Asymmetric synthesis of enantiomerically pure zingerols by lipase-catalyzed transesterification and efficient synthesis of their analogues

Article abstract of DOI:10.1016/j.tetasy.2013.04.013

The achiral zingerone 1, readily available from ginger, can be easily transformed into chiral derivatives. Zingerol 2, a reduced product of zingerone 1 is expected to be an important new medicinal lead compound. We have achieved a concise synthesis of optically active zingerol (R)-2 and (S)-2 by the lipase-catalyzed stereoselective transesterification of racemic 2. Under the optimized conditions, a lipase from Alcaligenes sp. (Meito QLM) and vinyl acetate in i-Pr₂O or hexane at 35 C within 1 h gave the alcohol (S)-2 and the acetate (R)-9 with high enantioselectivity without producing acetylated by-products. Since optically active (S)-2 and (R)-9 were obtained through lipase-catalyzed transesterification, other enantiomerically pure novel compounds could all be synthesized.

Full text of DOI:10.1016/j.tetasy.2013.04.013

Tetrahedron: Asymmetry 24 (2013) 621–627
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Asymmetric synthesis of enantiomerically pure zingerols by lipase-catalyzed
transesterification and efficient synthesis of their analogues
Takashi Kitayama a, , Sachiko Isomori a, Kaoru Nakamura b
⇑
a Department of Advanced Bioscience, Graduate School of Agriculture, Kinki University, Nara 631-8505, Japan
b Graduate School of Human Development and Environment, Faculty of Human Development, Kobe University, Kobe 657-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 February 2013
Accepted 16 April 2013
The achiral zingerone 1, readily available from ginger, can be easily transformed into chiral derivatives.
Zingerol 2, a reduced product of zingerone 1 is expected to be an important new medicinal lead com-
pound. We have achieved a concise synthesis of optically active zingerol (R)-2 and (S)-2 by the lipase-cat-
alyzed stereoselective transesterification of racemic 2. Under the optimized conditions, a lipase from
Alcaligenes sp. (Meito QLM) and vinyl acetate in i-Pr2O or hexane at 35 °C within 1 h gave the alcohol
(S)-2 and the acetate (R)-9 with high enantioselectivity without producing acetylated by-products. Since
optically active (S)-2 and (R)-9 were obtained through lipase-catalyzed transesterification, other enanti-
omerically pure novel compounds could all be synthesized.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
various biological functions,3,4 such as an activity that attracts a
wide range of fruit fly species,3 as shown in Scheme 1.
The stereochemical aspects of optically active compounds often
control biological function. The use of small chiral building blocks
in the search for new biologically active molecules has great poten-
tial, since the range of derivatization would increase when the lead
compound has a small compact frame. Since numerous natural
products have reactive groups suitable for organic synthesis,1,2
we have focused on comparatively small molecules that are readily
available or easily obtained by derivatization of small natural prod-
ucts. Therefore, the synthesis of derivatives from biologically active
natural products with a small compact frame as potential lead
compounds is an important challenge.
Zingerol 2, a reduced product of 1, inhibits colonic motility in
rats5 and shows the same biological activity as zingerone.3 This
is expected to play an important role as a novel medicinal lead
compound. Moreover, the stereochemistry of 2 might affect the
specific affinity for a target receptor or enzyme. For example, 1-
phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMPs) with
a stereogenic secondary alcohol binding to a phenyl group, showed
different biological activities for each different stereochemistry.6,7
Establishing an efficient method for synthesizing optically ac-
tive zingerol 2 as a chiral building block is important in order to
synthesize various derivatives and exploit them as tools of medic-
inal chemistry. Despite its very simple structure, synthetic meth-
ods for optically active zingerol 2 are not well known. (R)-
Zingerol (R)-2, isolated from Taxus baccata by Das et al.,8 has not
yet been synthesized. Hamada et al. obtained (S)-zingerol (S)-2 as
Herein we focused on achiral 4-(4-hydroxy-3-methoxy-
phenyl)butan-2-one
1 (zingerone) from Zingiber officinale, an
essential aromatic compound with a phenylbutane frame, showing
O
OH
O
OH
*
H3CO
HO
H3CO
HO
*
HO
raspberry ketone
HO
1
2
3
4
rhododendrol
zingerone
zingerol
Scheme 1.
⇑
Corresponding author. Fax: +81 742 43 8976.
E-mail address: kitayama@nara.kindai.ac.jp (T. Kitayama).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.04.013

622
T. Kitayama et al. / Tetrahedron: Asymmetry 24 (2013) 621–627
an intermediate in low yield via the asymmetric reduction of 1
using cultured cells of Phytolacca americana.9 The precise determi-
nation of the specific rotation of these compounds has not yet been
achieved.
phy (GC) using a capillary column (InertCap5) and the enantio-
meric excess (ee) was also checked by GC using a capillary
column (DEX-CB). Since the separation of the enantiomers of the
alcohols was difficult, the alcohols were isolated and the ee of
these products was determined after acetylation.
