ABSTRACT 16β‐Hydroxylpseudobufarenogin ( 1 ), isolated from the venom of Bufo bufo gargarizans , has potent anticancer activity. The U‐shaped steroidal structure of 1 possesses a cis ‐fused AB‐ring system, a densely oxidized cis ‐fused CD‐ring system, and a β‐oriented 2‐pyrone at C17. Herein, we present a new convergent strategy for assembling this complex steroidal architecture, culminating in the first total synthesis of 1 in 28 steps from (+)‐Wieland–Miescher ketone. The AB‐ and D‐ring fragments were coupled by Pd/Ag‐promoted Suzuki–Miyaura coupling. Following the Co‐catalyzed hydration of the D‐ring, the C‐ring was stereoselectively constructed by Ir‐catalyzed radical‐relay cyclization. Subsequent C‐ring hydroxylation and installation of the β‐oriented 2‐pyrone through Pd/Cu‐promoted Stille coupling and stereospecific epoxide rearrangement delivered 1 . Because of its high chemo‐ and stereoselectivity, the present methodology would be applicable to the total synthesis of diverse oxygenated bufadienolides by simply altering the fragment structures.
Shigematsu et al. (Mon,) studied this question.