The first enzymatic resolution of quaternary α′-acetoxy α,β-unsaturated cyclohexenones and cyclopentenones

Article abstract of DOI:10.1016/j.tetasy.2005.11.016

The enantioselective resolution of various quaternary α′- acetoxy α,β-unsaturated cyclohexenones and cyclopentenones was performed with the commercially available enzyme CCL in pH = 8.0 phosphate buffer. Various parameters that would affect the enantiosel

Full text of DOI:10.1016/j.tetasy.2005.11.016

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 4050–4055
The first enzymatic resolution of quaternary a0-acetoxy
a,b-unsaturated cyclohexenones and cyclopentenones
b
a
Cihangir Tanyeli,a, Fazilet Devrim Ozdemirhan and C¸ ig˘dem Iyigun
_
*
¨
¨
aDepartment of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
b
_
Department of Chemistry, Abant Izzet Baysal University, 14280 Bolu, Turkey
Received 10 October 2005; accepted 10 November 2005
Abstract—The enantioselective resolution of various quaternary a0-acetoxy a,b-unsaturated cyclohexenones and cyclopentenones
was performed with the commercially available enzyme CCL in pH = 8.0 phosphate buffer. Various parameters that would affect
the enantioselectivities were tested and the best enzymatic resolution conditions were found to afford the enantiomerically enriched
quaternary acetoxylated substrates with high ee varying between 36% and 99%.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
The classical method for the preparation of optically
active tertiary alcohols is via separation of their properly
derivatized diastereomers.9 Another common method
involves multistep transformation from chiral pools of
natural products, such as terpenes, amino acids, and
carbohydrates.10 Asymmetric synthesis by the addition
of chiral organometallic reagents to unsymmetric
ketones is a promising approach for obtaining optically
active tertiary alcohols.11 The catalytic asymmetric
synthesis by dihydroxylation of 1,1-disubstituted olefins
is so far the most effective method.12 The catalytic asym-
metric epoxidation of 1,1-disubstituted olefins followed
by treatment with either a base or a nucleophile, leads
to various tertiary alcohols.13 In addition to these, sev-
eral studies have also been directed toward the stereo-
selective synthesis of enantiomerically pure a-hydroxy
ketones.14 One direct method consists of the asymmetric
oxidation of enolates.15 However, microbial or enzy-
matic methods including lipases proved unsuccessful,
since tertiary alcohols are usually too bulky to have
access to the active sites of lipases.16
A broad repertoire of chiral auxiliaries, reagents, and
catalysts can be utilized for the reliable generation of
tertiary stereocenters.1 In contrast, the asymmetric con-
struction of molecules with quaternary carbon stereo-
centers, that is, carbon stereocenters with four different
non-hydrogen substituents, represents a very challeng-
ing and dynamic area in organic synthesis. The prepara-
tion of compounds with these centers with catalytic
enantioselective reactions is also particularly demand-
ing.2 Tertiary alcohols and their derivatives containing
tertiary C–O bonds are useful building blocks for many
drugs and natural products, such as a prostaglandin
analogue,3 frontalin,4 and a vitamin D3 metabolite.5 In
comparison with the process for preparing optically
active secondary alcohols, the synthesis of enantiomeri-
cally pure tertiary alcohols is still a challenging
problem. The a-hydroxy carbonyl array is a common
feature of many biologically important molecules and
key intermediates in the synthesis of natural products.6
Some of the biologically important compounds contain
quaternary a-hydroxy carbonyl moieties, such as scy-
phostatin, which is the specific inhibitor of neutral
sphingomyelinase,7 and the anthracycline antitumor
antibiotics adriamycin and daunomycin.8
