Lipase-mediated preparation of sugar building blocks

Article abstract of DOI:10.1055/s-1999-3545

A chiral sugar building block having a dioxabicyclooctane framework has been prepared in enantiomerically pure form, along with two analogs carrying a different protecting group, in an enantiocomplementary way by employing lipase-mediated kinetic resolution as the key step.

Full text of DOI:10.1055/s-1999-3545

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Takahiko Taniguchi, Miwako Takeuchi, Kohei Kadota, Adel S. ElAzab, Kunio Ogasawara*
Pharmaceutical Institute, Tohoku University, Aobayama, Sendai 980-8578, Japan
Fax +81(22)2176845; E-mail: konol@mail.cc.tohoku.ac.jp
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$EVWUDFWꢆ A chiral sugar building block having a dioxabicyclooc-
tane framework has been prepared in enantiomerically pure form,
along with two analogs carrying a different protecting group, in an
enantiocomplementary way by employing lipase-mediated kinetic
resolution as the key step.
.H\ꢅ ZRUGVꢆ lipase-mediated transesterification, lipase-mediated
ester-hydrolysis, chiral building block, oxidative ring-expansion,
sugar building block
We have recently developed an integrated enantio- and di-
astereo-controlled route to the eight possible hexoses
starting from the chiral enone ꢀD having a dioxabicyclooc-
tane framework1,2 (Scheme 1). The starting chiral enone1
ꢀD as well as its analogues ꢀE3 and ꢀF1 carrying a different
protecting group have been prepared in both enantiomeri-
cally pure forms from the @ꢂ2-furfurydenethyl ethers ꢂD±
F in three steps involving the Sharpless asymmetric
dihydroxylation4 and the Achmatowicz rearrangement.5
Although the synthesis allowed the generation of the
enantiomerically pure enones ꢀD±F in satisfactory overall
yields, we sought an alternative synthetic procedure
which may be carried out in a large scale without using the
rather expensive AD-mix reagents used in the Sharpless
asymmetric dihydroxylation. We report here a highly ef-
ꢃF, and the acetates, (±)-ꢈE and (±)-ꢈF, in comparable
yields, respectively (Scheme 2).
ficient synthesis of the chiral enone ꢀD and its two analogs
ꢀE and ꢀF carrying a different protecting group by em-
ploying either lipase-mediated kinetic transesterification
or hydrolysis reaction as the key step.
Among the lipases examined, lipase PS (Q†rˆq‚€‚‚†
sp., Amano) brought about the best results under both
transesterification and hydrolysis conditions.7-9 Thus,
when the alcohol (±)-ꢃD was stirred with vinyl acetate in
tetrahydrofuran for 24 hours at room temperature in the
presence of lipase PS, a clear-cut enantiomeric discrimi-
nation occurred to afford the enantiomerically pure ace-
tate (–)-ꢈD and the enantiomerically pure alcohol (+)-ꢃD in
yields of 47 and 47% with E value of >1057.10,11 Absolute
configurations of the products were determined after their
transformation into the enone ꢀD. The acetate (–)-ꢈD, on
alkaline methanolysis, gave quantitatively the alcohol (–)-
ꢃD which, on oxidation with pyridinium chlorochromate
(PCC) in dichloromethane, gave the enone (+)-ꢀD, identi-
cal with the material obtained via the AD-mix-a dihy-
droxylation in 89% overall yield, while the alcohol (+)-ꢃD
afforded the enantiomeric enone (–)-ꢀD, identical with the
material obtained via the AD-mix-b dihydroxylation in
93% yield on PCC oxidation (Scheme 3). Enantiomeric
purities of the resolution products were determined as the
acetates, (–)-ꢈD from (–)-ꢃD and (+)-ꢈD from (+)-ꢃD, to be
We first prepared the racemic dioxabicyclooctenone (±)-
ꢀD in 58% overall yield from 2-(2-furfurydene)ethyl 2-
naphthylmethyl ether ꢂD via a sequential osmate glycoly-
sis, the peracid-mediated Achmatowicz rearrangement
and acidic cyclization1 via the glycol (±)-ꢁD and the 3-py-
rone ꢇD, quite similar to the chiral counterpart except for
the asymmetric dihydroxylation step. Employing the
same procedure, Pꢂbenzyl enone (±)-ꢀE and PꢂTBS
enone (±)-ꢀF were prepared in comparable overall yields
from the corresponding furfurydenethyl ether ꢂE and ꢂF,
respectively. The enone (±)-ꢀD was then reduced with so-
dium borohydride/cerium (III) chloride6 to give diastere-
oselectively the rq‚-alcohol (±)-ꢃD in 93% yield, serving
as the substrate for the lipase-mediated kinetic transester-
ification. The alcohol (±)-ꢃD thus obtained was further
transformed into the acetate (±)-ꢈD, for subsequent lipase-
mediated kinetic hydrolysis, in 98% yield under standard
conditions. Employing the same procedure, both the Pꢂ
benzyl enone (±)-ꢀE and the PꢂTBS enone (±)-ꢀF were
transformed into the corresponding enols, (±)-ꢃE and (±)-
Synthesis 1999, No. 8, 1325–1330 ISSN 0039-7881 © Thieme Stuttgart · New York

ꢀꢁꢂꢈ
T. Taniguchi et al.
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>99% ee, respectively, by HPLC using a column with a ee. As was observed, the enzymatic reactions occurred in
chiral stationary phase.
an enantiocomplementary way under the transesterifica-
tion conditions and the hydrolysis conditions as expect-
ed.7,8 Quite similarly, both the enones ꢀE and ꢀF having a
different protecting group were obtained both in >99% ee
with E values of >105710,11 from the racemic alcohols ꢃE
and ꢃF and the racemic acetates ꢈE and ꢈF in an enantio-
complementary way via the same lipase-mediated trans-
esterification and hydrolysis conditions, respectively
(Scheme 3).
