Second-Generation Atroposelective Synthesis of KRAS G12C Covalent Inhibitor GDC-6036.

A chromatography-free asymmetric synthesis of GDC-6036 ( 1 ) was achieved via a highly atroposelective Negishi coupling of aminopyridine 5 and quinazoline 6b catalyzed by 0.5 mol % [Pd(cin)Cl] 2 and 1 mol % ( R , R )-Chiraphite to afford the key intermediate ( R a )- 3 . An alkoxylation of ( R a )- 3 with ( S )- N -methylprolinol ( 4 ) and a global deprotection generates the penultimate heterobiaryl intermediate 2 . A controlled acrylamide installation by stepwise acylation/sulfone elimination and final adipate salt formation and crystallization delivered high-purity GDC-6036 ( 1 ).