Effects of reaction temperature and acyl group for lipase-catalyzed chiral binaphthol synthesis

Article abstract of DOI:10.1016/j.tetlet.2006.05.056

Candida antarctica lipase-catalyzed hydrolysis of O-butyryl-BINOL [(±)-3] or O-butyryl-6,6′-dibromo-BINOL [(±)-5] yielded optically active BINOL [(R)-1] or 6,6′-dibromo-BINOL [(R)-4] with high enantiomeric excess at 80 °C. Reaction temperature and acyl group of substrate had a great influence on the reactivity and enantioselectivity, respectively, of lipase-catalyzed hydrolysis for chiral binaphthol synthesis.

Full text of DOI:10.1016/j.tetlet.2006.05.056

Tetrahedron Letters 47 (2006± 4797–4801
Effects of reaction temperature and acyl group for
lipase-catalyzed chiral binaphthol synthesis
*
Naoto Aoyagi, Naomi Ogawa and Taeko Izumi
Department of Chemistry and Chemical Engineering, Graduate School of Science and Engineering, Yamagata University,
Jyonan, Yonezawa, Yamagata 992-8510, Japan
Received 23 January 2006; revised 6 May 2006; accepted 11 May 2006
0
Abstract—Candida antarctica lipase-catalyzed hydrolysis of O-butyryl-BINOL [(± ±-3] or O-butyryl-6,6 -dibromo-BINOL [(± ±-5]
0
yielded optically active BINOL [(R±-1] or 6,6 -dibromo-BINOL [(R±-4] with high enantiomeric excess at 80 °C. Reaction tempera-
ture and acyl group of substrate had a great influence on the reactivity and enantioselectivity, respectively, of lipase-catalyzed hydro-
lysis for chiral binaphthol synthesis.
Ó 2006 Elsevier Ltd. All rights reserved.
0
0
Chiral 2,2 -dihydroxy-1,1 -binaphthyl (BINOL± deriva-
tives have been widely used as chiral ligands of catalysts
with other enzymes, BINOL derivatives can be resolved
2
0a,b
only by lipase from Pseudomonas species.
It can be
1
for asymmetric synthesis. Illustration of recent asym-
metric reactions using BINOL ligands are alkynylation
seen that reactivity of BINOL in the presence of lipase
catalyst is affected by steric hindrance of bulky binaph-
thyl ring. Our previous work demonstrated that
2
of aldehydes, hydrogenation of olefines and allylic
3
4
0
alkylation, cyanation of aldehydes, Mannich-type
lipase-catalyzed amidation of 1,1 -binaphthyl amines
5
6
reactions, Diels–Alder reactions, Michael and epoxi-
or esters was also ineffective in the case of amino or ester
groups directly bonded to the aromatic ring, whereas the
enzymatic resolution was successful when the amino or
ester group was located on the alkyl side chain.2
7
8
dation reactions, aldol reactions, and addition of
diethyl zinc to benzaldehyde. Additionally, chiral
BINOL derivatives have received much attentions in
the context of chiral resolving agent, chiral host com-
pounds, liquid crystals, and chiral polymers, that
include the biaryl unit.
9
1
1
0
1
1
12
13
Candida antarctica lipase B (CALB± can induce high
2
2
enantioselectivity on a broad range of substrates,
2
3
including secondary alcohols and other compounds.
CALB is an interesting lipase with potential application
in a number of industrial processes such as the synthesis
A wide range of oxidative coupling methods for the
preparation of chiral BINOL derivatives have been
developed in the presence of chiral transition metal
catalyst, for example, diamine-copper(I±, schiff-cop-
amino ester-oxovanadium(IV±
ruthenium complexes. Recently, palladium-catalyzed
2
4
25
of triglycerides, esterification of terpenic alcohols,
1
4
etc. In addition, immobilized CALB is thermostable
1
5
16
per(I±,
and salen-
and can be used at 60–80 °C for long periods of time
1
7
26
without loss of activity. Consequently, the applicabil-
0
kinetic resolution of 1,1 -biaryls by alcoholysis of their
ity of immobilized CALB-catalyzed resolutions using
BINOL derivatives at high temperature became an area
of research interest.
