Preparation of all stereoisomers of 2-allyl-2-methyl-3-hydroxycyclopentanone by desymmetric processes based on a microbial oxidation and reduction system

Article abstract of DOI:10.1016/j.tetlet.2009.06.080

All stereoisomers of 2-allyl-3-hydroxy-2-methylcyclopentanones 2-5 were prepared in high conversion and in an optically pure form by microbial reduction and oxidation. The reduction of symmetric diketone 1 by Geotrichum candidum NBRC 4597 under anaerobic conditions gave 2 in 83% yield (98% conversion), >99% de, and >99% ee, whereas the reduction of 1 by G. candidum NBRC 5767 under aerobic conditions gave 3 in 75% yield (99% conversion), >99% de, and >99% ee. Oxidation of meso-diol 6 by G. candidum NBRC 5767 under aerobic conditions afforded 4 in 83% yield (99% conversion) and >99% ee, while oxidation of meso-diol 7 by Mucor heimalis IAM 6095 in the presence of cyclohexanone as a co-oxidant afforded 5 in 68% yield (75% conversion) and >99% ee.

Full text of DOI:10.1016/j.tetlet.2009.06.080

Tetrahedron Letters 50 (2009) 4941–4944
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Preparation of all stereoisomers of 2-allyl-2-methyl-3-hydroxycyclopentanone
by desymmetric processes based on a microbial oxidation and reduction system
b
a
b
Mikio Fujii a, , Minoru Takeuchi , Hiroyuki Akita , Kaoru Nakamura
*
a Faculty of Pharmaceutical Sciences, Toho University, 2-2-1 Miyama, Funabashi, Chiba 247-8510, Japan
b Institute for Chemical Research, Kyoto University, Uji, Kyoto 611-0001, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
All stereoisomers of 2-allyl-3-hydroxy-2-methylcyclopentanones 2–5 were prepared in high conversion
and in an optically pure form by microbial reduction and oxidation. The reduction of symmetric diketone
1 by Geotrichum candidum NBRC 4597 under anaerobic conditions gave 2 in 83% yield (98% conversion),
>99% de, and >99% ee, whereas the reduction of 1 by G. candidum NBRC 5767 under aerobic conditions
gave 3 in 75% yield (99% conversion), >99% de, and >99% ee. Oxidation of meso-diol 6 by G. candidum NBRC
5767 under aerobic conditions afforded 4 in 83% yield (99% conversion) and >99% ee, while oxidation of
meso-diol 7 by Mucor heimalis IAM 6095 in the presence of cyclohexanone as a co-oxidant afforded 5 in
68% yield (75% conversion) and >99% ee.
Received 25 May 2009
Revised 13 June 2009
Accepted 16 June 2009
Available online 18 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
reversibly but the R-enzyme afforded the R-alcohol irreversibly.5
Since oxygen in air enhanced the oxidation of the S-alcohol, the
Stereoselective and regioselective reduction of 2,2-dialkylcy-
cloalkane-1,3-diones such as 2-allyl-2-methylcyclopentane-1,3-
dione 1 is a useful method for the preparation of optically active
compounds possessing a chiral quaternary carbon.1 Desymmetriza-
tion of the meso compound allows 100% yield of the optically pure
compound, while optical resolution gives only 50% yield.2 Bakers’
yeast reduction of 2,2-dialkylcycloalkane-1,3-dione is recognized
as a valuable approach for accessing highly optically active 2,2-dial-
kyl-3-hydroxycycloalkanones through desymmetrization. For
example, bakers’ yeast reduction of 1 was reported to afford
(2S,3S)-2-allyl-3-hydroxy-2-methylcyclopentanone 2 and (2R,3S)-
2-allyl-3-hydroxy-2-methylcyclopentanone 3 in 75% yield as a dia-
stereomeric mixture with 80% de (2:3 = 9:1).3 Optically pure 2 is a
chiral synthon for coriolin, possessing antibacterial and antitumor
activities (Scheme 1).3b
We have reported that a single microbe afforded both enantio-
mers of a secondary alcohol stereoselectively by changing the reac-
tion conditions.4 Oxygen concentration in the reaction atmosphere,
for example, changes the stereochemical course of microbial
reduction (Scheme 2). Under anaerobic conditions, reduction of
acetophenone by Geotrichum candidum NBRC 5767 afforded (S)-
1-phenylethanol in 98% yield and >99% enantiomeric excess (ee).
