Total Synthesis and Biological Evaluation of the Glycosylated Macrocyclic Antibiotic Mangrolide A

Abstract

The macrocyclic antibiotic mangrolide Ah as been described to exhibit potent activity against an umber of clinically important Gram-negative pathogens.R eported is the first enantioselective total synthesis of mangrolide Aa nd derivatives.S alient features of this synthesis include ah ighly convergent macrocycle preparation, stereoselective synthesis of the disaccharide moiety,a nd two b-selective glycosylations. The synthesis of mangrolide Aa nd its analogues enabled the re-examination of its activity against bacterial pathogens,a nd only minimal activity was observed.

Isolation, Structure, and Total Synthesis of the Marine Macrolide Mangrolide D

“…Gademann and coworkers, based on their very elegant synthesis of the structurally related macrolide fidaxomicin (3), 2 recently reported the total synthesis of mangrolide A (2). 3 While this study fully corroborated the structure disclosed for the isolated natural product sample, 1 synthetic mangrolide A was found to be devoid of any antibacterial activity. 3 Through our own synthetic work, we had come to the same disconcerting conclusion that our synthetic mangrolide A (2), 4,5 as well as ultra-purified re-isolated natural material, failed to register the Gram-negative activity reported for the original batch of fermented mangrolide A.…”

“…3 While this study fully corroborated the structure disclosed for the isolated natural product sample, 1 synthetic mangrolide A was found to be devoid of any antibacterial activity. 3 Through our own synthetic work, we had come to the same disconcerting conclusion that our synthetic mangrolide A (2), 4,5 as well as ultra-purified re-isolated natural material, failed to register the Gram-negative activity reported for the original batch of fermented mangrolide A. Therefore, we postulated that the Gram-negative activity of the original sample could be derived from a minor contaminating or interfering metabolite, a phenomenon not uncommon in the field of natural product isolation and bioactivity.…”

Total Synthesis of Tiacumicin B: Implementing Hydrogen Bond Directed Acceptor Delivery for Highly Selective β‐Glycosylations

“…b) The rhamnosylation was carried out on the macrolide, using an imidate donor ( α / β : 1/4, β : 62 %). Following similar strategies, Gademann also synthesized three congeners of Tcn‐B: tiacumicin A and mangrolides A and D . In 2019, de Brabander also reported a total synthesis of mangrolide D .…”

Chemistry and Biology of the Clinically Used Macrolactone Antibiotic Fidaxomicin

“…In the following section, the different approaches will be presented and compared. Apart from these syntheses, also total syntheses of natural products containing a similar macrocyclic scaffold, mangrolides A and D, have been recently synthetically prepared …”