Towards Precursor-Directed Biosynthesis and Synthesis of Myriaporone-Tedanolide Analogues

This thesis details the synthetic progress towards the preparation of myriaporone-tedanolide analogues through novel precursor-directed biosynthesis as well as general organic synthesis. With the recent completion of the total synthesis of the cytotoxic natural products myriaporones 1, 3 and 4 in our group, our focus has switched to prepare analogues of myriaporones, including more structurally complex myriaporone-tedanolide hybrids. By generating these analogues that are biased toward specific conformations, we hope to maximize biological activity and learn more about the relationship between the myriaporones and tedanolides. Here, we are exploring an alternative synthesis of these compounds through the use of modular polyketide synthase.An efficient synthetic sequence toward the diketide biosynthesis precursor in 7 linear steps is discussed in this thesis. The enzymes, module 2 and module 3 plus thioesterase of 6-deoxyerythronolide B synthase, are successfully expressed in Escherichia coli BAP1 and purified. Another synthetic sequence towards the preparation of the biosynthesis product was close to be finished to help identify it.