In contrast, the reduction of ketone by G. candidum NBRC 5767
under aerobic conditions afforded (R)-1-phenylethanol in 99%
yield and >99% ee, this phenomenon is possibly due to deracemiza-
tion as shown in Scheme 2.4a The S-enzyme afforded the S-alcohol
S-alcohol produced by the reduction was re-oxidized to ketone in
aerobic conditions, and finally the R-alcohol accumulated through
irreversible reduction. In anaerobic conditions, oxidation of the
S-alcohol was inhibited, and the faster reaction affording the
S-alcohol was dominant. This procedure was considered useful
for providing several enantiomers by only changing the reaction
conditions. In this work we attempted to prepare an optically pure
chiral synthon 2 of coriolin and its stereoisomers 3-5 using a
microbial oxidation and reduction system (Fig. 1).
Compound 1wasreducedundernormalconditionsbyG.candidum
NBRC 5767 to obtain 2 in 92% conversion with 76% diastereomeric
excess (de) (Table 1, entry 1). To control the diastereose-
lectivity of microbial reduction, a reduction system using XAD-7
under anaerobic conditions was employed (Table 1, entry 2).6 How-
ever, the de of 2 decreased to 8%. Thus reduction under anaerobic con-
ditions gave 2 in 80% conversion, 80% de, and >99% ee together with
the minor stereoisomer 3 (>99% ee) (Table 1, entry 3). High diastere-
oselectivity and excellent enantioselectivity were observed on the
Bakers' yeast
O
O
+
O
OH
HO
O
75% yield
2
3
1
>99% ee
>99% ee
9 : 1
* Corresponding author. Tel./fax: +81 47 472 1825.
E-mail address: mfujii@phar.toho-u.ac.jp (M. Fujii).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.080

4942
M. Fujii et al. / Tetrahedron Letters 50 (2009) 4941–4944
OH
aerobic conditions
G. candidum 5767
O
OH
anaerobic conditions
G. candidum 5767
XAD-7
(R)-1-phenylethanol
99% yield, >99% ee
(S)-1-phenylethanol
98% yield, >99% ee
aerobic conditions
activation
OH
O
OH
inhibition
anaerobic conditions
proposed reaction path
Scheme 2.
G. candidum 5767
OH
G. candidum 5767
O
O
O
HO
O
O
OH
HO
O
HO
O
O
OH
1
2
3
2 (2S,3S)
3 (2R,3S)
4 (2R,3R)
5 (2S,3R)
100
80
Figure 1. Four stereoisomers of 2-allyl-3-hydroxy-2-methylcyclopentanone (2–5).
1
: 2
: 3
:
reduction of 1 by G. candidum NBRC 5767. It was found that the
obtained 2 was the same major stereoisomer as that of bakers’ yeast
reduction. Onthe otherhand, the reduction inaerobicconditionsgave
3 in 95% conversion with 98% de and 99% ee (Table 1, entry 4). The
reduction by G. candidum NBRC 5767 has been found to afford two
stereoisomers by changing only reaction atmosphere.4 The time
course of the reaction under aerobic conditions is shown in Figure 2.
Initially, reduction of 1 by G. candidum NBRC 5767 under aerobic con-
ditions afforded 2 dominantly over 3, the degree of conversion of 2
reached 60% after 6 h, and reduced with increasing reaction time.
The degree of conversion of 3 transiently increased and reached 98%
after 40 h. In order to improve the diastereoselectivity of the reduc-
tion affording2, another strainG. candidumNBRC4597 wasemployed
for the reduction of 1 to afford 2 in 98% conversion with 99% de and
>99% ee (Table 1, entry 5). Finally, we succeeded in the preparation
of 2 and 3 in high yield with satisfactory stereoselectivities. The high
stereoselectivity of the reduction system under aerobic conditions
was due to the high stereoselectivity of oxidation.6 Moreover, the
60
40
20
0
30
0
10
20
Time(h)
40
Figure 2. Time course of the reduction of 1 by G. candidum 5767 under aerobic
conditions.
enzyme catalyzing oxidation of 2 recognized the chirality of the adja-
cent quaternary carbon at the 2-position of 2.
