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

• Type of Material: Article
• Authors: Justin A Shapiro, Emory University; Savannah J Post, Emory University; Gavin Smith, Emory University; William M Wuest, Emory University
• Language: English
• Date: 2023-12-18
• Publisher: American Chemical Society
• Publication Version: Final Published Version
• Copyright Statement: © 2023 The Authors. Published by American Chemical Society
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://pubs.acs.org/doi/10.1021/acs.orglett.3c03993
• Title of Journal or Parent Work: Organic Letters
• Volume: 25
• Issue: 51
• Start Page: 9243
• End Page: 9248
• Grant/Funding Information: We are grateful to the NIH (GM119426 to W.M.W.; F32 GM133091 to J.A.S.), NSF (DGE1937971 to S.J.P), and ACS MEDI (Fellowship to G.A.S.) for financial support.
• Keywords: Scaffolds; Peptides and proteins; Molecular structure; Pharmaceuticals; Chemical structure
• Research Categories: Engineering, Chemical; Chemistry, Pharmaceutical

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.