Absolute configuration of 2-hydroxy-2-(1-naphthyl)propionic acid as determined by the 1H NMR anisotropy method

Article abstract of DOI:10.1016/S0957-4166(99)00451-6

Enantiopure 2-hydroxy-2-(1-naphthyl)propionic acid (+)-2 was prepared by the stereoselective Grignard reaction of 1-naphthylmagnesium bromide with (1R,3R,4S)-menthyl pyruvate 3 or (1R,3R,4S)-8-phenylmenthyl pyruvate 4, and the absolute configuration of acid (+)-2 was unambiguously determined to be S by the ¹H NMR anisotropy method.

Full text of DOI:10.1016/S0957-4166(99)00451-6

Pergamon
Tetrahedron: Asymmetry 10 (1999) 4075–4078
Absolute configuration of 2-hydroxy-2-(1-naphthyl)propionic
acid as determined by the 1H NMR anisotropy method
Akio Ichikawa,a,∗ Shuntaro Hiradate,b Akinori Sugio,c Shunsuke Kuwahara,c
Masataka Watanabe c and Nobuyuki Harada c,∗
aDepartment of Insect Technology, National Institute of Sericultural and Entomological Science, 1-2 Owashi, Tsukuba, Ibaraki
305-8634, Japan
bDepartment of Environmental Biology, National Institute of Agroenvironmental Sciences, Tsukuba, Ibaraki 305-8604, Japan
cInstitute for Chemical Reaction Science, Tohoku University, 2-1-1 Katahira, Aoba, Sendai 980-8577, Japan
Received 18 September 1999; accepted 6 October 1999
Abstract
Enantiopure 2-hydroxy-2-(1-naphthyl)propionic acid (+)-2 was prepared by the stereoselective Grignard re-
action of 1-naphthylmagnesium bromide with (1R,3R,4S)-menthyl pyruvate 3 or (1R,3R,4S)-8-phenylmenthyl
1
pyruvate 4, and the absolute configuration of acid (+)-2 was unambiguously determined to be S by the H NMR
anisotropy method. © 1999 Elsevier Science Ltd. All rights reserved.
2-Methoxy-2-(1-naphthyl)propionic acid 1 (αMNPA) had been designed as a chiral auxiliary useful
for enantioresolution of various alcohols (Fig. 1).1,2 Namely, diastereomeric esters prepared from
enantiopure acid 1 and racemic alcohol were separated by HPLC, and from the diastereomer separated,
enantiopure alcohol was recovered. One of the authors has succeeded in the enantioresolution of (ꢀ)-
citronellol and (ꢀ)-3,7-dimethyl-1-octanol by this method.3 The merit of this chiral auxiliary is that the
α-position of the carboxylic acid group, the stereogenic center of acid 1, is fully substituted and is,
therefore, inert towards racemization. In addition, αMNPA 1 may be useful as a chiral auxiliary4 for
1
determining the absolute stereochemistry of chiral alcohols by H NMR anisotropy methods.5,6 On the
other hand, 2-hydroxy-2-(1-naphthyl)propionic acid 2 (αHNPA) may be another possible chiral auxiliary
1
for the H NMR anisotropy method. In this paper, we report the preparation of enantiopure 2-hydroxy-
1
2-(1-naphthyl)propionic acid (+)-2 and the determination of its absolute configuration by the H NMR
anisotropy method.
(1R,3R,4S)-(−)-Menthyl pyruvate 3 ([α]30 −94.0 (c 1.14, CHCl3)) was prepared by heating a mixture
D
of (1R,3R,4S)-(−)-menthol and pyruvic acid with p-toluenesulfonic acid in toluene. The reaction of 1-
naphthylmagnesium bromide (1.0 equiv.) with (−)-menthyl pyruvate 3 in tetrahydrofuran (THF) at −40°C
yielded a diastereomeric mixture of menthyl 2-hydroxy-2-(1-naphthyl)propionate 4 (65%) together with
∗
Corresponding authors.
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00451-6

