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

Article abstract of DOI:10.1016/S0957-4166(00)00233-0

2-Methoxy-2-(2-naphthyl)propionic acid 1 and 2-hydroxy-2-(2-naphthyl)propionic acid 2 were prepared by the Grignard reaction of 2-naphthylmagnesium bromide with (1R,2S,5R)-(-)-menthyl pyruvate. The absolute configurations of (+)-1 and (+)-2 were determined to be S by the ¹H NMR anisotropy method. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00233-0

Tetrahedron: Asymmetry 11 (2000) 2669±2675
Absolute con®guration of 2-methoxy-2-(2-naphthyl)propionic
1
acid as determined by the H NMR anisotropy method
Akio Ichikawa,a,* Syuntaro Hiradate,b Akinori Sugio,c Shunsuke Kuwahara,c
Masataka Watanabec and Nobuyuki Haradac,*
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, 3-1-1 Kannondai,
Tsukuba, Ibaraki 305-8604, Japan
cInstitute for Chemical Reaction Science, Tohoku University, 2-1-1 Katahira, Aoba, Sendai 980-8577, Japan
Received 21 March 2000; accepted 8 June 2000
Abstract
2-Methoxy-2-(2-naphthyl)propionic acid 1 and 2-hydroxy-2-(2-naphthyl)propionic acid 2 were prepared
by the Grignard reaction of 2-naphthylmagnesium bromide with (1R,2S,5R)-(^)-menthyl pyruvate. The
1
absolute con®gurations of (+)-1 and (+)-2 were determined to be S by the H NMR anisotropy method.
# 2000 Elsevier Science Ltd. All rights reserved.
1. Introduction
The importance of single-enantiomer drugs is increasing today. Novel enantiomeric resolution
reagents are useful for `racemic switch' applications and structure determination of biologically
active natural products. In 1989, Terunuma and Nohira stated the requirements for an enantio-
meric resolution reagent:1 (A) high enantiomeric purity; (B) chemically stable stereogenic center;
(C) equal reactivity for both enantiomers; and (D) suitable separation ability. Considering these
requirements, 2-methoxy-2-(2-naphthyl)propionic acid (MbNP acid, 1) and 2-methoxy-2-(1-
naphthyl)propionic acid (MaNP, 3) were designed as enantiomeric resolution reagents that pos-
sess high resolution characteristics and a stable stereogenic center (Fig. 1). Goto et al. synthesized
both enantiomers of 1 and 3, and used them for the enantiomeric resolution of methyl esters of
aminoic acids.2,3 One of the authors used 3 for the enantiomeric resolution of monoterpene
1
alcohols.4 The absolute con®guration of 3 was determined by X-ray crystallography5 and the H
NMR anisotropy method,6 along with that of 2-hydroxy-2-(1-naphthyl)propionic acid (HaNP
acid, 4).6 This paper reports the absolute con®guration of 2-methoxy-2-(2-naphthyl)propionic
acid (MbNP, 1) and 2-hydroxy-2-(2-naphthyl)propionic acid (HbNP acid, 2) as determined by the
1H NMR anisotropy acid method (Fig. 1).
* Corresponding authors. E-mail: ichikawa@a€rc.go.jp
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00233-0

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A. Ichikawa et al. / Tetrahedron: Asymmetry 11 (2000) 2669±2675
Figure 1. The absolute con®gurations of the naphthylpropionic acid derivatives 1, 2, 3 and 4
2. Results and discussion
In 1953, Prelog reported that the Grignard addition to (1R,2S,5R)-(^)-menthyl pyruvate (^)-5
prefers the Si-face.7 This stereoselectivity is rationalized by `Prelog's rule', which has been cited as
the basic rule for the 1,4-asymmetric induction reaction. The s-trans conformation7 had been
adopted to explain the stereoselectivity of the Grignard reaction preferring the Si face of (^)-5.
Recent studies on the reduction of pyruvate esters have proposed the s-cis chelate models8,9 to
explain the Si-face selectivity (Scheme 1). The Grignard reaction of 2-naphthylmagnesium bro-
mide with (^)-5 gave two diastereomers of (1R,2S,5R)-menthyl 2-hydroxy-2-(2-naphthyl)propio-
nate 6a (15%) and 6b (10%) together with recovered (^)-5 (63%) (Scheme 1). The separation was
achieved by preparative reversed phase HPLC (Capcellpak C18 AG120/5 mm, acetonitrile:water,
1
9:1), giving the ®rst and second eluted esters, (^)-6a (95% d.e. (determined by the H NMR
30
D
30
D
spectrum), ‰ꢀŠ =^52 (c 0.75, ethanol)) and (^)-6b (97% d.e., ‰ꢀŠ =^85 (c 0.28, ethanol)). The
1
hydroxyl protons of (^)-6a and (^)-6b in the H NMR spectra (3.96 ppm and 4.01 ppm, respec-
tively) and their absorption maxima in the IR spectra (1715 cm^1) reveal intramolecular hydrogen
Scheme 1. Preparation of MbNP and related compounds

