New chiral building blocks from acetovanillone using lipase A and B from Candida antarctica

Article abstract of DOI:10.1016/j.tetasy.2006.04.030

Acetovanillone has been used as the starting material for the synthesis of a series of secondary alcohols, which were resolved by lipase catalyzed esterification. 1-(4-Benzyloxy-3-methoxyphenyl)ethanol was efficiently resolved using immobilized lipase B from Candida antarctica (Novozym 435, CAL-B), whereas immobilized lipase A from C. antarctica (Novozym 735, CAL-A) was the lipase of choice for the resolution of the corresponding 2-bromo- and 2-chloro-derivatives. The enantioenriched alcohols are new building blocks for potential use in the synthesis of bioactive compounds.

Full text of DOI:10.1016/j.tetasy.2006.04.030

Tetrahedron: Asymmetry 17 (2006) 1290–1295
New chiral building blocks from acetovanillone using lipase A and
B from Candida antarctica
*
˚
Erik Fuglseth, Thorleif Anthonsen and Bard Helge Hoff
Department of Chemistry, Norwegian University of Science and Technology, N-7491, Norway
Received 24 March 2006; accepted 24 April 2006
Abstract—Acetovanillone has been used as the starting material for the synthesis of a series of secondary alcohols, which were resolved
by lipase catalyzed esterification. 1-(4-Benzyloxy-3-methoxyphenyl)ethanol was efficiently resolved using immobilized lipase B from Can-
dida antarctica (Novozym 435, CAL-B), whereas immobilized lipase A from C. antarctica (Novozym 735, CAL-A) was the lipase of
choice for the resolution of the corresponding 2-bromo- and 2-chloro-derivatives. The enantioenriched alcohols are new building blocks
for potential use in the synthesis of bioactive compounds.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
and ethanethiol,7,8 while the benzyl group is most conve-
niently removed by hydrogenolysis.
Nature is the primary source for new drug candidates. For
instance, extraction of plants and herbs used in folk medi-
cine revealed a number of bioactive molecules containing
the 3,4-dihydroxyphenyl-fragment. Examples include flav-
ones with hapatoprotective properties in Anastatica hiero-
chuntica,1 the antihepatoxic flavonolignan Silychristin,2,3
components in Salvia miltiorrhiza with activity against
myocardiac infarct and angina pectoris,4 potential antican-
cer agents from Aglaia silvestris5 and alkaloids from the In-
dian medical plant Alangium lamarckii.6 Furthermore, a
number of drugs on the market contain the 3,4-dihydroxy-
phenyl-motif including DOPA, isoprenaline, formoterol
and salbutamol. Most of the above mentioned drug and
drug candidates contain stereogenic centres, meaning that
methods for providing enantiopure starting materials are
required, for the synthesis of the target molecules and
potentially new analogues. Acetovanillone is a potential
starting material in synthetic routes to such compounds.
The molecule offers several sites for modification, including
halogenation of the a-carbonyl position, reaction at the
keto-function, protection of the free phenolic group and
substitution of the aromatic ring. The possibility of having
two different protecting groups in the aromatic part of the
molecule, adds flexibility in the design of a total synthesis.
The methoxy group can be removed by the use of AlCl3
Chain elongation of the alkyl part is also possible (Scheme
1). Reaction of the alcohol functionality with triethyl
orthoformate yields a new carboxylic acid,9 whereas cyana-
tion of halohydrins give access to the corresponding
nitriles.
CH2X
HO2C
HO
CH2X
O
CH3
OCH3
OR
HO
CH2CN
OCH3
OCH3
OR
OH
1
OCH3
OR
Scheme 1. Chain elongation of the alkyl part of acetovanillone 1.
There are several strategies available for obtaining enantio-
enriched secondary alcohols, lipase catalyzed kinetic reso-
lution is one option.
