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Stereoselective Synthesis of Spiropiperidines as BACE‑1 Aspartyl Protease Inhibitors via Late Stage N‑Arylation of a 1,8-Diazaspiro[4.5]dec-3-en-2-one Pharmacophore

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posted on 15.03.2013, 00:00 by Che-Wah Lee, Ricardo Lira, Jason Dutra, Kevin Ogilvie, Brian T. O’Neill, Michael Brodney, Christopher Helal, Joseph Young, Erik Lachapelle, Subas Sakya, John C. Murray
A stereoselective synthesis of spiropiperidine compounds, exemplified by compound 1, was developed, which was based upon the late stage N-arylation of a 1,8-diazaspiro[4.5]­dec-3-en-2-one pharmacophore. Previously, compound 1 was prepared in low overall yield from piperidinone 2 via the Strecker reaction. A new route was developed, which employed the stereospecific Corey–Link reaction of an enantiomerically pure trichloromethylcarbinol to give a template compound amenable to late stage N-arylation.