The influence of microwave irradiation on lipase-catalyzed kinetic resolution of racemic secondary alcohols

Article abstract of DOI:10.1016/j.tetasy.2007.06.035

The influence of microwave irradiation on the Novozyme 435 (Candida antarctica lipase) catalyzed kinetic resolution of secondary alcohols with different functional groups was studied in comparison to the use of conventional heating at 60 °C. p-Chlorophenyl acetate was used as an acyl donor and toluene as the solvent. (±)-1-Phenyl-1-propanol 1, (±)-1-(4-bromophenyl)-propan-1-ol 3, (±)-1-phenylbut-3-en-1-ol 5 and (±)-3-bromo-2-(2-hydroxypropyl)-1,4-dimethoxynaphthalene 7 were successfully resolved into their (S)-alcohols and (R)-esters, respectively, in good enantiomeric excess. Resolution of (±)-ethyl-5-(4-methoxybenyloxy)-3-hydroxypentanoate 9 afforded its (R)-alcohol and (S)-ester using this method. In addition, microwave-assisted lipase transesterification of meso-symmetric diol 11 effected desymmetrization to ester 12 with high enantiomeric excess. In all cases studied, the conversion value for the microwave-assisted lipase kinetic resolution of secondary alcohols was higher than that obtained using conventional heating.

Full text of DOI:10.1016/j.tetasy.2007.06.035

Tetrahedron: Asymmetry 18 (2007) 1618–1624
The influence of microwave irradiation on lipase-catalyzed kinetic
resolution of racemic secondary alcohols
Prabhakar Bachu, Jennifer S. Gibson, Jonathan Sperry and Margaret A. Brimble*
Department of Chemistry, The University of Auckland, 23 Symonds Street, Auckland, New Zealand
Received 15 June 2007; accepted 28 June 2007
Abstract—The influence of microwave irradiation on the Novozyme 435ꢀ (Candida antarctica lipase) catalyzed kinetic resolution of sec-
ondary alcohols with different functional groups was studied in comparison to the use of conventional heating at 60 ꢁC. p-Chlorophenyl
acetate was used as an acyl donor and toluene as the solvent. ( )-1-Phenyl-1-propanol 1, ( )-1-(4-bromophenyl)-propan-1-ol 3, ( )-1-
phenylbut-3-en-1-ol 5 and ( )-3-bromo-2-(2-hydroxypropyl)-1,4-dimethoxynaphthalene 7 were successfully resolved into their (S)-alco-
hols and (R)-esters, respectively, in good enantiomeric excess. Resolution of ( )-ethyl-5-(4-methoxybenyloxy)-3-hydroxypentanoate 9
afforded its (R)-alcohol and (S)-ester using this method. In addition, microwave-assisted lipase transesterification of meso-symmetric diol
11 effected desymmetrization to ester 12 with high enantiomeric excess. In all cases studied, the conversion value for the microwave-
assisted lipase kinetic resolution of secondary alcohols was higher than that obtained using conventional heating.
ꢂ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
organic synthesis (MAOS) include reduced chemical reac-
tion time, reduced side reactions, increased yields and
improved reproducibility. MAOS has been applied to the
synthesis of several natural products as well as peptides,
peptoids and carbohydrates.16–19
Biocatalysts are an attractive alternative to conventional
methods for effecting asymmetric organic transformations,
offering unique characteristics when compared to chemical
(homogeneous and heterogeneous) catalysts. Very high
enantio-, regio- and chemoselectivities can be achieved
using biocatalysts due to the strict recognition of the sub-
strate by the enzyme. Biocatalytic reactions are also gener-
ally safe and the reaction conditions are mild.1–3
Microwave-assisted lipase-catalyzed transesterification has
emerged as a useful tool in organic synthesis. To date
few reports are available that have been limited to the
use of a relatively small number of secondary alcohol sub-
strates.20–23 A recent paper investigating microwave-
assisted lipase-catalyzed transesterification of methyl aceto-
acetate in toluene suggested that microwave heating in
fact had no noticeable effect on the reaction.23 Studies on
the kinetic resolution of alcohols that contain additional
functionality and the position of the hydroxyl group rela-
tive to an aromatic ring have not been reported. Previous
studies on the microwave-assisted kinetic resolution of
alcohols have also used potentially toxic and explosive sol-
vents with reaction temperatures varying from 35 ꢁC to
95 ꢁC.20–22
Lipases (triacylglycerol acyl hydrolases, EC 3.1.1.3) can
be used as biocatalysts in hydrolysis reactions, acylation
reactions, ester aminolysis and peracid formation.4–7
Applications of lipase-catalyzed reactions include efficient
syntheses of chiral building blocks, drugs and fra-
grances.8–14 The kinetic resolution of secondary alcohols
or their carboxylates either via esterification or hydrolysis
has been extensively studied with different lipases, where
the enzyme discriminates between the two enantiomers
present in a racemic mixture.2 Microwave-assisted high
speed synthesis has also attracted considerable interest in
recent years.15 The advantages of microwave-assisted
We herein report our studies on microwave-assisted
lipase kinetic resolution of secondary alcohols which
contain additional functionality. The position of the
hydroxyl group relative to the aromatic ring is also
investigated.