*
Although resolution has the disadvantage of giving a max-
imum of only 50% yield of each enantiomer, other factors
Corresponding author. Tel.: +47 73 593 973; fax: +47 73 550 877; e-mail:
Bard.Helge.Hoff@chem.ntnu.no
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.04.030

E. Fuglseth et al. / Tetrahedron: Asymmetry 17 (2006) 1290–1295
1291
might favour enzymatic resolution over asymmetric reduc-
tion in a commercial setting, such as clean reactions, the
possibility of recycling the unwanted enantiomer, and ease
of catalyst recycling. In enzyme kinetic resolution, the
enantiomeric excesses of the products depend on the degree
of conversion. This makes it possible to obtain high ee’s
provided that lower yield can be accepted. Moreover, in
most cases enzymatic resolutions, can be performed in
multi-purpose equipment, whereas a more advanced set-up
is required for asymmetric reductions.
as a crystalline material. The major by-product was
2,2-dibromo-1-(4-(benzyloxy)-3-methoxyphenyl)ethanone.
Reduction of a-bromoketone 4 gave racemic alcohol 5.
The corresponding chloroalcohol 7 was obtained from 5 by
transformation to epoxide 6 followed by hydrochlorination
aided by b-cyclodextrin.14 Low yields were experienced in
this reaction.
2.2. Kinetic resolution
In enzyme catalyzed resolutions of secondary alcohols, the
latter usually have one bulky and one small substituent at
the stereogenic centre. Thus provided that steric effects are
the primary selection factor, high values are expected.
Replacement of a hydrogen at the smaller substituent with
a halogen, gives valuable information about the substrate–
enzyme interaction. In such cases, electronic effects play a
crucial role.
Racemic alcohols 3, 5 and 7 (Scheme 3) were resolved with
various lipases using dichloromethane and dichlorometh-
ane/hexane 1:1 as solvent systems. A fivefold excess of
vinyl acetate was used as the acyldonor.
HO
CH2R
AcO
CH2R
HO
CH2R
Lipase
+
Some structurally related compounds have been resolved
using lipases. These include 1-(4-benzyloxy-3-nitrophenyl)-
2-bromoethanol,10 1-(4-hydroxy-3-methoxyphenyl)-2,2,2-
trifluoroethanol,11 2,3-dihydro-a-methyl-1,4-benzodioxine-
6-methanol12 and 1-(4-hydroxy-3-methoxyphenyl)-2,2,2-
trifluoroethanol.13
Vinyl acetate
OCH3
OCH3
OCH3
OBn
OBn
OBn
(S)-3 R=H
(R)-5 R= Br
(R)-7 R= Cl
(R)-8 R=H
3 R=H
5 R= Br
7 R= Cl
(S)-9 R= Br
(S)-10 R= Cl
Scheme 3. Lipase catalyzed resolution of the secondary alcohols 3, 5 and
7.
2. Results and discussion
2.1. Synthesis of racemic starting materials
Alcohol 3 was the only substrate, which could be resolved
with a reasonable reaction rate in pure dichloromethane.
Table 1 gives a summary of the selectivity and the relative
rate of reaction in the two solvent systems.
The racemic alcohols were synthesized as shown in Scheme 2.
Acetovanillone 1 was benzylated using benzyl chloride
and potassium carbonate giving 1-(4-benzyloxy-3-methoxy-
phenyl)ethanone
sodium borohydride, gave the racemic alcohol 3.
2
in good yield. Reduction, using
The E-value of the reaction depended on the enzyme prep-
aration and the solvent used. High E-values were obtained
using Novozym 435 (CAL-B), Humicola lanuginosa (HLL)
and Lipozyme TL IM as catalysts. CAL-B has successfully
been employed in the resolution of secondary alcohols hav-
ing a methyl substituent and a very bulky substituent con-
nected to the stereogenic centre.15–17
Bromination of 1-(4-(benzyloxy)-3-methoxyphenyl) etha-
none was troublesome and several reaction systems were
investigated. The best was to slowly add bromine into a
highly dilute solution of ketone 2. Product 4 was isolated
O
CH3
HO
CH3
O
CH3
BnCl, K2CO3
NaBH4
OCH3
OCH3
OCH3
OBn
OBn
OH
1
2
3
Br2,
CHCl3
O
O
CH2Br
HO
CH2Br
HO
CH2Cl
HCl/
NaBH4
OCH3
NaOH, MeOH
OCH3
β-cyclodextrin
OCH3
OCH3
OBn
4
OBn
5
OBn
6
OBn
7
Scheme 2. Synthesis of racemic starting materials.

