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.