Asymmetric synthesis of flindersiachromanone using lipase-catalyzed reaction

Article abstract of DOI:10.3987/COM-05-10652

The (R)- and (S)-enantiomers of flindersiachromanone (2-(2-phenylethyl)-4-chromanone) were synthesized from the enantiomerically pure 1-phenyl-5-hexen-3-ol obtained via the lipase-catalyzed enantioselective transesterification.

Full text of DOI:10.3987/COM-05-10652

HETEROCYCLES, Vol. 68, No. 3, 2006
483
HETEROCYCLES, Vol. 68, No. 3, 2006, pp. 483 - 493. © The Japan Institute of Heterocyclic Chemistry
Received, 14th December, 2005, Accepted, 30th January, 2006, Published online, 31st January, 2006. COM-05-10652
ASYMMETRIC SYNTHESIS OF FLINDERSIACHROMANONE USING
LIPASE-CATALYZED REACTION
Masashi Kawasaki,*,1 Hikaru Yoshikai,2 Hiroko Kakuda,3 Naoki Toyooka,4 Akira
Tanaka,2 Michimasa Goto,5 and Tadashi Kometani5
1: Department of Liberal Arts and Sciences, Faculty of Engineering, Toyama
Prefectural University, 5180 Kurokawa, Imizu, Toyama-Ken 939-0398, Japan; 2:
Department of Bioresources Science, College of Technology, Toyama Prefectural
University, 5180 Kurokawa, Imizu, Toyama-Ken 939-0398, Japan; 3: Laboratory
of Chemistry, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan 4:
Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani,
Toyama 930-0194, Japan; 5: Department of Chemical and Biochemical
Engineering, Toyama National College of Technology, 13 Hongo, Toyama
939-8630, Japan
Abstract
-
The (R)- and (S)-enantiomers of flindersiachromanone
(2-(2-phenylethyl)-4-chromanone) were synthesized from the enantiomerically
pure 1-phenyl-5-hexen-3-ol obtained via the lipase-catalyzed enantioselective
transesterification.
INTRODUCTION
A variety of 2-substituted 4-chromanones (2-substituted 2,3-dihydro-4H-benzopyran-4-ones) are present
in nature,1 and it is known that many of these compounds including non-natural products possess
biological and pharmacological activities.1a Several 2-substituted 4-chromanones are exemplified
below.2 Flavanones (1) are the representative compounds and have been isolated from plants.3
The
flavanone with a 7-methoxy group (1b) was found to be a potent inhibitor of MCF-7 breast cancer cell
growth.4 As other examples, 2b is among compounds that show some fly killing activity,5 and a weak
anthelmintic activity has been demonstrated for 2c.6

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HETEROCYCLES, Vol. 68, No. 3, 2006
OH
O
O
O
O
Me
HO
O
Me
R
R
OMe O
1a: R=H
2a: R=H
2b: R=6-Me
2c: R=7-OH
3
1b: R=7-OMe
1c: R=5-OH and 7-OMe
O
Me
O
Me
O
O
4
5
Despite this interesting potential of the 2-substituted 4-chromanones, there are few reports on their
asymmetric synthesis. Both enantiomers of 1a and 2a were prepared via the ring-opening reaction of
chiral epoxides with a dithiane anion, followed by the intramolecular Mitsunobu reaction.7
described two approaches to (S)-1a and (R)-2a.8
One of the approaches utilized the oxidation of the
preformed chiral 2-substituted chromans and another approach involved the intramolecular Mitsunobu
reaction. The latter methodology was also used for the synthesis of (S)-1c. Other successful
examples include the diastereoselective conjugated addition of cuprates to homochiral
3-(p-tolylsulfinyl)chromones9 and an approach based on the Houben-Hoesch reaction.10
We recently
Hodgetts
described the synthesis of both enantiomers of 1a based on the intermolecular Mitsunobu reaction
between phenol and chiral 1-phenyl-3-buten-1-ol prepared via a lipase-catalyzed kinetic resolution,
followed by the oxidative cleavage of the double bond and subsequent intramolecular Friedel-Crafts
acylation (Scheme 1).11
O
HO
HO
b, c, d
a
O
(R)-1a
Scheme 1: Reagents and conditions: a: lipase, vinyl acetate, isooctane, rt (40%, >99%
ee); b: PhOH, PPh3, diisopropyl azodicarboxylate, THF, rt (61%, 97% ee);
c: KMnO4, NaIO4, K2CO3, H2O-t-BuOH, rt (67%); d: TFAA, TFA, CH2Cl2, rt (49%,
96% ee).
We now report an application of our methodology to the asymmetric synthesis of flindersiachromanone
(5) isolated from the extracts of the bark of Flindersia laevicarpa by Picker et al.,2g and the determination
of the absolute configuration of 5.

