2-Methoxy-2-(1-naphthyl)propionic acid, a powerful chiral auxiliary for enantioresolution of alcohols and determination of their absolute configurations by the 1H NMR anisotropy method

Article abstract of DOI:10.1016/S0957-4166(00)00053-7

Racemic 2-methoxy-2-(1-naphthyl)propionic acid (1, MαNP acid) was enantioresolved as its esters derived from various chiral alcohols. For example, a diastereomeric mixture of esters prepared from (±)-1 and (1R,3R,4S)-(-)-menthol was easily separated by HP

Full text of DOI:10.1016/S0957-4166(00)00053-7

Tetrahedron: Asymmetry 11 (2000) 1249±1253
2-Methoxy-2-(1-naphthyl)propionic acid, a powerful
chiral auxiliary for enantioresolution of alcohols and
determination of their absolute con®gurations by the
1H NMR anisotropy method
Nobuyuki Harada,a,* Masataka Watanabe,a Shunsuke Kuwahara,a Akinori Sugio,a
Yusuke Kasaia and Akio Ichikawab
aInstitute for Chemical Reaction Science, Tohoku University, 2-1-1 Katahira, Aoba, Sendai 980-8577, Japan
bDepartment of Insect Technology, National Institute of Sericultural and Entomological Science, 1-2 Owashi, Tsukuba,
Ibaraki 305-8634, Japan
Received 5 January 2000; accepted 3 February 2000
Abstract
Racemic 2-methoxy-2-(1-naphthyl)propionic acid (1, MaNP acid) was enantioresolved as its esters
derived from various chiral alcohols. For example, a diastereomeric mixture of esters prepared from (þ)-1
and (1R,3R,4S)-(^)-menthol was easily separated by HPLC on silica gel yielding esters (^)-2a and (^)-2b,
1
the separation factor a=1.83 being unusually large. The H NMR chemical shift di€erences, Ád=d(R)±
d(S), between diastereomers 2a and 2b, are much larger than those of conventional chiral auxiliaries, e.g.
Mosher's MTPA and Trost's MPA acids. This acid 1 is therefore very powerful for determining the abso-
lute con®guration of chiral alcohols by the 1H NMR anisotropy method. Solvolysis of the separated esters
yielded enantiopure acids (S)-(+)-1 and (R)-(^)-1, which are useful for enantioresolution of racemic alcohols.
# 2000 Elsevier Science Ltd. All rights reserved.
Almost two decades ago, (^)-2-methoxy-2-(1-naphthyl)propionic acid (1, MaNP acid) was
designed as a chiral auxiliary useful for enantioresolution of amines derived from amino acids,
although the absolute con®guration of (^)-1 remained undetermined.1 Recently, we have
unambiguously determined the S absolute con®guration of acid (+)-1 by X-ray crystallography
and chemical correlation (Fig. 1)2 and also reported the S absolute con®guration of (+)-2-hydroxy-
2-(1-naphthyl)propionic acid (HaNP acid) as determined by the 1H NMR anisotropy method.3 In
those studies, we predicted that the acid 1 would be a promising chiral auxiliary useful for
1
determining the absolute con®guration of alcohols by the H NMR anisotropy method. In this
paper, we report the application of this acid 1 to con®gurational studies of chiral alcohols,
* Corresponding author. E-mail: n-harada@icrs.tohoku.ac.jp
0957-4166/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(00)00053-7

