SYNTHESIS OF AVENOLIDE AND OTHER GAMMA-BUTYROLACTONE DERIVATIVES TO ACCESS CRYPTIC BIOSYNTHETIC GENE CLUSTERS

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.