A new and efficient chemoenzymatic route to both enantiomers of α′-acetoxy and α′-hydroxy-α-methoxy cyclic enones

Article abstract of DOI:10.1016/j.tetasy.2006.01.025

A chemoenzymatic synthesis of both enantiomers of the pharmacologically interesting α′-acetoxy and α′-hydroxy-α-methoxy cyclic enones starting from α-hydroxy cyclic enones is described. Protection of 1,2-diketones, manganese(III) acetate-mediated acetoxyl

Full text of DOI:10.1016/j.tetasy.2006.01.025

Tetrahedron: Asymmetry 17 (2006) 786–791
A new and efficient chemoenzymatic route to both enantiomers of
a0-acetoxy and a0-hydroxy-a-methoxy cyclic enones
Ayhan S. Demir,a,* Zerrin Caliskan,a,b A. Ebru Aydinc and Isil Bicera
aDepartment of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
bDepartment of Biology, Yildiz Technical University, 34010 Davutpasa, Istanbul, Turkey
cDepartment of Chemistry, Mustafa Kemal University, 31040 Hatay, Turkey
Received 4 January 2006; accepted 24 January 2006
Available online 23 February 2006
Abstract—A chemoenzymatic synthesis of both enantiomers of the pharmacologically interesting a0-acetoxy and a0-hydroxy-a-
methoxy cyclic enones starting from a-hydroxy cyclic enones is described. Protection of 1,2-diketones, manganese(III) acetate-med-
iated acetoxylation followed by enzyme-mediated hydrolysis of a0-acetoxy enones gives acetoxy enones 3a–d and hydroxy enones
4a–d with high enantiomeric excesses (up to 99%) and good yields. The transesterification of rac-4b in the presence of DMAP affor-
ded (+)-4b and (ꢀ)-3b in high enantiomeric excesses (91–94%) and good chemical yields.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
O
O
R2
R1O
R2
R1O
R2
R2
Chiral cyclic polyoxygenated compounds, such as A
(Fig. 1), are important structural units in many biologi-
cally active compounds and are also important synthons
for the asymmetric synthesis of natural products.1 It is,
therefore, of considerable interest to develop efficient
methods for the preparation of these compounds in
enantiomerically pure forms.
*
*
*
*
HO
OCH3
OCH3
OH
R1= H, Ac; R2 = H, Me, CH2OH
Figure 2.
fungus-mediated resolution of acyloxy enones to obtain
A few examples have been published for the preparations
of these compounds in racemic form,1,2 but no examples
have given enantiopure products. In our ongoing work,
we have published several papers concerning the
Mn(OAc)3-mediated direct acetoxylation and acyloxyl-
ation of cyclic enones followed by the enzymatic- and
enantiomerically pure a-hydroxy ketones (Fig. 2).3
Due to the multifunctional nature of chiral a0-acetoxy
and a0-hydroxy-a-methoxy cyclic enones, they can take
part in several stereoselective transformations. This led
us to explore a chemoenzymatic method for obtaining
them in their enantiomerically pure forms, and we
report herein an efficient chemoenzymatic route to the
three-step synthesis of both enantiomers of 3 and 4,
starting from 3-alkyl-2-hydroxy-cyclic enones 1a–d,
which are representative examples for the simple enan-
tioselective synthesis of a0-acetoxy and a0-hydroxy-a-
methoxy cyclic enones.
O
R1 = Ac, H
R1O
OR2
R3
R2 = Alkyl
R3 = Alkyl
n
A
Figure 1.
