title: First total synthesis of WLIP: on the importance of correct protecting group choice.
abstract: Cyclic lipodepsipeptides (CLPs) are a group of metabolites produced by Pseudomonas bacteria, involved in various biological functions and displaying a wide range of properties, including antibacterial and antifungal activities. The white line-inducing principle (WLIP) is a member of the viscosin group featuring a Glu2 amino acid. Recently, a total synthesis of pseudodesmin A - the Gln2 counterpart of WLIP - was described, and we here expand this route to Glu2 containing CLPs. We report the first total synthesis of WLIP and at the same time establish that the Gln2 to Glu2 substitution has an adverse impact on the crude purity and overall yield. A comparative study of different CLP analogues reveals the importance of the nature of the Glx2 protecting group in determining these outcomes. Replacement of the conventional tBu protecting group by the larger benzyl group for the Glu residue in our synthesis strategy indeed resulted in an improved conversion. Next to achieving the first WLIP total synthesis, we thus show the importance of a careful choice of protecting groups for the success of this type of solid-phase synthesis approaches towards CLPs.
authors: Department of Organic and Macromolecular Chemistry, Organic and Biomimetic Chemistry Research Group, Ghent University, Krijgslaan 281 S4, 9000, Ghent, Belgium.|Department of Organic and Macromolecular Chemistry, NMR and Structure Analysis Unit, Ghent University, Krijgslaan 281 S4, 9000, Ghent, Belgium.
authors: Matthias
authors: M
authors: De Vleeschouwer
authors: Department of Organic and Macromolecular Chemistry, NMR and Structure Analysis Unit, Ghent University, Krijgslaan 281 S4, 9000, Ghent, Belgium.
authors: José C
authors: JC
authors: Martins
authors: Department of Organic and Macromolecular Chemistry, Organic and Biomimetic Chemistry Research Group, Ghent University, Krijgslaan 281 S4, 9000, Ghent, Belgium.
authors: Annemieke
authors: A
authors: Madder
mesh_terms: D019943:Amino Acid Substitution; D001426:Bacterial Proteins / Q000138:chemical synthesis*; D047630:Depsipeptides / Q000138:chemical synthesis*; D018698:Glutamic Acid / Q000737:chemistry; D005973:Glutamine / Q000737:chemistry; D006801:Humans; D055666:Lipopeptides / Q000138:chemical synthesis*; D011549:Pseudomonas / Q000737:chemistry; D060327:Solid-Phase Synthesis Techniques / Q000379:methods*
chemical_list: D001426:Bacterial Proteins; D047630:Depsipeptides; D055666:Lipopeptides; D005973:Glutamine; D018698:Glutamic Acid
keywords: CLP; Peptide synthesis; Pseudomonas; WLIP; protecting groups; total synthesis