Total syntheses of chaetocin and ent-chaetocin

The first total synthesis of chaetocin (1), a potent histone methyltransferase inhibitor, is described in detail. Key reactions were radical bromination for α-oxidation of the diketopiperazine ring, and reductive radical coupling for construction of the dimeric core structure. Stereoselective construction of the disulfide bridges was achieved via substitution reaction with H2S. The total synthesis of 1 was accomplished in nine steps starting from known d-amino acid derivatives. Total synthesis of non-natural ent-chaetocin (ent-1) was also achieved via the established synthetic route, starting from l-amino acid derivatives.