Lipase-catalyzed kinetic resolution of (+/-)-cis-flavan-4-ol and its acetate: synthesis of chiral 3-hydroxyflavanones.

Article abstract of DOI:10.1271/bbb.66.1772

Lipase-catalyzed kinetic resolution of (+/-)-cis-flavan-4-ol and its acetate led to enantiomerically enriched flavan-4-ol and its acetate. These chiral compounds were converted to (2R, 3R)- and (25, 3S)-3-hydroxyflavanones.

Full text of DOI:10.1271/bbb.66.1772

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Lipase-Catalyzed Kinetic Resolution of (±)-cis-
Flavan-4-ol and Its Acetate: Synthesis of Chiral 3-
Hydroxyflavanones
Tamotsu TODOROKIa, Akiko SAITOb & Akira TANAKAa
a College of Technology, Toyama Prefectural University Kosugi, Toyama 939-0398, Japan
b Japan Science and Technology Corporation, Domestic Research Fellow Kosugi, Toyama
939-0398, Japan
Published online: 22 May 2014.
To cite this article: Tamotsu TODOROKI, Akiko SAITO & Akira TANAKA (2002) Lipase-Catalyzed Kinetic Resolution of (±)-cis-
Flavan-4-ol and Its Acetate: Synthesis of Chiral 3-Hydroxyflavanones, Bioscience, Biotechnology, and Biochemistry, 66:8,
1772-1774, DOI: 10.1271/bbb.66.1772
To link to this article: http://dx.doi.org/10.1271/bbb.66.1772
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Biosci. Biotechnol. Biochem., 66 (8), 1772–1774, 2002
Note
±
Lipase-Catalyzed Kinetic Resolution of ( )-cis-Flavan-4-ol and Its Acetate:
Synthesis of Chiral 3-Hydroxy‰avanones
1,
†
Tamotsu TODOROKI,1 Akiko SAITO,2 and Akira TANAKA
1College of Technology, Toyama Prefectural University, Kosugi, Toyama 939-0398, Japan
2Japan Science and Technology Corporation, Domestic Research Fellow, Kosugi, Toyama 939-0398, Japan
Received February 6, 2002; Accepted March 25, 2002
8)
Lipase-catalyzed kinetic resolution of
‰avan-4-ol and its acetate led to enantiomerically
enriched ‰avan-4-ol and its acetate. These chiral com-
( )-cis-
±
In 1992, Izumi et al
resolution of (
lipase PS (Amano) resulted in the formation of (2
)-3 (93 ee) and (2 , 4 )-4 (95 ee). On the
other hand, the transesteriˆcation of ( )-3 with the
.
reported that the kinetic
±
)-cis-‰avan-4-ol acetate (4) with
R
,
pounds were converted to (2
hydroxy‰avanones.
R, 3R )- and (2S, 3S )-3-
4
R
z
S
S
z
±
same enzyme, using vinyl acetate as the acyl donor
aŠorded acetate 4, but with no optical rotation. In
order to further examine the potent resolving ability
of lipases, we conducted a kinetic resolution experi-
ment on some lipases (lipase PS, lipase M, lipase A,
lipase R and lipase AY). Among them, lipase AY
(Amano) was the most e‹cient enzyme for both
kinetic hydrolysis and transesteriˆcation.
Key words: kinetic resolution; lipase; 3-hydroxy‰ava-
none
3-Hydroxy‰avanones are widely distributed in the
plant kingdom1) and some of them show interesting
biological activities involving a hepatoprotective
eŠect. In association with the synthetic work on con-
densed tannins,1,2) we needed chiral 3-hydroxy‰ava-
nones which could be promising monomeric sources
for the synthesis of condensed tannins having the
oligomeric structure of ‰avan-3-ols. Three methods
for accessing chiral 3-hydroxy‰avanones have been
reported to date: 1) enzymatic resolution of racemic
3-hydroxy‰avanone,3) 2) conversion of the epoxy
ketones obtained by asymmetric epoxidation of chal-
cone derivatives,4,5) 3) synthesis via asymmetric di-
hydroxylation of cinnamic esters.6) These methods,
however, involve the disadvantages of low enantio-
meric purity of the products and multi-step reaction
sequences. We have recently developed a novel ap-
proach to accessing enantiomerically enriched 3-
hydroxy‰avanones.
