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
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 and Jinhua J. Song*,
{"title":"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":"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 and Jinhua J. Song*, ","doi":"10.1021/acs.oprd.3c00363","DOIUrl":null,"url":null,"abstract":"<p >The development of a scalable asymmetric synthesis of KRAS G12C inhibitor building block <b>1</b> is described. The all-carbon quaternary stereocenter was installed enantioselectively via Shi epoxidation, followed by a newly discovered regioselective LaCl<sub>3</sub>·2LiCl-catalyzed epoxide opening. Subsequent organocatalyzed oxidation provided the requisite ketone, which underwent the final assembly of the heterocyclic core, delivering <b>1</b> with high chemical and enantiomeric purities in 40% overall yield in only five steps, enabling robust and rapid manufacturing of over 300 kg of <b>1</b>.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 1","pages":"78–91"},"PeriodicalIF":3.1000,"publicationDate":"2024-01-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.oprd.3c00363","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
引用次数: 0
Abstract
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 LaCl3·2LiCl-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.
期刊介绍：
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.
京公网安备 11010802042870号
京ICP备2023020795号-1
分享
求助内容：
应助结果提醒方式：
扫码关注我们
