On the Total Synthesis of Archaeal and Mycobacterial Natural Products

This thesis describes the total synthesis of archaeal and mycobacterial natural products. The synthesis of the tricyclic biphytanediol of crenarchaeol is reported, involving the stereoselective construction of the 5-6-ring motif. Detailed structural analysis of the synthetic material and comparison with analytical data of natural crenarchaeol enabled structure revision of crenarchaeol. Furthermore, this thesis shows the total synthesis of three mycobacterial diacyl trehaloses (DAT1, DAT2 and DAT3) and pentaacyl trehalose (PAT). The synthetic DATs were evaluated for their activation potential of the innate immune receptor Mincle and DAT3 was identified as potent Mincle ligand. Analysis by HPLC-MS and comparison with membrane extracts of Mtb revealed that the structure of synthetic DAT2 does not correspond to naturally occuring DAT2 and it was hypothesized that they are stereoisomers. The total synthesis of PAT included the stereoselective construction of the non-symmetrically substituted trehalose core by glycosylation. The total synthesis of PAT ultimately revealed a mismatch of synthetic and natural PAT. Consequently, research is continuing to revise the chemical structure of natural PAT.