The biosynthesis of sulphur-containing dioxopiperazines
This thesis records an investigation into the biosynthesis of the
aranotins, a group of sulphur-containing dioxopiperazine metabolites
produced by the fungi Aspergillus terreus and Amauroascus aureus.
A series of analogues of the known aranotin precursor, cyclo(
L-phenylalanyl-L-phenylalanyl), fluorinated on one or both aromatic
rings, was prepared, both unlabelled and labelled with 14C• These
compounds were fed to Aspergillus terreus, as were £-, ~-, and ~-fluorophenylalanines,
and their metabolism was followed by 19F n.m.r.
spectroscopy of the extracts. A fluorinated bisdethiodi(methylthio)-
acetylapoaranotin was isolated from cultures which had been fed
DL-~-fluorophenylalanine or cyclo-(L-phenylalanyl-L-~-fluorophenylalanyl)
A new natural metabolite of A. terreus, cis-~,~'-di(methylthio)cyclo-(
phenylalanyl-phenylalanyl), of unknown absolute configuration,
was isolated and characterised. Several fluorinated analogues of this
compound were detected spectroscopically in extracts which had been
fed fluorinated precursors.
monodeuteriated at the methylene group of the E-fluorophenylalanyl
residue, was fed to A. terreus, and it was shown that neither the 3Rnor
the 3S-deuterium was lost obligatorily during the conversion of
this compound into cis-~,~'-di(methylthio)-cyclo-(phenylalanyl-E-fluorophenylalanyl),
although there was a partial loss from each position.
The natural product, cis-cA,c(' -di (methylthio) -cyclo-(phenylalanylphenylalanyl),
was synthesised as a racemate. The compound, labelled
with 35S , was fed to A. terreus, and was not significantly incorporated
into bisdethiodi(methylthio)acetylaranotin. The racemic epidisulphide,
~,~'-epidithio-cyclo-(phenylalanyl-phenylalanyl), was synthesised.
This compound, doubly labelled with 3H and 35S , was fed to A. terreus,
and was incorporated into acetylaranotin and bisdethiodi(methylthio)acetylaranotin,
with some changes in the isotopic ratios. An "intermediate
trapping" experiment confirmed the ability of the fungus to
biosynthesise ~,~'-epidithio-cyclo-(phenylalanyl-phenylalanyl), of
unknown absolute configuration, from L-phenylalanine.