approach

Article abstract of DOI:10.1016/j.tetlet.2012.04.034

Sequential combination of Ugi-MCR and click chemistry has been employed for the synthesis of triazole linked cyclic glycopeptidomimetics. The protocol employs Poc-amino alkyl isonitriles, sugar-1-amines, azido acids, and simple aldehydes as precursors. The dual nature of the propargyloxycarbonyl (Poc) group was explored for amine protection as well as cycloaddition with an azide. All the cyclic glycopeptidomimetics are isolated and characterized.

Full text of DOI:10.1016/j.tetlet.2012.04.034

Tetrahedron Letters xxx (2012) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A simple protocol for the synthesis of triazole-linked cyclic
glycopeptidomimetics: a sequential Ugi-MCR and azide–alkyne cycloaddition
approach
⇑
M. Samarasimhareddy, Hosahalli P. Hemantha, Vommina V. Sureshbabu
#109, Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Bangalore University, Dr. B.R. Ambedkar Veedhi, 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:
Sequential combination of Ugi-MCR and click chemistry has been employed for the synthesis of triazole
linked cyclic glycopeptidomimetics. The protocol employs Poc-amino alkyl isonitriles, sugar-1-amines,
azido acids, and simple aldehydes as precursors. The dual nature of the propargyloxycarbonyl (Poc)
group was explored for amine protection as well as cycloaddition with an azide. All the cyclic
glycopeptidomimetics are isolated and characterized.
Received 26 March 2012
Revised 6 April 2012
Accepted 7 April 2012
Available online xxxx
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cyclic glycopeptidomimetic
Poc-amino alkyl isonitrile
Ugi multi-component reaction
Click chemistry
Affluence of cyclic glycopeptides1 in natural sources and the
knowledge about their biological and structural significance
emphasize the importance of the development of synthetic meth-
odologies for such molecules and related analogs. From the bio-
chemist’s perspective, glycopeptide cyclization is an interesting
aspect of study that may lead to valuable architectural repertoire
in a sequential manner so as to modify the Ugi-product to obtain
1
1
desired products. Till recently, isocyano esters, prepared by N-
modification of amino acid esters were the isonitrile components
generally used in the MCRs. Sureshbabu and co-workers described
another class of amino acid derived isonitriles by modifying the C-
terminus of N-protected amino acids and the resulted N-protected
amino alkyl isonitriles have been employed as key substrates in a
2
possessing structurally and pharmacologically useful properties.
1
2
Cyclic glycopeptides do not possess ionizable N- and C-terminals
rendering them with improved membrane permeability and stabil-
ity to in vivo enzymatic degradation.3 However, cyclization is, in
general, yield-limiting and synthetically a difficult step. This
evokes to suitably design the sites for gluing the head to tail afford-
ing a ring structure in an efficient manner through the establish-
ment of a native or non-native linkage.4 On the other hand,
substantial focus has been paved toward development of new pro-
couple of MCRs to obtain a few peptidomimetics. The Cu-cata-
1
3
lyzed azide–alkyne cycloaddition (‘click’ chemistry) is a robust
chemical transformation in bridging two components. This reaction
has accelerated the research in drug discovery due to the efficient
and non-sensitive reaction conditions, thus ideal for the synthesis
of a library of compounds. Triazole has been used as a surrogate
to the native bond in the synthesis of cyclic peptidomimetic and
1
4
glycopeptidomimetic scaffolds involving multistep protocol. Our
interest in the development of a useful strategy for accessing cyclic
neoglyco-peptidomimetics led us to explore a sequential combina-
tion of Ugi-MCR and azide–alkyne cycloaddition as a tool to synthe-
size the title compounds.
5
tocols for the construction of glycopeptidomimetics and peptido-
6
mimetcis. In the former, the carbohydrate is linked to peptide
backbone through a non-native linkage and in the latter class of
molecules, one or more amide bonds in the backbone are replaced
by artificial tethers.
