Retro-inverso isomerization of peptides: Side reactions in the synthesis of N,N'-diacyl-1,1-diamino-2-phenylethane derivatives

In general, the synthesis of retro-inverso peptides requires the formation of diacylated gem-diaminoalkyl structures. One way to prepare these gem-diaminoalkyl residues involves the Curtius rearrangement of the N-acylated amino acid hydrazides to the corresponding N-acyl-α-aminoalkyl isocyanates which are subsequently trapped by an alcohol. We have found that the side reactions associated with alcohol addition to the isocyanate vary with the nature of the N-acylating group on the-amino function and the ratio of alcohol to isocyanate. These side reactions can be minimized by using only small excesses of alcohol over isocyanateor by performing the Curtius rearrangement on hydrazides derived from N-acetyl residues rather than on N-alkoxycarbonyl amino acids.