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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

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

Authors :
Tan, Zhulin
Ju, Xuan
Wu, Hao
Dong, Weitong
Leung, Joyce C.
Hou, Xiaowen
Lee, Heewon
Granger, Alice
Paolillo, Joshua M.
DiMeo, Susan V.
Chen, Chengsheng
Wu, Linglin
Lorenz, Jon C.
Sarvestani, Max
Buono, Frederic
Frutos, Rogelio
Tampone, Thomas G.
Huang, Xiaojun
Zhang, Gulin
Wang, Yuwen
Spinelli, Earl
Lei, Zhen
Song, Jinhua J.
Source :
Organic Process Research & Development; January 2024, Vol. 28 Issue: 1 p78-91, 14p
Publication Year :
2024

Abstract

The development of a scalable asymmetric synthesis of KRAS G12C inhibitor building block 1is 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 1with high chemical and enantiomeric purities in 40% overall yield in only five steps, enabling robust and rapid manufacturing of over 300 kg of 1.

Details

Language :
English
ISSN :
10836160 and 1520586X
Volume :
28
Issue :
1
Database :
Supplemental Index
Journal :
Organic Process Research & Development
Publication Type :
Periodical
Accession number :
ejs65107909
Full Text :
https://doi.org/10.1021/acs.oprd.3c00363