Solid-phase synthesis of octapeptin lipopeptides

Abstract

Octapeptins are naturally derived cyclic lipopeptide antibiotics with activity against a range of Gram-negative pathogens, including highly resistant strains. Octapeptin C4, an exemplar of the class, was synthesized using a combination of Fmoc solid-phase peptide synthesis (SPPS) and solution-phase cyclization. Utilizing H-l-Leu-2-chlorotrityl resin, peptide couplings were performed using HCTU and collidine in DMF. The linear sequence was terminated by N-acylation with 3-(R)-hydroxydecanoic acid. The residue Dab-2 was orthogonally protected with 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)isovaleryl group (ivDde) to enable selective side-chain deprotection prior to resin cleavage. Resin cleavage was accomplished with hexafluoroisopropanol in DCM, followed by cyclization with diphenylphosphoryl azide (DPPA) and solid sodium bicarbonate in DMF.