1
8
vinyl ethers has been reported. However, synthesis of
BINOL vinyl ethers need hard condition or expensive
reagent. For another approach to chiral BINOL deriva-
tives, chemical and enzymatic resolution of racemic
mixtures have been reported. Although lipases have
been widely employed as catalysts in the synthesis of
extensive optically active compounds in comparison
1
9
20
0 0
Racemic mixtures of 2-acetoxy-2 -hydroxy-1,1 -binaph-
0
0
thyl (± ±-2 and 2-butyroxy-2 -hydroxy-1,1 -binaphthyl
2
0b,27
(± ±-3 were synthesized by known procedures.
6,6 -Dibromo-2-butyroxy-2 -hydroxy-1,1 -binaphthyl (± ±-
was obtained from BINOL via two steps (Scheme 1±.
0
0
0
2
8
5
*
Corresponding author. Tel.: +81 238 26 3126; fax: +81 238 26
413; e-mail: tp455@dip.yz.yamagata-u.ac.jp
At first, we chose cyclopentyl methyl ether (CPME± as
a solvent of lipase-catalyzed hydrolysis, because the
3
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.056

4798
N. Aoyagi et al. / Tetrahedron Letters 47 (2006) 4797–4801
Br
Br
Br
Br
OH
OH
Br2
CH CN
OH
OH
(
n
-PrCO±2O
OCOPr
OH
OCOPr
OCOPr
+
Py / DMAP
toluene / CH Cl2
3
2
o
Br
o
Br
0
C, 2.5 h
0 C - r.t., 4.5 h
(
± ±-1
(± ±-4, 99%
(± ±-5, 80%
(± ±-6, 13%
Scheme 1. Synthesis of substrate (± ±-5.
chemical properties of CPME is similar to methyl tert-
butyl ether (MTBE± and diisopropyl ether (DIPE± which
are very useful for solvent of enzymatic resolutions. In
addition, CPME has high boiling point (106 °C± and
can be used at high temperature in lipase-catalyzed
hydrolysis. As shown in Table 1, CALB-catalyzed
hydrolysis of (± ±-2 was initially attempted at
50
40
30
20
10
8
6
3
0 ºC
0 ºC
0 ºC
2
9,30
3
0 °C.
However, (± ±-2 was not a substrate of choice
at 30 °C condition (entry 1±. In the case of 60 °C condi-
tion, hydrolysis of (± ±-2 proceeded to 35% yield after
0
0
9
6 h (entry 2±, with poor selectivity (28% ee±. The reac-
tion rate at 80 °C was more rapid than 60 °C condition
entry 3±. When the reaction temperature was increased,
the reaction rate evidently increased as shown in Figure
. However, enantioselectivity of (± ±-2 was not satisfac-
24
48
72
96
(
Reaction time (h)
Figure 1. Time conversion for CALB-catalyzed hydrolysis of (± ±-2 at
various temperatures.
1
tory (Fig. 2±.
Next, (± ±-3 was used as substrate of enzymatic hydro-
lysis with the view of high enantioselective resolution.
Similar to the lipase-catalyzed hydrolysis of (± ±-2, ester
be seen that enantioselectivity of monoacylated BINOL
in the presence of CALB catalyst was affected by alkyl
size of the substituted acyl group.