The present study involves the design of suitable starting com-
ponents for MCR that would yield a linear molecule which can be
cyclized through click reaction. A combination of an isonitrile,
amine, aldehyde, and a carboxy compound would lead to a linear
peptidic derivative wherein the isonitrile and carboxy acid compo-
nents flank at either terminus. This directed us to deposit the
alkyne and azide groups required to operate post-MCR step, in
the isonitrile and carboxy substrates before initiating the MCR. In
this context, it is to note that both azide and alkyne groups are
compatible to Ugi reaction conditions. The azido acid was an
Multi-component reactions such as Ugi-MCR7 and Passerini-
8
3
CR are being utilized for accessing complex molecules from sim-
9
ple substrates. Isonitrile based MCRs, especially those involving
isocyano esters have emerged as tools of choice to access peptide-
like constructs. It is useful to tag MCRs with another reaction(s)
1
0
⇑
Corresponding author. Tel.: +91 80 2296 1339, mobile: +91 09986312937.
E-mail addresses: hariccb@hotmail.com, hariccb@gmail.com, sureshbabuvom
mina@rediffmail.com (V.V. Sureshbabu).
0
040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.034
Please cite this article in press as: Samarasimhareddy, M.; et al. Tetrahedron Lett. (2012), http://dx.doi.org/10.1016/j.tetlet.2012.04.034

2
M. Samarasimhareddy et al. / Tetrahedron Letters xxx (2012) xxx–xxx
immediate choice as one of the components because it serves as
amino acid precursor in peptide bond formation. Another key as-
pect is to obtain a linear peptidic unit possessing both isonitrile
and alkyne groups as terminals. The dual utility of propargyloxy-
carbonyl (Poc) group can be explored for amino protection as well
as a reactant for Huisgen’s cycloaddition reaction.1 Thus, Poc-pro-
tected amino alkyl isonitriles are chosen as suitable substrates in
this protocol. The sugar component was selected as an amino com-
ponent which can be prepared easily. The aldehydes were selected
from the commercially available sources.
The preparation of the substrates was straightforward and sim-
ple. Briefly, azido acids were prepared by a reaction of amino acids
with imidazole-1-sulfonyl azide as reported by Goddard-Borger.16
For the preparation of 2,3,4,6-tetra-O-acetyl glucosyl-1-amine,
glucose was reacted with acetyl chloride and the resulting
5
1,2,3,4,6-penta-O-acetyl-a,b-D-glucopyranose was reacted with
HBr in AcOH to obtain 2,3,4,6-tetra-O-acetyl glycopyranosyl-1-bro-
mide. Replacement of bromide with azide followed by catalytic
hydrogenation of the azido group afforded 2,3,4,6-tetra O-acetyl
1
7
glucopyranosyl-1-amine.
Poc-amino acids were prepared by
O
R3
NH
2
O
O
(XO)
4
X = Ac, Bn
4
a-h
N
3
(
OX)
CuSO
4
N
H
N
O
R2
:
4
Ugi-MCR
O
Sodium ascorbate
[2+3] "Click"
2
NC
H
R
R1
2a-h
O
O
1a-h
NH
O
O
N
3
OH
a-h
N
H
a-5h
O
R3
R1
R3
5
N
3
N
N
O
O
N
(OX)4
O
R2
O
O
HN
NH
6a-6h
R1
Scheme 1. Synthesis of triazole linked cyclic glycopeptidomimetics 6 via Ugi products 5.
Table 1
List of Ugi products 5a–5h and cyclic glycopeptidomimetics 6a–6h
Entry
Poc-Xaa-
w
2
[CH NC] (1)
Aldehyde (2)
Azido acid (3)
Sugar amines (4)
Ugi-product (5)
Cyclic product (6)
Yield (%)
Yield (%)
OHC
AcO
AcO
AcO
AcO
O
1
2
3
4
5
Phe
Ala
Gly
Leu
Leu
Gly
NH2
NH2
NH2
75
71
69
73
66
64
61
65
62
68
CHO
CHO
BzlO
BzlO
O
Leu
BzlO
BzlO
AcO
O
AcO
Gly
AcO
AcO
AcO
O
CHO
O
O
O
AcO
Val
NH2
NH2
AcO
AcO
AcO
CHO
OHC
AcO
Leu
AcO
AcO
AcO
AcO
NH2
6
Ala
Phe
AcO
67
66
AcO
BzlO
O
BzlO
7
8
Isoleucine
Phe
HCHO
Val
Ala
NH2
NH2
72
65
59
60
BzlO
BzlO
BzlO
O
CHO
O
BzlO
BzlO
BzlO
Please cite this article in press as: Samarasimhareddy, M.; et al. Tetrahedron Lett. (2012), http://dx.doi.org/10.1016/j.tetlet.2012.04.034

M. Samarasimhareddy et al. / Tetrahedron Letters xxx (2012) xxx–xxx
3
treating amino acids with Poc-OPfp according to Chandrasekaran
References and notes
1
8
and co-workers The carboxy terminus was modified into methy-
lene isonitrile through a series of operations as described previ-
1.