HETEROCYCLES, Vol. 68, No. 3, 2006
485
RESULTS AND DISCUSSION
Compound ((S)-5) was synthesized according to the route shown in Scheme 2.
The most important
point of the present synthesis is to prepare the 1-phenyl-5-hexen-3-ol (6) in the highly enantiomerically
active form. Significant results have
There are many reports for the asymmetric synthesis of 6.12
been obtained using the catalytic enantioselective allylation of 3-phenylpropanal and a stoichiometric
amount of allyl metal compounds bearing chiral ligands. Although Maruoka et al. reported the highly
enantioselective catalytic allylation (>98% ee),12i,12m they have used organotin compound with potential
toxicity. Therefore, we adopted our previously reported method that secondary alcohols structurally
related to (±)-6 could be resolved with a high enantioselectivity via the lipase-catalyzed
transesterification.11,13
HO
a
Br
+
OHC
(±)-6
O
HO
b
+
O
(S)-7
(R)-6
O
c
d
(R)-6
(S)-8
O
O
O
O
e
HO
(S)-9
(S)-5
Scheme 2: Reagents and conditions: a: In, H2O, rt (91%); b: lipase PS, vinyl acetate,
rt (51% and 96% ee for (S)-7, 48% and >99% ee for (R)-6); c: PhOH, PPh3, diisopropyl
azodicarboxylate, toluene, 0o-rt (76%, >99% ee); d: KMnO4, NaIO4, K2CO3,
H2O-t-BuOH, rt (85%); e: TFAA, TFA, CH2Cl2, rt (94%, >99% ee).

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HETEROCYCLES, Vol. 68, No. 3, 2006
The racemic secondary alcohol ((±)-6) was prepared from the purified 3-phenylpropanal and allyl
bromide with indium in 91% yield. Six commercially available lipases from different origins were
screened to obtain an efficient catalyst for the enantioselective acetylation of (±)-6. The obtained
results are summarized in Table 1. While Amano AY, Meito ALC, and Meito PLC showed only a low
activity (<20%, Entries 3, 5, and 6), Amano PS, Amano AK, and Novozym 435 showed high levels of
activity (Entries 1, 2, and 4). These lipases followed the empirical rule for the enantiopreference of
several lipases toward secondary alcohols,14 and therefore, (S)-6 was acetylated faster than (R)-6.
However, the lipases showed a different degree of enantioselectivity.
Among them, Amano PS
produced the best enantioselectivity (E15=747, Entry 1).
This result agrees with the high
enantioselectivity of this lipase observed in the discrimination of enantiomers of the secondary alcohols
structurally related to (±)-6. 11,13
Table 1. Lipase-catalyzed transesterification of (±)-6 with vinyl acetate in hexanea
Entry
Lipaseb
Time (h) Conversion (%)c (S)-7 ee (%)
(R)-6 ee (%)
Ec
747
371
-
1
2
3
4
5
6
Amano PS
Amano AK
Amano AY
Novozym 435
Meito ALC
Meito PLC
66
49
49
3d
50
1d
16d
99
98
-
95
95
-
41
51
75
65
-
65
-
9
51
-
51.5
-
-
-
a Conditions: lipase (20 mg/ml), (±)-6 (60 mM), vinyl acetate (120 mM), room temperature.
b
Amano PS from Burkholderia cepacia, Amano AK from Pseudomonas fluorecens, Amano AY from
Candida rugosa, Novozym 435 from Candida antarctica, Meito ALC from Achromobacter sp., Meito
PLC from Alcaligenes sp.
c Calculated from ees of (S)-7 and (R)-6.15
d Determined by GC analysis.
On the basis of these results, we conducted the large scale resolution of (±)-6 with the lipase PS as the
asymmetric catalyst to obtain (R)-6 with >99% ee {[α]23D +22.4° (c 1.2, CHCl3); lit.,12a [α]20D -9.6° (c 4.2,
CHCl3), 48% ee, (S)} in 48% yield and (S)-7 with 96% ee in 51% yield. The coupling of (R)-6 with
phenol by using of diisopropyl azodicarboxylate in the presence of triphenylphosphine gave the phenyl