(
1
(
± ±-3 was not a substrate under 30 °C condition (Table
, entry 4±. In the case of 60 °C condition, hydrolysis of
± ±-3 proceeded at a low reaction rate, although this
We optimized the solvents for the reaction at 80 °C con-
dition. As shown in Table 2, toluene resulted in the
excellent yields (entries 7, 8±, with higher enantioselectiv-
ities than hydrolysis using CPME. Hydrolysis conver-
sions using other solvents were very low (entries 1–6±,
although these reactions afforded high enantioselectivi-
ties, with the exception of using N,N-dimethylform-
amide (DMF±. The scale-up reaction in toluene was
carried out at 100 °C in order to obtain the isolated
reaction gave high enantioselectivity (entry 5±. CALB-
catalyzed hydrolysis of (± ±-3 at 80 °C proceeded to
4
3% yield after 72 h (entry 6±, with high enantioselectiv-
ity (91% ee±. As shown in Figure 3, temperature effect
for hydrolysis of (± ±-3 was shown more evidently than
hydrolysis of (± ±-2. In addition, enantioselectivity with
(
± ±-3 was higher than that with (± ±-2 (Fig. 4±. It could
a
Table 1. Effects of temperature and acyl group for CALB-catalyzed hydrolysis of (± ±-2 and 3
O
O
O
R
CALB
OH
OH
O
R
+
OH
n
-BuOH
CPME
OH
o
3
0 ~ 80 C
2: R = Me
(
± ±-2 or 3
(R±-1
(S±-2 or 3
3
: R =
n
-Pr
c
c
d
Entry
Substrate
Temperature (°C±
Time (h±
Diol (R±-1
Monoester (S±-2 or 3
E value
b
c
b
c
Yield (%±
ee (%±
Yield (%±
ee (%±
1
2
3
4
5
6
(± ±-2
(± ±-2
(± ±-2
(± ±-3
(± ±-3
(± ±-3
30
60
80
30
60
80
96
96
48
96
96
72
Not detected
35
52
Not detected
12
43
Recovery
65
48
Recovery
88
57
—
2
2
—
233
42
28
23
14
24
99
91
16
65
a
Reaction conditions: 0.0672 mmol of substrate, 0.672 mmol of n-butanol, 40 mg of CALB, 2 mL of CPME, 2.0 mg of acetophenone (standard
substance±.
b
c
Determined by internal standard method of HPLC using Chiralcel OG (254 nm, 0.5 mL/min, n-hexane/IPA = 15:1±.
Configuration and enantioselectivity were determined by HPLC analysis using Chiralcel OG (254 nm, 0.5 mL/min, n-hexane/IPA = 15:1±.
d
ꢀ1
ꢀ1
E = ln[(ee
p
(1 ꢀ ee
s
±±(ee
p
+ ee
s
±
] /ln[(ee
p
(1 + ee
s
±±(ee
p
+ ee ± ]; see Ref. 31.
s

N. Aoyagi et al. / Tetrahedron Letters 47 (2006) 4797–4801
4799
100
100
8
6
4
2
0
0
0
0
0
80
(
R)-1
(S)-2
60
4
2
0
0
0
(
(
R)-1
S)-3
0
20
40
60
0
20
40
60
Conversion (%)
Conversion (%)
Figure 2. Conversion versus ee plots for CALB-catalyzed hydrolysis of
± ±-2 at 80 °C.
Figure 4. Conversion versus ee plots for CALB-catalyzed hydrolysis of
± ±-3 at 80 °C.
(
(
5
4
3
2
1
0
chiral BINOLs and to decrease the amount of CALB.32
This reaction temperature could permit high isolated
yield [(R±-1, 51%; (S±-3, 48%] with high enantioselectivity
[(R±-1, 92% ee; (S±-3, 93% ee] even at half amount of
CALB in comparison with 80 °C condition.
0
0
0
0
0
8
6
0 ºC
0 ºC
30 ºC
Finally, in order to compare the reactivity of (± ±-3,
0
lipase-catalyzed hydrolysis was carried out using 6,6 -di-
3
3
bromo substituted (± ±-5. The hydrolysis of (± ±-5 gave
R±-4 with moderate enantioselectivity (68% ee±,
although this reaction took place more rapidly than
± ±-3 (Table 3, entry 1±. To explore the effect of alcohol-
(
0
24
48
72
96
(
Reaction time (h)
ysis agent, we examined reaction of (± ±-5 using alcohol
other than the n-butanol. Although 2-chloroethanol was
the best alcoholysis agent in terms of enantioselectivity
Figure 3. Time conversion for CALB-catalyzed hydrolysis of (± ±-3 at
various temperatures.
a
Table 2. Effect of solvents for CALB-catalyzed hydrolysis of (± ±-3 and 2 at 80 °C
O
O
O
R
CALB
OH
OH
O
R
+
OH
n
-BuOH
OH
Org. Solv.
o
8
0 C
3: R = n-Pr
2: R = Me
(± ±-3 or 2
(R±-1
(S±-3 or 2
b
d
d
e
Entry
Substrate
Solvent
Time (h±
Diol (R±-1
Monoester (S±-3 or 2
E value
c
d
c
d
Yield (%±
ee (%±
Yield (%±
ee (%±
1
2
3
4
5
6
7
8
(± ±-3
(± ±-3
(± ±-3
(± ±-3
(± ±-3
(± ±-3
(± ±-3
(± ±-2
Dioxane
CH CN
MEK
72
72
72
72
72
72
72
36
7
5
6
7
7
5
51
53
99
99
99
4
99
99
93
48
93
95
94
93
93
95
49
47
7
4
7
1
7
3
92
47
213
207
213
1
213
205
91
3
DMF
1,2-DCE
n-BuOH
Toluene
Toluene
4
cf.