The lack of known syntheses of enantiomerically
enriched quaternary a0-acetoxy-a,b-unsaturated cyclic
ketones 2 prompted us toward the development of a new
method. In connection with our work on the develop-
ment of novel procedures for the manganese(III) acetate
based direct oxidation of an alkyl substituted a0-position
on cyclic a,b-unsaturated ketones 1,17 we herein report
the enzymatic resolution of them into enantiomerically
enriched forms. Over the course of our studies on all
*
Corresponding author. Tel.: +90 312 210 3222; fax: +90 312 210
1280; e-mail: tanyeli@metu.edu.tr
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.11.016

C. Tanyeli et al. / Tetrahedron: Asymmetry 16 (2005) 4050–4055
4051
on the pH, temperature and the addition of a co-solvent,
screening reactions were performed by changing these
parameters. The effect of temperature was examined
by changing it from 14 to 28 ꢁC. No change in the reac-
tion was observed. Upon changing co-solvents (DMSO,
i-propanol, tert-butyl methyl ether, and n-butanol), no
new effect was recorded. It was decided to examine the
effect of pH on the reaction. Substrate 3a was subjected
to pH 7.50 and pH 8.00 buffers in the absence of
enzyme. It was observed that the substrate does not under-
go any autohydrolysis between this pH range. Finally,
substrate 3a was subjected to enzymatic hydrolysis by
the addition of 100 lL PLE in pH 7.50 and pH 8.00 buf-
fers, respectively. It was recorded that in pH 8.00 buffer,
the enzymatic hydrolysis started in 48 h. There was no
hydrolysis at pH 7.50. Around 50% conversion was
completed within 96 h in a pH 8.00 buffer system with
PLE. The crude product was separated by flash column
chromatography. (ꢀ)-6-Acetoxy-3,6-dimethyl-2-cyclo-
hexen-1-one 2a was obtained in 42% yield and 5% ee.
Although the enantioselectivity was low, this first exam-
ple showed that a0-substituted a0-acetoxy a,b-unsatu-
rated cyclic ketones can be resolved by hydrolase type
enzymes. From this, it was decided to examine the enzy-
matic hydrolysis reactions of the model compound 3a
with the other hydrolases like CCL, PPL, and HLE.
The screening reactions were first performed to find
out the optimum conditions in the hydrolysis reactions.
All reactions were performed in a 1:0.5 substrate:enzyme
molar ratio at pH 7.00. At this pH, no hydrolysis was
recorded. The pH was increased to pH 8.00 by the addi-
tion of 1 M NaOH. The hydrolysis reactions of the
substrate 3a with CCL was completed within 78 h with
48% ee at 20 ꢁC. No hydrolysis was recorded with
PPL and HLE. When the pH was increased to 8.50,
complete racemization of the substrate was recorded.
Hence, the optimum pH in the hydrolysis should be
pH 8.00. The temperature effect was also investigated.
The temperature was changed from 14 to 28 ꢁC, and
the optimum temperature was found to be 20 ꢁC for
the enzyme CCL. Next, we focused on the enzymatic
hydrolysis reactions with CCL and the optimum condi-
tions found to be pH 8.00 buffer system, at 20 ꢁC, with
DMSO used as co-solvent. The substrate:enzyme molar
ratio was changed from 1:0.5 to 1:1, and the ee increased
to 99%. When the enzyme was used in a stoichiometric
amount, the enantioselectivity increased. (ꢀ)-6-Acet-
oxy-3,6-dimethyl-2-cyclohexen-1-one 3a was synthesized
in 46% isolated yield in 99% ee at pH 8.00 buffer, at
20 ꢁC. CCL, which is generally known for its stereoselec-
tivity in the hydrolysis of secondary alcohols, appeared
to be the best enzyme tested.
O
O
OAc
R
R
a
*
R'
R'
n
n
1
2
n = 0, 1
R = Me, Et, PhCH2
Scheme 1. Reagents and conditions: (a) Mn(OAc)3, benzene, reflux.
biotransformations, screening reactions were first com-
pleted with various hydrolases (i.e., PLE, CCL, HLE,
and PPL) using a substrate:enzyme ratio from 1:1 to
1:0.5. Among the hydrolases studied, CCL proved suit-
able for the enantioselective hydrolysis of the substrates.
