Asymmetric Synthesis of KRAS G12C Inhibitor MK-1084 via a Crystallization-Induced Diastereomer Transformation (CIDT)

Organic Letters 2026

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Authors: Hongming Li, Gao Shang, Zhiguo J. Song, Xin Wen, Yonggang Chen, Lushi Tan, Kai‐Jiong Xiao, Xu Jj, Aaron C. Sather, Jongrock Kong, Kevin M. Belyk, Heather C. Johnson
+13 more Jonathan M. E. Hughes, Christopher C. Nawrat, Eugene E. Kwan, Cyndi Qixin He, Yu‐hong Lam, Jin Zhang, Chao Fan, Zhiyan Song, Guiquan Liu, B. Wan, Yongpeng Yuan, Matthew L. Maddess, Jingjun Yin
DOI: 10.1021/acs.orglett.5c04646
Cited by: 1
References: 36

Abstract

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 C–C and N–C 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.

Fields of Study & Subjects

Axial and Atropisomeric Chirality Synthesis Coordination Chemistry and Organometallics Chemical Synthesis and Analysis

Publication details

Journal / source
Organic Letters
Publisher
American Chemical Society (ACS)
Volume
28
Issue
3
Pages
923–928
Publication date
13 January 2026
Language
EN