The first enzymatic resolution of quaternary α-acetoxy α-substituted cyclic ketones

Article abstract of DOI:10.1016/j.tetasy.2006.04.012

The enantioselective resolution of quaternary α-acetoxy α-substituted indanone and 1-tetralone derivatives was performed with commercially available enzyme CRL in pH = 8.0 phosphate buffer. Various parameters that would affect the enantoselectivities were tested, and the optimal enzymatic resolution condition was found to afford the enantiomerically enriched quaternary acetoxylated substrates with high ees (varied between 81% and 85%).

Full text of DOI:10.1016/j.tetasy.2006.04.012

Tetrahedron: Asymmetry 17 (2006) 1125–1128
The first enzymatic resolution of quaternary a-acetoxy
a-substituted cyclic ketones
_
_
Cihangir Tanyeli,* Idris M. Akhmedov and C¸ ig˘dem Iyigun
¨
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
Received 20 March 2006; accepted 10 April 2006
Abstract—The enantioselective resolution of quaternary a-acetoxy a-substituted indanone and 1-tetralone derivatives was performed
with commercially available enzyme CRL in pH = 8.0 phosphate buffer. Various parameters that would affect the enantoselectivities
were tested, and the optimal enzymatic resolution condition was found to afford the enantiomerically enriched quaternary acetoxylated
substrates with high ees (varied between 81% and 85%).
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
ketones.11 To the best of our knowledge, enzymatic resolu-
tion of tertiary a-hydroxy or acetoxy ketones has not yet
been reported in the literature, since tertiary alcohols are
usually too bulky to have access to the active sites of
lipases.12
The synthesis of optically active compounds with quater-
nary carbon stereocenters, that is, carbon stereocenters
with four different non-hydrogen substituents, continues
to be an exciting challenge in organic synthesis. Chiral ter-
tiary a-hydroxy ketones and their derivatives containing
tertiary C–O bonds are useful building blocks for many
drugs and natural products. This is particularly true of
the tetralone ring system where this structural unit is
featured in the anthracycline antitumor antibiotics,1 the
phytoalexin lacinilene C,2 the antitumor alkaloid camptho-
thecin,3 and the homoisoflavanone eucomol.4 This unit is
also used as a reagent for the deracemization of amino
acids.5
It is well known in the literature that Mn(OAc)3 efficiently
oxidizes aromatic ketones as well as enones13, and as an
extension of this method, we previously published the re-
sults of a regioselective oxidation method with Mn(OAc)3
applied to various a0- and a-substituted a,b-unsaturated
cyclic ketones14a,14b and cyclic aromatic ketones,14b respec-
tively, to afford the corresponding substances with a qua-
ternary a0- and a-acetoxy moiety. As an extension of the
study, quaternary a0-acetoxy a,b-unsaturated cyclic ke-
tones were subjected to enzymatic resolution.14c In connec-
tion with our work on the development of novel procedures
for the direct oxidation of a-substituted indanone and tetr-
alone derivatives with Mn(OAc)3 in the synthesis of ( )-2-
acetoxy-2-ethyl-1-indanone 2a, ( )-2-acetoxy-2-acetyl-
1-tetralone 2b, and ( )-2-acetoxy-2-methyl-1-tetralone
2c,14b we herein report the results of Pb(OAc)4 mediated
oxidation and subsequent CRL catalyzed enzymatic reso-
lution of these into enantiomerically enriched forms.
Chiral tertiary a-hydroxy ketones have been prepared by
the addition of Grignard reagents to a-keto ketals.6 One
of the most attractive methods involves the asymmetric
oxidation of ketone enolates7 and silyl enol ethers8 using
various chiral oxaziridines. The catalytic enantioselective
oxidation of achiral a-substituted ketones has been
achieved with molecular oxygen, by the use of chiral phase
transfer catalysts derived from cinchona alkaloids9 and by
chiral monoaza-crown ethers.10 Several microbial and
enzymatic methods have been developed for the prepara-
tion of optically active secondary a-hydroxy and acetoxy
Over the course of our study on all biotransformations,
screening reactions were first completed with various
hydrolases (i.e., PLE, CRL, HLE, and PPL) using a
substrate:enzyme ratio from 1:1 to 1:0.5. Among the
hydrolases studied, CRL proved suitable for the enantiose-
lective hydrolysis of the substrates.
*
Corresponding author. Tel.: +90 312 210 3222; fax: +90 312 210 1280;
e-mail: tanyeli@metu.edu.tr
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.04.012

