Asymmetric total synthesis of inthomycin c and studies towards the total synthesis of oxazolomycin b

Thesis

This thesis describes research towards the total syntheses of two bacterial polyene natural products, inthomycin C and oxazolomycin B, as well as preliminary studies on the biological activity of inthomycin C and structural analogues against human cancer cell lines. A novel total synthesis of inthomycin C has been accomplished in 11.4% yield and 89% ee over ten linear steps from oxazole. This synthesis is the shortest and highest yielding asymmetric total synthesis of inthomycin C to date and, unlike all previous syntheses, it avoids the use of toxic organotin reagents. Main features of this synthesis include cross-metathesis as key C–C bond-forming step, methoxy group elimination to construct the triene moiety and asymmetric Mukaiyama–Kiyooka aldol addition to install the (3R) alcohol stereocenter on inthomycin C. Both NMR data and optical rotation data for the sample of inthomycin C synthesised in this work are in agreement with those previously reported. Viability and cytotoxicity assays of inthomycin C and analogues against various human cancer cell lines have been carried out for the first time. Despite all compounds tested having proved inactive against all cancer cell lines, an ester derivative of inthomycin C has been found to exhibit weak reversible proteasome inhibition activity against two cancer cell lines. On the other hand, and building on previous work in the Donohoe group, the synthesis of an advanced amide intermediate in the route towards oxazolomycin B has been achieved, which contains the complete carbon backbone of oxazolomycin B. Key features of this synthesis include a highly diastereoselective organocerium nucleophilic addition to an aldehyde precursor, a Nozaki–Hiyama–Kishi reaction and an amide coupling to access the final amide fragment.

Authors: Garcia, S

• DOI: 10.5287/ora-pvgn6pnwq
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: inthomycin; oxazolomycin; total synthesis
• Subjects: Chemistry, Organic