Efficient synthesis of modular amino acid derivatives containing selenium with pronounced GPx-like activity

Article abstract of DOI:10.1002/ejoc.200900485

New chiral selenide- and diselenide amino acid derivatives have been synthesized. By a simple and efficient two-step route, these new compounds were obtained from inexpensive and commercially available L-amino acids. The products, with a highly modular ch

Full text of DOI:10.1002/ejoc.200900485

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900485
Efficient Synthesis of Modular Amino Acid Derivatives Containing Selenium
with Pronounced GPx-Like Activity
Eduardo E. Alberto,[a] Letiére C. Soares,[a] Jéssie H. Sudati,[a] Antonio C. A. Borges,[b]
João B. T. Rocha,*[a] and Antonio L. Braga*[a,c]
Keywords: Selenium / Amino acids / Biological activity / Chalcogens
New chiral selenide- and diselenide amino acid derivatives
have been synthesized. By a simple and efficient two-step
excellent yields. Selected examples were also efficiently
used as GPx mimics, catalyzing the reduction of H2O2 to
route, these new compounds were obtained from inexpen- water at the expense of PhSH.
sive and commercially available
with a highly modular character, were obtained in good to
L
-amino acids. The products,
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
nary number of different reactions, including carbon–car-
bon bond formation, under relatively mild reaction condi-
tions.[8] Moreover, chiral selenide- and diselenide-contain-
ing ligands offer attractive and practical options in the de-
velopment of asymmetric transformations.[9]
Introduction
The interest in organochalcogen compounds has been
growing since the 1970s, when many reports described the
identification of various selenoproteins, which are involved
in a wide number of mammals’ biochemistry mechanisms.[1]
Synthetic developments and the design of new organoselen-
ium compounds have been attracting considerable atten-
tion,[2] especially because these compounds have the ca-
pacity to mimic natural compounds with important bio-
logical proprieties (e.g., antioxidant, antitumor, anti-inflam-
matory, and anti-infective activity).[3] One of the most im-
pacting studies determined that selenium plays a pivotal
role in glutathione peroxidase enzymes (GPx), which pro-
tect organisms from oxidative stress, inherent from oxygen
metabolism.[4] More important, selenium is considered an
essential trace element,[5] and it is appointed as an impor-
tant agent in cancer prevention, immunology, aging, male
reproduction, neurodegenerative diseases, including Alzhei-
mer’s and Parkinson’s disease, and other physiological pro-
cesses.[6]
As part of our growing interest in amino acid derivatives
containing chalcogens, as chiral building blocks in organic
synthesis[10] or for biological screenings,[11] and in connec-
tion with the increasing importance of the synthesis of
small libraries of compounds with programmed variations
of substituents, we describe herein an easy, inexpensive, and
two-step synthetic route for the preparation of a series of
chiral amino acid derivatives containing selenium. Our ap-
proach allows a modular construction, affording the prod-
ucts in a short synthetic route in good to excellent yields,
avoiding the use of protecting group chemistry. Some of
these new compounds were also efficiently used as GPx
mimics, catalyzing the reduction of H2O2 to water at the
expense of PhSH.
Selenium-based methods have developed rapidly over the
past years and have become a useful tool in the hands of
organic chemists.[7] Organoselenium compounds have found
such wide utility because of their effects on an extraordi-
Results and Discussion
According to our aim, initially we promoted the synthe-
sis of key chiral bromo amides 2a–h. The treatment of
bromo carboxylic acids with N-methylmorpholine (NMM)
and ethyl chloroformate produced the mixed anhydride in
situ,[12] which was then treated with -amino esters and an-
other equivalent of NMM to form the amide bond in good
yields under very mild conditions (Scheme 1). A series of
compounds was synthesized through variation of the amino
acid residues and the chain length between the bromide
atom and the amino ester moiety.
