Amide-forming ligation reactions allow the chemical synthesis of proteins by the union of unprotected peptide segments, and enable the preparation of protein derivatives not accessible by expression or bioengineering approaches. The native chemical ligation (NCL) of thioesters and N-terminal cysteines is unquestionably the most successful approach, but is not ideal for all synthetic targets. Here we describe the synthesis of an Fmoc-protected oxazetidine amino acid for use in the α-ketoacid-hydroxylamine (KAHA) amide ligation. When incorporated at the N-terminus of a peptide segment, this four-membered cyclic hydroxylamine can be used for rapid serine-forming ligations with peptide α-ketoacids. This ligation operates at low concentration (100 μM-5 mM) and mild temperatures (20-25 °C). The utility of the reaction was demonstrated by the synthesis of S100A4, a 12 kDa calcium-binding protein not easily accessible by NCL or other amide-forming reactions due to its primary sequence and properties.

Three-ring circus! Surprisingly complex molecular acrobatics are observed in the mechanism of the α-ketoacid-hydroxylamine amide-forming ligation reaction. Although this remarkable reaction can already be used for the chemoselective union of large, unprotected peptide fragments the elucidated mechanism provides important clues to extending its application to larger and more complex biological targets.

We present the first productive ring-closing metathesis reaction that leads to the construction of cyclic alkenyl bromides. Efficient catalysis employing commercially available Grubbs II catalyst is possible through appropriate modification of the starting bromoalkene moiety.

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Efficient Ring-Closing Metathesis of Alkenyl Bromides: The Importance of Protecting the Catalyst During the Olefin Approach. -Introduction of a (Z)-phenyl group into alkenyl bromides as well as alkenyl chlorides allows efficient ring-closing metathesis yielding synthetically important cyclic haloalkenes. -(GATTI, M.; DRINKEL, E.; WU, L.; PUSTERLA, I.; GAGGIA, F.; DORTA*, R.; J. Am. Chem. Soc. 132 (2010) 43, 15179-15181, http://dx.