(± ±-3
CPME
CPME
72
48
43
52
91
23
57
48
65
24
42
2
(± ±-2
a
Reaction conditions: 0.0672 mmol of substrate, 0.672 mmol of n-butanol, 40 mg of CALB, 2 mL of solv., 2.0 mg of acetophenone (standard
substance±.
MEK: methylethylketone, DMF: N,N-dimethylformamide, 1,2-DCE: 1,2-dichloroethane.
b
c
Determined by internal standard method of HPLC analysis using Chiralcel OG (254 nm, 0.5 mL/min, n-hexane/IPA = 15:1±.
Configuration and enantioselectivity were determined by HPLC analysis using Chiralcel OG (254 nm, 0.5 mL/min, n-hexane/IPA = 15:1±.
d
e
ꢀ1
ꢀ1
E = ln[(ee
p
(1 ꢀ ee
s
±±(ee
p
+ ee
s
±
] /ln[(ee
p
(1 + ee
s
±±(ee
p
+ ee
s
±
]; see Ref. 31.

4800
N. Aoyagi et al. / Tetrahedron Letters 47 (2006) 4797–4801
a
Table 3. Effect of alcoholysis agent for CALB-catalyzed hydrolysis of (± ±-5 at 80 °C
Br
Br
Br
Br
O
O
O
CALB
OH
OH
O
+
OH
alcoholysis agent
toluene
OH
o
Br
80 C
Br
(
± ±-5
(R±-4
(S±-5
c
c
d
Entry
Substrate
Alcohol
Time (h±
Diol (R±-4
Monoester (S±-5
E value
b
c
b
c
Yield (%±
ee (%±
Yield (%±
ee (%±
1
2
3
4
(± ±-5
(± ±-5
(± ±-5
(± ±-5
n-BuOH
n-BuOH
48
72
48
48
61
54
34
68
62
79
92
52
39
46
66
63
97
94
47
10
17
30
38
PhCH
ClCH
2
OH
CH
2
2
OH
178
cf.
(± ±-3
n-BuOH
72
51
93
49
92
91
a
Reaction conditions: 0.0672 mmol of substrate, 0.672 mmol of alcohol, 40 mg of CALB, 2 mL of toluene, 2.0 mg of acetophenone (standard
substance±.
b
c
Determined by internal standard method of HPLC analysis using Chiralcel OD (254 nm, 0.5 mL/min, n-hexane/IPA = 9:1±.
Configuration and enantioselectivity were determined by HPLC analysis using Chiralcel OD (254 nm, 0.5 mL/min, n-hexane/IPA = 9:1±.
d
ꢀ1
ꢀ1
E = ln[(ee
p
(1 ꢀ ee
s
±±(ee
p
+ ee
s
±
] /ln[(ee
p
(1 + ee
s
±±(ee
p
+ ee ± ]; see Ref. 31.
s
(
(R±-4, 92% ee±, rate of alcoholysis reaction was slower
11. Mazaleyrat, J. P.; Wright, K.; Azzini, M. V.; Gaucher, A.;
Wakselman, M. Tetrahedron Lett. 2003, 44, 1741–1745.
than n-butanol condition (entry 4±.
1
2. (a± Piao, G.; Akagi, K.; Shirakawa, H.; Kyotani, M. Curr.
Appl. Phys. 2001, 1, 121–123; (b± Akagi, K.; Piao, G.;
Kaneko, S.; Higuchi, I.; Shirakawa, H.; Kyotani, M.
Synth. Met. 1999, 102, 1406–1409.
