Enantioresolution of 2-methoxy-2-(1-naphtyl)propionic acid using diastereomeric salt formation with chiral phenylethylamine

Article abstract of DOI:10.1016/j.tetlet.2014.05.037

An enantioresolution of 2-methoxy-2-(1-naphtyl)propionic acid (MαNP acid) using the diastereomeric salt with chiral (R)-phenylethylamine was achieved to give enantiopure (R)-MαNP acid in 29% yield with >99% ee based on rac-MαNP acid. X-ray crystallographi

Full text of DOI:10.1016/j.tetlet.2014.05.037

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioresolution of 2-methoxy-2-(1-naphtyl)propionic acid using
diastereomeric salt formation with chiral phenylethylamine
Miho Kusakari, Yurie Ohta, Hideaki Nakagawa, Hiroshi Katagiri, Tatsuro Kijima, Satoshi Murakami,
⇑
Shigeru Matsuba, Bunpei Hatano
Department of Biochemical Engineering, Graduate School of Science and Engineering, Yamagata University, 4-3-16 Jonan, Yonezawa 992-8510, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
An enantioresolution of 2-methoxy-2-(1-naphtyl)propionic acid (M
a
NP acid) using the diastereomeric
NP acid in 29% yield with
NP acid. X-ray crystallographic analysis of diastereomeric salt revealed that (R)-
NP acid was tightly arranged by four independent hydrogen bonds and one CH– interaction with (R)-
phenylethylamine.
Received 1 April 2014
Revised 25 April 2014
Accepted 9 May 2014
Available online xxxx
salt with chiral (R)-phenylethylamine was achieved to give enantiopure (R)-M
>99% ee based on rac-M
a
a
Ma
p
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Enantioresolution
2-Methoxy-2-(1-naphtyl)propionic acid
(MaNP acid)
Phenylethylamine
Diastereomeric salt
Chiral resolving reagent
Chiral 2-methoxy-2-(1-naphtyl)propionic acid (MaNP acid) (1)
H2N
MeO
COOH
is a powerful reagent for the resolution of enantiopure alcohols
and the simultaneous determination of their absolute configura-
tions on the basis of the 1H NMR anisotropy effect, as well as
Mosher’s reagent.1–3 Chiral 1 has been prepared by the separation
(R)-1b • (R)-2b
diastereomeric salt 3
M
NP acid
1-PEA
α
rac-1a : rac-form
rac-2a : rac-form
of diastereomeric esters of rac-1a with L-menthol using preparative
(R)-1b : (R)-form
(R)-2b : (R)-form
HPLC method. The alternative preparation method of chiral 1 is
desired because preparative HPLC, which is suitable for the small
scale separation, is generally a low efficiency and high cost tech-
nique for the separation of diastereomer. Recently, we focused on
the formation of the inclusion complex based on hydrogen bonding
network.4 In our previous reports, we reported that the enantiores-
olution of 2,20-bis(diphenylphosphino)-1,10-binaphthyl oxide
(BINAPO) is achieved using the formation of the stereoselective
inclusion complex with chiral (R)-2,2-dihydroxy-1,10-binaphthyl
(BINOL) to give chiral BINAPO in 43% yield with 98% ee from rac-
BINAPO.5
Herein, we report a practical and efficient enantioresolution of
rac-1a using diastereomeric salt formation with commercially
available chiral amine (Fig. 1). We achieved the formation of the
diastereomeric salt 3 of (R)-1b with (R)-2b from rac-1a in 85%
EtOH to give almost enantiopure (R)-1b in 41% yield with 95% ee
in one operation after protonation of the obtained diastereomeric
(S)-1c
(S)-2c
: (S)-form
: (S)-form
Figure 1. Structures related with enantioresolution.
salt 3. Furthermore, we could also obtain enantiopure (R)-1b
(>99% ee) from (R)-1b (95% ee). X-ray structure of the obtained dia-
stereomeric salt 3 revealed the strong crystalline structure due to
the four independent hydrogen bonds and one CH–
between (R)-1b and (R)-2b.