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N. Harada et al. / Tetrahedron: Asymmetry 11 (2000) 1249±1253
emphasizing that the acid 1 is very powerful for both enantioresolution of racemic alcohols and
determination of absolute con®gurations of chiral alcohols including natural products.
Figure 1. (R)-(^)- and (S)-(+)-2-Methoxy-2-(1-naphthyl)propionic acids 1
Racemic acid 1 was routinely prepared according to a slight modi®cation of the scheme
previously reported.2 The acid 1 was condensed with (1R,3R,4S)-(^)-menthol yielding a mixture of
diastereomeric esters 2a and 2b; a mixture of (þ)-1, (^)-menthol (1.2 equiv.), 4-dimethylamino-
pyridine (DMAP, 0.5 equiv.), and 1,3-dicyclohexylcarbodiimide (DCC, 1.7 equiv.) in CH2Cl2 was
stirred at room temperature overnight, yielding a diastereomeric mixture of esters (Scheme 1).
The mixture was easily separated by HPLC on silica gel (hexane:EtOAc 15:1): separation factor
23
a=1.83; resolution factor Rs=2.26. The ®rst-eluted ester (^)-2a (49%, ‰ꢀŠ ^62.5 (c 1.346,
D
23
D
CHCl3)) and the second one (^)-2b (46%, ‰ꢀŠ ^35.8 (c 1.305, CHCl3)) were obtained.
Scheme 1. (a) (^)-Menthol, DCC, DMAP, CH2Cl2, (^)-2a, 49%; (^)-2b, 46%; (b) NaOCH3/CH3OH and then H2O,
87±94%; (c) CH2N2/diethyl ether, 99%
Fig. 2(a) shows HPLC separation of two diastereomers 2a and 2b. It was quite surprising to
®nd such clean separation of two diastereomeric organic compounds composed of only carbon,
hydrogen, and oxygen atoms. Trost's chiral acid,4 a-methoxyphenylacetic acid (MPA acid), also
brings similar separation of diastereomers. For example, diastereomeric esters synthesized from
(^)-menthol and (þ)-MPA acid were separated by HPLC on silica gel using hexane:EtOAc 20:1:
a=1.21, Rs=1.19. However, its separation and resolution factors are smaller than those of esters
2a and 2b. On the other hand, Mosher's a-methoxy-a-tri¯uoromethylphenylacetic acid (MTPA
acid)5 is unsuitable for such diastereomeric separation: a=1.28, Rs=0.82 (hexane:EtOAc 50:1).
The strong power of this acid 1 for diastereomer separation is also demonstrated by the case of
2-butanol. Commercially available (S)-(+)-2-butanol was esteri®ed with racemic acid 1; the
obtained mixture of diastereomeric esters 3a and 3b was almost base-line separated by HPLC on
silica gel (hexane:EtOAc 20:1) as shown in Fig. 2(b): a=1.15, Rs=1.18. The acid 1 thus has a
great ability to recognize the small di€erence between methyl and ethyl groups. It is well known

N. Harada et al. / Tetrahedron: Asymmetry 11 (2000) 1249±1253
1251
Figure 2. (a) Separation of diastereomers (^)-2a and (^)-2b by HPLC on silica gel (hexane:EtOAc 15:1); (b) separation
of esters 3a and 3b (hexane:EtOAc 20:1)
that chiral discrimination between methyl and ethyl groups is the most dicult in enantioresolution
and also even in asymmetric reactions. Now we have obtained a facile method to get enantiopure
2-butanol. In fact, using enantiopure acid 1, racemic 2-butanol was enantioresolved.
To recover the enantiopure carboxylic acid, puri®ed ester (^)-2a was treated with NaOCH3 in
26
D
methanol and then with water, yielding (S)-(+)-1: ‰ꢀŠ +67.4 (c 1.39, CHCl3); methyl ester of
24
D
(S)-(+)-1, ‰ꢀŠ +37.8 (c 1.205, CHCl3), CD (EtOH) lext 280.0 nm (Á" ^0.51), 226.0 (+9.1). The
27
absolute con®guration of acid (+)-1 was assigned as S by comparison with the authentic sample
{Ref. 2, methyl ester of (S)-(+)-1, ‰ꢀŠ +34.8 (c 2.62, CHCl3)}. In a similar way, solvolysis of
D
23
D
23
D
ester (^)-2b a€orded acid (R)-(^)-1: ‰ꢀŠ ^67.4 (c 1.305, CHCl3); methyl ester of (R)-(^)-1, ‰ꢀŠ
^39.4 (c 1.12, CHCl3), CD (EtOH) lext 280.8 nm (Á" +0.58), 226.4 (^8.9).
1
Another great merit of this acid 1 is the strong anisotropy e€ect in the H NMR spectra of its
esters. The chemical shift data of diastereomeric esters (S)-(^)-2a and (R)-(^)-2b are listed in Fig.
3(a) together with the Ád values (ppm): Ád=d(R)±d(S). The protons of the iso-propyl group are
largely up-®eld shifted by the diamagnetic anisotropy e€ect of naphthalene moiety in ester 2b,
while the protons at the 2-position are up-®eld shifted in ester 2a. Since the absolute con®gur-
ations of the MaNP acid and (^)-menthol are already known as discussed above, those anisotropy
data lead to the preferred conformations of esters 2a and 2b as illustrated in Fig. 3(a).
These preferred conformations of esters 2a and 2b are supported by the following fact:
the chemical shift data of 2a and 2b and hence their Ád values are very similar to those of the
corresponding HaNP esters, in which the rotational conformations are ®xed by the intramolecular
hydrogen bonding between free hydroxyl and ester carbonyl groups3 as shown in Fig. 3(b).
Therefore it is concluded that MaNP esters 2a and 2b take conformations similar to HaNP esters.
1
It is well known that the H NMR anisotropy methods using MTPA, MbNA (2-methoxy-2-(2-
naphthyl)acetic acid), and MPA acids are very useful for determining the absolute con®gurations
of chiral alcohols including natural products.4±6 The Ád values of 2a and 2b observed here are
much larger than those of the corresponding MTPA, MbNA, and MPA esters (Fig. 3c±e).
Therefore, as a chiral auxiliary for the 1H NMR anisotropy method, MaNP acid 1 is superior to
MTPA, MbNA, and MPA acids. Another merit of acid 1 is the point that the a-position of
carboxylic acid, a stereogenic center, is fully substituted and therefore it is inert toward racemization.
Although MbNA acid has been proposed as a chiral auxiliary giving large Ád values (Fig. 3d),5,6
it has a demerit to racemize.