2. Result and discussion
*
1,2-Diketones 1a and 1b were synthesized according to
the literature procedure starting from the corresponding
Corresponding author. Tel.: +90 312 210 3242; fax: +90 312 210
1280; e-mail: asdemir@metu.edu.tr
0957-4166/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.01.025

A. S. Demir et al. / Tetrahedron: Asymmetry 17 (2006) 786–791
787
enones2a,4 while 1c and 1d are commercially available
compounds. 1,2-Diketones were converted to the 3-
methoxy-2-methyl cyclic enones 2a–d using a procedure
already reported in the literature.2,5 As an initial reac-
tion (Scheme 1), oxidation of enone 2a–d with manga-
nese(III) acetate in benzene was performed to obtain
the desired a0-acetoxy enones, rac-3a–d, in 88–95% yield
after purification by column chromatography.6
reaction was monitored by TLC analysis and HPLC
with a chiral column using rac-3a, and rac-4a (synthe-
sized from rac-3a).3j,k Careful monitoring of the reac-
tions with TLC and HPLC provided the acetoxy
enone (ꢀ)-3a (25–97% ee) and hydroxy enone (+)-4a
(57–90% ee) (Table 1). For a preparative scale synthesis
of (ꢀ)-3a, CCL was used, and when an approximately
50% conversion was attained, the crude product was
separated by flash column chromatography to provide
(ꢀ)-4-methoxy-3-methyl-2-oxocyclohex-3-enyl acetate,
(ꢀ)-3a in 44% yield. For the preparative scale synthesis
of (+)-4a, Mucor miehei lipase was used and the product
obtained in 46% yield. The enzyme preferentially trans-
formed the (+)-enantiomer.
Lipase type enzymes are used extensively for the synthe-
sis of enantiomerically pure compounds via the resolu-
tion of racemic mixtures. The high stereoselectivity in
organic media and their low cost make them very useful
catalysts for enantioselective resolution.7
Based on preliminary information available to us from
our previous work with biocatalyst-mediated reac-
tions,3e–k we tested a series of enzymes for screening
the enantioselective hydrolysis of acetoxy enone rac-
3a. As shown in Table 1, 11 enzymes showed activity
as measured by the hydrolysis of rac-3a at pH 7 in tolu-
ene with high ee. For the kinetic resolution step, the fol-
lowing conditions provided the best results.
For the enantioselective hydrolysis of acetoxy enone rac-
3b, we tested a series of enzymes at various pH values (5,
7, 9) and solvents (toluene, THF, acetonitrile, DMSO).
As shown in Table 2, only toluene and DMSO at
pH 7 provided results with high enantiomeric excesses
for hydroxyl enone (60–99% ee). Aspergillus exhibited
a high enantioselectivity for the hydroxy enone and this
enzyme was used for preparative scale synthesis of 4b
(>99% ee, 48% yield). The enzyme preferentially trans-
formed the (+)-enantiomer.
In a typical experiment, for the enzymatic hydrolysis,
the racemic 4-methoxy-3-methyl-2-oxocyclohex-3-enyl
acetate, rac-3a, was dissolved in toluene, then phosphate
buffer (pH 7.0) was added and the mixture stirred at
room temperature in the presence of the enzyme. The
We next examined the transesterification of rac-4b under
various conditions. As shown in Scheme 2, asymmetric
transesterification of rac-4b was carried out with several
O
O
O
Lit.2,5
OMe
R1
OMe
R1
OH
R1
O
Mn(OAc)3,
benzene, reflux
2
R2
R2
R
R2
R2
O
R2
n
n
n
rac-3a-d
1
2a-d
Enzyme
O
O
OMe
R1
n=1; R1= Me; R2 = H 1a
n=1; R1= Me; R2 = Me 1b
n=0; R1= Me; R2 = H 1c
n=0; R1= Et; R2 = H 1d
O
OMe
HO
R2
+
2
R1
n
O
R
R2
n
R2
(RS)-3a-d
(RS)-4a-d
Scheme 1.
Table 1. Enzymatic hydrolysis of 3-methoxy-4-methyl-2-oxocyclohex-3-enyl acetate rac-3a in toluenea
Entry
Enzyme
Reaction time
Acetate eeb (%)
Alcohol eeb (%)
Conversion8 (%)
E8
1
2
3
4
5
6
7
8
Aspergillus
Amano PS
QLM
Lipase PL
Lipase TL
Pseudomonas fluorescens
Mucor miehei
Rhizopus arrhius
Porcine Pancrease
Candida cylindracea
Lipase AL
20 h
18 h
22 h
22 h
2 d
4 d
8 d
10 d
7 d
4 d
25
83
69
70
64
78
85
59
88
97
66
57
85
61
73
70
88
90
75
83
86
68
30
49
53
49
48
47
49
44
51
53
49
4.6
31
8.3
13
10
37
51
12
31
55
10
9
10
11
10 d
a All hydrolyses of rac-3a were carried out in toluene/buffer pH = 7.
b Enantiomeric excesses were determined by HPLC equipped with an appropriate chiral column using racemic compounds as references.