1292
E. Fuglseth et al. / Tetrahedron: Asymmetry 17 (2006) 1290–1295
Table 1. Resolution of 3
in many cases. However, high E-values have been observed
when a bulky group is located in close vicinity to the stereo-
genic centre.27 For Novozym 735 catalyzed resolution, the
E-value is increased when the substrate is changed from 3
to 7, whereas an E-value of 89 was observed for the resolu-
tion of 5. The rate of reaction was not significantly different
for the resolution of 3, 5 and 7. CAL-A is the enzyme of
choice for the resolution 5 and 7.
Catalyst
E-value
Solvent 1
E-value
Solvent 2
Relative rate
Solvent 2/solvent 1
Novozym 435
Novozym 735
HLL
RML
Lipozyme TL IM
94
28
81
58
34
108
24
125
152
97
28
6
11
7
2
E-values for different catalysts and solvent systems. Solvent 1; CH2Cl2,
solvent 2; CH2Cl2/hexane 1:1.
H. lanuginosa catalyzed resolution of 3 and 7 with high
E-values, whereas 5 was resolved with a moderate E-value
of 49. The rate of reaction was low compared to the other
lipases.
Whereas the enantiomeric ratios in the resolution of 3, 5
and 7 catalyzed by the Candida antarctica lipases were only
moderately affected by solvent, a significant effect was ob-
served for the other lipases. Higher E-values were obtained
using dichloromethane/hexane as the solvent system.
The use of Lipozyme TL IM also gave good E-values in the
cases of 3 and 7. However, the rate of reaction was extre-
mely low. It is interesting to note that HLL in all cases gave
a higher selectivity than Lipozyme TL IM. This might be
due to physical changes caused by the immobilization or
trace impurities of other lipolytic enzymes.
As expected, the rate of reaction was largely affected by the
solvent. Lipase B from C. antarctica was more sensitive to
the choice of solvent than the other lipases. For all lipases,
CH2Cl2/hexane 1:1 gave the highest rate of reaction.
Rhizomucor lipase (RML) catalyzed the conversion of 3
with a high E-value. The introduction of the halides seems
to slow down the conversion considerably, probably by
decreasing the reaction rate for the faster reacting enantio-
mer. Other substrates containing –CH2Cl as the medium
sized substituent have been resolved with a high E-value
using this lipase.20,28
As both rate and enantiomeric ratio were favoured by the
use of dichlormethane/hexane as solvent, 5 and 7 were re-
solved in this system. The E-values in resolutions per-
formed in this solvent system for the secondary alcohols
3, 5 and 7 are summarized in Table 2.
Table 2. E-values obtained in lipase catalyzed resolution of 3, 5 and 7 in
dicloromethane/hexane
The substrates were preparatively resolved in order to
characterize the specific rotation properties of these new
pairs of enantiomers. Novozym 435 was used for the
resolution of 3, whereas Novozym 735 was used for the
resolution of 5 and 7. The specific rotation data and ee-values
are summarized in Table 3.
Catalyst
E-value
3
5
7
Novozym 435
Novozym 735
HLL
RML
Lipozyme TL IM
108
24
125
152
97
No conversion
Slow conversion
89
49
No conversion
25
>200
133
24
Table 3. Enantiomeric excesses and specific rotation data for alcohols 3, 5
and 7 and esters 8, 9 and 10
85
20
20
Catalysts
Alcohol %ee
½aꢀD
Acetate %ee
ester
½aꢀD
Novozym 435 was unable to convert 5 to the correspond-
ing esters and reaction of 7 proceeded very slowly with a
low E-value. This can be explained by the electronic envi-
ronment at the active site of the enzyme.18,19 Unfavourable
interactions between the halides (at the small sized substi-
tuent of the substrate) with the active site of the enzyme,
slow down the conversion for the faster reacting enantio-
mer. This has been observed for a number of substrate
classes, including alkyl 4-chloro-3-hydroxybutanoates,20
1-aryloxy-3-halo-2-propanols21–23 and 1-halo-2-alkanols.
