Date of Award

Spring 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Chemistry

First Advisor

Herzon, Seth

Abstract

In the first chapter of this thesis, I describe the development of two convergent, fragment-based strategies to prepare the oxidized carbon scaffold of diaporthein B (1). Diaporthein B (1), initially isolated from the fungal genus Diaporthe, is an antimycobacterial pimarane diterpene that exhibited a minimum inhibitory concentration (MIC) of 3.1 µg⋅mL–1 against M. tuberculosis, as well as half-maximal inhibitory concentrations of 1.5–3 µM against HCT and LoVo colon cancer cell lines. The first synthetic approach towards diaporthein B (1) furnished the tricyclic carbon skeleton 154 in 9 steps from (R)-carvone through a diastereoselective 1,2-addition between two elaborated cycloalkenones, a novel carbonylative Stille cross-coupling, and a silyl migration-mediated aldol cyclization–deprotection cascade. The second route accessed the oxidized scaffold 175 in 10 steps from 3-methylanisole through a diastereoselective Mukaiyama–Michael addition of a bicyclic silyloxyfuran to a γ-hydroxy enone followed by an epoxidation–ring opening sequence.In the second chapter of this thesis, I describe the development of a modular, stereospecific approach to the C31 Trp3–Lys5 crosslink in the antibiotic darobactin A (181). Darobactin A (181) is a ribosomally synthesized and post-translationally modified peptide isolated from the nematode-symbiotic genus Photorhabdus. Modifications to the heptapeptide include an unusual C–C crosslink from the C6 indole of Trp3 to the β-carbon of Lys5 at C31, and an unprecedented aromatic–aliphatic ether crosslink from the C7 indole of Trp1 to the β-carbon of Trp3 at C17. Darobactin A (181) exhibits promising antibacterial activity, with MICs in the single-digit µg⋅mL–1 range against multidrug-resistant, Gramnegative pathogens A. baumannii, P. aeruginosa, and members of Enterobacteriaceae. I developed an 8-aminoquinoline (AQ) directed, C–H activation sequence to stereospecifically synthesize the C31 Trp3–Lys5 crosslink en route to the tripeptide 267. Finally, I describe our efforts to complete the Trp3–Ser4–Lys5 macrocycle via traditional head-to-tail amide condensations and via C–H activation.

Download

Share

COinS