Journal of Organic Chemistry
Journal of Organic Chemistry
4 years ago

Spiropiperidine Sultam and Lactam Templates: Diastereoselective Overman Rearrangement and Metathesis followed by NH Arylation

Spiropiperidine Sultam and Lactam Templates: Diastereoselective Overman Rearrangement and Metathesis followed by NH Arylation
Luis A. Martinez-Alsina, Mark W. Bundesmann, Leanne M. Buzon, Joseph M. Young, John C. Murray, Brian T. O’Neill
We report the diastereoselective synthesis of novel spiropiperidine templates for use in SAR studies of β-secretase (BACE) inhibitors and also as versatile ligands for other receptor types. The overall synthetic approach stems from chiral starting material benzyl (S)-2-methyl-4-oxopiperidine-1-carboxylate and employs an Overman rearrangement to control the stereochemistry at the quaternary center. This process is followed by a Grubbs metathesis to close a five-membered “top” ring to form an α,β-unsaturated lactam or an α,β-unsaturated sultam. We also demonstrate that this chemistry can accommodate additional substituents on the lactam/sultam ring and allows late stage sequential functionalization of the amine and amide nitrogens to rapidly produce diverse analogues.

Publisher URL: http://dx.doi.org/10.1021/acs.joc.7b02096

DOI: 10.1021/acs.joc.7b02096

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