General Synthetic Entry to Dihydrooxepine-spiroisoxazoline Natural Products: Total Synthesis of Psammaplysin A

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