Enantiomerically Pure Octahydronaphthalenone and Octahydroindenone: Elaboration of the Substrate Overcame the Specificity of Yeast-Mediated Reduction

Article abstract of DOI:10.1002/adsc.200303004

Substrate specificity on the reduction of bicyclic diketones with a yeast strain, Torulaspora delbrueckii IFO10921, was investigated. Although this yeast efficiently reduces the isolated carbonyl group involved in the (S)-enantiomer of Wieland-Miescher ke

Full text of DOI:10.1002/adsc.200303004

FULL PAPERS
Enantiomerically Pure Octahydronaphthalenone and
Octahydroindenone: Elaboration of the Substrate Overcame the
Specificity of Yeast-Mediated Reduction
Ken-ichi Fuhshuku, Mina Tomita, Takeshi Sugai*
Department of Chemistry, Keio University, Hiyoshi, Yokohama 223 8522, Japan
Fax: ( ‡ 81)-45-566-1697, e-mail: sugai@chem.keio.ac.jp
Received: January 10, 2003; Accepted: March 12, 2003
Abstract: Substrate specificity on the reduction of hydroxy ketone equivalents by yeast-mediated reduc-
bicyclic diketones with a yeast strain, Torulaspora tion. The products were isolated as cyclic hemiacetals,
delbrueckii IFO10921, was investigated. Although such as (1S,6S)-3-ethyl-3-hydroxy-6-methyl-2-oxabi-
this yeast efficiently reduces the isolated carbonyl cyclo[4.4.0]decan-7-one and (1S,6S)-3-hydroxy-3,6-di-
group involved in the (S)-enantiomer of Wieland
Miescher ketone with high enantioselectivity (E ˆ
methyl-2-oxabicyclo[4.3.0]nonan-7-one. In addition,
the reduction worked well with use of an air-dried,
126), the introduction of a substituent on the octahy- long-term preservable cell preparation. The subse-
dronaphthalene skeleton as well as the structural quent chemical transformation warranted the stereo-
change into an octahydroindene skeleton retarded the chemistry and the stereochemical purity of the
enzymatic reduction and the enantioselectivity fell to products, which are related to octahydronaphthale-
E ˆ 5 16. Further structural variation into a bicy- none and octahydroindenone systems that, in turn,
clo[3.3.0] skeleton led to an exclusive 1,4-conjugate are of considerable value as starting materials for
reduction of the a,b-unsaturated carbonyl group, and terpenoid synthesis.
the above results suggested the participation of plural
oxidoreductive enzymes in the whole cell. In turn, Keywords: chiral building block; desymmetrization;
among the 2,2-disubstituted cycloalkanediones there kinetic resolution; prochiral substrate; reduction;
were found good substrates to give the corresponding terpenoid; whole cell biocatalyst; yeast
Introduction
and enzyme-mediated preparation of mono- and bicy-
clic chiral building blocks of natural product synthesis[4]
Torulaspora delbrueckii IFO10921 was found to be a prompted us to investigate the scope and limitation of
yeast strain that enables the reduction of racemic this yeast-mediated reduction. Based on an extensive
Wieland Miescher ketone (1) with high enantioselec- study of substrate specificity, here we report a successful
tivity as shown in Scheme 1.[1] The enantiomerically approach towards the preparation of (R)-3 and (R)-4, as
enriched products of this kinetic resolution have been well as their synthetic equivalents.
utilized as the starting material for naturally occurring
terpenoids.[2,3] Recent efforts towards microorganism-
Results and Discussion
Attempted Reduction of Bicyclic Substrates
In their pioneering work, Prelog and co-workers dis-
closed the microbial production of the Wieland Miesch-
er ketone (1) and its analogues.[5] In the subsequent
years, Inayama, Shimizu and co-workers extensively
studied the substrate specificity on the related com-
pounds.[6] In turn, recently, Kodama applied baker×s
yeast reduction to the Wieland Miescher ketone (1) and
its hydroindenone analogue, Hajos Parrish ketone
Scheme 1.
(4).[7] Our first candidates were the analogous substrates
766
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/adsc.200303004
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Enantiomerically Pure Octahydronaphthalenone and Octahydroindenone
FULL PAPERS
Table 1. Yeast-mediated reduction of carbonyl compounds towards the kinetic resolution of racemic substrates.
Entry
Substrate
Product
Recovery
Yield [%]
E value
Yield [%]
% de
% ee
% ee
1
2
3
4
3
4
5
6
(4aS,5S)-9a
(1S,7aS)-10a
no reaction
(3aS,4S)-11a
6
20
73.9
61.8
87.7
63.8
87
78
3.4
15.5
16
5
46
70.268.0
54
56.9
9
[( Æ )-3 to ( Æ )-8]; however, the results were rather
disappointing and somewhat confusing as shown in
Table 1.
Compared with a high level of enantiomer recogni-
tion,[8] E ˆ 126 for ( Æ )-1, the enantiomeric ratio drop-
ped to 16 (for 3, entry 1), 5 (for 4, entry 2), and 9 (for 6,
entry 4). The introduction of a dimethyl substituent even
into arather remote position (C-3) in 1severely retarded
the reduction, which resulted in the lack of reaction of 5.
The above results suggested that plural enzymes work[9]
in the whole cell of T. delbrueckii, and the activity of
oxidoreductive enzyme which was responsible for the
highly enantioselective and efficient reduction in (S)-1 is
easily suppressed, as being susceptible to the introduc-
tion of substituents as 3 and 5, or the change in the Scheme 2.
skeleton of the vinylogous diketone system.