HETEROCYCLES, Vol. 68, No. 3, 2006
487
1
ether ((S)-8) in 76% yield.
The H-NMR spectral data showed that (S)-8c was contaminated by the
triphenylphosphine oxide.16
However, the triphenylphosphine oxide did not interfere with the
following reaction. The oxidative cleavage of the double bond of (S)-8 with KMnO4 and NaIO4
afforded the corresponding acid ((S)-9) in 85% yield. The intramolecular Friedel-Crafts acylation of
(S)-9 using trifluoroacetic acid and trifluoroacetic anhydride afforded (S)-5 with >99% ee {[α]24 -77.8°
D
(c 1.2, MeOH); lit.,2g [α]D -1.6° (c 5%, MeOH)} in 94% yield.
racemization occurred during the conversion processes from (R)-6 to (S)-5.
and the sign of the specific rotation were in agreement with the published data.2g Therefore, 5 isolated
by Picker et al. has the (S)-configuration. However, the specific rotation was considerably higher than
the published value. Such a discrepancy was observed with the simpler analogue (S)-2b by Hodgetts
Judging from the ee value, no
The 1H-NMR spectral data
et al., who described the possibility of the partial racemization of the material isolated from a natural
source via the reversible elimination of the pyran oxygen during isolation.9a
We also synthesized (R)-5, not a natural product, from (S)-7 according to the route shown in Scheme 3.
Because (S)-7 did not have an ee (96%) high enough for use, we tried the hydrolysis of (S)-7 to (S)-6 to
increase the ee with the lipase PS.
Therefore, (S)-7 was hydrolyzed to (S)-6 using NaOH and the resultant (S)-6 was again subjected to the
lipase PS-catalyzed transesterification to increase the ee. The obtained ester ((S)-7) was then
Unfortunately, (S)-6 with a higher ee could not be obtained.
hydrolyzed in a similar manner to give (S)-6 with >99% ee, and (S)-6 was converted to (R)-5 with >99%
ee {[α]24D +77.6° (c 1.1, MeOH)} according to the same route as that used to prepare (S)-5.
O
HO
a
O
(S)-7
(S)-6
O
b
c
O
(S)-7
HO
O
O
d, e, f
(S)-6
(R)-5
Scheme 3: Reagents and conditions: a: NaOH, EtOH-H2O, rt (89%, 96% ee); b: lipase
PS, vinyl acetate, hexane, rt (89%, >99% ee); c: NaOH, EtOH-H2O, rt (90%, >99% ee);
d: PhOH, PPh3, diisopropyl azodicarboxylate, toluene, 0o-rt (68%, >99% ee);
e: KMnO4, NaIO4, K2CO3, H2O-t-BuOH, rt (89%); f: TFAA, TFA, CH2Cl2, rt (88%,
>99% ee).