To find optimum conditions for the formation of the diastereo-
meric salt 3 of (R)-1b with (R)-2b from rac-1a, we studied the for-
mation of diastereomeric salt 3 in several solvents. The preparation
of rac-1 was carried out according to the literature reported by
Kasai and co-workers with slight modification (Scheme 1).6
A typical experimental procedure of enantioresolution using the
diastereomeric salt formation is as follows: rac-1a and (R)-2b were
dissolved in the solvents at refluxed temperature. Then, the mix-
ture was kept at room temperature to crystallize an insoluble dia-
stereomeric salt 3 of (R)-1b with (R)-2b. The simple protonation of
the obtained diastereomeric salt 3 with aqueous HCl liberated free
p interaction
⇑
Corresponding author. Tel.: +81 238 26 3117; fax: +81 238 26 3413.
E-mail address: hatano@yz.yamagata-u.ac.jp (B. Hatano).
http://dx.doi.org/10.1016/j.tetlet.2014.05.037
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kusakari, M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.037

2
M. Kusakari et al. / Tetrahedron Letters xxx (2014) xxx–xxx
rac-1a + (R)-2b in 85% EtOH
Br
HO
COOMe
NaH / CH3I
1) Mg / THF
O
3
diastereomeric salt
AcOEt-3N HCl
85% EtOH solution
evaporation
(S)-1c rich residue
AcOEt-3N HCl
2)
COOCH3
4
5
rac-alcohol
AcOEt solution 3N HCl solution
MeO
COOMe
MeO
COOH
(R)-1b
(41%, 95% ee)
3N HCl solution
1) KOH
2) HCl
AcOEt solution
(S)-1c
(55%, 70% ee)
second operation
rac-methyl ester 6
rac-1a
(R)-1b
(29%, > 99% ee)
recrystallization from toluene
Scheme 1. Synthesis of rac-1a.
1c
(S)- poor crystal toluene solution
Table 1
(16%, 15% ee)
Enantioresolution of rac-1a with (R)-2b in several conditions
1c
(S)-
Entry Solvent
Feed ratio (1a:2b) Salta (1b:2b)
1b
Yieldb,c (%) eed (%)
(37%, 95% ee)
Scheme 2. Experimental procedure of the enantiomeric solution of rac-1a.
1
2
3
4
5
6
7
Toluene 4:1
CHCl3
Et2O
EtOH
EtOH
EtOH
EtOH
1:1
22
46
32
15
24
29
35
84
66
20
95
91
89
84
4:1
4:1
4:1
4:2
4:3
4:4
1:1
1:1
1:1
1:1
1:1
1:1
salt 3 (entry 1). In 85% and 80% EtOH, the yields were improved
(entries 2 and 3). Similar results were also obtained in the case
of MeOH and i-PrOH solution (entries 4 and 5).
This method was also applicable to a large scale enantioresolu-
tion of rac-1a as shown in Scheme 2. When rac-1a (10.0 g,
43 mmol) and (R)-2b (4.0 g, 32 mmol) were dissolved in hot 85%
EtOH (250 mL, EtOH: H2O = 85:15, by volume), a crystalline diaste-
reomeric salt 3 was obtained. After protonation of the obtained
diastereomeric salt 3, (R)-1b with 95% ee was obtained in 41%
yield. From the filtrate left after separation of diastereomeric salt
3, (S)-1c with 70% ee was obtained in 55% yield. High enantiopure
(S)-1c (37% yield, 95% ee) was obtained, after the precipitate poor
in (S)-1a was crystallized out in 16% yield with 15% ee from tolu-
ene. It is noteworthy that a single diastereomeric salt formation
from rac-1a with (R)-2b and a single crystallization from the pre-
cipitate rich in (S)-1c led to both enantiomers in good yields with
high enantiomeric excesses. Of course, further enhancement of
enantiopurity can be achieved by additional single recrystallization
(up to 97% ee) of both enantiomers, and enantiopure 1 (29% yield,
>99% ee) could also be obtained from the second operation of the
formation of the diastereomeric salt 3 from chiral 1 with 95% ee
and the corresponding chiral 2 in 85% EtOH.
a
b
c
The included ratio of 3 was determined by 1H NMR.