Further dramatic alteration of the leading role was
observed in the case of the bicyclo[3.3.0] system in which (R)-7 were obtained in enaniomerically pure state
both carbocycles were replaced with a cyclopentane (Table 2, entry 3). A side reaction is the spontaneous
ring. The reduction of isolated carbonyl groups so far non-enzymatic 1,4-hydration of the unsaturated ketone
consistently observed in the substrates (1, 3, 4, 6) was to give 13, which was observed even in a buffer solution
suppressed, and the 1,4-conjugate reduction[10] of the without any microorganism (entry 4). This reaction
a,b-unsaturated carbonyl group proceeded as shown in lowered the yield of the recovered substrate (R)-7 after
Scheme 2. This enzyme showed not only enantiofacial prolonged incubation; however, the hydration product
selection, but also enantiomeric kinetic resolution, and 13 could be isolated and recycled to the starting material
both the product (1S,5R)-12 and the recovered substrate after the dehydration under appropriate conditions. In
contrast to the bicyclic diketone, the yeast-mediated
reduction of a spiro diketone 8 proceeded with no
enantioselectivity, together with the further reduced
product, a hydroxy ketone 15.
Table 2. Yeast-mediated 1,4-conjugate reduction of ( Æ )-7.
Entry
Time
[h]
Product
Recovery
13
Yield
[%]
% ee
Yield
[%]
% ee
Yield
[%]
1
2
3
2
>199.9
> 99.9
> 99.9
57
3289.8
17
36.8
34
> 99.9
22
6
34
3
18
18
38
45
74
4[a]
26
[a]
Blank experiment: substrate was incubated in a buffer
solution without yeast cells.
Figure 1.
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Ken-ichi Fuhshuku et al.
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brewer×s yeast.[11] Another side product 24 (14%) is
probably due to the non-enzymatic intramolecular aldol
reaction; however, this aspect was not pursued in the
present work. The introduction of a dimethyl group (25)
and one methylene group subtraction between the
quaternary center and the side-chain carbonyl group
(26) only resulted in the very low activity of enzymes.
Transformation of Octahydronaphthalenone and
Octahydroindenone
The next task was the derivation of cyclic hemiacetals of
the bicyclic octahydronaphthalenone and octahydroin-
denone via hemiacetal ring-opening reaction and the
subsequent intramolecular aldol reaction.[1] This trans-
formation would unambiguously establish both the
stereochemistry and the enantiomeric purities of hemi-
acetals 20 and 22.
First, the hemiacetal 20 was acetylated with concom-
itant ring-opening to give the open-chain acetate 27 in
98% yield. Treatment of 27 with p-TsOH provided a
bicyclic acetate 9b in 83% yield as shown in Scheme 4.
The suggested (1S,8aR) configuration[12] of 9b was
confirmed by the comparison with an authentic sample
obtained as follows. The triketone 19 was submitted to
asymmetric Robinson annulation in the presence of l-
phenylalanine to give (S)-3.[13] The isolated ketone was
reduced to give an alcohol (4aS,5S)-9a whose angular
methyl group and hydroxy group are located in a syn
relationship.[13] The stereochemistry of the secondary
alcohol was inverted via a chloromethanesulfonate[14]
(1S,8aS)-9c to give (1R,8aS)-9b. The 1H NMR spectrum
of this sample and the sign of rotation (see Experimental
Section) were compared with those of the product from
microbial origin, whose absolute configuration was
confirmed to be (1S,8aR). In turn, the absolute config-
Scheme 3.
Reduction of Cyclic Triketones
Our previous study also revealed that T. delbueckii
catalyzes the enantiotopic group-selective reduction of
triketone 16[1] to give a cyclic hemiacetal (1S,3S,6S)-18,
the equivalent of (2S,3S)-17 in high enantioselectivity.
As expected, the reduction ofthe analogous triketone 19
worked well to give hemiacetal 20 in 56% yield.
Cyclopentanetrione 21 was also accepted by this micro-
organism and the desired product 22 was obtained in
63% yield. In contrast to our previous examples, two by-
products were isolated in this case. The first was the
open-chain form of hydroxy ketone 23a (7%), whose
relationship between the hydroxy group and the meth-
ylene side chain was trans. The determination of stereo-
chemistry is shown in the following section. Judged from
the ratio of the formation of 22 and 23a, the enantiotopic
group selectivity was ca. 9.3:1. Our T. delbrueckii
preferred the pro-(R)-carbonyl group. The formation
of minor isomer 23a is compatible with the findings with
a microorganism with an opposite pro-(S)-preference, Scheme 4.
768
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Enantiomerically Pure Octahydronaphthalenone and Octahydroindenone
FULL PAPERS
23a, the by-product of yeast-mediated reduction, was
converted to (1S,7aS)-10b and the absolute configura-
tion of 23a was unambiguously determined. In this case,
the raw material of the yeast-mediated reaction showed
the enantiomeric homogeneity.
Preparation of Long-Term Preservable Cells
If preservable whole cells of this yeast were available,
the applicability of this yeast-mediated reduction in
synthetic organic chemistry would greatly increase.
Three contrasting methods of preparation were tried:
1) freeze-drying at low temperature under high vacuum;
2) oven-drying for a short period; 3) air-drying at
ambient temperature. The activity of the preparations
was compared on the Wieland Miescher ketone 1 and
the results are shown in Table 3. As can clearly be seen,
air-dried cells (entry 4) were the most effective both in
terms of activity and enantioselectivity, accompanied
with the maintenance of a co-factor regeneration. The E
value (123, entry 4) in the kinetic resolution of racemic
Wieland Miescher ketone 1 was nearly equal with that
of the freshly harvested cells (126, entry 6). Moreover,
the air-dried cells showed a long-term stability. The
activity was almost same, even after storage in a
refrigerator (48C) for sixty days (entry 5).
This air-dried cell preparation was also effective for
the reduction of prochiral triketones 16, 19 and 21 as
shown in Table 4, in regard to both the activity of
enzymes as well as the regio- and enantioselectivity.
Also, the activity of enzymes responsible to 1,4-reduc-
tion of ( Æ )-7 was conserved.
Scheme 5.
uration of cyclic hemiacetal 20 was (1S,6S). The ee of the
product was 98.7%, determined at the stage of (1S,8aR)-
9b by HPLC analysis with Chiralcel OJ, and this could be
further enhanced to>99.9% by recrystallization of
(1S,6S)-20.