±
When ( )-3 was treated with lipase AY and vinyl
acetate at 25
ee) and unreacted (2
were obtained (Fig. 1). (2
)-‰avanone (
the enantiomeric purity by HPLC. Similarly, (2
)-4 was converted to ( )-1 via hydrolysis (K2CO3
CH3OH) and subsequent oxidation.
The kinetic hydrolysis of
acetate 4 in a phosphate buŠer (pH 6.8) with the
same enzyme gave (2 , 4 )-3 (40 yield, 96 ee)
9
C for 6 d, (2
R
, 4
)-3 (55
, 4
R
)-4 (44
z
yield, 61
yield, 93
z
ee)
S
, 4
S
z
z
S
S
)-3 was oxidized to
(
S
S )-1 with PCC CH2Cl2 to determine
W
R
,
W
4
R
R
(
±
)-cis-‰avan-4-ol
R
R
z
z
We have observed earlier that treatment of the
enolate derived from racemic ‰avanone 1 with 2-
(phenylsulfonyl)-3-phenyloxaziridine7) below „80
9C
gave 3-hydroxy‰avanone 2 in a good yield (Fig. 3). In
this case, temperature control was crucial, because
elevation of the reaction temperature caused easy
opening of the pyranone ring. This useful experimen-
tal technique that could aŠord 3-hydroxy‰avanones
from ‰avanones in high yields required the develop-
ment of a more e‹cient method for the preparation
of enantiomerically enriched ‰avanones. In this
paper, we report the synthesis of enantiomerically
enriched 3-hydroxy‰avanones via lipase-catalyzed
±
kinetic resolution of ( )-cis-‰avan-4-ol (3) and its
Fig. 1.
＠
pu-toyama.ac.jp
acetate 4.
†
To whom correspondence should be addressed. Fax: +81-766-56-0396; E-mail: atanaka

Synthesis of Chiral 3-Hydroxy‰avanones
1773
Fig. 3.
Data for (2
R
, 4
R
9
)-4: mp 95–96 C; [a c
]2D0„33.4 (
1.68, CHCl3); IR (nujol) n
max cm„1: 1740, 1610, 1580,
1240, 1060, 1030, 750, 700; 1H-NMR (CDCl3)
(3H, S), 2.21 (1H, ddd,
d
: 2.11
＝
J
10, 11, 13 Hz), 2.64 (1H,
＝
＝
ddd,
6.20 (1H, dd,
7.20–7.25 (2H, m), 7.28–7.58 (5H, m). Data for (2
J
2, 6, 13 Hz), 5.22 (1H, dd,
J
2, 11 Hz),
6, 10 Hz), 6.92–6.99 (2H, m),
＝
J
Fig. 2.
S
,
4
S
)-3: mp 125–126
9
9
C; [
C; [
a c 1.0, CHCl3)
]2D0+7.9 (
and unreacted (2
(Fig. 2). The ee values of these compounds were also
determined by an HPLC analysis of ( )- and ( )-
)-1 obtained by the same
S
, 4
S
)-4 (47
z
yield, 88
z
ee)
s
(nujol)
lit.,8) mp 115–116
a t; IR
]2D0+11.2 (CHCl3)
n
max cm„1: 3300, 3200, 1605, 1580, 1230,
1
R
S
900, 750, 700; H-NMR (CDCl3)
d
: 1.75 (1H, d,
10, 11, 13 Hz), 2.54
2, 8, 13 Hz), 5.12 (1H, dd, 9,
2, 12 Hz), 6,90 (1H, dd,
＝
＝
J
‰avanones (
R
)-1 and (
S
J
9 Hz), 2.14 (1H, ddd,
(1H, ddd,
16 Hz), 5.19 (1H, dd,
process as that just described.
