Synthesis and Evaluation of Enantiomeric Purity of Protectedα-Amino and Peptide Aldehydes

Abstract

The synthesis of enantiomerically pure Ac-Tyr-Val-Ala-Asp(OtBu)-H dimethyl acetal ((S)-1) is reported, a protected tetrapeptide C-terminal aldehyde belonging to a class of potent, reversible inhibitors of cysteine proteases (e.g., interleukin-1β-converting enzyme (ICE), also called caspase-1). The coupling of the precursors Ac-Tyr-Val-Ala-OH ((S)-8) and H-Asp(OtBu)-H dimethyl acetal ((S)-6) gave (S)-1 in a yield of 85%, with epimerization of <2% at the alanine and aspartic-acid residue. (S)-6 itself was synthesized in four steps in an overall yield of 83% with an ee >98%.