788
A. S. Demir et al. / Tetrahedron: Asymmetry 17 (2006) 786–791
Table 2. Enzymatic hydrolysis of 3-methoxy-4,6,6-trimethyl-2-oxocyclohex-3-enyl acetate (rac-3b)
Entry
Enzyme
Reaction time (d), solv., pH
Conversion8 (%)
Acetate eea (%)
Alcohol eea (%)
E8
1
2
Hog pancrease
Rhizopus niveus
Rhizopus niveus
Rhizopus niveus
Aspergillus
32, DMSO, 7
42, DMSO, 7
15, THF, 7
15, CH3CN, 7
15, DMSO, 7
15, THF, 7
15, CH3CN, 7
5, Toluene, 7
18, Toluene, 5
20, Toluene, 9
40
37
—
—
13
—
—
42
27
51
48
35
—
—
11
—
—
73
31
78
72
60
—
—
76
—
—
>99
83
74
9.8
5.6
—
—
8.2
—
—
>200
14
3b
4b
5
6b
7b
8
Aspergillus
Aspergillus
Aspergillus
Aspergillus
Aspergillus
9
10
15
a Enantiomeric excesses were determined by HPLC equipped with an appropriate chiral column using racemic compounds as references.
b No reaction was observed.
O
O
O
O
OCH3
HO
OCH3
OAc
solvent, additive
enzyme,
HO
OCH3
*
*
+
O
(-)-3d
(+)-4b
rac-4b
Scheme 2.
lipases in either various solvents (DMSO, toluene, aceto-
nitrile, hexane) or without solvent. In all cases, only
trace amounts of the products were formed.
THF) at pH 7. Careful monitoring of the reactions by
TLC and HPLC provided the acetoxy enone (+)-3c
(15–87% ee) and hydroxy enone (ꢀ)-4c (25–96% ee).
Amano PS (in THF and DMSO) and CCL (in THF)
exhibited high enantioselectivity for acetoxy enone
(86–87% ee), and CCL (in DMSO, THF), PLE and
Amano PS (in DMSO) exhibited high enantioselectivity
for hydroxy enone (82–96% ee) (Table 4). All enzymes
preferentially recognized the (ꢀ)-enantiomer of rac-3c.
It is known that addition of crown ethers, amino alco-
hols, and bases affects the hydrolysis of esters, and that
addition of bases also enhances the rate of transesterifi-
cation with use of enzymes in apolar organic solvents.9
Enzyme mediated transesterification was carried out
using several bases (DMAP, 2,4-lutidine, 2,6-lutidine,
and pyridine). Among those bases examined, DMAP,
in particular, which is the most basic of these additives,
considerably enhanced the reaction rate.
As shown in Table 4, CCL exhibited solvent dependent
substrate selectivity for the hydroxyl- and acetoxy en-
one, and this enzyme in THF was used for preparative
scale synthesis of (+)-3c (47%) and the same enzyme
was used in DMSO for the preparative scale synthesis
of (ꢀ)-4c (42%).
In the transesterification of rac-4b, only lipase TL dis-
played any reactivity toward rac-4b in the presence of
DMAP (5 equiv). In regards to the ee of the remaining
substrate (+)-4b (91–94%) and that of the product (ꢀ)-
3b (57–76%), lipase TL was only the promising lipase
employed in the transesterification of rac-4b in hexane.
Lipase TL in hexane at room temperature was applied
for the preparative synthesis of (ꢀ)-3b (43%). The
enzyme preferentially transformed the (ꢀ)-enantiomer
(Table 3).
Under the above mentioned conditions, as described for
rac-3c, the enantioselective hydrolysis of 3-ethyl-4-meth-
oxy-2-oxocyclopent-3-enyl acetate rac-3d was screened
with various enzymes in different solvents (DMSO,
toluene, acetonitrile, hexane, THF) at pH 7. CCL in
DMSO exhibited high enantioselectivity for hydroxy
enone (99% ee) (Table 5). PLE exhibited high enantio-
selectivity for the hydroxy enone in THF (95% ee) and
high enantioselectivity for the acetoxy enone in DMSO
(93% ee). All enzymes preferentially recognized the
(ꢀ)-enantiomer of rac-3d. Preparative scale synthesis
The enantioselective hydrolysis of 4-methoxy-3-methyl-
2-oxocyclopent-3-enyl acetate (rac-3c) was investigated
with several available enzymes in solvents (DMSO,
Table 3. Transesterification of 6-hydroxy-2-methoxy-3,5,5-trimethylcyclohex-2-en-1-one rac-4b
Entry
Enzyme
Solvent
Additive
Reaction time (d)
Acetate eea (%)
Alcohol eea (%)
Conversion8 (%)
E8
1
2
3
Lipase TL
Lipase TL
Lipase TL
Hexane
Hexane
—
DMAP (rt)
DMAP (5 °C)
DMAP
2
4
2
76
57
73
91
94
93
54
62
56
22
12
21
a Enantiomeric excesses were determined by HPLC equipped with an appropriate chiral column using racemic compounds as references.

