Concise total synthesis of the thiazolyl peptide antibiotic GE2270 A

Chemistry. 2008;14(8):2322-39. doi: 10.1002/chem.200701823.

Abstract

The potent antibiotic thiazolylpeptide GE2270 A was synthesized starting from N-tert-butyloxycarbonyl protected valine in a longest linear sequence of 20 steps and with an overall yield of 4.8 %. Key strategy was the assembly of the 2,3,6-trisubstituted pyridine core by consecutive cross-coupling reactions starting from 2,6-dibromo-3-iodopyridine. The complete Southern fragment was installed by Negishi cross-coupling of 3-zincated 2,6-dibromopyridine at the terminal 2-iodothiazole of a trithiazole (87 %). The substituent at C-6 representing the Northern part of the molecule was introduced in form of the truncated tert-butyl 2-bromothiazole-4-carboxylate after metalation to a zinc reagent by another Negishi cross-coupling (48 %). Decisive step of the whole sequence was the macrocyclization to a 29-membered macrolactam, which was conducted as an intramolecular Stille cross-coupling occurring at C-2 of the pyridine core and providing the desired product in 75 % yield. The required stannane was obtained by amide bond formation (87 %) between a complex dithiazole fragment representing the Eastern part of GE2270 A and a 3,6-disubstituted 2-bromopyridine. Final steps included attachment of a serine-proline amide dipeptide to the Northern part of the molecule (65 %), formation of the oxazoline ring and silyl ether deprotection (55 % overall).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides / chemistry
  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Cross-Linking Reagents / chemistry
  • Lactams / chemistry
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Structure
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Pyridines / chemistry
  • Thiazoles / chemical synthesis*
  • Thiazoles / chemistry

Substances

  • Amides
  • Anti-Bacterial Agents
  • Cross-Linking Reagents
  • Lactams
  • Peptides, Cyclic
  • Pyridines
  • Thiazoles
  • GE 2270 A