Total synthesis of the proposed structure of talarolide A

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.

Hydroxamate siderophores: Natural occurrence, chemical synthesis, iron binding affinity and use as Trojan horses against pathogens

“…In some artificial siderophores, the hydroxamate moiety was embedded in the backbone through α-N-hydroxy amino acids prepared indirectly from other closely related acids. For example, α-benzyloxyglycine was obtained by reacting bromoacetic acid tert-butyl ester and O-benzylhydroxylamine [96]. N-benzyloxyalanine (or Nbenzyloxyphenylalanine) was prepared starting from D-lactic acid (or D-phenyllactic) acid t-butyl ester by converting the α-OH to a triflate intermediate, followed by the reaction with O-benzylhydroxylamine [97].…”

“…The SN2 attack of the benzolyxyamine resulted with inverted configuration of α-carbon. The amide bond was then formed by condensing the hydroxylated α-N with an α-COOH of another amino acid using an effective form of activated acid [96,98]. All these methods followed the green route of Scheme 1 by introducing the alkyl part into a previously prepared benzyl protectedhydroxyl amine (Scheme 6).…”

“…Their medical use can be therapeutic or diagnostic [110]. The presence of hydroxy substituents on the amide bonds of an active peptide enhances its stability against enzymatic degradation [96]. Furthermore, hydroxamic acids inhibit methionine aminopeptidase (MetAP), an essential enzyme in protein synthesis in a variety of organisms.…”

“…Furthermore, hydroxamic acids inhibit methionine aminopeptidase (MetAP), an essential enzyme in protein synthesis in a variety of organisms. This inhibition enables the use of hydroxamic acids as potent antibacterial or antitumor agents [96,111]. Also, these acids have the potential to inhibit metalloproteases and HIV protease, and they show activity in immune suppression [96].…”

“…This inhibition enables the use of hydroxamic acids as potent antibacterial or antitumor agents [96,111]. Also, these acids have the potential to inhibit metalloproteases and HIV protease, and they show activity in immune suppression [96].…”