4076
A. Ichikawa et al. / Tetrahedron: Asymmetry 10 (1999) 4075–4078
Figure 1. (S)-(+)-2-Methoxy-2-(1-naphthyl)propionic acid 1 and (S)-(+)-2-methoxy-2-(1-naphthyl)propionic acid 2
recovered 3 (16%) (Scheme 1).7 The diastereomeric mixture of 4 was separated by reverse phase
HPLC (CAPCELL PAK C18 AG120/5 µm, MeOH:H2O, 85:15) giving the first-eluted ester (−)-4a
(39%, [α]29 −84.0 (c 0.48, CHCl3)) and the second-eluted (+)-4b (26%, [α]30 +7.6 (c 0.32, CHCl3)).
D
D
The configuration and conformation of esters (−)-4a and (+)-4b were determined as follows: the two-
dimensional (2D) NMR spectra including COSY, CH-COSY, HOHAHA, HMBC, and NOESY were
measured leading to the full assignment of all signals as shown in Fig. 2. The hydroxyl proton peaks
of esters (−)-4a and (+)-4b appeared as sharp singlet peaks at δ 3.67 and 3.78 ppm, respectively,
indicating intramolecular hydrogen bonding with the ester carbonyl oxygen. The hydrogen bonding was
also supported by the lower shift of the carbonyl stretching bands in IR spectra; both hydroxyl esters (−)-
4a and (+)-4b exhibit C_O bands in CHCl3 at 1713 and 1716 cm−1, respectively: in KBr, both exhibit at
1720 cm−1. On the other hand, (1R,3R,4S)-menthyl 2-methoxy-2-(1-naphthyl)propionates prepared from
(−)-menthol and 2-methoxy-2-(1-naphthyl)propionic acid (ꢀ)-1 exhibit the corresponding bands at 1750
cm−1 in KBr. The rotational conformation around the C10–C20 single bond is thus fixed in esters (−)-4a
and (+)-4b as illustrated in Fig. 2.
Scheme 1. Preparation of (S)-(+)-αHNPA and related compounds
1
In the H NMR spectra, the 2-axial proton of diastereomer (−)-4a appears at δ 0.51 ppm, while that
of (+)-4b appears at δ 0.87 ppm (Fig. 2). Namely, a high field shift of 0.36 ppm is observed in (−)-4a,
because the 2-axial proton is above the naphthalene plane and subject to the diamagnetic ring current
effect. In addition, the NOESY data shown in Fig. 2 indicate that the methyl group of the acid moiety is
close to the isopropyl group at the 4-position in (−)-4a. On the other hand, protons of the isopropyl group
of (+)-4b appear at a higher field than those of (−)-4a: for (+)-4b, 8-CH3, δ 0.13 and 0.26 ppm, 8-H, δ
0.46 ppm; for (−)-4a, 8-CH3, δ 0.67 and 0.77 ppm, 8-H, δ 1.65 ppm. Therefore, the naphthyl group of
(+)-4b is close to the isopropyl group at the 4-position. From these results, the absolute configurations
of the acid moieties in esters (−)-4a and (+)-4b are unambiguously determined as S and R, respectively.
The stereochemical assignment obtained is consistent with that derived from Prelog’s rule.7

A. Ichikawa et al. / Tetrahedron: Asymmetry 10 (1999) 4075–4078
4077
Figure 2. The NMR chemical shift and NOE data of esters (−)-4a and (+)-4b
Alkaline hydrolysis of ester (−)-4a gave enantiopure 2-hydroxy-2-(1-naphthyl)propionic acid (S)-(+)-
2 (98%, [α]29 +40 (c 0.21, CHCl3)) (Scheme 1). Methylation of hydroxyl and carboxylic acid groups
D
of (+)-2 with sodium hydride in dimethyl formamide (DMF) and iodomethane yielded (S)-(+)-methyl
2-methoxy-2-(1-naphthyl)propionate 5 (93%, [α]30 +31 (c 0.22, CHCl3)), which was identical to the
D
authentic sample of 5 ([α]25 +34.8 (c 2.62, CHCl3)).7 The S absolute configuration of the authentic
D
methyl ester (+)-5 had been established by X-ray crystallography and chemical correlation.8
The Grignard reaction of 1-naphthylmagnesium bromide (1.0 equiv.) was similarly applied to
(1R,3R,4S)-(−)-8-phenylmenthyl pyruvate 6 ([α]31 −5.2 (c 1.04, CHCl3)) at −78°C in THF yielding
D
a diastereomeric mixture of esters 7 (33%), which was separated by reverse phase HPLC (CAPCELL
PAK C18 AG120/5 µm, CH3CN:H2O, 4:1) giving the first-eluted major ester (−)-7a (30%, [α]30 −51.0
D
(c 0.13, CHCl3)) and the second-eluted minor ester 7b (3%), while the starting material 6 was also
recovered (32%) (Scheme 2). As in the case of esters 4a and 4b, most proton NMR peaks of the major
product (−)-7a were assigned by 2D NMR spectra. The hydroxyl proton captured in the intramolecular
hydrogen bonding appeared as a sharp singlet at δ 3.25 ppm. The IR band at 1715 cm−1 in CHCl3 also
confirmed the intramolecular hydrogen bonding. Since the 2β axial proton of the major ester appeared at
δ 0.42 ppm, the absolute configuration of the major product was determined as S, which agrees with the
reaction mechanism proposed by Whitesell et al.9 Hydrolysis of ester (−)-7a with NaOMe in MeOH
afforded α-hydroxy acid (+)-2 (38%, [α]31 +35 (c 0.02, CHCl3)), which was identical to (S)-(+)-2
D
derived from ester (−)-4a.
Scheme 2. Preparation of (S)-(+)-αHNPA using ester (−)-6
As discussed above, the absolute configuration of α-hydroxy acid (+)-2 was unambiguously determi-
1
ned to be S by the H NMR anisotropy method, which was in agreement with the determination using

