Dynamic kinetic resolution of racemic N-phthalyl amino acids using (S)-α-methylpantolactone as the chiral auxiliary

Article abstract of DOI:10.1016/S0957-4166(00)00017-3

A dynamic kinetic resolution of racemic N-phthalyl amino acids by stereoselective esterification was examined using (S)-α-methylpantolactone as the chiral auxiliary. The reaction of various racemic N-phthalyl amino acids with this chiral alcohol in the presence of both DCC and DMAP afforded predominantly the (S,S)-esters in nearly quantitative yield. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00017-3

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 737–741
Dynamic kinetic resolution of racemic N-phthalyl amino acids
using (S)-α-methylpantolactone as the chiral auxiliary
Monique Calmes,∗ Christèle Glot, Thibaut Michel, Marc Rolland and Jean Martinez
Laboratoire des Aminoacides, Peptides et Protéines, UMR-CNRS 5810-Universités Montpellier I et II, UM II,
Place E. Bataillon, 34095 Montpellier cedex 5, France
Received 3 December 1999; accepted 10 January 2000
Abstract
A dynamic kinetic resolution of racemic N-phthalyl amino acids by stereoselective esterification was examined
using (S)-α-methylpantolactone as the chiral auxiliary. The reaction of various racemic N-phthalyl amino acids
with this chiral alcohol in the presence of both DCC and DMAP afforded predominantly the (S,S)-esters in nearly
quantitative yield. © 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
Kinetic resolution of racemic mixtures is an effective tool for the preparation of enantiomerically
enriched compounds,1 but in this reaction the expected product can be obtained at most in 50% yield.
Procedures which allow in situ epimerisation of the substrate prior to the reaction, viz dynamic kinetic
resolution,2 have the advantage of theoretically quantitative conversion of the starting material into a
single stereoisomer.
Dynamic kinetic resolution processes have been used previously for the synthesis of optically active
α-amino acids or esters via stereoselective amination of the corresponding α-bromo compounds.3
Moreover, the direct dynamic kinetic resolution of racemic α-amino acid derivatives has also been
reported4 but essentially only for enzymatically catalyzed reactions.
Yus et al.5 have described the kinetic resolution of racemic carboxylic acids by using the dicyclo-
hexylcarbodiimide (DCC) esterification method with optically active alcohols. With one equivalent
each of DCC and 4-dimethylaminopyridine (DMAP), this reaction applied to N-protected amino acids
should allow a dynamic kinetic resolution process due to the propensity of the corresponding acyl
(4-dimethylamino)pyridinium salt to racemize6 (Scheme 1). Therefore, we decided to examine this
∗
Corresponding author. Fax: 04 67 14 48 66; e-mail: monique@ampir1.univ-montp2.fr
0957-4166/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00017-3
tetasy 3240

