The first asymmetric esterification of free carboxylic acids with racemic alcohols using benzoic anhydrides and tetramisole derivatives: an application to the kinetic resolution of secondary benzylic alcohols

Article abstract of DOI:10.1016/j.tetlet.2007.09.135

A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic secondary benzylic alcohols using free carboxylic acids with benzoic anhydride and tetramisole derivatives. 4-Methoxybenzoic anhydride (PMBA) is the best rea

Full text of DOI:10.1016/j.tetlet.2007.09.135

Available online at www.sciencedirect.com
Tetrahedron Letters 48 (2007) 8314–8317
The first asymmetric esterification of free carboxylic
acids with racemic alcohols using benzoic anhydrides
and tetramisole derivatives: an application to the
kinetic resolution of secondary benzylic alcohols
Isamu Shiina* and Kenya Nakata
Department of Applied Chemistry, Faculty of Science, Tokyo University of Science, Kagurazaka, Shinjuku-ku, Tokyo 162-8601, Japan
Received 27 July 2007; revised 12 September 2007; accepted 19 September 2007
Available online 25 September 2007
Abstract—A variety of optically active carboxylic esters are produced by the kinetic resolution of racemic secondary benzylic alco-
hols using free carboxylic acids with benzoic anhydride and tetramisole derivatives. 4-Methoxybenzoic anhydride (PMBA) is the
best reagent to use in producing the corresponding esters in high ee when the reaction is catalyzed by (+)-benzotetramisole
(BTM); by contrast, when non-substituted benzoic anhydride is used as a coupling reagent, the resulting optically active alcohols
are obtained with high selectivities. This protocol directly produces chiral carboxylic esters from free carboxylic acids and racemic
secondary alcohols by utilizing the trans-acylation process to generate mixed anhydrides from acid components and benzoic anhy-
dride derivatives under the influence of chiral catalysts.
Ó 2007 Elsevier Ltd. All rights reserved.
Synthesis of optically active secondary alcohols and
their derivatives is one of the most important topics in
the field of basic science.1 Recently, some acylation
methods have been developed for the kinetic resolution
of racemic alcohols that use acyl halides or carboxylic
anhydrides to produce the corresponding chiral esters
in high ee.2 As far as we know, however, the kinetic res-
olution of racemic alcohols using free carboxylic acids
has not yet been achieved. A reaction using carboxylic
acids as acyl donors would have great general and syn-
thetic utility if achieved.
atives and a chiral nucleophilic catalyst developed
recently by Birman et al.4
First, 1-phenyl-1-propanol (( )-1) and 3-phenylprop-
ionic acid were chosen as model substrates for optimiza-
tion of the structure of the substituted benzoic
anhydrides (Table 1).5 As a nucleophilic catalyst, (–)-
tetramisole (commercially available as a hydrochloride
salt) was used for chiral induction according to the
reported kinetic resolution procedure with propionic
anhydride.4c As shown in entry 1, benzoic anhydride
afforded relatively good enantioselectivity of the corres-
ponding carboxylic ester 2 (90% ee), and the s-value6
of the reaction was excellent (s = 22). Furthermore,
4-methoxybenzoic anhydride (PMBA) afforded the
desired ester with good enantioselectivity (88% ee), and
the s-value was also over 20 (entry 5). As shown in
entries 8–12, we found that all substituted benzoic anhy-
drides with electron-withdrawing groups gave poor re-
sults. For example, the desired ester was obtained in
only 4% yield when 2-methyl-6-nitrobenzoic anhydride
(MNBA) was used in this model system (entry 12), even
though MNBA is a very powerful reagent for the
production of lactones, including highly-oxygenated
medium- and large-sized ring compounds.3 On the
other hand, substituted benzoic anhydrides with
In recent years, we developed an effective method for
esterification and lactonization that uses benzoic anhy-
dride derivatives as condensation reagents to produce
the desired coupling products from free carboxylic acids
and alcohols (or x-hydroxycarboxylic acids).3 In this
report, we study the novel and useful kinetic resolution
of racemic secondary benzylic alcohols using free carbox-
ylic acids by the promotion of benzoic anhydride deriv-
Keywords: Asymmetric esterification; Kinetic resolution; Free carbox-
ylic acid; Benzoic anhydride; Tetramisole derivative.
*
Corresponding author. Tel.: +81 3 5228 8263; fax: +81 3 3260
5609; e-mail: shiina@ch.kagu.tus.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.135

