Synfacts 2018; 14(06): 0555
DOI: 10.1055/s-0037-1609518
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Verubecestat

Contributor(s):
Philip Kocienski
Chen W. * Meng D. N’Zemba B. Morris WJ. Merck & Co, Inc., Rahway, USA
Palladium-Catalyzed Enantioselective Synthesis of Cyclic Sulfamidates and Application to a Synthesis of Verubecestat.

Org. Lett. 2018;
20: 1265-1268
Further Information

Publication History

Publication Date:
17 May 2018 (online)

 

Significance

Verubecestat (MK-8931) is a β-secretase inhibitor that is of interest for the treatment of Alzheimer’s disease. The key step in the μmol-scale synthesis depicted is the construction of the aza-quaternary center in fragment D through a palladium-catalyzed, enantioselective addition of arylboronic acid B to cyclic imino­sulfate A. The desired cyclic sulfamidate D was obtained in 90% yield and 99% ee.


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Comment

The scope of the palladium-catalyzed enantioselective arylation reaction was explored using seven cyclic iminosulfates and eleven arylboronic acids. The reaction tolerates electron-rich, electron-poor, and ortho-substituted arylboronic acids and provides cyclic sulfamidates in high yields with excellent enantioselectivities. This palladium catalyst system significantly expands the scope for the asymmetric arylation of ketimines.


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