(a) Herzner, H.; Reipen, T.; Schultz, M.; Kunz, H. Chem. Rev. 2000, 100, 4495–
4538; (b) Li, H.; Li, B.; Song, H.; Breydo, L.; Baskakov, I. V.; Wang, L. J. Org. Chem.
1
9
ously by us.
2005, 70, 9990–9996; (c) Motiei, L.; Rahimipour, S.; Thayer, D. A.; Wong, C.;
The Ugi MCR was initiated by mixing equimolar quantities of
the four reactants in MeOH. In a typical reaction, Poc-Val-
Ghadiri, R. M. Chem. Commun. (Camb.) 2009, 7, 3693–3695.
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2
.
w
[CH
of furfural 2d and 2,3,4,6-tetra O-acetyl glucopyranosyl-1-amine
d in MeOH under nitrogen (Scheme 1). The course of the reaction
2
NC] 1d, azido-Leucine 3d were added to a stirred solution
(
b) Hadatsch, B.; Butz, D.; Schmiederer, T.; Steudle, J.; Wohlleben, W.;
Sussmuth, R.; Stegmann, E. Chem. Biol. 2007, 14, 1078–1089; (c) Chen, J.;
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4
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006, 47, 1969–1972.
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573–1582; (b) Webb, R. L.; Yasay, G. D.; McMartin, C.; McNeal, R. B.;
was monitored through TLC. After 24 h, the crude reaction mixture
was column chromatographed to obtain the desired linear peptidic
product 5d as solid in 73% yield. As expected, the product was a
mixture of two diastereomers. The chiral HPLC analysis revealed
that the two compounds were present in the ratio-95:5; however,
the isomers were not separated any further. The same protocol was
utilized to prepare a series of examples of Ugi adducts 5a–5h
3.
1
Zimmerman, M. B. J. Cardiovasc. Pharmacol. 1989, 2, 285–293; (c) Wittmann, V.;
Seeberger, S. Angew. Chem., Int. Ed. 2004, 43, 900–903; (d) Ohta, T.; Miura, N.;
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2
0
(
Table 1). In the ultimate step, the head to tail cyclization of thus
5
.
(a) Ryul, M. L.; Jiyong, L.; Injae, S. Synlett 2002, 9, 1463–1466; (b) Kim, J. M.;
Roy, R. Tetrahedron Lett. 1997, 38, 3487–3490; (c) Kieburg, C.; Sadalapure, K.;
Lindhorst, T. K. Eur. J. Org. Chem. 2000, 2035–2040.
obtained linear molecule was undertaken.
During the cyclization reactions, dimerization and oligomeriza-
2
1
6. (a) Li, Y.; Yu, Y.; Giulianotti, M.; Houghten, R. A. J. Org. Chem. 2009, 74, 2183–
185; (b) Fletcher, M. D.; Campbell, M. M. Chem. Rev. 1998, 98, 763–796; (c)
tion are a concern. This aspect is usually circumvented by taking
millimolar concentration of the reaction mixture. However, the
2
Grauer, A.; Konig, B. Eur. J. Org. Chem. 2009, 5099–5111; (d) Angell, Y. L.;
Burgess, K. Chem. Soc. Rev. 2007, 36, 1674–1689.
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2772; (b) Owens, T. D.; Semple, J. E. Org. Lett. 2001, 3, 3301–3304.
problem will not be so serious if the ring size is large so as to keep
the strain at minimum.22 In the present case, when the linear mol-
7.
