A Formal Synthesis of Ezetimibe via Cycloaddition/Rearrangement Cascade Reaction
The Journal of Organic Chemistry2011Vol. 76(16), pp. 6931–6936
Citations Over TimeTop 10% of 2011 papers
Michał Michalak, M. Stodulski, Sebastian Stecko, Adam Mames, Irma Panfil, Magdalena Soluch, Bartłomiej Furman, Marek Chmielewski
Abstract
A formal synthesis of a powerful cholesterol inhibitor, ezetymibe 1, is described. The crucial step of the synthesis is based on Cu(I)-mediated Kinugasa cycloaddition/rearrangement cascade reaction between terminal acetylene derived from acetonide of L-glyceraldehyde and suitable C,N-diarylnitrone. The adduct with (3R,4S) configuration at the azetidinone ring, obtained with high stereoselectivity, was subsequently subjected to deprotection of the diol side chain followed by glycolic cleavage and base-induced isomerization at the C3 carbon atom to afford the (3S,4S) aldehyde, which has been already transformed into ezetimibe by the Schering-Plough group.
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