738
M. Calmes et al. / Tetrahedron: Asymmetry 11 (2000) 737–741
esterification reaction starting from various racemic N-phthaloyl amino acids and a chiral alcohol. The
use of the phthalimido protecting group has the advantage of being easily introduced and removed.
Scheme 1. Dynamic kinetic resolution of N-phthalyl amino acids using DCC/DMAP and a chiral alcohol
2. Results and discussion
To obtain a dynamic kinetic resolution under the experimental conditions used, with for example
formation of (αS)-3 compound, 2 should easily racemize and both krac/ka and ka/kb values should
be sufficiently high (Scheme 1). Therefore we first verified that a total racemization of different
enantiomerically pure N-phthalyl amino acids takes place rapidly in the presence of one equivalent each
of DCC and DMAP. Initially, we decided to use (R)-pantolactone as the chiral alcohol since it is both an
efficient auxiliary3b,7 and commercially available. We tested the esterification reaction of various racemic
N-phthalyl amino acids using this chiral alcohol and DCC/DMAP at different temperatures. Under these
conditions the corresponding esters were formed quantitatively after 15 hours but with no significant
diastereoselectivity. It was reasonable to speculate that the absence of stereoselectivity obtained by using
(R)-pantolactone might result from too small a difference between krac, ka and kb. These results are close
to those obtained by Koh et al.8 and Camps et al.9 in the case of esterification of α-bromo carboxylic
acids with the same alcohol.
We then investigated the use of a tertiary instead of a secondary alcohol with the aim of modifying the
values of the reaction constants thus allowing a dynamic kinetic resolution process. To conserve the pan-
tolactone structure, we decided to synthesize and to test the enantiomerically pure α-methyl substituted
derivative (S)-9: (S)-3,4,4-trimethyl-3-hydroxy-γ-butyrolactone or (S)-α-methyl pantolactone.
To prepare (S)-9, pantolactone 4 was first converted into the corresponding benzyl ether as described
recently10 (Scheme 2). Then, alkylation of 5 was achieved in good yield in THF after deprotonation at
low temperature (−40°C) by using lithium diisopropylamine as base and DMPU as co-solvent. The
benzyl ether was easily cleaved by hydrogenolysis affording racemic 7 which was then transform-
ed, using DCC/DMAP and (1S)-camphanic acid chloride, into the diastereoisomeric mixture of 8.
Enantiomerically pure (3S,60S)-8 was isolated by fractional crystallization of the mixture of the two
diastereoisomers 8,11 and (S)-9 was then obtained by simple saponification. The structure of (3S,60S)-8

M. Calmes et al. / Tetrahedron: Asymmetry 11 (2000) 737–741
739
was ascertained from the spectral data,12 and its stereochemistry from the X-ray diffraction analysis (Fig.
1).13 The stereochemistry of (3S,60S)-8 allowed us to establish that of compound (S)-9.14
Scheme 2. Synthesis of (S)-9
Fig. 1. ORTEP drawing of ester (3S,60S)-8
We first studied the dynamic kinetic resolution of racemic N-phthalyl alanine using (S)-9 and one
equivalent of DCC and DMAP under various conditions of solvent, temperature and reaction time (Table
1).15
A dynamic kinetic resolution was observed in each case since a non-equivalent mixture of the two
diastereoisomers was obtained in nearly quantitative yield. Therefore, under the experimental conditions
used, the racemization of the N-phthalyl alanine was sufficiently rapid with respect to the esterification
rate. Moreover, the reaction rates of (R)-2 and (S)-2 with (S)-α-methyl pantolactone were substantially
different. This was confirmed by similar results obtained starting from (RS), (R) or (S)-N-phthalyl alanine.
The best results were obtained after 15 hours at room temperature (Table 1, entries 3 and 6). The
diastereoselectivity was affected by the solvent. Toluene gives better results than dichloromethane but

740
M. Calmes et al. / Tetrahedron: Asymmetry 11 (2000) 737–741
Table 1
Dynamic kinetic resolution of racemic N-phthalyl alanine
in this case, the yields are slighty lower probably due to a lower solubility of the substrate. Moreover, a
noticeable decrease in diastereoselectivity was obtained when the reaction mixture was allowed to stand
for several days at room temperature, probably due to the prolonged exposure of the substrate to the basic
DMAP (Table 1, entries 4 and 5). When the reaction was carried out at 0°C an important decrease in yield
was observed, whatever the solvent with no increase in stereoselectivity (Table 1, entries 7 and 8). On
the other hand, after only 30 minutes in refluxing dichloromethane, the same stereoselectivity as at room
temperature was observed. However, the reaction took place in only 50% yield, and prolonged reaction
times provided lower stereoselectivity (Table 1, entries 9, 10 and 11).
Reaction of (S)-9 at room temperature with other racemic N-phthalyl amino acids was then studied. In
each case we observed after one night, as previously, a dynamic kinetic resolution process affording in
high yield the corresponding optically active esters (Table 2). Variation of the R side chain of the amino
acid was possible without significant influence on yields or stereoselectivity. As in the case of N-phthalyl
alanine, toluene afforded slightly higher diastereoselectivity except when the less soluble phenylalanine
compound was used, in which case essentially no reaction took place.
Table 2
Dynamic kinetic resolution of various racemic N-phthalyl amino acids
Hydrolysis of 3 under acidic conditions7c gave the corresponding (S)-amino acids in good yield. The
(S) configuration was assigned by the specific rotation values and by HPLC analysis after derivatization