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C. Tanyeli et al. / Tetrahedron: Asymmetry 17 (2006) 1125–1128
2. Synthesis of racemic substrates
O
O
OAc
R
OAc
R
a
Quaternary a-acetoxy a-substituted indanone and tetr-
alone derivatives ( )-2a–c were prepared using our previ-
ously published method with Mn(OAc)314b, and with
Pb(OAc)4. By using Pb(OAc)4 as an oxidizing agent (with
cyclohexane as the solvent), we improved slightly the yields
of the oxidation products 2a–c (Scheme 1). The results of
the selective oxidation methods are shown in Table 1.
n
n
(
R
R
)-(+)-2a
(+)-2b
)-(+)-2c
rac-2a-c
(
2a: n=1, R= Et
2b: n=2, R= Ac
2c: n=2, R= Me
Scheme 2. Reagents and conditions: (a) lipases, DMSO, pH = 8.00
phosphate buffer, 20 ꢁC.
3. Enzymatic hydrolyses of racemic substrates
Various lipases (PLE, CRL, HLE, and PPL) were tested
with all racemic substrates. Treatment of the substrates in
the absence of an enzyme revealed that they do not under-
go autohydrolysis. It was decided to examine the hydrolysis
reaction of quaternary a-acetoxy cyclic ketones 2a–c by
PLE, which is known for its broad substrate specificity
and high stereoselectivity. The enzymatic hydrolysis reac-
tion was performed according to the procedure developed
in our group (Scheme 2).14c To a stirred solution of 2a–c
(100 mg) in phosphate buffer (pH 8.00, 10 mL), with
DMSO as a co-solvent, PLE (100 lL) was added in one
portion and the reaction mixture stirred at 20 ꢁC. The
reaction was monitored by TLC. Among the racemic
substrates, only ( )-2-acetoxy-2-methyl-1-tetralone 2c
afforded enzymatic hydrolysis. Around 50% conversion
was completed within 96 h in the pH 8.00 buffer system
with PLE. The crude product was separated by flash col-
umn chromatography. (ꢀ)-2-Acetoxy-2-methyl-1-tetralone
2c was obtained in 48% yield and 7% ee. Absolute config-
uration of compound (ꢀ)-2c was assigned as (R) by com-
parison of its specific rotation with the literature data of
the isolated (S)-(+)-2-hydroxy-2-methyl-1-tetralone.7d No
hydrolysis was recorded with PPL and HLE. Next, we fo-
cused on the enzymatic hydrolysis reactions with CRL and
found that the optimum conditions were a pH 8.00 buffer
system, at 20 ꢁC, with DMSO used as co-solvent. The sub-
strate:enzyme ratio was changed from 1:0.5 to 1:1. When
the enzyme was used in a stoichiometric amount, the
enantioselectivity increased. (R)-(+)-2-Acetoxy-2-methyl-
1-tetralone 2c was synthesized in 45% isolated yield in
81% ee in pH 8.00 buffer, at 20 ꢁC. CRL appeared to be
the best enzyme tested.
Quaternary a-acetoxy indanone and tetralone derivatives
( )-2-acetoxy-2-ethyl-1-indanone 2a and ( )-2-acetoxy-2-
acetyl-1-tetralone 2b, respectively, were subjected to hydro-
lysis by CRL. The results of the enzymatic resolutions on
different substrates are summarized in Table 2. The reac-
tion was performed according to the following procedure:
substrate (100 mg) was added to pH 8.00 buffer (20 mL)
in 1 mL of DMSO. CRL (100 mg) was then added to the
solution and shaken for 72–136 h with TLC monitoring
at 20 ꢁC.
O
O
OAc
R
a
R
n
n
1a-c
2a-c
1a: n=1, R= Et
1b: n=2, R= Ac
1c: n=2, R= Me
Scheme 1. Reagents and conditions: (a) Pb(OAc)4, cyclohexane, reflux.
4. Conclusion
Table 1. Selective oxidation of a-substituted aromatic ketones
Entry Reactant
Product
2
Time Yield
(h)
Herein, we have demonstrated the first enzymatic resolu-
tions of quaternary a-acetoxy a-substituted cyclic ketones.
Among the enzymes used in hydrolysis conditions, CRL
showed the best enantioselectivity. We have found out that
the pH factor was the critical point for high enantioselec-
tivity. Commercially available and inexpensive enzyme
CRL renders the process very attractive for large scale
preparations.
(%)a,b
with
Pb(OAc)4
O
O
OAc
1
rac-2a 12
rac-2b 12
52
68
O
O
O
OAc
O
2
5. Experimental
1
The H and 13C NMR spectra were recorded in CDCl3 on
O
O
OAc
a Brucker Spectrospin Avance DPX 400 spectrometer.
Chemical shifts are given in parts per million downfield
from tetramethylsilane. Apparent splittings are given in
all cases. Infrared spectra were obtained from KBr pellets
on a Mattson 1000 FT-IR spectrophotometer. Mass spec-
3
rac-2c 12
67
a Yields (%) are given as the isolated yields.
b For Mn(OAc)3 oxidation, see Ref. 14b.