1.1. Synthesis of racemic substrates
a0-Substituted a,b-unsaturated cyclopentanones and
cyclohexanones 1 were prepared from the corresponding
a,b-unsaturated cyclic ketones using the slightly modi-
fied literature procedures,18 with LDA and correspond-
ing alkyl halides at ꢀ78 ꢁC, which subsequently allowed
us to react with Mn(OAc)3. a0-Alkyl a,b-unsaturated
cyclopentanones and cyclohexanones 1 (with dry ben-
zene as the solvent) underwent selective oxidation with
Mn(OAc)3 to afford products 2 (Scheme 1).17
1.2. Enzymatic hydrolyses of racemic substrates
Various lipases (PLE, CCL, HLE, and PPL) were tested
with all racemic substrates. It has been reported by us
that ( )-6-acetoxy-3-methyl-2-cyclohexen-1-one can be
resolved by PLE catalyzed hydrolysis to afford an enan-
tiomerically enriched 6-hydroxy derivative with 95%
ee.19 Therefore, it was decided to examine the hydrolysis
reaction of a0-substituted a0-acetoxy a,b-unsaturated
cyclic ketones 2 by PLE, which is known for its broad
substrate specificity and high stereoselectivity. ( )-6-
Acetoxy-3,6-dimethyl-2-cyclohexen-1-one 3a was cho-
sen as a model compound and subjected to enzymatic
resolution with PLE (Scheme 2). Treatment of the sub-
strate in the absence of enzyme revealed that it does
not undergo autohydrolysis. The enzymatic hydrolysis
reaction was performed according to the following pro-
cedure. To a stirred solution of 3a (100 mg) in phos-
phate buffer (pH 7.00, 10 mL), PLE (100 lL) was
added in one portion and the reaction mixture stirred
at 20 ꢁC. The reaction was monitored by TLC. How-
ever, no hydrolysis was recorded after 156 h. Since the
enantioselectivity of the enzymatic reactions depends
In order to examine the effect of substituents on the
cyclohexenone ring system, various a0-methyl substi-
tuted a0-acetoxy cyclohexenones were subjected to
hydrolysis by CCL. The results of enzymatic resolutions
on different substrates are summarized in Table 1. The
reaction was performed according to the following pro-
cedure: Substrate (100 mg) was added to pH 8.00 buffer
(20 mL) in 1 mL of DMSO. CCL (100 mg) was then
added to the solution and shaken for 96–148 h by
TLC monitoring at 20 ꢁC. The presence of substituents
O
O
OAc
CH3
OAc
CH3
a
*
*
R
R
(-)-3a-d
rac-3a-d
Scheme 2. Reagents and conditions: (a) Lipases, DMSO, pH = 8.00
phosphate buffer, 20 ꢁC.

4052
C. Tanyeli et al. / Tetrahedron: Asymmetry 16 (2005) 4050–4055
Table 1.
20
Entry
Substrate
3
Acetoxylated product
Time (h)
96
Yield (%)a
46
ee (%)b
99
½aꢁD
O
1
(
)-3a
(ꢀ)-3a
ꢀ13.1
OAc
O
OAc
2
3
(
(
)-3b
)-3c
(ꢀ)-3b
(ꢀ)-3c
108
122
51
52
62
94
ꢀ1.8
O
OAc
ꢀ42.2
O
OAc
4
(
)-3d
(ꢀ)-3d
136
48
73
ꢀ29.2
Ph Ph
a Yields (%) are given as isolated yields.
b Enantiomeric excesses were determined by the Chiralcel ODH chiral column HPLC analysis.
at the fifth position, near the carbon atom of the stereo-
genic center, significantly decreases the enantioselectiv-
ity of the enzyme (entry 2). Substrates 3c and 3d
(entries 3 and 4) were employed to test the effect of the
substitution on the fourth carbon. In entry 3, substrate
3c was resolved with 94% ee as high as substrate 3a.
In entry 4, a rapid decrease in enantioselectivity was
observed (73% ee). This can be attributed to the solubi-
lity problem of the diphenyl substituted substrate.
