Synthesis and Antimicrobial Testing of Nepetoidins and Vinyl Isocyanides

Abstract

This thesis focuses on the synthesis and antimicrobial studies of a range of natural product compounds that were considered as potential new antibiotics.

The introduction outlines the historical milestones of natural products in antibiotic discovery and discusses the mode of action of common antibiotics, including inhibition of cell wall or protein synthesis, interference with DNA and RNA synthesis, disruption of cell membranes, and inhibition of key metabolic pathways. Despite these advances, the rapid spread of antibiotic resistance highlights the need for new antibiotics with novel mechanisms of action.

Chapter 2 details efforts to synthesise and minimum inhibitory concentration (MIC) test the natural product nepetoidin B, nepetoidin B analogues, and their hydrolysis products. Nepetoidin B was successfully obtained through a three-step synthetic route involving Claisen–Schmidt condensation, Oxone®-mediated Baeyer–Villiger oxidation, and TMSI-mediated deprotection. Several nepetoidin analogues and hydrolysis products of nepetoidins were also prepared. MIC testing against E. coli showed that all compounds displayed moderate antibacterial activity.

Chapter 3 presents the improved synthesis of antibacterial (E)-vinyl isocyanides. A new route using Suzuki–Miyaura coupling, acetylation and reduction, and a key Horner–Wadsworth–Emmons (HWE) reaction to install the vinyl isocyanide was used. Three vinyl isocyanides were prepared using this route and showed strong activity against methicillin-resistant and methicillin-sensitive Staphylococcus aureus strains, which demonstrate their potential as new antimicrobial leads.

Chapter 4 focuses on developing a new method for accessing (Z)-vinyl isocyanides. A modified HWE reaction was optimised to give vinyl isocyanides with (Z)-selectivity using Et-PhosMIC and potassium tert-pentoxide with 18-crown-6 (27%-75% yield, 8 examples). An alternative method to access (E)-selective vinyl isocyanides used sodium tert-butoxide and iPr-PhosMIC (33%-72% yield, 8 examples) was also developed based on the screening condition results. These methods provide a convenient synthetic route that allows the selective preparation of either (E)- or (Z)-vinyl isocyanides, offering an efficient approach for further investigations into the biological activity of vinyl isocyanides.

Chapter 5 describes an attempted synthesis of the vinyl isocyanide natural product Rhabduscin. The route started from D-glucose and produced several key intermediates. However, difficulties at the primary amine synthesis stage prevented the completion.

Date of Award	20 May 2026
Original language	English
Awarding Institution	University of Bath
Supervisor	Steven Bull (Supervisor), James Taylor (Supervisor) & Maisem Laabei (Supervisor)