An improved scalable synthesis of orthogonally functionalized methoxyaspartate, the chiral hinge region element in cystobactamids, is reported. This improvement sets the stage for the total synthesis of four new cystobactamids along with cystobactamid 861-2, whose antibacterial properties are determined and compared. The cyano derivative of cystobactamide 861-2 shows superior antibacterial activity against Gram-negative bacteria to any natural cystobactamide tested so far.T he group of cystobactamids was reported by Muller et al. in 2014 as part of a search for new secondary metabolites in Cystobacter sp. Cbv34. The extracts inhibited the growth of several Gram-negative and Gram-positive bacteria, and HPLCassisted bioactivity-guided screenings provided cystobactamids 919-1 (1) and 919-2 (2) as active compounds (Figure 1). 1 These oligoamides contain p-aminobenzoic acid building blocks and either an iso-β-methoxyasparagine or a β-methoxyasparagine unit. Later additional derivatives such as the cystobactamids 920-1 (3), 920-2 (4), and 862-1 (5) were reported that structurally differ in the D-and E-rings and the hinge region. 2 To date cystobactamid 862-1 is the most active natural member inhibiting several clinically relevant Gram-positive and Gramnegative strains (Acinetobacter baumannii: MIC = 0.5 μg/mL, Citrobacter f reundii: MIC = 0.06 μg/mL, carbapenem-resistant E. coli WT-III marRΔ74bp: MIC = 0.5 μg/mL, carbapenemresistant P. aeruginosa CRE: MIC = 1.0 μg/mL and Proteus vulgaris: MIC = 0.25 μg/mL) 2 by inhibiting bacterial type IIa topoisomerases. To date, three total syntheses of cystobactamids 861-2, 919-2, and 920-1 have been published by the Trauner group and by us. 2,3 These endeavors were essential to revise and
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