Scalable Protecting-Group-Free Total Synthesis of Resibufogenin and Bufalin

A chemoenzymatic synthesis access to resibufogenin and bufalin was developed in seven steps without protecting groups. Starting with androstenedione (AD), an α-OH was introduced directly at C14 by hydroxylase P-450lun, which was further used as the directing group for hydrogenation to fully control the C17 configuration in the β-orientation after Suzuki cross-coupling. Dehydration of 14α-OH followed by an epoxidation delivered resibufogenin. Simultaneously, bufalin was also obtained via a challenging anaerobic Mukaiyama hydration.