In a similar manner, the hemiacetal 22 was converted
to a bicyclic acetate (1S,7aR)-10b in a total 70% yield as
shown in Scheme 5, whose absolute and relative con-
figuration was determined by the comparison with an
authentic sample.[14,15] Independently, hydroxy ketone
Table 4. Reduction of prochiral triketones with air-dried cells.
Sub-
Product
Air-dried Cell
Fresh Cell
strate
Yield
[%]
% ee
Yield % ee
[%]
16
19
21
(1S,3S,6S)-18 6299.4
60
97.8
99.8
> 99.9
98.7
> 99.9
(1S,6S)-20
(1S,6S)-22
50
51
56
74
Table 3. Reduction of ( Æ )-1 with dried cells towards the kinetic resolution of racemic substrate.
Entry
Method of preparation
Storage [days]
Cell wt. [g][a]
Reaction time [h]
Conversion [%]
E value
1
Freeze-dry
0
3.0
0
0
60
3.0
1246.4
34.6
50
2Freeze-dry
7
8
61
3
4
5
6
Oven-dry
Air-dry
Air-dry
Fresh Cells
1.230
1.24
1.24
0.6
11.3
41.3
37.8
9
2
12
3
110
26.3
2
126
[a]
Cell weight per 100 mg of the substrate.
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Ken-ichi Fuhshuku et al.
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Conclusion
(s, 3H), 2.06 2.19 (m, 3H), 2.38 2.52 (m, 3H), 2.62 2.74 (m,
2H), 2.83 2.93 (m, 2H). Its IR and NMR spectra were
identical with those reported previously.[13] Based on the
HPLC analysis [column, Daicel Chiralcel OJ, 0.46 cm  2 5 cm;
hexane/2-propanol (9/1); flow rate 0.5 mL/min]: tR ˆ 26.7 min
for (R)-3, 28.7 min for (S)-3, the ee of (R)-3 was determined to
be 3.4%.
Further elution of the column [hexane/ethyl acetate (1/1)]
afforded (4aS,5S)-9a; yield: 6.0 mg (6%); IR: nmax ˆ 3427, 1653,
1606 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 1.18 (s, 3H), 1.30
1.49 (m, 1H), 1.64 1.94 (m, 8H), 2.02 2.15 (m, 2H), 2.32 2.61
(m, 2H), 2.65 2.76 (m, 1H), 3.42 [dd, J ˆ 4.4, 11.7 Hz, (4aS,5S),
1H], 3.60 [m, (4aR,5S), 1H]. Its IR and NMR spectra were
identical with those reported previously.[13] Judging from the
area of signals at d ˆ 3.42for (4a S,5S)-9a and d ˆ 3.60 for
(4aR,5S)-9a, the de of (4aS,5S)-9a was determined to be 73.9%.
Avery small portion of (4aS,5S)-9a was oxidized with the Jones
reagent and the resultant (S)-3 was directly analyzed by HPLC
to have 87.7% ee.
As mentioned above, the substrate specificity of Tor-
ulaspora delbrueckii and this yeast-mediated reduction
offer a new way towards enantiomerically pure octahy-
dronaphthalenone and octahydroindenone. Since a
long-term preservable form of air-dried whole cell
preparation was effective, this yeast-mediated reduction
should be widely applied in the future.
Experimental Section
All mps are uncorrected. IR spectra were measured as films for
oils or KBr disks for solids on a Jasco FT/IR-410 spectrometer.
1H NMR spectra were measured in CDCl3 at 270 MHz on a
Jeol JNM EX-270 or at 400 MHz on a Jeol JNM GX-400
spectrometer. HPLC data were recorded on SSC-3461 and
SSC-5410 (Senshu Scientific Co., Ltd) liquid chromatographs.
GLC data were recorded on a GC-353 (GL Science Co., Ltd)
gas chromatograph. Optical rotation values were recorded on a
Jasco DIP 360 polarimeter. Merck silica gel 60 F254 thin-layer
plates (1.05744) and silica gel 60 (spherical; 100 210 mm,
37558 79) from Kanto Chemical Co., were used for prepara-
tive thin-layer chromatography and column chromatography,
respectively. Peptone and yeast extract were purchased from
Kyokuto Pharmaceutical Co., for the cultivation of the micro-
organism.
Reduction of ( Æ )-7a-Methyl-2,3,7,7a-tetrahydro-1H-
indene-1,5(6H)-dione (4)
The enone ( Æ )-4[16] (49.4 mg, 0.301 mmol) was incubated with
cells (0.3 g) for 3 h at 308C. After the work-up, the crude
residue was purified by preparative thin-layer chromatography
[developed with hexane/ethyl acetate (1/1)].
(R)-4; yield: 38.4 mg (78%); [a]D21: À 45.4 (c 0.77, toluene)
{lit.[7] [a]D25: À 355 (c 1.0 toluene)}; IR: nmax ˆ 1744, 1699,
1665 cmÀ1; 1H NMR (270 MHz, CDCl3): d ˆ 1.32(s, 3H), 1.85
(ddd, J ˆ 6.2, 13.4, 13.4 Hz, 1H), 2.12 (ddd, J ˆ 2.5, 5.0, 13.4 Hz,
1H), 2.36 2.61 (m, 3H), 2.70 3.04 (m, 3H), 5.98 (d, J ˆ 1.6 Hz,
1H). Its IR and NMR spectra were identical with those
reported previously.[15] Based on the GLC analysis [column,
Supelco BETA DEXTM 225, 30 m  0.25 mm  0.25 mm; flow
rate 50 mL/min; pressure 180 kPa; oven temperature 1608C]:
tR ˆ 58.8 min for (S)-4, 60.8 min for (R)-4, the ee of (R)-4 was
determined to be 15.5%.