I. Shiina, K. Nakata / Tetrahedron Letters 48 (2007) 8314–8317
8315
Table 1. Kinetic resolution of secondary benzylic alcohols using benzoic anhydride esterification with tetramisole
Entry
Xn
Yield of 2 (%)
2/3
Yield of 1 (%)
ee (2/1) (%)
s
1
2
3
4
5
6
7
8
9
H
4-Me
2-Me
3,5-Me2
4-MeO [PMBA]
3,5-(MeO)2
3,4,5-(MeO)3
4-Cl
2,6-Cl2
2,4,6-Cl3
14
38
5
94/6
98/2
96/4
97/3
98/2
98/2
96/4
97/3
93/7
nd
68
42
66
37
63
72
51
25
73
nd
72
nd
90/17
77/66
67/17
81/73
88/36
87/26
81/63
16/31
42/4
22
15
6
21
22
18
18
2
39
29
23
35
60
12
Trace
16
4
2
10
11
12
nd/nd
79/15
nd/nd
nd
10
nd
2-MeO-4-Cl
2-Me-6-NO2 [MNBA]
96/4
nd
electron-donating groups, such as PMBA, produced
comparatively better chemical yields and enantioselec-
tivities for 2, as shown in entries 2–7. Although a small
amount of the undesired benzoates 3 was obtained in
every case, the chemoselectivities of 2 versus 3 were gen-
erally satisfactory (>96/4 in entries 2–8, 11).
used in combination with BTM, as shown in Table 2.
Almost all of these reactions produced very good
results, and the corresponding carboxylic esters 2 and
alcohols 1 were produced in high ee (s = >30). When
the reaction was carried out using non-substituted ben-
zoic anhydride (entry 1), the desired ester was obtained
in 48% yield with good enantioselectivity (89% ee) and
an excellent s-value (s = 46).7 Furthermore, we also
found that PMBA functions as a suitable coupling
reagent that gives the desired products with high enanti-
oselectivities (entry 4; s = 43).8 We subsequently exam-
ined other factors such as reaction temperature and
solvent by changing the reaction conditions, but we
obtained poor results. For instance, when the reaction
was carried out using benzoic anhydride coupled with
BTM at 5 °C for 48 h, the corresponding ester 2 was
produced in 55% yield with 57% ee (s = 8). Further-
more, the use of a DMF solvent at room temperature
afforded the desired ester in 58% yield, and the ee of
the product decreased to 76% (s = 11).
Next, (+)-benzotetramisole (BTM), an advanced acyla-
tion catalyst developed by Birman4c was used as a chiral
promoter in further studies (Table 2). Benzoic anhydride
and five other kinds of substituted derivatives, which
produced the high s-values shown in Table 1, were
Table 2. Kinetic resolution of secondary benzylic alcohols using
benzoic anhydride esterification with BTM
The esterification of several free carboxylic acids with
secondary benzylic alcohols was examined to assess
the generality of this new method. The results are
summarized in Table 3. As shown in entries 1–11, high
s-values were attained for the reaction using benzoic
anhydride, and the resulting alcohols (S)-1 were recov-
ered with high ee because the reaction proceeded at a
good rate. On the other hand, the reaction using PMBA
afforded the corresponding esters (R)-2 with high enanti-
oselectivities because the rates of the reactions in entries
12–22 are relatively low as compared to those of the
reactions accelerated by the non-substituted benzoic
anhydride. All of the s-values of reactions using PMBA,
shown in entries 12–22, are excellent (s = 12–88); as a
result, the desired carboxylic esters, derived from a variety
Entry Xn
Yield of 2/3
2 (%)
Yield of ee (2/1)
s
1 (%)
(%)
1
2
3
4
5
6
H
48
49
31
98/2 47
99/1 45
99/1 61
98/2 46
98/2 52
98/2 39
89/85
83/94
90/48
90/75
90/48
84/90
46
38
30
43
30
35
4-Me
3,5-Me2
4-MeO [PMBA] 41
3,5-(MeO)2
3,4,5-(MeO)3
34
46

