Total Synthesis of Ripostatin B and Structure-Activity Relationship Studies on Ripostatin Analogs

J Org Chem. 2018 Jul 6;83(13):7150-7172. doi: 10.1021/acs.joc.8b00193. Epub 2018 Mar 29.

Abstract

Described is the total synthesis of the myxobacterial natural product ripostatin B and of a small number of analogs. Ripostatin B is a polyketide-derived 14-membered macrolide that acts as an inhibitor of bacterial RNA-polymerase, but is mechanistically distinct from rifamycin-derived RNA-polymerase inhibitors that are in use for tuberculosis treatment. The macrolactone ring of ripostatin B features two stereocenters and a synthetically challenging doubly skipped triene motif, with one of the double bonds being in conjugation with the ester carbonyl. Appended to the macrolactone core are an extended hydroxy-bearing phenylalkyl side chain at C13 and a carboxymethyl group at C3. The triene motif was established with high efficiency by ring-closing olefin metathesis, which proceeded in almost 80% yield. The side chain-bearing stereocenter α to the ester oxygen was formed in a Paterson aldol reaction between a methyl ketone and a β-chiral β-hydroxy aldehyde with excellent syn selectivity (dr >10:1). The total synthesis provided a blueprint for the synthesis of analogs with modifications in the C3 and C13 side chains. The C3-modified analogs showed good antibacterial activity against efflux-deficient Escherichia coli but, as ripostatin B, were inactive against Mycobacterium tuberculosis, in spite of significant in vitro inhibition of M. tuberculosis RNA-polymerase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • DNA-Directed RNA Polymerases / chemical synthesis*
  • DNA-Directed RNA Polymerases / chemistry
  • Lactones / chemical synthesis*
  • Lactones / chemistry
  • Structure-Activity Relationship

Substances

  • Anti-Bacterial Agents
  • Lactones
  • ripostatin B
  • DNA-Directed RNA Polymerases