C. Tanyeli et al. / Tetrahedron: Asymmetry 17 (2006) 1125–1128
Table 2. CRL resolution of a-substituted aromatic ketones
1127
20
Entry
Substrate
Time (h)
Acetoxy pdt.a
Yield (%)b
Conversion (%)c
½aꢁD
ee (%)d
O
OAc
1
rac-2a
85
46
49
+14.8
83
(R)-(+)-2a
O
OAc
2
3
rac-2b
rac-2a
72
49
45
50
49
+4.4
+2.6
85
81
O
(+)-2b
O
OAc
136
(R)-(+)-2c
a The absolute configurations of (+)-2a and (+)-2c were assigned as (R) by comparison of their specific rotations with the literature data Refs. 10 and 7d,
respectively.
b Yields (%) are given as the isolated yields.
c Conversions were determined by the Thermo Hypersil-Keystone column HPLC analysis.
d Enantiomeric excesses were determined by the Chiralcel ODH chiral column HPLC analysis.
tra 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 mea-
surements were performed with ThermoFinnigan Spectra
System instrument. Separations were carried out on Ther-
mo Hypersil-Keystone analytical column (100 · 4.60 mm)
and Chiralcel OD-H analytical column (250 · 4.60 mm)
with hexane/2-propyl alcohol as eluent. Column chroma-
tography 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 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, respectively. CRL (Lipase, Type
VII, from Candida rugosa) and PPL (Lipase, Type II, from
Porcine Pancreas) were purchased from Aldrich. 2-Ethyl
indanone 1a and 2-acetyl tetralone 1b were purchased from
Aldrich. 2-Methyl tetralone 1c was synthesized and is in
accordance with the literature data.14b
3.35 (1H, d, J = 17 Hz, CHaHb), 3.15 (1H, d, J = 17 Hz,
CHaHb), 2.02 (3H, s, MeCO2), 1.75–1.86 (1H, m, Me-
CHaHb), 1.63–1.72 (1H, m, MeCHaHb), 0.87 (3H, t,
J = 7 Hz, MeCH2); dC (100.6 MHz, CDCl3) 202.8, 170.4,
149.8, 135.6, 135.3, 128.1, 126.2, 124.7, 85.1, 37.9, 30.1,
21.2, 8.0; m/z (EI) 220 (15), 219 (100), 160 (6), 159 (9);
HRMS (EI) M+, found 218.0937, C13H14O3 requires
218.0943.
5.1.2. ( )-2-Acetoxy-2-acetyl-1-tetralone 2b. This (1.84 g,
68%) was obtained as a colorless oil, Rf (EtOAc/hexane
1:4) 0.41; mmax (neat) 2254, 1794, 1709, 1662, 1363, 1095,
910, 753, 715 cmꢀ1; dH (400 MHz, CDCl3) 8.58 (1H, d,
J = 8 Hz, Ar), 8.20 (1H, d, J = 8 Hz, Ar), 7.35–7.65 (2H,
m, Ar), 2.79–3.02 (4H, m, CH2CH2), 2.26 (3H, s, MeCO2),
2.23 (3H, s, MeCO); dC (100.6 MHz, CDCl3) 210.3, 204.2,
198.7, 162.6, 143.6, 134.4, 129.0, 127.5, 112.5, 68.4, 32.5,
30.1, 26.3, 25.1; m/z (EI) 199 (42), 190 (14), 189 (100),
147 (17); HRMS (EI) M+, found 246.0902, C14H14O4