A. Ichikawa et al. / Tetrahedron: Asymmetry 11 (2000) 2669±2675
2671
1
bonds. The H NMR chemical shifts of the Grignard adducts (^)-6a and (^)-6b are assigned in
Fig. 2 by the two-dimensional NMR spectra (COSY, CH-COSY, HMBC, HOHAHA, and
NOESY). The Áꢁ (=ꢁR±ꢁS) values are shown in Fig. 3. The distribution of the Áꢁ values shows
that the absolute con®guration of HbNP in the major diastereomer, (^)-6a, is the S-con®guration
(Fig. 2). This stereoselectivity coincides with the early observation by Prelog (vide ante). The
alkaline hydrolysis of the major Grignard adduct (^)-6a gave (S)-(+)-2-hydroxy-2-(2-naphthyl)-
propionic acid ((S)-(+)-2, ‰ꢀŠ2D9=+38 (c 0.07, ethanol)).
Figure 2. The 1H NMR chemical shifts of Grignard adducts (^)-6a and (^)-6b and their methyl ethers (^)-7a and (^)-7b
(600 MHz, CDCl3)
Figure 3. The 1H NMR Áꢁ (=ꢁ(R)±ꢁ(S)) values of MbNP, HbNP, MaNP, and HaNP esters of (1R,2S,5R)-(^)-menthol
(600 or 400 MHz, CDCl3)

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A. Ichikawa et al. / Tetrahedron: Asymmetry 11 (2000) 2669±2675
The hydroxyl groups of the major Grignard adduct (^)-6a were methylated by NaH and CH3I
in DMF, giving (^)-7a (‰ꢀŠ2D9=^49 (c 0.29, ethanol)). The minor Grignard adduct (^)-6b gave
30
1
(^)-7b (‰ꢀŠD =^89 (c 0.17, ethanol)) by the same methylation reaction. The H NMR signals of
(^)-7a and (^)-7b were assigned from two-dimensional NMR spectra (COSY, CH-COSY,
HMBC, HOHAHA, and NOESY) as shown in Fig. 2. There was no systematic rule for the dis-
tribution of Áꢁ (=ꢁR±ꢁS) values obtained from the two methyl ethers (^)-7a and (^)-7b. Their 1H
NMR chemical shifts were close: ((^)-7a) C2b proton; 0.95 ppm, isopropyl group; 0.56 ppm, 0.64
ppm, 1.48 ppm ((^)-7b) C2b proton; 0.91 ppm, isopropyl group; 0.52 ppm, 0.59 ppm, 1.39 ppm.
These chemical shifts show that the methyl ethers (^)-7a and (^)-7b are the conformational
mixtures for the C(ˆO)±Ca bonds. The Áꢁ values obtained for (S)- and (R)-MbNP esters of
(1R,2S,5R)-(^)-menthol suggest that MbNP acid is not suitable for Mosher±Trost-type analyses10,11
of the absolute con®gurations of secondary alcohols. Compounds (^)-7a and (^)-7b can be sepa-
rated by reversed phase HPLC analysis (Capcellpak C18 AG120 /5 mm, methanol:water, 8:1) and
normal phase HPLC analysis (Silica SG80, hexane:ethanol, 199:1). The alkaline hydrolysis of (^)-
7a gave 2-methoxy-2-(2-naphthyl)propionic acid (S)-(+)-1, ‰ꢀŠ3D0=+47 (c 0.14, ethanol).
Fig. 3 shows the Áꢁ (=ꢁR±ꢁS) values of the MbNP, HbNP, MaNP, and HaNP esters of
1
(1R,2S,5R)-(^)-menthol in the H NMR spectra. The Áꢁ values of the HaNP esters and the
HbNP esters are positive at the C5 and C6 positions of the menthyl group, and negative at C2,
C3, and the isopropyl group. These phenomena show that the methine protons at C1 position of the
menthyl group, the carbonyl group, and the hydroxyl group are located in the same plane in the
HbNP esters and the HaNP esters (see Fig. 2). The Áꢁ values of the MaNP esters are very close
to those of the HaNP esters, suggesting that the MaNP esters' conformations are similar to those
of the HaNP esters, in spite of the absence of hydrogen bonds. As already discussed, the MbNP
esters of (1R,2S,5R)-(^)-menthol are the conformational mixtures.
In this paper, the absolute con®gurations of (+)-2-methoxy-2-(2-naphthyl)propionic acid (+)-1
and (+)-2-hydroxy-2-(2-naphthyl)propionic acid (+)-2 were determined to be S. In addition, the
conformations of the HbNP esters of (1R,2S,5R)-(^)-menthol (^)-6a and (^)-6b were determined
1
by the H NMR anisotropy method. MbNP acid will contribute to the exploratory research of
agrochemicals and medicines, along with MaNP acid.
3. Experimental
3.1. General
The NMR spectra were obtained using either a JEOL JNM a 600 or a Bruker ARX 400, in
CDCl3 with tetramethylsilane (TMS) as the internal standard. The IR spectra were recorded on a
Perkin±Elmer 1760X. The MS data were obtained with a JEOL JMS SX102A. 3-Nitrobenzyl
alcohol was used as the matrix for FAB-MS measurement. The optical rotations were determined
on a JASCO DIP1000 spectropolarimeter. Kieselgel 60 (Merck) and Wakogel C-200 (Wako) were
used for the open column chromatography.
3.2. Grignard reaction
A solution of (^)-5 (430 mg, 1.9 mmol) in 2 ml of THF in a dried ¯ask, under nitrogen, was
cooled to ^78ꢀC and treated with 2-naphthylmagnesium bromide (1.9 mmol in 2 ml of THF,