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HETEROCYCLES, Vol. 68, No. 3, 2006
In conclusion, we have been able to easily synthesize the (R)- and (S)-enantiomers of 5.
EXPERIMENTAL
All commercially available reagent chemicals were obtained from Aldrich, Nacalai Tesque, Tokyo Kasei
and Wako Chemicals, and generally used without further purification.
Na/benzophenone under Ar. Benzene, hexane, dichloromethane, and pyridine were distilled from
CaH2 under Ar. Vinyl acetate was distilled from molecular sieves 4A under Ar. Amano PS and
Toluene was distilled from
Amano AK were purchased from Amano Enzyme, Inc., and dried over P2O5. Amano AY, Meito ALC,
Meito PLC, and Novozym 435 were generous gifts from Amano Enzyme, Inc., Meito Sangyo Co., Ltd.,
1
and Novozymes Japan, Inc.
The H-NMR spectra were recorded using a JEOL JNM-LA 400
spectrometer for solutions in CDCl3 with TMS as the internal standard, and the J values are given in hertz.
The IR spectra were obtained using a JASCO FT/IR-410 spectrophotometer. The MS spectra were
obtained using a JEOL JMS-GCmate spectrometer.
JMS-AX505HAD spectrometer and the electron ionization method.
measured with a Horiba SEPA-300 polarimeter. The gas chromatograms were recorded using a
The HRMS spectra were obtained using a JEOL
The optical rotations were
Shimadzu GC-14B with an OV 101 bonded capillary column (GL Sciences), 17 m × 0.25 mm. The
HPLC analyses were carried out on a Hitachi L-6250 intelligent pump with a Hitachi L-4000 UV detector
using Chiralcel OJ (Daicel), 250 × 4.6 mm and Chiralcel OD-H (Daicel), 250 × 4.6 mm.
Purification of 3-phenylpropanal. Commercially available 3-phenylpropanal was dissolved in ether.
The organic phase was washed with 10% Na2CO3 solution (three times) and a saturated Na2SO3 solution,
and then dried over MgSO4.
After removal of the solvents, the residue was distilled under reduced
pressure (73.0-78.0 °C/0.6 mm Hg).
1-Phenyl-5-hexen-3-ol ((±)-6). A mixture of 3-phenylpropanal (6.809 g, 50.75 mmol), allyl bromide
(12.279 g, 101.50 mmol), and indium (11.675 g, 101.7 mmol) in water (400 mL) was stirred for 6 h at rt
under Ar. The allyl bromide (3.425 g, 28.31 mmol) and indium (3.171 g, 27.62 mmol) were added to
the mixture to completely consume the 3-phenylpropanal, and the resulting mixture was stirred overnight
at rt under Ar.
The reaction mixture was quenched at 0 °C with 6 M HCl (120 mL) and extracted three
The organic phase was washed with deionized water, a saturated NaHCO3 solution
times with ether.
and a saturated NaCl solution, then dried over Na2SO4.
chromatographed {silica gel, hexane-ethyl acetate 5:1 (v/v)} to give (±)-6 (8.054 g, 91%) as a colorless
oil.
The 1H-NMR spectral data of this sample were identical to those described in the literature.12b
After removal of the solvents, the residue was