*
Corresponding author. Tel.: +64 9 3737599; fax: +64 9 3737422; e-mail:
m.brimble@auckland.ac.nz
0957-4166/$ - see front matter ꢂ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.06.035

P. Bachu et al. / Tetrahedron: Asymmetry 18 (2007) 1618–1624
1619
2. Results and discussion
tion of several different racemic secondary alcohols was
carried out (Scheme 1) using p-chlorophenyl acetate 13 in
toluene at 60 ꢁC. For these microwave-assisted reactions,
the CEM Discover systemꢀ with a circular single mode
and focused waves was used, resulting in formation of a
homogeneous field pattern surrounding the sample. Con-
ventional heating reactions were carried out for the same
reaction time as the microwave-assisted lipase reactions.
The enantiomeric excess of the substrate (ees) and the prod-
uct (eep) was measured using chiral HPLC. For each
transesterification, the conversion (Conv) was calculated
according to Sih and Chen.28 The results obtained are sum-
marized in Table 1.
Immobilized Candida antarctica lipase (CALB) was chosen
for these transesterification studies. C. antarctica, available
under the trade name of Novozyme 435ꢀ (immobilized on
a macroporous acrylic resin), has proven to be an efficient
biocatalyst for lipase transesterifications22,25–27 demon-
strating good thermal stability with a maximum activity
in the range of 70–90 ꢁC.22
The use of vinyl acetate or isopropenyl acetate as the acyl
donor is disadvantageous due to its propensity to cause
undesired side reactions.24 To date, p-chlorophenyl acetate
13 has not been used for microwave-assisted lipase trans-
esterifications, despite the fact that it is a versatile acyl
donor for use in conventional lipase (Novozyme 435ꢀ)
transesterifications.24 p-Chlorophenol is released as a
non-interfering by-product,28 thus prompting us to employ
p-chlorophenyl acetate 13 as the acyl donor in the present
work.
Under microwave irradiation for 4 h, lipase kinetic resolu-
tion of racemic alcohol 1 afforded (ꢀ)-(S)-alcohol 1 (42%,
99% ee) and (+)-(R)-ester 2 (45%, 99% ee) with a conver-
sion value of 50%. Under conventional heating for the
same period, racemic alcohol 1 proceeded to (ꢀ)-(S)-alco-
hol 1 (81%, 55% ee) and (+)-(R)-ester 2 (17%, >99% ee)
with a lower conversion value of 36%.
The choice of solvent is important, as it can influence the
enantioselectivity observed for a given reaction. Toluene
is an efficient solvent compared to other solvents, with
respect to the enantiopurity of the products obtained.29–32
Kazlauskas and Park demonstrated that the trend is
towards higher reaction rates in less polar solvents.32 With
its higher boiling point, toluene appeared to be an excellent
solvent for the investigation of microwave-assisted kinetic
resolution.
It was next decided to investigate the influence of a halogen
substituent at the para-position on alcohol 3. Under micro-
wave irradiation for 5 h, lipase kinetic resolution of race-
mic alcohol 3 afforded (ꢀ)-(S)-alcohol 3 (48%, 92% ee)
and (+)-(R)-ester 4 (39%, 99% ee). Under conventional
heating, racemic alcohol 3 was converted into (ꢀ)-(S)-alco-
hol 3 (62%, 56% ee) and (+)-(R)-ester 4 (30%, >99% ee).
The microwave irradiation method gave a higher conver-
sion value of 48% when compared to the 35% obtained
using conventional heating.
Our objective was to study the influence of microwave irra-
diation on Novozyme 435ꢀ catalyzed kinetic resolution of
several secondary alcohols 1, 3, 5, 7, 9 and 11 which con-
tain different functional groups on the aryl ring and which
also vary in the position of the hydroxyl group relative to
the aryl ring. The Novozyme 435ꢀ catalyzed kinetic resolu-
Having secured an efficient approach for the resolution of
secondary alcohols 1 and 3, our subsequent efforts focussed
on the use of allyl alcohol 5. In this case, microwave-
assisted lipase kinetic resolution for 6 h effected resolution
O
O
O
CH3
lipase, toluene, 13 , 60 oC
OH
OH
O
CH3
+
R'
*
*
microwave, 70W
*
R
R'
R
R'
R
or
conventional heating
13
Cl
acyl donor
OR
OR
OR
OMe
OMe
Br
OR
Br
1 R = H
3 R = H
5 R = H
6 R = COCH3
7 R = H
2 R = COCH3
4 R = COCH3
8 R = COCH3
OR
O
OR
O
O
9 R = H
MeO
11 R = H
OH 12 R = COCH3
10 R = COCH3
Scheme 1. Lipase-catalyzed kinetic resolution of racemic secondary alcohols.

1620
P. Bachu et al. / Tetrahedron: Asymmetry 18 (2007) 1618–1624
Table 1. Comparison of microwave-assisted lipase kinetic resolution and conventional heating assisted lipase kinetic resolution of secondary alcohols
Substrate Timed (h)
Microwave heating Conventional heating
Ester ee %a (yield %) Alcohol ee %a (yield %) Conv.b (%) Ester ee %a (yield %) Alcohol ee %a (yield %) Conv.b (%)
1
3
4
5
6
6
12
12
>99 (45)
>99 (39)
>99 (24)
>99 (44)
99 (38)
99 (42)
92c (48)
58 (71)
93 (40)
43 (48)
—
50
48
37
48
30
—
>99 (81)
>99 (30)
>99 (2)
99 (26)
94 (9)
55 (17)
53c (62)
6 (89)
26 (73)
6 (73)
—
36
35
6
21
6
5
7
9
11
99 (81)
No reaction
—
a Determined by HPLC (Chiralcel OD–H, hexane–i-PrOH).
