Hindered Biaryl Bond Construction and Subsequent Diastereomeric Crystallization to Produce an Atropisomeric Covalent KRASG12C Inhibitor ARS-2102

A scaleup route for a first-generation covalent KRASG12C inhibitor ARS-2102 was devised, featuring an “early cross-coupling” strategy to construct the tetra-substituted atropisomeric biaryl scaffold. An iterative diastereomeric recrystallization enabled an effective chiral resolution of key intermediate 24. A global deprotection followed by chemoselective functionalization afforded ARS-2102 in excellent yield and diastereomeric enrichment. This chromatography-free sequence was successfully executed on kilogram scale.