A. S. Demir et al. / Tetrahedron: Asymmetry 17 (2006) 786–791
789
Table 4. Enzymatic hydrolysis of 3-methoxy-4-methyl-2-oxocyclopent-3-enyl acetate (rac-3c)
Entry
Enzyme
Reaction time (h)
Solvent
Acetate eea (%)
Alcohol eea (%)
Conversion8 (%)
E8
1
2
3
4
5
6
CCL
PLE
Amano PS
CCL
Amano PS
PLE
6
41
1
21
1
DMSO
DMSO
DMSO
THF
THF
THF
15
63
87
87
86
32
96
83
85
82
67
25
14
43
51
51
56
56
56
20
34
28
13
2.2
82
a Enantiomeric excesses were determined by HPLC equipped with an appropriate chiral column using racemic compounds as references.
Table 5. Enzymatic hydrolysis of 4-ethyl-3-methoxy-2-oxocyclopent-3-enyl acetate rac-3d
Entry
Enzyme
Reaction time (min)
Solvent
Acetate eea (%)
Alcohol eea (%)
Conversion8 (%)
E8
1
2
3
4
5
6
7
CCL
PLE
Amano PS
PPL
PLE
85
85
25
85
110
25
DMSO
DMSO
DMSO
DMSO
THF
79
93
61
50
51
75
12
99
52
41
79
95
55
28
44
64
60
39
35
58
30
>200
10
4.3
13
64
7.5
2
Amano PS
PLE
THF
THF
52 h
a Enantiomeric excesses were determined by HPLC equipped with an appropriate chiral column using racemic compounds as references.
of acetoxy enone was carried out by using PLE in
DMSO (50%) and preparative scale synthesis of hydro-
xyl enone was carried out by using PLE in THF (42%).
4.2. General procedure for the a0-acetoxylation of a,b-
unsaturated ketones6
A solution of 8 mmol a,b-unsaturated ketone and
12 mmol Mn(OAc)3 in 30 mL benzene/AcOH (10:1)
was stirred at reflux (Dean–Stark apparatus), during
which the dark brown color of Mn(OAc)3 disappeared
over time, which was also monitored by GC–MS and
TLC. After all starting material was consumed, the reac-
tion mixture was diluted with ether and washed with
brine. The resulting organic phase was dried over
MgSO4 and concentrated under vacuum. If necessary,
the crude products were purified by column chromato-
graphy using EtOAc/hexane as eluent. In some cases,
direct filtering of the reaction mixture through a pad
of silica provided pure acetoxy enones.
3. Conclusion
These results show that manganese(III) acetate-medi-
ated acetoxylation of protected 1,2-diketones followed
by enzyme-mediated hydrolysis of the acetoxy group
provides hydroxy enones 4a–d, and acetoxy enones
3a–d with high enantiomeric excesses (up to 99%) and
in good chemical yields. This method provides a simple
new entry to the synthesis of cyclic hydroxy enones,
which are important precursors for pharmacologically
interesting compounds. As we reported earlier for
related systems, racemization free interconversion of
acetate to alcohol and vice versa gives additional
flexibility to this method.3j,k
4.3. 3-Methoxy-4-methyl-2-oxocyclohex-3-enyl acetate
3a2a
Brown solid (1.46 g, 92%), mp 91.2–92.3 °C; IR (KBr):
4. Experimental
m = 1745, 1693, 1638 cmꢀ1 1H NMR (400 MHz,
;
CDCl3) d 1.95 (s, 3H, CH3), 2.09 (ddd, J = 5.3, 11.8,
25.1 Hz, 1H, CH2, H-5), 2.17 (s, 3H, COCH3), 2.21
(m, 1H, CH2, H-5), 2.41 (m, 1H, CH2, H-4), 2.59 (m,
1H, CH2, H-4), 3.66 (s, 3H, OCH3), 5.28 (dd, J = 5.3,
13.3 Hz, 1H, CH, H-6); 13C NMR (100 MHz, CDCl3)
d 17.4, 20.7, 27.9, 28.4, 59.5, 73.5, 143.8, 147.9, 169.6,
188.9.