(1S,7aS)-10a; yield: 9.8 mg (20%); IR: nmax ˆ 3410, 1669,
1651 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 1.14 (s, 3H), 1.70
1.87 (m, 3H), 2.08 2.19 (m, 2H), 2.21 2.61 (m, 3H), 2.67 2.76
(m, 1H), 3.85 [m, (1S,7aS), 1H], 3.99 [m, (1S,7aR), 1H], 5.79 [s,
(1S,7aS), 1H], 5.91 [s, (1S,7aR), 1H]. Its IR and NMR spectra
were identical with those reported previously.[7] Judging from
the area of signals at d ˆ 3.85 for (1S,7aS)-10a and d ˆ 3.99 for
(1S,7aR)-10a, the de of (1S,7aS)-10a was determined to be
61.8%. The alcohol (1S,7aS)-10a was converted to (S)-4, [a]D23:
‡ 229.2 (c 0.075, toluene). The ee was confirmed to be 63.8%
by GLC analysis as described above.
Preincubation of T. delbrueckii IFO10921
A small portion of yeast cells of T. delbrueckii IFO10921 grown
on the agar-plate culture was aseptically inoculated to aglucose
medium [containing glucose (5.0 g), peptone (2.0 g), yeast
extract (0.5 g), KH2PO4 (0.3 g), K2HPO4 (0.2g), at pH 6.5,
total volume 100 mL] in a 500-mL Erlenmeyer cultivating flask
with two internal projections and then shaken on a gyrorotary
shaker (180 rpm) for 2days at 30 8C. The wet cells were
harvested by centrifugation (3,000 rpm) and washed with
phosphate buffer (0.1 M, pH 6.5). The weight of combined wet
cells was ca. 3 g from 100 mL of the broth.
Reduction of ( Æ )-1,4a-Dimethyl-4,4a,7,8-
tetrahydronaphthalene-2,5(3H,6H)-dione (3)
The combined wet cells of T. delbrueckii IFO10921 (0.6 g)
incubated as described above were resuspended in a reaction
medium [containing glucose (0.2g), phosphate buffer (0.1 M,
pH 6.5), total volume of 10 mL] in a test tube (21 mm  2 0 cm),
together with ( Æ )-3[16] (100 mg, 0.520 mmol) and shaken on a
reciprocal shaker (250 cpm) for 36 h at 308C. The reaction
mixture was filtered through a Celite pad and extracted with
ethyl acetate. The combined organic layer was washed with
saturated aqueous sodium hydrogen carbonate solution and
brine, dried over anhydrous sodium sulfate, and concentrated
under vacuum. The residue was charged on a silica gel column
(13 g). Elution with hexane/ethyl acetate (5/1 to 2/1) afforded
(R)-3; yield: 87.1 mg (87%); [a]D23: À 2.8 (c 0.89, methanol)
{lit.[13] [a]D: À 140 (c 0.200, methanol)}; IR: nmax ˆ 1712, 1665,
1611 cmÀ1; 1H NMR (270 MHz, CDCl3): d ˆ 1.43 (s, 3H), 1.82
Reduction of ( Æ )-4,5-Dihydro-7a-methyl-2H-indene-
2,7(1H,6H)-dione (6)
The enone ( Æ )-6 (50.0 mg, 0.305 mmol) was incubated with
cells (0.3 g) for 18 h 308C. After the work-up, the crude residue
was purified by preparative thin-layer chromatography [de-
veloped with hexane/ethyl acetate (1/1)].
(R)-6; yield: 27.2 mg (54%); [a]D22; ‡ 25.5 (c 0.95, chloro-
form) {lit.[17] [a]20: ‡ 47.3 (c 0.42, chloroform)}; IR: nmax ˆ 1712,
1683, 1623 cmÀ1D; 1H NMR (400 MHz, CDCl3): d ˆ 1.53 (s, 3H),
770
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Enantiomerically Pure Octahydronaphthalenone and Octahydroindenone
FULL PAPERS
1.66 1.79 (m, 1H), 2.14 (d, J ˆ 19.0 Hz, 1H), 2.23 2.31 (m,
1H), 2.42 2.48 (m, 1H), 2.69 2.83 (m, 2H), 2.84 2.90 (m,
1H), 3.20 (d, J ˆ 19.0 Hz, 1H), 5.81 (s, 1H). Its IR and NMR
spectra were identical with those reported previously.[17] Based
on the HPLC analysis [column, Daicel Chiralcel OJ, 0.46 cm Â
25 cm; hexane/2-propanol (48/1); flow rate 0.5 mL/min]: tR ˆ
102.9 min for (S)-6, 112.4 min for (R)-6, the ee of (R)-6 was
determined to be 56.9%.
(3aS,4S)-11a; yield: 23.1 mg (46%); IR: nmax ˆ 3413, 1683,
1618 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 1.23 (s, 3H), 1.33
1.45 (m, 1H), 1.62 2.86 (m, 8H), 3.46 [dd, J ˆ 4.4, 11.2Hz,
(3aS,4S), 1H], 3.90 [br s, (3aR,4S), 1H], 5.83 [d, J ˆ 2.0 Hz,
(3aS,4S), 1H], 5.90 [d, J ˆ 1.5 Hz, (3aR,4S), 1H]. Judging from
the area of signals at d ˆ 3.46 for (3aS,4S)-11a and d ˆ 3.90 for
(3aR,4S)-11a, the de of (3aS,4S)-11a was determined to be
70.2%. The alcohol (3aS,4S)-11a was converted to (S)-6, [a]D22:
À 37.7 (c 0.185, chloroform). The ee was confirmed to be
68.0% by HPLC analysis as described above.
13; yield: 45.4 mg (46%); IR: nmax ˆ 3451, 1742, 1733 cmÀ1;
1H NMR (400 MHz, CDCl3): d ˆ 1.20 (s, 3H), 2.17 2.29 (m,
4H), 2.40 2.49 (m, 2H), 2.55 2.74 (m, 3H); 13C NMR
(100 MHz, CDCl3): d ˆ 15.6, 32.0, 35.3, 46.6, 50.6, 56.4, 82.8,
212.9, 218.1.
Reduction of ( Æ )-Spiro[5.5]undec-7-ene-1,9-dione (8)
Treatment of ( Æ )-8[19] (308 mg, 1.73 mmol) with cells (1.8 g)
for 15 h at 308C, and subsequent purification afforded the
products shown in Scheme 2.