b Conversion was calculated according to the formula Conv = ees/(ees + eep).29 eep = enantiomeric excess of ester. ees = enantiomeric excess of alcohol.
c Calculation based on specific rotation.
d Reaction time for both microwave heating method and conventional heating method.
of racemic alcohol 5 into (ꢀ)-(S)-alcohol 5 (71%, 58% ee)
and (+)-(R)-ester 6 (24%, >99% ee) with a conversion value
of 37%. Under conventional heating, racemic alcohol 5 was
converted into (ꢀ)-(S)-alcohol 5 (89%, 6% ee) and (+)-(R)-
ester 6 (2%, >99% ee) with a conversion value of 6%. Thus,
the microwave-assisted kinetic resolution proceeded with a
sixfold higher conversion than conventional heating.
microwave irradiation for 12 h at 60 ꢁC in toluene using
Novozyme 435ꢀ and p-chlorophenyl acetate 13 as the acyl
donor. The rate of reaction was enhanced 32-fold over con-
ventional heating which mainly afforded the recovered
starting material. This example thus provides an excellent
illustration of the considerable rate enhancement observed
for lipase kinetic resolutions carried out using microwave
irradiation.
Next, the presence of an additional aromatic ring with the
hydroxyl group b to the aryl ring was investigated using
naphthyl alcohol 7. Using microwave-assisted lipase kinetic
resolution for 6 h, racemic alcohol 7 was resolved into (+)-
(S)-alcohol 7 (40%, 93% ee) and (+)-(R)-ester 8 (44%, 99%
ee). Under conventional heating, racemic alcohol 7 was
resolved into (+)-(S)-alcohol 7 (73%, 26% ee) and (+)-
(R)-ester 8 (26%, >99% ee). This reflected a twofold higher
conversion value for the microwave method over conven-
tional heating.
In all cases, except for 9, the enzymatic resolution fits Kazl-
auskas rule with the (R)-ester and (S)-alcohols being
obtained. In alcohol 9, the size of the substituents attached
to the carbon atom bearing the hydroxyl group may be the
reason for the deviation from this pattern.
Some conclusions can be derived from these experiments;
the conversions observed using this microwave-assisted
lipase kinetic resolution varied depending on the nature
of the substituent attached to the secondary alcohol. The
observed conversion increased in the order: 9 < 5 < 7 6 3,
1.
In order to test the utility of our approach for the resolu-
tion of multifunctional secondary alcohols, our attention
next turned to the resolution of b-hydroxy ester 9 (Scheme
1). Using the microwave-assisted lipase kinetic resolution
method, racemic alcohol 9 was resolved into (+)-(R)-alco-
hol 9 (48%, 43% ee) and (+)-(S)-ester 10 (38%, 99% ee)
after 12 h. Under conventional heating, racemic alcohol 9
was resolved into (+)-(R)-alcohol 9 (73%, 6% ee) and
(+)-(S)-ester 10 (9%, >94% ee). The microwave irradiation
method proved to be the optimum method with a conver-
sion value of 30%, which is a fivefold increase over conven-
tional heating.
The position of the hydroxyl group was also found to be an
important factor in these lipase kinetic resolutions. Based
on these experiments, it can be concluded that the presence
of a substituent a- to the hydroxyl group in the secondary
alcohol substrates resulted in a higher conversion than the
presence of a substituent at a position more remote to the
hydroxyl group. Thus, a-substituted alcohol 1 showed a
higher conversion than b-substituted alcohol 7. The
c-substituted alcohol 9 showed even less conversion than
both a-substituted alcohol 1 and b-substituted alcohol 7.
Desymmetrization of meso-compounds or prochiral diols
and diacetates using a lipase enzyme has become a practical
approach for the preparation of chiral compounds due to
its high specificity and reproducibility. meso-Diol 11 has
been used as a starting material for the enantioselective
synthesis of (+)-panepophenanthrin,8 hygromycin A9 and
(+)-Sch642305.10 Takano et al.33 also reported the mono-
acetylation of meso-symmetric diol 11 with vinyl acetate
in the presence of lipase PS in 79% yield with the reaction
stirred for 16 days at 28 ꢁC.
The effect of the position of the substituents present on
the aromatic ring was also found to be important. The
observed conversion rate in the order 7 < 3 < 1 supports
the notion that the presence of a halogen substituent at
the ortho- or para-position on the aromatic ring results in
decreased conversion.
The nature of the aromatic ring system was also investi-
gated. Naphthyl substituted alcohol 7 afforded less selectiv-
ity than the phenyl substituted alcohols 1 and 3. The
presence of an allyl group also had an effect in that alcohol
5 resulted in less conversion than 1, even though 5 still con-
tains an a-substituted phenyl ring. Longer substituents
We therefore evaluated the use of microwave-assisted
lipase-catalyzed desymmetrization of meso-symmetric diol
11. Ester 12 was obtained in 81% yield (99% ee) after

P. Bachu et al. / Tetrahedron: Asymmetry 18 (2007) 1618–1624
1621
resulted in lower conversion rates as demonstrated by the
conversion rates 9 < 5 < 3, 1. Notably during the kinetic
resolution of 9, no intramolecular lactonization or hydroly-
sis of the ester functionality was observed.
was stirred at 60 ꢁC in a microwave reactor (single mode
CEM Discoverꢀ Focused Microwave Synthesis System)
at 70 W for the time shown in Table 1. When the reaction
was complete (as indicated by TLC analysis) the mixture
was filtered through cotton wool to remove the enzyme
and washed with dichloromethane (2 · 3 mL). The com-
bined organic extracts were concentrated under reduced
pressure and the residue was purified by flash chromatogra-
phy using hexane–ethyl acetate as eluent to yield the corre-
sponding alcohol and ester.