In conclusion, we have found that the CALB-catalyzed
hydrolysis reactions at high temperature (80 °C± of
monoacylated binaphthols are able to give chiral BI-
NOLs. It is proved that these reactions are influenced
by the reaction temperature and configuration of the
substituted acyl group. The hydrolysis of butyryl group
containing (± ±-3 in toluene at 80 °C was the optimum
condition. Hydrolysis of 6,6 -dibromo substituted (± ±-
5
anol as alcoholysis agent. Currently, this method is
applied to the CALB-catalyzed resolution of amino
and ester substituted 1,1 -binaphthyls.
1
3. Cheng, Y. X.; Chen, L. W.; Song, J. F.; Zou, X. W.; Liu,
T. D. Polym. J. 2005, 37, 355–362.
1
4. Nakajima, M.; Miyoshi, I.; Kanayama, K.; Hashimoto,
S.; Noji, M.; Koga, K. J. Org. Chem. 1999, 64, 2264–2271.
15. Gao, J.; Reibenspies, J. H.; Martell, A. E. Angew. Chem.,
Int. Ed. 2003, 42, 6008–6012.
0
1
1
6. Barhate, N. B.; Chen, C. T. Org. Lett. 2002, 4, 2529–2532.
7. Irie, R.; Masutani, K.; Katsuki, T. Synlett 2000, 1433–
gave high enantioselectivity by the use of 2-chloroeth-
1
436.
0
18. Aoyama, H.; Tokunaga, M.; Kiyosu, J.; Iwasawa, T.;
Obora, Y.; Tsuji, Y. J. Am. Chem. Soc. 2005, 127, 10474–
1
0475.
1
9. (a± Li, Z.; Liang, X.; Wu, F.; Wan, B. Tetrahedron:
Asymmetry 2004, 15, 665–669; (b± Schanz, H. J.; Linseis,
M. A.; Gilheany, D. G. Tetrahedron: Asymmetry 2003, 14,
2763–2769; (c± Periasamy, M.; Venkatraman, L.; Siva-
kumar, S.; Sampathkumar, N.; Ramanathan, C. R.
J. Org. Chem. 1999, 64, 7643–7645.
References and notes
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. (a± Brunel, J. M. Chem. Rev. 2005, 105, 857–897; (b± Chen,
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3
. Takita, R.; Yakura, K.; Ohshima, T.; Shibasaki, M. J.
Am. Chem. Soc. 2005, 127, 13760–13761.
. Reetz, M. T.; Bondarev, O. G.; Gais, H. J.; Bolm, C.
Tetrahedron Lett. 2005, 46, 5643–5646.
20. (a± Hernandez, M. J.; Johnson, D. V.; Holland, H. L.;
McNulty, J.; Capretta, A. Tetrahedron: Asymmetry 2003,
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Oda, J. Agric. Biol. Chem. 1989, 53, 1879–1884; (c±
Kazlauskas, R. J. Am. Chem. Soc. 1989, 111, 4953–
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21. (a± Aoyagi, N.; Izumi, T. Tetrahedron Lett. 2002, 43,
5529–5531; (b± Aoyagi, N.; Kawauchi, S.; Izumi, T.
Tetrahedron Lett. 2003, 44, 5609–5612.
4
5
. Qin, Y. C.; Liu, L.; Pu, L. Org. Lett. 2005, 7, 2381–2383.
. Ihori, Y.; Yamashita, Y.; Ishitani, H.; Kobayashi, S. J.
Am. Chem. Soc. 2005, 127, 15528–15535.
6
7
. Kano, T.; Konishi, T.; Konishi, S.; Maruoka, K. Tetra-
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. Kumaraswamy, G.; Jena, N.; Sastry, M. N. V.; Rao, G.
V.; Ankamma, K. J. Mol. Catal. A: Chem. 2005, 230, 59–
22. Anderson, E. M.; Karin, M.; Kirk, O. Biocatal. Biotrans-
form. 1998, 16, 181–204.
6
7.
23. Uppenberg, J.; Ohrner, N.; Norin, M.; Hult, K.; Kley-
wegt, G. J.; Patkar, S.; Waagen, V.; Anthonsen, T.; Jones,
T. A. Biochemistry 1995, 34, 16838–16851.
24. Akoh, C. C. Biotechnol. Lett. 1993, 15, 949–954.
25. Claon, P. A.; Akoh, C. C. Enzyme Microb. Technol. 1994,
16, 835–838.
