Concise Total Synthesis and Biological Evaluation of Pargamicin A and its Diastereomer, Piperazic Acid-containing Cyclopeptides.

Abstract

We have accomplished the total synthesis, structure determination, and biological evaluation of pargamicin A and one of its diastereomers. Two key tripeptide segments were synthesized using a linear peptide elongation process that includes the direct coupling of a poorly nucleophilic piperazic acid derivative. The resulting tripeptides were coupled using triphosgene/collidine at ambient temperature leading to a precursor for the final cyclization step. T3P-promoted macrolactamization under high-dilution conditions, followed by the removal of the benzyl protecting group was used to furnish two putative structures of pargamicin A. Comparison of the 1 H and 13 C NMR spectra and the antibacterial activity of the natural and synthetic products successfully revealed that the absolute configuration of the N-hydroxy-Ile residue of pargamicin A is 2S,3S. A biological evaluation of synthetically obtained pargamicin A and its diastereomer suggested that the stereostructure of the cyclic peptide scaffold of the natural product plays a crucial role in determining the strength of its antibacterial activity.