3. Conclusion
Microwave-assisted Novozyme 435ꢀ kinetic resolution of
secondary alcohols in toluene using 4-chlorophenyl acetate
13 as an acyl donor at a temperature of 60 ꢁC at 70 W has
proven to be a versatile method to effect the kinetic resolu-
tion of secondary alcohols of varying substitution patterns
compared to conventional heating.
4.3. General procedure for lipase-catalyzed kinetic resolution
using conventional heating
A mixture of racemic alcohol (1.0 mmol) and p-chloro-
phenyl acetate (3.0 mmol) in toluene (5 mL) was flushed
with argon for 1 min followed by the addition of Novo-
zyme 435ꢀ (Sigma–Aldrich) (50 mg). The resulting mixture
was stirred at 60 ꢁC with heating on a sand bath for the
time shown in Table 1. When the reaction was complete
(as indicated by TLC analysis) the mixture was filtered
through cotton wool to remove the enzyme and washed
with dichloromethane (2 · 3 mL). The combined organic
extracts were concentrated under reduced pressure and
the residue purified by flash chromatography using hex-
ane–ethyl acetate as eluent to yield the corresponding alco-
hol and ester.
4. Experimental
4.1. General details
All reactions were carried out in either oven-dried or flame-
dried glassware under a nitrogen atmosphere unless other-
wise stated. Analytical thin layer chromatography was
performed using 0.2 mm Kieselgel F254 (Merck) silica
plates and compounds were visualized under 365 nm ultra-
violet irradiation followed by staining with either alkaline
permanganate or ethanolic vanillin solution. Flash chro-
matography was performed using Riedel-de Ha¨en Kieselgel
or Merck Kieselgel 60 F (both 230–400 mesh) with the indi-
cated solvents. Infrared spectra were obtained using a
Perkin–Elmer Spectrum One Fourier Transform Infra-
red spectrometer as a thin film between sodium chloride
plates. Absorption maxima are expressed in wavenumbers
(cmꢀ1). Optical rotations were measured using a Perkin–
Elmer 341 polarimeter at k = 598 nm and are given in
10ꢀ1 deg cm2 gꢀ1. Melting points were recorded on an
Electrothermalꢀ melting point apparatus and are uncor-
rected. NMR spectra were recorded as indicated on either
a Bruker DRX-400 spectrometer operating at 400 MHz for
1H nuclei and 100 MHz for 13C nuclei or on a Bruker
Avance 300 spectrometer operating at 300 MHz and
75 MHz for 1H and 13C nuclei, respectively. Chemical
shifts are reported in parts per million (ppm) relative to
the tetramethylsilane peak recorded as d 0.00 ppm in
CDCl3/TMS solvent, or the residual chloroform peak at
d 7.25 ppm. The 13C NMR values were referenced to the
residual chloroform peak at d 77.0 ppm. 13C NMR values
are reported as chemical shift d, multiplicity and assign-
4.3.1. (ꢀ)-(S)-1-Phenyl-1-propanol 134 and (+)-(R)-1-phen-
yl-1-propyl acetate 2.34 Using the microwave-assisted
kinetic resolution procedure described above with racemic
alcohol 1 (113 mg, 0.8 mmol), the title compound 1 (47 mg,
0.33 mmol, 42%) was afforded as a colourless liquid,
20
22
½aꢁD ¼ ꢀ46:0 (c 0.80, CHCl3) {lit.35 ½aꢁD ¼ ꢀ43:9 (c 1.7,
CHCl3)}, 99% ee. The enantiomeric excess (ee) was deter-
mined by high pressure liquid chromatography (Waters-
600) using
a
chiral column (Chiralcel OD–H,
0.43 cm · 1 cm, Daicel Chemical Ind. Ltd) and 2-propa-
nol–hexane (1:99) as eluent with a flow rate of 0.5 mL/
min. The retention time for the minor peak was 23 min
and the retention time for the major peak was 33 min; vmax
(film)/cmꢀ1: 3406 (OH); dH (400 MHz, CDCl3): 0.77 (3H, t,
J3,2 = 7.5 Hz, 3-H), 1.54–1.68 (2H, m, 2-H), 3.79 (1H, br s,
OH), 4.34 (1H, t, J1,2 = 6.6 Hz, 1-H), 7.11–7.22 (5H, m,
Ar-H); dC (100 MHz, CDCl3): 9.7 (CH3, C-3), 31.4 (CH2,
C-2), 75.2 (CH, C-1), 125.7 (CH, C-2 and C-6), 126.7
(CH, C-4), 127.8 (CH, C-3 and 5), 144.4 (quat., C-1).
The spectroscopic data were in agreement with that
reported in the literature.34
1
ment. H NMR shift values are reported as chemical shift
d, relative integral, multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet), coupling constant (J in
Hz) and assignment. High resolution mass spectra were
recorded on a VG-70SE mass spectrometer at a nominal
accelerating voltage of 70 eV.