J
＝
J
＝
＝
J
Finally, the enantiomerically enriched (
S
R
)- and
, 3 )-
＝
＝
(
R
)-‰avanones (1) were transformed into (2
R
J
1, 8 Hz), 6.99 (1H, dt,
7.33–7.47 (5H, m), 7.52 (1H, d, J
J
1, 7 Hz), 7.21 (1H, m),
8 Hz).
and (2
(Fig. 3). Thus, the reaction between the enolate der-
ived from ( )- or ( )-1 and the oxaziridine reagent
at „85 C with subsequent hydrolytic work-up led to
(2 , 3 )- or (2 , 3 )-2, each in a good yield.
S
, 3
S
)-3-hydroxy‰avanones (2), respectively
＝
S
R
Kinetic Resolution of Racemic cis-Flavan-4-ol
±
Acetate 4 with Lipase AY. A solution of ( )-
9
R
R
S
S
cis-‰avan-4-ol acetate9) (4; 30 mg, 0.133 mmol) in tol-
uene (0.5 ml) was stirred with a mixture of lipase AY
(150 mg), a phosphate buŠer (pH 6.8, 2 ml) and H2O
Experimental
9
(5 ml) at 25 C for 5 d. The reaction mixture was
All melting point (mp) data are uncorrected. Opti-
cal rotation was measured with a HORIBA SEPA-
300 spectrometer, and IR spectra were taken with a
JASCO IR-810 spectrometer. H-NMR spectra were
measured with a JEOL JNM-LA 400 spectrometer.
HPLC analyses were conducted with SHIMADZU
ˆltered through a Celite} pad and extracted with
CHCl3. Puriˆcation of the crude mixture by
preparative TLC (hexane:AcOEt
)-(3) (12 mg, 40 ) and unreacted (2
mg, 47 ).
The enantiomeric purity [(2
, 4 )-(4): 88 ee] of these compounds was deter-
mined by the same procedure as that just described.
＝
3:1) aŠorded (2
R,
1
4
R
z
S
, 4 )-(4) (14
S
z
z
R, 4R )-(3): 96 ee;
LC 10AD apparatus equipped with a UV VIS detec-
tor and CHIRALCEL OD (DAICEL) column.
(2
S
S
z
W
Data for (2
0.98, CHCl3)
(CHCl3)
Data for (2
1.26, CHCl3)
(CHCl3)
R
, 4
R
)-3: mp 118–119
9
C; [
a
]2D0„13.7 (
c
Kinetic Resolution of Racemic cis-Flavan-4-ol
s
lit.,8) mp 115–116
9
C; [
a
]2D0„14.4
±
±
(
)-
3
with Lipase AY. A suspension of ( )-cis
-
t.
‰avan-4-ol9)
(
)-3 (60 mg, 0.265 mmol), vinyl
S
, 4
S
s
)-4: mp 96–97
9
C; [a
]2D0+34.6 (
c
±
acetate (4 ml) and lipase AY (Amano) (600 mg) was
lit.,8) mp 94–95
9
C;
[a
]2D0+23.9
stirred at 25
9
C for 6 d. Filtration through a Celite}
t.
pad and evaporation of the solvent left a mixture of
products which was separated by preparative TLC
Conversion of (2S, 4S)- and (2R, 4R)-Alcohols,
＝
(hexane:AcOEt 3:1) to give (2
44 ) and unreacted (2 , 4 )-3 (33 mg, 55
The enantiomeric purity of these compounds was
determined to be 93 ee for (2 , 4 )-4 and 61 ee
for (2 , 4 )-3 by their conversion to ( )- and ( )-
)-1 and ( )-1 and by an HPLC analy-
R
, 4
R
)-4 (29 mg,
(2S, 4S)- and (2R, 4R)-3, to (S)- and (R)-Flavanones,
z
S
S
z
).
