An effective kinetic resolution of racemic α-arylpropanoic acids, α-arylbutanoic acids, and β-substituted-α-arylpropanoic acids with bis(9-phenanthryl)methanol as a new achiral nucleophile in the asymmetric esterification using carboxylic anhydrides and the acyl-transfer catalyst

Article abstract of DOI:10.1016/j.tetlet.2010.08.008

A general method for the kinetic resolution of racemic α-arylalkanoic acids with achiral alcohols is described. It was determined that bis(9-phenanthryl)methanol is a suitable nucleophile which reacts with the intermediary mixed anhydrides generated from aromatic anhydrides with α-arylpropanoic acids or β-substituted-α-arylpropanoic acids in the presence of (+)-benzotetramisole to produce the corresponding optically active esters with high ee's under very mild conditions.

Full text of DOI:10.1016/j.tetlet.2010.08.008

Tetrahedron Letters 51 (2010) 5666–5669
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Tetrahedron Letters
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An effective kinetic resolution of racemic
-arylbutanoic acids, and b-substituted-
a
-arylpropanoic acids,
a
a
-arylpropanoic acids with
bis(9-phenanthryl)methanol as a new achiral nucleophile in the asymmetric
esterification using carboxylic anhydrides and the acyl-transfer catalyst
⇑
Kenya Nakata, Yu-suke Onda, Keisuke Ono, Isamu Shiina
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, 1-3 Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A general method for the kinetic resolution of racemic
a-arylalkanoic acids with achiral alcohols is
Received 26 July 2010
Accepted 2 August 2010
Available online 18 August 2010
described. It was determined that bis(9-phenanthryl)methanol is a suitable nucleophile which reacts
with the intermediary mixed anhydrides generated from aromatic anhydrides with -arylpropanoic acids
or b-substituted- -arylpropanoic acids in the presence of (+)-benzotetramisole to produce the corre-
sponding optically active esters with high ee’s under very mild conditions.
a
a
Keywords:
Kinetic resolution
Ó 2010 Elsevier Ltd. All rights reserved.
a-Arylalkanoic acid
Bis(9-phenanthryl)methanol
Aromatic anhydride
Benzotetramisole
We recently reported the first asymmetric esterification of achi-
ral carboxylic acids with racemic benzylic alcohols (Scheme 1, Eq.
1)1 via the in situ formation of the mixed anhydride using aromatic
anhydrides, such as p-methoxybenzoic anhydride (PMBA; 3), and
the chiral acyl-transfer catalysts, such as (ꢀ)-tetramisole and (+)-
benzotetramisole ((+)-BTM), which were introduced by Birman
et al.2 Because this protocol utilized the transacylation process to
generate the mixed anhydride, we expected that not only racemic
secondary alcohols, but also racemic carboxylic acids could be
applicable for the asymmetric esterification in the same manner.
In fact, we succeeded in the development of a new method for
the kinetic resolution of the racemic
achiral alcohols using chiral acyl-transfer catalysts (Eq. 2).3,4 In this
reaction, bis( -naphthyl)methanol (4a) functions as a very effec-
tive nucleophile for producing the optically active esters from race-
mic -arylpropanoic acids with high ee’s in the presence of an
aromatic anhydride as a coupling reagent with the benzotetrami-
sole derivatives. Various racemic -arylpropanoic acids and non-
a-arylpropanoic acids with
a
a
a
steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen,
ketoprofen, fenoprofen, flurbiprofen, and naproxen, were success-
fully resolved to produce the corresponding chiral carboxylic acids
and their esters with high s-values5 via the asymmetric esterifica-
tion. However, there exists a limitation when applying this method
to other substrates; that is, the only kinetic resolution of racemic
Scheme 1. Our previous results (Eqs. 1 and 2) and limitation (Eq. 3).
mono-substituted propanoic acids was attained to give the opti-
cally active esters with high enantioselectivities. For instance, the
reaction of racemic 2,3-diphenylpropanoic acid with 4a in the
presence of 3 and (+)-BTM afforded the corresponding ester in
⇑
Corresponding author. Tel.: +81 3 5228 8263; fax: +81 3 3260 5609.
E-mail address: shiina@rs.kagu.tus.ac.jp (I. Shiina).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.08.008