(+)-(R)-1-Phenyl-1-propyl acetate 2 (66 mg, 0.37 mmol,
45%) was also obtained as
a
colourless liquid,
20
½aꢁD ¼ þ98:2 (c 1.308, CHCl3), 99% ee. The enantiomeric
excess (ee) was determined by high pressure liquid chroma-
tography (Waters-600) using a chiral column (Chiralcel
OD–H, 0.43 cm · 1 cm, Daicel Chemical Ind. Ltd) and 2-
propanol–hexane (1:99) as eluent with a flow rate of
0.5 mL/min. The retention time for the minor peak was
7 min and the retention time for the major peak was
10 min; vmax (film)/cmꢀ1: 1735 (C@O), 1236 (C–O); dH
(400 MHz, CDCl3): 0.87 (3H, t, J3,2 = 7.4 Hz, 3-H), 1.65–
1.86 (1H, m, 2-H), 1.87–1.96 (1H, m, 2-H), 2.07 (3H, s,
4.2. General procedure for microwave-assisted lipase-cata-
lyzed kinetic resolution
A mixture of racemic alcohol (1.0 mmol) and p-chloro-
phenyl acetate (3.0 mmol) in toluene (5 mL) was flushed
with argon for 1 min followed by the addition of Novo-
zyme 435ꢀ (Sigma–Aldrich) (50 mg). The resulting mixture

1622
P. Bachu et al. / Tetrahedron: Asymmetry 18 (2007) 1618–1624
OCOCH3), 5.67 (1H, t, J1,2 = 6.8 Hz, H-1), 7.25–7.34 (5H,
m, Ar-H); dC (100 MHz, CDCl3): 9.8 (CH3, C-3), 21.2
(CH3, C-2), 29.2 (CH2, C-2), 77.3 (CH, C-1), 126.5 (CH,
C-2 and C-6), 127.8 (CH, C-4), 128.3 (CH, C-3 and 5),
140.5 (quat., C-1), 170.4 (quat., C-1). The spectroscopic
data were in agreement with that reported for the racemic
material in the literature.34
tion time for the minor peak was 19 min and the retention
time for the major peak was 28 min; vmax (film)/cmꢀ1: 3406
(OH); dH (400 MHz, CDCl3): 2.21 (1H, br s, OH), 2.47–
2.51 (2H, m, 2-H), 4.70 (1H, t, J1,2 = 6.1 Hz, 1-H), 5.11–
5.17 (2H, m, 4-H), 5.78 (1H, dd, J = 6.3 Hz, J = 7.7 Hz,
3-H), 7.23–7.34 (5H, m, Ar-H); dC (100 MHz, CDCl3):
43.7 (CH2, C-2), 73.2 (CH, C-1), 118.3 (CH, C-4), 125.8
(CH, C-2 and C-6), 127.5 (CH, C-4), 128.3 (CH, C-3 and
C-5), 134.4 (CH, C-3), 143.83 (quat., C-1). The spectro-
scopic data were in agreement with that reported in the
literature.37,38
4.3.2. (ꢀ)-(S)-1-(4-Bromophenyl)propan-1-ol 335,36 and (+)-
(R)-1-(4-bromophenyl)-1-propyl acetate 4. Using the
microwave-assisted kinetic resolution procedure with race-
mic alcohol 3 (107 mg, 0.5 mmol), the title compound 3
(51 mg, 0.24 mmol, 48%) was afforded as a colourless li-
(+)-(R)-1-Phenylbut-3-en-1-yl acetate 6 (35 mg, 0.16 mmol,
20
20
20
quid, ½aꢁD ¼ ꢀ38:9 (c 1.91, CHCl3) {lit.35 ½aꢁD ¼ ꢀ35:2 (c
1.9, CHCl3), 83% ee}, 92% ee; vmax (film)/cmꢀ1: 3375
(OH), 1009 (C–Br); dH (400 MHz, CDCl3): 0.83 (3H, t,
J3,2 = 6.4 Hz, 3-H), 1.60–1.73 (2H, m, 2-H), 3.00 (1H, br
s, OH), 4.43 (1H, t, J1,2 = 6.5 Hz, 1-H), 7.11 (2H, d,
J = 8.4 Hz, 2-H and 6-H), 7.41 (2H, d, J = 8.4 Hz, 3-H
and 5-H); dC (100 MHz, CDCl3): 9.8 (CH3, C-3), 31.6
(CH2, C-2), 75.0 (CH, C-1), 120.9 (quat., C-4), 127.6
(CH, C-2 and C-6), 131.2 (CH, C- 3 and C-5), 143.4 (quat.,
C-1) The spectroscopic data were in agreement with that
reported in the literature.35,36
24%) was also obtained as a colourless liquid, ½aꢁD ¼ þ67:4
(c 0.45, CHCl3) {lit.38 [a]D = +30.4 (c 1.2, CHCl3)}, >99%
ee. The enantiomeric excess (ee) was determined by high
pressure liquid chromatography (Waters-600) using a chi-
ral column (Chiralcel OD–H, 0.43 cm · 1 cm, Daicel
Chemical Ind. Ltd) and 2-propanol–hexane (1:99) as eluent
with a flow rate of 0.5 mL/min. The retention time for the
minor peak was 8 min and the retention time for the major
peak was 10 min; vmax (film)/cmꢀ1: 1739 (C@O), 1215 (O–
C); dH (400 MHz, CDCl3): 2.06 (3H, s, OCOCH3), 2.55–
2.69 (2H, m, 2-H), 5.03–5.10 (2H, m, 4-H), 5.66–5.73
(1H, m, 1-H), 5.81 (1H, dd, J = 6.1 Hz, J = 7.7 Hz, 3-H),
7.25–7.36 (5H, m, Ar-H); dC (100 MHz, CDCl3): 21.2
(CH3, C-2), 40.7 (CH2, C-2), 75.1 (CH, C-1), 117.9 (CH2,
