Solid-Phase Synthesis of Five-Membered Heterocycle-Fused Tryptanthrin via a Two-Site Oxidation Reaction.

Tryptanthrin (tryp) is being studied as a lead compound with pharmacological activity that is found in nature. To date, synthetic and pharmacological studies on trypanthrin have focused on substitution patterns on the A and D rings, while structural modifications of the A ring system have yet to be explored synthetically. In this study, we synthesized a tryp derivative containing a five-membered heterocyclic ring (thiazole and thiophene) on ring A using solid-phase synthesis. In the synthesis, two-site oxidation of sulfide and benzylic positions using an oxidant was successfully performed. A total of 53 derivatives were synthesized, and the yield per step in six steps was 46-96%. In addition, it was observed that oxidizing agents such as FeCl3 and H5IO6 caused oxidation of the Merrifield resin, leading to damage of the resin. This study demonstrates the feasibility of introducing diverse five-membered heterocycles into natural product frameworks.