Our previous studies10,11 presented a guide for the selection of
the solvent to be used in lipase-catalyzed high-enantioselective
transesterifications. In the case of zerumbone derivatives with a
medium cyclic compound, a hydrophobic solvent such as hexane,
was recommended and exhaustive drying of the lipase of an Alca-
ligenes sp. (Meito QLM), acyl donor, and substrate gave rapid reac-
tivity against lipase-catalyzed transesterification.11 Therefore, we
believe that the lipase-catalyzed transesterification of racemic 2
using our method is one of the best ways to obtain both enantio-
mers. Optically active rhododendrol 4, a zingerol analogue, ob-
tained by the reduction of 4-(4-hydroxyphenyl)butan-2-one 3
(raspberry ketone) which was isolated from Rubus idaeus and has
the same framework as 1, was obtained by lipase-catalyzed transe-
sterification using Pseudomonas fluorescens (Amano PS) as the li-
pase.12 The results showed that the reaction was very slow but
that the stereoselectivity was reasonable. After this problem was
resolved, the synthesis of (R)-zingerol and then the efficient pro-
duction of (S)-zingerol using lipase-catalyzed transesterification
were achieved and moreover, several novel optically active ana-
logues were obtained. All of these structures are shown in
Scheme 1.
Yuasa et al.12 showed that 96 h was required for the transeste-
rification to achieve 50% conversion and to obtain the correspond-
ing optically active compounds with high ee in run 1. In the case of
zerumbone derivatives with a medium cyclic structure, exhaustive
drying together with a hydrophobic solvent such as hexane, a sub-
strate, vinyl acetate, and lipase Meito QLM gave rapid reactivity
and excellent enantioselectivity for the lipase-catalyzed transeste-
rification.11 Of those tested in run 2, an exhaustive drying system
was applied for the transesterification. The reaction rate and stere-
oselectivity increased markedly and the reaction time was short-
ened by approximately 8-fold compared to that in run 1. Our
method for the medium cyclic compounds was also applicable to
phenyl alkanol. A low water content in the reaction system might
give advantageous reactivity and stereoselectivity for the transe-
sterification. However, when hexane was used as a hydrophobic
solvent, the reactivity and stereoselectivity did not change greatly
compared with using i-Pr2O as the solvent.
As shown in Table 2, the transesterification of 4 with two li-
pases, Meito QLM and lipase B from Candida antarctica (CAL-B),
was studied in i-Pr2O. The reaction rate was markedly increased
using both lipases compared with Amano PS. Notably, the reaction
finished in 10 min using CAL-B without generating any by-prod-
ucts, (S)-5 and (R)-7; moreover the stereoselectivity was excellent.
Lipase CAL-B gave the fastest reaction time, 10 min, and a high E
value13 of over 1000. The reaction was approximately 600-fold
shorter than that in run 1 (Table 1) using Amano PS as the lipase.
When hexane was employed as a hydrophobic solvent, the reac-
tivity and stereoselectivity using Meito QLM as a lipase did not
show any major changes compared with using i-Pr2O as the sol-
2. Results and discussion
2.1. Optically active rhododendrol
Raspberry ketone 3 was reduced with sodium borohydride to
afford racemic 4 in quantitative yield.12 The lipase-catalyzed enan-
tioselective transesterification of
(Scheme 2).
4
was then investigated
OH
OH
+
NaBH4 / EtOH
O
HO
AcO
OH
rt
quant.
lipase Amano PS
(S)-4
(S)-5
i-Pr2O, vinyl acetate, 35°C
HO
OAc
OAc
HO
3
raspberry ketone
rhododendrol 4
+
HO
AcO
(R)-6
(R)-7
Scheme 2.
Table 1 shows the results from the transesterification of racemic
4 with vinyl acetate in i-Pr2O in the presence of Amano PS (runs 1,
2). The transesterification of 4 was monitored by gas chromatogra-
vent, although the reactivity was markedly reduced using CAL-B
as a lipase. This suggested that the steric structure at the active site
of CAL-B was affected extensively by the solvent polarity. More-
Table 1
Kinetic resolution of racemic 4 by lipase-catalyzed transesterification using Amano PS
Run
Solvent
Time (h)
Conversion (%)a
(S)-4 (% ee)
(S)-5 (% ee)
(R)-6 (% ee)
(R)-7 (% ee)
1b
2
3
i-Pr2O
i-Pr2O
Hexane
96
12
12
42 (78)
31 (99)
55 (78)
7 (78)
19 (99)
1 (77)
42 (98)
37 (98)
32 (99)
9 (98)
13 (98)
12 (99)
a
Determination of the quantity by GC.
Ref. 12
B

T. Kitayama et al. / Tetrahedron: Asymmetry 24 (2013) 621–627
623
Table 2
Kinetic resolution of racemic 4 by lipase-catalyzed transesterification using various lipases
Run
Lipase
Solvent
Time (h)
Conversiona (%)
E Value
(S)-4 (% ee)
(S)-5 (% ee)
(R)-6 (% ee)
(R)-7 (% ee)
1
2
3
4
5
6
7
Meito QLM
Meito QLM
Meito QLM
Meito QLM
CAL-B
i-Pr2O
i-Pr2O
i-Pr2O
Hexane
i-Pr2O
i-Pr2O
Hexane
1
2
5
5
43 (63)
34 (91)
36 (95)
27 (97)
50 (>99)
40 (99)
92 (8)
19 (59)
19 (84)
15 (95)
23 (99)
0
28 (99)
32 (99)
28 (98)
22 (99)
50 (>99)
52 (79)
8 (99)
10 (99)
15 (99)
21 (99)
28 (99)
0
—
—
—
—
>1000
—
—
10 min
1
10 min
CAL-B
CAL-B
4(99)
0
4 (72)
0
a
Determination of the quantity by GC.
over, the acetylation seemed to proceed on the hydroxyl group at
the stereogenic carbon stereoselectively and then on the phenolic
hydroxyl group.