(entries 1–3), the selectivity drastically decreased from
99% ee to 53% and 43% ee, respectively. In entry 4,
( )-5-acetoxy-2,3,5-trimethyl-2-cyclopenten-1-one
5d
afforded (ꢀ)-5d in 90% ee as expected.
2. Conclusion
Herein, we have reported the first enzymatic resolutions
of various quaternary a0-acetoxy-a,b-unsaturated cyclic
ketones and have shown that the substituents on the
quaternary and on the neighboring center drastically
influence the enantioselectivity of the enzyme. Among
the enzymes used under the hydrolysis conditions,
CCL showed the best enantioselectivity. We have found
out that the pH factor is crucial for high enantioselectiv-
ity. Commercially available and inexpensive enzyme
CCL renders the process very attractive for large-scale
preparations.
The effects of the relatively bulkier substituents on the
stereogenic center were examined by CCL hydrolysis
of ethyl and benzyl substituted acetoxy cyclohexenones
4a–d (Scheme 3). When the resolution of methyl substi-
tuted substrate 3a was compared with ethyl and benzyl
substituted substrates 4a and 4b, the bulkier ethyl and
benzyl groups decreased the enantioselectivity to 71%
and 61% ee, respectively (entries 1 and 2 in Table 2).
A similar steric effect was observed for substrates 4c
and 4d by comparing methyl substituted substrate 3b
as 45% and 36% ee, respectively.
3. Experimental
Enzymatic resolution with CCL was also applied to a0-
substituted 5-acetoxy cyclopentenones 5a–d (Scheme 4).
The results are summarized in Table 3. When the substi-
tuent was changed from methyl to either ethyl or benzyl
The H and 13C NMR spectra were recorded in CDCl3
1
on a Brucker Spectrospin Avance DPX 400 spectrome-
ter. Chemical shifts are given in ppm downfield from tetra-
methylsilane. Apparent splittings are given in all cases.
Infrared spectra were obtained from KBr pellets on a
Mattson 1000 FT-IR spectrophotometer. Mass spectra
were recorded on a Varian MAT 212. Optical rotations
were measured in a 1 dm cell using a Rudolph Research
Analytical Autopol III polarimeter at 20 ꢁC. HPLC
measurements were performed with ThermoFinnigan
Spectra System instrument. Separations were carried
out on Chiralcel OD-H analytical column (250 ·
4.60 mm) with hexane/2-propyl alcohol as eluent. Col-
umn chromatography was performed on silica gel (60-
mesh, Merck). TLC was carried out on Merck 0.2-mm
silica gel 60 F254 analytical aluminum plates. PLE (Pig
O
O
OAc
R
OAc
R
a
*
*
R'
R'
(-)-4a and 4c
(+)-4b and 4d
rac-4a-d
R: Et 4a and 4c
R: PhCh2 4b and 4d
Scheme 3. Reagents and conditions: (a) CCL, DMSO, pH = 8.00
phosphate buffer, 20 ꢁC.

C. Tanyeli et al. / Tetrahedron: Asymmetry 16 (2005) 4050–4055
4053
Table 2.
20
Entry
Substrate
4
Acetoxylated product
Time (h)
148
Yield (%)a
47
ee (%)b
71
½aꢁD
O
OAc
1
2
(
)-4a
)-4b
(ꢀ)-4a
ꢀ12.5
O
O
O
OAc
Ph
(
(+)-4b
142
48
61
+0.4
OAc
3
4
(
(
)-4c
)-4d
(ꢀ)-4c
(+)-4d
132
138
49
45
45
36
ꢀ3.2
OAc
Ph
+0.2
a Yields (%) are given as isolated yields.
b Enantiomeric excesses were determined by Chiralcel ODH chiral column HPLC analysis.
O
O
3.1. General procedure for the Mn(OAc)3 oxidations of
a0-alkyl a,b-unsaturated ketones ( )-3a–d, ( )-4a–d,
and ( )-5a–d
OAc
R
OAc
R
a
*
*
R'
R'
A mixture of Mn(OAc)3 (3.25 g, 14.0 mmol) in benzene
(150 mL) was refluxed for 45 min using a Dean–Stark
trap. The mixture was cooled to room temperature
and the a0-alkyl a,b-unsaturated (7.0 mmol) gradually
added. The mixture was allowed to reflux until the dark
brown color disappeared and also monitored by TLC.