On the other hand, when the racemic acetate (±)-ꢈD was
stirred in a mixture of a phosphate buffer and acetone (9:1
v/v) in the presence of lipase PS, a clear-cut enantiomeric
discrimination also occurred to give the enantiomerically
pure alcohol (–)-ꢃD and the acetate (+)-ꢈD in yields of 46
and 46% with E value of >1057.10,11 Enantiomeric purities
were determined by HPLC using a column with a chiral
stationary phase as above which were shown to be >99%
Synthesis 1999, No. 8, 1325–1330 ISSN 0039-7881 © Thieme Stuttgart · New York

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Lipase-Mediated Preparation of Sugar Building Blocks
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3.53 (dd, 1 H, E = 9.8, 5.5 Hz), 2.95 (d, 1 H, E = 4.7 Hz), 2.76 (d, 1
H, E = 5.2 Hz).
with its two analogs ꢀE and ꢀF employing a lipase-medi- HRMS: €/“ calcd for C18H18O4 (M+) 298.1205. Found 298.1206.
In summary, we have developed an alternative procedure
for the preparation of the sugar building block ꢀD along
ated enantiocomplementary kinetic resolution procedure
which exhibited comparable synthetic efficiency to the
previously established procedure employing the Sharpless
asymmetric hydroxylation. Since the present lipase-medi-
ated procedure allowed facile preparation of highly func-
tionalized bicyclic enones in both enantiomeric forms in
enantiomerically pure states without using expensive AD-
Anal. calcd for C18H18O4: C, 72.47; H, 6.08. Found C, 72.57; H,
6.36.
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The ether ꢂE (40 g, 187 mmol) was treated with OsO4 (0.2 M in
THF, 9.5 mL, 1.87 mmol) and NMO (26.2 g) in THF/H2O (1:1 v/v,
600 mL) under the same conditions described for (±)-ꢁD to give (±)-
ꢁE (43.9 g, 95%); mp 37.0–38.0°C (EtOAc).
mix reagents, the enones thus obtained may be more wide- IR (nujol): n = 3406 cm-1.
1H NMR (CDCl3, 300 MHz): d = 7.38–7.27 (m, 6 H), 6.35–6.32 (m,
2 H), 4.75 (dd, 1 H, E = 5.5, 4.8 Hz), 4.57 (d, 1 H, E = 11.7 Hz), 4.51
(d, 1 H, E = 11.7 Hz), 4.13–4.06 (m, 1 H), 3.58 (dd, 1 H, E = 9.9, 3.7
Hz), 3.49 (dd, 1 H, E = 9.9, 5.5 Hz), 2.97 (d, 1 H, E = 4.4 Hz), 2.75
(d, 1 H, E = 5.5 Hz).
ly used as versatile chiral building blocks not only for the
enantiocontrolled construction of sugar derivatives but
also for a variety of chiral materials.
Melting points are uncorrected. IR spectra were recorded on a Jas-
coꢂIR-700 spectrometer. 1H NMR spectra were recorded on a Gem-
ini 2000 (300 MHz) or Jeol JMX-GX500 (500 MHz) spectrometers.
Mass spectra were recorded on a Jeol JMTꢂDX303 instrument.
Enantiomeric purities were determined on a Gilson Model-307 in-
strument equipped with a chiral column. Optical rotations were
measured with a JascoꢂDIPꢂ370 digital polarimeter.
HRMS: €/“ calcd for C14H16O4 (M+) 248.1048. Found 248.1033.
Anal. calcd for C14H16O4: C, 67.73; H, 6.50. Found C, 67.54; H,
6.65.
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The ether ꢂF (18 g, 75.6 mmol) was treated with OsO4 (0.2 M in
THF, 3.8 mL, 756 mmol) and NMO (10.6 g, 90.7 mmol) in THF/
H2O (1:1 v/v, 360 mL) under the same conditions described for (±)-
ꢁD to give (±)-ꢁF (17.8 g, 86%) as a colorless oil.
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To a stirred solution of ꢃ@ꢄ-3-(2-furyl)prop-2-enol (3.70 g, 30
mmol) in THF (70 mL) was added NaH (60% in oil, 1.5 g, 36 mmol)
at 0°C. After the H2 gas evolution had ceased, benzyl bromide (4.7
mL, 39 mmol) and Bu4NI (1.3 g, 35.2 mmol) were added to the mix-
ture at the same temperature and stirred for 8 h at r.t. The mixture
was then treated with MeOH (1 mL, 25 mmol) and NaH (60% in oil,
1.0 g, 24.5 mmol) and diluted with EtOAc (100 mL). The organic
layer was washed with H2O (20 mL) and brine (10 mL), dried
(MgSO4), evaporated under reduced pressure and chromatographed
on a silica gel column (100 g, elution with EtOAc/hexane, 1:200
then 1:30) to give ꢂE (6.1 g, 95%) as a colorless oil.
IR (film): n = 3404 cm-1.
1H NMR (CDCl3, 300 MHz): d = 7.40 (t, 1 H,ꢀE = 1.4 Hz), 6.36 (d,
2 H,ꢀE = 1.4 Hz), 4.74 (dd, 1 H, E = 5.5, 4.1 Hz), 3.98–3.92 (m, 1 H),
3.72 (dd, 1 H, E = 10.4, 4.0 Hz), 3.61 (dd, 1 H, E = 10.4, 4.9 Hz),
3.61 (d, 1 H, E = 4.1 Hz), 2.72 (d, 1 H, E = 6.3 Hz), 0.91 (s, 9 H),
0.07 (s, 6 H).
13C NMR (CDCl3, 75 MHz): d = 153.9, 142.3, 128.1, 110.3, 107.6,
73.1, 68.2, 63.9, 25.7, 18.1, –5.7.
HRMS: €/“ calcd for C13H23O3Si (M+–OH) 255.1417. Found
255.1418.
1H NMR (CDCl3, 300 MHz): d = 7.37–7.28 (m, 6 H), 6.46 (br d, 1
H,ꢀ E = 15.8 Hz), 6.36 (dd, 1 H,ꢀ E = 3.3, 1.8 Hz), 6.25 (dt, 1 H,
E = 15.8, 5.9 Hz), 6.24 (d, 1 H, E = 3.3 Hz), 4.57 (s, 2 H), 4.17 (dd,
2 H,ꢀE = 5.9, 1.1 Hz).
Anal. calcd for C13H24O4Si: C, 57.32; H, 8.89. Found C, 57.34; H,
8.88.