From the results of the screening experiments shown in Tables
1 and 2, we found that run 5 in Table 2 represented the optimum
reaction conditions. A large-scale experiment using this system
showed the same results as on a screening scale.
trin-B-236-M-19). Surprisingly, compounds 8 and 9 with, simple
structures, were novel compounds.
Of those tested in i-Pr2O under an exhaustive drying system, the
stereoselectivity of the lipase-catalyzed transesterification was
higher using Meito QLM and CAL-B as was the transesterification
of rhododendrol 4, as shown in Table 3. The reactivity and stere-
oselectivity of the transesterification of 4 using Amano PS under
the optimized conditions were almost the same as those for 2
without generating acetylated by-products 8 and 10. CAL-B and
Meito QLM gave a short reaction time and Meito QLM gave a good
E value although CAL-B reduced the stereoselectivity. Under the
optimized conditions, Meito QLM and vinyl acetate in i-Pr2O or
hexane at 35 °C within 1 h gave the alcohol (S)-2 and the acetate
(R)-9, with an E value of 300 without producing the acetylated
by-products. When hexane was employed as the hydrophobic sol-
2.2. Optically active zingerol 2
Compound 1 was reduced with sodium borohydride to afford
racemic 2 in quantitative yield.14 The lipase-catalyzed kinetic
transesterification of 2 was then investigated using Amano PS,
Meito QLM, and CAL-B as lipases based on the above results, as
shown in Scheme 3.
OH
OH
H3CO
HO
H3CO
+
OH
O
NaBH4 / EtOH
rt
AcO
H3CO
HO
H3CO
HO
quant.
lipase
(S)-2
(S)-8
i-Pr2O or hexane,
vinyl acetate, 35°C
OAc
OAc
zingerol 2
zingerone 1
H3CO
HO
H3CO
AcO
+
(R)-9
(R)-10
Scheme 3.
The transesterification of 2 was monitored by GC using a capil-
lary column (InertCap5) and the conversion was assessed by GC.
The ee of (R)-9 and (R)-10 were determined directly and those of
(S)-2 and (S)-8 were determined after synthesizing the correspond-
ing acetates by GC using a capillary column (CP-CD; CP-cyclodex-
vent, the reactivity and stereoselectivity were not improved using
Amano PS and CAL-B compared with using i-Pr2O as a solvent;
however, Meito QLM showed a similar result when using hexane
as the solvent. From these results, exhaustive drying in combina-
tion with a hydrophobic solvent such as i-Pr2O and any lipases
Table 3
Kinetic resolution of racemic 2 by lipase-catalyzed transesterification using various lipases
Run
Lipase
Solvent
Time (h)
Conversiona (%)
E Value
(S)-2(% ee)
(S)-8 (% ee)
(R)-9 (% ee)
(R)-10 (% ee)
1
2
3
4
5
6
7
8
9
AmanoPS
AmanoPS
Meito QLM
Meito QLM
Meito QLM
CAL-B
CAL-B
CAL-B
CAL-B
i-Pr2O
Hexane
i-Pr2O
i-Pr2O
Hexane
i-Pr2O
i-Pr2O
i-Pr2O
Hexane
4
4
53 (88)
66(51)
68 (46)
46 (91)
58 (59)
52 (86)
46 (95)
41 (99)
93 (7)
0
0
0
47 (99)
34 (99)
32 (99)
45 (99)
37 (99)
48 (92)
54 (80)
59 (70)
7 (99)
0
0
0
600
—
300
—
—
70
—
30 min
1
6 (91)
5 (59)
3 (99)
1
0
0
0
0
0
10 min
20 min
1
0
0
0
0
—
10 min
a
Determination of the quantity by GC.

624
T. Kitayama et al. / Tetrahedron: Asymmetry 24 (2013) 621–627
gave good results for stereoselectivity and reactivity of the lipase-
catalyzed transesterification.
(S)-2 and (R)-9 were obtained through lipase-catalyzed transeste-
rification, all enantiomerically pure compounds, (R)-2, (R)- and
(S)-8, (S)-9, (R)- and (S)-10, could be synthesized using this
method.
It should be noted that when Meito QLM was employed as the
catalyst, the stereoselectivity and reactivity increased for zingerol.
It is worth noting that the combination of Meito QLM and hexane
with exhaustive drying gave the desired effect on the stereoselec-
tivity and reactivity of the phenylbutane derivative with a chain
structure during lipase-catalyzed transesterification as well as
zerumbone with a medium cyclic structure; it was confirmed that
our method11 can be applied to various structures.
From the results of the screening experiment shown in Table 3,
we found that run 3 represented the optimum conditions. A large-
scale experiment using this system showed the same results as on
the screening scale.
2.3. Absolute configuration
The absolute configuration of (R)-8 and (S)-9zingerol 2 and their
specific optical rotation have been reported . The synthesis and
determination of the absolute configuration of (S)- and (R)-8, (S)-
and (R)-9, and (S)- and (R)-10 were achieved by a combination of
reactions using (S)-2 and (R)-9 as the starting materials as shown
in Scheme 4.
The transesterification of 2 produced a less acetylated by-prod-
uct than that of 4, perhaps due to the steric hindrance or electronic
efficiency of the 30-methoxy group. Lipase-catalyzed transesterifi-
cation of phenol 11 and o-methoxyphenol 12, to give acetates 13
and 14, using three lipases was studied in an effort to elucidate
the reactivity of the acetylation in the presence of the 30-methoxy
group on the phenolic frame, as shown in Table 4.