14; yield: 248 mg (80%); IR: nmax ˆ 1704, 1698 cmÀ1;
1H NMR (400 MHz, CDCl3): d ˆ 1.60 1.68 (m, 2H), 1.74
1.82 (m, 4H), 1.87 1.93 (m, 2H), 2.28 2.38 (m, 4H), 2.44
2.52 (m, 4H); 13C NMR (100 MHz, CDCl3): d ˆ 21.1, 28.0, 33.2,
37.7, 38.6, 39.2, 48.0, 211.2, 215.0; anal. calcd. for C11H16O2: C
73.30, H 8.95; found: C 73.16, H 8.75.
15; yield: 30.7 mg (10%); IR: nmax ˆ 3448, 1707 cmÀ1;
1H NMR (400 MHz, CDCl3): d ˆ 1.17 1.63 (m, 8H), 1.69
2.05 (m, 5H), 2.33 (br s, 4H), 3.53 (d, J ˆ 7.8 Hz, 1H);
13C NMR (100 MHz, CDCl3): d ˆ 21.1, 23.2, 27.4, 30.4, 31.2,
34.2, 36.8, 75.4, 212.7.
Reduction of ( Æ )-1-Methylbicyclo[3.3.0]oct-5-ene-
2,7-dione (7)
Treatment of ( Æ )-7 (69.7 mg, 0.464 mmol) with cells (0.4 g) for
18 h at 308C, and subsequent purification afforded the
products shown in Scheme 2.
Reduction of 2-Methyl-2-(3-oxopentyl)-1,3-
cyclohexanedione (19)
(1S,5R)-12; yield: 27.0 mg (38%). A bulb-to-bulb distillation
gave an analytical sample of (1S,5R)-12; bp 110 1208C/2.0
mmHg. This solidified upon standing to give needles, mp 59.0
60.0 8C; [a]2D0: ‡ 144.8 (c 0.67, chloroform); IR: nmax ˆ 1745,
1733 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 1.22 (s, 3H), 1.66
Treatment of 19 (1.03 g, 4.88 mmol) with cells (6.0 g) for 24 h at
308C, and subsequent purification afforded (1S,6S)-20; yield:
578 mg (56%). This was employed for the next step without
further purification. Recrystallization from hexane/ethyl ace-
tate gave an analytical sample of (1S,6S)-20 as needles, mp
ˆ
(ddd, J 8.8, 14.4, 21.6 Hz, 1H), 2.03 2.31 (m, 3H), 2.38 2.53
(m, 3H), 2.56 2.64 (m, 2H); 13C NMR (100 MHz, CDCl3): d ˆ
21.4, 25.0, 36.1, 43.3, 44.2, 46.0, 52.6, 215.7, 219.9; anal. calcd. for
C9H12O2: C 71.03, H 7.95; found: C 71.01, H 7.94.
107.0 108.08C; [a]D20: À 102.0 (c 1.03, chloroform); IR: nmax
ˆ
3490, 1698 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 0.87 (t, J ˆ
7.3 Hz, 3H), 0.93 1.00 (m, 1H), 1.13 (s, 3H), 1.41 1.67 (m,
5H), 1.84 (s, 2H), 1.99 2.28 (m, 4H), 2.40 2.59 (m, 1H), 4.20
(s, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 7.62, 21.3, 24.4, 26.5,
27.4, 29.1, 36.0, 37.9, 47.4, 75.2, 97.3, 214.4; anal. calcd for
C12H20O3: C 67.89, H 9.50; found: C 67.80, H 9.13.
For the determination of the ee of this product by means of
chromatographic method, authentic ( Æ )-(1S*,5R*)-12 was
prepared in the following manner. A mixture of ( Æ )-7, ethanol
and a catalytic amount of palladium on charcoal was vigorously
stirred for 1 h at room temperature under H2. The reaction
mixture was filtered through a Celite pad, and the filtrate was
concentrated under vacuum to afford ( Æ )-(1S*,5R*)-12. The
GLC analysis [column, TCI Chiraldex B-PM, 30 m Â
0.25 mm  0.125 mm; flow rate 50 mL/min; pressure 180 kPa;
oven temperature 1208C]: tR ˆ 86.7 min over 89.7 min. In turn,
an authentic specimen (1R,5S)-12, prepared in the same
manner from (R)-7 coincided with the peak of 86.7 min. The
absolute configuration of 12 of microbial origin was unambig-
uously confirmed to be (1S,5R) and its ee was determined to
be>99.9%.
Reduction of 2-Methyl-2-(3-oxobutyl)-1,3-
cyclopentanedione (21)
Treatment of 21 (1.51 g, 8.29 mmol) with cells (9.0 g) for 24 h at
308C, and subsequent purification afforded the products
shown in Scheme 3.
(1S,6S)-22; yield: 961 mg (63%). This was employed for the
next step without further purification. Recrystallization from
hexane/ethyl acetate gave an analytical sample of (1S,6S)-22 as
needles, mp 61.0 63.08C; [a]D19: ‡ 44.4 (c 1.02, chloroform);
(R)-7; yield: 11.5 mg (16%); [a]D21: À 78.5 (c 0.18, chloro-
form) {lit. [18] [a]2D0: À 104 (c 0.80, chloroform) for (R)-7 (79%
1
1
ee)}; IR: nmax ˆ 1752, 1713, 1634 cmÀ1; H NMR (400 MHz,
IR: nmax ˆ 3490, 1698 cmÀ1; H NMR (400 MHz, CDCl3): d ˆ
CDCl3): d ˆ 1.35 (s, 3H), 2.32 (d, J ˆ 18.1 Hz, 1H), 2.45 (ddd,
J ˆ 8.8, 8.8, 19.2Hz, 1H), 2.60 (d, J ˆ 18.1 Hz, 1H), 2.92 3.17
(m, 3H), 5.97 (s, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 23.3,
24.5, 38.3, 44.7, 56.8, 126.1, 184.6, 207.4, 212.3. Its IR and NMR
spectra were identical with those reported previously.[18] Based
on the HPLC analysis [column, Daicel Chiralcel OJ, 0.46 cm Â
25 cm; hexane/2-propanol (9/1); flow rate 0.5 mL/min]: tR ˆ
46.5 min for (S)-7, 49.4 min for (R)-7, the ee of (R)-7 was
determined to be>99.9%.