HRMS: €/“ calcd for C14H14O2 (M+) 214.0993. Found 214.0992.
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Anal. calcd for C14H14O2: C, 78.48; H, 6.59. Found: C, 78.39; H,
6.63.
To a stirred solution of (±)-ꢁD (4.61 g, 15.47 mmol) in CH2Cl2 (100
mL) was added €CPBA (70%, 4.19 g, 17.01 mmol) at 0°C and the
mixture was stirred at r.t. for 3 h. The mixture was filtered through
a Celite pad and evaporated under reduced pressure to give the
crude pyranone ꢇD. Without purification, the crude ꢇD was then re-
fluxed in benzene (100 mL) in the presence of ƒꢂTsOH (29 mg, 0.15
mmol) for 10 h. After cooling, the mixture was diluted with EtOAc
(100 mL) and the organic phase was washed with satd aq NaHCO3
solution (3 î 10 mL) and brine (10 mL), and dried (MgSO4). After
evaporation of the solvent under reduced pressure, the residue was
chromatographed on a silica gel column (100 g, elution with hex-
ane/EtOAc, 8:1 v/v) to give the bicyclic enone diol (±)-ꢀD (3.11 g,
68%) as colorless prisms; mp 80–83°C (hexane/EtOAc). Spectro-
scopic data were identical with those of (+)-ꢀD.1
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To a stirred solution of ꢂD1 (1.8 g, 6.8 mmol) and Iꢂmethylmorpho-
line Iꢂoxide (NMO) (985 mg, 8.2 mmol) in a mixture of THF/H2O
(1:1 v/v, 30 mL) was added OsO4 (0.2 M in THF, 350 mL, 70 mmol)
at 0°C and the mixture was stirred at r.t. for 10 h. To the mixture was
then added satd aq Na2SO3 solution (10 mL) and, after 10 min, the
mixture was extracted with EtOAc (100 mL). The extract was
washed with H2O (5 mL) and brine (5 mL), dried (MgSO4) and
evaporated under reduced pressure. The residue was chromato-
graphed on a silica gel column (100 g, elution with hexane/EtOAc,
2:1 v/v) to give the diol (±)-ꢁD (1.73 g, 85%) as colorless needles;
mp 83–85°C (EtOAc).
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IR (nujol): n = 3379 cm-1.
The diol (±)-ꢁE (20 g, 80.6 mmol) was treated with €CPBA (70%,
30 g, 120.9 mmol) in CH2Cl2 (400 mL) under the same conditions
described for (±)-ꢀD to give the crude pyranone ꢇE. The pyranone
ꢇE was then refluxed in benzene (400 mL) in the presence of ƒꢂ
TsOH (200 mg, 1.05 mmol) to give the enone (±)-ꢀE (13.3 g, 67%)
as colorless prisms; mp 56.0–57.0°C (hexane/EtOAc).
1H NMR (CDCl3, 300 MHz): d = 7.85–7.81 (m, 3 H), 7.75 (s, 1 H),
7.52–7.43 (m, 3 H), 7.36 (t, 1 H, E = 1.1 Hz), 6.34–6.31 (m, 2 H),
4.78 (d, 1 H, E = 4.7 Hz), 4.74 (d, 1 H, E = 11.7 Hz), 4.67 (d, 1 H,
E = 11.7 Hz), 4.16–4.09 (m, 1 H), 3.62 (dd, 1 H, E = 9.8, 3.8 Hz),
Synthesis 1999, No. 8, 1325–1330 ISSN 0039-7881 © Thieme Stuttgart · New York

ꢀꢁꢂꢎ
T. Taniguchi et al.
3$3(5
IR (film): n = 1721, 1690 cm-1.
give the alcohol (±)-ꢃF (654 mg, 99%). Spectroscopic data were
identical with those of (+)-ꢃF.1
1H NMR (CDCl3, 500 MHz): d = 7.30–7.19 (m, 5 H), 7.05 (dd, 1 H,
E = 9.8, 3.1 Hz), 6.01 (d, 1 H, E = 9.8 Hz), 5.75 (d, 1 H, E = 3.1 Hz),
4.52 (s, 2 H), 3.96–3.93 (m, 1 H), 3.56 (dd, 1 H,ꢀE = 9.8, 6.1 Hz),
3.46 (dd, 1 H,ꢀE = 9.8, 6.8 Hz).
13C NMR (CDCl3, 125 MHz): d = 194.0, 147.3, 137.6, 128.5, 127.9,
127.8, 126.9, 96.6, 81.8, 73.5, 73.0, 69.8.
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To a mixture of ꢃD (1.55 g, 5.2 mmol) and pyridine (630 mL, 7.8
mmol) in CH2Cl2 (20 mL) was added Ac2O (590 mL, 6.2 mmol) at
r.t. and the stirring was continued for 12 h at the same temperature.
The mixture was diluted with EtOAc (120 mL) and the solution was
washed with 10% HCl (2 î 5 mL), H2O (5 mL) and brine (5 mL),
dried (MgSO4), evaporated under reduced pressure, and the residue
was chromatographed on a silica gel column (130 g, elution with
hexane/EtOAc, 6:1 v/v) to give the acetate (±)-ꢈD (1.73 g, 98%) as
a pale yellow oil.
FABMS: €/“ = 245 (M+ – 1).
Anal. calcd for C14H14O4: C, 68.28; H, 5.73. Found C, 67.96; H,
5.93.
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The diol (±)-ꢁF (3.61 g, 13.2 mmol) was treated with €CPBA (70%,
3.59 g, 14.6 mmol) in CH2Cl2 (80 mL) under the same conditions
described for (±)-ꢀD to give the crude pyranone ꢇF. The pyranone ꢇF
was then refluxed in benzene (80 mL) in the presence of ƒꢂTsOH
(25 mg, 0.13 mmol) to give the enone (±)-ꢀF (2.47 g, 69%). Spec-
troscopic data were identical with those of (+)-ꢀF.1
IR (film): n = 1741 cm-1.
