title: Asymmetric phase-transfer catalyzed glycolate alkylation, investigation of the scope, and application to the synthesis of (-)-ragaglitazar.
abstract: [Reaction: see text]. 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 degrees 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 alpha-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.
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, C100 BNSN, Provo, Utah 84602-5700, USA. mbandrus@chem.byu.edu
authors.forename: Merritt B
authors.initials: MB
authors.lastname: Andrus
authors.forename: Erik J
authors.initials: EJ
authors.lastname: Hicken
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Stephens
authors.forename: D Karl
authors.initials: DK
authors.lastname: Bedke
mesh_terms: D000098:Acetophenones / Q000737:chemistry; D000478:Alkylation; D002384:Catalysis; D003460:Crystallization; D004952:Esters / Q000737:chemistry; D006016:Glycolates / Q000737:chemistry*; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism
chemical_list: D000098:Acetophenones; D004952:Esters; D006016:Glycolates; D010078:Oxazines; D010666:Phenylpropionates; C031149:glycolic acid; C432703:ragaglitazar; C038699:acetophenone