[a] Departamento de Química, Universidade Federal de Santa Ma-
ria,
97105-900 Santa Maria, RS, Brazil
Fax: +55-55-3220-8998
E-mail: albraga@qmc.ufsc.br
[b] Instituto de Química, Universidade Federal do Rio Grande do
Sul,
Porto Alegre, RS, Brazil
[c] Departamento de Química, Universidade Federal de Santa Cat-
arina,
Florianópolis, SC, Brazil
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900485.
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J. B. T. Rocha, A. L. Braga et al.
Table 1. Synthesis of selenides 3a–n.
SHORT COMMUNICATION
Scheme 1. Conditions: bromo carboxylic acid (1 mmol), NMM
(1 mmol), ethyl chloroformate (1 mmol), -amino ester (1 mmol),
NMM (1 mmol), CHCl3 (5 mL).
With the bromo amides in hands we promoted the inser-
tion of the organochalcogen moiety, through the nucleo-
philic attack of selenium anions generated by reaction of
diselenides with NaBH4 in a mixture of THF and ethanol
(Table 1).
The target compounds were obtained in good to excel-
lent yields; compound 3a was achieved in 92% yield
(Table 1, Entry 1). When the chain length between the bro-
mide atom and the amino ester moiety was increased, the
yield of compound 3e was still high, but a slight decrease
in comparison to that of 3a–d was observed (Table 1, En-
try 5). The change of the amino acid residue did not pro-
duce a pronounced effect on the yield of the products
(Table 1, Entries 6–8). At this point, we turned our atten-
tion to check if steric and electronic diversity in the aryl
moiety attached to selenium would promote some changes
in the yield of the given products (Table 1, Entries 9–12).
We found that electronic effects did not display an impor-
tant role in the formation of the products. Compounds 3i
with methyl and 3j with chlorine attached in the para posi-
tion of the benzyl ring showed almost the same results
(Table 1, Entries 9 and 10). In contrast, when we employed
these same substituents, but in the ortho position, the yields
were drastically lower (Table 1, Entries 11 and 12). We also
used dibenzyl and dibutyl diselenides as selenium sources,
producing compounds 3m and 3n in good yields (Table 1,
Entries 13 and 14).
One of the major advantages of this developed strategy
is its modular construction, where modifications in the
structure of the products can be easily introduced. In this
way, and as a further extension of the present methodology,
we attempted the synthesis of diselenides 4a–h (Table 2).
Bromo amides 2a–h were added to a THF solution of
Li2Se2, affording diselenides 4a–h in good yields. The yields
of the diselenide series from -phenylalanine derivatives
were not affected by the increase in the carbon chain length.
Diselenides 4a–e were produced with yields from 55 to 76%
(Table 2, Entries 1–5). Diselenides with other amino acid
residues were also prepared, affording the desired products
in good yields (Table 2, Entries 6–8).
Recently we developed a series of telluro amino acid de-
rivatives with remarkable GPx-like activity.[13] Although the
telluro analogues showed high catalytic activity (T50 about
[a] Isolated yields.
2 min), the selenide ones were not able to promote the re- well-known ability of diselenides to act as GPx mimics,[14]
duction of H2O2 at an appreciable rate. Encouraged by the we selected diselenides 4a–c to evaluate their GPx like ac-
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Synthesis of Modular Selenium-Containing Amino Acid Derivatives
Table 2. Synthesis of diselenides 4a–h.
Figure 1. GPx-like behavior of catalysts 4a–c.
Table 3. T50 values of catalysts 4a–b and PhSeSePh.
Catalyst[a,b]
T50 [min][c]
4a
4b
93.03 (Ϯ5.77)[d]
51.38 (Ϯ2.45)[d]
45.15 (Ϯ3.17)[d]
51.80 (Ϯ2.83)[d]
4c
PhSeSePh
[a] Under these conditions, addition of H2O2 in the absence of cata-
lyst did not produce any significant oxidation of PhSH. [b] MeOH
(1 mL), catalyst (0.025 m), PhSH (1.9 m), H2O2 (8.8 m). [c] T50
is the time required, in minutes, to reduce the thiol concentration
to 50% after the addition of H2O2. [d] The experimental error is
given in parentheses.
