Plusbacin A
3 (1), which was isolated from
Pseudomonas sp. PB-6250, has five
nonproteinogenic amino acids, D-
allo-threonine, two
trans-3-hydroxy-L-prolines,
L-
threo-β-hydroxyaspartic acid, and D-
threo-β-hydroxyaspartic acid (Figure 1). Plusbacin A
3 exhibits a potent antibacterial activity against drug-resistant pathogens including Methicillin-resistant
S. aureus (MRSA) and vancomycin-resistant enterococci (VRE)
[1]. Since the mode of action of plusbacin A
3 differs from existing antibacterial drugs, plusbacin A
3 is expected to be a lead compound as a novel antibacterial drug. We planned to synthesize plusbacin A
3 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 (Scheme 1). Moreover, we found that the solvent effect of HFIP
became stronger when using more nucleophilic isocyanides (Table 1).
With the diastreoselective JU-3CR in hand, we applied the reaction to the synthesis
of plusbacin A
3. Peptides containing hydroxyproline 4 and 6 were synthesized from the cyclic imine 2 via the JU-3CR (Scheme 3). Then, transformation by several steps afforded
plusbacin A
3 (1) (Scheme 4). Furthermore, it was revealed that plusbacin A
3 induces only low-level resistance (Figure 3a).
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