De novo synthesis, structural assignment and biological evaluation of pseudopaline, a metallophore produced by Pseudomonas aeruginosa† †Electronic supplementary information (ESI) available. CCDC 1850196 and 1863986. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9sc01405e

The first total synthesis and isolation of pseudopaline was reported, which allows determination and confirmation of the absolute configuration of the natural product. Pseudopaline is an opine carboxylate metallophore produced by Pseudomonas aeruginosa for harvesting divalent metals. However, the structure of pseudopaline is not fully elucidated. Herein, we report the first de novo total synthesis and isolation of pseudopaline, which allows unambiguous determination and confirmation of both the absolute and the relative configuration of the natural product. The synthesis highlights an efficient and stereocontrolled route using the asymmetric Tsuji–Trost reaction as the key step. The preliminary structure–activity relationship study indicated that one pseudopaline derivative shows comparable activity to pseudopaline. Moreover, a pseudopaline-fluorescein conjugate was prepared and evaluated, which confirmed that pseudopaline could be transported in the bacteria. Since the metal acquisition by P. aeruginosa is crucial for its ability to cause diseases, our extensive structural and functional studies of pseudopaline may pave the way for developing new therapeutic strategies such as the “Trojan horse” antibiotic conjugate against P. aeruginosa .