8
.
ecule 5d was subjected to Cu catalyzed azide–alkyne cycloaddi-
tion, the designed triazole linked cyclic neoglycopeptide was
formed as a major component along with only a small amount of
dimer and meager quantities of other unidentified byproducts. It
can be reasoned that the target molecule is a 15-membered ring
and thus the ring strain is less due to which mono-cyclization is
the major reaction.
9. Ramachary, D. B.; Kishor, M.; Babul Reddy, G. Org. Biomol. Chem. 2006, 4, 1641–
646.
1
1
0. (a) Nixey, Y.; Kelly, M.; Hulme, K. Tetrahedron Lett. 2000, 41, 8729–8733; (b)
Ugi, I. Angew. Chem., Int. Ed. 1982, 21, 810–819; (c) Hulme, C.; Morrissette, M.
M.; Volz, F. A.; Burns, C. J. Tetrahedron Lett. 1998, 39, 1113–1116; (d) Keating, T.
A.; Armstrong, R. W. J. Org. Chem. 1996, 61, 8935–8939; (e) Kim, Y. B.; Choi, E.
H.; Keum, G.; Kang, S. B.; Lee, D. H.; Koh, H. Y.; Kim, Y. Org. Lett. 2001, 3, 4149–
4152.
In the initial experiment for the cyclization of 5d, the catalytic
11. (a) Marcaccini, S.; Torroba, T. Multicomponent React. 2005, 33–75; (b) Neo, A.
G.; Marcos, C. F.; Marcaccini, S.; Pepino, R. Tetrahedron Lett. 2005, 46, 7977–
t
system comprising CuSO
4
Á5H
2
O/sodium ascorbate in BuOH/water
7979; (c) Zanze, I. A.; Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron Lett.
was used. It led to 6d in 62% yield in about 10 h at rt. In order to
improve the yield as well as to reduce the duration of reaction,
other catalysts CuI/DIPEA in acetonitrile and CuBr/1,8-Diazabicy-
clo[5.4.0] undec-7-ene (DBU) in toluene were explored. Both sys-
tems yielded only 40% and 46% of the cyclized product 6d. In
2004, 45, 3421–3423.
12. (a) Vishwanatha, T. M.; Narendra, N.; Sureshbabu, V. V. Tetrahedron Lett. 2011,
3, 5620–5624; (b) Narendra, N.; Vishwanatha, T. M.; Nagendra, G.;
4
Sureshbabu, V. V. Tetrahedron 2010, 68, 1992–2000.
1
3. (a) Meldal, M.; Tornoe, C. W. Chem. Rev. 2008, 108, 2952–3015; (b) Kolb, H. C.;
Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001, 40, 2004–2021.
4. (a) Kuijpers, B. H. M.; Groothuys, S.; Keereweer, A. B. R.; Quaedflieg, P. J. L. M.;
Blaauw, R. H.; Delft, F. K. V.; Rutjes, F. P. J. T. Org. Lett. 2004, 6, 3123–3126; (b)
Gruner, S. A. W.; Locardi, E.; Lohof, E.; Kessler, H. Chem. Rev. 2002, 102, 491–
514; (c) Pedersen, D. S.; Abell, A. Eur. J. Org. Chem. 2011, 2399–2411; (d) Bock,
V. D.; Perciaccante, R.; Jansen, T. P.; Hiemstra, H. H.; Maarseveen, J. H. V. Org.
Lett. 2006, 5, 919–922.
1
light of these results, the CuSO
4
/sodium ascorbate was finally cho-
sen and thus was utilized in the synthesis of 6a–6h. In a typical
2
3
reaction,
CuSO
4
(0.02 equiv, 0.64 mg), sodium ascorbate
(
0.3 equiv, 7.6 mg) were added to the solution of linear peptidic
t
component 5d (100 mg 0.128 mmol) in BuOH/water (3:1;
20:40 mL). The resulting solution was allowed to stir for 10 h at
15. Hemantha, H. P.; Lamani, R. S.; Sureshbabu, V. V. Int. J. Pept. Res. Ther. 2010, 16,
1
267–275.