3. Conclusion
The enantiomerically pure zingerols (R)-2 and (S)-2 were syn-
thesized by the lipase-catalyzed stereoselective transesterifica-
tion of racemic 2. Under the optimized conditions, Meito QLM
and vinyl acetate in i-Pr2O at 35 °C for 30 min gave (S)-2 and
(R)-9 with E values of over 1000 without producing acetylated
by-products. It is worth noting that the combination of Meito
QLM and hexane with exhaustive drying had the desired effect
on the stereoselectivity and reactivity of phenylbutane deriva-
tives with a chain structure during lipase-catalyzed transesterifi-
cations. Since enantiomerically pure (S)-2 and (R)-9 were
obtained through lipase-catalyzed transesterification, the enanti-
omerically pure derivatives (R)-2, (R)- and (S)-8, (S)-9, (R)- and
(S)-10 could be synthesized and could be employed as chiral
building blocks with a small molecular framework. An efficient
Table 4
Transesterification of phenol and o-methoxyphenol using various lipases
HO
AcO
11
13
phenol
lipase
H3CO
HO
H3CO
AcO
i-Pr2O, vinyl acetate
route to optically active zingerol
2 and its derivatives was
35°C
achieved enantioselectively by lipase-catalyzed transesterification
using Meito QLM and vinyl acetate in an i-Pr2O system under
exhaustive drying. This opens up a route to using this readily
available small molecule as a starting material for conversion to
useful chiral products.
o-methoxyphenol 12
14
Run
Substrate
Lipase
Time (h)
Conversiona (%)
13
14
1
2
3
4
5
6
11
12
11
12
11
12
AmanoPS
Amano PS
Meito QLM
Meito QLM
CAL-B
2
4
2
2
4
5
—
20
—
5
—
5
—
11
4. Experimental
4.1. General
CAL-B
24
—
0
a
Column chromatography was performed on silica gel (70–230
mesh). TLC was performed on Merck 60 F254 silica gel plates. GC
data were recorded on a Shimadzu GC-2010. The enantiomeric ex-
cess (ee) values were determined by chiral GC (CHROMPACK, CP-
CD; CP-cyclodextrin-B-236-M-19 and DEX-CB). NMR spectra were
recorded on a Bruker instrument at 400 MHz for 1H, and 100 MHz
for 13C in CDCl3 with tetramethylsilane (TMS) as the internal stan-
dard. Chemical shifts (d) are reported in ppm from TMS. Infrared
spectra were recorded on a Shimadzu FRIR-8200D spectrophotom-
eter. Mass spectra were recorded at 70 eV, and high-resolution
mass spectra (HRMS) were obtained by direct injection. Optical
rotations were measured on a JASCO DIP-140 polarimeter. Chemi-
cals were of commercially available reagent grade, and used with-
out further purification.
Determination of the quantity by GC.
The transesterification of the secondary alcohol was faster than
that of the phenolic alcohol while the esterification of o-methoxy-
phenol was slower than that of phenol. The o-methoxy group re-
duced the rate of acetylation. The relative reactivity for the
lipase-catalyzed transesterification of 11 and 12 was almost the
same as that for 4 and 2, respectively. This result suggested that
the butyl group in 2 or 4 did not affect the esterification of the phe-
nolic alcohol and that the acetylation proceeded independently
regardless of the type of lipase.
Since enantiomerically pure (S)-2 and (R)-9 were obtained
through lipase-catalyzed transesterification using adequate condi-
tions, as shown in Table 3, we attempted to synthesize their deriv-
atives (R)-2, (R)- and (S)-8, (S)-9, and (R)- and (S)-10. As shown in
Scheme 4, a mixture of (S)-2, 1 or 5 equiv of acetic anhydride, and
several drops of pyridine was stirred at room temperature for
20 min or 1 h to afford (S)-8 and (S)-10 in 83% and 80% yield,
respectively. A powdered form of K2CO3 was added to (S)-10 in
MeOH and the mixture was stirred at room temperature for 4 h
to afford (S)-9 quantitatively. Acetylation of the phenolic hydrox-
ide was faster than that of the normal hydroxide and hydrolysis
proceeded at the phenolic position. Since enantiomerically pure
4.2. Preparation of substrates, racemic zingerol 2
Zingerone 1 (1.0 g, 5.3 mmol) in MeOH (2 mL) was added to the
suspension of NaBH4 (150 mg, 3.9 mmol) in MeOH (1 mL) and stir-
red at room temperature for 2.5 h. After consumption of the sub-
strate, H2O (10 mL) was added to the reaction mixture. The
aqueous solution was extracted with ethyl acetate (3 ꢀ 10 mL).
The combined organic extracts were washed with brine
(3 ꢀ 30 mL), dried over Na2SO4, and concentrated on a rotary evap-

T. Kitayama et al. / Tetrahedron: Asymmetry 24 (2013) 621–627
625
OH
OH
OAc
OH
Lipase
K2CO3
H3CO
HO
H3CO
HO
H3CO
HO
H3CO
HO
MeOH, rt, 2 h
99% ee
99% ee
90%, 99% ee
2
9
(R)-
(S)-
(R)-2
2
Ac2O (5 eq), pyridine
rt, 1 h
Ac2O (1 eq), pyridine
rt, 20 min
Ac2O (1.5 eq), pyridine
rt, 1 h
Ac2O (1 eq), pyridine
rt, 20 min
OAc
OH
OAc
OH
H3CO
AcO
H3CO
AcO
H3CO
H3CO
AcO
AcO
96%, 99% ee
(R)-10
82%, 99% ee
(R)-8
99%, 99% ee
(S)-10
83%, 99% ee
(S)-8
Na2CO3 / MeOH
rt, 1 h
OAc
H3CO
HO
99%, 99% ee
(S)-9
Scheme 4.
