Stereochemical Editing via Coupled Epimerization and Optical Resolution to Sustainably Manufacture a Key Adagrasib Building Block

Epimerization and recycling of an unwanted piperazine stereoisomer enabled a more sustainable, concise, and high-yielding synthesis of a chiral adagrasib building block. The unselective bond formation thus resembled a formal enantioselective aza-Michael reaction. This strategy shortened development timelines, eliminated the handling of sodium cyanide, removed two chemical bond-forming operations, and decreased the process mass intensity nearly 3-fold. The overall yield was improved from 34 to 74%. Widely available commodity chemicals were selected as building blocks.