HETEROCYCLES, Vol. 68, No. 3, 2006
489
1-(2-Phenylethyl)-3-butenyl acetate ((±)-7). Compound ((±)-7) was prepared as an authentic sample.
To a solution of (±)-6 (0.094 g, 0.53 mmol) and dry pyridine (0.212 g, 2.68 mmol) in dry benzene (3 mL)
at 0 °C, acetyl chloride (0.101 g, 1.29 mmol) was slowly added.
The reaction mixture was stirred
overnight at rt and quenched at 0 °C with 1 M HCl. The resulting mixture was extracted with ether.
The organic phase was washed in order with deionized water, a saturated NaHCO3 solution, and a
saturated NaCl solution, and then dried over Na2SO4.
After removal of the solvents, the residue was
chromatographed {silica gel, hexane-ethyl acetate 5:1 (v/v)} to give (±)-7 (0.115 g, 99%) as a colorless
1
oil; H-NMR: 7.28 (2H, t, J=7.0), 7.16-7.20 (3H, m), 5.75 (1H, ddt, J=17.0, J=10.2, J= 7.1), 5.06-5.11
(2H, m), 4.97 (1H, quintet, J=6.2), 2.56-2.71 (2H, m), 2.34 (2H, t, J=6.7), 2.03 (3H, s), 1.85-1.91 (2H,
m); IR (neat): 1738, 1643, 995, 919 cm-1; MS m/z (%): 218 (M+, 2), 159 (66), 158 (100), 129 (67), 118
(100), 117 (100), 105 (71), 104 (100), 92 (60), 91 (100), 65 (72); HRMS calcd for C14H18O2 (M+),
218.1307. Found: 218.1319; Anal. Calcd for C14H18O2: C, 77.03; H, 8.31. Found: C, 76.89; H, 8.23.
Resolution of (±)-6 (screening experiments). In a typical run, lipase PS (20 mg) was placed in a vial
containing a 1 mL hexane solution of (±)-6 (60 µmol) and the vinyl acetate (120 µmol).
The resulting
suspension was then magnetically stirred at rt. Samples were withdrawn from the vial and analyzed by
gas chromatography (OV 101, 120 °C). The reaction was stopped by filtration of the lipase at about a
50% conversion, and the filtrate was concentrated under reduced pressure.
The residue was
chromatographed {silica gel, hexane-ethyl acetate 10:1 – 5:1 (v/v)} with a short column (10 mm × 80
mm) to give (S)-7 and (R)-6. The E value and the conversion of the reaction were calculated from the
ees of (S)-7 and (R)-6.15
Conditions for the determination of the ees of (S)-7 and (R)-6 are as follows.
Compound ((S)-7):
HPLC (Chiralcel OJ), hexane:2-propanol = 40:1 (v/v), flow rate=0.5 mL/min, retention times: (S)-7, t=17
min; (R)-7, t=19 min; Compound ((R)-6): HPLC (Chiralcel OD-H), hexane:2-propanol = 10:1 (v/v), flow
rate=0.5 mL/min, retention times: (S)-6, t=13 min; (R)-6, t=18 min.
Preparative resolution of (±)-6. Lipase PS (12.00 g) was added to a solution of (±)-6 (4.002 g, 22.71
mmol) and vinyl acetate (5.975 g, 69.40 mmol) in dry hexane (400 mL).
The mixture was stirred for
29 h at rt. The reaction was quenched by filtration and the filtrate was concentrated under reduced
pressure. The residue was chromatographed {silica gel, hexane-ethyl acetate 5:1 - 2:1 (v/v)} to give
(S)-7 and (R)-6 as colorless oils.
1
Compound ((S)-7): yield: 2.485 g (51%); ee: 96%; The H-NMR spectral data of this sample were
identical to those of (±)-7.