1H NMR (CDCl3, 300 MHz): d = 7.85–7.82 (m, 3 H), 7.77 (s, 1 H),
7.49–7.44 (m, 3 H), 6.01 (ddd, 1 H, E = 9.6, 3.0, 1.6 Hz), 5.75–5.68
(m, 2 H), 5.57 (d, 1 H, E = 3.0 Hz), 4.76 (d, 1 H,ꢀE = 13.7 Hz), 4.71
(d, 1 H, E = 13.7 Hz), 4.53–4.48 (m, 2 H), 3.65 (dd, 1 H, E = 9.6, 5.4
Hz), 3.51 (dd, 1 H, E = 9.6, 6.9 Hz), 2.00 (s, 3 H).
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To a stirred solution of (±)-ꢀD (595 mg, 2 mmol) and CeCl3•7H2O
(899 mg, 2.4 mmol) in MeOH (12 mL) was added NaBH4 (91 mg,
2.4 mmol) at 0°C and the stirring was continued for 15 min at the
same temperature. After evaporation of the solvent under reduced
pressure, the residue was dissolved in EtOAc (60 mL) and the or-
ganic layer was washed with H2O (5 mL) and brine (5 mL), and
dried (MgSO4), and evaporated under reduced pressure. The residue
was chromatographed on a silica gel column (60 g, elution with hex-
ane/EtOAc, 4:1 v/v) to give the alcohol (±)-ꢃD (555 mg, 93%) as
colorless needles; mp 80–81°C (hexane/EtOAc).
HRMS: €/“ calcd for C20H20O6 (M+) 356.1259. Found 340.1302.
Anal. calcd for C20H20O6: C, 70.57; H, 5.92. Found C, 70.60; H,
5.92.
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The alcohol (±)-ꢃE (1.0 g, 4.0 mmol) was treated with Ac2O (431
mL, 4.8 mmol) and pyridine (485 mL, 6.0 mmol) in CH2Cl2 (10 mL)
under the same conditions described for (±)-ꢈD to give the acetate
(±)-ꢈE (1.1 g, 94%) as a colorless oil.
IR (film): n = 1743 cm-1.
IR (nujol): n = 3274 cm-1.
1H NMR (CDCl3, 300 MHz): d = 7.38–7.20 (m, 5 H), 6.00 (ddd, 1
H,ꢀE = 9.3, 3.3, 1.4 Hz), 5.73 (m, 1 H), 5.73 (d, 1 H,ꢀE = 2.2 Hz), 5.56
(d, 1 H,ꢀE = 3.3 Hz), 4.59 (d, 1 H,ꢀE = 12.1 Hz), 4.55 (d, 1 H,ꢀE = 12.1
Hz), 4.50–4.44 (m, 2H), 3.61 (dd, 1 H,ꢀE = 9.6, 5.5 Hz), 3.45 (dd, 1
H,ꢀE = 9.6, 6.9 Hz), 2.01 (s, 3 H).
1H NMR (CDCl3, 300 MHz): d = 7.85–7.82 (m, 3 H), 7.78 (s, 1 H),
7.51–7.44 (m, 3 H), 5.90 (ddd, 1 H, E = 9.9, 3.0, 1.9 Hz), 5.70 (dt, 1
H, E = 9.9, 1.9 Hz), 5.54 (d, 1 H, E = 3.0 Hz), 4.80–4.72 (m, 3 H),
4.54 (ddd, 1 H, E = 6.0, 5.8, 1.6 Hz), 4.28 (dt, 1 H, E = 4.7, 1.6 Hz),
3.63 (dd, 1 H, E = 9.9, 5.8 Hz), 3.55 (dd, 1 H,ꢀE = 9.9, 6.0 Hz), 1.91
(d, 1 H, E = 5.5 Hz).
HRMS: €/“ calcd for C16H18O5 (M+) 290.1153. Found 290.1177.
Anal. calcd for C16H18O5: C, 66.18; H, 6.35. Found C, 66.38; H,
6.55.
HRMS: €/“ calcd for C18H18O5 (M+) 298.1205. Found 298.1208.
Anal. calcd for C18H18O5: C, 72.47; H, 6.08. Found C, 72.53; H,
6.19.
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OR[\PHWK\OꢄꢈꢌꢎꢄGLR[DELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQHꢅ>ꢊ“ꢋꢄꢈF@
ꢊ“ꢋꢄꢊꢀ56ꢌꢂ65ꢂꢃ65ꢂꢉ56ꢋꢄꢉꢄ%HQ]\OR[\PHWK\OꢄꢈꢌꢎꢄGLR[DELF\Fꢄ
OR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQꢄꢂꢄROꢅ>ꢊ“ꢋꢄꢃE@
The enone (±)-ꢀE (1.0 g, 4.1 mmol) was reduced with NaBH4 (184
mg, 4.9 mmol) and CeCl3•7H2O (1.8 g, 4.9 mmol) in MeOH (20
mL) under the same conditions described for (±)-ꢀD to give the al-
cohol (±)-ꢃE (984 mg, 98%).
The alcohol (±)-ꢃF (700 mg, 2.57 mmol) was treated with Ac2O
(323 mL, 3.10 mmol) and pyridine (312 mL, 3.86 mmol) in CH2Cl2
(10 mL) under the same conditions described for (±)-ꢈD to give the
acetate (±)-ꢈF (750 mg, 93%) as a colorless oil.
IR (film): n = 1749 cm-1.
1H NMR (CDCl3, 300 MHz): d = 6.02 (ddd, 1 H,ꢀE = 9.6, 3.0, 1.6
Hz), 5.73 (m, 1 H), 5.68 (m, 1 H), 5.52 (d, 1 H,ꢀE = 3.0 Hz), 4.46 (dt,
1 H,ꢀE = 4.7, 1.6 Hz), 4.31 (m, 1 H), 3.72 (dd, 1 H,ꢀE = 9.9, 4.9 Hz),
3.48 (dd, 1 H,ꢀE = 9.9, 8.5 Hz), 2.08 (s, 3 H), 0.89 (s, 9 H), 0.07 (s,
3 H), 0.06 (s, 3 H).
HRMS: €/“ calcd for C11H17O5Si (M+ – C4H10) 257.0844. Found
257.0847.
IR (film): n = 3420 cm-1.
