Easy separation of optically active secondary alcohols by enzymatic hydrolysisof solublepolymer-supported carbonates

Article abstract of DOI:10.1246/bcsj.20090271

The enzyme-mediated enantioselective hydrolysisof middlemolecular weight poly(ethylene glycol) (PEG)- supported carbonates isdisclosed. The representative water-soluble substrate was prepared by the immobilization of (±)-1-phenylethanol onto a monomethoxy PEG (MPEG, av. M_w 5000) or PEG (av. MM_w 4600) through a carbonate linker. Porcine pancreas lipase (PPL) enantioselectively catalyzed the hydrolysisof the polymer-supported substrate ina mixed solvent (hexane/buffer = 9/1) at 0°C to afford the corresponding optically active compounds. In this system, the separation of the remaining (S)-substrate and the resulting (R)-alcohol was achieved by a simple procedure without any laborious column chromatography. The substrate was easily hydrolyzed with NaOH in MeOH-H₂Oto give the (S)- alcohol.This procedure was also applicable to the preparation of other optically active secondary alcohols. As expected, an introduction of a hydrophobic spacer between the MPEG moiety and the carbonate linker affected both the reactivity and enantioselectivity. An o-substitution produced a lower conversion than those of the reaction of the m- and p-substituted substrates. While the substrate with a p-phenylethyl spacer gave the best E value (>200) with low conversion, the reaction of the substrate with a p-phenylmethyl spacer smoothly proceeded with high enantioselectivity (E value = 151).

Full text of DOI:10.1246/bcsj.20090271

182
Bull. Chem. Soc. Jpn. Vol. 83, No. 2, 182–189 (2010)
© 2010 The Chemical Society of Japan
Easy Separation of Optically Active Secondary Alcohols by Enzymatic
Hydrolysis of Soluble Polymer-Supported Carbonates
Masayuki Okudomi, Megumi Shimojo, Masaki Nogawa, Ayae Hamanaka,
Natsue Taketa, Takuya Nakagawa, and Kazutsugu Matsumoto*
Department of Chemistry, Meisei University, 2-1-1 Hodokubo, Hino, Tokyo 191-8506
Received October 9, 2009; E-mail: mkazu@chem.meisei-u.ac.jp
The enzyme-mediated enantioselective hydrolysis of middle molecular weight poly(ethylene glycol) (PEG)-
supported carbonates is disclosed. The representative water-soluble substrate was prepared by the immobilization of
(«)-1-phenylethanol onto a monomethoxy PEG (MPEG, av. Mw 5000) or PEG (av. Mw 4600) through a carbonate linker.
Porcine pancreas lipase (PPL) enantioselectively catalyzed the hydrolysis of the polymer-supported substrate in a mixed
solvent (hexane/buffer = 9/1) at 0 °C to afford the corresponding optically active compounds. In this system, the
separation of the remaining (S)-substrate and the resulting (R)-alcohol was achieved by a simple procedure without any
laborious column chromatography. The substrate was easily hydrolyzed with NaOH in MeOH-H2O to give the (S)-
alcohol. This procedure was also applicable to the preparation of other optically active secondary alcohols. As expected,
an introduction of a hydrophobic spacer between the MPEG moiety and the carbonate linker affected both the reactivity
and enantioselectivity. An o-substitution produced a lower conversion than those of the reaction of the m- and
p-substituted substrates. While the substrate with a p-phenylethyl spacer gave the best E value (>200) with low
conversion, the reaction of the substrate with a p-phenylmethyl spacer smoothly proceeded with high enantioselectivity
(E value = 151).
Optically active secondary alcohols are versatile intermedi-
substrates, and the easy separation of the products by an
extraction procedure was achieved. However, for the isolation
of the MPEG-supported compounds through all processes of
the substrate syntheses, the column chromatography steps were
still needed because the compounds were liquids. We now
disclose the enzyme-mediated kinetic resolution of higher-
molecular weight MPEG (av. Mw 5000) and PEG (av. Mw
4600)-supported carbonates, which are solids and easier to
handle.18 We also report the introduction of an appropriate
hydrophobic spacer between the PEG moiety and the carbonate
linker, and the structure of the linker affects both the reactivity
and enantioselectivity.
ates in organic syntheses. The kinetic resolution of racemic
alcohols and esters using hydrolytic enzymes is one of the
practical methods for the preparation of optically active
compounds, and a significant number of examples have been
reported.1 During the reaction, the enantiomers, the remaining
substrate, and the resulting product, should be separated,
however the tedious and wasteful separation step by column
chromatography is still a big problem for an easy operation and
a sustainable product. Although several easy separation process
studies have been published,2-5 facile and efficient procedures
are still desired.
On the other hand, solid-phase chemistry using insoluble
polymers (polystyrene, silica gel, etc.) has been developed,
especially in the field of combinatorial chemistry. Although
enzymatic transformation on a polymer support is also an
attractive method for the easy isolation of the products, there
have been relatively few reports on polymer-supported reac-
tions by enzymes.6-12 Recently, poly(ethylene glycol) (PEG)
has been recognized as an inexpensive and convenient soluble
polymer,13-16 and the synthetic approach using a soluble
polymer is termed liquid-phase chemistry. We noticed that a
PEG-supported strategy could be suitable for an enzymatic
transformation and potentially useful for the easy isolation of
the products, and we have already succeeded in the kinetic
resolution of a low-molecular weight monomethoxy PEG
(MPEG, av. Mw 550 and 750)-supported substrate with a
carbonate linker using a hydrolytic enzyme (porcine pancreas
lipase (PPL), lipase Type II from Sigma).17 The broad
solubility of PEG facilitated the analysis of the PEG-supported
Results and Discussion
We selected the carbonate («)-1 as the basic substrate
without a spacer (Scheme 1). The carbonate is a typical linker
used in organic synthesis on a polymer support, and («)-1 was
easily prepared by the coupling of a racemic imidazolide («)-2
derived from 1-phenylethanol ((«)-3) with MPEG5000-OH (4).
