(S)-(−)-α-METHOXY-α-(TRIFLUOROMETHYL)PHENYLACETIC ACID 1

(S)-(−)-ααα-Methoxy-ααα-(trifluoromethyl)-phenylacetic Acid

Ph CO2H

MeO CF3

[17257-71-5] C10H9F3O3 (MW 234.19)InChI = 1/C10H9F3O3/c1-16-9(8(14)15,10(11,12)13)7-5-3-2-4-

6-7/h2-6H,1H3,(H,14,15)/t9-/m0/s1/f/h14HInChIKey = JJYKJUXBWFATTE-FKOBDKTLDX

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

Alternate Name: MTPA.Physical Data: bp 115–117 ◦C/1.5 mmHg; [α]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 resolu-

tion of the racemic acid with α-phenylethylamine.1 Other pro-cedures have been described.2

Analysis of Reagent Purity: the enantiomeric purity of the reagentcan be evaluated by capillary GC analysis of its methyl ester ona chiral stationary phase,3 HPLC analysis of the correspond-ing 1-(α-naphthyl)ethylamide,2 or by LiAlH4 reduction to thecorresponding alcohol, which is analyzed by chiral GC.4

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

Determination of the Enantiomeric Purity of Alcohols,Amines, and Other Compounds by Derivatization. The enan-tiomeric purity of a variety of chiral amines and alcohols can beassayed by reaction with chiral MTPA, followed by determina-tion 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 typeof experiment may provide the desired information and in factthey are often used in combination. MTPA is frequently con-verted to the corresponding acid chloride (MTPA-Cl) by reflux-ing in Thionyl Chloride After distillation, MTPA-Cl is treatedwith the desired amine or alcohol.1 An improved procedure forthe microscale preparation of MTPA-Cl with Oxalyl Chloride,which does not require distillation of the MTPA-Cl prior to reac-tion with the alcohol/amine, has been described.5 Alternatively,MTPA reacts directly with amines and alcohols in the presence ofcondensing agents such as 1,3-Dicyclohexylcarbodiimide6 or 2-chloro-1-methylpyridinium chloride.7 Inherent in the successfuluse of these procedures is the need to ensure complete derivati-zation of the alcohol/amine, so that the diastereomeric purity ofthe derivative is truly reflective of the enantiomeric purity of thealcohol/amine under scrutiny.8

Alcohols. When using the 1H NMR spectra of MTPA esters todetermine the enantiomeric purity of alcohols, the MTPA methoxypeaks 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 hasbeen determined this way. The enantiomeric purity of primaryalcohols (3)11 and (4),12,13 in which the asymmetric center is notthe carbinol carbon, has also been determined by 1H NMR analysisof their MTPA esters. A slight variation of this methodology is theuse of shift reagents like Eu(fod)3 to increase the chemical shiftseparation between diastereotopic MeO peaks; this procedure hasbeen used in the analysis of alcohols (5)14 and (6).15

OHO

O

t-Bu

OH

(1) (2) (3)

HOC9H19

O

(4)

HO OTBDMS

i-Pr

(5) (6)

OH OH

19F NMR is also extremely useful in the analysis of MTPAesters, and is often used in combination with 1H NMR.1 TheCF3 peak(s) is easy to observe, being unencumbered by unrelatedpeaks. Enantiomeric analysis of primary alcohols, e.g. (7),16,17 aswell as secondary alcohols (8)18 and (9)19 has been performedutilizing this method. 19F NMR analysis of MTPA esters in thepresence of shift reagents has also been utilized to increase theseparation between diastereomeric 19F peaks.15

(7) (8)

N

OH

i-Pr

OCOPh

OH

OH

(9)

Ph

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

(10)

OH

Almost every available chromatographic technique has beenutilized in the analysis of MTPA esters. For example, capillaryGLC was used to evaluate the diastereomeric composition of theMTPA esters of chiral alcohols (5),14 (11),21 and (12).22 HPLC isroutinely used, for analytical as well as preparative purposes (seebelow).

