Asymmetric Synthesis of KRAS G12C Inhibitor MK-1084 via a Crystallization-Induced Diastereomer Transformation (CIDT)
MK-1084 is a potent KRAS G12 inhibitor characterized by a complex macrocyclic ring system incorporating two atropisomeric axes from a restricted rotation around both <i>C-C</i> and <i>N-C</i> bonds. Herein, we report an efficient synthetic approach to manufacture MK-1084 to enable clinical trials. By leveraging the in-depth understanding of the inherent properties of axial chirality, we discovered and developed a one-pot crystallization-induced diastereomer transformation (CIDT)/carbonylation process to establish the unique and challenging macrocyclic core with double axial chiral centers from a racemic advanced precursor and readily available raw materials.
Authors
- Kevin M. Belyk (ORCID: https://orcid.org/0000-0003-1585-0430)
- Christopher C. Nawrat (ORCID: https://orcid.org/0000-0003-4550-9954)
- Xin Wen (ORCID: https://orcid.org/0000-0002-2589-5117)
- Kai‐Jiong Xiao (ORCID: https://orcid.org/0000-0001-5613-2035)
- Gao Shang
- Eugene E. Kwan (ORCID: https://orcid.org/0000-0001-7037-0531)
- Zhiyan Song (ORCID: https://orcid.org/0009-0004-8425-3124)
- Zhiguo J. Song (ORCID: https://orcid.org/0000-0002-6769-1120)
- Matthew L. Maddess (ORCID: https://orcid.org/0000-0002-7273-528X)
- Xu Jj
- Heather C. Johnson (ORCID: https://orcid.org/0000-0003-0570-9556)
- Aaron C. Sather (ORCID: https://orcid.org/0000-0002-1737-7512)
- Jonathan M. E. Hughes (ORCID: https://orcid.org/0000-0002-5708-2882)
- Hongming Li (ORCID: https://orcid.org/0000-0001-6934-1928)
- Lushi Tan
- Jin Zhang (ORCID: https://orcid.org/0009-0007-4510-6844)
- Yongpeng Yuan
- B. Wan
- Jingjun Yin
- Chao Fan
- Jongrock Kong
- Yu-hong Lam
- Yonggang Chen
- Guiquan Liu
Institutions
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- Pharmaron (United Kingdom) (GB)
- Shanghai Institute of Pharmaceutical Industry (CN)
Publication Details
- Journal
- Organic Letters
- Published
- 2026-01-13
- DOI
- https://doi.org/10.1021/acs.orglett.5c04646
- Primary Topic
- Axial and Atropisomeric Chirality Synthesis
- Type
- article
- Field-Weighted Citation Impact
- 0.00