We are also interested in the affect of a hydrophobic spacer
between the MPEG moiety and the carbonate linker. The
substrates («)-5a-5e, which contain the ortho-, meta-, and
para-substituted spacers on the benzene ring, were also
synthesized in 3 steps from the mesylate 6 and the correspond-
ing esters 7a-7e. By making use of MPEG5000-OH, which has
been utilized in many studies, as the basic matrix, it allows us
to isolate and purify the intermediates 8 and 9 and the
substrates («)-1 and -5 by a simple precipitation procedure
from diethyl ether.14 In a similar manner, the substrate («)-10
supported by PEG4600-OH (11) was prepared from an imida-
Published on the web January 29, 2010; doi:10.1246/bcsj.20090271

M. Okudomi et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 2 (2010)
183
O
Ph
Me
O
Ph
Me
a)
b)
N
N
O
O
O
( )-2
( )-1 (98%)
OH
OMe
MPEG5000
OMe
n-1
c)
HO
Ph
4
n-1
OMs
6 (99%)
O
O
O
O
7a-e
8a (92%) 8d (96%)
8b (94%) 8e (97%)
8c (97%)
O
a: n = 1 (ortho)
b: n = 1 (meta)
c: n = 1 (para)
d: n = 2 (para)
e: n = 3 (para)
OH
O
O
Me
d)
a)
n-1
O
n-1
9a (95%) 9d (90%)
9b (96%) 9e (89%)
9c (97%)
( )-5a (90%) ( )-5d (95%)
( )-5b (91%) ( )-5e (99%)
( )-5c (98%)
Ph
O
O
Ph
a)
OH
HO
Me
O
O
O
O
Me
MPEG4600
( )-10 (99%)
11
Scheme 1. a) («)-2, DMAP/DMF, 100 °C (1 and 5) or 120 °C (10); b) MsCl, Et3N/CH2Cl2, rt; c) 7a-7e, Cs2CO3/DMF, 70 °C; and
d) DIBAL/CH2Cl2, 0 °C.
O
Ph
zolide («)-2. On the other hand, the substrates («)-12 and -13
were also constructed by the coupling of an imidazolide («)-14
from («)-1-phenyl-1-propanol (15) or («)-16 from («)-4-
benzyloxy-2-butanol (17) with 9c and 9d (Scheme 2). The
yields of the PEG-supported compounds were based on the
weights of the starting materials. The purities were determined
by 1H NMR analysis, and the terminal methyl group and/or the
PEG-methylenes were used as the reference. Moreover, the
productions of the PEG-supported substrates were also con-
firmed by ESI-TOFMS. For example, Figure 1a shows a part of
the mass spectrum obtained for MPEG5000-OH (4). Because the
spectrum shows the characteristic PEG series of ions with m/z
22 spacing, the most abundant ion is estimated to be 2352 Da
and the molecular mass of 4 is determined to be ca. 4658 Da
([CH3O(CH2CH2O)105H¢2Na]2+; z = +2). On the other hand,
the mass spectrum series of the compound («)-5c is shifted to a
higher m/z range (Figure 1b). The estimated m/z of 5c is then
2479 Da as the most abundant ion, and the molecular mass is
evaluated at ca. 4912 Da. This result is fairly consistent with the
calculated mass (4909 Da) from CH3O(CH2CH2O)105C16H15O3.
The PPL-catalyzed reactions of («)-1 were examined under
various reaction conditions, and the results are shown in
Table 1. In a typical experiment, 125 mg of («)-1 (sub. concn.
5 mM) and 10 mg of PPL were added to a medium (5 mL) in a
test tube, and the mixture was stirred for 24 h at a constant
temperature. At first, the reaction was carried out in 0.1 M
phosphate buffer (pH 6.5) at 30 °C (Entry 1).17 Although the
hydrolysis of («)-1 proceeded, both the reactivity and enantio-
selectivity were moderate (conv. = 0.27, E value = 12).19 In
general, lipases works at an interface between organic phase
and water. In our case, the reaction was examined in a
homogeneous system, which was not suitable for PPL. More-
a)
O
O
O
Et
( )-12c (98%)
9c
O
OBn
b)
a)
O
O
O
O
Me
( )-13c (97%)
O
Ph
O
O
Et
( )-12d (89%)
9d
O
OBn
Me
b)
N
O
O
O
( )-13d (95%)
O
Ph
O
OBn
Me
N
O
Et
N
N
O
( )-14
( )-16
Scheme 2. a) («)-14, DMAP/DMF, 100 °C (12c) or 120 °C
(12d) and b) («)-16, DMAP/DMF, 130 °C.
over, the procedure had few advantages for easy preparation
versus using low molecular-weight MPEG550-supported sub-
strates because the unreacted 1 should be extracted from the
mixture by EtOAc. We then tried to examine the reaction in a

184
Bull. Chem. Soc. Jpn. Vol. 83, No. 2 (2010)
Enzymatic Reaction of Polymer-Bound Carbonate
Table 1. Enantioselective Hydrolysis of MPEG5000
Supported Carbonates («)-1 without a Spacera)
-
(a)
2352
O
Ph
PPL
500
O
O
Me
organic solvent-buffer
24 h
( )-1
Intensity
O
Ph
Me
OH
+
O
O
Me
Ph
(S)-1
(R)-3
Organic solvent Temp Ee of Ee of
(ratio of media)b) /°C 1/%c) 3/%d)
Entry
Conv.e) E valuef)
0
1
2
3
4
5
6
7
8
9
® (0/10)
30
30
30
30
30
30
30
30
30
30
20
10
0
29
18
28
28
30
88
83
15
18
4
80
73
79
78
82
65
61
78
78
36
88
93
96
0.27
0.20
0.26
0.26
0.27
0.58
0.58
0.16
0.19
0.10
0.36
0.31
0.16
12
8
m/z
1800
3200
hexane (1/9)
hexane (3/7)
hexane (5/5)
hexane (7/3)
hexane (9/1)
hexane (40/1)
toluene (9/1)
i-Pr2O (9/1)
OH
11
11
14
13
10
9
10
2
26
41
58
4
(b)
2479
500
Intensity
10 Et2O (9/1)
11 hexane (9/1)
12 hexane (9/1)
13 hexane (9/1)
50
41
18
0
a) The reaction was performed using 5 mM of the substrates
with PPL in a medium (organic solvent-0.1 M phosphate
buffer (pH 6.5)) for 24 h. b) A ratio in parentheses reveals the
volume of organic solvent against the volume of buffer. c)
Determined by GLC analysis after hydrolysis of the unreacted
substrates. d) Determined by GLC analysis. e) Calculated by
ee(1)/[ee(1) + ee(3)]. f) Calculated by ln[(1 ¹ conv.)(1 ¹
ee(1))]/ln[(1 ¹ conv.)(1 + ee(1))].
m/z
1800
3200
O
Ph
O
O
O
Me
( )-5c
Figure 1. The ESI-TOFMS spectra of MPEG5000-supported
compounds: (a) the original MPEG5000-OH (4) and (b) the
MPEG5000-supported carbonate with a spacer («)-5c.
