Synthesis of Mimics of Pramanicin
from Pyroglutamic
Acid and Their Antibacterial Activity
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Abstract
Epoxypyrrolidinones are available
by epoxidation of carboxamide-activated
bicyclic lactam substrates derived from pyroglutamate using aqueous
hydrogen peroxide and tertiary amine catalysis. In the case of an
activating Weinreb carboxamide, further chemoselective elaboration
leads to the efficient formation of libraries of epoxyketones. Deprotection
may be achieved under acidic conditions to give epoxypyroglutaminols,
although the ease of this process can be ameliorated by the presence
of internal hydrogen bonding. Bioassay against <i>S. aureus</i> and <i>E. coli</i> indicated that some compounds exhibit
antibacterial activity. These libraries may be considered to be structural
mimics of the natural products pramanicin and epolactaene. More generally,
this outcome suggests that interrogation of bioactive natural products
is likely to permit the identification of “privileged”
structural scaffolds, providing frameworks suitable for optimization
in a short series of chemical steps that may accelerate the discovery
of new antibiotic chemotypes. Further optimization of such systems
may permit the rapid identification of novel systems suitable for
antibacterial drug development