Stereo-divergent Synthesis of Nonproteinogenic Amino Acids and Synthetic Study for Biologically Active Cyclopeptides

Abstract

Naturally occurring cyclopeptides are potential middle-molecule drug candidates beyond Lipinski's rule of five. This paper focuses on the structural determination and structure-activity relationship (SAR) study of two cyclopeptides: asperterrestide A and decatransin. The proposed asperterrestide A was synthesized by solution-phase peptide elongation, followed by macrolactamization. NMR analysis and molecular modeling studies revealed the stereochemistry at the two α-positions of amino acid residues as opposite to each other. This was further confirmed by the total synthesis of the revised asperterrestide A. SAR study of synthetic products revealed that the β-hydroxy group in the nonproteinogenic amino acid residue was not essential for its cytotoxicity. In addition, N-alkyl-enriched peptide fragments of decatransin were synthesized in solution-phase without diketopiperadine formation. The putative candidates of decatransin was synthesized by convergent peptide coupling, followed by macrocyclization under modified Mitsunobu conditions. The structure of the natural decatransin, including its absolute configuration, was determined through a comparison of spectral data and the cytotoxicity exhibited by the synthetic products.