orator to obtain a white solid. Chromatography on silica gel, elut-
ing with a 4:1 mixture of hexane and ethyl acetate, afforded race-
mic 2 quantitatively as a white solid. Structural data were
confirmed when compared with known data.14
The reaction was followed by GC using a column of InertCap5
(detector and injection temperature, 200 °C; column temperature,
170 °C; carrier gas, He; linear velocity: 30 cm/s, FID detector). Un-
der these conditions, the retention times of 4, 5, 6, and 7 were 7.6,
10.9, 11.8, and 17.2 min, respectively. The enantiomeric excess of 6
and 7 were determined directly and those of 4 and 5 were deter-
mined after synthesizing the corresponding acetates by GC using
a column of DEX-CB (detector and injection temperature, 200 °C;
column temperature, 160 °C; carrier gas He; linear velocity:
30 cm/s, FID detector). Under these conditions, the retention times
of (R)- and (S)-4, (R)- and (S)-5, (R)-6, (S)-6, (R)-7, and (S)-7 were
11.0, 8.1, 13.6, 13.1, 8.8, and 8.3 min, respectively. Structural data
were confirmed by being compared with known data.12
4.3. Preparation of substrate, racemic rhododendrol 4
Raspberry ketone 3 (1.0 g, 6.2 mmol) in MeOH (2 mL) was
added to a suspension of NaBH4 (180 mg, 4.6 mmol) in MeOH
(1 mL) and stirred at room temperature for 2 h. After consumption
of the substrate, H2O (10 mL) was added to the reaction mixture.
The aqueous solution was extracted with ethyl acetate
(3 ꢀ 10 mL). The combined organic extracts were washed with
brine (3 ꢀ 30 mL), dried over Na2SO4, and concentrated on a rotary
evaporator to obtain a white solid. Chromatography on silica gel,
eluting with a 4:1 mixture of hexane and ethyl acetate, afforded
racemic 4 quantitatively as a white solid. Structural data were con-
firmed when compared with known data.12
4.5. General procedure for the lipase-catalyzed
transesterification of rhododendrol 4 on a gram scale
After exhaustive drying of THF, substrate, and lipase under
0.1 mmHg conditions, substrate 4 (5.00 g, 30.0 mmol), vinyl ace-
tate (3.87 g, 45.0 mmol), and the lipase (dry CAL-B, 2.50 g) in i-
Pr2O (75.0 mL) with molecular sieves 4 Å were stirred for approx-
imately 10 min at 35 °C until the conversion was approximately
50%. The reaction was followed by GC using a column of InertCap5
and ee was determined by GC using a column of DEX-CB. The reac-
tion mixture was filtered and the filtrate was concentrated. Chro-
matography on silica gel, eluting with a 4:1 mixture of hexane
and ethyl acetate, afforded (S)-rhododendrol (S)-4 and (R)-4-(40-
hydroxyphenyl)-2-butyl acetate (R)-6 in 50% and 50% yield, and
97% and 98% ee, respectively.
4.4. General procedure for the lipase-catalyzed
transesterification of rhododendrol 4
After exhaustive drying of THF, substrate, and lipase under
0.1 mmHg conditions, substrate 4 (50 mg, 0.30 mmol), vinyl ace-
tate (38.7 mg, 0.45 mmol), and the lipase (dry CAL-B, 25 mg) in i-
Pr2O (0.75 mL) with molecular sieves 4 Å were stirred for approx-
imately 10 min at 35 °C until the conversion was approximately
50%. The reaction mixture was filtered and the filtrate was con-
centrated. Chromatography on silica gel, eluting with a 4:1 mix-
ture of hexane and ethyl acetate, afforded (S)-rhododendrol (S)-4,
and (R)-4-(40-hydroxyphenyl)-2-butyl acetate (R)-6 in 50 and 50%
yield, respectively. (S)-4-(40-Acetyloxyphenyl)-2-butanol (S)-5,
and (R)-4-(40-acetyloxyphenyl)-2-butyl acetate (R)-7 were ob-
tained under other conditions of lipase-catalyzed transesterifica-
tion, as shown in Table 2, and purified by silica gel column
chromatography using a 4:1 mixture of hexane and ethyl acetate
as the eluent.
4.5.1. (S)-Rhododendrol (S)-4
½
a 2D4
ꢁ
¼ þ16:9 (c 0.896, EtOH) 99% ee, ½a D24
¼ þ12:7 (c 1.10,
ꢁ
EtOH) 79% ee.12 1H NMR (CDCl3): d 1.23 (d, 3H, J = 6.2 Hz, CH3 at
C1), 1.64 (s, 1H, OH at C2), 1.71–1.78 (m, 2H, CH2 at C3), 2.57–
2.71 (m, 2H, CH2 at C4), 3.83 (m, 1H, CH at C2), 4.99 (s, 1H, OH
at Ar), 6.75 (ddd, 2H, J = 8.5, 4.4, and 0.1 Hz, H at C30 and C50),
7.00 (ddd, 2H, J = 8.5, 4.4, and 0.1 Hz, H at C20 and C60).

626
T. Kitayama et al. / Tetrahedron: Asymmetry 24 (2013) 621–627
4.5.2. (S)-4-(40-Aacetyloxyphenyl)-2-butanol (S)-5
in 67 and 33% yield, and 46% and 99% ee, respectively. Enantiome-
rically pure (S)-2 was obtained after same treatment with the
above method under other conditions of lipase-catalyzed transe-
sterification using Meito QLM or CAL-B as shown in Table 3.
