Journal of Organic Chemistry
Journal of Organic Chemistry
5 years ago

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

Asymmetric Formal Synthesis of the Long-Acting D-4 Inhibitor Omarigliptin
Peter G. Dormer, Cheng-yi Chen, Mark McLaughlin, Zhiguo J. Song, Feng Peng, Baoqiang Wan, Robert A. Reamer, Amude Kassim, John Y. L. Chung, Edward C. Sherer, Yonggang Chen, Lushi Tan, Matthew T. Tudge
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.

Publisher URL: http://dx.doi.org/10.1021/acs.joc.7b01467

DOI: 10.1021/acs.joc.7b01467

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