Second-Generation Atroposelective Synthesis of KRAS G12C Covalent Inhibitor GDC-6036
Jie Xu, Ngiap‐Kie Lim, Jacob C. Timmerman, Jeff Shen, Kyle Clagg, Ugo Orcel, Raphael Bigler, Etienne Trachsel, Roland Meier, Nicholas A. White, Johannes A. Burkhard, Lauren E. Sirois, Qingping Tian, Rémy Angelaud, Stephan Bachmann, Haiming Zhang, Francis Gosselin
Abstract
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 ).