Oxazepin-4-ones via Hypervalent Iodine Mediated Ring Expansion

Significance

Reported is the synthesis of a series of aminopeptidase inhibitor derived oxazepin-4-ones utilizing a hypervalent iodine mediated ring expansion as the key step. Beginning with hydrochloride salt of serine methyl ester, homoallylic alcohol 1 was synthesized in seven steps and 41% overall yield. Exposure of this key intermediate to Mitsunobu conditions in the presence of phenol 2 provided ether 3, which was elaborated utilizing the Mizoroki-Heck reaction to afford the pyran 4 poised for the ring expansion. Treatment of 4 with PhI(OH)OTs (Koser’s reagent) gave the oxapinone 5, which upon acidic deprotection afforded 6, isolated as hydrobromide salt. The ring expansion of the corresponding tetrahydroquinoline failed. The scope of the reaction was not extensively investigated, but tolerance of the reaction to acetamide substitution on the aromatic ring was demonstrated.