Synthesis of the 1,5-Diazabicyclo[6.3.0]dodecane Core Structure of Xevinapant

Abstract

Inhibitors of apoptosis proteins (IAPs) are key targets in cancer therapy due to their role in promoting cancer cell survival. The second mitochondria-derived activator of caspases (SMAC) mimetics, which antagonize IAPs, have shown therapeutic potential for cancers. 1,5-Diazabicyclo[6.3.0]dodecanone amino acid scaffold serves as an important scaffold for developing SMAC mimetics, including clinical candidates like Xevinapant and Dasminapant. Herein, we report a novel, efficient, and potentially scalable synthesis of the core structure of Xevinapant achieved in 7 steps from a pyroglutamic acid derivative, with an overall yield of 8.4%, facilitating further development of IAP inhibitors.