[a] Isolated yields.
Conclusions
tivity as a preview study. We also used PhSeSePh under the
same conditions to compare the results. The catalytic be-
havior of these compounds, as GPx model enzymes, was
tested according to the Tomoda method, using benzenethiol
as a glutathione alternative.[15] The reduction of H2O2 was
monitored through the UV absorption increase at 305 nm,
resulting from diphenyl disulfide formation. Linear in-
creases in absorbance were observed by mixing MeOH,
PhSeSePh or catalysts 4a–c (1.3 mol-%), PhSH, and H2O2
(Figure 1).
Taking advantage of the modular characteristic of our
catalysts, we evaluated the influence of the chain length be-
tween the diselenide moiety and the amino acid residue in
the reduction of hydrogen peroxide. Compounds 4c and 4b
derived from -phenylalanine with longer chain length
showed better results than PhSeSePh (T50 = 45.15 min and
51.38 min, respectively; Table 3). Compound 4a, with a
shorter chain length, was the least effective catalyst in this
screening (T50 = 93.03 min).
In summary, we have described the synthesis of a new
class of chiral selenide- and diselenide amino acid deriva-
tives. These compounds were prepared by a concise and
flexible synthetic route in good to excellent yields, which
permitted the preparation of a wide range of compounds
with a highly modular character. Indeed, we have tested
some of these diselenides as GPx mimics, catalyzing the re-
duction of H2O2 to water at the expense of thiophenol by
using just 1.3 mol-% of catalyst. Diselenide 4c considerably
accelerated the reaction exhibiting a T50 value of 45.15 min,
whereas only a marginal accelerating effect was observed
for the already known GPx mimic PhSeSePh, which showed
a T50 of value 51.80 min. Biological screenings of these new
selenium amino acid derivatives are currently under investi-
gation in our laboratory.
Supporting Information (see footnote on the first page of this arti-
cle): General experimental procedures and 1H and 13C NMR spec-
tra of selected compounds.
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J. B. T. Rocha, A. L. Braga et al.
SHORT COMMUNICATION
Bright, M. R. Detty, J. Org. Chem. 2008, 73, 6849; f) D. M.
Freudendahl, S. A. Shahzad, T. Wirth, Eur. J. Org. Chem. 2009,
1649.
Acknowledgments
The authors gratefully acknowledge Coordenação de Aper-
feiçoamento de Pessoal de Nível Superior–Programa Brasil Alem-
anha (CAPES–PROBRAL), Conselho Nacional de Desenvolvi-
mento Científico e Tecnológico (CNPq), and Institutos Nacionais
de Ciência e Tecnologia-Catálise (INCT-Catálise) for financial sup-
port. E. E. A. and L. C. S. also thank CNPq for PhD and Masters
fellowships.
[9] For a comprehensive review about the use of chiral organose-
lenium compounds in asymmetric catalysis, see: a) T. Wirth,
Tetrahedron 1999, 55, 1; b) T. Wirth, Angew. Chem. Int. Ed.
2000, 39, 3740; c) A. L. Braga, D. S. Lüdtke, F. Vargas, R. C.
Braga, Synlett 2006, 1453; d) A. L. Braga, D. S. Lüdtke, F.
Vargas, Curr. Org. Chem. 2006, 10, 1921.
[10] For selected examples, see: a) A. L. Braga, S. J. N. Silva, D. S.
Lüdtke, R. L. Drekener, C. C. Silveira, J. B. T. Rocha, L. A.
Wessjohann, Tetrahedron Lett. 2002, 43, 7329; b) A. L. Braga,
O. E. D. Rodrigues, M. V. Paixão, H. R. Appelt, C. C. Silveira,
D. P. Bottega, Synthesis 2002, 2338; c) A. L. Braga, D. S.
Lüdtke, M. W. Paixão, O. E. D. Rodrigues, Org. Lett. 2003, 5,
2635; d) A. L. Braga, D. S. Lüdtke, E. E. Alberto, J. A.