Resolution of 1-(1,3-dithiane-2-yl)-3-chloro-2-propanol
was resolved with a high E-value, however the low rate
of reaction indicates the same effect.24 When the small sized
substituent contains a chloro-, bromo- or iodo-substituent,
CAL-B is not the ideal choice of catalyst. Switching to
hydrolytic media seems to be favourable for such
substrates.23
Novozym 435
Novozym 735
Novozym 735
3
5
7
99 (S) ꢁ27.9
94 (R) +5.8
97 (R) ꢁ12.1 10
8
9
92 (R) +78.6
98 (S) +43.1
95 (S) +39.4
The solvent used for 3, 5, 8, 9 and 10 was chloroform. Methanol was used
for compound 7.
3. Conclusions
Methods have been found for the resolution of a new class
of chiral building blocks, which are potentially useful for
the preparation of new bioactive molecules. As expected,
CAL-B (Novozym 435) displayed high selectivity towards
3, whereas low activity was observed in the resolution of
other substrates. The opposite was true for CAL-A (Novo-
zym 735), giving moderate E-value in the case of 3 and
preparatively useful E-values in resolution of the bromo-
hydrin 5 and chlorohydrin 7. What this means, in terms of
enzyme-substrate interactions, remains to be understood.
CAL-A has some unique catalytic properties.25 Among
others, this lipase catalyzes the esterification of tertiary
alcohols.26 The active site of this lipase appears to be rather
wide, resulting in low discrimination between enantiomers
For this substrate class, the Candida antarctica lipases
are complementary in terms of selectivity. The methods

E. Fuglseth et al. / Tetrahedron: Asymmetry 17 (2006) 1290–1295
1293
developed could also be useful for resolving structural
analogues.
(0.12 mmol) and vinyl acetate (50 mg, 0.60 mmol) were
mixed in the solvent (3 mL) and the reactions started by
the addition of lipase (20 mg). Chiral HPLC analyses gave
ees- and eep-values, from which the degree of conversion
was determined according to c = ees/(ees + eep). In con-
trolled experiments under the reaction conditions without
enzyme, no acylation was observed. Larger scale reactions
were performed as described below.
4. Experimental
4.1. General
All enzyme preparations were gifts from Novozymes, Bags-
værd, Denmark. Acetovanillone was provided by Borreg-
aard Synthesis, Sarpsborg, Norway. Other chemicals were
purchased from Fluka. Column and flash chromatogra-
phies were performed using silica gel 60A from Fluka, pore
size 40–63 lm.
4.5. Syntheses
1-(4-(Benzyloxy)-3-methoxyphenyl)ethanone 2: Aceto-
vanillone 1 (11.05 g, 66.5 mmol), potassium carbonate
(6.50 g, 0.47 mmol) and benzyl chloride (11.00 g,
86.0 mmol) were mixed in DMF (50 mL) and reacted at
100 ꢁC for 1 h. The solution was then cooled to 50 ꢁC
and water (50 mL) was added over 30 min. The crystalline
product was isolated by filtration, washed with water
(600 mL), dried and re-crystallized from MeOH to give
16.5 g (97%) of 2, mp: 86–88 ꢁC. MS (m/z): 256.1 (MÅ+),
4.2. Analyses
Optical rotations were determined using a Perkin–Elmer
243 B instrument, concentrations are given in g/100 mL.
NMR was recorded with Bruker Avance DPX 300 and
Bruker Avance DPX 400 operating at 300 MHz and 400
for 1H and 75 and 100 MHz for 13C. Chemical shifts
are in parts per million relative to TMS while coupling con-
stants are in hertz. The mass spectra were recorded using
a MAT 95 XL (ThermoQuest Finnigan) with EI probe
(DIP) as ionization source. Melting points were determined
using a Sanyo Gallenkamp melting point instrument.