4.1. Materials and methods
NMR spectra were recorded on a Bruker DPX 400.
Chemical shifts d are reported in parts per million rela-
tive to CHCl3 (1H: d = 7.27), CDCl3 (13C: d = 77.0) and
CCl4 (13C: d = 96.4) as internal standards. Column
chromatography was conducted on silica gel 60 (40–
63 lm). TLC was carried out on aluminum sheets pre-
coated with silica gel 60F254 (Merck), and the spots were
visualized with UV light (k = 254 nm). Enantiomeric
excesses were determined by HPLC analysis using a
Thermo Finnigan Surveyor equipped with an appropri-
ate chiral phase column, as described in the experimen-
4.4. 3-Methoxy-4,6,6-trimethyl-2-oxocyclohex-3-enyl
acetate 3b
Yellow semi-solid (1.71 mg, 95%); IR (KBr): m = 1742,
1
1686, 1630, 1239 cmꢀ1; H NMR (400 MHz, CDCl3) d
0.97 (s, 3H, CH3), 1.08 (s, 3H, CH3), 1.87 (s, 3H,
CH3), 2.13 (d, J = 18.1 Hz, 1H, CH2), 2.19 (s,
3H, COCH3), 2.54 (d, J = 18.1 Hz, 1H, CH2), 3.63 (s,
tal part. Optical rotations were measured with a Kruss
¨
P3002RS automatic polarimeter.

790
A. S. Demir et al. / Tetrahedron: Asymmetry 17 (2006) 786–791
3H, OCH3), 5.15 (s, 1H, CH, s); 13C NMR (100 MHz,
CDCl3) d 17.4, 19.8, 20.5, 27.3, 37.4, 44.2, 59.3, 80.6,
140.4, 147.3, 169.8, 188.5. Anal. Calcd for C12H18O4
(226.27): C, 63.70; H, 8.02. Found: C, 63.51; H, 7.98.
4.10. (+)-3-Methoxy-4,6,6-trimethyl-2-oxocyclohex-3-
enyl acetate (+)-3b
25
Yellow semi-solid (49 mg, 43% yield), ½aꢁD ¼ ꢀ39:5
(c 0.6, CHCl3) for 76% ee; HPLC: Chiralcell OB
column, UV detection at 254 nm, eluent: hexane/2-pro-
panol = 98:2, flow 0.8 mL minꢀ1, 20 °C, Rf for (+)-3b:
18.57 min; (ꢀ)-3b: 23.72 min.
4.5. 3-Methoxy-4-methyl-2-oxocyclopent-3-enyl acetate
rac-3c2a
Colorless oil (130 mg, 88%), IR (CHCl3): m = 1668,
1
1620 cmꢀ1; H NMR (400 MHz, CDCl3) d 1.89 (s, 3H,
4.11. (+)-6-Hydroxy-2-methoxy-3-methylcyclohex-2-
en-1-one (+)-4a
CH3), 2.08 (s, 3H, COCH3), 2.24 (d, J = 17.4 Hz, 1H,
H-4), 2.76 (dd, J = 6.7, 17.5 Hz, 1H, H-4), 3.85 (s, 3H,
OCH3), 5.00 (dd, J = 2.6, 6.8 Hz, 1H, H-5) 13C NMR
(100 MHz, CDCl3) d 13.8, 19.7, 34.2, 57.2, 69.3, 149.5,
150.0, 169.1, 195.7.