OH
Me
Ph
Ph
O
O
Ph
Me
(R)-3, 93% ee
PPL
hexane-buffer
0 °C, 24 h
OH
Me
O
O
O
O
NaOH
( )-10
Me
Ph
MeOH-H2O
Conv. = 0.21
E value = 35
(S)-3, 24% ee
Scheme 3.
two-phase system, and we selected hexane as an additional
hydrophobic organic solvent (Entries 2-7). While the reaction
in a solvent containing 10% hexane proceeded in the lowest
conversion with the lowest E value, increasing the ratio of
hexane improved both the reactivity and enantioselectivity. In
particular, the conversion and E value were up to 0.58 and 13,
respectively, in the case of a mixed solvent containing 90%
hexane (Entry 6). Interestingly, the reaction also smoothly
proceeded in hexane with a small amount of water (hexane/
water = 40/1; Entry 7), but the E value (=10) was smaller than
that in the case of Entry 6. Unfortunately, changing the organic
solvent to toluene, i-Pr2O, and Et2O (Entries 8-10) decreased
both the reactivity and enantioselectivity. For kinetically
controlled reactions, lowering the temperature could improve
the enantioselectivity in many cases.20 We then investigated the
temperature effect of the reaction (Entries 11-13), and it was
found that the reaction at a lower temperature proceeded with a
higher enantioselectivity. For the reaction at 0 °C (Entry 13),
the E value was up to 58 and (R)-3 with a 96% ee was obtained,
although the conversion apparently decreased to 0.16. This
reaction was applicable to the reaction of the PEG4600
-
supported substrate («)-10, and the conversion and E value
were 0.21 and 35, respectively (Scheme 3). In this case, two
molecules of optically active 3 could be released from one
molecule of the racemic substrate 10. On the other hand, for the
reaction of the methyl carbonate («)-18 under the same
conditions (Scheme 4), the reaction scarcely proceeded. In
the same way, the acetate («)-19 was slowly hydrolyzed

M. Okudomi et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 2 (2010)
185
(conv. = 0.11) without any enantioselectivity. These results
indicate that the hydrophilic MPEG5000 matrix could signifi-
cantly change the physical properties of the alcohol 3
and that the substrate would favorably fit the enzyme active
site.
In order to improve the conversion of the reaction, we next
considered that a suitable spacer could increase the affinity to
the active site of the enzyme, which had many hydrophobic
amino residues inside the binding pocket. The results using the
substrates with a spacer are shown in Table 2. Beyond our
expectation, the introduction of the spacer and the substitution
pattern on the benzene ring of the spacer drastically increased
During the reaction, we also achieved an easier separation
procedure of the products due to the use of the MPEG5000-OH
(4) as the basic matrix and the two-phase reaction system. The
separation process in the case of («)-1 is illustrated in
Scheme 5. First, the resulting alcohol (R)-3 was already
extracted in the hexane layer, and was isolated after evapo-
ration. Second, CH2Cl2 was added to the aqueous layer, and
dried over anhydrous Na2SO4. After evaporation, the residue
was poured into Et2O to precipitate the mixture of the (S)-
carbonate and 4 as a white solid, which was collected by simple
filtration. Third, chemical hydrolysis with NaOH in MeOH-
H2O gave the optically active (S)-3. In all cases, we succeeded
in developing a facile work-up procedure to separate the
enantiomers.
Table 2. Enantioselective Hydrolysis of MPEG5000
Supported Carbonates («)-5 with a Spacera)
-
O
Ph
PPL
O
O
Me
hexane-buffer
0 °C, 24 h
n-1
O
( )-5
O
Ph
Me
OH
O
O
+
Me
Ph
n-1
O
(R)-3
(S)-5
O
a: n = 1 (ortho)
b: n = 1 (meta)
c: n = 1 (para)
d: n = 2 (para)
e: n = 3 (para)
O
OMe
Ph
PPL
hexane-buffer
0 °C, 24 h
no reaction
Entry Substrate Ee of 5/%b) Ee of 3/%c) Conv. E value
Me
O
( )-18
1
2
3
4
5
5a
5b
5c
5d
5e
46
82
76
31
42
95
94
97
99
96
0.33
0.47
0.44
0.24
0.30
61
83
151
>200
74
O
O
Me
O
Me
OH
PPL
hexane-buffer
0 °C, 24 h
+
Me
Ph
( )-19
Me
Ph
( )-19
Me
( )-3
Ph
a) The reaction was performed using 5 mM of the substrates
with PPL in a mixed medium (hexane/0.1 M phosphate
buffer (pH 6.5) = 9/1) for 24 h at 0 °C. b) Determined by
GC analysis after hydrolysis of the unreacted substrates.
c) Determined by GC analysis.
Conv. = 0.11
E value ≈ 1
Scheme 4.
(2) Precipitation
(1) Separation
1) addition
of CH2Cl2
2) dehydration
over Na2SO4
3) evaporation
Hexane layer
OH
Aqueous layer
Me
Ph
CH2Cl2
Et2O
(R)-3
Solid
(3) Hydrolysis
OH
O
Ph
Me
O
O
(S)-1
NaOH
+
Me
Ph
MeOH-H2O
(S)-3
OH
OH
4
Scheme 5.

186
Bull. Chem. Soc. Jpn. Vol. 83, No. 2 (2010)
Enzymatic Reaction of Polymer-Bound Carbonate
Table 3. Enantioselective Hydrolysis of MPEG5000
-
Table 4. Hydrolysis of MPEG5000-Supported Carbonates
(«)-1a)
Supported Carbonates («)-12 and -13a)
R2
O
Ph
O
PPL
PPL
O
O
O
R1
hexane-buffer
0 °C, 24 h
O
O
Me
hexane-buffer
0 °C, 24 h
n-1
( )-1
( )-12 and 13
O
R2
OH
O
Ph
Me
OH
+
O
R1 R2
O
O
R1
+
O
O
Me
Ph
n-1
(S)-12 and 13
(R)-15 and 17
(S)-1
(R)-3
12c: n = 1, R1 = Et, R2 = Ph
Ee of Ee of
1/% 3/%
13c: n = 1, R1 = Me, R2 = -CH2CH2OBn
12d: n = 2, R1 = Et, R2 = Ph
Entry Enzyme
Conv. E value
15: R1 = Et, R2 = Ph
17: R1 = Me, R2 = -CH2CH2OBn
1
2
3
¡-Chymotrypsinb)
Cholesterol esterasec)
Purified PPLd)
ca. 0
93
®
48
96
trace
0.66
0.01
®
9
49
13d: n = 2, R1 = Me, R2 = -CH2CH2OBn
Ee of
Ee of
1
Entry Substrate
Conv. E value
substrate/%b) product/%c)
a) The reaction was performed using 5 mM of («)-1 with the
enzyme in a mixed medium (hexane/0.1 M phosphate buffer
(pH 6.5) = 9/1) for 24 h at 0 °C. b) Using 5 mg (30000
U mg¹1). c) Using 1 mg (54 U mg¹1). d) Using 2.5 mg (20100
U mg¹1).
