Asymmetric Phase-Transfer Catalyzed Glycolate Alkylation, Investigation of the Scope, and Application to the Synthesis of (−)-Ragaglitazar

Asymmetric glycolate alkylation using a protected acetophenone surrogate under solid−liquid phase-transfer conditions is a new approach to the synthesis of 2-hydroxy esters and acids. Diphenylmethyloxy-2,5-dimethoxyacetophenone 1 with a trifluorobenzyl cinchonidinium bromide catalyst 9 (10 mol %) and cesium hydroxide provided S-alkylation products 2 at −35 °C in high yield (80−99%) and with excellent enantioselectivities using a wide range of electrophiles (80−90% ee). Alkylated products were elaborated to useful α-hydroxy intermediates 3 using bis-TMS peroxide Baeyer−Villiger conditions and selective transesterification reactions. The ester products have been enantioenriched by simple recrystallization from ether to give a single isomer (99% ee). A tight ion-pair model is proposed for the observed S-stereoinduction that includes van der Waals contacts between the extended enolate and the isoquinoline of the catalyst. To demonstrate the utility of the new methodology, the anti-diabetes drug (−)-ragaglitaz...