0.95 (s, 3H), 1.24 1.33 (m, 1H), 1.35 (s, 3H), 1.60 (ddd, J ˆ 2.4,
2.4, 13.6 Hz, 1H), 1.75 (ddd, J ˆ 4.9, 13.6, 13.6 Hz, 1H), 1.90
2.00 (m, 3H), 2.11 2.20 (m, 1H), 2.34 2.38 (m, 2H), 4.26 (d,
J ˆ 3.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 21.5, 24.5,
25.5, 30.3, 31.8, 33.8, 48.2, 76.8, 95.3, 220.8; anal. calcd for
C10H16O3: C 65.19, H 8.75; found: C 65.46, H 8.79.
24; yield: 205 mg (14%); IR: nmax ˆ 3247, 3168, 1767,
1726 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 1.07 (s, 3H), 1.40
(s, 3H), 1.53 1.88 (m, 5H), 2.53 (dd, J ˆ 7.3, 19.5 Hz, 1H), 2.79
Adv. Synth. Catal. 2003, 345, 766 774
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Ken-ichi Fuhshuku et al.
FULL PAPERS
(d, J ˆ 7.8 Hz, 1H), 3.04 (d, J ˆ 19.5 Hz, 1H). Its IR and NMR
spectra were identical with those reported previously.[20]
(2R,3S)-23a; yield: 105 mg (7%); [a]D19: À 49.4 (c 1.15,
chloroform) {lit.[11] [a]D8 : À 45.4 (c 2.03, chloroform)}; IR:
nmax ˆ 3448, 2968, 1732, 1714 cmÀ1; 1H NMR (400 MHz,
CDCl3): d ˆ 0.98 (s, 3H), 1.67 (ddd, J ˆ 7.3, 7.3, 14.6 Hz, 1H),
1.78 (ddd, J ˆ 7.3, 7.3, 14.6 Hz, 1H), 1.88 (dddd, J ˆ 7.3, 7.3, 9.8,
12.3 Hz, 1H), 2.15 (s, 3H), 2.17 2.31 (m, 2H), 2.42 2.56 (m,
3H), 4.00 (dd, J ˆ 6.3, 6.3 Hz, 1H). Its IR and NMR spectra
were identical with those reported previously.[11]
26.8, 30.8, 33.7, 39.7, 77.7, 130.7, 158.8, 170.3, 198.3; anal. calcd
for C14H20O3: C 71.16, H 8.53; found: C 70.99, H 8.55.
For the confirmation of the absolute configuration of 9b of
microbial origin, an authentic (1R,8aS)-9b was prepared as
described in Scheme 4;[13,14] [a]D19: ‡ 77.0 (c 0.915, chloroform)
for (1R,8aS)-9b. HPLC analysis [column, Daicel Chiralcel OJ,
0.46 cm  25 cm; hexane/2-propanol (9/1); flow rate 0.5 mL/
min]: tR ˆ 31.4 min over 34.5 min. In turn, an authentic
specimen (1R,8aS)-9b showed a major peak at 31.4 min and
that was revealed to be 84.3% ee. The absoluteconfiguration of
9b of microbial origin was unambiguously confirmed to be
(1S,8aR) and its ee was determined to be>99.9%.
(1S,2S)-2-Methyl-3-oxo-2-(3-oxopentyl)cyclohexyl
Acetate (27)
(1S,2S)-2-Methyl-3-oxo-2-(3-oxobutyl)cyclopentyl
Acetate (23b)
A mixture of (1S,6S)-20 (263 mg, 1.24 mmol), anhydrous
pyridine (4 mL), acetic anhydride (4 mL), and a catalytic
amount of 4-dimethylaminopyridine was stirred for 16 h at
room temperature. The reaction mixture was poured into
water and extracted with ethyl acetate. The combined organic
layer was washed with 6 M hydrochloric acid, water, saturated
aqueous sodium hydrogen carbonate solution and brine, dried
over anhydrous sodium sulfate, and concentrated under
vacuum. The residue was charged on a silica gel column
(10 g). Elution with hexane/ethyl acetate (4/1 to 2/1) afforded
(1S,2S)-27; yield: 308 mg (98%). This was employed for the
next step without further purification. A bulb-to-bulb distil-
lation gave an analytical sample of (1S,2S)-27 as an oil, bp 170
A mixture of (1S,6S)-22 (305 mg, 1.66 mmol), anhydrous
pyridine (4 mL), acetic anhydride (3 mL), and a catalytic
amount of 4-dimethylaminopyridine was stirred for 24 h at
room temperature. The extraction and work-up were per-
formed as described above. The residue was charged on a silica
gel column (20 g). Elution with hexane/ethyl acetate (4/1 to 1/
2) afforded (1S,2S)-23b; yield: 371 mg (99%). This was
employed for the next step without further purification.
Recrystallization from hexane/ethyl acetate gave an analytical
sample of (1S,2S)-23b as needles, mp 76.5 77.58C; [a]D28:
‡ 51.9 (c 1.08, chloroform); IR: nmax ˆ 1731, 1706, 1245 cmÀ1;
1H NMR (400 MHz, CDCl3): d ˆ 1.03 (s, 3H), 1.70 (ddd, J ˆ
5.0, 5.0, 19.5 Hz, 1H), 1.88 (ddd, J ˆ 5.0, 5.0, 15.2Hz, 1H),
1.97 2.05 (m, 1H), 2.07 (s, 3H), 2.13 (s, 3H), 2.24 2.49 (m,
4H), 2.57 (ddd, J ˆ 5.9, 10.3, 17.6 Hz, 1H), 5.11 (dd, J ˆ 5.1,
5.1 Hz, 1H); 13C NMR (100 MHz, CDCl3): d ˆ 19.5, 21.1, 24.3,
25.3, 30.1, 34.4, 37.9, 50.9, 79.1, 170.2, 207.8, 218.3; anal. calcd
for C12H18O4: C 63.70, H 8.02; found: C 63.83, H 8.06.
