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 route, these new compounds were obtained from inexpen- sive and commercially available L-amino acids. The products, with a highly modular character, were obtained in good to 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] 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- [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. Eur. J. Org. Chem. 2009, 4211–4214 © 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 4211 excellent yields. Selected examples were also efficiently used as GPx mimics, catalyzing the reduction of H 2 O 2 to water at the expense of PhSH. (© 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] 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 H 2 O 2 to water at the expense of PhSH. 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.