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Prior work in NCL at phenylalanine (Phe) employed \u03b2\u2010mercapto or \u03b2\u2010seleno (alkyl) derivatives. Herein, we describe an alternative approach to NCL at Phe, via an aryl thiol on the novel Phe surrogate\n                    <jats:italic>ortho\u2010<\/jats:italic>\n                    mercaptophenylalanine (2\u2010mercaptophenylalanine). Commercially available Boc\u20102\u2010iodo\u2010phenylalanine was incorporated at the N\u2010terminus of the peptide. A solid\u2010phase copper mediated cross\u2010coupling reaction with thioacetic acid was conducted on fully synthesized peptides with an N\u2010terminal Boc\u20102\u2010I\u2010Phe to introduce, after TFA cleavage and deprotection, a nucleophilic aryl thiolate in the resultant N\u2010terminal residue 2\u2010mercaptophenylalanine (p\n                    <jats:italic>K<\/jats:italic>\n                    <jats:sub>a<\/jats:sub>\n                    \u2009=\u20095.1, substantially lower than alkyl thiols). Alternatively, 2\u2010mercaptophenylalanine could be incorporated via the short synthesis of Boc\u20102\u2010(S\u2010\n                    <jats:italic>tert\u2010<\/jats:italic>\n                    butyl)mercaptophenylalanine and coupling to peptide on resin. Peptides containing 2\u2010mercaptophenylalanine rapidly underwent NCL reactions with peptides containing C\u2010terminal thioesters. NCL reactions with the thioesters of Gly, Ala, Leu, and Phe were complete in 5\u2009min1\u2009h at room temperature at 0.52\u2009mM peptide concentrations. Reactions with Val and Pro thioesters also proceeded in high yield, in 6\u2009h and 12\u2009h, respectively. NCL reactions with 2\u2010mercaptophenylalanine also proceeded efficiently at pH 5. The peptide ligation product was desulfurized using nickel boride to generate phenylalanine. These results, using commercially available reagents and the possibility of amino acid synthesis on the solid phase which eliminates the requirement for solution\u2010phase amino acid synthesis, represent a practical approach to NCL at phenylalanine.\n                  <\/jats:p>","DOI":"10.1002\/cbic.70290","type":"journal-article","created":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T14:32:39Z","timestamp":1776954759000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Native Chemical Ligation at Phenylalanine via\n                    <i>Ortho<\/i>\n                    \u2010Mercaptophenylalanine"],"prefix":"10.1002","volume":"27","author":[{"given":"Christina R.","family":"Forbes","sequence":"first","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Delaware  Newark Delaware USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brice A.","family":"Ludwig","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry University of Delaware  Newark Delaware USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glenn P. 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