Scalable multigram practical total syntheses of amatoxins: amaninamide and α-amanitin for new antibody–drug conjugates

Amatoxins, a class of highly toxic octapeptides isolated from mushroom Amanita phalloides, are potential payloads for ADCs. The total synthesis of amaninamide and α-amanitin is a formidable synthetic challenge for chemists and medical biologists. Herein, we report the first multigram scalable practical total synthesis of the amaninamide and α-amanitin via a concise approach through twelve isolated intermediates with total yields of 3.69% and 1.73%, respectively, which are the highest yields reported to date. A new synthetic strategy was developed for amatoxins. The key to this practical total synthesis was the scalable asymmetric synthesis of the unnatural chiral amino acids DHIle and 6-Htp (>500 G). An asymmetric Rh/Cu cocatalyzed allylation was developed to achieve the DHIle intermediate in 95% yield, > 99% ee and > 9:1 dr, and DHIle was synthesized through the developed method and Sharpless asymmetric dihydroxylation. This is the most efficient practical total synthesis of amaninamide and α-amanitin, solving the world's bottleneck challenges of amanitin-based ADCs-targeted anticancer drugs.