Atroposelective Negishi Coupling Optimization Guided by Multivariate Linear Regression Analysis: Asymmetric Synthesis of KRAS G12C Covalent Inhibitor GDC-6036.

An efficient asymmetric synthesis of a potent KRAS G12C covalent inhibitor, GDC-6036 ( 1 ), is reported. The synthesis features a highly atroposelective Negishi coupling to construct the key C-C bond between two highly functionalized pyridine and quinazoline moieties by employing a Pd/Walphos catalytic system. Statistical modeling by comparing computational descriptors of a range of Walphos chiral bisphosphine ligands to a training set of experimental results was used to inform the selection of the best ligand, W057-2 , which afforded the desired Negishi coupling product ( R _a )-3 in excellent selectivity. A subsequent telescoped reaction sequence of alkoxylation, global deprotection, and acrylamide formation, followed by a final adipate salt formation, furnished GDC-6036 ( 1 ) in 40% overall yield from starting materials pyridine 5 and quinazoline 6 .