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Sec has found wide utility in synthetic peptides, especially as a replacement for cysteine. One limitation of using Sec in synthetic peptides is that it can undergo \u03b2\u2010syn elimination reactions after oxidation, rendering the peptide inactive due to loss of selenium. This limitation can be overcome by substituting C\u03b1\u2010H with a methyl group. The resulting Sec derivative is \u03b1\u2010methylselenocysteine ((\u03b1Me)Sec). Here, we present a new strategy for the synthesis of (\u03b1Me)Sec by alkylation of an achiral methyl malonate through the use of a selenium\u2010containing alkylating agent synthesized in the presence of dichloromethane. The seleno\u2010malonate was then subjected to an enzymatic hydrolysis utilizing pig liver esterase followed by a Curtius rearrangement producing a protected derivative of (\u03b1Me)Sec that could be used in solid\u2010phase peptide synthesis. We then synthesized two peptides: one containing Sec and the other containing (\u03b1Me)Sec, based on the sequence of glutathione peroxidase. This is the first reported incorporation of (\u03b1Me)Sec into a peptide as well as the first reported biochemical application of this unique amino acid. The (\u03b1Me)Sec\u2010containing peptide had superior stability as it could not undergo \u03b2\u2010syn elimination and it also avoided cleavage of the peptide backbone, which we surprisingly found to be the case for the Sec\u2010containing peptide when it was incubated for 96\u00a0hours in oxygenated buffer at pH\u00a08.0.<\/jats:p>","DOI":"10.1002\/psc.3173","type":"journal-article","created":{"date-parts":[[2019,5,10]],"date-time":"2019-05-10T04:49:45Z","timestamp":1557463785000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Synthesis of alpha\u2010methyl selenocysteine and its utilization as a glutathione peroxidase mimic"],"prefix":"10.1002","volume":"25","author":[{"given":"Robert J.","family":"Wehrle","sequence":"first","affiliation":[{"name":"School of Mathematics and Natural Sciences, Chemistry and Biochemistry University of Southern Mississippi  Hattiesburg 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