Table 1
Stereochemical control on reduction of 1 by G. candidum
G. candidum
O
O
+
O
OH
HO
O
1
2
3
Entry
Microbe
Conditions
Conv. (%)
de (%)
ee (%) (2)
ee (%) (3)
1
2
3
4
5
G. candidum NBRC 5767
G. candidum NBRC 5767
G. candidum NBRC 5767
G. candidum NBRC 5767
G. candidum NBRC 4597
92
54
80
95
98
76 (2)
8 (2)
80 (2)
98 (3)
>99 (2)
>99
>99
>99
—
>99
>99
>99
>99
>99
Ar, XAD-74
Ar4
a
Aerobic4
Ar4
b
—
Conditions: see Ref. 4 (reaction time: 24 h.).
GC analysis: after acetylation of products treated with acetic anhydride and pyridine, GC analysis was performed (Chirasil-DEX CB, 110 °C, 0.25 mm  25 m, Ar: 2 mL/min).
Retention time: 2-acetate; 23.3 min, 5-acetate; 24.4 min, 4-acetate; 22.3 min, 3-acetate; 19.8 min.
a
Compound 5 was not observed.
Compound 4 was not observed.
b

M. Fujii et al. / Tetrahedron Letters 50 (2009) 4941–4944
4943
anaerobic conditions
G. candidum
G. candidum 5767
aerobic conditions
HO
O
O
OH
O
O
3
1
2
G. candidum 5767
80% conv., 80% de, >99% ee
99% conv., 75% yield,
>99% de, >99% ee
G. candidum 4597
98% conv., 83% yield,
>99% de, >99% ee
G. candidum 5767
G. candidum 5767
HO
OH
HO
O
HO
OH
O
OH
aerobic conditions
aerobic conditions
99% conv.
83% yield
6
5
4
7
99% yield, >99% ee
Scheme 3.
Reduction on a preparative scale was performed under both
conditions. Reduction of 1 under anaerobic conditions gave 2 in
83% isolated yield and >99% ee (Scheme 3).7 As with the reduction
of 1 by G. candidum NBRC 5767 under anaerobic conditions, a pro-
longed reaction time was employed and 3 was obtained in 75%
isolated yield (99% conv.) with >99% de and >99% ee.8
although alcohols possessing the (2S,3S) configuration, such as 2
and 6, were oxidized by G. candidum NBRC 5767, alcohols possess-
ing the (2R,3S) configuration, such as 3 and 7, could not be oxidized
by G. candidum NBRC 5767.
The ability of several microbes to afford 5 selectively was tested
(Table 2). Mucor heimalis IAM 6095 (entry 5) had comparatively
higher activity in affording 5 than the other microbes tested. In
our experience, oxidation of secondary alcohols by Mucor species
is not promoted by aerobic conditions. Thus, a biphasic system
using cyclohexanone as a co-oxidant in a water–hexane co-solvent
system was applied to the oxidation of 7 to enhance oxidation.11
The addition of 45 mM cyclohexanone to the reaction system
increased the conversion rate of 7 into 5 to 45% (entry 8). The addi-
tion of 90 mM cyclohexanone further increased the conversion rate
up to 75% (entry 9), and optically pure 5 was isolated in 68%
yield.12
In summary, we demonstrated a microbial oxidation and
reduction system affording four different isomers of 2-allyl-3-hy-
droxy-2-methylcyclopentanones 2–5 in high conversion and in
an enantiomerically pure form (Scheme 4). Moreover, by changing
the reaction conditions, the reduction of 1 by G. candidum NBRC
5767 afforded two stereoisomers (2 and 3) and the oxidation of 6
by G. candidum NBRC 5767 under aerobic conditions afforded 4
(Scheme 3). In our previous study,4,5 reversible reductases, S-en-
Next we attempted to obtain the other stereoisomers of 2.
