The Aziridine-Mediated Ligation and Efforts Towards a General Synthesis of N-terminal Aziridinyl Peptides
Dyer, Frank Brock
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Herein is described the Aziridine-Mediated Ligation's discovery, conceptual development, and the efforts to develop a general synthetic method for the synthesis of unprotected peptide chains terminated in an aziridine. The Aziridine Mediated Ligation is a chemical ligation of a C-terminal thioacid and N-terminal aziridinyl peptide in the presence of active copper(II) ion. The process was demonstrated to be chemoselective for the desired reaction in the presence of a wide array of other free functional groups under denaturing aqueous conditions. It is proposed that the copper(II) activates the C-terminal thioacid, creating a water-stable "active ester" which shows an enhanced reactivity for aziridines over a typical amine.The scope of the Aziridine-Mediated Ligation is limited because of the difficulties synthesizing and isolating unprotected aziridinyl peptides from aqueous media. A thorough examination of known protecting groups led to the discovery of a photo-released precursor to the aziridine coupling partner, which readily participates in the Aziridine-Mediated Ligation. The photolysis by-products appear to be inert to the Aziridine-Mediated Ligation as well. The stability of the aziridinyl peptide derivatives to harsh aqueous acidic conditions has also been established, providing a proof-of-principle that this method will be compatible with standard 9-fluoronylmethoxycarbonyl (Fmoc)-based solid phase peptide synthesis techniques. Also noteworthy is the use of a photo-deprotection of an aziridine, which was previously unreported and may find applications to total chemical synthesis of natural products as well the studies of enzyme mechanisms.