(2-naphthyl)glycolic acid: A tailored resolving agent for p-substituted 1-arylethylamines

Article abstract of DOI:10.1016/S0957-4166(98)00242-0

A tailored resolving agent for p-substituted l-arylethylamines, which was designed on the basis of a criterion derived from our crystal-structure study, namely that the racemate and the resolving agent should have similar molecular lengths, is described. The designed enantiopure (2- naphthyl)glycolie acid (2-NGA) showed excellent resolving ability for a wide variety of p-substituted l-arylethylamines.

Full text of DOI:10.1016/S0957-4166(98)00242-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 9 (1998) 2219–2222
(2-Naphthyl)glycolic acid: a tailored resolving agent for p-
substituted 1-arylethylamines
Kazushi Kinbara, Yoshiko Harada and Kazuhiko Saigo ∗
Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, Hongo, Bunkyo-ku,
Tokyo 113-8656, Japan
Received 27 May 1998; accepted 15 June 1998
Abstract
A tailored resolving agent for p-substituted 1-arylethylamines, which was designed on the basis of a criterion
derived from our crystal-structure study, namely that the racemate and the resolving agent should have similar
molecular lengths, is described. The designed enantiopure (2-naphthyl)glycolic acid (2-NGA) showed excellent
resolving ability for a wide variety of p-substituted 1-arylethylamines. © 1998 Elsevier Science Ltd. All rights
reserved.
Resolution via diastereomeric salt formation is one of the most practical methods for obtaining
enantiopure compounds.1 Despite its importance, the method, however, requires a lot of trial-and-error to
choose a suitable resolving agent, since the chiral discrimination mechanism during resolution is not clear
at present. In order to clarify the chiral discrimination mechanism during resolution via diastereomeric
salt formation and to present criteria for the selection of a suitable resolving agent, we recently carried out
a systematic study on the resolution of 1-arylalkylamines with enantiopure mandelic acid.2,3 As a result,
it was found that the resolution efficiency depended on the position of the substituent of the amines to
a considerable extent, and a further detailed study on the basis of the crystallographic analyses of the
diastereomeric salts revealed that complementarity in molecular length between the resolving agent and
the target racemates was essentially the most important factor for a successful resolution. On the basis
of these results, we established a criterion for designing a resolving agent for 1-arylethylamines, namely
that the racemate and the resolving agent (α-hydroxy acid) should have similar molecular lengths.
Our previous study showed that even though mandelic acid could efficiently resolve non- and o-
substituted 1-arylethylamines, the resolution efficiency for p-substituted 1-arylethylamines was poor.2
The resolution efficiency for these amines was significantly improved by using p-substituted mandelic
acids as resolving agents. The results were, however, not sufficient for practical resolution;2 it is
considered that the flexibility of the substituent on the p-position of the aromatic ring of the resolving
agents makes its molecular length ambiguous, diminishing the resolution efficiency. We then designed a
∗
Corresponding author. Fax: 81-3-5802-3348; e-mail: saigo@chiral.t.u-tokyo.ac.jp
0957-4166/98/$ - see front matter © 1998 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(98)00242-0

