Total synthesis and antimicrobial evaluation of xylapeptide A

Abstract

Xylapeptide A is a cyclopentapeptide, [cyclo-D-Ala-L-Val-N-Me-L-Phe-L-Pip-L-Leu], first isolated from Xylaria sp. Â Sophora tonkinensis, together with its analogue, xylapeptide B, which differ by only one residue, proline in xylapeptide B is replaced by pipecolinic acid (Pip) in xylapeptide A. Both xylapeptides A and B possess antimicrobial properties against several bacteria and fungi. Herein, we describe the first total synthesis and antimicrobial evaluation of xylapeptide A containing two non-proteinogenic residues, N-Me-phenylalanine and pipecolinic acid. The synthesis of xylapeptide A was achieved by a combination of solid-and solution-phase methods that were applied for the synthesis of xylapeptide B. Interestingly, the cyclization of linear xylapeptide A was more straightforward yielding 22% compared to 8.9% for xylapeptide B, suggesting that the presence of pipecolinic acid in the linear precursor affected the cyclization process. NMR analysis of synthetic xylapeptide A revealed that the chemical shifts of all protons and carbons of xylapeptide A are highly similar to the natural product. The synthetic xylapeptide A, together with xylapeptide B, were evaluated for their antimicrobial properties, showing that synthetic xylapeptide A has moderate antimicrobial activity and better antimicrobial properties compared to synthetic xylapeptide B. The presence of pipecolinic acid in xylapeptide A is an important requirement for antimicrobial activity.