Solid-phase synthesis of coralmycin A/epi-coralmycin A and desmethoxycoralmycin A

Abstract

The total synthesis of the natural product coralmycin A/epi-coralmycin A, as well as a desmethoxy analogue is described. Synthesis was achieved via a divergent, bidirectional solid-phase strategy, including a key on-resin O-acylation, O to N acyl shift, and O-alkylation protocol to incorporate the unusual 4-amino-2-hydroxy-3-isopropoxybenzoic acid motifs. The synthetic natural product was generated as a 1 : 1 mixture of epimers at the central β-methoxyasparagine residue and exhibited potent antibacterial activity against a panel of ten Gram-negative and seven Gram-positive organisms. The desmethoxy analogue possessed significantly more potent antimicrobial activity against this panel with minimal inhibitory concentrations (MICs) as low as 50 nM.