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Compound ((R)-6): yield: 1.898 g (48%); ee: >99%; [α]23D: +22.4° (c 1.2, CHCl3) {lit.,12a [α]20D -9.6° (c
4.2, CHCl3), 48% ee, (S)}; The 1H-NMR spectral data of this sample were identical to those of (±)-6.
6 M NaOH (3.6 mL, 22 mmol) was added to a solution of (S)-7 (2.406 g, 11.02 mmol) obtained above in
ethanol (15 mL).
The mixture was stirred for 1.5 h at rt. After removal of the solvent, the residue
was extracted three times with ether.
The organic layer was washed with a saturated NaCl solution,
then dried over Na2SO4 and concentrated.
The residue was chromatographed {silica gel, hexane-ethyl
1
acetate 3:1 (v/v)} to give (S)-6 (1.723 g, 89%) as a yellow oil.
sample were identical to those of (±)-6.
The H-NMR spectral data of this
According to the procedures described above, (S)-6 obtained here was again subjected to the lipase
PS-catalyzed transesterification with vinyl acetate to give the optically purer (S)-7; lipase PS (5.169 g),
(S)-6 (1.723 g, 9.776 mmol), vinyl acetate (2.764 g, 32.11 mmol), dry hexane (170 mL), reaction time (13
h), yield of (S)-7 (1.882 g, 89%, >99% ee).
those of (±)-7.
The 1H-NMR spectral data of this sample were identical to
Thus the obtained optically purer (S)-7 was again hydrolyzed with NaOH to give (S)-6; (S)-7 (1.864 g,
8.539 mmol), 6 M NaOH (3 mL, 18 mmol), ethanol (15 mL), reaction time (18 h), yield of (S)-6 (1.365 g,
91%, >99% ee).
The 1H-NMR spectral data of this sample were identical to those of (±)-6.
Lipase-catalyzed hydrolysis of (S)-7.
Amano PS (10.0 mg) was placed in a vial containing a
suspension of (S)-7 (10.0 mg, 45.8 µmol, 96% ee) in 0.07 M phosphate buffer (KH2PO4 and Na2HPO4,
pH 7, 1 mL). The resulting suspension was then magnetically stirred for 43 h at rt. A sample was
withdrawn from the vial and analyzed by GC (OV 101, 120 °C) and HPLC {(Chiralcel OD-H),
hexane:2-propanol = 10:1 (v/v)}.
Phenyl (S)-1-(2-phenylethyl)-3-butenyl ether ((S)-8). A solution of diisopropyl azodicarboxylate
(2.931 g, 14.49 mmol) in dry toluene (10 mL) was dropwise added to a mixture of (R)-6 (1.684 g, 9.555
mmol, >99% ee), phenol (1.859 g, 20.14 mmol), and triphenylphosphine (4.101 g, 15.64 mmol) in dry
toluene (20 mL) at 0 °C under Ar.
toluene, a mixture of ether and hexane {1:1 (v/v)} was added to the viscous residue. The suspended
solid was filtered with suction, and the filtrate was concentrated. Chromatography {silica gel,
The mixture was stirred overnight at rt. After evaporation of the
hexane-ethyl acetate 40:1 (v/v)} of the crude product provided (S)-8 (1.826 g, 76%, >99% ee) as a
1
colorless oil.
The H-NMR spectral data showed that (S)-8c was contaminated by triphenylphosphine
oxide (0.449 g).
The yield described here was estimated from the 1H-NMR spectral analysis; 1H-NMR:
7.25-7.29 (4H, m), 7.15-7.20 (3H, m), 6.87-6.95 (3H, m), 5.84 (1H, ddt, J=17.1, J=10.2, J=7.1),
5.07-5.13 (2H, m), 4.27-4.33 (1H, m), 2.78-2.85 (1H, m), 2.66-2.73 (1H, m), 2.38-2.51 (2H, m),

