Plusbacin A3, which was isolated from Pseudomonas sp. PB-6250, has five nonproteinogenic amino acids, D-allo-threonine, two trans-3-hydroxy-L-prolines, L-threo-b-hydroxyaspartic acid, and D-threo-b-hydroxyaspartic acid. Plusbacin A3 exhibits a potent antibacterial activity against drug-resistant pathogens including Methicillin-resistant S. aureus (MRSA) and vancomycin-resistant enterococci (VRE). Since the mode of action of plusbacin A3 differs from existing antibacterial drugs, plusbacin A3 is expected to be a lead compound as a novel antibacterial drug. We planned to synthesize plusbacin A3 by a convergent synthetic route via Joullié-Ugi reaction (JU-3CR), which can be applicable to investigate its structure-activity relationship. First, we investigated that diastreoselectivity of JU-3CR was influenced by a polarity of solvents. Thus, in a non-polar solvent such as toluene, the reaction afforded a cis product. By contrast, in a polar solvent such as hexafluoroisopropanol (HFIP), the reaction afforded a trans product. Moreover, we found that the solvent effect of HFIP became stronger when using more nucleophilic isocyanides. With the diastreoselective JU-3CR in hand, we applied the reaction to the synthesis of plusbacin A3. Peptides containing hydroxyproline were synthesized from the cyclic imine via the JU-3CR. Then, transformation by several steps afforded plusbacin A3. The mode of action of plusbacin A3 is known to be the inhibition of bacterial cell-wall biosynthesis via Ca2+-dependent binding to lipid II, which is the final precursor of peptidoglycan, resulting in the cessation of polymerization. To investigate detailed mechanism of plusbacin A3, we planned to synthesize lipid II analogue, and the analogue was synthesized by solid-phase peptide synthesis.

Total synthesis of plusbacin A3

256th National Meeting (2018)

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