BIOACTIVITY-GUIDED RETROSYNTHESIS: “UPPING THE ANTE” FOR NATURAL PRODUCT TOTAL SYNTHESIS

In recent years, great efforts have been made to improve the efficiency of the total synthesis of complex bioactive natural products through atom and step economy, avoidance of protecting groups, development of complexity-generating cascade processes minimizing step count and purifications. Our continued interest in understanding the mechanism of action of bioactive natural products, including identification of their cellular receptors, has led us to consider adding another requirement to our retrosynthetic strategies. Namely, we have sought to introduce a hypothesized pharmacophore early in the synthetic sequence to enable biological studies to be initiated at an early stage of a total synthesis effort. This approach is most readily applicable to natural products that likely covalently modify their putative cellular receptors, however application to non-covalent protein interactors is also beginning to show promise. Several cases studies implementing this strategy will be presented along with biological studies.