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N. Harada et al. / Tetrahedron: Asymmetry 11 (2000) 1249±1253
Figure 3. (a) The NMR chemical shift data of esters (^)-2a and (^)-2b and Ád values (ppm); (b) the corresponding
chemical shift data and Ád values using HaNP group (Ref. 3); (c) Ád values of MTPA ester (Ref. 5); (d) MbNA ester
(Ref. 5); (e) MPA ester
Figure 4. The Ád values (=d(R)±d(S), ppm) of MaNP ester of chiral alcohols (400 or 600 MHz, CDCl3)

N. Harada et al. / Tetrahedron: Asymmetry 11 (2000) 1249±1253
1253
1
The H NMR anisotropy method using MaNP acid was applied to other chiral alcohols, and
the Ád values obtained are listed in Fig. 4. As seen in these data, the Ád values strongly correlates
with the absolute con®guration of chiral alcohols. The most striking characteristic of our method
is the fact that, in all cases in Fig. 4, racemic acid (þ)-1 could be used, because diastereomeric
esters formed were easily separated by HPLC on silica gel. To determine the absolute con®gur-
ation of the acid part, a small portion of esters separated was converted to MaNP acid methyl
ester, the CD spectrum of which was measured. The negative CD Cotton e€ect at 280 nm corre-
1
sponds to the S con®guration of the acid part, the positive one to the R con®guration. The H
NMR Ád values, combined with CD data, thus lead to the determination of the absolute
con®guration of the alcohol part. In cases where diastereomeric esters are inseparable by HPLC,
enantiopure acids (R)-1 and (S)-1 are used to form diastereomeric esters as usual. Extension of
this strategy and further application to various alcohols are now in progress.
Acknowledgements
This work was supported in part by grants from the Ministry of Education, Science, Sports,
and Culture, Japan (scienti®c 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 Novartis Foundation (Japan) for the Pro-
motion of Science (to N.H.).
References
1. Goto, J.; Hasegawa, M.; Nakamura, S.; Shimada, K.; Nambara, T. Chem. Pharm. Bull. 1977, 25, 847. Goto, J.;
Hasegawa, M.; Nakamura, S.; Shimada, K.; Nambara, T. J. Chromatogr. 1978, 152, 413.
2. Kuwahara, S.; Fujita, K.; Watanabe, M.; Harada, N.; Ishida, T. Enantiomer 1999, 4, 141.
3. Ichikawa, A.; Hiradate, S.; Sugio, A.; Kuwahara, S.; Watanabe, M.; Harada, N. Tetrahedron: Asymmetry 1999,
10, 4075.
4. 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.
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. Seco, J. M.; Latypov, Sh. K.; Quinoa, E.; Riguera, R. Tetrahedron Lett. 1994, 35, 2921. Latypov, Sh. K.; Seco,
J. M.; Quinoa, E.; Riguera, R. J. Org. Chem. 1995, 60, 504.