Enantiomeric ratios, E, were calculated based on ping-
pong bi-bi kinetics using the computer program E & K
Calculator 2.1b.29
1
92.2, 91.1, 65.1. H NMR (CDCl3) d: 2.52 (3H, s), 3.91
(3H, s), 5.20 (2H, s), 6.87 (1H, d, J = 8.4 Hz), 7.29–7.53
(7H, m). 13C NMR (CDCl3) d: 26.25, 56.06, 70.78,
110.52, 112.13, 123.14, 127.26 (2C), 128.16, 128.73 (2C),
130.73, 136.33, 149.50, 152.41, 196.80.
1-(4-(Benzyloxy)-3-methoxyphenyl)ethanol 3: 1-(4-(Benzyl-
oxy)-3-methoxyphenyl)ethanone 2 (3.84 g, 15 mmol) was
dissolved in MeOH (15 mL) and reduced using sodium
borohydride (0.76 g, 20 mmol). Excess sodium borohydride
was quenched with dilute HCl. Crystallization from di-iso-
propyl ether gave 3.50 g (90%) of white crystalline 3, mp:
47–50 ꢁC. MS (m/z): 258.0 (MÅ+), 240.0, 167.0 150.0,
92.0, 91.0, 65.0. 1H NMR (CDCl3) d: 1.48 (3H, d,
J = 6.4 Hz), 1.84 (1H, s), 3.90 (3H, s), 4.82 (1H, q,
J = 6.4 Hz), 5.14 (2H, s), 6.82–6.96 (3H, m), 7.28–7.45
(5H, m). 13C NMR (CDCl3) d: 25.47, 56.41, 70.63, 71.50,
109.60, 114.29, 117.93, 127.68 (2C), 128.21, 128.94 (2C),
137.62, 139.53, 147.90, 150.16.
Chiral analyses were performed with a Varian HPLC cou-
pled to a Varian 2550 UV detector. The HPLC column
used was a Diacel Chiracel OD-H (i.d. 4.6 mm, length
25 cm, particle size 5 lm). Hexane and isopropanol were
used as eluents. Conditions: alcohol 3: hexane/isopropanol
(90:10), flow rate: 1 mL/min, retention times: 16.4 min (S)-
3, 19.7 min (R)-3, RS = 2.1, alcohol 5: hexane/isopropanol
(95:5), flow rate: 1 mL/min, retention times: 58.1 min (R)-5,
70.3 min (S)-5, RS = 1.7, alcohol 7: hexane/isopropanol
(90:10), flow rate: 1 mL/min, retention times: 33.8 min
(R)-7, 42.5 min (S)-7, RS = 2.5. Acetate 8: hexane/isopro-
panol (98:2), flow rate: 1 mL/min, retention times:
24.4 min (S)-8, 28.9 min (R)-8, RS = 1.9. Acetate 9: hex-
ane/isopropanol (95:5), flow rate: 1 mL/min, retention
times: 48.1 min (S)-9, 54.5 min (R)-9, RS = 1.5. Acetate
10: hexane/isopropanol (95:5), flow rate: 1 mL/min, reten-
tion times: 20.2 min (S)-10, 22.7 min (R)-10, RS = 1.5.
2-Bromo-1-(4-(benzyloxy)-3-methoxyphenyl)ethanone 4:
Under an N2 atmosphere, 1-(4-(benzyloxy)-3-methoxyphen-
yl)ethanone 2 (5.00 g, 19.5 mmol) was dissolved in dry
CHCl3 (100 mL) and bromine (19.7 mmol) dissolved in
dry CHCl3 (200 mL) was added during 3 h. The reaction
was continued for 12 h more. The CHCl3 solution was
washed with NaHCO3 solution (3 · 100 mL) and water
(3 · 100 mL) and dried over MgSO4. The crude product
was crystallized from EtOH yielding 2.45 g (38%), mp:
106–108 ꢁC. MS (m/z): 336.2/334.2 (MÅ+), 256.3, 92.1,
4.3. Determination of absolute configurations
1
91.1, 85.0, 83.0, 65.1. H NMR (CDCl3) d: 3.96 (3H, s),
The absolute configuration of the faster reacting enantio-
mer in lipase catalyzed resolution was determined by the
known enatiopreference of CAL-B. All enzyme prepara-
tions showed the same enatiopreference. Moreover, the elu-
tion orders on Diacel Chiracel OD-H of the faster reacting
enantiomers were the same.