1808C/2.0 mmHg; [a]D20: ‡ 40.8 (c 1.12, chloroform); IR: nmax
ˆ
1738, 1712, 1235 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ 1.02(t,
J ˆ 7.3 Hz, 3H), 1.07 (s, 3H), 1.63 1.71 (m, 1H), 1.80 (ddd, J ˆ
5.4, 5.4, 15.2 Hz, 1H), 1.90 2.13 (m, 7H), 2.15 2.24 (m, 1H),
2.27 2.42 (m, 5H), 4.85 (dd, J ˆ 3.4, 7.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3): d ˆ 7.9, 19.1, 20.5, 21.1, 25.7, 25.9, 36.1,
36.3, 37.5, 52.1, 78.2, 170.0, 210.6, 212.0; anal. calcd for
C14H22O4: C 66.12, H 8.72; found: C 66.05, H 8.77.
(1S,7aR)-2,3,5,6,7,7a-Hexahydro-7a methyl-5-oxo-
1H-indenyl Acetate (10b)
(1S,8aR)-1,2,3,4,6,7,8,8a-Octahydro-5,8a dimethyl-6-
A mixture of (1S,2S)-23b (191 mg, 0.844 mmol), benzene
(15 mL), and a catalytic amount of p-toluenesulfonic acid
was stirred under reflux for 77 h with azeotropic removal of
water. The extraction and work-up were performed as
described above. The residue was charged on a silica gel
column (20 g). Elution with hexane/ethyl acetate (4/1 to 1/1)
afforded (1S,7aR)-10b; yield: 124 mg (71%). A bulb-to-bulb
distillation gave an analytical sample of (1S,7aR)-10b as an oil,
bp 1508C/2.0 mmHg; [a]D27: À 5.5 (c 1.11, chloroform); IR:
nmax ˆ 1741, 1671, 1241 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ
1.20 (s, 3H), 1.71 (ddd, J ˆ 2.0, 5.4, 13.2 Hz, 1H), 1.89 (ddd, J ˆ
4.0, 8.4, 15.0 Hz, 1H), 2.03 (s, 3H), 2.04 2.11 (m, 1H), 2.25
2.42 (m, 2H), 2.52 (ddd, J ˆ 5.4, 14.4, 17.8 Hz, 1H), 2.64 (ddd,
J ˆ 1.7, 8.5, 19.5 Hz, 1H), 2.70 2.76 (m, 1H), 5.04 (d, J ˆ
4.9 Hz, 1H), 5.86 (s, 1H); 13C NMR (100 MHz, CDCl3): d ˆ
21.1, 21.7, 28.3, 28.5, 28.8, 33.0, 46.7, 81.3, 122.8, 170.2, 174.6,
198.5; anal. calcd for C12H16O4: C 69.21, H 7.74; found: C 68.95,
H 7.74.
oxonaphthyl Acetate (9b)
A mixture of (1S,2S)-27 (191 mg, 0.750 mmol), benzene
(15 mL), and a catalytic amount of p-toluenesulfonic acid
was stirred under reflux for 10 h with azeotropic removal of
water. The reaction mixture was poured into saturated
aqueous sodium hydrogen carbonate solution and extracted
with ethyl acetate. The combined organic layer was washed
with water and brine, dried over anhydrous sodium sulfate, and
concentrated under vacuum. The residue was charged on a
silica gel column (12g). Elution with hexane/ethyl acetate (4/1
to 2/1) afforded (1S,8aR)-9b; yield: 147 mg (83%). This was
employed for the next step without further purification.
Recrystallization from hexane/ethyl acetate gave an analytical
sample of (1S,8aR)-9b as needles, mp 78.0 78.58C; [a]D21:
À 90.2( c 1.00, chloroform) {lit.[12] [a]D30: À 79(c 1.4, chloroform)
for (1S,8aR)-9b}; IR: nmax ˆ 1726, 1664, 1606, 1243 cmÀ1;
1H NMR (400 MHz, CDCl3): d ˆ 1.28 (s, 3H), 1.46 (ddd, J ˆ
3.3, 5.2, 13.3 Hz, 1H), 1.63 1.77 (m, 3H), 1.79 (s, 3H), 1.84
2.01 (m, 1H), 2.04 (m, 3H), 2.11 2.20 (m, 2H), 2.41 2.55 (m,
2H), 2.73 2.79 (m, 1H), 4.80 (dd, J ˆ 2.9, 2.9 Hz, 1H);
13C NMR (100 MHz, CDCl3): d ˆ 11.3, 20.1, 21.3, 22.2, 25.6,
For the determination of the absolute configuration of 10b
of microbial origin, an authentic (1R,7aS)-10b was prepared as
described in Scheme 5;[14,15] [a]D20: ‡ 9.5 (c 0.18, chloroform) for
(1R,7aS)-10b. HPLC analysis [column, Daicel Chiralcel OJ,
003 WI7L7E2¹Y-2VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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Enantiomerically Pure Octahydronaphthalenone and Octahydroindenone
FULL PAPERS
0.46 cm  25 cm; hexane/2-propanol (15/1); flow rate 0.5 mL/
min]: tR ˆ 62.5 min over 72.3 min. In turn, an authentic
specimen (1R,7aS)-10b showed a major peak at 62.5 min and
that was revealed to be 98.1% ee. The absolute configuration of
10b of microbial origin was unambiguously confirmed to be
(1S,7aR) and its ee was determined to be>99.9%.