HETEROCYCLES, Vol. 68, No. 3, 2006
491
1.91-2.10 (2H, m); IR (neat): 1640, 1240, 1029, 998, 918 cm-1; MS m/z (%): 252 (M+, 10), 117 (34), 94
(33), 92 (11), 91 (100), 77 (12), 65 (23); HRMS calcd for C18H20O (M+), 252.1514. Found: 252.1521.
The enantiomeric excess was determined by HPLC analysis on a Chiralcel OJ column
{hexane:2-propanol = 10:1 (v/v)}, flow rate=0.5 mL/min, retention times: (R)-8, t=12 min; (S)-8, t=13
min.
(S)-3-Phenoxy-5-phenylpentanoic acid ((S)-9). A solution of NaIO4 (14.370 g, 67.18 mmol) and
KMnO4 (0.704 g, 4.45 mmol) in deionized water (200 mL) was treated with a solution of K2CO3 (9.282 g,
67.16 mmol) in deionized water (100 mL), and then with tert-butyl alcohol (75 mL).
solution of (S)-8 (1.876 g, 7.434 mmol) accompanied by triphenylphosphine oxide in tert-butyl alcohol
(75 mL) was slowly added. The resulting purplish suspension was stirred for 15 min at rt. The
suspension was treated with ethylene glycol (20 mL), stirred for 3 h, acidified to pH 4 with 1 M HCl (120
mL) at 0 °C, and extracted three times with ethyl acetate. The organic layer was washed with a
saturated NaCl solution, then dried over Na2SO4 and concentrated under reduced pressure. The residue
To the mixture, a
was chromatographed {silica gel, hexane-ethyl acetate 1:2 - hexane-acetone 1:1 (v/v)} to give (S)-9
(1.702 g, 85%) as a colorless viscous oil; 1H-NMR: 7.25-7.29 (4H, m), 7.15-7.22 (3H, m), 6.90-6.98 (3H,
m), 4.71 (1H, quintet, J=6.1), 2.83 (1H, dd, J=15.6, J=6.1), 2.69-2.83 (2H, m), 2.64 (1H, dd, J=15.9,
J=6.4), 1.99-2.14 (2H, m); IR (neat): 1712, 1237, 1038 cm-1; MS m/z (%): 270 (M+, 17), 176 (19), 117
(43), 94 (70), 91 (100), 65 (20); HRMS calcd for C17H18O3 (M+), 270.1256. Found: 270.1281; Anal. Calcd
for C17H18O3: C, 75.53; H, 6.71. Found: C, 75.46; H, 6.74.
Flindersiachromanone (2-(2-Phenylethyl)-4-chromanone) ((S)-5). To a solution of (S)-9 (1.678 g,
6.208 mmol) in anhydrous CH2Cl2 (16 mL) was slowly added a mixture of trifluoroacetic acid (7.8 mL,
100 mmol) and trifluoroacetic anhydride (7.8 mL, 55 mmol).
poured onto crushed ice in a beaker, and K2CO3 was added to the resulting mixture until the evolution of
CO2 gas ceased. The mixture was extracted three times with CH2Cl2. The extract was washed with
The mixture was stirred for 25 min at rt,
a saturated NaCl solution, then dried over Na2SO4 and concentrated under reduced pressure. The
residue was chromatographed {silica gel, hexane-ethyl acetate 5: 1 (v/v)} to give (S)-5 (1.466 g, 94%,
>99% ee) as a colorless viscous oil; [α]24D: -77.8° (c 1.2, MeOH); 1H-NMR: 7.88 (1H, dd, J=8.0, J=1.7),
7.47-7.51 (1H, m), 7.19-7.32 (5H, m), 6.99-7.03 (2H, m), 4.40-4.47 (1H, m), 2.80-2.95 (2H, m),
2.65-2.77 (2H, m), 2.18-2.28 (1H, m), 1.95-2.04 (1H, m); IR (neat): 1692, 1607, 1577, 1227, 1031 cm-1;
MS m/z (%): 252 (M+, 51), 161 (26), 160 (6), 148 (8), 147 (62), 121 (64), 120 (37), 117(12), 92 (69), 91
(100), 65 (38); HRMS calcd for C17H16O2 (M+), 252.1150. Found: 252.1153; Anal. Calcd for C17H16O2: C,
80.92; H, 6.93. Found: C, 80.77; H, 6.46.
The enantiomeric excess was determined by HPLC analysis

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on a Chiralcel OD-H column {hexane:2-propanol = 2:1 (v/v)}, flow rate=0.5 mL/min, retention times:
(S)-5, t=17 min; (R)-5, t=27 min.
2-(2-Phenylethyl)-4-chromanone ((R)-5). Compound ((R)-5) was prepared from (S)-6 (>99% ee) in
three steps according to the procedures described above; colorless viscous oil; 54% from (S)-6; >99% ee;
[α]24D: +77.6° (c 1.1, MeOH); The 1H-NMR spectral data of this sample were identical to those of (S)-5.
ACKNOWLEDGEMENTS
The authors thank Amano Enzyme, Inc., Meito Sangyo Co., Ltd., and Novozymes Japan, Inc., for kindly
providing the lipases. The authors also thank the researchers at the Biotechnology Research Center,
1
Toyama Prefectural University, for their generous support with the H-NMR spectroscopic and optical
rotation measurements.
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