K. Nakata et al. / Tetrahedron Letters 51 (2010) 5666–5669
5667
Table 1
Kinetic resolution of ( )-1 with several kinds of achiral alcohols
Entry
Ar2CHOH (4)
Conditionsa
Yield (2 ; 1) [%]
ee (2 ; 1) [%]
s
1
2
4a
4a
A
B
53 ; 29
28 ; 44
87 ; 57
90 ; 32
27
25
3
4
4b
4b
A
B
32 ; 39
21 ; 46
89 ; 34
77 ; 17
24
9
5
6
4c
4c
A
B
24 ; 29
14 ; 55
89 ; 28
91 ; 10
23
23
7
8
4d
4e
A
A
NRb
NRb
—
—
—
—
9
4f
A
NRb
—
—
10
11
4g
4g
A
B
42 ; 33
42 ; 42
89 ; 48
91 ; 52
27
37
a
Conditions A (see Ref. 6); Anhydride = Bz2O, time = 6 h. Conditions B (see Ref. 7); Anhydride = PMBA (3), time = 12 h.
No reaction.
b
Table 2
Kinetic resolution of racemic
a-arylpropanoic acid derivatives 5a–h, including nonsteroidal anti-inflammatory drugs (NSAIDs)
Entry
Ar
Acid (5)
Conditionsa
Yield (6 ; 5) [%]
ee (6 ; 5) [%]
s
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
4-MeC6H4
5a
5a
5b
5b
5c
5c
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
42 ; 19
41 ; 44
36 ; 25
39 ; 42
53 ; 24
47 ; 43
36 ; 33
39 ; 30
49 ; 19
53 ; 43
54 ; 36
47 ; 39
41 ; 28
48 ; 32
50 ; 27
49 ; 42
87 ; 54
85 ; 44
78 ; 48
82 ; 49
80 ; 54
80 ; 57
90 ; 42
89 ; 49
75 ; 43
72 ; 60
78 ; 50
78 ; 60
88 ; 44
81 ; 64
88 ; 61
87 ; 61
24
19
13
16
15
16
27
27
11
11
14
15
23
18
30
26
4-MeOC6H4
4-CIC6H4
4-i-BuC6H4
3-BzC6H4
Ibuprofen (5d)
5d
Ketoprofen (5e)
5e
Fenoprofen (5f)
5f
Flurbiprofen (5g)
5g
3-PhOC6H4
3-F-4-PhC6H3
2-(6-MeO-Np)
Naproxen (5h)
5h
a
Conditions A (see Ref. 6); Anhydride = Bz2O, time = 6 h. Conditions B (see Ref. 7); Anhydride = PMBA (3), time = 12 h.

5668
K. Nakata et al. / Tetrahedron Letters 51 (2010) 5666–5669
55% yield with a moderate selectivity (58% ee) as shown by Eq. 3
(s = 5.5), therefore, further improvements are required for estab-
lishing a reliable and more useful synthetic technology to produce
alcohols 4d–f possessing large substituents on the o- and o0-posi-
tions did not take place at all (entries 7–9). Fortunately, it was
found that the kinetic resolution of ( )-1 with bis(9-phenan-
thryl)methanol (4g) successfully proceeded to afford the desired
optically active ester (R)-2g in good yield with a high enantioselec-
tivity as shown in entry 10 (s = 27). Similar to the preceding re-
sults,3 PMBA (3) also functions as an effective coupling reagent
for the reaction of ( )-1 with 4a, 4c, and 4g by the combined use
of (+)-BTM, and almost all the resolutions demonstrated in Table 1
produced satisfactory s-values as shown by entries 2, 6, and 11 ex-
cept for entry 4 (s = 25, 23, and 37).
the chiral b-substituted-
report a widely applicable mixed-anhydride method for producing
the optically active -arylalkanoic acids and those esters starting
a-arylpropanoic acid derivatives. We now
a
from the racemic materials by the combined use of aromatic anhy-
drides, achiral alcohols, and the chiral acyl-transfer catalyst.
First, we examined the kinetic resolution of racemic 2-phenyl-
propanoic acid (( )-1) with several achiral alcohols in the presence
of benzoic anhydride and a catalytic amount of (+)-BTM in order to
determine the suitable structure of the nucleophiles (Table 1).
Table 2 displays a variety of examples of the kinetic resolution
When the reaction was carried out using bis(
a
-naphthyl)methanol
of a-arylpropanoic acid derivatives 5a–h with 4g under the above
(4a) under the modified standard reaction conditions established
in a preceding paper,3 the asymmetric esterification smoothly pro-
ceeded and a good s-value (s = 27) was obtained (entry 1). We fur-
ther investigated the use of benzhydrols 4b and 4c having alkyl
substituents at the o- and o0-positions on the aromatic rings and
relatively good stereoselectivities were also observed (entries 3
and 5: cf. entry 1). On the other hand, the reactions with very bulky
optimized conditions A6 (Table 1, entry 10) and B7 (Table 1, entry
11). As shown by entries 1–6, all the kinetic resolutions of 2-(4-
methylphenyl)propanoic acid (5a), 2-(4-methoxyphenyl)propa-
noic acid (5b), and 2-(4-chlorophenyl)propanoic acid (5c) provided
the optically active carboxylic esters in good enantiomeric excesses
(78–87% ee), irrespective of the substituents at the 4-position on
the aromatic rings of the 2-arylpropanoic acid derivatives. Further-
more, we examined the asymmetric acyl-transfer reaction of sev-
eral NSAIDs, such as ibuprofen (5d), ketoprofen (5e), fenoprofen
(5f), flurbiprofen (5g), and naproxen (5h), as listed in entries 7–
16. Although the kinetic resolution of 5e under both conditions,
A and B, gave medium enantioselectivities (entries 9 and 10,
s = 11, in each case), other reactions produced the corresponding
chiral NSAIDs esters in high ee’s (78–90% ee) with good s-values
(s = 14–30) in every case (entries 7, 8, 11–16).
Scheme 3. Deprotection of bis(9-phenanthryl)methyl esters to form the chiral b-
Scheme 2. Improved kinetic resolution of a variety of racemic b-substituted-
a-
substituted-a-arylpropanoic acid derivatives ((R)-7a, (R)-7b, and (S)-7c) and (R)-
arylpropanoic acid derivatives (7a–d) (Eqs. 4, 6, 8, and 10).
ibuprofen ((R)-5d).

