Mosher’s acid chloride

Acylation of various oxygen functions by use of common and commercially available fluonnated carboxylic acid denvatives such as trifluoroacetic anhydride or the corresponding acyl halides have already been discussed sufficiently in the first edition [10] Therefore only exceptional observations will be described in this section In the past 15 years, many denvatizations of various nonfluonnated oxygen compounds by fluoroacylation were made for analytical purposes. Thus Mosher s acid chlorides for example became ready-to-use reagents for the determination of the enantiomeric purity of alcohols and amines by NMR or gas-liquid chromatographic (GLC) techniques [//] (equation 1)... 

No resolvable separation of the signals of the diastereomers formed from reaction of the amino acid with (5)-2-bromopropionyl chloride or Mosher s acid chloride are observed. However, with common amino acids, the latter reagent can be successfully used under similar Schotten -Baumann conditions for the detection of differences in 19F spectra57. The a-alkylated amino acids are particularly challenging. However, by proper choice of solvent and signal, sufficient peak separation can be obtained. No measurable amount of kinetic resolution occurs during acylation of the acids. 

In order to determine the absolute configuration or the enantiomeric excess of a compound containing a hydroxy group, it is often esterified with a pure enantiomer of Mosher s acid (3,3,3-trifluoro-2-methoxy-2-phenylpropanoic acid, MTPA). Which configuration has the ester derived from (S)-l-phenyl-propan-l-ol and (R)-Mosher s acid chloride ... 

The reaction with Mosher s acid chloride is a normal esterification reaction with retention of configuration of the chirality centres of both reactants. Since, however, the chlorine atom in the acid chloride is replaced, nevertheless the descriptor for the Mosher s acid part of the product will change. 

The mild reaction conditions employed enables the preparation of chlorides without disrupting chiral or other sensitive functionality. The use of hexane has been found particularly suitable for microscale preparation of high purity Mosher s acid chloride as it enables residual DMFCl to be filtered from solution (eq 2). ... 

Reduction is also observed in the reaction of acid chlorides with Grignard reagents Whitmore, F.C., Whitaker, J.S., Mosher, W.A., Brevick, O.N., Wheeler,... 

The enantiomeric excess was determined to be >99% by capillary GLC analysis (30 ra x 32 tim WCOT column coated with Carbowax 20 M, hydrogen carrier gas, linear velocity ca. 94 cra/s, oven temperature 225°C) of the imide derived from the Mosher acid chloride. ... 

The enantiomeric excess (% ee) of these compounds was determined by the submitters as follows. The ester and acids were first reduced to the corresponding alcohols with DIBAL and LAH, respectively. The alcohols were then allowed to react with 100% excess of (S)-(+)-o-methoxy-o-trifluoromethylphenylacetyl chloride (Mosher s reagent) in (1 1) pyridine-carbon tetrachloride for 18 hr. The diastereomeric ratio of these derivatives was finally determined by isothermal gas chromatography on a capillary OV-17 column at 160°C. 

The keto acid could not be resolved as easily as it was synthesized. Formation of salts with various optically pure bases invariably yielded oils. Ketalization of the keto ethyl ester with ethylene glycol followed by reduction with lithium aluminum hydride and treatment with Mosher s reagent, (+)-a-methoxy-a-trifluoromethylphenylacetyl chloride (17,18,19>, gave a diastereomeric mixture (Scheme 7), which unfortunately was not resolvable by HPLC. 

Assay for enantiomeric purity To a magnetically stirred suspension of diphenylprolinol sulfate (30 mg) in tetrahydrofuran (1 mL) is added 1 M aqueous sodium hydroxide (210 pL). The mixture is stirred for 15 min, then (R)-Mosher acid chloride (20 pL) is added. By TLC (EM Si-60, 8 2 hexane/EtOAc, R diphenylprolinol = 0.05, Rf Mosher amide = 0.4) the reaction is complete in 1 hr. The reaction mixture is diluted into hexane (9 mL). then eluted through a Baker Silica SPE (1 g) column (previously washed with hexane). The column was eluted with additional 9 1 hexane/tetrahydrofuran (5 mL). The combined eluates were than analyzed by capillary GC Column 0.33 mm x 30 m DB-23 (J W Scientific) Oven Temperature 250°C Injector/Detector Temperature 275°C Carrier Gas Helium (21 lbs/in2), ca. 30 1 split Injection 1 pL Detection FID Retention Times (R.R)-Mosher amide 25.9 min (R.S)-Mosher amide 29.6 min. The enantiomeric purity is 99 1. 

Alternative Reagents. 1-(1-Phenyl)ethyl isocyanate (PEI) is a cheaper alternative to NEI however, diastereomers formed from NEI are usually easier to separate by liquid chromatography. Other alternatives are also used, e.g. in determining the enantiomeric purity of 3-aminoquinuclidine, PEI, NEI, 2,3,4,6-tetraacetyl-p-D-glucopyranosyl isothiocyanate, and (R,R)- and (S,S)-0,0-dibenzoyltartaric acid anhydride are all employed successfully. Mandelic Acid and Mosher s reagent, a-methoxytrifluoromethylphenylacetyl chloride, may not be quite as effective as NEI when resolutions are carried out by liquid chromatography. ... 

The absolute stereochemistry of lyconesidine B (54) was elucidated by applying a modified Mosher s method (65) as follows. The hydroxy group at C-16 of 54 was protected with a triphenyl methyl (trityl) group and then esterified with its (S)- and (R)-MTPA chlorides, followed by hydrolysis of the trityl ester with formic acid to give its (S)- and (R)-MTPA esters. The values of AS [ (A-MTPA ester) - S(R-MTPA ester)]... 

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