The reaction mixture was diluted with an equal amount
of ethyl acetate and the organic phase washed with 1 M
HCl, followed by saturated NaHCO3 and brine. The
organic phase was dried over MgSO4 and evaporated
in vacuo. The crude product was separated by flash col-
umn chromatography using ethyl acetate/hexane as
eluent.
(-)-5a, 5b and 5d
(+)-5c
rac-5a-d
R: Me 5a, 5d
R: Et 5b
R: PhCh2 5c
Scheme 4. Reagents and conditions: (a) CCL, DMSO, pH = 8.00
phosphate buffer, 20 ꢁC.
Liver Esterase) and HLE (Horse Liver Esterase) were
purchased from Sigma as a suspension in ammonium
sulfate solution (3.2 mol/L) and as a powder, respec-
tively. CCL (Lipase, Type VII, from Candida Rugosa)
and PPL (Lipase, Type II, from Porcine Pancreas) were
purchased from Aldrich.
Compounds 3a–d, 4c, and 5a–c were synthesized and all
are in accordance with the literature data.17
Table 3.
20
Entry
Substrate
5
Acetoxylated product
Time (h)
94
Yield (%)a
48
ee (%)b
99
½aꢁD
O
OAc
1
(
)-5a
(ꢀ)-5a
ꢀ33.6
O
O
OAc
OAc
2
3
4
(
(
(
)-5b
)-5c
)-5d
(ꢀ)-5b
(+)-5c
(ꢀ)-5d
100
136
98
52
47
46
53
43
90
ꢀ8.4
+1.2
Ph
O
OAc
ꢀ23.8
a Yields (%) are given as isolated yields.
b Enantiomeric excesses were determined by the Chiralcel ODH chiral column HPLC analysis.

4054
C. Tanyeli et al. / Tetrahedron: Asymmetry 16 (2005) 4050–4055
3.1.1.
( )-6-Acetoxy-6-ethyl-3-methyl-2-cyclohexen-1-
3.2.1.
(ꢀ)-6-Acetoxy-3,6-dimethyl-2-cyclohexen-1-one
20
one ( )-4a. (0.97 g, 72%) as a colorless oil, Rf (EtOAc/
hexane 1:4) 0.22; mmax (neat) 3421, 2968, 1735, 1663,
1447 cmꢀ1; dH (400 MHz, CDCl3) 6.02 (1H, s, @CH),
2.71–2.82 (2H, m, @CCH2), 2.38–2.47 (2H, m,
CH2COAc), 2.01 (3H, s, MeCO2), 1.87 (3H, s, MeC@),
1.53–1.74 (2H, m, MeCH2), 0.85 (3H, t, J = 7 Hz,
MeCH2); dC (100.6 MHz, CDCl3) 208.0, 171.1, 158.1,
124.9, 81.3, 47.3, 37.4, 30.0, 27.8, 21.1, 19.2; HRMS
(EI) M+, found 196.1098, C11H16O3 requires 196.1100.
(ꢀ)-3a. (46 mg, 46%) as a colorless oil; 99% ee ½aꢁD ¼
ꢀ13:1 (c 1.0, CHCl3). Chiralcel OD-H chiral column
(n-hexane/2-propanol 88:12), 1.0 mL/min flow rate,
254 nm t1 = 15.6 min (major), t2 = 17.2 min (minor).
3.2.2. (ꢀ)-6-Acetoxy-3,5,5,6-tetramethyl-2-cyclohexen-1-
one (ꢀ)-3b. (51 mg, 51%) as a colorless oil; 62% ee
20
½aꢁD ¼ ꢀ1:8 (c 1.0, CHCl3). Chiralcel OD-H chiral col-
umn (n-hexane/2-propanol 85:15), 1.0 mL/min flow
rate, 254 nm t1 = 12.1 min (major), t2 = 13.6 min
(minor).