4.40 (2H, s), 5.26 (2H, s), 6.92 (1H, d, J = 8.4 Hz), 7.38–
7.54 (7H, m). 13C NMR (CDCl3) d: 30.41, 56.13, 70.87,
99.99, 111.27, 112.12, 123.67, 127.21, 127.27, 128.23,
128.76 (2C), 136.04, 149.78, 153.18 and 190.08.
2-Bromo-1-(4-(benzyloxy)-3-methoxyphenyl)ethanol 5: 2-
Bromo-1-(4-(benzyloxy)-3-methoxyphenyl)ethanone
4
4.4. Enzymatic reactions
(1.68 g, 5.0 mmol) was dissolved in MeOH (50 mL) at
0 ꢁC and NaBH4 (0.19 g, 5.0 mmol) was added over
5 min. The reduction was continued for 1 h. The reaction
mixture was quenched with water and dilute HCl and the
Test reactions were performed in a Minitron Incubator
Shaker at 30 ꢁC agitating at 200 rpm. Racemic alcohol

1294
E. Fuglseth et al. / Tetrahedron: Asymmetry 17 (2006) 1290–1295
water fraction extracted with CH2Cl2 (2 · 40 mL). The or-
ganic fraction was washed with dilute HCl and brine, dried
over MgSO4 and concentrated in vacuum yielding an oil.
Upon addition of di-isopropyl ether, orange crystals
formed. They were isolated by filtration yielding 1.30 g
(77%), mp: 61–64 ꢁC. MS (m/z): 338.2/336.2 (MÅ+), 243.2,
240.3, 149.2, 92.1 and 91.1. 1H NMR (CDCl3) d: 2.04
(1H, s), 3.54 (1H, dd, J = 9.2 and 10.4 Hz), 3.61 (1H, dd,
J = 3.3 and 10.4 Hz), 3.92 (3H, s), 4.86 (1H, dd, J = 3.3
and 9.2 Hz), 5.17 (2H, s), 6.85–6.97 (3H, m), 7.31–7.35
(5H, m). 13C NMR (CDCl3) d: 40.29, 56.05, 71.02, 73.68
109.45, 113.88, 118.38, 127.25 (2C), 127.90, 128.58 (2C),
133.37, 136.98, 148.23, 149.85.
phenyl)ethanol (S)-3: Yield 428 mg (47%) ee (HPLC)
20
99%, ½aꢀD ¼ ꢁ27:9 (c 1.00 CHCl3), mp: 47–50 ꢁC. (R)-1-
Acetoxy-1-(4-(benzyloxy)-3-methoxyphenyl)ethane (R)-8:
20
Yield 454 mg (43%), ee (HPLC) 92%, ½aꢀD ¼ þ78:6 (c
1.00 CHCl3), mp: 54–56 ꢁC.
(R)-1-(4-(Benzyloxy)-3-methoxyphenyl)ethanol (R)-3: Ace-
tate (R)-8 (454 mg, 1.51 mmol) was hydrolyzed to the cor-
responding alcohol (R)-8 by standard methods. Yield
20
280 mg (65%), ee (HPLC) 92%, ½aꢀD ¼ þ26:8 (c 1.00
CHCl3), mp: 47–50 ꢁC.
(S)-1-Acetoxy-1-(4-(benzyloxy)-3-methoxyphenyl)ethane
(S)-8: Alcohol (S)-3 (428 mg, 1.66 mmol) was acetylated
2-(4-(Benzyloxy)-3-methoxyphenyl)oxirane 6: To a solu-
tion of 2-bromo-1-(4-(benzyloxy)-3-methoxyphenyl)etha-
nol 5 (950 mg, 2.8 mmol) in MeOH (20 mL) was added
NaOH (120 mg, 3.0 mmol) while keeping the temperature
at 20 ꢁC. The reaction was agitated for 2 h prior to dilution
with water (30 mL) and extraction with dichloromethane
(2 · 20 mL). The organic fraction was washed further with
water (40 mL) and brine (40 mL). The crude product was
purified by column chromatography (EtOAc/pentane,
4:1) giving 415 mg (58%) of the epoxide 6. MS (m/z):
under standard conditions. Yield 337 mg (68%), ee (HPLC)
99%, ½aꢀD ¼ ꢁ92:2 (c 1.00 CHCl3), mp: 54–56 ꢁC.