1H NMR (CDCl3, 300 MHz): d = 7.38–7.26 (m, 5 H), 5.91 (ddd, 1
H,ꢀE = 9.6, 3.0, 1.6 Hz), 5.71 (m, 1 H), 5.53 (d, 1 H, E = 3.0 Hz), 4.77
(m, 1 H), 4.60 (s, 2 H), 4.60–4.46 (m, 2 H), 4.28 (dt, 1 H,ꢀE = 4.7,
1.9 Hz), 3.59 (dd, 1 H,ꢀE = 9.9, 5.5 Hz), 3.52 (dd, 1 H, E = 9.9, 6.3
Hz).
HRMS: €/“ calcd for C14H16O4 (M+) 248.1049. Found 248.1024.
Anal. calcd C15H28O5Si: C, 57.11; H, 8.63. Found C, 57.38; H, 8.55.
Anal. calcd for C14H16O4: C, 67.71; H, 6.49. Found C, 67.43; H,
6.38.
ꢊ±ꢋꢄꢊꢀ6ꢌꢂ5ꢌꢃ5ꢌꢉ6ꢋꢄꢂꢄ$FHWR[\ꢄꢉꢄꢊꢂꢄQDSKWK\OPHWK\OR[\PHWK\Oꢋꢄ
ꢈꢌꢎꢄGLR[DELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQHꢅ>ꢊ±ꢋꢄꢈD@ꢅDQGꢅꢊꢐꢋꢄꢊꢀ5ꢌꢂ6ꢌꢃ6ꢌꢉ5ꢋꢄ
ꢉꢄꢊꢂꢄ1DSKWK\OPHWK\OR[\PHWK\OꢋꢄꢈꢌꢎꢄGLR[DELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄ
HQꢄꢂꢄROꢅ>ꢊꢐꢋꢄꢃD@ꢅIURPꢅWKHꢅ5DFHPLFꢅ$OFRKROꢅꢊ“ꢋꢄꢃDꢍꢅ7\SLFDOꢅ3URꢄ
FHGXUH
ꢊ“ꢋꢄꢊꢀ56ꢌꢂ65ꢂꢃ65ꢂꢉ56ꢋꢄꢉꢄWHUWꢄ%XW\OGLPHWK\OVLOR[\PHWK\Oꢄꢈꢌꢎꢄ
GLR[DELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQꢄꢂꢄROꢅ>ꢊ“ꢋꢄꢃF@
The enone (±)-ꢀF (658 mg, 2.44 mmol) was reduced with NaBH4
(411 mg, 2.92 mmol) and CeCl3•7H2O (1.09 g, 2.92 mmol) in
MeOH (25 mL) under the same conditions described for (±)-ꢀD to
To a stirred solution of the racemic alcohol (±)-ꢃD (370 mg, 1.24
mmol) in THF (9 mL) and vinyl acetate (1.1 mL, 12.4 mmol) was
Synthesis 1999, No. 8, 1325–1330 ISSN 0039-7881 © Thieme Stuttgart · New York

3$3(5
Lipase-Mediated Preparation of Sugar Building Blocks
ꢀꢁꢂꢑ
added lipase PS (370 mg) at r.t. and the suspension was stirred at the
same temperature for 24 h. After filtration through a Celite pad, the
filtrate was evaporated under reduced pressure. The residue was
chromatographed on a silica gel column (40 g, elution with hexane/
EtOAc, 5:1 v/v) to give the acetate (–)-ꢈD as an oil (175 mg, 47%);
ed under reduced pressure. The residue was chromatographed on a
silica gel column (40 g, elution with hexane/EtOAc, 5:1 v/v) to give
the acetate (+)-ꢈD as an oil (166 mg, 46%); [a]D30+23.9 (p = 1.0,
CHCl3); and the alcohol (–)-ꢃD as colorless needles (145 mg, 46%);
[a]D28 –6.15 (p 0.8, CHCl3); mp 79–81°C (hexane/EtOAc). Enanti-
omeric purities of the products were determined as >99% ee as the
acetate ꢈD by HPLC using a column with a stationary phase
(CHIRALCEL OD, elution with 3% vꢂPrOH/hexane). Spectral data
of both products were identical with those of (±)-ꢃD and (±)-ꢈD.
29
[a]D –24.9 (p = 1.0, CHCl3); the alcohol (+)-ꢃD as colorless nee-
dles (153 mg, 47%); [a]D29+6.76 (p = 1.0, CHCl3); mp 80–81°C
(hexane/EtOAc). Enantiomeric purities of the products were deter-
mined as >99% ee as the acetate ꢈD by HPLC using a column with
a chiral stationary phase [CHIRALCEL OD, elution with 3% vꢂ
PrOH/hexane, retention time:32.1 min for (–)-ꢈD and 36.4 min for
(+)-ꢈD at 0.5 mL/min]. Spectral data were identical with those of
(±)-ꢃD and (±)-ꢈD.
ꢊ±ꢋꢄꢊꢀ6ꢌꢂ5ꢌꢃ5ꢌꢉ6ꢋꢄꢉꢄ%HQ]\OR[\PHWK\OꢄꢈꢌꢎꢄGLR[DELF\FOR>ꢁꢏꢂꢏꢀ@ꢄ
RFWꢄꢁꢄHQꢄꢂꢄROꢅ>ꢊ±ꢋꢄꢃE@ꢅDQGꢅꢊꢐꢋꢄꢊꢀ5ꢌꢂ6ꢌꢃ6ꢌꢉ5ꢋꢄꢂꢄ$FHWR[\ꢄꢂꢄEHQꢄ
]\OR[\PHWK\OꢄꢈꢌꢎꢄGLR[DELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQHꢅ>ꢊꢐꢋꢄꢈE@ꢅIURPꢅWKHꢅ
5DFHPLFꢅ$FHWDWHꢅꢊ“ꢋꢄꢈE
ꢊ±ꢋꢄꢊꢀ6ꢌꢂ5ꢌꢃ5ꢌꢉ6ꢋꢄꢂꢄ$FHWR[\ꢄꢉꢄEHQ]\OR[\PHWK\OꢄꢈꢌꢎꢄGLR[DELF\ꢄ
FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQHꢅ>ꢊ±ꢋꢄꢈE@ꢅDQGꢅꢊꢐꢋꢄꢊꢀ5ꢌꢂ6ꢌꢃ6ꢌꢉ5ꢋꢄꢉꢄEHQ]\OR[\ꢄ
PHWK\OꢄꢈꢌꢎꢄGLR[DELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQꢄꢂꢄROꢅ>ꢊꢐꢋꢄꢃE@ꢅIURPꢅWKHꢅ
5DFHPLFꢅ$OFRKROꢅꢊ“ꢋꢄꢃE
The racemic alcohol (±)-ꢃE (1.0 g, 4.0 mmol) was treated with vinyl
acetate (3.7 mL, 40 mmol) in THF (20 mL) in the presence of lipase
PS (1.0 g) under the same conditions described for (±)-ꢃDꢅto give the
acetate (–)-ꢈE (590 mg, 50%) and the alcohol (+)-ꢃE (450 mg, 49%)
after 24 h. Spectral data of the products were identical with those of
the racemates.