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K. Kinbara et al. / Tetrahedron: Asymmetry 9 (1998) 2219–2222
novel resolving agent, (2-naphthyl)glycolic acid (2-NGA), which has a rigid skeleton and an appropriate
molecular length according to the above-mentioned criterion.
Although some procedures have been reported for the preparation of optically active 2-NGA, they
could not be applied to the synthesis of enantiopure 2-NGA on a practical scale.4 We then tried to develop
a new method for the practical-scale preparation of enantiopure 2-NGA. At first, the synthesis of racemic
2-NGA was examined. As a result, the synthesis of racemic 2-NGA could be accomplished, following the
procedure reported for the synthesis of mandelic acid (Scheme 1);5 racemic 2-NGA could be prepared
in 48% overall yield from commercially available 2-acetonaphthone. For a large-scale preparation this
method was found to be more convenient than other known procedures.6
Scheme 1.
Next, the resolution of racemic 2-NGA by enantiopure amines was studied. As a result, enantiopure 2-
NGA could be obtained using (R)- or (S)-1-phenylethylamine (PEA) as a resolving agent (Scheme 2). Re-
crystallization of the 2-NGA·(R)-PEA salt from aqueous ethanol four times gave pure (R)-2-NGA·(R)-
PEA salt in 28% overall yield. Treatment of the (R)-2-NGA·(R)-PEA salt with hydrochloric acid afforded
crystalline crude (R)-2-NGA, which was further purified by recrystallization from chloroform/ethanol to
give enantiopure (R)-2-NGA in 25% overall yield.7 Moreover, enantiopure (S)-2-NGA could also be
obtained by repeated recrystallization (three times) of the salt of (S)-enriched 2-NGA, recovered from
the filtrate of the first recrystallization of the (R)-2-NGA·(R)-PEA salt, with (S)-PEA.7
Scheme 2.
The resolution of various p-substituted 1-arylethylamines was performed using (R)- or (S)-2-NGA as
a resolving agent. The results are summarized in Table 1. In order to make crystallization conditions as
similar as possible and to avoid the problem of polymorphs, crystallization was performed only once
from a protic solvent at a constant temperature (30°C). The amount of the solvent was adjusted to control
the yield of the precipitated salt as close as possible within the range 50–80%.
As can be seen from Table 1, 2-NGA has excellent resolving ability over a range of amines,
although the crystallization conditions were not optimized at all. In the case of the resolution of 1-
(p-chlorophenyl)ethylamine (entry 6), which is a valuable intermediate for pharmaceuticals,8 an addi-
tional recrystallization afforded diastereomerically pure (S)-2-NGA·(S)-1-(p-chlorophenyl)ethylamine
salt (67% overall yield). Since the absolute configurations of the amines in the less-soluble salts per-

K. Kinbara et al. / Tetrahedron: Asymmetry 9 (1998) 2219–2222
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Table 1
Optical resolution of p-substituted 1-arylethylamines by 2-NGAa
fectly correlated with that of 2-NGA used, it is strongly implied that the resolution of p-substituted 1-
arylethylamines occurs via a common chiral discrimination mechanism. Noteworthy is that even amines
having a largely bulky substituent in the p-position could be efficiently resolved by 2-NGA (entry 5).
In addition, even when a group capable of strong hydrogen bond formation such as a nitro group was
present on the phenyl group of the amine, the resolution efficiency remained very high (entry 8). Since a
slight change in the molecular structure of a racemate usually exerts a dramatic effect on the resolution
efficiency,2 this high resolving ability of 2-NGA for such a wide variety of amines is remarkable.
As is described, we have succeeded in the design of a tailored resolving agent, 2-NGA, which
shows excellent resolving ability for a variety of p-substituted 1-arylethylamines. This result indicates
that systematic study on the correlation between the crystal structures of diastereomeric salts and their
resolution efficiencies would provide direction for the design of new resolving agents.
Acknowledgements
The present work was supported by Grants-in-Aid for Scientific Research (No. 09450330) from the
Ministry of Education, Science, Sports and Culture of Japan and by Nagase Science and Technology
Foundation.

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References
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7. Enantiomeric excesses were determined by HPLC on Daicel CHIRALCEL OJ-R. (a) (R)-2-NGA: m.p.: 162.0–163.5°C;
IR (KBr): ν=3350–3250, 1690, 1400, 1280, 830 cm−1; 1H NMR (300 MHz, [D6]DMSO): δ=5.21 (s, 1H, CH), 6.00 (br
s, 1H, OH), 7.50–7.58, 7.88–7.94 (m, 4H, C10H7); 13C NMR (300 MHz, [D6]DMSO): δ=72.80 (CH), 125.08, 125.64,
126,27, 126.49, 127.78, 127.96, 128.08, 132.78, 132.93, 138.05, (C10H7), 174.30 (COOH); [α]20 −144.7 (c 0.98 in
D
EtOH). (b) (S)-2-NGA: m.p.: 163.5–167.0°C; IR (KBr): ν=3350–3250, 1690, 1400, 1280, 830 cm−1; 1H NMR (300 MHz,
[D6]DMSO): δ=5.21 (s, 1H, CH), 6.00 (br s, 1H, OH), 7.50–7.58, 7.88–7.94 (m, 4H, C10H7); 13C NMR (300 MHz,
[D6]DMSO): δ=72.80 (CH), 125.08, 125.63, 126.27, 126.49, 127.78, 127.96, 128.08, 132.78, 132.93, 138.05, (C10H7),
174.30 (COOH); [α]20 +145.6 (c 0.98 in EtOH).
D
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