1
2
3
4
12c
13c
12d
13d
86
68
49
7
94
81
93
91
0.48
0.46
0.35
0.07
90
19
45
23
a) The reaction was performed using 5 mM of the substrate
with PPL in a mixed medium (hexane/0.1 M phosphate
buffer (pH 6.5) = 9/1) for 24 h at 0 °C. b) Determined by
GC analysis after hydrolysis of the unreacted substrates.
c) Determined by GC analysis.
proceeded, and the results were not inconsistent with the cases
of 3 described above.
Although commercially available PPL (Type II, Sigma)
works well in this enzymatic reaction, the crude enzyme
contains a number of hydrolases besides the true PPL. The
existence of the several active enzymes might affect the
reactivity and enantioselectivity. In our previous paper, we
found that the hydrolysis of MPEG550-supported carbonate in
buffer could be catalyzed by not the true PPL, but another
unknown enzyme.17b In order to evaluate the accuracy of the
results for MPEG5000-supported substrates under the two phase
system, we then investigated the reaction using commercially
available purified PPL (lipase Type VI-S, Sigma) and two kinds
of major contaminant hydrolases, ¡-chymotrypsin (Type-II,
Sigma) and cholesterol esterase (Sigma), and the results are
shown in Table 4. While ¡-chymotrypsin did not show the
hydrolytic activity (Entry 1), cholesterol esterase showed a
very low E value (Entry 2). It is noteworthy that the purified
PPL catalyzed the hydrolysis of («)-1 with a high enantio-
selectivity, although the conversion was very low (Entry 3).
These results suggest that the enantioselectivity in this reaction
could be due to the true PPL, and the reaction using crude PPL
proceeds with a lower enantioselectivity because of a contam-
ination of cholesterol esterase. Further detailed investigations
are now in progress.
not only the conversion, but also the enantioselectivity. When
using the phenylmethyl spacers («)-5a, -5b, and -5c (n = 1;
ortho-, meta-, and para-substitutions, respectively), the con-
versions were up to 0.33, 0.47, and 0.44, respectively (Entries
1-3). In addition, the reactions also proceeded with higher
enantioselectivities. In particular, the carbonate («)-5c with a
para-substitution was hydrolyzed with an excellent enantio-
selectivity and the E value was up to 151. The carbon number
in the spacer also affected the E value, and the phenylpropyl
spacers («)-5e (n = 3) gave almost the same result
(conv. = 0.30, E value = 74) as the case of («)-5a (Entry 5).
In these cases, we assumed that the substrates would more
favorably fit the enzyme active site than the original substrate
(«)-1. On the other hand, the phenylethyl spacer («)-5d
(n = 2) proceeded with the highest enantioselectivity
(E value > 200) to afford the almost optically pure (R)-3,
although the conversion was not apparently improved over that
of the substrate («)-1 (Entry 4). This result suggests that
the introduction of the phenylethyl spacer could drastically
decrease the reactivity of (S)-enantiomer of 5d, thus this
phenomenon could lead to the lower conversion and higher
enantioselectivity. A 48-h reaction was also performed using
3.6 g of the substrate («)-5d in a recovery flask. In this case, we
Conclusion
In summary, we have demonstrated the enzyme-mediated
kinetic resolution of soluble polymer (MPEG5000 and PEG4600)-
supported carbonates to afford optically active secondary
alcohols 3, 15, and 17. Moreover, we have disclosed that the
reactivity and enantioselectivity can be controlled using a
suitable hydrophobic spacer between the MPEG moiety and the
carbonate linker. In our method, the separation and isolation of
the reaction products were achieved by a simple precipitation
technique without using time- and solvent-consuming column
chromatography. The method was also applicable to gram-scale
experiments. Moreover, the use of the PEG matrix changed the
18
finally obtained (R)-3 (98% ee, ½¡ꢀD = +32.8 (c 0.96, MeOH);
20
lit.21 ½¡ꢀD = +45 (c 5.15, MeOH)) in 12% and (S)-3 (58% ee,
25
½¡ꢀD = ¹21.0 (c 1.06, MeOH)) in 46% isolated yields
(conv. = 0.37, E value = 179). The concept of this reaction
was applicable to the preparation of the other optically active
alcohols (Table 3). The reactions of the substrates («)-12 and
-13 also enantioselectively proceeded to afford the correspond-
ing optically active compounds 15 and 17. Comparing the
reactions using 12c and 13c bearing a phenylmethyl spacer, the
reactions of 12d and 13d bearing a phenylethyl spacer slowly

M. Okudomi et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 2 (2010)
187
washed with 2 M HCl, and dried over Na2SO4. After evaporation,
the residue was poured into Et2O to precipitate the compound 8a as
physical properties of the substrates, and that lead to improved
reactivity. We anticipate that the concept of the enzymatic
reaction using PEG-supported substrates can provide a useful
protocol in not only organic chemistry, but also medicinal
chemistry for the development of PEG-supported pro-drugs,
which gradually release native drugs by enzymatic hydrolysis.
a white solid in 92% yield (935 mg; purity, ca. >99%); IR (KBr):
¹1
2886, 1734, 1466, 1342, 1281, 1242, 1113, 962, 843 cm
;
1H NMR (500 MHz, CDCl3): ¤ 3.38 (s, 3H), 3.47-3.81 (m, PEG-
methylenes), 3.88 (s, 3H), 3.91 (t, J = 5.0 Hz, 2H), 4.20 (t, J =
5.0 Hz, 2H), 6.97-7.01 (m, 2H), 7.45 (ddd, J1 = 1.5 Hz, J2 =
9.0 Hz, J3 = 9.0 Hz, 1H), 7.78 (dd, J1 = 1.5 Hz, J2 = 8.0 Hz, 1H);
13C NMR (125 MHz, CDCl3): ¤ 51.8, 58.9, 68.8, 69.4, 70.4 (PEG),
70.5, 70.9, 71.8, 113.6, 120.4, 120.5, 131.5, 133.3, 158.2, 166.6.