20
Colorless oil (36 mg, 46% yield), ½aꢁD ¼ þ81:6 (c 0.2,
CHCl3) for 90% ee; HPLC: Chiralcell OB column, UV
detection at 254 nm, eluent: hexane/2-propanol = 90:10,
flow 0.8 mL minꢀ1, 20 °C, Rf for (ꢀ)-4a: 9.21 min; (+)-
4a: 11.43 min. IR (KBr): m = 3472, 1677, 1635, 1210
4.6. 4-Ethyl-3-methoxy-2-oxocyclopent-3-enyl acetate
rac-3d
cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 1.84 (ddd,
J = 5.24, 12.24, 25.7 Hz, 1H, CH2, H-4), 1.95 (s, 3H,
CH3), 2.34 (m, 2H, CH2, H-5), 2.55 (m, 1H, CH2, H-
4) 3.63 (s, 1H, OH), 3.69 (s, 3H, OCH3), 4.09 (dd,
J = 5.4, 13.5 Hz, 1H, CH); 13C NMR (100 MHz, CDCl3)
d 17.5, 22.7, 33.4, 59.52, 73.7, 144.1, 148.3, 198.6. Anal.
Calcd for C8H12O3 (156.18): C, 61.52; H, 7.74. Found:
C, 61.68; H, 7.88.
Colorless oil (144 mg, 91%), IR (CHCl3): m = 1714,
1655 cmꢀ1 1H NMR (400 MHz, CDCl3) d 1.0 (t,
;
J = 7.5 Hz, 3H, CH3), 2.08 (s, 3H, COCH3), 2.30 (d,
J = 7.3 Hz, 1H, H-4), 2.40 (m, 2H, CH2), 2.88 (dd, J =
6.7, 17.7 Hz, 1H, H-4), 3.80 (s, 3H, OCH3), 5.05 (dd,
J = 2.7, 6.7 Hz, 1H, H-5). 13C NMR (100 MHz, CDCl3)
d 11.2, 20.7, 21.7, 32.5, 58.2, 70.2, 150.0, 156.3, 170.3,
197.3. Anal. Calcd for C10H14O4 (198.22): C, 60.59; H,
7.12. Found: C, 60.31; H, 7.34.
4.12. (+)-6-Hydroxy-2-methoxy-3,5,5-trimethylcyclo-
hex-2-en-1-one (+)-4b
25
4.7. General procedure for the lipase-catalyzed kinetic
resolution
Colorless oil (44 mg, 48% yield), ½aꢁD ¼ þ111 (c 0.3,
CHCl3) for 99% ee; HPLC: Chiralcell OD column, UV
detection at 254 nm, eluent: hexane/2-propanol = 99:1
flow 0.8 mL minꢀ1, 20 °C, Rf for (+)-4b: 12.42 min;
(ꢀ)-4b: 14.47 min. IR (KBr): m = 3414, 1670, 1643,
Lipase (200–300 mg) was dissolved in phosphate buffer
(pH 7, 30 mL) and added to a solution of the pure sub-
strate (0.5 mmol) in solvent (3 mL) and the reaction
mixture left to stir at rt. Conversion was monitored by
TLC and HPLC up to 50%. After filtration the filtrate
was extracted with dichloromethane, dried over MgSO4,
concentrated, and purified by column (n-hexane/ethyl
acetate, 4:1).
1283 cmꢀ1; H NMR (400 MHz, CDCl3): 0.88 (s, 3H,
1
CH3), 1.21 (s, 3H, CH3), 1.91 (s, 3H, CH3), 2.12 (d,
J = 18.1 Hz, 1H, CH2, H-4), 2.49 (d, J = 18.1 Hz, 1H,
CH2, H-4), 3.61 (br s, 1H, OH), 3.69 (s, 3H, OCH3),
3.90 (s, 1H, CH); 13C NMR (100 MHz, CDCl3) d 17.6,
18.0, 27.7, 39.3, 44.1, 59.4, 80.2, 143.2, 146.7, 195.2.
Anal. Calcd for C10H16O3 (184.23): C, 65.19; H, 8.75.
Found: C, 65.43; H, 8.91.
4.8. General procedure for the lipase-catalyzed trans-
esterification in the presence of additives
4.13. (+)-3-Methoxy-4-methyl-2-oxocyclopent-3-enyl
acetate (+)-3c2a
To a stirred solution of rac-6-hydroxy-2-methoxy-3,5,5-
trimethylcyclohex-2-en-1-one rac-4b (0.5 mmol), vinyl
acetate (10 mmol) and 2.5 mmol DMAP in hexane
(10 mL) were added in one portion and the reaction
mixture was stirred at rt. The reaction was monitored
by TLC up to 50%. After filtration, the filtrate was
extracted with dichloromethane, dried over MgSO4,
and concentrated.
