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Synthetic Approaches for Piperidone-Based Templates as Scaffolds to Access Chirally Enriched Donepezil Analogues.

ABSTRACT: A concise and high-yielding double aza-Michael reaction is presented as an atom-efficient method to access chiral 2-substituted 4-piperidone building blocks from divinyl ketones. The piperidones were further converted into analogues of donepezil, an acetylcholinesterase inhibiting drug used in the treatment of Alzheimer's disease. The donepezil analogues were obtained as inseparable diastereomeric mixtures with resolved stereochemistry in position 2 of the piperidine ring. Biological evaluation of the acetylcholinesterase inhibition by these analogues provides a new insight into structure-activity relationship studies with regard to donepezil's piperidine moiety toward stereochemical enhancement.

SUBMITTER: Poeschl A

PROVIDER: S-EPMC7017409 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Synthetic Approaches for Piperidone-Based Templates as Scaffolds to Access Chirally Enriched Donepezil Analogues.

Poeschl Anna A Mountford David M DM Hider Robert C RC Cilibrizzi Agostino A

ACS omega 20200203 5

A concise and high-yielding double <i>aza</i>-Michael reaction is presented as an atom-efficient method to access chiral 2-substituted 4-piperidone building blocks from divinyl ketones. The piperidones were further converted into analogues of donepezil, an acetylcholinesterase inhibiting drug used in the treatment of Alzheimer's disease. The donepezil analogues were obtained as inseparable diastereomeric mixtures with resolved stereochemistry in position 2 of the piperidine ring. Biological eval ...[more]

PMID: 32064399

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