A. Ichikawa et al. / Tetrahedron: Asymmetry 11 (2000) 2669±2675
2673
uncorrected). After 6 h, the reaction mixture was quenched by addition of 2.5 ml of 5% HCl,
worked up with AcOEt and water, and dried (Na2SO4). The solution was evaporated, and the residue
was puri®ed by open column chromatography to give the mixture of (^)-6a and (^)-6b (15 and 10%,
respectively). The adducts (^)-6a and (^)-6b were separated by preparative reversed phase HPLC.
3.2.1. (1R,2S,5R)-Menthyl (S)-2-hydroxy-2-(2-naphthyl)propionate (^)-6a
1H NMR (600 MHz): 8.04 (1H, br s), 7.84 (1H, m), 7.82 (1H, m), 7.81 (1H, d, J=9 Hz), 7.64
(1H, dd, J=9, 1.5 Hz), 7.47 (2H, m), 4.77 (1H, td, J=11, 4 Hz), 3.96 (1H, s), 1.86 (3H, s), 1.83
(2H, m), 1.67 (1H, m), 1.65 (1H, m), 1.44 (1H, tt, J=11, 4 Hz), 1.44 (1H, m), 1.04 (1H, qd, J=11,
4 Hz), 0.88 (1H, m), 0.86 (3H, d, J=6.5 Hz), 0.83 (1H, m), 0.82 (3H, d, J=6.5 Hz), 0.74 (3H, d,
0
00
00
00
13
J=6.5 Hz); C NMR (151 MHz): 175.2 (s, C1 ), 140.3 (s, C2 ), 133.0 (s, C8 a), 132.8 (s, C4 a),
128.3 (d, C800), 127.9* (d, C500), 127.5* (d, C400), 126.1 (d, C600), 126.1 (d, C700), 124.0 (d, C100),
123.5 (d, C300), 76.8 (d, C1), 75.9 (s, C20), 47.0 (d, C2), 40.2 (t, C6), 34.1 (t, C4), 31.3 (d, C5), 26.5
(q, C30), 26.1 (d, C7), 23.2 (t, C3), 21.8 (q, C10), 20.7 (q, C9), 16.0 (q, C8), *: exchangable; IR
(CHCl3 solution in NaCl cell): 3525 cm^1, 2950, 2920, 2870, 1715, 1455, 1375, 1260, 1245, 1180,
1140, 955, 905, 815; MS (FAB) m/z: 377 ([M+Na]+1, 12%), 337 (12), 224 (5), 221 (7), 199 (88), 171
(100), 155 (16), 153 (16), 139 (20); ‰ꢀŠ3D0=^52 (c 0.75, ethanol).
3.2.2. (1R,2S,5R)-Menthyl (R)-2-hydroxy-2-(2-naphthyl)propionate (^)-6b
1H NMR (600 MHz): 8.01 (1H, br s), 7.83 (1H, m), 7.81 (1H, m), 7.80 (1H, d, J=9 Hz), 7.64
(1H, dd, J=9, 1.5 Hz), 7.47 (2H, m), 4.68 (1H, td, J=12, 3 Hz), 4.01 (1H, s), 2.02 (1H, br d,
J=12 Hz), 1.88 (3H, s), 1.65 (1H, br d, J=12 Hz), 1.58 (1H, dq, J=12, 3 Hz), 1.48 (1H, tt, J=12,