(S)- and (R)-
1.
a) Synthesis of (S)-
1
from (2S, 4S)-3. (2S, 4S )-al-
z
R
R
z
S
cohol 3 (12 mg, 0.053 mmol) was treated with PCC
(34 mg) and molecular sieves 4A (50 mg) in CH2Cl2
(2 ml) at room temperature for 15 min. Ether was
added, and the solution was ˆltered through a
S
S
R
‰avanones (
sis.
R
S

1774
T. TODOROKI et al.
Celite} pad. Evaporation of the solvent gave a
residue which was passed through a short SiO2
column using ether. The crude sample was puriˆed
80
lit.,2) mp 189–190
(CH2Cl2) ; IR (nujol)
z), mp 187–1889C; [a c 0.34, CH2Cl2)
]2D0„18 (
s
9C for 59z [a
ee; lit.,6) ]2D0„25.0
t
n
max cm„1: 3450, 1680, 1610,
1
by preparative TLC to give pure (
S
)-1 (10 mg, 85
z),
1580, 1310, 1230, 1150, 1040, 760, 700; H-NMR
which was then submitted to an HPLC analysis to de-
termine the enantiomeric purity.
(CDCl3)
d
: 3.67 (1H, d,
J
＝
2 Hz, OH), 4.65 (1H, dd,
＝
＝
＝
12 Hz), 7.06 (1H, d,
J
J
2, 12 Hz), 5.15 (1H, d,
J
]2D0„39.0 (
c
0.49,
12 Hz), 7.12 (1H, t,
J
7 Hz), 7.42–7.50 (3H, m),
＝
Data for (
CHCl3)
lit.,8) mp 75–77
b) Synthesis of (R)-
S
)-1: mp 75–76
C; [
from (2R, 4R)-
9
a
C; [
a
]2D0„54.1 (CHCl3)
t
7.54–7.60 (3H, m), 7.94 (1H, dd,
b) Synthesis of (2S, 3S)-
Hydroxy‰avanone 2 was obtained from (
82 yield by the same procedure as that just de-
scribed for (2 , 3 )-2.
, 3 )-2: mp 186–187
J
2, 8 Hz).
. (2 , 3
)-1 in an
＝
s
9
1
3
. This reac-
2
from (R)-
1
S
S )-3-
tion was carried out by the same procedure as that
R
just described for (
Data for ( )-1: mp 76–77
CHCl3) C; [
lit.,8) mp 76–77
S
)-1.
z
R
9
a
C; [
a
]2D0+61 (c 0.86,
R
R
s
9
]2D0+66.5 (CHCl3)
t.
Data for (2
S
S
9
C; [
a
]2D0+22.8 (
c
0.6, CH2Cl2).
Conversion of (2R, 4R)- and (2S, 4S)-Acetates
(R)- and (S)-Flavanones
a) Synthesis of (R)-
4
to
)-
1
.
References
1
from (2R, 4R)-
4
. (2
R
, 4
R
1) Harborne, J. B., and Baxter, H., The Handbook of
Natural Flavonoids, John Wiley & Sons, New York
(1999).
acetate 4 (26 mg, 0.097 mmol) was then treated with
K2CO3 (19 mg) in MeOH (0.5 ml) at room tempera-
ture for 15 min. A sat. NaCl solution was added and
the solution was extracted with CHCl3. Evaporation
of the solvent gave a crude alcohol which was
dissolved in CH2Cl2 (2 ml) and treated with PCC
(62 mg) and molecular sieves 4A (70 mg) as just
described. Puriˆcation of the crude product by
2) Harborne, J. B., The Flavonoids: Advances in
Research from 1986, Chapman and Hall, London
(1993).