(12)

NMe2

OH

OH

(11)

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2 (S)-(−)-α-METHOXY-α-(TRIFLUOROMETHYL)PHENYLACETIC ACID

Amines. In a manner similar to alcohols, the enantiomericpurity of primary and secondary amines can be assayed by 1HNMR analysis of their MTPA amides.1 The technique has beenparticularly useful for amino acid derivatives,23 e.g. (13),24 (14),25

and (15).26

(14)

O

NH2

CO2MeNH

AcO

CO2Me NH

MeO2C

i-Pr

(15)(13)

19F NMR spectroscopy is extremely sensitive in the stereo-chemical evaluation of MTPA amides of a wide range of aminoacids (as low as 0.05% of the minor isomer detectable).27,28 HPLCanalysis of diastereomeric MTPA amides may provide valuableanalytical information on the enantiomeric composition of chiralprimary and secondary amines.29

Other Compounds. In theory, any chiral compound with areactive functional group can be derivatized with (S)- or (R)-MTPA in order to assess its enantiomeric purity. An example is thederivatization of cyclic carbamates, followed by 1H NMR anal-ysis (eq 1).30 Similarly, axially chiral biaryls bearing amine oralcohol substituents, e.g. (16) and (17), have been analyzed viathe corresponding MPTA derivatives.31

OHN

O

ON

OO

MeO

PhF3C

OMeO

PhF3C(1)

OH

Et3N, DMAPTHF

Ph Ph

NH2OH

OH

(17)(16)

Noncovalent MTPA Derivatives. The enantiomeric purity ofsome chiral amines can be determined by 1H NMR with (S)- or(R)-MTPA as a chiral solvating agent.32,33 The method is partic-ularly useful for chiral tertiary amines that are not amenable toconversion into MTPA amides, e.g. (18) and (19),34 although ithas been utilized for primary and secondary amines as well, e.g.(20).35

Br N

Pr

MeO

(18) (19)

NH

O2N

HNi-Pr

(20)

N

H

H

Determination of Absolute Configuration in Alcohols andAmines. The configuration of chiral alcohols and amines (wherethe heteroatom is attached to the stereocenter) has been correlatedwith the 19F chemical shifts of their MTPA derivatives.36 Themodel is not fully predictive, although the exceptions can oftenbe rationalized. However, 1H NMR spectroscopy of MTPA es-ters and amides has been more widely used in the assignmentof configuration to chiral alcohols and amines.37 Analysis ofthe chemical shifts of the MTPA methoxy peaks, in the pres-ence of shift reagents, allows the correct stereochemical analy-sis of a series of bicyclic alcohols, such as (6).15 The 1H NMRshifts of the hydrogens directly attached to the carbinol carbonsin MTPA esters have also been used to establish the configura-tion of chiral acyclic secondary alcohols.38 Other peaks in theMTPA derivatives have been used in the stereochemical eluci-dation of a series of alcohol natural products.39 Although lesscommonly used, 13C NMR spectroscopy of MTPA derivativeshas been used in the stereochemical study of a large group ofchiral alcohols.40 The stereochemistry of amino acids has alsobeen amenable to study by 1H NMR spectroscopy of their MTPAderivatives.23,41

Preparative Uses of MTPA Derivatives. Resolution ofracemic compounds on a preparative scale is always a challengingendeavor. Conversion of the enantiomeric mixture into a mixtureof diastereomers, each with unique physical properties, makesit possible to separate the components by a variety of physicalmethods, such as fractional recrystallization, distillation, or chro-matography. One of the earliest uses of MTPA was the resolutionof racemic alcohols via the separation of diastereomeric MTPAesters by preparative gas–liquid chromatography, followed byalcohol regeneration with Lithium Aluminum Hydride (eq 2).1

More frequently, diastereomeric MTPA esters have been separatedby high performance liquid chromatography (HPLC), followed byalcohol regeneration either by ester hydrolysis (eq 3)42 or reduc-tion (eq 4).43

OMeO

PhF3C

(2)

OH

CF3

OH

racemic

py, –70 oC

O

MeO

PhF3CO

CF3

CF3

OH*

LiAlH4

HO

OHO

1. (+)-MTPA-Cl2. HPLC3. KOH, H2O, MeOH

HO

OHO

(3)86%

OHOMEM

1. (+)-MTPA-Cl2. HPLC

OMTPOMEM

OMTPOMEM

(4)+

HO

HO HO

separation

A list of General Abbreviations appears on the front Endpapers

(S)-(−)-α-METHOXY-α-(TRIFLUOROMETHYL)PHENYLACETIC ACID 3

This procedure is useful even when the carbinol carbon is notthe asymmetric center of the molecule (eq 5).44

1. (+)-MTPA-Cl DMAP2. HPLC

ca. 10:1 ratio of enantiomers

OO

OHOH

(5)OO

OMTPOH

88%

Far fewer examples of diastereomeric ester separations by frac-tional recrystallization have been described. However, this proce-dure is extremely practical for the resolution of a series of bromo-hydrins (eq 6).45

MTPA-ClBr

OH

Br

OMTP

(6)

Br

OMTP

+

separable by fractionalrecrystallization

py

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Juan C. JaenParke-Davis Pharmaceutical Research, Ann Arbor, MI, USA

Avoid Skin Contact with All Reagents