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

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-carbo...

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Bibliographic Details
Published in:Journal of organic chemistry 2017-12, Vol.82 (23), p.12246-12256
Main Authors: Martinez-Alsina, Luis A, Murray, John C, Buzon, Leanne M, Bundesmann, Mark W, Young, Joseph M, O’Neill, Brian T
Format: Article
Language:English
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Summary: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.
ISSN:0022-3263
1520-6904
DOI:10.1021/acs.joc.7b02096