Under an argon atmosphere, DIBAL-H (0.627 mL, 1.0 M
solution in toluene) was added to a solution of 8a (805 mg,
0.157 mmol) in CH2Cl2 (5.6 mL) at 0 °C, and the solution was
warmed to room temperature. After stirring overnight, the reaction
was quenched with water, and the suspension was filtrated through
a celite pad. After evaporation, the residue was precipitate into
Et2O to afford the compound 9a as a white solid in 95% yield
(756 mg; purity, ca. >99%); IR (KBr): 3460, 2887, 1649, 1466,
1360, 1342, 1281, 1242, 1115, 964, 843 cm¹1; 1H NMR (500 MHz,
CDCl3): ¤ 3.25 (t, J = 6.5 Hz, 1H), 3.38 (s, 3H), 3.45-3.82 (m,
PEG-methylenes), 3.86 (t, J = 4.5 Hz, 2H), 4.21 (t, J = 4.5 Hz,
2H), 4.66 (d, J = 7.0 Hz, 2H), 6.89 (d, J = 8.0 Hz, 1H), 6.95 (dt,
J1 = 1.0 Hz, J2 = 7.5 Hz, 1H), 7.23-7.28 (m, 2H); 13C NMR
(125 MHz, CDCl3): ¤ 58.9, 61.8, 67.7, 69.4, 70.4 (PEG), 70.5,
71.7, 112.0, 121.0, 128.6, 128.8, 130.2, 156.7.
Experimental
General Procedure and Instruments. 1H (500 MHz) and 13
C
(125 MHz) NMR spectra were recorded on a JEOL ¡-500 with
tetramethylsilane as the internal standard. ESI-TOF mass spectra
were measured in MeOH-H2O solution including AcONa with a
JEOL JMS-T100. IR spectra were recorded on a Shimadzu
Prestige-21 FT-IR Spectrometer. All enzymatic reactions were
performed in a SANYO incubator MIR-253. Analytical TLC was
performed on Kieselgel 60 F254 Art. 5715 (E. Merck). Preparative
TLC was performed on Kieselgel 60 F254 Art. 5744 (E. Merck).
The optical rotations were measured with a Jasco DIP-1000
polarimeter. HPLC data were obtained on a Shimadzu LC-10ADvp,
SPD-10Avp, and sic 480II date station (System Instruments Inc.).
GLC data were obtained on GL Sciences GC 353B and sic 480 II.
MPEG5000-OH (4) was purchased from Fluka, PEG4600-OH (11)
from Aldrich. All other chemicals were also obtained from
commercial sources. The synthetic procedure of imidazolides
(«)-2, -14, and -16 have already been reported.17
Preparation of MPEG5000-Supported Carbonate Coupled
with 1-Phenylethanol (3) without a Spacer ((«)-1). Under an
argon atmosphere, imidazolide («)-2 (131 mg, 0.605 mmol) and
DMAP (73.8 mg, 0.604 mmol) were added to a solution of 4
(1.01 g, 0.201 mmol) in DMF (13 mL), and the solution was stirred
for 12 h at 100 °C. After evaporation in vacuo, the residue was
precipitated into Et2O to afford the compound («)-1 as a white
Under an argon atmosphere, («)-2 (84.9 mg, 0.393 mmol) and
DMAP (46.2 mg, 0.378 mmol) were added to a solution of 9a
(641 mg, 0.126 mmol) in DMF (8.4 mL), and the solution was
stirred for 12 h at 100 °C. After the solution was evaporated in
vacuo, the residue was precipitate into Et2O to afford the compound
(«)-5a as a white solid in 90% yield (593 mg; purity, ca. >99%); IR
(KBr): 2882, 1746, 1651, 1466, 1360, 1342, 1279, 1242, 1113, 964,
843 cm¹1; 1H NMR (500 MHz, CDCl3): ¤ 1.59 (d, J = 6.5 Hz, 3H),
3.38 (s, 3H), 3.45-3.87 (m, PEG-methylenes), 4.13 (t, J = 5.0 Hz,
2H), 5.19 (d, J = 12.5 Hz, 1H), 5.22 (d, J = 12.5 Hz, 1H), 5.74 (q,
J = 6.5 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 6.93 (dt, J1 = 1.0 Hz,
J2 = 7.5 Hz, 1H), 7.23-7.40 (m, 7H); 13C NMR (125 MHz, CDCl3):
¤ 22.3, 58.9, 64.9, 67.8, 69.5, 70.4 (PEG), 70.6, 70.8, 71.8,
76.2, 111.5, 120.5, 123.8, 125.9, 128.0, 128.4, 129.5, 129.6, 141.0,
154.5, 156.5; ESI-TOF MS m/z 2479 Da (2477 Da calcd for
[CH3O(CH2CH2O)105C16H15O3¢2Na]2+).
solid in 98% yield (1.02 g; purity, ca. >99%); IR (KBr): 2887,
¹1
1744, 1636, 1466, 1342, 1281, 1113, 964, 843 cm
;
1H NMR
(500 MHz, CDCl3): ¤ 1.59 (d, J = 6.5 Hz, 3H), 3.38 (s, 3H), 3.45-
3.85 (m, PEG-methylenes), 4.23 (td, J1 = 4.5 Hz, J2 = 12.0 Hz,
1H), 4.28 (td, J1 = 5.0 Hz, J2 = 12.0 Hz, 1H), 5.72 (q, J = 6.5 Hz,
1H), 7.23-7.39 (m, 5H); 13C NMR (125 MHz, CDCl3): ¤ 22.2,
58.8, 66.7, 68.7, 70.4 (PEG), 70.6, 71.7, 76.3, 125.9, 127.9, 128.3,
140.8, 154.3; ESI-TOF MS m/z 2426 Da (2424 Da calcd for
[CH3O(CH2CH2O)105C9H9O2¢2Na]2+).
Other substrates were synthesized by the same procedure.