C-4), 126.5 (CH, C-2 and C-6), 127.9 (CH, C-4), 128.4
(CH, C-3 and C-5), 133.3 (CH, C-3), 140.1 (quat., C-1),
170.2 (quat., C-1). The spectroscopic data were in agree-
ment with that reported in the literature.27,38
(+)-(R)-1-(4-Bromophenyl)-1-propyl acetate
4 (50 mg,
0.19 mmol, 39%) was also obtained as a colourless liquid,
20
½aꢁD ¼ þ85:0 (c 0.50, CHCl3), 99% ee. The enantiomeric
excess (ee) was determined by high pressure liquid chroma-
tography (Waters-600) using a chiral column (Chiralcel
OD–H, 0.43 cm · 1 cm, Daicel Chemical Ind. Ltd) and 2-
propanol–hexane (1:99) as eluent with a flow rate of
0.5 mL/min. The retention time for the minor peak was
7 min and the retention time for the major peak was
10 min; HRMS (EI): Found M+, 256.0092, 258.0077;
C11H1379BrO2, C11H1381BrO2 requires 256.0099, 258.0078;
4.3.4. (+)-(S)-3-Bromo-2-(2-hydroxypropyl)-1,4-di methoxy-
naphthalene 739 and (+)-(R)-3-bromo-2-(2-acetoxypropyl)-
1,4-dimethoxynaphthalene 8. Using the microwave-
assisted kinetic resolution procedure with racemic alcohol
7 (200 mg, 0.6 mmol), the title compound 7 (80 mg,
vmax (film)/cmꢀ1
:
1735 (C@O), 1236 (O–C); dH
(300 MHz, CDCl3): 0.86 (3H, t, J3,2 = 7.4 Hz, 3-H), 1.72–
1.93 (2H, m, 2-H), 2.06 (3H, s, OCOCH3), 5.60 (1H, t,
J1,2 = 6.9 Hz, 1-H), 7.17–7.21 (2H, m, 2-H and 6-H),
7.44–7.47 (2H, m, 3-H and 5-H); dC (75 MHz, CDCl3):
9.7 (CH3, C-3), 21.1 (CH3, C-2), 29.1 (CH2, C-2), 76.6
(CH, C-1), 121.7 (quat., C-4), 128.3 (CH, C-2 and C-6),
131.5 (CH, C-3 and C-5), 139.6 (quat., C-1), 170.2 (quat.,
C-1); m/z (EI, %): 258 (M+, 81Br, 13), 256 (M+, 79Br, 13),
229 (17), 227 (17), 187 (26), 185 (30), 43 (100).
0.24 mmol, 40%) was afforded as a white solid, mp 118–
20
120 ꢁC (lit.39 mp 118–120 ꢁC), ½aꢁD ¼ þ40:8 (c 0.001,
CHCl3) {lit.39 [a]D = +8.1 (c 2.05, CHCl3)}, 93% ee. The
enantiomeric excess (ee) was determined by high pressure
liquid chromatography (Waters-600) using a chiral column
(chiralcel OD–H, 0.43 cm · 1 cm, Daicel Chemical Ind.
Ltd) and 2-propanol–hexane (1:99) as eluent with a flow
rate of 0.5 mL/min. The retention time for major peak
was 32 min and the retention time for the minor peak
was 41 min; HRMS (EI): Found M+, 324.0360, 326.0347;
C15H1779BrO3, C15H1781BrO3 requires 324.0361, 326.0341;
vmax (film)/cmꢀ1: 3433 (OH); dH (400 MHz, CDCl3): 1.32
(3H, d, J3,2 = 6.4 Hz, 3-H), 3.17 (2H, d, J1,2 = 8.0 Hz, 1-
H), 3.93 (3H, s, 4-OMe), 3.96 (3H, s, 1-OMe), 4.14–4.20
(1H, m, 2-H), 7.49–7.57 (2H, m, 6-H and 7-H), 8.01–8.11
(2H, m, 5-H and 8-H); dC (100 MHz, CDCl3): 23.5 (CH3,
C-3), 39.8 (CH2, C-1), 61.3 (CH3, 1-OMe or 4-OMe),
62.0 (CH3, 4-OMe or 1-OMe), 68.1 (CH, C-2), 116.6 (quat.,
C-3), 122.6 (CH, C-5 or C-8), 122.6 (CH, C-8 or C-5), 126.7
(CH, C-6 or C-7), 126.7 (CH, C-6 or C-7), 127.6 (quat., C-
2), 127.8 (quat., C-4a or C-8a), 128.2 (quat., C-4a or C-8a),
150.3 (quat., C-1 or C-4), 151.1 (quat., C-1 or C-4); m/z
(EI, %): 326 (M+, 81Br, 38), 324 (M+, 79Br, 38), 282 (40),
280 (44), 267 (74), 265 (77), 185 (100), 186 (50), 171 (48),
4.3.3. (ꢀ)-(S)-1-Phenylbut-3-en-1-ol 537,38 and (+)-(R)-1-
Phenylbut-3-en-1-yl acetate 6.27,38 Using the microwave-
assisted kinetic resolution procedure with racemic alcohol
5 (112 mg, 0.8 mmol), the title compound 5 (80 mg,
0.57 mmol, 71%) was afforded as a colourless liquid,
20
½aꢁD ¼ ꢀ46:0 (c 0.80, CHCl3) {lit.38 [a]D = ꢀ28.5 (c 1.2,
CHCl3)}, 58% ee. The enantiomeric excess (ee) was deter-
mined by high pressure liquid chromatography (Waters-
600) using a chiral column (Chiralcel OD–H, 0.43 cm ·
1 cm, Daicel Chemical Ind. Ltd) and 2-propanol–hexane
(1:99) as eluent with a flow rate of 0.5 mL/min. The reten-
The enantiomeric excess was calculated based on the observed specific
rotation.