(R)-1b was isolated after protonation of 3.
The presented yield was based on initially used rac-1a.
d
The enantiomeric excess was determined by HPLC using a Chiralcel OZ-RH
column.
(R)-1b as white solid. The results are summarized in Table 1. In tol-
uene, a 1:1 crystalline diastereomeric salt 3 of (R)-1b with (R)-2b
was formed to give (R)-1b in a moderate yield with moderate
enantioselectivity after protonation (entry 1). The enantioselectiv-
ity was not improved in CHCl3 and Et2O (entries 2 and 3). The high
enantioselectivity was achieved in EtOH to give (R)-1b in 15% yield
with 95% ee (entry 4). Next, we studied the influence of the
amounts of (R)-2b against rac-1a on the diastereomeric salt forma-
tion. In any amounts of (R)-2b, a 1:1 crystalline diastereomeric salt
3 was obtained (entries 5–7). From the viewpoint of the yield and
enantioselectivity, the best result was obtained using 0.75 equiv of
(R)-2b against rac-1a in feed (entry 6).
In order to elucidate some aspects of the diastereomeric salt
formation, an X-ray analysis of diastereomeric salt 3, which was
obtained from large scale enantioresolution, was done. As shown
in Figure 2, (R)-1b molecule is accommodated through four
In order to improve both the yield and enantioselectivity in
enantioresolution, we next studied the influence of the additive
to alcohol solution. Although we first attempted to use triethyl-
amine as an additive,7 the large improvement in the yield and
enantioselectivity was not observed. Surprisingly, the addition of
H2O led to the drastic increase of the yield and enantioselectivity.
The results are summarized in Table 2. The use of 90% EtOH gave
(R)-1b in 36% yield with 95% ee after protonation of diastereomeric
(A)
O3
O3
N1
Table 2
N1
N1
Enantioresolution of rac-1a with (R)-2b in alcohol–water solutiona
O2
O2
O1
O1
O1
Entry
Solvent (by volume)
Salt 1b:2bb
1b
Yield (%)c,d
O2
O2
N1'
N1'
ee (%)e
O1 ••••• N1 2.790 Å O2 ••••• N1 2.916 Å O2 ••••• N1' 2.775 Å
1
2
3
4
5
EtOH/H2O
EtOH/H2O
EtOH/H2O
MeOH/H2O
i-PrOH/H2O
(90/10)
1:1
1:1
1:1
1:1
1:1
36
39
38
35
42
95
95
94
97
90
O3 ••••• N1 2.957 Å CH ••••• π 3.144 Å
(85/15)
(80/20)
(85/15)
(85/15)
(B)
H
O
Me
H
Me
a
b
c
rac-1a (4.0 mmol) and (R)-2b (3.0 mmol) were used in feed.
The included ratio of 3 was determined by 1H NMR.
(R)-1b was isolated after protonation of 3.
The presented yield was based on initially used rac-1a.
The enantiomeric excess was determined by HPLC using a Chiralcel OZ-RH
N
H
O
O
H
Me
d
e
Figure 2. X-ray structure of diastereomeric salt (A) and schematic structure (B)
from rac-1a and (R)-2b.
column.
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M. Kusakari et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
independent hydrogen bonds with three (R)-2b molecules and one
CH– interaction with a (R)-2b. The three hydrogen bonds are
Supplementary data
p
formed between carboxyl oxygens of (R)-1b and amino groups of
three different (R)-2b molecules, and another one is formed
between methoxy oxygen of (R)-1b and amino group of (R)-2b.
