Partially modified retro‐inverso peptides: Comparative Curtius rearrangements to prepare 1,1‐diaminoalkane derivatives

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.