Sehnem, Tetrahedron 2005, 61, 11664; e) A. L. Braga, J. A.
Sehnem, F. Vargas, R. C. Braga, J. Org. Chem. 2005, 70, 9021;
f) A. L. Braga, M. W. Paixão, G. Marin, Synlett 2005, 1675; g)
A. L. Braga, P. H. Schneider, M. W. Paixão, A. M. Deobald,
C. Peppe, D. P. Bottega, J. Org. Chem. 2006, 71, 4305; h) A. L.
Braga, D. S. Lüdtke, E. E. Alberto, J. Braz. Chem. Soc. 2006,
17, 11; i) A. L. Braga, F. Vargas, F. Z. Galetto, M. W. Paixão,
R. S. Schwab, P. T. Taube, Eur. J. Org. Chem. 2007, 5327; j) A.
Sharma, R. S. Schwab, A. L. Braga, T. Barcellos, M. W.
Paixão, Tetrahedron Lett. 2008, 49, 5172; k) A. L. Braga, R. S.
Schwab, E. E. Alberto, S. M. Salman, J. Vargas, J. B. Azeredo,
Tetrahedron Lett. 2009, 50, 2309; l) G. Marin, A. L. Braga,
A. S. Rosa, F. Z. Galetto, R. A. Burrow, H. Gallardo, M. W.
Paixão, Tetrahedron 2009, 65, 4614; m) A. L. Braga, W. A. S.
Filho, R. S. Schwab, O. E. D. Rodrigues, L. Dornelles, H. C.
Braga, D. S. Lüdtke, Tetrahedron Lett. 2009, 50, 3005.
[1] a) D. L. Klayman, H. H. Günter in Organoselenium Com-
pounds: Their Chemistry and Biology, Wiley, New York, 1973;
b) J. T. Rotruck, A. L. Pope, H. E. Ganther, A. B. Swanson,
D. G. Hafeman, W. G. Hoekstra, Science 1973, 179, 588; c) L.
Flohé, E. A. Günzler, H. H. Schock, FEBS Lett. 1973, 32, 132;
d) R. J. Shamberger in Biochemistry of Selenium, Plenum Press,
New York, 1983; e) L. Flohé, J. R. Andreesen, R. Brigelius-
Flohé, M. Maiorino, F. Ursini, IUBMB Life 2000, 49, 411; f)
C. Jacob, G. I. Giles, N. M. Giles, H. Sies, Angew. Chem. Int.
Ed. 2003, 42, 4742.
[2] a) P. P. Phadnis, G. Mugesh, Org. Biomol. Chem. 2005, 3, 2476;
b) C. Mukherjee, P. Tiwari, A. K. Misra, Tetrahedron Lett.
2006, 47, 441; c) P. Tiwari, A. K. Misra, Tetrahedron Lett. 2006,
47, 2345; d) R. Caputo, S. Capone, M. D. Greca, L. Longob-
ardo, G. Pinto, Tetrahedron Lett. 2007, 48, 1425; e) M. Abdo,
S. Knapp, J. Am. Chem. Soc. 2008, 130, 9234; f) L. A.
Wessjohann, A. Schneider, Chem. Biodiversity 2008, 5, 375 and
references cited therein.
[3] C. W. Nogueira, G. Zeni, J. B. T. Rocha, Chem. Rev. 2004, 104,
6255.
[4] a) G. Mugesh, H. Singh, Chem. Soc. Rev. 2000, 29, 347; b) G. [11] Selected examples: a) M. Farina, N. B. V. Barbosa, C. W. Nog-
Mugesh, W. W. du Mont, H. Sies, Chem. Rev. 2001, 101, 2125;
c) B. K. Sarma, G. Mugesh, Org. Biomol. Chem. 2008, 6, 965.
[5] K. Schwars, C. M. Foltz, J. Am. Chem. Soc. 1957, 79, 3292.
[6] a) R. F. Burk in Selenium in Biology and Human Health,
Springer, New York, 1994; b) L. C. Clark, G. F. Combs, B. W.