The bond lengths are 2.790 Å (O1ꢀ ꢀ ꢀN1), 2.916 Å (O2ꢀ ꢀ ꢀN1),
2.775 Å (O2ꢀ ꢀ ꢀN10), and 2.957 Å (O3ꢀ ꢀ ꢀN1), respectively. The etha-
nol and water used as solvents were not included at all. The
obtained crystal structure of diastereomeric salt 3 is almost the
same as in the literature by Ichikawa et al.8 They reported that
the diastereomeric salt 3 formed from (R)-1b with (R)-2b was more
stable than the one formed from (S)-1c with (R)-2b due to an aro-
Supplementary data (experimental procedures, NMR spectra, X-
ray crystallographic data (CIF file) of 3, and HPLC data) associated
with this article can be found, in the online version, at http://
dx.doi.org/10.1016/j.tetlet.2014.05.037.
References and notes
1. Recently review for chiral anisotropy reagent, see: (a) Harada, N. Chirality 2008,
20, 691–723; (b) Wenzel, T. J.; Wilcox, J. D. Chirality 2003, 15, 256–270.
2. Selected references to concern Mosher’s reagent, see: (a) Goldberg, Y.; Alper, H.
J. Org. Chem. 1992, 57, 3731–3732; (b) Dale, J. A.; Mosher, H. S. J. Am. Chem. Soc.
1973, 24, 512–519; (c) Dale, J. A.; Dull, D. A.; Mosher, H. S. J. Org. Chem. 1969, 34,
2543–2549.
matic CH–
same CH–
p
p
interaction between (R)-1b and (R)-2b. In our crystal,
interaction was observed (3.144 Å). These facts sup-
3. Selected references to concern MaNP acid, see: (a) Kasai, Y.; Taji, H.; Fujita, T.;
ported that the diastereomeric salt 3 of (R)-1b with (R)-2b formed
more favorably than one of (S)-1c with (R)-2b in the enantioreso-
lution of rac-1a with (R)-2b.
In summary, the practical and efficient enantioresolution of rac-
1a was achieved using (R)-2b as a resolving agent to give enantio-
pure (R)-1b (>99% ee). The X-ray structural analysis revealed that
Yamamoto, Y.; Akagi, M.; Sugio, A.; Kuwahara, S.; Watanabe, M.; Harada, N.;
Ichikawa, A.; Schurig, V. Chirality 2004, 16, 569–585; (b) Harada, N.; Watanabe,
M.; Kuwahara, S.; Sugio, A.; Kasai, Y.; Ichikawa, A. Tetrahedron: Asymmetry 2000,
11, 1249–1253; (c) Kuwahara, S.; Fujita, K.; Watanabe, M.; Harada, N.; Ishida, T.
Enantiomer 1999, 4, 141–145.
4. (a) Hatano, B.; Aikawa, A.; Katagiri, H.; Tagaya, H.; Takahashi, H. Chem. Lett.
2007, 36, 1272–1273; (b) Hatano, B.; Aikawa, A.; Tagaya, H.; Takahashi, H. Chem.
Lett. 2004, 33, 1276–1277; (c) Hatano, B.; Hirano, S.; Yanagihara, T.; Toyota, S.;
Toda, F. Synthesis 2001, 1181–1184.
four independent hydrogen bonds and one CH–p interaction
played a key role in the diastereomeric salt 3.
5. Hatano, B.; Hashimoto, K.; Katagiri, H.; Kijima, T.; Murakami, S.; Matsuba, S.;
Kusakari, M. J. Org. Chem. 2012, 77, 3595–3597.
6. Racemic 1a was prepared according to the literature, see, Ref. 3a.
7. Pope, W. J.; Peachey, S. J. J. Chem. Soc. 1899, 75, 1066–1093.
Acknowledgments
8. The diastereomeric salt 3, which was prepared from chiral-1 with chiral-2 in
CHCl3–MeOH solvent system, was analyzed by X-ray crystallography, see:
Ichikawa, A.; Ono, H.; Echigo, T.; Mikata, Y. CrystEngComm 2011, 13, 4536–4548.
This work was supported by a Grant-in-Aid for Scientific
Research (C) (No. 23550187) from the Japan Society for the Promo-
tion of Science (JSPS). We express our thanks to Dr. Masataka
Watanabe for advice concerning the preparation of rac-1a.
Please cite this article in press as: Kusakari, M.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.037