Total Synthesis of Farnesyl Lipid I/II Analogues and Contributions to the Total Synthesis of Neaumycin B

Abstract

The rapidly increasing resistance of bacteria against common used antibiotics presents a threat to human health. As the main building block of the cell wall of <em>Gram</em> positive bacteria, lipid II presents a readily available target on the outside of the cell. Additionally, the availability of lipid II is crucial for the cell's survival. Moreover, basically no changes of the glycosylphosphate moiety of lipid II are found, which pledges for a highly conserved motif that is less prone to mutations potentially causing antibiotic resistance. The first part of this study focussed on finishing the synthesis of farnesyl lipid II analogue found in <em>S. pneumoniae</em> and <em>E. faecalis</em>. Herein, the solid-phase peptide synthesis (SPPS) method established in the group by <em>L. Wingen</em>, introducing a side chain modification, was verified to be widely applicable. Since the chemoenzymatic conversion as the last step of the synthesis of farnesyl lipid II gave low yields and required a tedious purification process to obtain pure product, the investigation towards a fully chemical route towards farnesyl lipid II was commenced.<br /> The focus of the second part of this thesis was placed on the synthesis of the newly isolated macrolide neaumycin B, which was first isolated in 2012. Its structure and relative stereochemistry was proposed based on comprehensive mass and NMR spectroscopy interpretation. However, in 2018 a different structure of neaumycin B was published, containing a full stereochemical assignment. Moreover, "significant potency and selectivity towards U87 human glioblastoma" was found. Since neaumycin B resembled an interesting structure, combined with a high biological activity, a retrosynthetic analysis was conducted. This study focused on the synthesis of the eastern fragment, while the western fragment was part of the PhD thesis of <em>R. Wagner</em>. The synthesis was not concluded due to the publication of the total synthesis of the proposed structure of neaumycin B. Thereafter, instead of pursuing a total synthesis, the stereochemistry of neaumycin B should be revised, since the NMR data of the synthetic compound did not match the data published for the isolated natural product. In collaboration with <em>M. Adamek</em> (University of Tübingen) the stereochemistry was revised. To prove the proposed stereochemistry, two structures were synthesised.