(S)-(-)-a-Methoxy-a-(trifluoromethyl)phenylacetic Acid

[17257-71-5]  · C10H9F3O3  · (S)-(-)-a-Methoxy-a-(trifluoromethyl)phenylacetic Acid  · (MW 234.19)

(determination of enantiomeric purity and absolute configuration of alcohols and amines1)

Alternate Name: MTPA.

Physical Data: bp 115-117 °C/1.5 mmHg; [a]D -71.8° (c 3.28, MeOH); d 1.344 g cm-3.

Solubility: readily sol hexane, ether, THF, CH2Cl2, benzene.

Form Supplied in: both enantiomers are commercially available and generally possess similar applications.

Preparative Methods: both enantiomers are available by resolution of the racemic acid with a-phenylethylamine.1 Other procedures have been described.2

Analysis of Reagent Purity: the enantiomeric purity of the reagent can be evaluated by capillary GC analysis of its methyl ester on a chiral stationary phase,3 HPLC analysis of the corresponding 1-(a-naphthyl)ethylamide,2 or by LiAlH4 reduction to the corresponding alcohol, which is analyzed by chiral GC.4

Handling, Storage, and Precautions: very stable; commercial samples remain useful after extended periods of time.

Determination of the Enantiomeric Purity of Alcohols, Amines, and Other Compounds by Derivatization.

The enantiomeric purity of a variety of chiral amines and alcohols can be assayed by reaction with chiral MTPA, followed by determination of the diastereomeric purity of the resulting amide or ester.1 This is usually done by chromatographic (HPLC, GC, TLC, etc.) or spectroscopic methods (1H NMR, 19F NMR, etc.). Either type of experiment may provide the desired information and in fact they are often used in combination. MTPA is frequently converted to the corresponding acid chloride (MTPA-Cl) by refluxing in Thionyl Chloride. After distillation, MTPA-Cl is treated with the desired amine or alcohol.1 An improved procedure for the microscale preparation of MTPA-Cl with Oxalyl Chloride, which does not require distillation of the MTPA-Cl prior to reaction with the alcohol/amine, has been described.5 Alternatively, MTPA reacts directly with amines and alcohols in the presence of condensing agents such as 1,3-Dicyclohexylcarbodiimide6 or 2-chloro-1-methylpyridinium chloride.7 Inherent in the successful use of these procedures is the need to ensure complete derivatization of the alcohol/amine, so that the diastereomeric purity of the derivative is truly reflective of the enantiomeric purity of the alcohol/amine under scrutiny.8

Alcohols.

When using the 1H NMR spectra of MTPA esters to determine the enantiomeric purity of alcohols, the MTPA methoxy peaks tend to be most useful. This technique can be sensitive enough to detect as little as 1% of the minor alcohol enantiomer. The enantiomeric purity of chiral alcohols (1)9 and (2)10 has been determined this way. The enantiomeric purity of primary alcohols (3)11 and (4),12,13 in which the asymmetric center is not the carbinol carbon, has also been determined by 1H NMR analysis of their MTPA esters. A slight variation of this methodology is the use of shift reagents like Eu(fod)3 to increase the chemical shift separation between diastereotopic MeO peaks; this procedure has been used in the analysis of alcohols (5)14 and (6).15

19F NMR is also extremely useful in the analysis of MTPA esters, and is often used in combination with 1H NMR.1 The CF3 peak(s) is easy to observe, being unencumbered by unrelated peaks. Enantiomeric analysis of primary alcohols, e.g. (7),16,17 as well as secondary alcohols (8)18 and (9)19 has been performed utilizing this method. 19F NMR analysis of MTPA esters in the presence of shift reagents has also been utilized to increase the separation between diastereomeric 19F peaks.15

13C NMR analysis of MTPA esters has not received much attention, but some examples have been described, e.g. the MTPA ester of (10).20

Almost every available chromatographic technique has been utilized in the analysis of MTPA esters. For example, capillary GLC was used to evaluate the diastereomeric composition of the MTPA esters of chiral alcohols (5),14 (11),21 and (12).22 HPLC is routinely used, for analytical as well as preparative purposes (see below).

Amines.

In a manner similar to alcohols, the enantiomeric purity of primary and secondary amines can be assayed by 1H NMR analysis of their MTPA amides.1 The technique has been particularly useful for amino acid derivatives,23 e.g. (13),24 (14),25 and (15).26

19F NMR spectroscopy is extremely sensitive in the stereochemical evaluation of MTPA amides of a wide range of amino acids (as low as 0.05% of the minor isomer detectable).27,28 HPLC analysis of diastereomeric MTPA amides may provide valuable analytical information on the enantiomeric composition of chiral primary and secondary amines.29

Other Compounds.

In theory, any chiral compound with a reactive functional group can be derivatized with (S)- or (R)-MTPA in order to assess its enantiomeric purity. An example is the derivatization of cyclic carbamates, followed by 1H NMR analysis (eq 1).30 Similarly, axially chiral biaryls bearing amine or alcohol substituents, e.g. (16) and (17), have been analyzed via the corresponding MPTA derivatives.31

Noncovalent MTPA Derivatives.

The enantiomeric purity of some chiral amines can be determined by 1H NMR with (S)- or (R)-MTPA as a chiral solvating agent.32,33 The method is particularly useful for chiral tertiary amines that are not amenable to conversion into MTPA amides, e.g. (18) and (19),34 although it has been utilized for primary and secondary amines as well, e.g. (20).35

Determination of Absolute Configuration in Alcohols and Amines.

The configuration of chiral alcohols and amines (where the heteroatom is attached to the stereocenter) has been correlated with the 19F chemical shifts of their MTPA derivatives.36 The model is not fully predictive, although the exceptions can often be rationalized. However, 1H NMR spectroscopy of MTPA esters and amides has been more widely used in the assignment of configuration to chiral alcohols and amines.37 Analysis of the chemical shifts of the MTPA methoxy peaks, in the presence of shift reagents, allows the correct stereochemical analysis of a series of bicyclic alcohols, such as (6).15 The 1H NMR shifts of the hydrogens directly attached to the carbinol carbons in MTPA esters have also been used to establish the configuration of chiral acyclic secondary alcohols.38 Other peaks in the MTPA derivatives have been used in the stereochemical elucidation of a series of alcohol natural products.39 Although less commonly used, 13C NMR spectroscopy of MTPA derivatives has been used in the stereochemical study of a large group of chiral alcohols.40 The stereochemistry of amino acids has also been amenable to study by 1H NMR spectroscopy of their MTPA derivatives.23,41

Preparative Uses of MTPA Derivatives.

Resolution of racemic compounds on a preparative scale is always a challenging endeavor. Conversion of the enantiomeric mixture into a mixture of diastereomers, each with unique physical properties, makes it possible to separate the components by a variety of physical methods, such as fractional recrystallization, distillation, or chromatography. One of the earliest uses of MTPA was the resolution of racemic alcohols via the separation of diastereomeric MTPA esters by preparative gas-liquid chromatography, followed by alcohol regeneration with Lithium Aluminum Hydride (eq 2).1 More frequently, diastereomeric MTPA esters have been separated by high performance liquid chromatography (HPLC), followed by alcohol regeneration either by ester hydrolysis (eq 3)42 or reduction (eq 4).43

This procedure is useful even when the carbinol carbon is not the asymmetric center of the molecule (eq 5).44

Far fewer examples of diastereomeric ester separations by fractional recrystallization have been described. However, this procedure is extremely practical for the resolution of a series of bromohydrins (eq 6).45


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Juan C. Jaen

Parke-Davis Pharmaceutical Research, Ann Arbor, MI, USA



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