Partially modified retro-inverso peptides. Comparative Curtius rearrangements to prepare 1,1-diaminoalkane...

Several synthetic routes are reported to prepare the hetero diprotected 1,1-diaminoalkanes from N-acylated amino acids or peptides for incorporation into partially modified retro-inverso peptides. The Curtius rearrangement was carried out on the N-protected aminoacyl azides obtained from the N-protected aminoacyl hydrazide by nitrosyl chloride or by sodium azide reaction with an appropriate mixed carboxylic carbonic acid anhydride. The resulting isocyanate was allowed to react with alcohol to give a urethane-type protecting group or, via a "one-pot" approach, directly with a carboxyl carrying component to yield the modified (reversed) peptide bond. The carboxyl component can be either an N-acylated amino acid or a malonic acid. The more standard route involves selective deprotection of the 1,1-diaminoalkane residue followed immediately by coupling with a carboxyl component to yield the same modified peptide derivative.