Total Synthesis of Enlicitide Decanoate
Hongming Li, David A. Thaisrivongs, Gao Shang, Yonggang Chen, Qinghao Chen, Lushi Tan, Kai‐Jiong Xiao, Reed T. Larson, Jeffrey T. Kuethe, Joshua E.-Y. Lee, Nicholas R. Deprez, Andrew Nolting, Marc Poirier, Paul G. Bulger, Erik L. Regalado, Mirlinda Biba, Fuh-Rong Tsay, Jimmy DaSilva, Chris K. Prier, Christopher A. Strulson, Kerstin Zawatzky, Zhu Liu, Justin A. Newman, Kathleen P. Sokolowsky, Weijuan Tang, Kari Hullen, Nimisha Thakur, Cody Welch, Smit Patel, Yu He, Jing Xu, Narayan Variankaval, Artis Klapars, Jongrock Kong, Richard Desmond, Richard J. Varsolona, Peter E. Maligres, Carlos A. Pons Siepermann, Lee Robison, Tiffany Piou, Clara Hartmanshenn, Anagha Chandra, Anisha Patel, M. Becker, Guiquan Liu, Jianjun Duan, Baoqiang Wan, Chengqian Xiao, Yongpeng Yuan, Xiaohui Cao, Chen Lü, Ruxia Yi, Zhenhua Wu, Minyi Feng, Donghong Li, Zhiyan Song, Yawei Dong, Julin Sun, Biao Li, Guangxin Shao, Louis‐Charles Campeau, Jingjun Yin
Abstract
We report the total synthesis of enlicitide decanoate, an orally bioavailable inhibitor of proprotein convertase subtilisin/kexin type 9 that is being developed for the treatment of atherosclerotic cardiovascular disease. It is a highly complex macrocyclic peptide with a significant number of nonpeptide structural elements that presents a daunting synthetic chemistry challenge. We describe the development of a convergent, efficient, and robust manufacturing process that enables the large-scale production of enlicitide.