New Piperidine Scaffolds via Nucleophilic Reactivity of (−)-Phenyloxazolopiperidine

Abstract

The present work illustrates the power of compound 2 as a chiral, nonracemic, and stable 2-piperideine (enamine) equivalent in the rapid and efficient construction of 3-substituted piperidines (carbon-carbon and carbon-sulfur bonds) such as 3-spiropiperidines. This methodology offers a new route to such systems that could compete with previously reported strategies.

Reactivity and stereoselectivity of oxazolopyridines with a ring‐junction nitrogen atom

“…The alkylation of lactam 51 with (1 equiv) of methyl vinyl ketone 52 as a Michael acceptor in boiling methanol gave the corresponding Michael adduct (2 R ,3 R )‐ 53 in satisfactory yield (63%) with a reasonable level of diastereomeric creation (de = 92%). The yield of the alkylated product depends on the temperature, in which the reaction at rt gave the same product with lower yield (Scheme ) …”

“…Treatment of lactam 51 with electrophilic thiolating agent such as S ‐methyl‐methane‐thiosulfonate (0.5 equiv) in methanol at rt gave the monosubstituted analogue 85 in a yield of 70%. The use of excess amount of the thiolating agent (10 equiv) under the same reaction conditions yielded a mixture of monosubstituted and disubstituted analogues 85 (30%) and 86 (30%) (Scheme ) …”

“…The reaction projected mechanistic route involved the attack of the enamine carbon on the ester carbonyl group at first step followed by dehydration of the formed quaternary alcohol and isomerization of the iminium intermediate A into the enamine 165 . No reaction took place on the iminium intermediate, which could have led to a saturated aliphatic piperidine 166 afterward decarboxylation (Scheme ) …”

“…The reaction mechanism was suggested on the basis of two paths (1 and 2) following the attack of the active methylene of one chain to the carbonyl group of the other side chain. The crotonization step was proceeded through the two possible pathways allowing the formation of two quaternary alcohols, followed by in situ dehydration to furnish the desired α,β‐unsaturated spiro analogues 282 and 283 (Scheme ) …”

Identification of Privileged Scaffolds from a Diversified Chemical Library forβ-Secretase Inhibition

“…Privileged structures are often based on semirigid architectures bearing various hydrophobic substituents such as the well-known benzodiazepine scaffold [7]. Biphenyles [8], 1,4-dihydropyridines [9] or spiropiperidines [10] are also based on semi-rigid architectures suitable for privileged structure library constitution.…”