8316
I. Shiina, K. Nakata / Tetrahedron Letters 48 (2007) 8314–8317
Table 3. Synthesis of a variety of the optically active carboxylic esters and alcohols using the asymmetric esterification
Entry
R1
R2
Anhydride
Yield (2/1) (%)
ee (2/1) (%)
s
1
2
3
4
5
6
7
8
9
Et
Et
Et
Et
Et
Et
Et
i-Pr
i-Pr
t-Bu
t-Bu
Et
Bz2O
Bz2O
Bz2O
Bz2O
Bz2O
Bz2O
Bz2O
Bz2O
Bz2O
Bz2O
Bz2O
47/30
48/47
49/40
43/33
52/35
55/29
45/41
50/43
54/46
30/58
34/55
86/87
89/85
82/90
82/72
77/95
55/98
63/64
83/91
83/90
86/43
86/50
38
46
31
22
28
14
8
34
33
20
22
Ph(CH2)2
Ph(CH2)3
Me2CH(CH2)2
CH2@CH(CH2)2
MeOCH2
c-C6H11
Et
Ph(CH2)2
Et
Ph(CH2)2
10
11
12
13
14
15
16
17
18
19
20
21
22
Et
Et
Et
Et
Et
Et
Et
i-Pr
i-Pr
t-Bu
t-Bu
Et
PMBA
PMBA
PMBA
PMBA
PMBA
PMBA
PMBA
PMBA
PMBA
PMBA
PMBA
40/40
41/46
39/45
43/38
47/38
32/51
40/53
39/43
38/53
32/67
36/54
89/76
90/75
90/69
83/71
86/91
82/38
76/51
90/81
92/64
93/44
96/58
39
43
39
23
42
15
12
47
46
42
88
Ph(CH2)2
Ph(CH2)3
Me2CH(CH2)2
CH2@CH(CH2)2
MeOCH2
c-C6H11
Et
Ph(CH2)2
Et
Ph(CH2)2
of carboxylic acids, were effectively obtained in high
enough purity for application to the asymmetric synthesis
of chiral compounds.
(94.0 lL, 0.540 mmol), BTM (3.8 mg, 0.015 mmol) and
( )-1-phenyl-1-propanol (40.8 lL, 0.300 mmol). The
mixture was stirred for 12 h at room temperature, and
then quenched with saturated aqueous NaHCO3. The
organic layer was separated and the aqueous layer was
extracted with diethyl ether (three times). 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 chroma-
tography on silica to afford the corresponding ester
(33.7 mg, 41%, 90% ee) and the recovered optically ac-
tive alcohol (18.7 mg, 46%, 75% ee) (Table 3, s=42.8, en-
try 13). (R)-1-Phenylpropyl 3-phenylpropanoate: HPLC
(CHIRALCEL AD-H, i-PrOH/hexane = 1/50, flow
rate = 0.5 mL/min); tR = 14.5 min (95.1%), tR =
20.3 min (4.9%); IR (neat): 3031, 1741, 1604, 1496,
Typical procedure for the synthesis of optically active
esters from racemic secondary alcohols using benzoic
anhydride with BTM is described: To a solution of
benzoic anhydride (61.0 mg, 0.270 mmol) and 3-phenyl-
propionic acid (34.1 mg, 0.226 mmol) in dichloro-
methane (1.5 mL) at room temperature were added
diisopropylethylamine (94.0 lL, 0.540 mmol), BTM
(3.8 mg, 0.015 mmol) and ( )-1-phenyl-1-propanol
(40.8 lL, 0.300 mmol). The mixture was stirred for
12 h at room temperature, and then quenched with
saturated aqueous NaHCO3. The organic layer was sepa-
rated and the aqueous layer was extracted with diethyl
ether (three times). The combined organic layer was
dried over Na2SO4. After filtration of the mixture and
evaporation of the solvent, the crude product was puri-
fied by preparative thin layer chromatography on silica
to afford the corresponding ester (39.7 mg, 48%, 89%
ee) and the recovered optically active secondary alcohol
(19.4 mg, 47%, 85% ee), (Table 3, s = 45.6, entry 2).
1
752, 700 cmꢀ1; H NMR (CDCl3): d 7.27–7.14 (m, 7H,
Ph), 7.13–7.07 (m, 3H, Ph), 5.59 (t, J = 7.0 Hz, 1H,
1-H), 2.90–2.83 (m, 2H, 20-H), 2.61 (ddd, J = 16.0, 9.0,
9.0 Hz, 1H, 30-H), 2.57 (ddd, J = 16.0, 9.6, 9.0 Hz, 1H,
30-H), 1.86–1.66 (m, 2H, 2-H), 0.76 (t, J = 7.5 Hz, 3H,
3-H); 13C NMR (CDCl3): d 172.2, 140.48, 140.46,
128.4, 128.3, 128.2, 127.7, 126.5, 126.2, 77.4, 36.1,
30.9, 29.3, 9.8; HR MS: calcd for C18H20O2Na
(M+Na+) 291.1356, found 291.1344.
Typical procedure for the synthesis of optically active
esters from racemic secondary alcohols using PMBA
with BTM is described: To a solution of PMBA
(77.4 mg, 0.270 mmol) and 3-phenylpropionic acid
(33.9 mg, 0.225 mmol) in dichloromethane (1.5 mL) at
room temperature were added diisopropylethylamine
In summary, we have developed a novel method for
producing optically active secondary alcohols and their
carboxylic esters: in other words, the kinetic resolution
of racemic benzylic secondary alcohols, using free