Preparation of MPEG5000-Supported Carbonate with an
Compound («)-5b: Yield 91% (purity, ca. >99%) from 9b;
IR (KBr): 2887, 1746, 1651, 1466, 1342, 1279, 1242, 1115, 964,
843 cm¹1; 1H NMR (500 MHz, CDCl3): ¤ 1.59 (d, J = 6.5 Hz, 3H),
3.38 (s, 3H), 3.45-3.82 (m, PEG-methylenes), 3.85 (t, J = 5.0 Hz,
2H), 4.11 (t, J = 5.0 Hz, 2H), 5.06 (d, J = 12.0 Hz, 1H), 5.11 (d,
J = 12.0 Hz, 1H), 5.73 (q, J = 6.5 Hz, 1H), 6.87 (dd, J1 = 2.0 Hz,
J2 = 8.0 Hz, 1H), 6.91 (s, 1H), 6.93 (d, J = 7.5 Hz, 1H), 7.25 (t,
J = 8.0 Hz, 1H), 7.28-7.38 (m, 5H); 13C NMR (125 MHz, CDCl3):
¤ 22.2, 58.9, 67.2, 69.2, 70.4 (PEG), 70.6, 70.7, 70.8, 71.8, 76.4,
114.1, 114.6, 120.4, 125.9, 128.0, 128.4, 129.4, 136.5, 140.8,
154.3, 158.7; ESI-TOF MS m/z 2479 Da (2477 Da calcd for
[CH3O(CH2CH2O)105C16H15O3¢2Na]2+).
Compound («)-5c: Yield 98% (purity, ca. 94%) from 9c; IR
(KBr): 2886, 1742, 1651, 1466, 1342, 1279, 1242, 1115, 964,
843 cm¹1; 1H NMR (500 MHz, CDCl3): ¤ 1.58 (d, J = 6.5 Hz, 3H),
3.38 (s, 3H), 3.45-3.82 (m, PEG-methylenes), 3.85 (t, J = 5.0 Hz,
2H), 4.12 (t, J = 5.0 Hz, 2H), 5.03 (d, J = 12.0 Hz, 1H), 5.08 (d,
J = 12.0 Hz, 1H), 5.72 (q, J = 6.5 Hz, 1H), 6.88 (d, J = 9.0 Hz,
2H), 7.18-7.40 (m, 5H), 7.28 (d, J = 9.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3): ¤ 22.2, 58.9, 67.3, 69.3, 69.5, 70.4 (PEG),
ortho-Phenylmethyl Spacer ((«)-5a).
Under an argon
atmosphere, methanesulfonyl chloride (0.35 mL, 4.51 mmol) and
triethylamine (1.50 mL, 10.8 mmol) were added to a solution of 4
(3.00 g, 0.60 mmol) in CH2Cl2 (13 mL), and the solution was
stirred overnight at room temperature. After evaporation in vacuo,
the residue was poured into Et2O to precipitate a white solid. After
the solid was washed with 2-propanol, evaporation and precip-
itation gave the mesylate 6 as a white solid in 99% yield (3.03 g;
purity, ca. >99%); IR (KBr): 2886, 1636, 1466, 1360, 1342, 1281,
1
1242, 1113, 962, 843 cm¹1; H NMR (500 MHz, CDCl3): ¤ 3.09
(s, 3H), 3.38 (s, 3H), 3.46-3.82 (m, PEG-methylenes), 4.39 (t,
J = 4.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): ¤ 37.6, 58.9, 68.9,
69.2, 70.4 (PEG), 70.5, 70.6, 71.8.
Under an argon atmosphere, methyl salicylate (7a, 60.5 mg,
0.398 mmol) and cesium carbonate (193 mg, 0.589 mmol) were
added to a solution of 6 (1.004 g, 0.1977 mmol) in DMF (6.5 mL),
and the solution was stirred overnight at 70 °C. The mixture was
filtrated through a celite pad, and the filtrate was evaporated in
vacuo. After the residue was dissolved in CH2Cl2, the solution was

188
Bull. Chem. Soc. Jpn. Vol. 83, No. 2 (2010)
Enzymatic Reaction of Polymer-Bound Carbonate
70.65, 70.70, 71.8, 76.3, 114.5, 125.9, 127.4, 128.0, 128.4, 130.1,
140.9, 154.4, 158.9; ESI-TOF MS m/z 2479 Da (2477 Da calcd for
[CH3O(CH2CH2O)105C16H15O3¢2Na]2+).
1.78-2.01 (m, 2H), 2.89 (t, J = 7.5 Hz, 2H), 3.37 (s, 3H), 3.44-
3.80 (m, PEG-methylenes), 3.82 (t, J = 5.0 Hz, 2H), 4.09 (t,
J = 5.0 Hz, 2H), 4.26 (dt, J1 = 2.0 Hz, J2 = 7.0 Hz, 2H), 4.47 (s,
2H), 4.88-4.97 (m, 1H), 6.84 (d, J = 9.0 Hz, 2H), 7.10 (d, J =
8.5 Hz, 2H), 7.22-7.36 (m, 5H); 13C NMR (125 MHz, CDCl3): ¤
20.0, 34.1, 35.8, 58.9, 66.2, 67.2, 68.1, 69.6, 70.4 (PEG), 70.6,
70.7, 71.8, 72.6, 72.9, 114.5, 127.4, 127.5, 128.2, 129.3, 129.7,
138.1, 154.5, 157.4; ESI-TOF MS m/z 2515 Da (2514 Da calcd for
[CH3O(CH2CH2O)105C20H23O4¢2Na]2+).
Compound («)-5d: Yield 95% (purity, ca. 99%) from 9d; IR
(KBr): 2886, 1744, 1638, 1468, 1342, 1281, 1242, 1111, 962,
843 cm¹1; 1H NMR (500 MHz, CDCl3): ¤ 1.58 (d, J = 6.5 Hz, 3H),
2.89 (t, J = 7.0 Hz, 2H), 3.38 (s, 3H), 3.45-3.82 (m, PEG-
methylenes), 3.84 (t, J = 5.0 Hz, 2H), 4.10 (t, J = 5.0 Hz, 2H),
4.26 (dt, J1 = 2.5 Hz, J2 = 7.0 Hz, 2H), 5.70 (q, J = 6.5 Hz, 1H),
6.83 (d, J = 8.5 Hz, 2H), 7.10 (d, J = 8.5 Hz, 2H), 7.28-7.40 (m,
5H); 13C NMR (125 MHz, CDCl3): ¤ 22.2, 34.1, 58.9, 67.3, 68.3,
69.6, 70.4 (PEG), 70.6, 70.7, 71.8, 76.2, 114.5, 125.9, 128.0, 128.4,
129.2, 129.7, 140.9, 154.3, 157.4; ESI-TOF MS m/z 2486 Da
(2484 Da calcd for [CH3O(CH2CH2O)105C17H17O3¢2Na]2+).
