The Total Synthesis of the Potent Anti-Bacterial Agent Platencin and Various Analogues

Abstract

For thousands of years Nature has provided humankind with the means for treating diseases. In more recent times, traditional knowledge of medicinally important natural products has gradually been linked to advances in chemistry. As a result, new methods for the isolation, chemical characterization and biological evaluation of the active principals associated with medicinal plants and other organisms have been developed. Single-compound and efficacious therapeutic agents have thus emerged for the treatment of an extraordinary range of human afflictions. In this context, the identification of new antibacterial agents showing efficacy against the rapidly growing number of drug-resistant bacteria is becoming a worldwide priority in medicine and healthcare. Platencin, a recently discovered secondary metabolite of Streptomyces platensis, exerts its anti-bacterial effects through a novel mode of action. Specifically, it is a potent and selective inhibitor of bacterial fatty acid synthases. As such this compound and certain co-metabolites have emerged as promising leads for the development of new-generation anti-bacterial therapies. There is even a suggestion that it could form the basis of anti-diabetic therapies. On this basis, and given its unusual molecular architecture, platencin has become the subject of intense scrutiny as target for chemical synthesis. The work presented in this thesis encompasses the development of a convergent and chemoenzymatic total synthesis of (−)-platencin and certain novel derivatives. The reaction sequence used involves, as starting material, the enantiomerically pure cis-1,2-dihydrocatechol derived from the whole-cell biotransformation of iodobenzene using a genetically engineered form of E.coli that over-expresses the responsible enzyme, namely toluene dioxygenase .