Turnbull, E. H. Slate, D. K. Chalker, J. Chow, L. S. Davis,
R. A. Glover, G. F. Graham, E. G. Gross, A. Krongrad, J. L.
Lesher, H. K. Park, B. B. Sanders, C. L. Smith, J. R. Taylor, J.
Am. Med. Assoc. 1996, 276, 1957; c) G. V. Kryukov, S. Castello,
S. V. Novoselov, A. V. Lobanov, O. Zehtab, R. Guigó, V. N.
Gladyshev, Science 2003, 300, 1439.
[7] Selected examples: a) G. J. Brink, J. M. Vis, I. W. C. E. Arens,
R. A. Sheldon, J. Org. Chem. 2001, 66, 2429; b) M. A. Good-
man, M. R. Detty, Synlett 2006, 1100; c) C. Santi, S. Santoro,
B. Battistelli, L. Testaferri, M. Tiecco, Eur. J. Org. Chem. 2008,
5387; d) G. Perin, E. J. Lenardão, R. G. Jacob, R. B. Panatieri,
Chem. Rev. 2009, 109, 1277.
[8] a) K. C. Nicolaou, N. A. Petasi in Selenium in Natural Products
Synthesis, CIS, Philadelphia, PA, 1984; b) D. Liotta in Organ-
oselenium Chemistry, Wiley, New York, 1987; c) T. G. Back in
Organoselenium Chemistry: A Practical Approach, Oxford Uni-
versity Press, Oxford, UK, 1999; d) T. Wirth in Topics in Cur-
rent Chemistry Vol. 208: Organoselenium Chemistry – Modern
Developments in Organic Synthesis, Springer, Heidelberg, Ger-
many, 2000; e) S. M. Bennett, Y. Tang, D. McMaster, F. V.
ueira, V. Folmer, G. Zeni, L. A. Andrade, A. L. Braga, J. B. T.
Rocha, Braz. J. Med. Biol. Res. 2002, 35, 636; b) M. Burger,
R. Fachinetto, L. Calegari, M. W. Paixão, A. L. Braga, J. B. T.
Rocha, Brain Res. Bull. 2004, 64, 339; c) D. S. Avila, M. C.
Beque, V. Folmer, A. L. Braga, G. Zeni, C. W. Nogueira,
F. A. A. Soares, J. B. T. Rocha, Toxicology 2006, 224, 100; d)
S. A. Sculaccio, E. M. Rodrigues, A. T. Cordeiro, A. Ma-
galhães, A. L. Braga, E. E. Alberto, O. H. Thiemann, Mol. Bi-
ochem. Parasitol. 2008, 162, 165.
[12] a) J. Eilers, J. Wilkens, J. Martens, Tetrahedron: Asymmetry
1996, 7, 2343; b) A. L. Braga, F. Vargas, C. C. Silveira, L. H.
Andrade, Tetrahedron Lett. 2002, 43, 2335; c) A. L. Braga,
D. S. Lüdtke, M. W. Paixão, E. E. Alberto, H. A. Stefani, L.
Juliano, Eur. J. Org. Chem. 2005, 4260.
[13] A. L. Braga, E. E. Alberto, L. C. Soares, J. B. T. Rocha, J. H.
Sudati, D. H. Ross, Org. Biomol. Chem. 2009, 7, 43.
[14] a) S. R. Wilson, P. A. Zucker, R. R. C. Huang, A. Spector, J.
Am. Chem. Soc. 1989, 111, 5936; b) T. Wirth, Molecules 1998,
3, 164; c) G. Mugesh, A. Panda, H. B. Singh, N. S. Punekar,
R. Butcher, J. Chem. Commun. 1998, 2227; d) G. Mugesh, A.
Panda, H. B. Singh, N. S. Punekar, R. J. Butcher, J. Am. Chem.
Soc. 2001, 123, 839.
[15] M. Iwaoka, S. Tomoda, J. Am. Chem. Soc. 1994, 116, 2557.
Received: May 5, 2009
Published Online: July 22, 2009
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