Compound («)-5e: Yield 99% (purity, ca. 96%) from 9e; IR
(KBr): 2884, 1742, 1638, 1512, 1466, 1344, 1281, 1252, 1113,
953, 843 cm¹1; 1H NMR (500 MHz, CDCl3): ¤ 1.59 (d, J = 6.5 Hz,
3H), 1.89-1.98 (m, 2H), 2.61 (t, J = 7.5 Hz, 2H), 3.37 (s, 3H),
3.45-3.81 (m, PEG-methylenes), 3.83 (t, J = 5.0 Hz, 2H), 4.086
(dt, J1 = 6.5 Hz, J2 = 10.5 Hz, 1H), 4.088 (t, J = 5.0 Hz, 2H), 4.12
(dt, J1 = 6.5 Hz, J2 = 10.5 Hz, 1H), 5.72 (q, J = 6.5 Hz, 1H), 6.81
(d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.5 Hz, 2H), 7.18-7.42 (m, 5H);
13C NMR (125 MHz, CDCl3): ¤ 22.2, 30.2, 30.8, 58.9, 67.0, 67.2,
69.6, 70.4 (PEG), 70.58, 70.62, 71.7, 76.1, 114.4, 125.8, 127.9,
128.4, 129.1, 133.0, 140.9, 154.4, 156.9; ESI-TOF MS m/z 2493
Da (2491 Da calcd for [CH3O(CH2CH2O)105C18H19O3¢2Na]2+).
Compound («)-12c: Yield 98% (purity, ca. 97%) from 9c; IR
(KBr): 2884, 1744, 1645, 1466, 1342, 1281, 1242, 1113, 962,
843 cm¹1; 1H NMR (500 MHz, CDCl3): ¤ 0.89 (t, J = 7.5 Hz, 3H),
1.77-2.03 (m, 2H), 3.37 (s, 3H), 3.44-3.87 (m, PEG-methylenes),
4.11 (t, J = 5.0 Hz, 2H), 5.02 (d, J = 12.0 Hz, 1H), 5.06 (d, J =
12.0 Hz, 1H), 5.49 (t, J = 6.5 Hz, 1H), 6.87 (d, J = 9.0 Hz, 2H),
7.25 (d, J = 9.0 Hz, 2H), 7.26-7.35 (m, 5H); 13C NMR (125 MHz,
CDCl3): ¤ 9.8, 29.3, 59.0, 67.3, 69.3, 69.6, 70.5 (PEG), 70.67,
70.72, 71.8, 81.5, 114.5, 126.4, 127.4, 128.0, 128.3, 130.1, 139.8,
154.6, 158.9; ESI-TOF MS m/z 2486 Da (2484 Da calcd for
[CH3O(CH2CH2O)105C17H17O3¢2Na]2+).
PEG4600-Supported Substrate Coupled with 1-Phenyletha-
nol ((«)-10): Yield 99% (purity, ca. 89%) from 11; IR (KBr):
¹1
2884, 1744, 1647, 1466, 1342, 1281, 1242, 1115, 964, 843 cm
;
1H NMR (500 MHz, CDCl3): ¤ 1.59 (d, J = 6.5 Hz, 6H), 3.45-3.82
(m, PEG-methylenes), 4.24 (td, J1 = 4.5 Hz, J2 = 12.0 Hz, 2H),
4.27 (td, J1 = 5.0 Hz, J2 = 11.5 Hz, 2H), 5.72 (q, J = 6.5 Hz,
2H), 7.17-7.45 (m, 10H); 13C NMR (125 MHz, CDCl3): ¤ 22.2,
66.7, 68.8, 70.4 (PEG), 70.5, 70.6, 76.4, 125.9, 128.0, 128.4,
140.8, 154.4; ESI-TOF MS m/z 2449 Da (2447 Da calcd for
[(CH2CH2O)103C18H18O5¢2Na]2+).
Typical Experimental Procedure for Enantioselective
Hydrolysis of PEG-Supported Substrates.
To a test tube
containing 125 mg of («)-1 (sub. concn., 5 mM) was added 4.5 mL
of hexane and 0.5 mL of 0.1 M phosphate buffer (pH 6.5). To the
mixture was added 10 mg of lipase from porcine pancreas (PPL;
Type II, Sigma) (187 U mg¹1, using olive oil at pH 7.7), and the
solution was stirred for 24 h at 0 °C. After the organic layer was
separated and evaporated in vacuo, the ee of the resulting (R)-
alcohol 3 (96% ee) in the residue was determined by GC analysis.
On the other hand, the aqueous layer was diluted with CH2Cl2, and
dried over Na2SO4. After evaporation, the residue was hydrolyzed
with 2 M NaOH aq. (1.0 mL) in MeOH (4.0 mL). The products
were extracted with hexane (©3), and the organic layer was dried
over Na2SO4. After evaporation, the ee of the corresponding (S)-3
(18% ee) was determined by GC analysis.
Other reactions were carried out by the same procedure.
Typical Preparative Scale Reaction of PEG-Supported
Substrates.
To a recovery flask containing 3.6 g of («)-5d
Compound («)-12d: Yield 89% (purity, ca. 61%) from 9d; IR
(KBr): 2886, 1748, 1638, 1466, 1342, 1281, 1242, 1115, 964,
843 cm¹1; 1H NMR (500 MHz, CDCl3): ¤ 0.90 (t, J = 7.5 Hz, 3H),
1.77-1.89 (m, 1H), 1.91-2.03 (m, 1H), 2.88 (t, J = 7.0 Hz, 2H),
3.37 (s, 3H), 3.44-3.88 (m, PEG-methylenes), 4.11 (t, J = 5.0 Hz,
2H), 4.25 (dt, J1 = 4.5 Hz, J2 = 7.5 Hz, 2H), 5.47 (t, J = 6.5 Hz,
1H), 6.82 (d, J = 9.0 Hz, 2H), 7.07 (d, J = 9.0 Hz, 2H), 7.21-7.36
(m, 5H); 13C NMR (125 MHz, CDCl3): ¤ 9.8, 29.2, 34.1, 58.9,
67.2, 68.3, 69.6, 70.4 (PEG), 70.6, 70.7, 71.8, 81.3, 126.3, 127.9,
128.3, 129.2, 129.7, 139.8, 154.5, 160.9; ESI-TOF MS m/z 2493
Da (2491 Da calcd for [CH3O(CH2CH2O)105C18H19O3¢2Na]2+).