rt. The reaction was monitored by RP-HPLC. A simple work-up
afforded the target compound along with small amounts of dimer
product. The desired cyclic glycopeptidomimetic 6d was then iso-
lated by column chromatography using n-hexane/EtOAc (40:60) in
16. Goddard-Borger, E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797–3800.
1
7. (a) Gangadharmath, U. D. S.; Chang, C. W. T. J. Org. Chem. 2006, 71, 5179; (b)
Thiem, J.; Wiemann, T. Angew. Chem., Int. Ed. Engl. 1990, 29, 80; (c) Ameijde, J.;
Albada, H. B.; Liskamp, R. M. J. J. Chem. Soc., Perkin Trans. 2002, 1, 1042.
18. (a) Bhat, R. G.; Kerouredan, E.; Porhiel, E.; Chandrasekaran, S. Tetrahedron Lett.
002, 43, 2467–2469; (b) Bhat, R. G.; Sinha, S.; Chandrasekaran, S. Chem.
2
6
2% yield (Table 1). The reaction worked well with other linear
Commun. 2002, 812–813.
molecules as well. All the products 6a–6h were characterized by
19. Sureshbabu, V. V.; Narendra, N.; Nagendra, G. J. Org. Chem. 2009, 74, 153–157.
1
mass and H NMR spectroscopy.
20. General procedure for the preparation of Ugi products 5a–h: To a stirred
solution of aldehyde 2 (0.1 mmol) and glucose amine 4 (0.1 mmol) in methanol
In summary, an effective protocol has been designed to access
cyclic glycopeptidomimetics by employing Ugi MCR and click reac-
tions in a sequential manner. Poc-amino alkyl isonitrile is used for
the first time in MCR reactions and the alkyne moiety of Poc group
is made to participate in the intramolecular cycloaddition with an
azide situated at the other terminus. The resulting cyclic neoglyco-
peptidomimetic was isolated in moderate yield and characterized.
Click reaction is very efficient in bringing out the cyclization with-
out considerable byproducts.
(
2
5 mL) Poc-AA-w[CH NC] 1 (0.1 mmol) and azido acid 3 (0.1 mmol) were
added under nitrogen atmosphere. The stirring was continued for 18 h. After
completion of the reaction by TLC, the solvent was evaporated and the residual
mass extracted into ethyl acetate. The organic layer was washed with water
(
2 Â 15 mL) and brine (1 Â 15 mL) and concentrated under reduced pressure to
yield the crude product. The crude was then purified by column
chromatography (35% AcOEt in n-hexane) to obtain the pure linear peptidic
component 5 as a solid (yield 73%).
Characterization data for compound 5d: Brown solid; mp = 76–78 °C; IR (KBr)
1
t
max = 1692, 1735, 2122, 3340 cm ; R
f
= 0.21 (EtOAc: n-hexane, 40:60); RP-
1
HPLC R
t
= 16.8 (20–100% CH
3 6
CN, 30 min); H NMR (DMSO-d , 400 MHz) d 0.87
(
d, 6H, J = 5.8 Hz), 0.93 (d, 6H, J = 6.4 Hz), 1.32 (m, 2H), 1.65 (m, 1H), 1.98 (s,
1
1
1
2H), 2.1 (t, 1H, J = 4.6 Hz), 2.31 (m, 1H), 2.48 (s, 1H), 3.46 (m, 2H), 4.10 (m,
H), 4.24 (d, 2H, J = 7.2 Hz), 4.53 (s, 2H), 4.61 (m, 1H), 4.69 (m, 1H), 4.98 (m,
H), 5.21 (m, 1H), 6.02 (s, 1H), 6.10-6.22 (m, 2H), 6.24 (d, 1H, J = 6.4 Hz), 6.89
Acknowledgment
13
We thank the Department of Science and Technology, Govern-
ment of India, New Delhi, for the financial assistance (Grant No.
SR/S1/OC-52/2011).