P. Bachu et al. / Tetrahedron: Asymmetry 18 (2007) 1618–1624
1623
20
127 (67), 115 (70), 77 (25). The spectroscopic data were in
agreement with that reported in the literature.39
less liquid, ½aꢁD ¼ þ6:0 (c 5.08, CHCl3), 99% ee. The enan-
tiomeric excess (ee) was determined by high pressure liquid
chromatography (Waters-600) using a chiral column (chi-
ralcel OD–H, 0.43 cm · 1 cm, Daicel Chemical Ind. Ltd)
and 2-propanol–hexane (1:99) as eluent with a flow rate
of 0.5 ml/min. The retention time for the major peak was
29 min and the retention time for the minor peak was
43 min; HRMS (EI): Found M+, 324.1576, C17H24O6
requires 324.1573; vmax (neat)/cmꢀ1: 1737 (C@O), 1246
(C–O); dH (400 MHz, CDCl3): 1.23 (3H, t, J2,1 = 7.2 Hz,
2-H), 1.91 (2H, q, J = 6.4 Hz, 4-H), 2.0 (3H, s, OCOCH3),
2.59 (2H, d, J2,3 = 6.4 Hz, 2-H), 3.43–3.52 (2H, m, 5-H),
3.79 (3H, s, 4-OMe), 4.12 (2H, q, J1,2 = 6.8 Hz, 1-H),
4.39 (2H, s, 7-H), 5.34 (1H, p, J = 6.5 Hz, 3-H), 6.84–
6.88 (2H, m, 5-H and 3-H), 7.21–7.25 (2H, m, 2-Hand
6-H); dC (100 MHz, CDCl3): 14.2 (CH3, C-2), 21.0 (CH3,
OCOCH3), 34.0 (CH2, C-4), 39.4 (CH2, C-2), 55.3 (CH3,
4-OMe), 60.6 (CH2, C-1), 66.0 (CH2, C-5), 68.5 (CH,
C-3), 72.7 (CH2, C-7), 113.8 (CH, C-5 and C-3), 129.3
(CH, C-2 and C-6), 130.3 (quat., C-1), 159.2 (quat., C-4),
170.2 (quat., OCOCH3), 170.3 (quat., C-1); m/z (EI, %):
324 (M+, 5), 281 (3), 263 (3), 233 (3), 176 (60), 137 (35),
121 (100), 97(6), 77 (10).
3-Bromo-2-(2-acetoxypropyl)-1,4-dimethoxynaphthalene 8
(100 mg, 0.27 mmol, 44%) was also obtained as a colourless
20
liquid, ½aꢁD ¼ þ17:8 (c 0.17, CHCl3), 99% ee. The enantio-
meric excess (ee) was determined by high pressure liquid
chromatography (Waters-600) using a chiral column (Chi-
ralcel OD–H, 0.43 cm · 1 cm, Daicel Chemical Ind. Ltd)
and 2-propanol–hexane (0.25:99.75) as eluent with a flow
rate of 0.5 ml/min. The retention time for the minor peak
was 47 min and the retention time for the major peak
was 55 min; HRMS (EI): Found M+, 366.0466, 368.0447;
C17H1979BrO4, C17H1981BrO4 requires 366.0467, 368.0446;
vmax (film)/cmꢀ1
(400 MHz, CDCl3): 1.29 (3H, d, J3,2 6.3 Hz, 3-H), 1.94
: 1732 (C@O), 1239 (C–O–C); dH
(3H, s, OCOCH3), 3.19 (1H, dd, Jgem = 13.3 Hz, J1A,2
6.2 Hz, 1-HA), 3.34 (1H, dd, Jgem = 13.3 Hz, J1B,2
=
=
6.2 Hz, 1-HB), 3.92 (3H, s, 4-OMe), 3.96 (3H, s, 1-OMe),
5.34–5.46 (1H, m, 2-H), 7.49–7.56 (2H, m, 6-H and 7-H),
8.01–8.09 (2H, m, 5-H and 8-H); dC (75 MHz, CDCl3):
19.7 (CH3, C-3), 21.2 (CH3, C-5), 36.2 (CH2, C-1), 61.3
(O–CH3, 1-OMe or 4-OMe), 62.2 (O–CH3, 4-OMe or
1-OMe), 70.3 (CH, C-2), 116.7 (quat., C-3), 122.5 (CH,
C-6 or C-7), 122.7 (CH, C-7 or C-6), 126.6 (CH, C-5 or
C-8), 126.6 (CH, C-8 or C-5), 126.9 (quat., C-2), 127.6
(quat., C-4a or C-8a), 128.2 (quat., C-8a or C-4a), 150.1
(quat., C-4 or C-1), 151.6 (quat., C-1 or C-4), 170.36 (quat.,
C-4); m/z (EI, %): 368 (M+, 81Br, 48), 366 (M+, 79Br, 48),
308 (100), 306 (100), 293 (27), 291 (30), 281 (15), 279
(20), 212 (50), 200 (45), 185 (50).