I. Shiina, K. Nakata / Tetrahedron Letters 48 (2007) 8314–8317
8317
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carboxylic acids coupled with benzoic anhydride and
tetramisole derivatives. We found that the reaction using
4-methoxybenzoic anhydride (PMBA) produced the
corresponding esters in high ee under mild conditions,
whereas the resulting optically active alcohols were
obtained with high selectivity when non-substituted ben-
zoic anhydride was used as a coupling reagent. This
protocol produces chiral carboxylic esters directly from
free carboxylic acids and racemic secondary alcohols by
using the trans-acylation process to generate mixed
anhydrides from acid components coupled with benzoic
anhydride derivatives under the influence of chiral cata-
lysts. Further studies on the reaction using benzoic
anhydrides, as well as other applications of this protocol
to the synthesis of optically active compounds, are now
in progress.
Acknowledgements
This study was partially supported by a Research Grant
from the Center for Green Photo-Science and Technol-
ogy, and Grants-in-Aid for Scientific Research from the
Ministry of Education, Science, Sports and Culture,
Japan.
5. For the systematic studies on the substituent effects of the
aromatic ring of benzoic anhydrides, see Ref. 3c.
6. The s-values were determined according to the litera-
ture method:2a,4c s = ln((1 ꢀ CHPLC)(1 ꢀ eeA))/ln((1 ꢀ
CHPLC)(1 + eeA)). The conversion CHPLC used in the above
equation was calculated as CHPLC = eeA/(eeE + eeA), where
eeE is the enantiomeric excess of ester and eeA is the
enantiomeric excess of unreacted alcohol. The conversion
values thus obtained were generally within 1–2% of the
values obtained by 1H NMR integration of the crude
reaction mixture.
7. The BTM-catalyzed reaction of ( )-1 with benzoic anhy-
dride in the absence of 3-phenylpropionic acid produced the
corresponding benzoate in 3% yield with 11% ee, accom-
panied by 97% recovery of the unreacted alcohol (1.5% ee),
as shown by Birman and Li4c The sense of the optical
rotation of the recovered alcohol is opposite to that of 1
produced in Table 2; therefore, the ee of (S)-1 in entry 1 was
somewhat reduced (ca. 3–4%) by this effect.
8. The BTM-catalyzed reaction of ( )-1 with PMBA in the
absence of 3-phenylpropionic acid produced the corre-
sponding 4-methoxybenzoate in 3% yield with 4.4% ee,
accompanied by 80% recovery of the unreacted alcohol
(1.5% ee). The sense of the optical rotation of the recovered
alcohol is opposite to that of 1 produced in Table 2;
therefore, the ee of (S)-1 in entry 4 was somewhat reduced
(ca. 3–4%) by this effect.
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