20
Colorless oil (43 mg, 47%) ½aꢁD ¼ þ10:6 (c 0.8, CHCl3)
for 87% ee; IR (CHCl3); HPLC: Chiralcell AD column,
UV detection at 254 nm, eluent: hexane/2-propanol =
98:2, flow 0.3 mL minꢀ1, 20 °C, Rf: for (ꢀ)-3c: 36.17 min;
(+)-3c: 46.83 min.
4.9. (ꢀ)-3-Methoxy-4-methyl-2-oxocyclohex-3-enyl
acetate (ꢀ)-3a
4.14. (+)-4-Ethyl-3-methoxy-2-oxocyclopent-3-enyl
acetate (+)-3d
20
Brown solid, mp 91.2–92.3 °C (44 mg, 44% yield),
Colorless oil (49.5 mg, 50%) ½aꢁD ¼ þ32:1 (c 1, CHCl3)
20
½aꢁD ¼ ꢀ140 (c 0.5, CHCl3) for 97% ee; HPLC: Chiral-
for 93% ee. HPLC: Chiralcell AD column, UV detection
at 254 nm, eluent: hexane/2-propanol = 96:4, flow
0.3 mL minꢀ1, 20 °C, Rf: for (ꢀ)-3d: 22.31 min; (+)-3d:
25.05 min.
cell OB column, UV detection at 254 nm, eluent: hex-
ane/2-propanol = 90:10, flow 0.8 mL minꢀ1, 20 °C, Rf
for (ꢀ)-3a: 12.73 min; (+)-3a: 20.48 min.

A. S. Demir et al. / Tetrahedron: Asymmetry 17 (2006) 786–791
791
Org. Lett. 2000, 2, 3833; (f) Schneider, D. F.; Viljoen, M.
S. Tetrahedron 2002, 58, 5307; (g) Schneider, D. F.;
Viljoen, M. S. Synth. Commun. 2002, 32, 1285; (h)
Schneider, D. F.; Viljoen, M. S. Synth. Commun. 1997,
27, 3349; (i) Munkombwe, N. M.; Maswabi, T.; Hughes,
N. A. Phytochemistry 1997, 45, 1217; (j) Davies, F. A.;
Chen, B. C. Chem. Rev. 1992, 92, 919.
4.15. (ꢀ)-5-Hydroxy-3-methyl-2-methoxy-2-cyclo-
pentene-1-one (ꢀ)-4c10,11
20
Colorless oil (30 mg, 42%) ½aꢁD ¼ ꢀ9:6 (c 0.8, CHCl3)
for 96% ee; HPLC: Chiralcell AD column, UV detection
at 254 nm, eluent: hexane/2-propanol = 98:2, flow
0.3 mL minꢀ1, 20 °C, Rf: for (ꢀ)-4c: 75.48 min; (+)-4c:
2. (a) Demir, A. S.; Saatc¸ioglu, A. Synth. Commun. 1993, 23,
571; (b) Demir, A. S.; Jeganathan, A. Synthesis 1992, 235.
3. (a) Demir, A. S.; Sayrac, T.; Watt, D. S. Synthesis 1990,
1119; (b) Demir, A. S.; Jeganathan, A.; Watt, D. S. J. Org.
Chem. 1989, 54, 4020; (c) Demir, A. S.; Gercek, Z.; Reis,
O.; Duygu, A. N.; Arikan, E. Tetrahedron 1999, 55, 2441;
69.53 min. IR (CHCl3): m = 3023, 1667, 1658 cmꢀ1; H
1
NMR (400 MHz, CDCl3) d 1.90 (s, 3H, CH3), 2.30 (d,
J = 17.2, 1H, H-4), 2.70 (dd, J = 6.55, 17.3 Hz, 1H, H-
4), 3.85 (s, 3H, OCH3), 4.05 (dd, J = 7.07, 19.4 Hz,
1H, H-5).
