Synthesis of two substrate mimics of thioesterase in the biosynthesis of cyclic depsipeptide WS9326A

WS9326 A is a tachykinin receptor antagonist and quorum sensing inhibitor discovered from several Streptomyces strains.The structure of WS9326 A features a(Z)-pentenylcinnamoyl moiety attached on a cyclic depsipeptide skeleton,which is biosynthesized by nonribosomal peptide synthetases(NRPS).The regioselective cyclization in the last step of NRPS catalysis,which is proposed to be catalyzed by a thioesterase(TE)domain in the last module,has not been experimentally characterized.We here report the synthesis of two substrate mimics(1 and 2)of the TE(WS9326 A-TE)in WS9326 A biosynthesis,by using Fmoc-based solid-phase peptide synthesis(SPPS)method.Compounds 1 and 2 are new compounds whose structures have been elucidated based on NMR and HRESIMS analyses.The N-terminal cinnamoyl moiety and C-terminal methylated L-Ser moiety in 2 were incorporated under the mild SPPS conditions.Given the isolation difficulties of substrate of WS9326 A-TE from the Streptomyces producers of WS9326 A,our synthesis of 1 and 2 set the stage for the reconstitution of WS9326 A-TE’s catalytic reaction in vitro in the future.