4 Hz), 1.30 (1H, tt, J=12, 3 Hz), 1.23 (1H, m), 1.02 (1H, q, J=12 Hz), 0.96 (1H, qd, J=12, 4
Hz), 0.91 (3H, d, J=6.5 Hz), 0.83 (1H, qd, J=12, 3 Hz), 0.55 (3H, d, J=6.5 Hz), 0.42 (3H, d,
J=6.5 Hz); C NMR (151 MHz): 175.5 (s, C10), 140.1 (s, 200), 133.0 (s, C800a), 132.8 (s, C400a),
13
128.2 (d, C800), 127.8* (d, C500), 127.5* (d, C400), 126.1 (d, C600), 126.1 (d, C700), 124.3 (d, C100),
123.6 (d, C300), 76.8 (d, C1), 75.7 (s, C20), 47.1 (d, C2), 40.6 (t, C6), 34.1 (t, C4), 31.4 (d, C5), 26.1
(q, C30), 25.6 (d, C7), 23.0 (t, C3), 21.9 (q, C10), 20.5 (q, C9), 15.6 (q, C8), *: exchangable; IR
(CHCl3, NaCl): 3565 cm^1, 2960, 2930, 2870, 1715, 1540, 1510, 1450, 1375, 1260, 1245, 1180,
1140, 955, 815; MS (FAB) m/z: 377 ([M+Na]+1, 42%), 354 (8), 337 (25), 221 (10), 216 (6), 199
(80), 171 (100), 139 (19); ‰ꢀŠ3D0=^85 (c 0.28, ethanol).
3.3. Methylation of (^)-6a; preparation of (^)-7a
NaH (60% in oil,188 mg) was washed with THF (0.5 mlÂ3) and suspended in DMF (1 ml).
The suspension was added to (^)-6a (9 mg) and an excess of CH3I (0.5 ml) followed. The mixture
was stirred for 60 min, then CH3I was removed by nitrogen. The mixture was diluted with ice-
water (5 ml), and extracted with AcOEt (0.5 mlÂ3). The solution was washed with brine and
dried over Na2SO4. After concentration in vacuo, the residual DMF solution was subjected to
SiO2 column chromatography to a€ord (^)-7a. The yield was 60%.
3.3.1. (1R,2S,5R)-Menthyl (S)-2-methoxy-2-(2-naphthyl)propionate (^)-7a
1H NMR (600 MHz): 7.95 (1H, br s), 7.83 (1H, m), 7.81 (2H, m), 7.57 (1H, dd, J=9, 1 Hz),
7.47 (2H, m), 4.73 (1H, td, J=12, 4 Hz), 3.35 (3H, s), 1.95 (1H, br d, J=12 Hz), 1.86 (3H, s), 1.63
(1H, br d, J=12 Hz), 1.59 (1H, dq, J=12, 3 Hz), 1.48 (1H, m), 1.46 (1H, m), 1.33 (1H, tt, J=12,
3 Hz), 0.98 (1H, m), 0.95 (1H, q, J=12 Hz), 0.86 (3H, d, J=6.5 Hz), 0.80 (1H, qd, J=12, 3 Hz),