20
Resolution of 2-bromo-1-(4-(benzyloxy)-3-methoxyphen-
yl)ethanol 5: 2-Bromo-1-(4-(benzyloxy)-3-methoxyphen-
yl)ethanol
5 (450 mg, 1.3 mmol) and vinyl acetate
(575 mg, 6.7 mmol) were dissolved in CH2Cl2/hexane (1:1
v/v, 20 mL). Novozym 735 (100 mg) was added and the
reaction agitated for 8 h at 30 ꢁC. The catalyst was filtered
off and the solvent removed. The product ester and the
remaining alcohol were separated by column chromatogra-
phy (CHCl3/EtOAc, 4:1). Results: (R)-2-Bromo-1-(4-(benz-
1
256.1 (MÅ+), 165.0, 137.0, 91.0. H NMR (CDCl3) d: 2.78
(1H, dd, J = 2.6 and 5.5 Hz), 3.11 (1H, dd, J = 4.1 and
5.2 Hz), 3.80 (1H, dd, J = 2.6 and 4.1 Hz), 3.90 (3H, s),
5.29 (2H, s), 6.77–6.86 (3H, m), 7.26–7.34 (5H, m). 13C
NMR (CDCl3) d: 51.07, 52.93, 56.02, 71.12, 108.54,
114.04, 118.35, 127.29 (2C), 127.86, 128.56 (2C), 130.62,
137.06, 148.21, 150.04.
yloxy)-3-methoxyphenyl)ethanol (R)-5: yield 198 mg
20
(44%), ee (HPLC): 94%, ½aꢀD ¼ þ5:8 (c 1.00 CHCl3), mp:
47–50 ꢁC. (S)-1-Acetoxy-2-bromo-1-(4-(benzyloxy)-3-meth-
oxyphenyl)ethane (S)-9: yield 231 mg (46%), ee
20
(HPLC): 98%, ½aꢀD ¼ þ43:1 (c 1.00 CHCl3), mp: 54–
56 ꢁC. MS (m/z): 379.8/377.8 (MÅ+), 319.8, 297.9, 239.0
1
2-Chloro-1-(4-(benzyloxy)-3-methoxyphenyl)ethanol 7: b-
Cyclodextrin (1135 mg, 1.0 mmol) was dissolved in water
(25 mL), shaken at 60 ꢁC, and 2-(4-(benzyloxy)-3-methoxy-
phenyl)oxirane (6) (256 mg, 1.0 mmol) dissolved in MeOH
(2 mL) was added. The solution was cooled to 20 ꢁC and
HCl (1.5 mL, 1 M, 1.5 mmol) was added. The reaction mix-
ture was left stirring for 2 days, before work up by extrac-
tion with EtOAc (3 · 25 mL). After washing with water,
the organic fraction was dried over MgSO4 and concen-
trated in vacuum. The crude product was crystallized from
CHCl3, yield 60 mg (21%), mp: 67–69.5 ꢁC. MS (m/z): 292/
294 (MÅ+, not observed), 274.1, 256.1, 243.1, 91.0. 1H
NMR (CHCl3) d: 3.62 (1H, dd, J = 8.3 and 11.1 Hz),
3.66 (1H, dd, J = 3.5 and 11.2 Hz), 3.89 (3H, s), 4.26
(1H, br), 4.70 (1H, dd, J = 3.3 and 8.3 Hz), 5.12 (2H, s),
6.83–6.98 (3H, m), 7.29–7.35 (5H, m). 13C NMR (CHCl3)
d: 56.00, 68.02, 71.06, 74.41, 109.77, 113.95, 118.31,
127.21 (2C), 127.82, 128.51 (2C), 133.69, 137.05, 147.89,
149.78.