Stereoselective and regioselective oxidation of meso-diols, such
as (1R,2S,3S)-2-allyl-2-methylcyclopentane-1,3-diol (6) and
(1R,2R,3S)-2-allyl-2-methylcyclopentane-1,3-diol (7), are also
desymmetrization processes capable of producing optically active
4 and 5 in high yield. For the preparation of meso-diol substrates,
1 was reduced by excess NaBH4 to afford 6 (31%), racemic
*
*
(1S ,3S )-2-allyl-2-methylcyclopentane-1,3-diol (41%), and
7
(15%).9
The oxidation of 6 by G. candidum NBRC 5767 under aerobic
conditions afforded 4 in 99% conversion (83% isolated yield)10 with
>99% ee; further oxidation to diketone 1 was not observed. We suc-
ceeded in affording three stereoisomers (2, 3, and 4) in high yield
and high ee using G. candidum (Scheme 3). Stereoselective oxida-
tion of 7 by G. candidum NBRC 5767 as a pathway to 5 was unsuc-
cessful. In the reduction of 1, the enzyme catalyzing the oxidation
of the alcohol appears to recognize the stereochemistry at the
2-position, leading to the oxidation of 7 to afford 5. That is,
Table 2
Screening of microbes to afford 5
Microbe
HO
OH
O
OH
HO
O
+
7
5
3
Entry
Microbe
Conditions
Conv. (%)
ee (%)
1
2
3
4
5
6
7
8
9
G. candidum NBRC 5767
G. candidum NBRC 4597
G. candidum ATCC 34614
M. javanicus IAM 6101
M. heimalis IAM 6095
A. niger IAM 4091
D. magnusii NBRC 4600
M. heimalis IAM 6095
M. heimalis IAM 6095
Aerobic4,5
Aerobic4,5
Aerobic4,5
Aerobic4,5
Aerobic4,5
Aerobic4,5
Aerobic4,5
0
7
3
13
17
0.4
3
45
75
—
38 (3)
4 (3)
>99a (5)
>99a (5)
>99a (5)
>99a (5)
>99a (5)
>99a (5)
Cyclohexanone: 45 M11
Cyclohexanone: 90 M11
Conditions: see Refs. 4 and 5 for entries 1–7 and Ref. 11 for entries 8 and 9 (reaction time: 3 d).
a
Compound 3 was not observed.

4944
M. Fujii et al. / Tetrahedron Letters 50 (2009) 4941–4944
anaerobic conditions
G. candidum 4597
aerobic conditions
G. candidum 5767
O
OH
O
O
HO
O
99% conv.
75% yield
98% conv.
83% yield
3
2
1
>99% de, >99% ee
>99% de, >99% ee
G. candidum 5767
M. heimalis 6095
cyclohexanone
HO
OH
HO
O
HO
OH
O
OH
aerobic conditions
99% conv.
83% yield
75% conv.
68% yield
6
4
7
5
>99% ee
>99% ee
Scheme 4.
Iwamoto, M.; Nakada, M. J. Org. Chem. 2005, 70, 4652–4658; (h) Fujieda, S.;
Tomita, M.; Fuhshuku, K.; Ohba, S.; Nishiyama, S.; Sugai, T. Adv. Synth. Catal.
2005, 347, 1099–1109.
zymes, affording S-alcohols, and irreversible reductases, R-en-
zymes, were involved in the reaction to afford both enantiomers
independently under different conditions. This work has found that
the reversible reductase affording the S-alcohol recognizes the
(2S,3S)-configuration of 2 and irreversible S-enzymes affording 3
are involved in the reaction. In fact, S-enzymes possessing different
stereoselectivities on the reduction of ethyl 2-methyl-3-oxobut-
anoate have been reported.13 Normally, a single microbe could
not afford different isomers in high enantio- and diastereoselectiv-
ity. However the unique enantio- selective and diastereoselective
oxidase in G. candidum was able to afford three isomers in high
enantio- and diastereoselectivity. Application of the reversibility
of the enzyme is a useful method for the preparation of optically
active compounds in high yield.
3. (a) Brooks, D. W.; Mazdiyasni, H.; Grothaus, P. G. J. Org. Chem. 1987, 52, 3223–
3232; (b) Brooks, D. W.; Grothaus, P. G.; Irwin, W. L. J. Org. Chem. 1982, 47,
2820–2821; (c) Brooks, D. W.; Grothaus, P. G.; Palmer, J. T. Tetrahedron Lett.
1982, 23, 4187–4190.
4. (a) Nakamura, K.; Takenaka, K.; Fujii, M.; Ida, Y. Tetrahedron Lett. 2002, 43,
3629–3631; (b) Nakamura, K.; Fujii, M.; Ida, Y. In Asymmetric Reduction of
Ketones: Synthesis of Both Enantiomers of 1-Phenylethanol by Reduction of
Acetophenone with Geotrichum candidum IFO 5767; Roberts, S. M., Ehittall, J.,
Eds.; Catalysts for Fine Chemical Synthesis; John Wiley: New York, 2007; Vol. 5,
pp 93–97.
5. Nakamura, K.; Fujii, M.; Ida, Y. J. Chem. Soc., Perkin Trans. 1 2000, 3205–3211.
6. Nakamura, K.; Fujii, M.; Ida, Y. Tetrahedron: Asymmetry 2001, 12, 3147–
3153.
