Building Chemical Probes Based on the Natural Products YM-254890 and FR900359: Advances toward Scalability

Abstract

The biological activity of natural products YM-254890 (YM) and FR900359 (FR) has led to significant interest in both their synthesis and the construction more simplified analogs. While the simplified analogs lose much of the potency of the natural products, they are of interest on their own right, and their synthesis has elucidated synthetic barriers to the family of molecules that need to be addressed if a scalable synthesis of YM and FR analogs are to be constructed. In the work described here, the synthetic route to simplified analogs of YM is examined and strategies for circumventing some of the challenges inherent to constructing the molecules forwarded.

A Building Block Approach for the Total Synthesis of YM‐385781

“…This was done to avoid a β-elimination reaction that cleaved the sidechain from the molecule, an elimination reaction that readily occurred in all synthetic intermediates prior to formation of the macrocycle. [23] While this strategy worked for a simplified molecule with no functionality in the bottom bridge, it was less attractive for the synthesis of more complex analogs. The bottom bridge of the molecule as shown in Scheme 1 can undergo the same elimination reaction (highlighted in red).…”

“…First, the synthesis of simple analogs that only contained the functionality on the left and right hand side of the molecule as shown in Scheme 1 was facilitated by adding the left‐hand sidechain last. This was done to avoid a β‐elimination reaction that cleaved the sidechain from the molecule, an elimination reaction that readily occurred in all synthetic intermediates prior to formation of the macrocycle [23] …”