UCSF

Macrolide antibiotics are a structurally diverse class of polyketide natural products, produced by bacteria, that exhibit antimicrobial activity through inhibition of bacterial protein synthesis. Macrolides and their semisynthetic derivatives are critical for the treatment of infectious disease, many of which are first-line therapeutics. Ketolides are a subclass of the macrolides which bear a ketone at the C3 position of the macrocycle. While predominantly semisynthetic, there are some ketolide natural products, like narbomycin, that have marked structural simplicity compared to other macrolides yet maintain good antibiotic activity. Here we report a modular, convergent synthesis of narbomycin, which we propose to be a minimal pharmacophore for macrolide antibiotics. This platform enables the facile incorporation of desired structural modifications to this minimal pharmacophore to generate novel unnatural products that can increase potency and overcome clinically relevant resistance mechanisms. In chapter 1, I describe our first attempts to synthesize narbomycin through a critical macrocyclization step using the thermolytic properties of a dioxinone moiety. A vinylogous Mukaiyama aldol was used to incorporate this dioxinone and set the C4/C5 stereochemical configuration. Despite screening for reaction conditions, the desired syn aldol products were unable to be obtained, but a method for anti vinylogous Mukaiyama dioxinone aldol products was successfully developed. Some mechanistic rationale for our findings is discussed. In chapter 2, I describe the successful total synthesis of narbomycin. This route uses a robust Liebeskind-Srogl coupling to join the two halves of the molecule together and employs an unprecedented macrocyclization strategy via direct intramolecular displacement of an oxazolidinone chiral auxiliary. Some of the challenges faced in the final steps of the synthesis involving a difficult reduction of an exocyclic alkene to a methyl group are also outlined.