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.

Scalable Lipase-Catalyzed Synthesis of (R)-4-(Acyloxy)pentanoic Acids from Racemic γ-Valerolactone

“…Enantiomeric ratios of the products were determined by 1 H NMR measurement of the diastereomeric ratio of the ester conjugates 13 – 15 (Scheme ) obtained by O-alkylation of the product with (1 R )-menthyl bromoacetate, a chiral derivatizing agent. ,, Diastereomeric ratios were determined by integrating the signals of H atoms of the glycolic acid moiety in the conjugate (Figure ). Products from the preparative syntheses (Table , entries 5, 13) were analyzed additionally in the form of p -bromophenacyl esters by chiral HPLC (Supporting Information), and results were in good agreement with NMR data analysis.…”

“…of the products, allowed optimization of the conversion of the preparative syntheses by determination of suitable conditions for the enzyme loading vs the amount and counterion of a nucleophile vs solvent vs substrate vs temperature vs reaction time. 32 Enantiomeric ratios of the products were determined by 1 H NMR measurement of the diastereomeric ratio of the ester conjugates 13−15 (Scheme 3) obtained by O-alkylation of the product with (1R)-menthyl bromoacetate, 33 a chiral derivatizing agent. 32,34,35 Diastereomeric ratios were determined by integrating the signals of H atoms of the glycolic acid moiety in the conjugate (Figure 1).…”

Stereoselective Synthesis of γ‐(Acyloxy)carboxylic Acids and γ‐Lactones Featuring the Switch of Stereopreference of Candida antarctica Lipase B in Sodium γ‐Hydroxycarboxylate Homologues

“…Enantiomeric ratios of γ‐(acyloxy)carboxylic acids (Table 1, column 9) have been determined by using chiral derivatization [47] with (1 R )‐menthyl bromoacetate to prepare diastereomeric menthyl glycolic ester conjugates [48] for 1 H NMR spectroscopic analysis or/and by using HPLC of corresponding p ‐bromophenacyl esters over chiral stationary phase or/and by GLC of γ‐lactones over chiral liquid phase (Supporting Information Scheme S5).…”

Synthesis and Explosion Hazards of 4-Azido-l-phenylalanine

“…39 Unfortunately, most esterification reactions employ the use of coupling agents in the presence of stoichiometric or excess base, which may not be conducive to maintaining stereochemistry at the α-carbon. 40 This problem has been mitigated in the past through use of multistep synthetic routes that avoid exposing the chiral acid to the destructive conditions of direct esterification 41 and more recently through the use of an apparently racemization-free coupling agent, ethyl 2-(tert-butoxycarbonyloxyimino)-2-cyanoacetate (Boc-Oxyma). 42 Oxyma-based acylation protocols have become a welcomed advancement in synthetic chemistry, owing to the reclassification of N-hydroxybenzotriazole (HOBt) as a UN0508, class 1.3C explosive in 2005.…”