K. Nakata et al. / Tetrahedron Letters 51 (2010) 5666–5669
5669
Next, the present protocol was applied to the kinetic resolution
of the racemic 2,3-diphenylpropanoic acid (7a), 2-phenylbutanoic
acid (7b), 3-methoxy-2-phenylpropanoic acid (tropic acid methyl
ether) (7c), and 2-cyclopentyl-2-phenylacetic acid (7d) using alco-
hol 4g as a nucleophile (Scheme 2). As demonstrated by Eqs. 4, 6, 8,
and 10, the combined use of benzoic anhydride and (+)-BTM affor-
ded the corresponding optically active esters (R)-8a, (R)-8b, (S)-8c,
and (R)-8d with high enantioselectivities (87%, 87%, 88%, and 90%
ee, respectively) under the established conditions A, and fairly
good s-values were observed for the reactions of the alcohol 4g
with 7a–d (s = 25, 17, 20, and 19, respectively). It is worth noting
that the effective kinetic resolutions of 7a–d have not been
achieved when the reaction was carried out in the presence of alco-
hol 4a as a nucleophile (Eqs. 5, 7, 9, and 11), which was explored in
our preliminary studies on this project (s = 5, 5, 18, and 3,
respectively).
The estimated reaction pathway is illustrated in Scheme 4. First,
a mixed anhydride ( )-MA forms as a key intermediate in situ from
aromatic anhydride with the racemic acid ( )-7 by the promotion
of (R)-(+)-BTM. In the next step, (R)- and (S)-MA would be acti-
vated again by (R)-(+)-BTM to form the corresponding zwitterionic
species (R,R)-int and (S,R)-int, and then (R,R)-int generated from
(R)-MA selectively reacts with 4g to afford the desired ester (R)-8
with high enantiomeric excess via the preferable transition struc-
ture (R,R)-ts. On the other hand, (S)-MA produces an unstable
structure (S,R)-ts, which has a higher energy derived from steric
repulsion between the substituent at the
a-position of (S)-7 and
the phenyl group at C-2 of (R)-(+)-BTM. Therefore, it is assumed
that the desired chiral ester (R)-8 was preferentially obtained by
the rapid transformation of (R)-MA through the stable transition
state (R,R)-ts.
In summary, we have developed a widely applicable method for
We then attempted the transformation of the optically active
bis(9-phenanthryl)methyl esters into free carboxylic acids in order
to obtain the corresponding 2-arylalkanoic acid derivatives
(Scheme 3). Under the conventional hydrogenation conditions to
remove the benzyl ester moiety, the cleavage of bis(9-phenan-
thryl)methyl esters (R)-8a, (R)-8b, (S)-8c, and (R)-6d was success-
the kinetic resolution of racemic a-arylalkanoic acids with achiral
alcohols. It was revealed that bis(9-phenanthryl)methanol reacted
with the intermediary mixed anhydrides generated from aromatic
anhydrides with
a-arylpropanoic acids or b-substituted-a-aryl-
propanoic acids in the presence of (+)-BTM to produce the corre-
sponding optically active esters with high ee’s. Further studies of
the mixed-anhydride method affording the chiral carboxylic acid
derivatives are now in progress in this laboratory.
fully carried out to give the chiral b-substituted-a-arylpropanoic
acids (R)-7a, (R)-7b, (S)-7c, and (R)-ibuprofen ((R)-5d), respectively.
Acknowledgment
This study was partially supported by a Research Grant from
Toray Science Foundation.
References and notes