(1S,2R)-2-Methyl-3-oxo-2-(3-oxobutyl)cyclopentyl
Acetate (23b)
A mixture of (2R,3S)-23a (31.3 mg, 0.169 mmol), anhydrous
pyridine (1 mL), and acetic anhydride (1.5 mL) was stirred for
12h at room temperature. The extraction and work-up were
performed as described above. The residue was purified by
preparative thin-layer chromatography [developed with hex-
ane/ethyl acetate (1/1)] to afford (1S,2R)-23b; yield: 29.0 mg
(quant.). This was employed for the next step without further
purification. [a]D22: ‡ 11.1 (c 1.45, chloroform) {lit.[11] [a]D27:
‡ 10.3 (c 3.58, chloroform)}; IR: nmax ˆ 1737, 1716, 1243 cmÀ1;
1H NMR (400 MHz, CDCl3): d ˆ 0.97 (s, 3H), 1.66 (ddd, J ˆ 5.6,
Figure 2. [A] Air-drier; [B] plastic bag; [C] cell suspension
in a sprayer.
9.0, 14.4 Hz, 1H), 1.77 (ddd, J ˆ 5.9, 9.0, 14.6 Hz, 1H), 1.90
2.07 (m, 1H), 2.06 (s, 3H), 2.13 (s, 3H), 2.27 2.46 (m, 4H), 2.55
(ddd, J ˆ 5.9, 9.1, 17.9 Hz, 1H), 5.18 (dd, J ˆ 4.4, 4.4 Hz, 1H). Its
IR and NMR spectra were identical with those reported
previously.[11]
domestic air-drier [A] for clothes (358C) was connected to a
plastic bag [B], and the cell suspension [C] was sprayed inside
and then dried. The cells were exposed to warm and dry air at
358C overnight, to give air-dried cells (ca. 6 g).
Freeze-drying: The wet cells of T. delbrueckii IFO10921
(15 g), skim milk (10 g) and glycerol (0.6 g) were resuspended
in 50 mL of phosphate buffer (0.1 M, pH 6.5) at 08C. After
stirring for 30 min at 08C, the suspension was frozen by
immersion in liquid N2, and then lyophilized at 0.03 torr
overnight to give freeze-dried cells (ca. 13 g).
Oven-drying: The wet cells of T. delbrueckii IFO10921 (9 g)
were resuspended in 20 mL of phosphate buffer (0.1 M,
pH 6.5) at 08C. The thick suspension was spread on a silicone-
coating cooking sheet in an as thin film as possible. This was
dried on an electric hot plate for 15 min at 808C to give oven-
dried cells (ca. 6 g).
(1S,7aS)-2,3,5,6,7,7a-Hexahydro-7a methyl-5-oxo-
1H-indenyl Acetate (10b)
A mixture of (1S,2R)-23b (23.1 mg, 0.102 mmol), benzene
(10 mL), and a catalytic amount of p-toluenesulfonic acid was
stirred under reflux for 48 h with azeotropic removal of water.
The extraction and work-up were performed as described
above. The residue was purified by preparative thin-layer
chromatography [developed with hexane/ethyl acetate (1/1)]
to afford (1S,7aS)-10b; yield: 16.9 mg (79%); [a]2D0: ‡ 28.7 (c
0.86, chloroform) {lit.[11] [a]D29: ‡ 28.6 (c 3.67, chloroform)}; IR:
nmax ˆ 1739, 1670, 1240 cmÀ1; 1H NMR (400 MHz, CDCl3): d ˆ
1.18 (s, 3H), 1.82 1.92 (m, 2H), 2.23 (ddd, J ˆ 2.4, 5.4, 13.1 Hz,
ˆ
1H), 2.09 (s, 3H), 2.24 2.54 (m, 4H), 2.76 (dddd, J 2.4, 2.4,
11.7, 19.5 Hz, 1H), 4.80 (dd, J ˆ 7.8, 9.8 Hz, 1H), 5.80 (s, 1H). Its
IR and NMR spectra were identical with those reported
previously.[11] Based on the HPLC analysis [column, Daicel
Chiralcel OJ, 0.46 cm  25 cm; hexane/2-propanol (9/1); flow
rate 0.4 mL/min]: tR ˆ 33.5 min for (1S,7aS)-10b, 35.8 min for
(1R,7aR)-10b, the ee of (1S,7aS)-10b was determined to
be>99.9%.
Typical Procedure of Reduction with Air-Dried Cells
A mixture of 21 (100 mg, 0.548 mmol), glucose (0.2g), air-
dried cells (1.0 g), and phosphate buffer (0.1 M, pH 6.5),
(10 mL) was shaken on a reciprocal shaker (250 cpm) in a test
tube for 20 h at 308C, and subsequent purification afforded the
product (1S,6S)-22; yield: 52.1 mg (51%). The ee of (1S,6S)-22
was confirmed to be 99.8% according to the method as
described before. Other results are summarized in Table 4.
Method of Preparation of Long-Term Preservable
Cells
Acknowledgements
Air-drying: The incubation of T. delbrueckii IFO10921 was
performed as described above. The freshly harvested wet cells
(9 g) were resuspended in 20 mL of phosphate buffer (0.1 M,
pH 6.5). The cell suspension was added to a solution of a
commercially available skim milk (6 g) in 10 mL of phosphate
buffer (0.1 M, pH 6.5) at 08C. The suspension was further
stirred for 30 min at 08C, and then sprayed into a balloon,
which was connected with an air-drier as shown in Figure 2. A
The authors thank Professor Susumu Kobayashi of Science
University of Tokyo and Dr. Ken-ichi Takao of Keio University
for their interests. This work was supported both by a Grant-in-
Aid for Scientific Research (No. 14560084) and the 21st Century
COE Program(KEIO LCC) fromthe Ministry of Education,
Culture, Sports, Science, and Technology, Japan, and acknowl-
edged with thanks.
Adv. Synth. Catal. 2003, 345, 766 774
asc.wiley-vch.de
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
773

Ken-ichi Fuhshuku et al.
FULL PAPERS
[7] H. Hioki, T. Hashimoto, M. Kodama, Tetrahedron
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[3] For recent examples from (S)-1, see: a) S. J. Danishefsky,
J. J. Masters, W. B. Young, J. T. Link, L. B. Snyder, T. V.
Magee, D. K. Jung, R. C. A. Isaacs, W. G. Bornmann,
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