Controlled Boc-Protection of Diketopiperazine Using Tributylphosphine

抄録

A method for chemoselective acylation of the vacant amide of diketopiperazines (DKPs) using di-tert-butyl dicarbonate (Boc₂O) was developed. Nucleophilic tributylphosphine reacts immediately with acid anhydride to form an active quaternary phosphonium cation. This intermediate induces acylation of the amide group on the empty side, resulting in chemoselectivity that could not be controlled by using N,N-dimethyl-4-aminopyridine (DMAP). This method achieved high yields of mono-acylated DKPs, avoiding the acylation of amino acids with bulky substituents. This reaction system also provides chemoselectivity based on the bulkiness of the protecting groups of active functional groups at the side chain, and enhances the range of substrate applicability by achieving acylation of the amido groups of amino acids, except for glycine. Furthermore, using the substrates prepared here, elongation reactions induced by introducing amino acid esters associated with ring opening were also successfully demonstrated under reaction conditions without any additives, highlighting the possibility to form peptides with a broad range of sequences.