1H-Azepine-4-amino-4-carboxylic acid: a new α,α-disubstituted ornithine analogue capable of inducing helix conformations in short Ala-Aib pentapeptides

Abstract

A very efficient synthesis of orthogonally protected 1H-azepine-4-amino-4-carboxylic acid, abbreviated as Azn, a conformationally restricted analogue of ornithine, was realized. It was obtained on a gram scale in good overall yield in five steps, three of which did not require isolation of the intermediates, starting from the readily available 1-amino-4-oxo-cyclohexane-4-carboxylic acid. Both enantiomers were used for the preparation of pentapeptide models containing Ala, Aib, and Azn. Conformational studies using both spectroscopic techniques (NMR, CD) and molecular dynamics on model 5-mer peptides showed that the (R)-Azn isomer possesses a marked helicogenic effect.