Abstract
The proposed structure of talarolide A, a cycloheptapeptide featuring a hydroxamate moiety within the peptide backbone, was successfully synthesized. An initial attempt to synthesize a linear peptide precursor containing a C-terminal N-benzyloxy glycine residue was problematic due to an unreported on-resin reduction of N-benzyloxy glycine to glycine. After repositioning the peptide cyclization point, a new linear peptide sequence was successfully prepared using Fmoc-solid-phase peptide synthesis. Subsequent solution-phase cyclization and removal of protecting groups furnished the synthetic talarolide A in good yield. Despite the mismatch of the NMR data between the synthetic talarolide A and the natural product, a detailed structural analysis using 2D NMR spectroscopy, together with re-synthesis of the same synthetic material using two additional cyclization sites, confirmed that our synthetic product has the reported structure of talarolide A.
Highlights
The N-hydroxylation of peptide backbones is an important strategy for peptide post-translational modification which has mainly been found in the metabolites of microorganisms.[1,2,3,4] Naturally-occurring peptides containing the N-hydroxy amide moiety have been reported as potential antibacterial and antitumor agents.[2,3,5,6] they can act as siderophores which chelate and transport metal ions essential for cell growth and proliferation.[1]
We envisaged that 1 could be constructed employing Fmocsolid-phase peptide synthesis (SPPS) to access the linear peptide precursor followed by a solution-phase head-to-tail cyclization
A side-chain-protected linear peptide could be initially assembled on a hyperacid-labile resin and the N-hydroxy amide moiety could be introduced by incorporating an N-benzyloxy glycine (3) building block into the sequence; after releasing the linear peptide precursor from the resin, 1 can be obtained through a solution-phase macrolactamization followed by subsequent final deprotection (Scheme 1)
Summary
The N-hydroxylation of peptide backbones is an important strategy for peptide post-translational modification which has mainly been found in the metabolites of microorganisms.[1,2,3,4] Naturally-occurring peptides containing the N-hydroxy amide moiety have been reported as potential antibacterial and antitumor agents.[2,3,5,6] they can act as siderophores which chelate and transport metal ions essential for cell growth and proliferation.[1]. We embarked on the first total synthesis of talarolide A (1) in order to confirm the proposed structure and establish a robust synthetic route towards this unusual family of peptides
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