A crystallization-induced asymmetric transformation to prepare (R)-4- chlorophenylalanine methyl ester

Article abstract of DOI:10.1016/S0957-4166(98)00343-7

A second order asymmetric transformation of racemic 4- chlorophenylalanine methyl ester was achieved via salt formation with (2S,3S)-(-)-tartaric acid in the presence of salicylaldehyde to afford the desired (R)-enantiomer of 4-chlorophenylalanine methyl ester in good yield and high enantiomeric purity.

Full text of DOI:10.1016/S0957-4166(98)00343-7

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 3247–3250
A crystallization-induced asymmetric transformation to prepare
(R)-4-chlorophenylalanine methyl ester
Cynthia A. Maryanoff, Lorraine Scott, Rekha D. Shah and Frank J. Villani Jr. ∗
The R. W. Johnson Pharmaceutical Research Institute, New Product Research, Department of Chemical Development,
Spring House, PA 19477-0776, USA
Received 10 July 1998; accepted 12 August 1998
Abstract
A second order asymmetric transformation of racemic 4-chlorophenylalanine methyl ester was achieved via salt
formation with (2S,3S)-(−)-tartaric acid in the presence of salicylaldehyde to afford the desired (R)-enantiomer of
4-chlorophenylalanine methyl ester in good yield and high enantiomeric purity. © 1998 Elsevier Science Ltd. All
rights reserved.
1. Introduction
p-Chlorophenylalanine is of considerable pharmacological interest, particularly in regards to its ability
to inhibit serotonin formation in the tissue of laboratory animals.1–3 The (R)- and (S)-enantiomers are
used in synthesizing biologically active compounds that often achieve important antagonistic effects.4–7
Over recent years, numerous syntheses of 4-chlorophenylalanine and its derivatives have been re-
ported. These diverse approaches exemplify the advances in asymmetric synthesis prompted by the need
for single enantiomers of unnatural and unusual amino acids.8 In particular, 4-chlorophenylalanine was
synthesized by O’Donnell using enantiomeric phase transfer catalyzed alkylation of a glycine imine.9
Another well-executed approach is the asymmetric reduction of the appropriate dehydroamino acid
derivative.10 When a source of the racemic compound is readily available, as is the case for 4-
chlorophenylalanine, enzyme-based kinetic resolution is an attractive alternative for generation of gram
to multi-gram quantities of the optically active amino acid derivative. Indeed, workers have used both
carboxypeptidase A mediated N-deacylation11,12 and α-chymotrypsin mediated hydrolysis of esters13,14
to gain access to both enantiomers of 4-chlorophenylalanine. A disadvantage of resolutions, of course, is
the maximal yield of 50% unless a suitable method for racemization of the undesired enantiomer is also
developed.
∗
Corresponding author. E-mail: fvillani@prius.jnj.com
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00343-7

3248
C. A. Maryanoff et al. / Tetrahedron: Asymmetry 9 (1998) 3247–3250
Faced with the need to synthesize a pseudo peptide target containing the R-enantiomer of 4-chloro-
phenylalanine as one ‘residue’, and given the ready synthetic availability of 4-chlorophenylalanine
methyl ester, we elected to examine a classical resolution through a diastereomeric salt as a first approach.
Then, with a suitable classical resolution identified, a means for recycling (through racemization)
the undesired (S)-enantiomer was developed. Eventually, (R)-4-chlorophenylalanine methyl ester was
synthesized via a one-pot resolution–racemization sequence, to give what is termed a crystallization-
induced asymmetric transformation.15,16
2. Results and discussion
Resolution of (RS)-4-chlorophenylalanine methyl ester (free base) using (−)-tartaric acid afforded the
diastereomeric (R)-4-chlorophenylalanine methyl ester (−)-tartrate salt (the ratio of free base:tartaric
acid in the salt was 2:1) in 32% yield and in 94.0% ee. Although diastereomeric resolution provides
a route to (R)-4-chlorophenylalanine methyl ester, the inherent loss of the undesired enantiomer is
a significant drawback. This limitation was overcome by incorporating an in situ racemization with
a classical resolution. Thus reacting (RS)-4-chlorophenylalanine methyl ester with one equivalent of
(−)-tartaric acid and a catalytic amount of salicylaldehyde in refluxing methanol effected resolution,
providing the (R)-amine methyl ester (−)-tartrate (2:1) in 68% yield (98% ee).
Scheme 1.
The mechanism of racemization of amino acids and derivatives under the influence of aldehydes is
generally known to involve formation of an imine (Schiff base)17,18 followed by a reversible 1,2-proton
shift, generating a 1,3-dipolar species as shown in Scheme 1. The presence of (−)-tartaric acid provides

