Synthesis and conformational preferences in solution and crystalline states of an aza-tripeptide

The aza-tripeptide Boc-Ala-AzPip-Ala-NHiPr (AzPip: 2-aza pipecolyl residue) was synthesized in seven steps using preferentially the diisopropylcarbodiimide/1-hydroxy-7-aza-benzotriazole (DIPCDI/AtOH) coupling method and via the Boc-AzPip-OBzl pivotal intermediate. Its crystal molecular structure is characterized by the presence of a βVI-like turn around the N-terminal Ala-AzPip sequence and stabilized by two intramolecular hydrogen bonds sharing the same (Boc)CO carbonyl acceptor. In solution (chloroform, DMSO), two isomers are in equilibrium, one of them resembling the stereoisomer found in the crystal, the other being unfolded, but keeping the cis-isomerism of the Ala-AzPip bond and the pronounced degree of pyramidicity of the axial 2-amide Nα nitrogen atom.