op3c00363_si_001.pdf (1.31 MB)
Development of a Scalable Synthesis toward a KRAS G12C Inhibitor Building Block Bearing an All-Carbon Quaternary Stereocenter, Part 2: Asymmetric Synthesis via Shi Epoxidation
journal contribution
posted on 2024-01-05, 06:04 authored by Zhulin Tan, Xuan Ju, Hao Wu, Weitong Dong, Joyce C. Leung, Xiaowen Hou, Heewon Lee, Alice Granger, Joshua M. Paolillo, Susan V. DiMeo, Chengsheng Chen, Linglin Wu, Jon C. Lorenz, Max Sarvestani, Frederic Buono, Rogelio Frutos, Thomas G. Tampone, Xiaojun Huang, Gulin Zhang, Yuwen Wang, Earl Spinelli, Zhen Lei, Jinhua J. SongThe development of a scalable asymmetric synthesis of
KRAS G12C
inhibitor building block 1 is described. The all-carbon
quaternary stereocenter was installed enantioselectively via Shi epoxidation,
followed by a newly discovered regioselective LaCl3·2LiCl-catalyzed
epoxide opening. Subsequent organocatalyzed oxidation provided the
requisite ketone, which underwent the final assembly of the heterocyclic
core, delivering 1 with high chemical and enantiomeric
purities in 40% overall yield in only five steps, enabling robust
and rapid manufacturing of over 300 kg of 1.
