Total Synthesis of the Reported Structure of Cahuitamycin A: Insights into an Elusive Natural Product Scaffold

• Authors: Justin A Shapiro, Emory University; Savannah J Post, Emory University; Gavin Smith, Emory University; William M Wuest, Emory University
• Journal Title: Organic Letters
• Volume: Volume 25, Number 51
• Publisher: American Chemical Society | 2023-12-18, Pages 9243-9248
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1021/acs.orglett.3c03993
• Subjects: Engineering, Chemical; Chemistry, Pharmaceutical
• Keywords: Chemical structure; Molecular structure; Peptides and proteins; Pharmaceuticals; Scaffolds

Abstract

In a 2016 screen of natural product extracts, a new family of natural products, the cahuitamycins, was discovered and found to inhibit biofilm formation in the human pathogen Acinetobacter baumannii. The proposed molecular structures contained an unusual piperazic acid residue, which piqued interest related to their structure/function and biosynthesis. Herein we disclose the first total synthesis of the proposed structure of cahuitamycin A in a 12-step longest linear sequence and 18% overall yield. Comparison of spectral and biological data of the authentic natural product and synthetic compound revealed inconsistentancies with the isolated metabolite. We therefore executed the diverted total synthesis of three isomeric compounds, which were also found to be disparate from the isolated natural product. This work sets the stage for future synthetic and biochemical investigations of an important class of natural products.