8
. Villano, R.; Acocella, M. R.; De Rosa, M.; Soriente, A.;
Scettri, A. Tetrahedron: Asymmetry 2004, 15, 2421–2424.
. Gadenne, B.; Hesemann, P.; Moreau, J. J. E. Tetrahedron:
Asymmetry 2005, 16, 2001–2006.
9
1
0. (a± Kang, C. Q.; Cheng, Y. Q.; Guo, H. Q.; Qiu, X. P.;
Gao, L. X. Tetrahedron: Asymmetry 2005, 16, 2141–2147;
26. Orsat, B.; Wirz, B.; Bischos, F. Chimia 1999, 53, 579–
584.
(
b± Deng, J. G.; Chi, Y. X.; Fu, F. M.; Cui, X.; Yu, K. B.;
Zhu, J.; Jiang, Y. Z. Tetrahedron: Asymmetry 2000, 11,
729–1732.
27. Compound (± ±-2: colorless crystal; mp 125–127 °C;
ꢀ
1
1
1
IRmmax (KBr±/cm
3460 (OH±, 1740, 1230 (OAc±; H

N. Aoyagi et al. / Tetrahedron Letters 47 (2006) 4797–4801
4801
NMR (500 MHz, CDCl
OH±, 7.03 (1H, d, J = 8.5 Hz, ArH±, 7.23–7.26 (2H, ArH±,
.31–7.35 (3H, ArH±, 7.40 (1H, d, J = 8.5 Hz, ArH±, 7.50
1H, t, J = 7.5 Hz, ArH±, 7.85 (1H, d, J = 8.0 Hz, ArH±,
.91 (1H, d, J = 8.5 Hz, ArH±, 7.97 (1H, d, J = 8.5 Hz,
ArH±, 8.07 (1H, d, J = 9.0 Hz, ArH±; FABMS (m/z± 329
3
± d 1.86 (3H, s, CH
3
±, 5.22 (1H, s,
29. The immobilized Candida antarctica lipase B (CALB± was
provided by Novo Nordisk Co., Ltd. as CHIRAZYME
L-2 (5 KU/g±.
7
(
7
30. General procedure: CALB (40 mg± and n-butanol
(0.672 mmol± were added to a solution of O-acyl binaph-
thol (± ±-2 or (± ±-3 (0.0672 mmol± and acetophenone
(2.0 mg, standard substance± in solvent (2 mL± and the
resulting mixture was stirred at 30–80 °C. The reaction
conversion and enantiomeric excess were determined using
HPLC (column, Daicel Chiralcel OG; mobile phase,
hexane/2-propanol = 15:1; flow rate, 0.5 mL/min; UV
detection at 254 nm±. E values were calculated according
to literature (see Ref. 31±. Absolute configurations of the
products were determined using HPLC (OG column± data
of commercially available (R± and (S± BINOL.
+
(
M+H± .
Compound (± ±-3: colorless crystal; mp 136–137 °C;
ꢀ
1
1
IRmmax (KBr±/cm 3410 (OH±, 1730, 1170 (OCOPr±; H
NMR (500 MHz, CDCl ± d 0.57 (3H, t, J = 7.5 Hz, CH ±,
3
3
2
1
.21 (2H, sex, J = 7.5 Hz, CH
2
±, 2.04–2.17 (2H, m, CH
±,
5
.21 (1H, s, OH±, 7.04 (1H, d, J = 9.0 Hz, ArH±, 7.23–7.27
(
1H, m, ArH±, 7.31–7.36 (4H, ArH±, 7.39 (1H, d,
J = 9.0 Hz, ArH±, 7.51 (1H, t, J = 7.5 Hz, ArH±, 7.84
1H, d, J = 8.0 Hz, ArH±, 7.90 (1H, d, J = 9.0 Hz, ArH±,
.97 (1H, d, J = 8.5 Hz, ArH±, 8.07 (1H, d, J = 9.0 Hz,
(
7
31. Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am.
Chem. Soc. 1982, 104, 7294–7299.
+
ArH±; FABMS (m/z± 357 (M+H± .
