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-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.