Access to Highly Enantioenriched Donepezil-like 1,4-Dihydropyridines as Promising Anti-Alzheimer Prodrug Candidates via Enantioselective Tsuji Allylation and Organocatalytic Aza-Ene-Type Domino Reactions

Mihaela-Liliana Tîntas (1) , R. Azzouz (2) , L. Peauger (2) , Vincent Gembus (2) , Emilie Petit (1) , Laëtitia Bailly (1) , Cyril Papamicaël (1) , Vincent Levacher (1)

1 COBRA - Chimie Organique et Bioorganique : Réactivité et Analyse
2 VFP Therapies Drugs : Highway to the Brain

This work aims at exploiting both the enantioselective Tsuji allylation of allyl carbonate 6 and an organocatalytic aza-ene-type domino reaction between enal 3a and β-enaminone 4a to develop a straightforward access to all of the four possible stereoisomers of a donepezil-like 1,4-dihydropyridine 1a (er up to 99.5:0.5; overall yield up 64%), an anti-Alzheimer’s prodrug candidate. This strategy was extended to the preparation of other enantioenriched 1,4-dihydropyridines 1b–i (eight examples), highlighting its potential in the development of these chiral AChE inhibitors.

Domaines: Chimie

Mihaela-Liliana Tîntas, R. Azzouz, L. Peauger, Vincent Gembus, Emilie Petit, et al.. Access to Highly Enantioenriched Donepezil-like 1,4-Dihydropyridines as Promising Anti-Alzheimer Prodrug Candidates via Enantioselective Tsuji Allylation and Organocatalytic Aza-Ene-Type Domino Reactions. Journal of Organic Chemistry, 2018, 83 (17), pp.10231-10240. ⟨10.1021/acs.joc.8b01442⟩. ⟨hal-02024535⟩