3.1.2. ( )-6-Acetoxy-6-benzyl-3-methyl-2-cyclohexen-1-
one ( )-4b. (1.07 g, 59%) as a colorless oil, Rf (EtOAc/
hexane 1:5) 0.32; mmax (neat) 3012, 2961, 1730, 1652,
3.2.3. (ꢀ)-6-Acetoxy-4,4,6-trimethyl-2-cyclohexen-1-one
20
(ꢀ)-3c. (52 mg, 52%) as a colorless oil; 94% ee ½aꢁD
¼
1493 cmꢀ1
; dH (400 MHz, CDCl3) 7.34 (2H, d,
ꢀ42:2 (c 1.0, CHCl3). Chiralcel OD-H chiral column
(n-hexane/2-propanol 90:10), 1.0 mL/min flow rate,
254 nm t1 = 14.5 min (major), t2 = 16.9 min (minor).
J = 6 Hz, Ph), 7.19–7.26 (3H, m, Ph), 5.93 (1H, s,
@CH), 3.58 (1H, d, J = 14 Hz, PhCHaHb), 3.19 (1H,
d, J = 14 Hz, PhCHaHb), 2.80–2.83 (2H, m, @CCH2),
2.28–2.34 (2H, m, CH2COAc), 2.05 (3H, s, MeCO2),
1.87 (3H, s, MeC@); dC (100.6 MHz, CDCl3) 194.5,
170.2, 159.1, 135.3, 130.4, 128.2, 127.4, 126.9, 125.1,
85.8, 40.3, 37.6, 35.0, 24.2, 21.5, 15.0; HRMS (EI)
M+, found 258.1254, C16H18O3 requires 258.1256.
3.2.4.
hexen-1-one (ꢀ)-3d. (48 mg, 48%) as a colorless oil;
(ꢀ)-6-Acetoxy-6-methyl-4,4-diphenyl-2-cyclo-
20
73% ee ½aꢁD ¼ ꢀ29:2 (c 1.0, CHCl3). Chiralcel OD-H
chiral column (n-hexane/2-propanol 88:12), 1.0 mL/
min flow rate, 254 nm t1 = 17.1 min (minor), t2 =
20.4 min (major).
3.1.3.
( )-6-Acetoxy-6-benzyl-3,5,5-trimethyl-2-cyclo-
3.2.5. (ꢀ)-6-Acetoxy-6-ethyl-3-methyl-2-cyclohexen-1-
hexen-1-one ( )-4d. (1.14 g, 57%) as a colorless oil,
Rf (EtOAc/hexane 1:5) 0.31; mmax (neat) 3014, 2950,
1734, 1652 cmꢀ1; dH (400 MHz, CDCl3) 7.31 (2H, d,
J = 7 Hz, Ph), 7.15–7.24 (3H, m, Ph), 5.83 (1H, s,
@CH), 3.68 (1H, d, J = 14 Hz, PhCHaHb), 2.92 (1H,
d, J = 14 Hz, PhCHaHb), 2.56 (1H, d, J = 18 Hz,
CHaHb), 2.31 (1H, d, J = 18 Hz, CHaHb), 2.05 (3H, s,
MeCO2), 1.93 (3H, s, @CMe), 0.94 (3H, s, CMeMe),
0.89 (3H, s, CMeMe); dC (100.6 MHz, CDCl3) 196.2,
169.0, 153.1, 137.0, 131.6, 130.4, 127.7, 127.4, 126.3,
126.2, 125.3, 110.5, 86.8, 44.8, 41.2, 33.5, 24.5, 22.5;
HRMS (EI) M+, found 286.1568, C18H22O3 requires
286.1569.
one (ꢀ)-4a. (47 mg, 47%) as a colorless oil; 71% ee
20
½aꢁD ¼ ꢀ12:5 (c 1.0, CHCl3). Chiralcel OD-H chiral col-
umn (n-hexane/2-propanol 87:13), 1.0 mL/min flow
rate, 254 nm t1 = 15.7 min (major), t2 = 18.5 min
(minor).
