Total Synthesis of the Dihydrooxepine-Spiroisoxazoline Natural Product Psammaplysin A

We report a general synthetic entry to dihydrooxepine-spiroisoxazoline (DOSI) natural products that culminated in the first racemic total synthesis of psammaplysin A. For the synthesis of the unique spirocyclic fragment we employed a strategy that features two key transformations: (1) a diastereoselective Henry reaction/cyclization sequence to access the C7 hydroxylated isoxazoline scaffold in one step and (2) a regioselective Baeyer-Villiger ring expansion to install the fully substituted dihydrooxepine and avoid the risk of a previously observed oxepine-arene oxide rearrangement. The overall synthesis proceeds in 13 steps from an inexpensive starting material.

Automated summary

A general synthetic approach to dihydrooxepine-spiroisoxazoline (DOSI) natural products was reported, leading to the first racemic total synthesis of psammaplysin A. The synthesis strategy involved two key transformations: a diastereoselective Henry reaction/cyclization sequence for the hydroxylated isoxazoline scaffold and a regioselective Baeyer-Villiger ring expansion for the dihydrooxepine fragment. The overall synthesis required 13 steps and utilized inexpensive starting materials.