3) Izumi, T., and Murakami, S., Enzymatic resolution
of trans-2,3-dihydro-3-hydroxy-2-phenyl-4H-1-ben-
zopyran-4-one(trans-‰avanon-3-ol) by lipase. J.
Heterocycl. Chem., 32, 1125–1127 (1995).
preparative TLC furnished pure (R )-1 (21 mg, 97
z
4) Takahashi, H., Kubota, Y., Miyazaki, H., and Onda,
M., Heterocycles. XV. Enantioselective synthesis of
chiral ‰avononols and ‰avan-3,4-diol. Chem. Pharm.
Bull., 32, 4852–4857 (1984).
5) van Rensburg, H., van Heerden, P. S.,
Bezuidenhoudt, B. C. B., and Ferreira, D.,
Stereoselective synthesis of ‰avonoids. Part 4.
Trans- and cis-dihydro‰avonoids. Tetrahedron, 53,
14141–14152 (1997).
from acetate). The enantiomeric purity of this sample
was determined by the HPLC analysis already de-
scribed.
Data for (
CHCl3)
lit.,8) mp 76–77
b) Synthesis of (S)-
tion was carried out by the same procedure as that
just described for ( )-1.
Data for ( )-1: mp 76–77
CHCl3) C; [
lit.,8) mp 75–77
R
)-1: mp 78–79
C; [
from (2S, 4S)-
9
C; [
]2D0+66.5 (CHCl3)
. This reac-
a c 0.38,
]2D0+57 (
s
9
a
t.
1
4
R
S
9
a
C; [
a c 0.20,
]2D0„55.0 (
6) Jew, S.-S., Kim, H.-A., Bae, S.-Y, Kim, J.-H., and
Park, H.-G., Enantioselective synthetic method for
s
9
]2D0„54.1 (CHCl3)
t.
3-hydroxy‰avanones: an approach to (2
-dimethyltaxifolin. Tetrahedron Lett., 41, 7925–
7928 (2000).
R, 3R )-3?,4?-
O
(2R, 3R)- and (2S, 3S)-3-Hydroxy‰avanones (2R,
3R)- and (2S, 3S)-
a) Synthesis of (2R, 3R)-
stirred solution of ( )-1 (63 mg, 0.281 mmol) in THF
2
.
7) For a review, see Davis, F. A., and Sheppard, A. C.,
Applications of oxaziridines in organic synthesis.
Tetrahedron, 45, 5703–5742 (1989).
8) Izumi, T., Hino, T., and Kasahara, A., Enzymatic
kinetic resolution of ‰avanone and cis-4-acetox-
y‰avan. J. Chem. Soc. Perkin Trans. 1, 1992, 1265–
1267.
2
from (S)-1. To a
S
(3 ml) was added sodium bis(trimethylsilyl)amide
(NAHMDS) (0.39 ml, 1 M in THF, 0.393 mmol)
below „80
2-(phenylsulfonyl)-3-phenyloxaziridine10)
0.393 mmol) in THF (1 ml) was added. Stirring was
continued for 4 h at „85 C and the reaction was
9
C and, after 5 min, a solution of
(102 mg,
9) Suzuki, M., Amano, J., Morioka, M., Mizuno, H.,
and Matsuura, R., Photochemical reactions of 4-
‰avanols in the presence of ketone sensitizers. Bull.
Chem. Soc. Jpn., 50, 1169–1172 (1977).
9
quenched with sat. NH4 Cl. After stirring at room
temperature for 2 h, the aq. solution was extracted
with CHCl3, and the organic layer was dried
(Na2SO4). Evaporation and preparative TLC
10) Vishwakarma, L. C., Stringer, O. D., and Davis,
F. A., (
±
)-trans-2-(Phenylsulfonyl)-3-phenyloxaziri-
dine. Org. Synth., Coll. Vol. VIII, 546–550 (1993).
＝
(hexane:AcOEt 2:1) gave pure (2R, 3R )-2 (54 mg,