3.2.6. (+)-6-Acetoxy-6-benzyl-3-methyl-2-cyclohexen-1-
one (+)-4b. (48 mg, 48%) as a colorless oil; 61% ee
20
½aꢁD ¼ þ0:4 (c 1.0, CHCl3). Chiralcel OD-H chiral col-
umn (n-hexane/2-propanol 85:15), 1.0 mL/min flow
rate, 254 nm t1 = 9.6 min (major), t2 = 11.8 min
(minor).
3.2.7.
hexen-1-one (ꢀ)-4c. (49 mg, 49%) as a colorless oil;
(ꢀ)-6-Acetoxy-6-ethyl-3,5,5-trimethyl-2-cyclo-
3.1.4. ( )-5-Acetoxy-2,3,5-trimethyl-2-cyclopenten-1-one
( )-5d. (0.61 g, 48%) as a colorless oil, Rf (EtOAc/hex-
ane 1:4) 0.17; mmax (neat) 3018, 2400, 1735, 1672,
20
45% ee ½aꢁD ¼ ꢀ3:2 (c 1.0, CHCl3). Chiralcel OD-H chi-
ral column (n-hexane/2-propanol 85:15), 1.0 mL/min
flow rate, 254 nm t1 = 12.4 min (major), t2 = 15.7 min
(minor).
1521 cmꢀ1
; dH (400 MHz, CDCl3) 2.80 (1H, d,
J = 18 Hz, CHaHb), 2.32 (1H, d, J = 18 Hz, CHaHb),
2.01 (3H, s, MeCO2), 1.88 (3H, s, @CMeCO), 1.82
(3H, s, MeC@), 1.16 (3H, s, MeCOAc); dC
(100.6 MHz, CDCl3) 205.4, 173.1, 170.2, 127.8, 81.4,
46.3, 30.1, 23.8, 21.3, 20.0; HRMS (EI) M+, found
182.0942, C10H14O3 requires 182.0943.
3.2.8.
(+)-6-Acetoxy-6-benzyl-3,5,5-trimethyl-2-cyclo-
hexen-1-one (+)-4d. (45 mg, 45%) as a colorless oil;
20
36% ee ½aꢁD ¼ þ0:2 (c 1.0, CHCl3). Chiralcel OD-H chi-
ral column (n-hexane/2-propanol 90:10), 1.0 mL/min
flow rate, 254 nm t1 = 10.4 min (major), t2 = 12.6 min
(minor).
3.2. General procedure for CCL hydrolysis of 3a–d, 4a–d,
and 5a–d
3.2.9. (ꢀ)-5-Acetoxy-3,5-dimethyl-2-cyclopenten-1-one
20
To a stirred solution of 100 mg substrate in 20 mL
pH 8.00 phosphate buffer and 1 mL DMSO, 100 mg
CCL was added in one portion and shaken at 20 ꢁC.
The conversion was monitored by TLC. The reaction
mixture was extracted with ethyl acetate, dried over
MgSO4, and concentrated under reduced pressure. The
product was purified by flash column chromatography
(EtOAc/hexane as an eluent).
(ꢀ)-5a. (48 mg, 48%) as a colorless oil; 99% ee ½aꢁD ¼
ꢀ33:6 (c 1.0, CHCl3). Chiralcel OD-H chiral column
(n-hexane/2-propanol 90:10), 1.0 mL/min flow rate,
254 nm t1 = 6.9 min (major), t2 = 9.8 min (minor).
3.2.10. (ꢀ)-5-Acetoxy-5-ethyl-3-methyl-2-cyclopenten-1-
one (ꢀ)-5b. (52 mg, 52%) as a colorless oil; 53% ee
20
½aꢁD ¼ ꢀ8:4 (c 1.0, CHCl3). Chiralcel OD-H chiral col-

C. Tanyeli et al. / Tetrahedron: Asymmetry 16 (2005) 4050–4055
4055
F.; Tanaka, M.; Hosoya, T.; Suzuki-Konagai, K.; Ogita,
T. J. Antibiot. 1999, 52, 525; (c) Nara, F.; Tanaka, M.;
Masuda-Inoue, S.; Yamamoto, Y.; Doi-Yoshioka, H.;
Suzuki-Konagai, K.; Kumamura, S.; Ogita, T. J. Antibiot.