M. Calmes et al. / Tetrahedron: Asymmetry 11 (2000) 737–741
741
with Marfey’s reagent16 indicating that the (S,R) ester was mainly formed during this dynamic kinetic
resolution process.
In conclusion, a new example of dynamic kinetic resolution using (S)-α-methyl pantolactone as the
chiral auxiliary has been developed. This method provides an easy access to optically active α-amino
acids and can be applied to other α-substituted acids.
References
1. Kagan, H. B.; Fiaud, J. C. Topics in Stereochem. 1988, 18, 249.
2. Ward, R. S. Tetrahedron: Asymmetry 1995, 6, 1475.
3. (a) Kubota, H.; Kubo, A.; Takahashi, M.; Shimizu, R.; Da-te, T.; Okamura, K.; Nunami, K. I. J. Org. Chem. 1995, 60, 6776;
Kubo, A.; Kubota, H.; Takahashi, M.; Nunami, K. I. Tetrahedron Lett. 1996, 37, 4957; (b) Koh, K.; Ben, R. N.; Durst, T.
Tetrahedron Lett. 1993, 34, 4473; (c) Camps, P.; Pérez, F.; Soldevilla, N.; Borrego, M. A. Tetrahedron: Asymmetry 1999,
10, 493; (d) Ben, R. N.; Durst, T. J. Org. Chem. 1999, 64, 7700.
4. Sano, K.; Mitsugi, K. Agric. Biol. Chem. 1978, 42, 2315; Bevinakatti, H. S.; Newadkar, R. V.; Banerji, A. A. J. Chem. Soc.,
Chem. Commun. 1990, 1091; Drauz, K.; Kottenhahn, M.; Makryaleas, K.; Klenk, H.; Bernd, M. Angew. Chem., Int. Ed.
Engl. 1991, 30, 712; Gu, R. L.; Lee, I. S.; Sih, C. J. Tetrahedron Lett. 1992, 33, 1953; Liang, J.; Ruble, J. C.; Fu, G. C.
J. Org. Chem. 1998, 63, 3154; Wegman, M. A.; Hacking, M. A. P.; Rops, J.; Pereira, P.; van Rantwijk, F.; Sheldon, R. A.
Tetrahedron: Asymmetry 1999, 10, 1739.
5. Chinchilla, R.; Najera, C.; Yus, M. Tetrahedron: Asymmetry 1991, 2, 101; Mazon, A.; Najera, C.; Yus, M. Tetrahedron:
Asymmetry 1992, 3, 1455.
6. Atherton, E.; Benoiton, N. L.; Brown, E.; Sheppard, R. C.; Williams, B. J. J. Chem. Soc., Chem. Commun. 1981, 336;
Benoiton, N. L.; Chen, F. M. J. Chem. Soc., Chem. Commun. 1981, 1225; Neises, B.; Andries, T.; Steglich, W. J. Chem.
Soc., Chem. Commun. 1982, 1132; Gamet, J. P.; Jacquier, R.; Verducci, J. Tetrahedron 1984, 40, 1995.
7. (a) Larsen, R. D.; Corley, E. G.; Davis, P.; Reider, P. J.; Grabowski, E. J. J. Am. Chem. Soc. 1998, 111, 7650; (b) Durst,
T.; Koh, K. Tetrahedron Lett. 1992, 33, 6799; (c) Calmès, M.; Daunis, J.; Mai, N. Tetrahedron: Asymmetry 1997, 8, 1641;
Calmès, M.; Daunis, J.; Mai, N. Tetrahedron 1997, 53, 13719.
8. Koh, K.; Benand, R. N.; Durst, T. Tetrahedron Lett. 1994, 35, 375.