The racemic acetate (±)-ꢈE (500 mg, 1.7 mmol) in a mixture of 0.1
M phosphate buffer (pH 7.0, 9 mL) and acetone (1 mL) was treated
with lipase PS (500 mg) under the same conditions described for
(±)-ꢈD to give the alcohol (–)-ꢃE (205 mg, 48%) and the acetate (+)-
ꢈE (245 mg, 49%) after 24 h. Spectral data of the products were
identical with those of the racemates.
(–)-ꢃE
[a]D24 –5.6 (p = 1.0, CHCl3). Enantiomeric purity was determined as
>99% ee after transformation into the acetate (+)-ꢈE.
(+)-ꢈE
(–)-ꢈE
[h]D26+25.1 (p = 1.0, CHCl3). >99% ee by HPLC (CHIRALCEL
OD, elution with 3% vꢂPrOH/hexane).
[a]D27 –24.8 (p = 1.1, CHCl3). Enantiomeric purity was determined
as >99% ee by HPLC using a column with a chiral stationary phase
[CHIRALCEL OD, elution with 3% vꢂPrOH-hexane, retention
time:24.7 min for (–)-ꢈE and 42.4 min for (+)-ꢈE].
ꢊ±ꢋꢄꢊꢀ6ꢌꢂ5ꢌꢃ5ꢌꢉ6ꢋꢄꢉꢄWHUWꢄ%XW\OGLPHWK\OVLOR[\PHWK\OꢄꢈꢌꢎꢄGLR[Dꢄ
ELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQꢄꢂꢄROꢅ>ꢊ±ꢋꢄꢃF@ꢅDQGꢅꢊꢐꢋꢄꢊꢀ5ꢌꢂ6ꢌꢃ6ꢌꢉ5ꢋꢄꢂꢄ$Fꢄ
HWR[\ꢄꢉꢄWHUWꢄEXW\OGLPHWK\OVLOR[\PHWK\OꢄꢈꢌꢎꢄGLR[DELF\FOR>ꢁꢏꢂꢏꢀ@ꢄ
RFWꢄꢁꢄHQHꢅ>ꢊꢐꢋꢄꢈF@ꢅIURPꢅWKHꢅ5DFHPLFꢅ$FHWDWHꢅꢊ“ꢋꢄꢈF
A mixture of the racemic acetate (±)-ꢈF (150 mg, 0.48 mmol), 0.1
M phosphate buffer (pH 7.0, 2.7 mL) and acetone (3 mL) was treat-
ed with lipase PS (150 mg) under the same conditions described for
(±)-ꢈD to give the alcohol (–)-ꢃF (63 mg, 49%) and the acetate (+)-
ꢈF (73 mg, 49%) after 24 h. Spectral data of the products were iden-
tical with those of the racemates.
(+)-ꢃE
[a]D27+5.4 (p = 1.1, CHCl3). Enantiomeric purity was determined as
>99% ee after transformation into the acetate (+)-ꢈE by HPLC using
a column with a chiral stationary phase.
ꢊ±ꢋꢄꢊꢀ6ꢌꢂ5ꢌꢃ5ꢌꢉ6ꢋꢄꢂꢄ$FHWR[\ꢄꢉꢄWHUWꢄEXW\OGLPHWK\OVLOR[\PHWK\Oꢄ
ꢈꢌꢎꢄGLR[DELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQHꢅ>ꢊ±ꢋꢄꢈF@ꢅDQGꢅꢊꢐꢋꢄꢊꢀ5ꢌꢂ6ꢌꢃ6ꢌꢉ5ꢋꢄ
ꢉꢄWHUWꢄEXW\OGLPHWK\OVLOR[\PHWK\OꢄꢈꢌꢎꢄGLR[DELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄ
HQꢄꢂꢄROꢅ>ꢊꢐꢋꢄꢃF@
The racemic alcohol (±)-ꢃF (200 mg, 0.73 mmol) in THF (4 mL)
was treated with vinyl acetate (677 mL, 7.3 mmol) in the presence
of lipase PS (200 mg) under the same conditions described for (±)-
ꢃD to give the acetate (–)-ꢈF (114 mg, 49%) and the alcohol (+)-ꢃF
(96 mg, 48%). Spectral data of the products were identical with
those of the racemates.
(–)-ꢃF
mp 46–48°C (hexane/EtOAc); [a]D30 –2.8 (p = 1.1, CHCl3).
(+)-ꢈF
mp 36–38°C (hexane/EtOAc); [a]D28 +15.5 (p = 1.0, CHCl3).
Enantiomeric purity of both products was determined as >99% ee
after transformation into benzoate by HPLC using a column with a
chiral stationary phase (CHIRALCEL OD, elution with 1% vꢂPrOH/
hexane).
(–)-ꢈF
mp 44–46°C (hexane/EtOAc); [a]D27 –16.5 (p = 1.0, CHCl3).