C. A. Maryanoff et al. / Tetrahedron: Asymmetry 9 (1998) 3247–3250
3249
a crystalline salt that is essentially removed from the system by virtue of its insolubility, driving the
equilibrium.
3. Conclusion
In conclusion, a crystallization-induced asymmetric transformation of racemic 4-chlorophenylalanine
methyl ester was developed to provide a convenient and practical route to enantiomerically enriched
(R)-4-chlorophenylalanine methyl ester via a (−)-tartaric acid mediated classical resolution and a
salicylaldehyde catalyzed racemization.
4. Experimental
4.1. General
Racemic 4-chlorophenylalanine methyl ester hydrochloride was prepared from 4-chlorobenzyl chlo-
ride using the acetamidomalonate route reported by Porter et al.12 followed by conversion to the methyl
ester with thionyl chloride/methanol13 (Scheme 2).
Scheme 2.
Enantiomeric purity of 4-chlorophenylalanine methyl ester was determined as the N-trifluoroacetyl
derivative by GC using a Hewlett Packard 5890 gas chromatograph fitted with a Chirasil-L-Val
(Chrompack) column 25 m×0.25 mm; helium carrier gas at 140 kPa; temperature isothermal @ 160°C;
injection 1 µl of a 2 mg/mL EtOAc solution; temperature 200°C; FID detection at 230°C; retention time:
(R)-enantiomer 3.90 min, (S)-enantiomer 4.09 min.
Preparation of N-trifluoroacetyl-4-chlorophenylalanine methyl ester (for analysis by enantiomeric
GC). To a mixture of 1 mL of diethyl ether and 1 mL of 50% aqueous K2CO3 was added 3 mg of
4-chlorophenylalanine methyl ester tartrate. After shaking and separating the layers, the organic layer
was evaporated in a stream of nitrogen and 1 mL of trifluoroacetic anhydride was added. Stirring was
continued for 10 min, followed by evaporation in a stream of nitrogen. The residue was dissolved in
EtOAc (1.5 mL).
4.2. Classical resolution of (RS)-4-chlorophenylalanine methyl ester from methanol
(RS)-4-Chlorophenylalanine methyl ester hydrochloride (10.0 g, 40.0 mmol) was dissolved in water
(30 mL), to which was added K2CO3 (10.0 g, 72.0 mmol). The solution was extracted with diethyl
ether (2×50 mL). The organic layer was separated and dried with K2CO3, then the solvent was removed