4078
A. Ichikawa et al. / Tetrahedron: Asymmetry 10 (1999) 4075–4078
X-ray crystallography.8 In light of the present results, the absolute configuration of acid 1 previously
reported by one of the authors3 should be revised.
The data of chemical shift difference (∆δ=δ(R)−δ(S)) between (R)-(+)-4b and (S)-(−)-4a are listed in
Fig. 3; based on these anisotropy data and the known absolute configuration of (−)-menthol, the absolute
configuration of α-hydroxy acid 2 was determined. These ∆δ values are much larger than those reported
for (1R,3R,4S)-menthyl α-methoxy-2-naphthylacetates.5 Therefore, if each enantiomer of α-hydroxy
acid 2 can be used for esterification of chiral alcohols, this acid would become a chiral auxiliary powerful
enough to determine the absolute configuration of alcohols by the 1H NMR anisotropy data.
Figure 3. The ∆δ values for (1R,3R,4S)-(−)-menthol using 2-hydroxy-2-(1-naphthyl)propionic acid:
∆δ=δ((R)-(+)-4b)−δ((S)-(−)-4a) (600 MHz, CDCl3)
Further studies along this methodology are now in progress.
Acknowledgements
The authors are grateful to Dr. K. Tanaka of the Fruit Tree Research Station for measurements of 400
MHz NMR spectra. This work was supported in part by grants from the Ministry of Education, Science,
Sports and Culture, Japan (Scientific Research (A) No. 07408032, (B) No. 10554035, (B) No. 11480159,
Priority Areas (A) No. 10146205, (B) No. 10208202, and International Joint No. 10045022 to N.H.;
Exploratory Research No. 09874129 to M.W.) and the Ciba-Geigy Foundation (Japan) for the Promotion
of Science (to N.H.).
References
1. Goto, J.; Hasegawa, M.; Nakamura, S.; Shimada, K.; Nambara, T. Chem. Pharm. Bull. 1977, 25, 847.
2. Goto, J.; Hasegawa, M.; Nakamura, S.; Shimada, K.; Nambara, T. J. Chromatogr. 1978, 152, 413.
3. Ichikawa, A. Chirality 1999, 11, 70.
4. Harada, N. To be published.
5. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113, 4092. Kusumi, T.; Takahashi, H.; Ping, X.;
Fukushima, T.; Asakawa, Y.; Hashimoto, T.; Kan, Y.; Inouye, Y. Tetrahedron Lett. 1994, 35, 4397. Kusumi, T.; Takahashi,
H.; Hashimoto, T.; Kan, Y.; Asakawa, Y. Chem. Lett. 1994, 1093.
6. Trost, B. M.; Belletire, J. L.; Godleski, S.; McDougal, P. G.; Balkovec, J. M.; Baldwin, J. J.; Christy, M. E.; Ponticello, G.
S.; Varga, S. L.; Springer, J. P. J. Org. Chem. 1986, 51, 2370.
7. Prelog, V. Helv. Chim. Acta 1953, 36, 308.
8. Kuwahara, S.; Fujita, K.; Watanabe, M.; Harada, N.; Ishida, T. Enantiomer 1999, 4, 141.
9. Whitesell, J. K.; Bhattacharya, A.; Henke, K. Chem. Commun. 1982, 988.