2
8. Compound (± ±-4: colorless solid; mp 202–204 °C; IRm
32. Large scale procedure: CALB (900 mg± and n-butanol
(2.24 g, 30.2 mmol± was added to a solution of (± ±-3
(1.08 g, 3.02 mmol± in toluene (90 mL± and the resulting
mixture was stirred at 100 °C. The reaction was monitored
periodically using HPLC. Upon completion (96 h±, the
reaction was terminated by removing the lipase via
filtration. The lipase portion was washed with toluene
(50 mL±. The filtrate and wash were combined, evapo-
rated, and the resulting crude residue was purified using
silica gel column chromatography with chloroform/meth-
anol (100:1± as the eluent to yield the (S±-3 {48%, 93%
max
ꢀ
1
1
(
KBr±/cm
3480, 3420 (OH±; H NMR (500 MHz,
3
CDCl ± d 5.00 (2H, s, OH±, 6.96 (2H, d, J = 9.0 Hz,
ArH±, 7.37 (2H, dd, J = 9.0, 2.0 Hz, ArH±, 7.40 (2H, d,
J = 9.0 Hz, ArH±, 7.90 (2H, d, J = 9.0 Hz, ArH±,
8
.05 (2H, ds, J = 2.0 Hz, ArH±; MS (m/z± 442, 444, 446
+
(
M ±.
Compound (± ±-5: colorless crystal; mp 159–160 °C;
ꢀ
1
1
IRmmax (KBr±/cm 3420 (OH±, 1730, 1180 (OCOPr±; H
NMR (500 MHz, CDCl
3
± d 0.60 (3H, t, J = 7.5 Hz, CH
3
±,
1
5
.24 (2H, sex, J = 7.5 Hz, CH ±, 2.06–2.19 (2H, m, CH
.19 (1H, s, OH±, 6.86 (1H, d, J = 9.0 Hz, ArH±, 7.08 (1H,
2
2
±,
2
0
ee, ½aꢁ ꢀ43.4 (c 1.0, THF±} and (R±-1 {51%, 92% ee,
D
2
0
d, J = 9.0 Hz, ArH±, 7.31 (1H, dd, J = 9.0, 2.0 Hz, ArH±,
.33 (1H, d, J = 9.0 Hz, ArH±, 7.40 (1H, d, J = 9.0 Hz,
½aꢁ +32.6 (c 1.0, THF±}.
D
7
33. Procedure of (R)-4 and (S)-5: CALB (40 mg± and alcohol
(0.672 mmol± were added to a solution of (± ±-5 (0.0672
mmol± and acetophenone (2.0 mg, standard substance± in
toluene (2 mL± and the resulting mixture was stirred at
80 °C. The reaction conversion and enantiomeric excess
were determined using HPLC (column, Daicel Chiralcel
OD; mobile phase, hexane/2-propanol = 9:1; flow rate,
0.5 mL/min; UV detection at 254 nm±. E values were
calculated according to literature (see Ref. 31±. Absolute
configurations of the products were determined using
HPLC (OD column± data of (R±-4 which was derived from
commercially available (R±-BINOL.
ArH±, 7.41 (1H, dd, J = 9.0, 2.0 Hz, ArH±, 7.81 (1H, d,
J = 9.0 Hz, ArH±, 7.98 (1H, d, J = 9.0 Hz, ArH±, 8.00
(
1H, ds, J = 2.0 Hz, ArH±, 8.14 (1H, ds, J = 2.0 Hz, ArH±;
+
MS (m/z± 512, 514, 516 (M ±.
Compound (± ±-6: pale yellow syrup; IRm
1
(
ꢀ
(KBr±/cm
1
max
1
760, 1180 (OCOPr±; H NMR (500 MHz, CDCl
3
± d 0.59
±, 2.06–
±, 7.04 (2H, d, J = 9.0 Hz, ArH±, 7.36
3 2
6H, t, J = 7.5 Hz, CH ±, 1.19–1.29 (4H, m, CH
2
.10 (4H, m, CH
2
(
2H, dd, J = 9.0, 2.0 Hz, ArH±, 7.42 (2H, d, J = 9.0 Hz,
ArH±, 7.90 (2H, d, J = 9.0 Hz, ArH±, 8.09 (2H, ds,
+
J = 2.0 Hz, ArH±; MS (m/z± 584, 586 (M ±.