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

被引：4

作者：

Tan, Zhulin ^{[1
]}

Ju, Xuan ^{[1
]}

Wu, Hao ^{[1
]}

Dong, Weitong ^{[1
]}

Leung, Joyce C. ^{[1
]}

Hou, Xiaowen ^{[1
]}

Lee, Heewon ^{[1
]}

Granger, Alice ^{[2
]}

Paolillo, Joshua M. ^{[1
]}

Dimeo, Susan V. ^{[1
]}

Chen, Chengsheng ^{[1
]}

Wu, Linglin ^{[1
]}

Lorenz, Jon C. ^{[1
]}

Sarvestani, Max ^{[1
]}

Buono, Frederic ^{[1
]}

Frutos, Rogelio ^{[1
]}

Tampone, Thomas G. ^{[1
]}

Huang, Xiaojun ^{[3
]}

Zhang, Gulin ^{[3
]}

Wang, Yuwen ^{[1
]}

Spinelli, Earl ^{[1
]}

Lei, Zhen ^{[1
]}

Song, Jinhua J. ^{[1
]}

机构：

[1] Boehringer Ingelheim Pharmaceut Inc, Dept Chem Dev, Ridgefield, CT 06877 USA

[2] Boehringer Ingelheim Pharmaceut Inc, Dept Mat & Analyt Sci, Ridgefield, CT 06877 USA

[3] Porton Pharma Solut Ltd, Shanghai Res & Dev Ctr, Shanghai 201100, Peoples R China

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2024年 / 28卷 / 01期

关键词：

enyne; Shi epoxidation; LaCl3 center dot 2LiCl; epoxide opening; pre-IBS; organocatalyst; HYDROGEN-PEROXIDE; MESO-EPOXIDES; OXIDATION; CATALYSTS; ALCOHOLS; ALKYNES;

D O I：

10.1021/acs.oprd.3c00363

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

The 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 center dot 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.

引用

页码：78 / 91

页数：14