Zhang H,
*,
Sigman MS.
* et al.
Genentech, Inc., South San Francisco and University of Utah, Salt Lake City, USA
Atroposelective Negishi Coupling Optimization Guided by Multivariate Linear Regression
Analysis: Asymmetric Synthesis of KRAS G12C Covalent Inhibitor GDC-6036.
J. Am. Chem. Soc. 2022;
144: 20955-20963
DOI:
10.1021/jacs.2c09917
Key words
Negishi coupling - axial chirality - multivariate linear regression - process chemistry
Significance
KRAS, a frequently mutated oncogene, has been linked to the progression of various
cancers and is therefore pursued as an anticancer target. Genentech has recently developed
GDC-6036, an irreversible covalent inhibitor of the KRAS G12C mutation which features an axial
chiral pyridine–quinazoline biaryl moiety that poses a significant synthetic challenge.
Comment
Utilizing high-throughput experimentation, the Walphos ligand class was found to yield
biaryl intermediate C via a Negishi coupling as either (R)- or (S)-atropisomer with moderate er values. However, no intuitive structure–selectivity
trends of the ligands tested could be identified. Therefore, multivariate linear regression
(MLR) analysis was employed which successfully predicted ligand D to be more selective. Using D, desired (R
a)-C was obtained with er = 98:2 and could be further elaborated to GDC-6036.