9. Camps, P.; Perez, F.; Soldevilla, N. Tetrahedron: Asymmetry 1997, 8, 1877.
10. Dueno, E. E.; Chu, F.; Kim, S.-I.; Jung, K. W. Tetrahedron Lett. 1999, 40, 1843.
11. All new described products were isolated by chromatography on silica gel, or by recrystallization, and satisfactory analytical
data have been obtained.
12. Fractional crystallization of (3SR,60S)-8 from a mixture of CH2Cl2 and hexane gave diastereomerically pure (3S,60S)-
8. (3S,60S)-8 has the following physical data: mp 186°C; [α]D=−11.5 (c=2 in CH2Cl2); HPLC (Chiraspher (Merck),
1
hexane:isopropanol: 97:3): rt 19.9 min; H NMR (CDCl3) δ=1.03 (s, 3H, 30-CH3), 1.14 (s, 3H, 4-CH3), 1.15 (s, 6H, 70-
CH3), 1.25 (s, 3H, 4-CH3), 1.65 (s, 3H, 3-CH3), 1.71 (m, 1H, 50-HCH), 1.96 (m, 1H, 50-HCH), 2.05 (m, 1H, 40-HCH), 2.45
(m, 1H, 40-HCH), 3.96 (d, J=8.8 Hz, 1H, 5-HCH), 4.14 (d, J=8.8 Hz, 1H, 5-HCH); 13C NMR (CDCl3) δ=10.0 (C7 (CH3)),
0
0
0
0
0
0
17.0 (C3(CH3)), 17.2 (C3 (CH3), C7 (CH3)), 21.2 (C4(CH3)), 22.3 (C4(CH3)), 29.3 (C5 ), 31.0 (C4 ), 43.2 (C4), 54.8 (C7 ),
0
0
0
55.2 (C3 ), 77.6 (C5 ), 85.3 (C3), 91.2 (C6 ), 166.2 (CO), 173.0 (CO), 178.3 (CO).
13. The diffraction data were collected on an Enraf–Nonius KappaCCD diffractometer using graphite-monochromate Mo-Kα
radiation and the φ-scan technique up to θ=25.41. Crystal data of (3S,60S)-8: Molecular formula C17H24O6, molecular
weight=324, triclinic, space group P1, cell constants: a=6.5157(3) Å, b=10.8843(6) Å, c=12.5148(7) Å, V=833.1(1) Å3,
Z=2, Dc=1.29 mg m−3, T=298 K, final R=0.032, final Rw=0.045. Details of the crystal structure determination have been
deposited at the Cambridge Crystallographic Data Centre (deposition number CCDC137179).
14. (S)-9 has the following physical data: mp 129°C; [α]D20=+30.5 (c=2.7 in D2O); 1H NMR (CDCl3) δ=1.08 (s, 3H, 4-CH3),
1.14 (s, 3H, 4-CH3), 1.34 (s, 3H, 3-CH3), 3.08 (br, 1H, OH), 3.92 (d, J=8.7 Hz, 1H, 5-HCH), 4.08 (d, J=8.7 Hz, 1H, 5-HCH);
13C NMR (CDCl3) δ=19.6 (C3(CH3)), 20.4 (C4(CH3)), 20.5 (C4(CH3)), 42.5 (C4), 76.6 (C3), 77.7 (C5), 180.6 (CO).
15. The diastereoisomeric composition was determined for the crude product from the NMR spectra (CDCl3) by integration
of the α-methyl signal of the pantolactonyl moiety of the pair of diastereoisomers and/or by HPLC (Chiraspher column
(Merck)).
16. Marfey, P. Carlsberg Res. Commun. 1984, 49, 591.