4.3.6. (+)-(1S,4R,4aS,5S,8R,8aS)-5-Acetoxy-1,4,4a,5,8,8a-
hexahydro-8-hydroxy-endo-1,4-methano naphthalene 12.33
Using the microwave-assisted kinetic resolution procedure
described above with racemic alcohol 11 (35 mg,
0.2 mmol), the title compound 12 (35 mg, 0.16 mmol,
81%) was afforded as colourless crystals, mp 87–88 ꢁC
20
(lit.33 mp 87–88 ꢁC), ½aꢁD ¼ þ30:5 (c 0.67, CHCl3)
30
4.3.5.
(+)-(R)-Ethyl-5-(4-methoxybenyloxy)-3-hydroxy-
{lit.33½aꢁD ¼ þ70:1 (c 1.02, CHCl3)}, 99% ee. The enantio-
pentanoate 940 and (+)-(S)-ethyl-5-(4-methoxybenzyloxy)-
3-acetoxypentanoate 10. Using the microwave-assisted
kinetic resolution procedure described above with racemic
alcohol 9 (180 mg, 0.6 mmol), title compound 9 (86 mg,
meric excess (ee) was determined by high pressure liquid
chromatography (Waters-600) using a chiral column
(Chiralcel OD–H, 0.43 cm · 1 cm, Daicel Chemical Ind.
Ltd) and 2-propanol–hexane (1:99) as eluent with a flow
rate of 0.5 ml/min. The retention time for the minor peak
was 24 min and the retention time for the major peak
was 33 min; dH (300 MHz, CDCl3): 1.29 (2H, q,
J = 8.1 Hz, 9-H), 1.92 (1H, br s, OH), 2.08 (3H, s,
OCOCH3), 2.79–2.85 (2H, m, 4a-H and 8a-H), 2.95–3.03
(2H, m, 4-H and 1-H), 4.41–4.45 (1H, m, 8-H), 5.25 (1H,
d, J = 10.3 Hz, 7-H or 6-H), 5.30–5.36 (1H, m, 5-H), 5.43
(1H, d, J = 10.3 Hz, 6-H or 7-H), 5.78 (1H, dd,
J = 2.8 Hz, J = 5.4 Hz, 2-H or 3-H), 5.85 (1H, dd,
J = 2.8 Hz, J = 5.4 Hz, 3-H or 2-H); dC (75 MHz, CDCl3):
21.07 (CH3, OCOCH3), 38.48 (CH, C-4a or C-8a), 41.73
(CH, C-8a or C-4a), 44.94 (CH, C-4 or C-1), 45.65 (CH,
C-1 or C-4), 48.88 (CH2, C-9), 66.45 (CH, C-8), 69.82
(CH, C-5), 126.79 (CH, C-6 or C-7), 132.02 (CH, C-7 or
C-6), 135.40 (CH, C-2 or C-3), 135.54 (CH, C-3 or C-2),
170.73 (quat., OCOCH3). The spectroscopic data were in
agreement with that reported in the literature.33
0.29 mmol, 48%) was afforded as a colourless liquid,
20
½aꢁD ¼ þ4:5 (c 3.44, CHCl3), 43% ee. The enantiomeric ex-
cess (ee) was determined by high pressure liquid chroma-
tography (Waters-600) using a chiral column (Chiralcel
OD–H, 0.43 cm · 1 cm, Daicel Chemical Ind. Ltd) and 2-
propanol–hexane (1:99) as eluent with a flow rate of
0.5 ml/min. The retention time for the minor peak was
42 min and the retention time for the major peak was
59 min; vmax (film)/cmꢀ1: 3448 (OH), 1735 (C@O), 1248
(C–O); dH (400 MHz, CDCl3): 1.27 (3H, t, J2,1 = 7.24 Hz,
2-H), 1.77–1.82 (2H, m, 4-H), 2.48 (2H, d, J2,3 = 6.3 Hz,
2-H), 3.38 (1H, br s, OH), 3.61–3.67 (2H, m, 5-H), 3.80
(3H, s, 4-OMe), 4.15 (2H, q, J1,2 = 7.0 Hz, 1-H), 4.19
(1H, m, 3-H), 4.45 (2H, s, 7-H), 6.86–6.88 (2H, m, 5-H
and 3-H), 7.23–7.26 (2H, m, 6-H and 2-H); dC (100 MHz,
CDCl3): 14.2 (CH3, C-2), 36.0 (CH2, C-4), 41.6 (CH2, C-
2), 55.3 (CH3, 4-OMe), 60.6 (CH2, C-1), 67.1 (CH, C-3),
67.7 (CH2, C-5), 72.9 (CH2, C-7), 133.8 (CH, C-3 and C-
5), 129.3 (CH, C-2 and C-6), 130.1 (quat., C-1), 159.2
(quat., C-4), 172.5 (quat., C-1). The spectroscopic data
were in agreement with that reported for the (S)-enantio-
mer in the literature.40
Acknowledgments
The authors thank the Department of Chemistry, Univer-
sity of Auckland, New Zealand, for the award of a Depart-
mental Scholarship (PB) for this work.
(+)-(S)-Ethyl-5-(4-methoxybenzyloxy)-3-acetoxypentanoate
10 (80 mg, 0.25 mmol, 38%) was also obtained as a colour-

1624
P. Bachu et al. / Tetrahedron: Asymmetry 18 (2007) 1618–1624
19. Bejugam, M.; Flitsch, S. L. Org. Lett. 2004, 6, 4001.
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