Synthesis and Evaluation of Enantiomeric Purity of Protected α-Amino and Peptide Aldehydes

The synthesis of enantiomerically pure Ac-Tyr-Val-Ala-Asp(O^tBu)-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(O^tBu)-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%.