1. (a) Shiina, I.; Nakata, K. Tetrahedron Lett. 2007, 48, 8314; (b) Shiina, I.; Nakata, K.;
Sugimoto, M.; Onda, Y.; Iizumi, T.; Ono, K. Heterocycles 2009, 77, 801; (c) Nakata,
K.; Shiina, I. Heterocycles 2010, 80, 169; (d) Shiina, I.; Nakata, K.; Ono, K.;
Sugimoto, M.; Sekiguchi, A. Chem. Eur. J. 2010, 16, 167.
2. (a) Birman, V. B.; Li, X. Org. Lett. 2006, 8, 1351; (b) Birman, V. B.; Guo, L. Org. Lett.
2006, 8, 4859.
3. (a) Shiina, I.; Nakata, K.; Onda, Y. Eur. J. Org. Chem. 2008, 5887; (b) Shiina, I.;
Nakata, K.; Ono, K.; Onda, Y.; Itagaki, M. J. Am. Chem. Soc. 2010, 132, 11629.
4. For other examples of asymmetric esterification of racemic carboxylic acids, see:
(a) Ishihara, K.; Kosugi, Y.; Umemura, S.; Sakakura, A. Org. Lett. 2008, 10, 3191;
(b) Sakakura, A.; Umemura, S.; Ishihara, K. Synlett 2009, 1647; (c) Yang, X.;
Birman, V. B. Adv. Synth. Cat. 2009, 351, 2301.
5. Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249.
6. Typical procedure for the esterification of 2-phenylpropanoic acid (( )-1) by
using Bz2O with (+)-BTM (Table 1, entry 10, Conditions A): To a solution of ( )-1
(29.5 mg, 0.196 mmol) and Bz2O (54.3 mg, 0.240 mmol) in dichloromethane
(2.0 mL) at room temperature were successively added diisopropylethylamine
(62.9
l
L,
0.360 mmol),
(+)-BTM
(2.5 mg,
9.9
l
mol),
and
bis(9-
phenanthryl)methanol (4g) (38.4 mg, 0.100 mmol). The mixture was stirred
for 6 h at room temperature and then it was quenched with saturated aqueous
NH4Cl. The organic layer was separated and the aqueous layer was extracted
with dichloromethane. The combined organic layer was dried over Na2SO4. After
filtration of the mixture and evaporation of the solvent, the crude product was
purified by preparative thin layer chromatography on silica to afford the
corresponding ester (R)-2g (42.3 mg, 42% yield, 89% ee) and a part of the
recovered optically active carboxylic acid. The aqueous layer was acidified by
1 M HCl to adjust to pH 2 and then the aqueous layer was extracted with
dichloromethane. The combined organic layer was dried over Na2SO4. After
filtration of the mixture and evaporation of the solvent, the crude product was
purified by preparative thin layer chromatography on silica to afford the
unreacted optically active carboxylic acid (S)-1 (totally 9.9 mg, 33% yield, 48%
ee). [s = 27.3].
7. Typical procedure for the esterification of 2-phenylpropanoic acid (( )-1) by
using PMBA (3) with (+)-BTM (Table 1, entry 11, Conditions B): To a solution of
( )-1 (29.7 mg, 0.198 mmol) and PMBA (68.7 mg, 0.240 mmol) in
dichloromethane (2.0 mL) at room temperature were successively added
diisopropylethylamine (62.9 lL, 0.360 mmol), (+)-BTM (2.5 mg, 9.9 lmol), and
bis(9-phenanthryl)methanol (4g) (38.4 mg, 0.100 mmol). The mixture was
stirred for 12 h at room temperature and then it was quenched with saturated
aqueous NH4Cl. After the usual work up as described in conditions A, the
corresponding ester (R)-2g (43.3 mg, 42% yield, 91% ee) and the unreacted
optically active carboxylic acid (S)-1 (12.4 mg, 42% yield, 52% ee) were obtained,
respectively. [s = 36.9].
Scheme 4. Plausible reaction pathway of the kinetic resolution of racemic
arylalkanoic acid (( )-7) to form the chiral bis(9-phenanthryl)methyl ester ((R)-8)
via the corresponding racemic mixed anhydride (( )-MA).
a-