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Asymmetric Formal Synthesis of the Long-Acting DPP-4 Inhibitor Omarigliptin

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journal contribution
posted on 04.08.2017, 00:00 by Feng Peng, Yonggang Chen, Cheng-yi Chen, Peter G. Dormer, Amude Kassim, Mark McLaughlin, Robert A. Reamer, Edward C. Sherer, Zhiguo J. Song, Lushi Tan, Matthew T. Tudge, Baoqiang Wan, John Y. L. Chung
A highly efficient asymmetric synthesis of the key tetrahydropyranol intermediate of DPP-4 inhibitor omarigliptin (1) is described. The successful development of a protecting-group- and precious-metal-free synthesis was achieved via the discovery of a practical asymmetric Henry reaction and the application of a one-pot nitro-Michael–lactolization–dehydration through-process. Other features of the synthesis include a highly efficient MsCl-mediated dehydration and a crystallization-induced dynamic resolution for exceptional ee and dr upgrade. The synthesis of this complex intermediate utilizes simple starting materials and proceeds in four linear steps.