7. Compound 2: From 1 (300 mg, 1.97 mmol) to (2S,3S)-2 (255 mg, 1.66 mmol,
83%, >99% ee); [
a] [a] +80.7 (c 0.4, CHCl3). IR
+106.2 (c 0.43, CHCl3), lit.3a
D D
(neat) ;
m
: 3457, 1730, 1640 cmÀ1 1H NMR (CDCl3, 200 MHz): d 0.97 (s, 3H),
1.70–2.56 (m, 7H), 3.98–4.14 (m, 1H), 5.01–5.18 (m, 2H), 5.76–5.95 (m, 1H);
13C NMR (CDCl3, 50 MHz); d 19.6, 27.7, 34.0, 35.3, 53.2, 77.3, 118.1, 134.3,
221.0; Anal. Calcd for C9H14O2: C, 70.10; H, 9.15. Found: C, 69.89; H. 9.15.
8. Compound 3: From 1 (100 mg, 0.64 mmol) to (2R,3S)-3 (76 mg, 0.49 mmol,
References and notes
1. (a) Gibian, H.; Kieslich, K.; Koch, H. J.; Kosmol, H.; Rufer, C.; Schroeder, E.;
Voessing, R. Tetrahedron Lett. 1966, 21, 2321–2330; (b) Schwarz, S.;
Truckenbrodt, G.; Meyer, M.; Zepter, R.; Weber, G.; Carl, C.; Wentzke, M.;
Schick, H.; Welzel, H. P. J. Prakt. Chem. 1981, 323, 729–736; (c) Brooks, D. W.;
Grothaus, P. G.; Mazdiyasni, H. J. Am. Chem. Soc. 1983, 105, 4472–4473; (d)
Kitahara, T.; Miyake, M.; Kido, M.; Mori, K. Tetrahedron: Asymmetry 1990, 1,
775–782; (e) Katoh, T.; Mizumoto, S.; Fudesaka, M.; Nakashima, Y.; Kajimoto,
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75%, >99% ee); [
a
]
À81.0 (c 0.59, CHCl3), lit.3a
[a
]
D
À86.5 (c 0.26, CHCl3); IR
D
(neat)
m
: 3434, 1732, 1640 cmÀ1 1H NMR (CDCl3, 200 MHz): d 0.98 (s, 3H),
;
1.78–1.194 (m, 1H) 2.01–2.50 (m, 6H), 4.48 (t, 1H, J = 6.4 Hz), 5.01–5.14 (m,
2H), 5. 26–5.83 (m, 1H); 13C NMR (CDCl3, 50 MHz): d 15.0, 27.5, 34.9, 39.7, 53.0,
75.2, 118.7, 133.5, 220.2; Anal. Calcd for C9H14O2: C, 70.10; H, 9.15. Found: C,
69.94; H. 9.09.
9. Gaultieri, F.; Melchiorre, C.; Giannella, M.; Pigini, M. J. Org. Chem. 1975, 40,
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10. Compound 4: From (1R,2R,3S)-6 (100 mg, 0.64 mmol) to (2R,3R)-4 (81 mg,
0.53 mmol, 83%, >99% ee). [
a
]
À105.0 (c 0.58, CHCl3). Spectral data including
D
1H NMR and 13C NMR were identical to those of 2.
11. Nakamura, K.; Inoue, Y.; Matsuda, T.; Misawa, I. J. Chem. Soc., Perkin Trans. 1
1999, 2397–2402.
2. (a) Urdiales, E. G.; Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105, 313–354; (b)
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2663–2665; (d) Iriuchijima, S.; Hasegawa, K.; Tsuchihashi, G. Agric. Biol. Chem.
12. Compound 5: From (1R,2R,3S)-7 (120 mg, 0.77 mmol) to (2R,3R)-5 (80 mg,
}
0.52 mmol, 68%, >99% ee). [a] H
D +85.4 (c 0.58, CHCl3). Spectral data including 1
1982, 46, 1907–1910; (e) Bjorkling, F.; Boutelje, J.; Gatenbeck, S.; Hult, K.;
Norin, T.; Szmulik, P. Tetrahedron 1985, 41, 1347–1352; (f) Schneider, M.; Engel,
N.; Boensmann, H. Angew. Chem., Int. Ed. Engl. 1984, 23, 66; (g) Watanabe, H.;
NMR and 13C NMR were identical to those of 3.
13. Kawai, Y.; Kawanobe, K.; Ohno, A. Bull. Chem. Soc. Jpn. 1997, 70, 1683–1686.