Total Synthesis of the Reported Structure of Cahuitamycin A

Abstract

In a 2016 screen of natural product extracts a new family of natural products, the cahuitamycins, was discovered and found to inhibit the formation of biofilms in the human pathogen <i>Acinetobacter baumannii</i>. The molecules contain an unusual piperazate residue that raises structure/function and biosynthesis questions and resemble iron-trafficking virulence factors from <i>A. baumannii</i>, suggesting a connection between metal homeostasis and biofilm-mediated pathogenicity. Here we disclose the first total synthesis of the reported structure of cahuitamycin A in a twelve-step longest linear sequence and 18% overall yield. Comparison of spectral data of the authentic natural product and synthetic target compound demonstrate that the reported structure is distinct from the isolated metabolite. Herein, we propose an alternative structure to reconcile our findings with the isolation report, setting the stage for future synthetic and biochemical investigations of an important class of natural products.