Fit-for-Purpose Synthesis of a KRASG12C Covalent Inhibitor, via a Diastereoselective Hayashi Arylation

An enabling, fit-for-purpose synthesis of stereochemically pure KRAS G12C covalent inhibitor 1, a potential new treatment for cancer, is described. The synthetic route provided 1 in 13 steps from commercially available 2-fluoro-5-methylaniline ( 2 ), tert -butyl ( S )-3-methylpiperazine-1-carboxylate ( 8 ) and ( S )-(1-methylpyrrolidin-2-yl)methanol ( 10 ). A key transformation in this sequence was the diastereoselective 1,4-addition of an aryl boronate derived from 2 with rac- 4-methylcyclohex-2-en-1-one ( rac- 4 ) in a Hayashi arylation that sets two relative stereocenters of the target molecule. This in turn inspired the development of an improved synthesis of ( R ) - 4-methylcyclohex-2-en-1-one (( R ) - 4 ) via optimized methodology for the asymmetric monohydrogenation of 1,4-dienes, thus setting the stage for a fully asymmetric synthesis of inhibitor 1 .