Racemic synthesis and solid phase peptide synthesis application of the chimeric Valine/Leucine derivative 2-amino-3,3,4-trimethyl-pentanoic acid

The synthesis of non natural amino acid 2-​amino-​3,​3,​4-​trimethylpentanoic acid (Ipv)​, ready for solid phase peptide synthesis, has been developed. Copper(I) chloride Michael addn., followed by a Curtius rearrangement are the key steps for the Ipv synthesis. The racemic valine​/leucine chimeric amino acid was then successfully inserted in position 5 of neuropeptide S (NPS) and the diastereomeric mixt. sepd. by reverse phase HPLC. The two diastereomeric NPS derivs. were tested for intracellular calcium mobilization using HEK293 cells stably expressing the mouse NPS receptor where they behaved as partial agonist and pure antagonist.