1999, 52, 531; (d) Kolter, T.; Sandhoff, K. Angew. Chem.,
Int. Ed. 1999, 38, 1532; (e) Izuhara, T.; Katoh, T.
Tetrahedron Lett. 2000, 41, 7651.
umn (n-hexane/2-propanol 90:10), 1.0 mL/min flow
rate, 254 nm t1 = 8.4 min (major), t2 = 10.7 min
(minor).
3.2.11. (+)-5-Acetoxy-5-benzyl-3-methyl-2-cyclopenten-
1-one (+)-5c. (47 mg, 47%) as a colorless oil; 43% ee
20
½aꢁD ¼ þ1:2 (c 1.0, CHCl3). Chiralcel OD-H chiral col-
8. (a) Davis, F. A.; Kumar, A.; Chen, B. C. Tetrahedron Lett.
1991, 32, 867; (b) Fujioka, H.; Yamamoto, H.; Kondo, H.;
Annoura, H.; Kita, Y. J. Chem. Soc., Chem. Commun.
1989, 1509.
umn (n-hexane/2-propanol 85:15), 1.0 mL/min flow
rate, 254 nm t1 = 5.9 min (minor), t2 = 7.7 min (major).
9. Hickman, J. R.; Kenyon, J. J. Am. Chem. Soc. 1955, 2051.
10. Hanessian, S. Total Synthesis of Natural Products: The
ÔChironÕ Approach; Pergamon Press: Oxford, 1983.
11. Weber, B.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1992,
31, 84.
3.2.12. (ꢀ)-5-Acetoxy-2,3,5-trimethyl-2-cyclopenten-1-
one (ꢀ)-5d. (46 mg, 46%) as a colorless oil; 90% ee
20
½aꢁD ¼ ꢀ23:8 (c 1.0, CHCl3). Chiralcel OD-H chiral
column (n-hexane/2-propanol 90:10), 1.0 mL/min flow
rate, 254 nm t1 = 13.5 min (major), t2 = 17.8 min
(minor).
12. Kolb, H. C.; Van Nieuwenhze, M. S.; Sharpless, K. B.
Chem. Rev. 1984, 94, 2483.
13. Jacobsen, E. N. Catalytic Asymmetric Synthesis, 1st ed.;
VCH: New York, 1983.
Acknowledgements
14. (a) Davis, F. A.; Chen, B.-C. Chem. Rev. 1992, 92, 919; (b)
Lohnay, B. B.; Enders, D. Helv. Chim. Acta 1989, 72, 980.
15. (a) Davis, F. A.; Weismiller, M. C.; Murphy, C. K.;
Reddy, R. T.; Chen, B.-C. J. Org. Chem. 1992, 57, 7274;
(b) Davis, F. A.; Sheppard, A. C.; Chen, B.-C.; Haque, M.
S. J. Am. Chem. Soc. 1990, 112, 6679; (c) Davis, F. A.;
Vishwakarama, L. C. Tetrahedron Lett. 1985, 26, 3539; (d)
Evans, D. A.; Morrissey, M. M.; Dorrow, R. L. J. Am.
Chem. Soc. 1985, 107, 4346; (e) Enders, D.; Bhushan, V.
Tetrahedron Lett. 1988, 29, 2437; (f) Taschner, M. J.;
Aminbhavi, A. S. Tetrahedron Lett. 1989, 30, 1029; (g)
Gore, M. P.; Vederas, J. C. J. Org. Chem. 1986, 51, 3700;
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615; (i) Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J.
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We thank the Turkish Scientific and Technical Research
Council for a grant [no. TBAG-2244(102T169)].
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