title: Synthesis and quantitative analysis of diastereomeric linked ester conjugates with remote stereocenters using high-field NMR and chiral HPLC.
abstract: A stereochemically safe high-yielding procedure for linking unprotected as well as protected hydroxycarboxylic acids to chiral secondary alcohols via glycolic acid linker is proposed. L-menthol has been linked with both enantiomers of mandelic, malic, and methoxyphenylacetic acid using bromo- or iodoacetyl group as a precursor of the glycolic acid linker. High-field nuclear magnetic resonance (NMR) and chiral high-performance liquid chromatography (HPLC) determination of high diastereomeric ratio (dr) (>99%) of the products bearing remote stereocenters was explored. Chiral HPLC allowed quantitation of the diastereomers up to dr 99.9/0.1. High-field NMR quantitation of the diastereomeric and parent alcoholic impurities in esters was demonstrated at the molar 0.3% and 0.03% levels, respectively. These analyses were done via comparison of integral intensities from major component (13)C satellites in (1)H or even in (13)C spectra to the (1)H or (13C signals of impurities. Despite lower sensitivity, the last option generally has much better selectivity. In this way the dynamic resolution is brought down by two orders.
authors.affiliation: Department of Chemistry, Tallinn University of Technology, Tallinn, Estonia.
authors.forename: Eva
authors.initials: E
authors.lastname: Doyle
authors.forename: Jaan
authors.initials: J
authors.lastname: Parve
authors.forename: Marina
authors.initials: M
authors.lastname: Kudryashova
authors.forename: Sven
authors.initials: S
authors.lastname: Tamp
authors.forename: Aleksander-Mati
authors.initials: AM
authors.lastname: Müürisepp
authors.forename: Ly
authors.initials: L
authors.lastname: Villo
authors.forename: Lauri
authors.initials: L
authors.lastname: Vares
authors.forename: Tõnis
authors.initials: T
authors.lastname: Pehk
authors.forename: Omar
authors.initials: O
authors.lastname: Parve
mesh_terms: D000438:Alcohols / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D002851:Chromatography, High Pressure Liquid; D004952:Esters; D006016:Glycolates / Q000138:chemical synthesis* / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D013237:Stereoisomerism
chemical_list: D000438:Alcohols; D004952:Esters; D006016:Glycolates; C031149:glycolic acid
keywords: L-menthol; O-alkylation of carboxylic acid; glycolic acid linker; lactic acid; malic acid; mandelic acid; prodrug homogeneity