3250
C. A. Maryanoff et al. / Tetrahedron: Asymmetry 9 (1998) 3247–3250
in vacuo. The resulting free base residue (7.28 g, 34.1 mmol) was dissolved in methanol (50 mL) and a
solution of (2S,3S)-(−)-tartaric acid (5.11 g, 34.0 mmol) in warm methanol (ca. 50°C, 50 mL) was added.
The mixture was cooled to ambient temperature, filtered and washed with methanol (2×30 mL), then air
dried to give 3.94 g (32%) of (R)-4-chlorophenylalanine methyl ester (−)-tartrate (2:1), enantiomeric
purity 94%.
4.3. Crystallization-induced asymmetric transformation of (RS)-4-chlorophenylalanine methyl ester
(RS)-4-Chlorophenylalanine methyl ester (20.0 g, 96.0 mmol, prepared from the hydrochloride as
described above) was combined with (2S,3S)-(−)-tartaric acid (7.20 g, 48.0 mmol), salicylaldehyde (1.17
g, 10 mmol) and methanol (300 mL). The mixture was refluxed overnight and allowed to cool to ambient
temperature. The resulting solid was filtered, washed with methanol (2×30 mL) and air dried to give
18.82 g (68%) of (R)-4-chlorophenylalanine methyl ester (−)-tartrate (2:1), enantiomeric purity 98%.
4.4. (R)-4-Chlorophenylalanine methyl ester
To a solution of potassium carbonate (3.0 g, 10 mmol) in distilled water was added (R)-4-
chlorophenylalanine methyl ester (−)-tartrate (2:1), enantiomeric purity 96% (prepared as described
above) followed by the addition of dichloroethane (25 mL). After complete solution the layers were
separated and the aqueous layer was extracted with dichloroethane (3×25 mL). The combined organic
layer was dried over potassium carbonate, filtered and concentrated under reduced pressure to give 2.14
g (96%) of the free base, (R)-4-chlorophenylalanine methyl ester, as a colorless oil.
References
1. Datla, K. P.; Curzon, G. Neuropharmacology 1996, 35, 315–320.
2. Dryden, S.; Frankish, H. M.; Wang, Q.; Williams, G. Brain Res. 1996, 724, 232–237.
3. Koe, B. K.; Weissman, A. J. Pharmacol. Exp. Ther. 1966, 154, 499–516.
4. Haviv, F.; Fitzpatrick, T. D.; Nichols, C. J.; Bush, E. N.; Diaz, G.; Bammert, G.; Nguyen, A. T.; Johnson, E. S.; Knittle, J.;
Greer, J. J. Med. Chem. 1994, 37, 701–705.
5. Rivier, J. E.; Porter, J.; Rivier, C. L.; Perrin, M.; Corrigan, A.; Hook, W. A.; Siraganian, R. P.; Vale, W. W. J. Med. Chem.
1986, 29, 1846–1851.
6. Salvadori, S.; Bianchi, C.; Lazarus, L. H.; Scaranari, V.; Attila, M.; Tomatis, R. J. Med. Chem. 1992, 35, 4651–4657.
7. Theobald, P.; Porter, J.; Rivier, C.; Corrigan, A.; William, H.; Siraganian, R.; Perrin, M.; Vale, W.; Rivier, J. J. Med. Chem.
1991, 34, 2395–2402.
8. O’Donnell, M. J. Tetrahedron. In Tetrahedron Symposia-in-Print, No. 33: alpha-Amino Acid Synthesis; Pergamon: Oxford,
1988; Vol. 44, pp. 5253–5614.
9. O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989, 111, 2353–2355.
10. Krause, H. W.; Kreuzfeld, H.-J.; Schmidt, U.; Dboler, C.; Michalik, M.; Taudien, S.; Fisher, C. Chirality 1996, 8, 173–188.
11. Day, A. R.; Freer, R. J. J. Labelled Compd. Radiopharm. 1978, 14, 381–391.
12. Porter, J.; Dydert, J.; Rivier, J. Int. J. Peptide Protein Res. 1987, 30, 13–21.
13. Brunner, H.; Hankofer, P.; Holzinger, U.; Treittinger, B.; Schonenberger, H. Eur. J. Med. Chem. 1990, 25, 35–44.
14. Cabezas, M. J.; Campo, C. D.; Llama, E.; Sinisterra, J. V.; Guisan, J. M. J. Mol. Catal. 1990, 62, 353–367.
15. Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; John Wiley: New York, 1994.
16. Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates, and Resolutions; John Wiley: New York, 1981.
17. Grigg, R.; Gunaratne, H. Q. N. Tetrahedron Lett. 1983, 24, 4457–4460.
18. Yamada, S.; Hongo, C.; Yoshioka, R.; Chibata, I. J. Org. Chem. 1983, 48, 843–846.