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

• Published in: Journal of organic chemistry 2005-11, Vol.70 (23), p.9470-9479
• Main Authors: Andrus, Merritt B, Hicken, Erik J, Stephens, Jeffrey C, Bedke, D. Karl
• Format: Article
• Language: English
• Subjects: Acetophenones - chemistry; Alkylation; Catalysis; Catalysts: preparations and properties; Chemistry; Crystallization; Esters - chemistry; Exact sciences and technology; General and physical chemistry; Glycolates - chemistry; Heterocyclic compounds; Heterocyclic compounds with n hetero atom and also o and/or s, se, te hetero atoms; Noncondensed benzenic compounds; Organic chemistry; Oxazines - chemical synthesis; Oxazines - chemistry; Phenylpropionates - chemical synthesis; Phenylpropionates - chemistry; Preparations and properties; Stereoisomerism; Theory of reactions, general kinetics. Catalysis. Nomenclature, chemical documentation, computer chemistry
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo051568z

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 (−)-ragaglitazar 24 was synthesized in six steps from a key 2-alkoxy-3-p-phenoxypropionic acid 26 that was made using PTC glycolate alkylation.