½
a 2D4
ꢁ
¼ þ15:8 (c 0.632, EtOH) 99% ee, ½a D24
¼ þ14:4 (c 1.32,
ꢁ
EtOH) 79% ee.12 1H NMR (CDCl3): d 1.23 (d, 3H, J = 6.2 Hz, CH3 at
C1), 1.73–1.79 (m, 2H, CH2 at C3), 2.29 (s, 3H, CH3 at COCH3),
2.63–2.79 (m, 2H, CH2 at C4), 3.84 (m, 1H, CH at C2), 6.99 (ddd,
2H, J = 8.5, 4.4, and 0.1 Hz, H at C30 and C50), 7.20 (ddd, 2H,
J = 8.5, 4.4, and 0.1 Hz, H at C20 and C60).
4.8. Hydrolysis of (R)-9
Compound (R)-9 in MeOH (1 mL) was added to K2CO3 (188 mg,
1.36 mmol) and stirred at room temperature for 2 h. Next, H2O
(10 mL) was added to the reaction mixture. The aqueous solution
was extracted with ethyl acetate (3 ꢀ 10 mL). The combined or-
ganic extracts were washed with brine (3 ꢀ 30 mL), dried over
Na2SO4, and concentrated on a rotary evaporator to obtain a color-
less oil. Chromatography on silica gel, eluting with a 4:1 mixture of
hexane and ethyl acetate, afforded (R)-2 in 90% yield.
4.5.3. (R)-4-(40-Hydroxyphenyl)-2-butyl acetate (R)-6
½
a 2D4
ꢁ
¼ þ2:3 (c 0.963, EtOH) 98% ee, ½a D24
¼ þ2:1 (c 1.42, EtOH)
ꢁ
98% ee.12 1H NMR (CDCl3): d 1.24 (d, 3H, J = 6.3 Hz, CH3 at C1),
1.71–1.94 (m, 2H, CH2 at C3), 2.03 (s, 3H, OCOCH3 at C2), 2.50–
2.64 (m, 2H, CH2 at C4), 4.91 (m, 1H, CH at C2), 6.75 (ddd, 2H,
J = 8.5, 4.6, and 0.2 Hz, H at C30 and C50), 7.03 (ddd, J = 8.5, 4.6,
and 0.2 Hz, 2H, H at C20 and C60).
4.5.4. (R)-4-(40-Acetyloxyphenyl)-2-butyl acetate (R)-7
4.9. Acetylation of (S)-2
½
a 2D4
ꢁ
¼ þ8:6 (c 0.244, EtOH) 99% ee), ½a D24
¼ þ6:1 (c 1.64, EtOH)
ꢁ
98% ee.12 1H NMR (CDCl3): d 1.24 (d, 3H, J = 6.3 Hz, CH3 at C1),
1.74–1.96 (m, 2H, CH2 at C3), 2.02 (s, 3H, OCOCH3 at C2), 2.28 (s,
3H, OCOCH3 at Ar), 2.56–2.70 (m, 2H, CH2 at C4), 4.93 (m, 1H, CH
at C2), 6.99 (ddd, 2H, J = 8.5, 4.5, and 0.1 Hz, H at C30 and C50),
7.17 (ddd, 2H, J = 8.5, 4.5, and 0.1 Hz, H at C20 and C60).
A mixture of (S)-2 (71 mg, 0.36 mmol), 1 and 5 equiv of acetic
anhydride, and several drops of pyridine was stirred at room tem-
perature for 20 min and 60 min. The progress of the acetylation
was monitored by TLC. After consumption of the substrate, H2O
(10 mL) was added to the reaction mixture. The aqueous solution
was extracted with ethyl acetate (3 ꢀ 10 mL). The combined or-
ganic extracts were washed with a saturated NaHCO3 solution
(3 ꢀ 30 mL) and brine (3 ꢀ 30 mL), dried over Na2SO4, and concen-
trated on a rotary evaporator to obtain a colorless oil. Chromatog-
raphy on silica gel, eluting with a 4:1 mixture of hexane and ethyl
acetate, afforded (S)-8 and (S)-10 in 83% and 99% yield,
respectively.
4.6. General procedure of lipase-catalyzed transesterification of
zingerol 2
After exhaustive drying of THF, substrate, and lipase under
0.1 mmHg conditions, substrate 2 (50 mg, 0.26 mmol), vinyl ace-
tate (33.5 mg, 0.39 mmol), and the lipase (dry MeitoQLM, 25 mg)
in i-Pr2O (0.75 mL) with molecular sieves 4 Å were stirred for
approximately 30 min at 35 °C. The reaction mixture was filtered
and the filtrate was concentrated. Chromatography on silica gel,
eluting with a 4:1 mixture of hexane and ethyl acetate, afforded
(S)-zingerol ((S)-2) and (R)-4-(40-hydroxy-30-methoxyphenyl)-2-
butyl acetate (R)-9 in 68 and 32% yield, respectively. (S)-4-(40-Acet-
yloxy-30-methoxyphenyl)-2-butanol (S)-8 and (R)-4-(40-acetyloxy-
30-methoxyphenyl)-2-butyl acetate (R)-10 were obtained under
other conditions of lipase-catalyzed transesterification, as shown
in Table 3, and purified by silica gel column chromatography using
a 4:1 mixture of hexane and ethyl acetate as an eluent.
