Gamma-butyrolactones (GBLs) are signaling molecules produced by Streptomyces that
play a key role in secondary metabolite production. Secondary metabolites, also known as natural
products, have been used extensively in medicine and agriculture due to their bioactive properties.
Genomic sequencing of the biosynthetic gene clusters (BGCs) from Streptomyces shows that only
a small fraction of their secondary metabolites has been discovered. Activation of these silent
BGCs has reinvigorated natural products chemistry as researchers become aware of the potential
reservoir of novel lead compounds that remain unmined. One such GBL produced by Streptomyces
is avenolide, responsible for activating production of avermectin, an anti-parasitic drug with over
$850 million annual sales. In the work presented here, progress was made towards accessing the
molecule avenolide in a synthesis commendable to derivatization with the aim of creating a library
of avenolide-like molecules that could potentially “unlock” cryptic biosynthetic gene clusters and
lead to the discovery of new bioactive secondary metabolites.