Divergent Total Synthesis of Isoflavone Natural Products and Their Potential as Therapeutic Agents for TTR Amyloidosis

We have achieved the divergent total synthesis of nine isoflavone natural products <b>1</b>-<b>9</b> starting from commercially available 2,4,6-trihydroxyacetophenone as a starting material. The isoflavone skeleton of <b>1</b>-<b>9</b> was constructed by the Suzuki-Miyaura coupling reaction as the key reaction. Investigation of the potential of <b>1</b>-<b>9</b> as therapeutic agents for transthyretin (TTR) amyloidosis revealed that millexatin F (<b>3</b>) showed the best efficacy in <i>ex vivo</i> competitive binding experiments and thioflavin-T fluorescence studies. Therefore, millexatin F (<b>3</b>) is promising as a seed compound for a novel TTR amyloidosis therapeutic agent.