Total synthesis of zervamicin IIB and its deuterium-labelled analogues.
For the first time the total synthesis of the peptaibol zervamicin IIB is described. Synthesis of this peptaibol was achieved by the Fmoc/tert-butyl strategy in solution using a fragment condensation approach. Three fragments of zervamicin IIB were obtained by stepwise elongation with Fmoc amino acids using BOP as a coupling reagent. For the introduction of the highly sterically hindered alpha-aminoisobutyric acid residues BOP/DMAP activation was applied. The fmoc group was removed by reaction with 0.1 M NaOH in dioxane/methanol/water (30/9/1, v/v/v). Peptide fragments were coupled by means of a new coupling reagent, CF3-PyBOP. Using the strategy developed, zervamicin IIB and two analogues specifically deuterium-labelled at different positions of the glutamine-11 residue have been synthesized in 40% overall yield based on the isotopically labelled amino acid and with 98 +/- 2% of isotope enrichment. FAB mass spectroscopy, 600 MHz 1H-NMR spectroscopy and high-performance liquid chromatography provided convincing evidence that the synthetic products, zervamicin IIB and its deuterium-labelled analogues, fully correspond to the naturally occurring zervamicin IIB.
Ogrel
A
A
Leiden Institute of Chemistry, Leiden University, The Netherlands.
Bloemhoff
W
W
Lugtenburg
J
J
Raap
J
J
D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry; D000890:Anti-Infective Agents / Q000138:chemical synthesis*; D002851:Chromatography, High Pressure Liquid; D003903:Deuterium; D007473:Ion Channels / Q000138:chemical synthesis*; D007553:Isotope Labeling; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D054848:Peptaibols; D010446:Peptide Fragments / Q000138:chemical synthesis; D010455:Peptides; D016339:Spectrometry, Mass, Fast Atom Bombardment
D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D007473:Ion Channels; D054848:Peptaibols; D010446:Peptide Fragments; D010455:Peptides; C077077:zervamicin IIB; D003903:Deuterium