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

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