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

共 2 条

[1] Development of a Scalable Synthesis toward a KRAS G12C Inhibitor Building Block Bearing an All-Carbon Quaternary Stereocenter, Part 1: From Discovery Route to Kilogram-Scale Production
Leung, Joyce C.
Xu, Yibo
Radomkit, Suttipol
Lee, Jaehee
Kim, Wan Shin
Reeves, Jonathan T.
Dong, Weitong
Jang, Hwanjong
Hou, Xiaowen
Lorenz, Jon C.
Shao, Xiaole
Byrne, Denis
Johnson, Joe
Brundage, Anthony
Valentin, Clement
Beyer, Phouvieng
Dimeo, Susan V.
Qu, Bo
Li, Ruoshi
Sarvestani, Max
Song, Jinhua J.
ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2024, 28 (01) : 67 - 77
[2] Synthesis of Chiral Bis(3-indolyl)methanes Bearing a Trifluoromethylated All-Carbon Quaternary Stereocenter via Nickel-Catalyzed Asymmetric Friedel-Crafts Alkylation Reaction
Zhu, Wen-Jing
Gong, Jun-Fang
Song, Mao-Ping
JOURNAL OF ORGANIC CHEMISTRY, 2020, 85 (15): : 9525 - 9537

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