(br, 2H), 7.18 (s, 2H); C NMR (DMSO-d
6
, 100 MHz) d 17.6, 20.8, 21.8, 22.1,
2.5, 30.6, 41.2, 53.4, 56.4, 56.6, 58.3, 59.1, 69.1, 69.2, 69.8, 76.2, 76.3, 78.6,
9.1, 106.4, 110.2, 141.8, 152.8, 155.3, 169.1, 173.2; HRMS Calcd for
2
7
Please cite this article in press as: Samarasimhareddy, M.; et al. Tetrahedron Lett. (2012), http://dx.doi.org/10.1016/j.tetlet.2012.04.034

4
2
M. Samarasimhareddy et al. / Tetrahedron Letters xxx (2012) xxx–xxx
+
C
35
H
48
6
N O
14 m/z 799.3100 [M+Na] . Found 799.3101, 155.3, 169.1, 173.2;
product was then isolated by giving water (1 Â 30 mL) and brine (1 Â 30 mL)
wash. The product was purified via chromatography (60% EtOAc in hexane) to
afford triazole linked cyclic neoglycopeptidomimetic 6d (62 mg, 62% yield) as a
solid.
+
HRMS Calcd for C35
1. (a) Maarseveen, J. H. V.; Horne, W. S.; Ghadiri, M. R. Org. Lett. 2005, 7, 4503–
506; (b) White, C. J.; Yudin, A. K. Nature 2011, 3, 509–524; (c) Jagasia, R.;
Holub, J. M.; Bollinger, M.; Kirshenbaum, K.; Finn, M. G. J. Org. Chem. 2009, 74,
964–2974.
48 6
H N O14 m/z 799.3100 [M+Na] . Found 799.3101.
4
Characterization data for compound 6d: Brown solid; mp = 137–141 °C; IR
À1
2
(KBr)
t
max = 1692, 1735, 2122, 3340 cm ; R
f
= 0.21 (EtOAc: n-hexane, 40:60);
1
2
2. Holub, J. M.; Kirshenbaum, K. Chem. Soc. Rev. 2010, 39, 1325–1337.
RP-HPLC R
t
= 16.8 (20–100% CH
3
CN, 30 min); H NMR (DMSO-d
6
, 400 MHz) d
2
3. Typical procedure for the preparation of triazole linked cyclic
0.93 (d, 6H, J = 6.8 Hz), 0.98 (d, 6H, J = 7.2 Hz), 1.20 (s, 12H), 1.73 (m, 1H), 1.89
(m, 2H), 2.32 (m, 1H), 3.48 (m, 2H), 4.16 (m, 1H), 4.26 (d, 2H, J = 5.8 Hz), 4.54 (t,
1H, J = 4.8 Hz), 4.63 (m, 1H), 4.66 (m, 1H), 4.96 (m, 1H), 5.23 (m, 1H), 5.28 (s,
2H), 6.06 (s, 1H), 6.12–6.21 (m, 2H), 6.24 (d, 1H, J = 6.2 Hz), 6.86 (br, 2H), 7.16
neoglycopeptidomimetic 6d: To
with linear peptidic component 5d (0.10 g, 0.128 mmol, 1 equiv) in BuOH
120 mL) and H O (40 mL) were added sodium ascorbate (7.6 mg, 0.038 mmol,
.3 equiv), CuSO4, andÁ5H O (0.64 mg, 0.0025 mmol, 0.02 equiv). The solution
a 250 mL round-bottomed flask charged
t
(
2
0
2
(s, 1H), 7.21 (s, 1H); 13C NMR (DMSO-d
6
, 100 MHz) d 17.4, 20.9, 21.9, 22.2, 30.6,
was then stirred at rt for about 10 h. Completion of the reaction was monitored
by RP-HPLC. The reaction mixture was then filtered through a pad of celite to
remove the salts and washed thoroughly with EtOAc (3 Â 25 mL). Crude
40.4, 45.3, 56.4, 58.2, 58.3, 59.2, 64.3, 67.6, 69.5, 69.8, 76.3, 79.2, 106.4, 110.2,
120.6, 141.8, 142.1, 152.1, 157.4, 170.6, 171.2, 173.2; HRMS calcd for
+
C
35
H
48
6
N O
14 m/z 799.3100 [M+Na] , found 799.3104.
Please cite this article in press as: Samarasimhareddy, M.; et al. Tetrahedron Lett. (2012), http://dx.doi.org/10.1016/j.tetlet.2012.04.034