Total Synthesis of (+)-Chaetocin and its Analogues: Their Histone Methyltransferase G9a Inhibitory Activity

(+)-Chaetocin (1) is a complex epidithiodiketopiperazine (ETP) alkaloid produced by Chaetronium minutum, which was isolated in 1970.1 In addition to its antibacterial and cytostatic activity,1,2 1 is known to be a potent inhibitor of lysine-specific histone methyltransferases (HMTs).3 Because methylation of histone proteins plays important roles in controlling gene expression patterns,4 synthetic study of 1 and its analogues would be helpful in developing biological tools for epigenetic research. However, total synthesis of 1 has not been reported to date. We herein describe the first total synthesis of (+)-1, as well as its antipode and sulfur-deficient analogues. We also examined the biological activity of these compounds toward H3K9 HMT G9a, which is a potential therapeutic target in human cancer.5 Following the early report by Nakagawa and Hino,6a elegant methodologies were developed to synthesize the dimeric octacycli