The reaction was followed by GC using a column of InertCap5
(detector and injection temperature, 220 °C; column temperature,
170 °C; carrier gas, He; linear velocity: 30 cm/s, FID detector). Un-
der these conditions, the retention times of 2, 8, 9 and 10 were 8.8,
15.4, 12.9, and 22.9 min, respectively. The enantiomeric excess of 9
and 10 were determined directly and those of 2 and 8 were deter-
mined after synthesizing the corresponding acetates by GC using a
column of CP-CD (detector and injection temperature, 200 °C; col-
umn temperature, 160 °C; carrier gas He; linear velocity: 30 cm/s,
FID detector). Under these conditions, the retention times of (R
and S)-2, (R and S)-8, (R)-9, (S)-9, (R)-10, and (S)-10 were 33, 68,
40, 39, 80, and 78 min, respectively.
4.10. Acetylation of (R)-2
A mixture of (R)-2 (71 mg, 0.36 mmol), 1 equiv of acetic anhy-
dride, and several drops of pyridine was stirred at room tempera-
ture for 20 min. The progress of the acetylation was monitored by
TLC. After consumption of the substrate, H2O (10 mL) was added to
the reaction mixture. The aqueous solution was extracted with
ethyl acetate (3 ꢀ 10 mL). The combined organic extracts were
washed with saturated NaHCO3 solution (3 ꢀ 30 mL) and brine
(3 ꢀ 30 mL), dried over Na2SO4, and concentrated on a rotary evap-
orator to obtain a colorless oil. Chromatography on silica gel, elut-
ing with a 4:1 mixture of hexane and ethyl acetate, afforded (R)-8
in 82% yield.
4.11. Acetylation of (R)-9
A mixture of (R)-9 (107 mg, 0.45 mmol), 1.5 equiv. of acetic
anhydride, and several drops of pyridine was stirred at room tem-
perature for 1 h. The progress of the acetylation was monitored by
TLC. After consumption of the substrate, H2O (10 mL) was added to
the reaction mixture. The aqueous solution was extracted with
ethyl acetate (3 ꢀ 10 mL). The combined organic extracts were
washed with saturated NaHCO3 solution (3 ꢀ 30 mL) and brine
(3 ꢀ 30 mL), dried over Na2SO4, and concentrated on a rotary evap-
orator to obtain a colorless oil. Chromatography on silica gel, elut-
ing with a 4:1 mixture of hexane and ethyl acetate, afforded (R)-10
in 96% yield.
4.7. General procedure for the lipase-catalyzed
transesterification of zingerol 2 on a gram scale
After exhaustive drying of THF, substrate, and lipase under
0.1 mmHg conditions, substrate 2 (5.00 g, 26.0 mmol), vinyl ace-
tate (3.35 g, 39.0 mmol), and the lipase (dry MeitoQLM, 2.50 g) in
i-Pr2O (75.0 mL) with molecular sieves 4 Å were stirred for approx-
imately 30 min at 35 °C. The reaction was followed by GC using a
column of InertCap5 and the ee was determined by GC using a col-
umn of CP-CD. The reaction mixture was filtered and the filtrate
was concentrated. Chromatography on silica gel, eluting with a
4:1 mixture of hexane and ethyl acetate, afforded (S)-2 and (R)-9
4.12. Hydrolysis of (S)-10
A powder of Na2CO3 (97.9 mg, 0.90 mmol) was added to (S)-
10 (87.1 mg, 0.30 mmol) in MeOH and the mixture was stirred
at room temperature for 4 h. After consumption of the substrate,
H2O (10 mL) was added to the reaction mixture. The aqueous
solution was extracted with ethyl acetate (3 ꢀ 10 mL). The

T. Kitayama et al. / Tetrahedron: Asymmetry 24 (2013) 621–627
627
combined organic extracts were washed with brine (3 ꢀ 30 mL),
4.13.3. 4-(40-Acetyloxy-30-methoxyphenyl)-2-butyl acetate, (S)-
and (R)-10
dried over Na2SO4, and concentrated on a rotary evaporator to
obtain a colorless oil. Chromatography on silica gel, eluting with
IR: 2977, 2937, 1764, 1733 cmꢂ1. 1H NMR (CDCl3): d 1.25 (d, 3H,
J = 6.2 Hz, H at C1), 1.75–1.98 (m, 2H, H at C3), 2.04 (s, 3H, OCOCH3 at
C2), 2.30(s, 3H, OCOCH3 at Ar), 2.55–2.70(m, 2H, Hat C4), 3.82 (s, 3H,
OCH3 at Ar), 4.96 (m, 1H, H at C2), 6.74 (dd, 1H, J = 1.5 and 8.0 Hz, H at
C60), 6.77 (d, 1H, J = 1.6, H at C20), 6.93 (d, 1H, J = 8.0 Hz, H at C50). 13C
NMR (CDCl3): d 20.1 (C1), 20.7 (Ar-OCOCH3), 21.4 (CHOCOCH3), 31.8
(C4), 37.5 (C3), 55.8 (OCH3), 70.1 (C2), 112.5 (C20), 120.3 (C60), 122.5
(C50), 137.8 (C40), 140.5 (C10), 150.8 (C30), 169.3 (Ar-OCOCH3), 170.8
(CHOCOCH3). HRMS (M+Na+) m/z calcd mass for C15H20ONa
a
4:1 mixture of hexane and ethyl acetate, afforded (S)-9
quantitatively.