(+)-ꢃF
ꢊ±ꢋꢄꢊꢀ6ꢌꢂ5ꢌꢃ5ꢌꢉ6ꢋꢄꢊꢂꢄ1DSKWK\OPHWK\OR[\PHWK\OꢋꢄꢈꢌꢎꢄGLR[DELꢄ
F\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQꢄꢂꢄROꢅ>ꢊ±ꢋꢄꢃD@ꢅIURPꢅꢊ±ꢋꢄꢊꢀ6ꢌꢂ5ꢌꢃ5ꢌꢉ6ꢋꢄꢂꢄ$FHꢄ
WR[\ꢄꢉꢄꢊꢂꢄQDSKWK\OPHWK\OR[\PHWK\OꢋꢄꢈꢌꢎꢄGLR[DELF\FORꢄ
>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQHꢅ>ꢊ±ꢋꢄꢈD@ꢍꢅ7\SLFDOꢅ3URFHGXUH
To a stirred solution of the acetate (–)-ꢈD (150 mg, 0.44 mmol) in
MeOH (2 mL) was added solid K2CO3 (61 mg, 0.44 mmol) at r.t.
and the stirring was continued at the same temperature for 0.5 h. The
mixture was diluted with H2O (3 ml) and extracted with AcOEt (10
ml). The extract was washed with H2O (3 ml) and brine (3 mL),
dried (MgSO4), evaporated under reduced pressure to give the alco-
hol (–)-ꢃD (130 mg, 99%); mp 83–85°C (EtOAc); [a]D28 –6.68 (p =
0.7, CHCl3). Spectral data were identical with those of (+)-ꢃD.
mp 48–50°C (hexane/EtOAc); [a]D26 +2.9 (p = 1.0, CHCl3).
Enantiomeric purity of both products was determined as >99% ee
by HPLC using a column with a chiral stationary phase after trans-
formation into the benzoate [CHIRALCEL OD, elution with 1% vꢂ
PrOH/hexane, retention time:11.5 min for (–)-ꢈF and 22.7 min for
(+)-ꢈF at 0.5 mL/min].
ꢊ±ꢋꢄꢊꢀ6ꢌꢂ5ꢌꢃ5ꢌꢉ6ꢋꢄꢉꢄꢊꢂꢄ1DSKWK\OPHWK\OR[\PHWK\OꢋꢄꢈꢌꢎꢄGLR[Dꢄ
ELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQꢄꢂꢄROꢅ>ꢊ±ꢋꢄꢃD@ꢅDQGꢅꢊꢐꢋꢄꢊꢀ5ꢌꢂ6ꢌꢃ6ꢌꢉ5ꢋꢄꢂꢄ$Fꢄ
HWR[\ꢄꢉꢄꢊꢂꢄQDSKWK\OPHWK\OR[\PHWK\OꢋꢄꢈꢌꢎꢄGLR[DELF\FORꢄ>ꢁꢏꢂꢏꢀ@ꢄ
RFWꢄꢁꢄHQHꢅ>ꢊꢐꢋꢄꢈD@ꢅIURPꢅWKHꢅ5DFHPLFꢅ$FHWDWHꢅꢊ“ꢋꢄꢈDꢍꢅ7\SLFDOꢅ
3URFHGXUHꢆ
To a stirred solution of the racemic alcohol (±)-ꢈD (360 mg, 1.18
mmol) in 0.1 M phosphate buffer (pH 7.0, 8.1 mL) and acetone (0.9
mL) was suspended lipase PS (360 mg) at r.t. and the suspension
was stirred at the same temperature for 24 h. After filtration though
a Celite pad, the filtrate was extracted with EtOAc (50 mL). The ex-
tract was washed with H2O and brine, dried (MgSO4), and evaporat-
In a similar manner, the enantiomeric (+)-ꢈD was converted to the
(+)-alcohol (+)-ꢃD;, mp 83–85°C (EtOAc); [a]D26 +6.31 (p = 1.0,
CHCl3) in 99% yield.
Similarly, (–)-ꢃE from (–)-ꢈE and (–)-ꢃF from (–)-ꢈF were obtained
in excellent yields, respectively.
Synthesis 1999, No. 8, 1325–1330 ISSN 0039-7881 © Thieme Stuttgart · New York

ꢀꢁꢁꢒ
T. Taniguchi et al.
3$3(5
ꢊ±ꢋꢄꢊꢀ6ꢌꢃ6ꢌꢉ5ꢋꢄꢉꢄꢊꢂꢄ1DSKWK\OPHWK\OR[\PHWK\OꢋꢄꢈꢌꢎꢄGLR[DELF\Fꢄ
OR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQꢄꢂꢄRQHꢅ>ꢊ±ꢋꢄꢀD@ꢅIURPꢅꢊꢐꢋꢄꢊꢀ5ꢌꢂ6ꢌꢃ6ꢌꢉ5ꢋꢄꢉꢄꢊꢂꢄ
1DSKWK\OPHWK\OR[\PHWK\OꢋꢄꢈꢌꢎꢄGLR[DELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQꢄꢂꢄ
ROꢅ>ꢊꢐꢋꢄꢃD@ꢍꢅ7\SLFDOꢅ3URFHGXUH
$FNQRZOHGJHPHQW
We are grateful for the Egyptian Associate Channel System Pro-
gram Scholarship (to A. S. ElAzab).
To a stirred suspension of (+)-ꢃD (100 mg, 0.34 mmol), NaOAc (55
mg, 0.67 mmol) and molecular sieves (4Å, 165 mg) in CH2Cl2 (2
mL) was added pyridinium chlorochromate (110 mg, 0.51 mmol) at
r.t. and the mixture was stirred at the same temperature for 3 h. The
mixture was filtered through a Celite pad and the filtrate was evap-
orated under reduced pressure and chromatographed on a silica gel
column (10 g, elution with hexane/EtOAc, 10:1 v/v) to give the
enone (–)-ꢀD (92 mg, 93%) as colorless prisms; mp 80–83°C (hex-
5HIHUHQFHV
(1) Takeuchi, M.; Taniguchi, T.; Ogasawara, K. T’‡ur†v†ꢀꢀꢑꢑꢑ,
341.
(2) Takeuchi, M.; Taniguchi, T.; Ogasawara, K. in preparation.
(3) Taniguchi, T.; Ohnishi, H.; Ogasawara, K. Eꢅꢀ8ur€ꢅꢀT‚p.,
8ur€.ꢀ8‚€€ˆ. ꢀꢑꢑꢈ, 1477.
(4) Johnson, R. A.; Sharpless, K. B. 8‚€ƒꢁrur†v‰rꢀPꢁthvpꢀ
T’‡ur†v†, Trost, B. M.; Fleming, I.; Eds.; Pergamon Press:
New York 1991, Vol. 7, p. 389.