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A. Ichikawa et al. / Tetrahedron: Asymmetry 11 (2000) 2669±2675
0.6040 (3H, d, J=6.050 Hz), 0.56 (3H, d, J=6.5 Hz); 13C NMR (151 MHz): 172.5 (s, C10), 138.7 (s,
C2 ), 133.0 (s, C8 a), 132.8 (s, C400a), 128.3 (d, C800), 127.9* (d, C500), 127.5* (d, C400), 126.1 (d,
C600), 126.1 (d, C700), 124.8 (d, C100), 123.7 (d, C300), 82.0 (s, C20), 75.5 (d, C1), 52.1 (q, -OCH3),
46.9 (d, C2), 40.5 (t, C6), 34.2 (t, C4), 31.4 (d, C5), 25.6 (d, C7), 23.0 (t, C3), 22.2 (q, C30), 22.0 (q,
C10), 20.6 (q, C9), 15.7 (q, C8), *: exchangable; IR (CHCl3, NaCl): 3000 cm^1, 2960, 2930, 2870,
1725, 1450, 1370, 1265, 1185, 1135, 955, 820; MS (EI): 368 (M+, 3%), 186 (13), 185 (100), 155
(18), 127 (2); ‰ꢀŠD29=^49 (c 0.29, ethanol).
3.4. Methylation of (^)-6b; preparation of (^)-7b
Compound (^)-7b was prepared from (^)-6b (12 mg) by the method used for the preparation of
(^)-7a. The yield was 60%.
3.4.1. (1R,2S,5R)-Menthyl (R)-2-methoxy-2-(2-naphthyl)propionate (^)-7b
1H NMR (600 MHz): 7.93 (1H, br s), 7.83 (1H, m), 7.82 (2H, m), 7.58 (1H, br d, J=9 Hz), 7.48
(2H, m), 4.68 (1H, td, J=12, 4 Hz), 3.32 (3H, s), 1.96 (1H, br d, J=12 Hz), 1.88 (3H, s), 1.63 (1H,
br d, J=12 Hz), 1.58 (1H, dq, J=12, 3 Hz), 1.46 (1H, m), 1.39 (1H, m), 1.27 (1H, tt, J=12, 3
Hz), 0.96 (1H, m), 0.91 (1H, m), 0.86 (3H, d, J=6.5 Hz), 0.79 (1H, qd, J=12, 3 Hz), 0.59 (3H, d,
J=6.5 Hz), 0.52 (3H, d, J=6.5 Hz); 13C NMR (151 MHz): 172.6 (s, C10), 138.3 (s, C200), 133.1 (s,
C800a), 132.9 (s, C400a), 128.2 (d, C800), 127.9* (d, C500), 127.5* (d, C400), 126.2** (d, C600), 126.1**
(d, C700), 125.3 (d, C100), 124.1 (d, C300), 81.7 (s, C20), 75.5 (d, C1), 52.0 (q, -OCH3), 46.9 (d, C2),
40.5 (t, C6), 34.2 (t, C4), 31.4 (d, C5), 25.6 (d, C7), 23.0 (t, C3), 22.0 (q, C10), 21.7 (q, C30), 20.5
(q, C9), 15.6 (q, C8), * and **: exchangable; IR (CHCl3, NaCl): 3000 cm^1, 2960, 2930, 2870,
1725, 1450, 1370, 1265, 1185, 1140, 960, 825; MS (EI): 368 (M+, 3%), 186 (13), 185 (100), 155
(18), 127 (2); ‰ꢀŠD30=^89 (c 0.17, ethanol).
3.5. Alkaline hydrolysis of (^)-6a; preparation of (S)-(+)-2-hydroxy-2-(2-naphthyl)propionic
acid (+)-2
The solution of sodium methoxide (250 mg) in aqueous methanol (2 ml) was added to (^)-6a
(16 mg), and the mixture was heated to re¯ux for 6 h. After elimination of the solvent at reduced
pressure, the residue was diluted with water, and washed with AcOEt (3 mlÂ3). The aqueous
solution was acidi®ed by 5% HCl and extracted with AcOEt (5 mlÂ3). The organic layer was
washed with brine, dried (Na2SO4), and evaporated under reduced pressure. Filtration through a
short silica gel column a€orded (+)-2. The yield was 99%. ‰ꢀŠ2D9=+38 (c 0.07, ethanol).
3.6. Alkaline hydrolysis of (^)-7a; preparation of (S)-(+)-2-methoxy-2-(2-naphthyl)propionic
acid (+)-1
Compound (+)-1 was prepared from (^)-7b (12 mg) by the method used for the preparation of
(+)-2 in 89% yield. ‰ꢀŠ3D0=+47 (c 0.14, ethanol).
Acknowledgements
A.I. would like to thank Dr. T. Nishide, Dr. H. Kato, and Dr. Y. Magoshi for their support.

A. Ichikawa et al. / Tetrahedron: Asymmetry 11 (2000) 2669±2675
2675
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