4.13. Zingerol (S)- and (R)-2
(S)-2: ½a 2D4
ꢁ
¼ þ14:1 (c 0.91, EtOH) 99% ee, ½a D24
¼ þ10:4 (c 0.29,
ꢁ
EtOH) ee: unknown.8 (R)-2: ½a D24
¼ ꢂ15:1 (c 1.10, EtOH,) 99% ee,
ꢁ
½
a 2D5
ꢁ
¼ ꢂ16:3 (c 0.26, EtOH) ee: unknown.8 IR: 3502, 2964,
1764 cmꢂ1
.
1H NMR (CDCl3): d 1.22 (d, 3H, J = 6.2 Hz, H at C1),
303.1208, found 303.1201. (S)-10: ½a D24
¼ ꢂ3:9 (c 0.96, EtOH) 99%
ꢁ
1.71–1.77 (m, 2H, H at C3), 2.60–2.69 (m, 2H, H at C4), 3.81–3.86
(m, 1H, H at C2), 3.86 (s, 3H,OCH3 at Ar), 5.62 (br s, 1H, OH), 6.68
(dd, 1H, J = 2.0 and 7.9 Hz, H at C60), 6.70 (d, 1H, J = 2.1, H at C20),
6.82 (d, 1H, J = 7.9 Hz, H at C50). 13C NMR (CDCl3): d 23.6 (C1),
31.8 (C4), 41.1 (C3), 55.8 (OCH3), 67.5 (C2), 110.0 (C20), 114.3
(C50), 120.8 (C60), 133.9 (C10), 143.7 (C40), 146.4 (C30). HRMS
(M+Na+) m/z calcd mass for C11H16O3Na 219.0997, found:
219.1023.
ee, (R)-10: ½a 2D4
¼ þ4:8 (c 1.00, EtOH) 99% ee.
ꢁ
4.14. General procedure for the lipase-catalyzed
transesterification of phenol 11 or o-methoxyphenol 12
After exhaustive drying of THF, substrate, and lipase under
0.1 mmHg conditions, substrate 11 (50 mg, 0.53 mmol) or 12
(50 mg, 0.40 mmol), vinyl acetate (33.5 mg, 0.39 mmol), and the li-
pase (dry MeitoQLM, 25 mg) in i-Pr2O (0.75 mL) with molecular
sieves 4 Å were stirred for approximately 30 min at 35 °C. The reac-
tion was followed by GC using a column of DB5 (detector and injec-
tion temperature, 280 °C; column temperature, 100 °C; carrier gas,
He; linear velocity: 30 cm/s, FID detector). Under these conditions
the retention times of 11, 12, 13, and 14 were 3.6, 5.8, 5.1, and
14.0 min, respectively. Conversion was assessed by GC.
4.13.1. (S)-4-(40-Acetyloxy-30-methoxyphenyl)-2-butanol, (S)-
and (R)-8
IR: 3502, 2964, 1764 cmꢂ1 1H NMR (CDCl3): d 1.24 (d, 3H,
.
J = 6.2 Hz, H at C1), 1.74–1.80 (m, 2H, H at C3), 2.31 (s, 3H, OCOCH3
at Ar), 2.62–2.79 (m, 2H, H at C4), 3.82 (s, 3H,OCH3 at Ar), 3.86 (m,
1H, H at C2), 6.77 (dd, 1H, J = 1.8 and 8.0 Hz, H at C60), 6.80 (d, 1H,
J = 1.8, H at C20), 6.92 (d, 1H, J = 8.0 Hz, H at C50).
13C NMR (CDCl3): d 20.6 (OCOCH3), 23.6 (C1), 32.0 (C4), 40.7
(C3), 55.7 (OCH3), 67.3 (C2), 112.5 (C20), 120.4 (C60), 122.4 (C50),
137.6 (C40), 141.1 (C10), 150.7 (C30), 169.2 (OCOCH3). HRMS (M +
Na+) m/z calcd mass for C13H18O4Na 261.1103, found: 261.1098.
References
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(S)-8: ½a 2D4
ꢁ
¼ þ12:9 (c 0.97, EtOH) 99% ee, (R)-8: ½a D24
¼ ꢂ13:9 (c
ꢁ
0.84, EtOH) 99% ee.
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4.13.2. 4-(40-Hydroxy-30-methoxyphenyl)-2-butyl acetate, (S)-
and (R)-9
IR: 3431, 2937, 1730 cmꢂ1 1H NMR (CDCl3): d 1.24 (d, 3H,
.
J = 6.3 Hz, CH3 at C1), 1.71–1.95 (m, 2H, CH2 at C3), 2.04 (s, 3H,
OCOCH3 at C2), 2.50–2.64 (m, 2H, CH2 at C4), 3.88 (s, 3H, OCH3
at Ar), 4.94 (m, 1H, CH at C2), 6.65 (dd, 1H, J = 2.0 and 8.2 Hz, H
at C60), 6.67 (br, 1H, H at C20), 6.83 (d, 1H, J = 8.3 Hz, H at C50).
13C NMR (CDCl3): d 20.0 (C1), 21.3 (OCOCH3), 31.5 (C4), 37.9
(C3), 55.8 (OCH3), 70.5 (C2), 110.9 (C20), 114.3 (C50), 120.8 (C60),
133.4 (C10), 143.7 (C40), 146.4 (C30), 170.8 (OCOCH3). HRMS
(M+Na+) m/z calcd mass for C13H18O4Na 261.1103, found:
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261.1101. (S)-9:
½
a 2D4
ꢁ
¼ ꢂ1:3 (c 1.14, EtOH) 99% ee; (R)-9:
½ ꢁ
a 2D4
¼ þ1:7 (c 1.00, EtOH) 99% ee.
14. Plourde, G. L. Tetrahedron Lett. 2002, 43, 3597–3599.