Compound («)-13c: Yield 97% (purity, ca. 69%) from 9c; IR
(KBr): 2886, 1734, 1647, 1466, 1342, 1281, 1242, 1115, 964,
843 cm¹1; 1H NMR (500 MHz, CDCl3): ¤ 1.31 (d, J = 6.0 Hz, 3H),
3.38 (s, 3H), 3.42-3.93 (m, PEG-methylenes), 4.12 (t, J = 5.0 Hz,
2H), 4.46 (s, 2H), 4.98 (td, J1 = 1.5 Hz, J2 = 6.5 Hz, 1H), 5.05 (d,
J = 12.0 Hz, 1H), 5.06 (d, J = 12.0 Hz, 1H), 6.89 (d, J = 9.0 Hz,
2H), 7.22-7.37 (m, 5H), 7.30 (d, J = 8.5 Hz, 2H); 13C NMR (125
MHz, CDCl3): ¤ 20.0, 35.8, 58.9, 66.2, 67.3, 69.0, 69.5, 70.4
(PEG), 70.6, 70.7, 71.8, 72.7, 72.9, 114.4, 114.5, 127.4, 127.5,
128.2, 130.1, 138.1, 154.5, 158.9; ESI-TOF MS m/z 2508 Da
(2506 Da calcd for [CH3O(CH2CH2O)105C19H21O4¢2Na]2+).
Compound («)-13d: Yield 95% (purity, ca. 89%) from 9d;
IR (KBr): 2886, 1738, 1645, 1468, 1342, 1281, 1242, 1111, 962,
843 cm¹1; 1H NMR (500 MHz, CDCl3): ¤ 1.29 (d, J = 6.5 Hz, 3H),
(sub. concn., 5 mM) was added 130.5 mL of hexane and 14.5 mL
of 0.1 M phosphate buffer. To the mixture was added 290 mg of
PPL, and the solution was stirred for 48 h at 0 °C. After the organic
layer was separated and evaporated in vacuo, the residue was
purified by preparative TLC (hexane/AcOEt = 2/1) to give (R)-3
18
(9.6 mg, 12%, 98% ee, ½¡ꢀD = +32.8 (c 0.96, MeOH)). On the
other hand, the aqueous layer was diluted with CH2Cl2, and dried
over Na2SO4. After the solution was evaporated in vacuo, the
residue was precipitate into Et2O to afford the compound (S)-5d as
a white solid. To a solution of the solid in MeOH (120 mL) was
added 2 M NaOH aq. (30 mL), and the solution was stirred for 1 h
at rt. The products were extracted with ether (©3), and the organic
layer was washed with brine and dried over Na2SO4. After
evaporation, the residue was purified by column chromatography
(hexane/EtOAc = 2/1) on silica gel to give the corresponding (S)-
25
3 (37.9 mg, 46%, 58% ee, ½¡ꢀD = ¹21.0 (c 1.06, MeOH)).
Several data of alcohols are as follows.
1-Phenylethanol (3): The spectral data were in full agreement
with that of a commercial source. GLC conditions: column, CP-
Cyclodextrin-B-236-M19 (Chrompack), 0.25 mm © 50 m; injec-
tion, 160 °C; detection, 160 °C; oven, 140 °C; carrier gas, He; head
pressure, 2.4 kg cm¹2; retention time, 8.9 (R) and 9.2 (S) min.
1-Phenyl-1-propanol (15): The spectral data were in full
30
agreement with that of a commercial source. (S)-15, ½¡ꢀD = ¹38.3
30
(c 1.02, CHCl3) (86% ee); (R)-15, ½¡ꢀD = +41.4 (c 1.20, CHCl3)

M. Okudomi et al.
Bull. Chem. Soc. Jpn. Vol. 83, No. 2 (2010)
J. S. Yadav, Tetrahedron Lett. 1999, 40, 5905.
189
20
(94% ee); lit.22 (S)-form, ½¡ꢀD = ¹47.0 (c 1.00, CHCl3). GLC
conditions: column, CP-Cyclodextrin-B-236-M19 (Chrompack),
0.25 mm © 50 m; injection, 140 °C; detection, 140 °C; oven,
120 °C; carrier gas, He; head pressure, 2.4 kg cm¹2; retention time,
22.6 (R) and 23.4 (S) min.
8
For lipase-catalyzed kinetic resolution with poly[(acryl-
amide)ethylene glycol] (PEGA)-based resin as a nucleophile, see:
R. V. Ulijn, N. Bisek, S. L. Flitsch, Org. Biomol. Chem. 2003, 1,
621.
4-Benzyloxy-2-butanol (17):
The spectral data were in
9
A. Córdova, M. R. Tremblay, B. Clapham, K. D. Janda,
29
full agreement with those reported.17b (R)-17, ½¡ꢀD = ¹14.9 (c
J. Org. Chem. 2001, 66, 5645.
10 R. L. Halcomb, H. Huang, C.-H. Wong, J. Am. Chem. Soc.
1994, 116, 11315.
11 a) H. Waldmann, A. Reidel, Angew. Chem., Int. Ed. Engl.
1997, 36, 647. b) B. Sauerbrei, V. Jungmann, H. Waldmann,
Angew. Chem., Int. Ed. Engl. 1998, 37, 1143.
12 a) R. V. Ulijn, B. Baragaña, P. J. Halling, S. L. Flitsch,
J. Am. Chem. Soc. 2002, 124, 10988. b) C. E. Humphrey, N. J.
Turner, M. A. M. Easson, S. L. Flitsch, R. V. Ulijn, J. Am. Chem.
Soc. 2003, 125, 13952. c) A. Basso, R. V. Ulijn, S. L. Flitsch, G.
Margetts, I. Brazendale, C. Ebert, L. De Martin, P. Linda, S.
Verdelli, L. Gardossi, Tetrahedron 2004, 60, 589. d) A. Basso, C.
Ebert, L. Gardossi, P. Linda, T. T. Phuong, M. Zhu, L. Wessjohann,
Adv. Synth. Catal. 2005, 347, 963.
29
1.08, MeOH) (97% ee); (S)-17, ½¡ꢀD = +2.1 (c 1.05, MeOH)
27
(13% ee)); lit.17b (S)-form, ½¡ꢀD = +19.0 (c 0.95, MeOH).
HPLC conditions: column, CHIRALCEL OD-H (Daicel Chemical
Industries, Ltd.); eluent, hexane/2-propanol = 90/10; flow rate,
0.5 mL min¹1; 254 nm; temperature, 25 °C; retention time, 13 (S)
and 14 (R) min.
We thank JEOL Ltd. for the ESI-TOFMS spectroscopic
analysis, and Material Science Research Center (Meisei
university) for the NMR analysis.
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