(5) Achmatowicz, O. PꢁthvpꢀT’‡ur†v†ꢀU‚qh’ꢀhqꢀU‚€‚ꢁꢁ‚,
Trost, B. M.; Hutchinson, C. R.; Eds.; Pergamon Press:
Oxford, 1980, pp. 307-325.
(6) Luche, J. -L. Eꢅꢀ6€ꢅꢀ8ur€ꢅꢀT‚p. ꢀꢑꢉꢉ, ꢆꢆ, 2226.
Gemal, A. L.; Luche, J. -L. Eꢅꢀ6€ꢅꢀ8ur€ꢅꢀT‚p. ꢀꢑꢎꢀ, ꢆ",
5454.
(7) Takano, S.; Yamane, T.; Takahashi, M.; Ogasawara, K.
Ur‡ꢁhurqꢁ‚)ꢀ6†’€€r‡ꢁ’ ꢀꢑꢑꢂ, ", 873.
29
ane/EtOAc); [a]D –156.5 (p = 0.6, CHCl3). Spectral data were
identical with those of (±)-ꢀD.
In a similar way, the enantiomeric (–)-ꢃD gave the enone (+)-ꢀD, mp
80–83°C (hexane/EtOAc); [a]D29 +148.3 (p = 0.6, CHCl3), in 90%
yield.
ꢊ±ꢋꢄꢊꢀ6ꢌꢃ6ꢌꢉ5ꢋꢄꢉꢄ%HQ]\OR[\PHWK\OꢄꢈꢌꢎꢄGLR[DELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄ
HQꢄꢂꢄRQHꢅ>ꢊ±ꢋꢄꢀE@ꢅIURPꢅꢊꢐꢋꢄꢊꢀ5ꢌꢂ6ꢌꢃ6ꢌꢉ5ꢋꢄꢉꢄ%HQ]\OR[\PHWK\Oꢄ
ꢈꢌꢎꢄGLR[DELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQꢄꢂꢄROꢅ>ꢊꢐꢋꢄꢃE@
The alcohol (+)-ꢃE (200 mg, 0.81 mmol) was oxidized with PCC
(259 mg, 1.22 mmol) in CH2Cl2 (5 mL) in the presence of NaOAc
(131 mg, 1.62 mmol) and molecular sieves (4Å) (390 mg) under the
same conditions described for (–)-ꢀD to give the enone (–)-ꢃE (185
Takano, S.; Setoh, M.; Ogasawara, K. Ur‡ꢁhurqꢁ‚)ꢀ
6†’€€r‡ꢁ’ ꢀꢑꢑꢁ, #, 157.
Takano, S.; Suzuki, M.; Ogasawara, K. Ur‡ꢁhurqꢁ‚)ꢀ
6†’€€r‡ꢁ’ ꢀꢑꢑꢁ, #, 1043.
Takano, S.; Yamada, O.; Iida, H; Ogasawara, K. T’‡ur†v†
ꢀꢑꢑꢇ, 592.
27
mg, 93%) as colorless prisms, mp 66–68 °C (hexane/EtOAc); [a]D
–187.7 (p = 1.1, CHCl3). Spectral data were identical with those of
(±)-ꢃE.
On similar treatment, the (–)-alcohol (–)-ꢃEꢅafforded the enantio-
meric enone (+)-ꢀEꢍ mp 64–66°C (hexane/EtOAc); [a]D25 +191.8 (p
= 1.4, CHCl3), in 96% yield.
(8) A pertinent monograph, see: Wong, C. H.; Whitesides, G. M.ꢀ
@“’€r†ꢀvꢀT’‡ur‡vpꢀPꢁthvpꢀ8ur€v†‡ꢁ’, Pergamon, Oxford,
1994.
(9) Pertinent reviews, see: Roberts, S. M.; Eꢅꢀ8ur€ꢅꢀT‚pꢅꢇ Qrꢁxvꢀ
Uꢁh†ꢅꢀ ꢀꢑꢑꢎ, 157 and ꢀꢑꢑꢑ, 1.
(10) Chen, C. -S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. Eꢅꢀ6€ꢅꢀ
8ur€. T‚p. ꢀꢑꢎꢂ, ꢆ#, 7294.
(11) E value was calculated by estimating enantiomeric purities of
the products as 99% ee.
ꢊ±ꢋꢄꢊꢀ6ꢌꢃ6ꢌꢉ5ꢋꢄꢉꢄWHUWꢄ%XW\OGLPHWK\OVLOR[\PHWK\OꢄꢈꢌꢎꢄGLR[DELF\ꢄ
FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQꢄꢂꢄRQHꢅ>ꢊ±ꢋꢄꢀF@ꢅIURPꢅꢊꢐꢋꢄꢊꢀ5ꢌꢂ6ꢌꢃ6ꢌꢉ5ꢋꢄꢉꢄWHUWꢄ
%XW\OGLPHWK\OVLOR[\PHWK\OꢄꢈꢌꢎꢄGLR[DELF\FOR>ꢁꢏꢂꢏꢀ@RFWꢄꢁꢄHQꢄꢂꢄROꢅ
ꢊꢐꢋꢄꢃF
The alcohol (+)-ꢃF (180 mg, 0.66 mmol) was oxidized with PCC
(213 mg, 0.99 mmol) in CH2Cl2 (4 ml) in the presence of NaOAc
(108 mg, 1.32 mmol) and molecular sieves (4Å) (320 mg) under the
same conditions described for (–)-ꢀD to give the enone (–)-ꢀF (145
mg, 81%) as a colorless oil; [a]D27 –187.7 (p 1.1, CHCl3). Spectral
data were identical with those of (±)-ꢀF.
Article Identifier:
1437-210X,E;1999,0,08,1325,1330,ftx,en;F12099SS.pdf
In a similar way, the alcohol (–)-ꢃFꢅafforded the enantiomeric enone
(+)-ꢀF in 88% yield; [a]D25 +191.8 (p = 1.4, CHCl3)
Synthesis 1999, No. 8, 1325–1330 ISSN 0039-7881 © Thieme Stuttgart · New York