206.9, 164.9, 148.9, 92.0, 91.0. H NMR (CDCl3) d: 2.11
(3H, s), 3.56 (1H, dd, J = 4.6 and 10.8 Hz), 3.63 (1H, dd,
J = 8.5 and 10.8 Hz), 3.88 (3H, s), 5.13 (2H, s), 5.88 (1H,
dd, J = 4.6 and 8.5 Hz), 6.82–6.89 (3H, m) 7.27–7.45
(5H, m). 13C NMR (CDCl3) d: 21.46, 34.68, 56.49, 71.34,
75.19, 110.67, 114.04, 119.48, 127.62 (2C), 128.33, 128.98
(2C), 131.02, 137.29, 149.00, 150.07, 170.30.
Resolution of 2-chloro-1-(4-(benzyloxy)-3-methoxyphen-
yl)ethanol 7: 2-Chloro-1-(4-(benzyloxy)-3-methoxyphen-
yl)ethanol
7 (92 mg, 0.32 mmol) and vinyl acetate
(138 mg, 1.6 mmol) were dissolved in CH2Cl2/hexane (1:1
v/v, 10 mL). Novozym 735 (55 mg) was added and the
reaction was shaken at 30 ꢁC with an agitation rate of
200 rpm. The reaction stopped after 8 h by filtering off
the enzyme. The solvent was removed and ester 10 and
alcohol 7 were separated by column chromatography
(EtOAc/pentane, 4:1). Results: (R)-2-Chloro-1-(4-(benz-
yloxy)-3-methoxyphenyl)ethanol (R)-7: yield 35 mg
20
(38%), ee (HPLC): 97%, ½aꢀD ¼ ꢁ12:1 (c 1.00 MeOH),
Resolution of 1-(4-(benzyloxy)-3-methoxyphenyl)ethanol
3: 1-(4-(Benzyloxy)-3-methoxyphenyl)ethanol 3 (903 mg,
3.5 mmol) and vinyl acetate (1507 mg, 17.5 mmol) were dis-
solved in CH2Cl2/hexane (1:1, v/v, 20 mL) and Novozym
435 (100 mg) were added. While keeping the temperature
at 30 ꢁC, the mixture was agitated at 200 rpm using a sha-
ker incubator. The reaction was stopped after 24 h by re-
moval of the catalysts by filtration. Ester 8 and alcohol 3
were separated by column chromatography using CHCl3
as mobile phase. Results: (S)-1-(4-(Benzyloxy)-3-methoxy-
mp: 67–69.5 ꢁC. (S)-1-Acetoxy-2-chloro-1-(4-(benzyloxy)-
3-methoxyphenyl)ethane (S)-10: yield 27 mg (25%), ee
20
(HPLC): 95%, ½aꢀD ¼ þ39:4 (c 1.00, CHCl3) MS (m/z):
334/336 (MÅ+, not observed), 298.1, 256.1, 243.1, 207.1,
1
91.0. H NMR (CDCl3) d: 2.10 (3H, s), 3.88 (3H, s), 4.29
(2H, m), 5.14 (2H, s), 5.95 (1H, dd, J = 5.0 and 7.2 Hz),
6.85–6.89 (3H, m) 7.26–7.36 (5H, m). 13C NMR (CDCl3)
d: 21.10, 56.05, 66.02, 70.95, 73.11, 110.53, 113.76,
119.24, 127.18 (2C), 127.85, 128.54 (2C), 129.42, 136.92,
148.44, 149.66, 170.00.

E. Fuglseth et al. / Tetrahedron: Asymmetry 17 (2006) 1290–1295
1295
12. Keller, R.; Holla, W.; Fuelling, G. Hoechst A.-G., F. R. G.,
Ed. 88-121274[321918]. EP. 20-12-1988, 1988; pp 12-
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13. Kazlauskas, R. J.; Weissfloch, A. N. E.; Rappaport, A. T.;
Cuccia, L. A. J. Org. Chem. 1991, 56, 2656–2665.
14. Reddy, M. A.; Surendra, K.; Bhanumathi, N.; Rao, K. R.
Tetrahedron 2002, 58, 6003–6008.
Acknowledgement
We thank Novozymes, Bagsværd, Denmark, for kind gifts
of enzymes.
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