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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
- 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