(d) Demir, A. S.; C¸ amkerten, N.; Akgun, H.; Tanyeli, C.;
¨
Mahasneh, A. S.; Watt, D. S. Synth. Commun. 1990, 20,
2279; (e) Demir, A. S.; Hamamci, H.; Doganel, F.;
Camkerten, N.; Aksoy-Cam, H. Turkish J. Chem. 2000,
4.16. (+)-3-Ethyl-5-hydroxy-2-methoxy-2-cyclopentene-
1-one (+)-4d
¨
24, 141; (f) Demir, A. S.; Aybey, A.; Sesenoglu, O.; Polat,
20
F. Tetrahedron: Asymmetry 2003, 14, 1489; (g) Demir, A.
S.; Fındık, H.; Ko¨se, E. Tetrahedron: Asymmetry 2004, 15,
777; (h) Gercek, Z.; Karakaya, D.; Demir, A. S. Tetra-
hedron: Asymmetry 2005, 16, 1743; (i) Demir, A. S.;
Senocak, D. Tetrahedron: Asymmetry 2004, 15, 2641; (j)
Demir, A. S.; Sesenoglu, O. Org. Lett. 2002, 4, 2021; (k)
Demir, A. S.; Sesenoglu, O. Tetrahedron: Asymmetry
2002, 13, 667.
Colorless oil (33 mg, 42%), ½aꢁD ¼ þ15:2 (c 0.8, CHCl3)
for 95% ee; HPLC: Chiralcell AD column, UV detection
at 254 nm, eluent: hexane/2-propanol = 96:4, flow
0.3 mL minꢀ1, 20 °C, Rf: for (ꢀ)-4d: 46.7 min; (+)-4d:
1
49.95 min. IR (CHCl3): m = 3017, 1669, 1652 cmꢀ1; H
NMR (400 MHz, CDCl3) d 1.05 (t, J = 7.5 Hz, 3H,
CH3), 2.28 (dd, J = 6.6, 17.3 Hz, 1H, H-4), 2.30 (d,
J = 7.5 Hz, 1H, H-4), 2.40 (m, 2H, CH2), 3.80 (s, 3H,
OCH3), 4.02 (dd, J = 2.5, 6.5 Hz, 1H, H-5) 13C NMR
(100 MHz, CDCl3) d 11.3, 21.8, 33.9, 57.8, 69.9, 96.2,
156.1, 202.9. Anal. Calcd for C8H12O3 (156.18): C,
61.52; H, 7.74. Found: C, 661.33; H, 7.86.
4. (a) Ponaras, A. A. Tetrahedron Lett. 1980, 21, 4803; (b)
Rissafi, B.; Rachiqi, N.; Louzi, A. E.; Loupy, A.; Petit, A.;
Fkih-Tetouani, S. Tetrahedron 2001, 57, 2761.
5. (a) Schow, S. R.; Bloom, J. D.; Thompson, A. S.;
Winzenberg, K. N.; Smith, A. B. J. Am. Chem. Soc.
1986, 108, 2662; (b) Wenkert, E.; Golob, N. F.; Sathe, S.
S.; Smith, R. A. J. Synth. Commun. 1973, 3, 205.
¨
6. Demir, A. S.; Reis, O.; Igdir, A. C. Tetrahedron 2004, 60,
Acknowledgments
3427.
7. (a) Bornscheuer, U. T.; Kazlauskas, R. J. Hydrolases in
Organic Synthesis—Regio- and Stereoselective Biotransfor-
mations; Wiley-VCH: Weinheim, 1999; (b) Liese, A.;
Seelbach, K.; Wandrey, C. Industrial Biotransformations;
Wiley-VCH: Weinheim, 2000; (c) Faber, K. Biotransfor-
mations in Organic Chemistry, 4th ed.; Springer: Berlin,
2000.
8. Chen, C. S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am.
Chem. Soc. 1982, 104, 7294, E values are calculated using
the program ‘Selectivity’ by K. Faber and H. Hoenig,
http://www.cis.TUGraz.at/orgc/.
Financial support was funded by the Middle East Tech-
nical University (BAP-2003), the Scientific and Technical
Research Council of Turkey (TUBITAK), the Turkish
Academy of Sciences (TUBA), and the Turkish State
Planning Organization (DPT) is gratefully acknowl-
edged. We would like to thank MEITO SANGYO Co.,
Ltd Tokyo Japan, for the enzymes TL, SL, QLM.
References
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11. According to 1H NMR spectra slow, isomerization of this
product to 2,3-dihydroxy-4-methylcyclopent-2-enone at rt
is observed; this subject is currently under investigation.