An Alternative Scalable Process for the Synthesis of the Key Intermediate of Omarigliptin

An alternative scalable process for the synthesis of the key intermediate of omarigliptin is described. The asymmetric synthesis relies on the initial diastereoselective alkylation and subsequent aluminum-catalyzed substrate-controlled Meerwein–Ponndorf–Verley reduction. A highly regioselective 5-exo-dig iodocyclization followed to afford 11b, which was then subjected to ring-opening cycloetherification to give product 1 with >99:1 dr and >99% ee in 31.2% overall yield in nine steps. This synthetic strategy has been successfully applied for multikilogram scale production.