requires 246.0892.
5.1. General procedure for the Pb(OAc)4 oxidations of
a-substituted cyclic ketones ( )-1a–c
5.1.3. ( )-2-Acetoxy-2-methyl tetralone 2c. This (1.61 g,
67%) was obtained as a white solid, mp 258–260 ꢁC; Rf
(EtOAc/hexane 1:3) 0.50; mmax (neat) 2260, 1783, 1710,
1652, 1358 cmꢀ1; dH (400 MHz, CDCl3) 8.00 (1H, d, J =
8 Hz, Ar), 7.41 (1H, t, J = 8 Hz, Ar), 7.26 (1H, t,
J = 8 Hz, Ar), 7.15 (1H, d, J = 8 Hz, Ar), 2.89–2.99
(3H, m, CH2CHaHbCMeOAc), 2.00 (3H, s, MeCO2),
1.97–1.99 (1H, m, CH2CHaHbCMeOAc), 1.47 (3H, s,
MeCOAc); dC (100.6 MHz, CDCl3) 195.2, 170.1, 142.4,
134.0, 131.6, 129.0, 128.8, 127.4, 81.3, 33.4, 27.3, 22.0,
21.7; HRMS (EI) M+, found 218.0941, C13H14O3 requires
218.0943.
A mixture of Pb(OAc)4 (5.00 g, 11.0 mmol) and the a-
substituted cyclic ketone (11.0 mmol) in cyclohexane
(50 mL) was allowed to reflux for 12 h and 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 column
chromatography using ethyl acetate/hexane as eluent.
5.1.1. ( )-2-Acetoxy-2-ethyl-indanone 2a. This (1.25 g,
52%) was obtained as a colorless oil, Rf (EtOAc/hexane
1:4) 0.31; mmax (neat) 3410, 3019, 1724, 1609, 1466,
1257 cmꢀ1; dH (400 MHz, CDCl3) 7.71 (1H, d, J = 8 Hz,
Ar), 7.53 (1H, t, J = 8 Hz, Ar), 7.30–7.33 (2H, m, Ar),
5.2. General procedure for CRL hydrolysis of ( )-2a–c
To a stirred solution of 100 mg substrate in phosphate buf-
fer (0.1 M, pH 8.00, 20 mL) and 1 mL DMSO, 100 mg

1128
C. Tanyeli et al. / Tetrahedron: Asymmetry 17 (2006) 1125–1128
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CRL 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 eluent).
5.2.1.
(R)-(+)-2-Acetoxy-2-ethyl-indanone
(R)-(+)-2a.
This (46 mg, 46%) was obtained as a colorless oil; 83% ee
20
½aꢁD ¼ þ14:8 (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 = 14.3 min (minor), t2 = 15.4 min (major).
5.2.2. (+)-2-Acetoxy-2-acetyl-1-tetralone (+)-2b. This
(49 mg, 49%) was obtained as a colorless oil; 85% ee
20
½aꢁD ¼ þ4:4 (c 1.0, CHCl3). Chiralcel OD-H chiral column
(n-hexane/2-propanol 85:15), 1.0 mL/min flow rate,
254 nm t1 = 12.7 min (minor), t2 = 13.3 min (major).
8. Solladie-Cavallo, A.; Lupattelli, P.; Jierry, L.; Bovicelli, P.;
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5.2.3. (R)-(+)-2-Acetoxy-2-methyl tetralone (R)-(+)-2c.
This (45 mg, 45%) was obtained as a white solid; 81% ee
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20
½aꢁD ¼ þ2:6 (c 1.0, CHCl3). Chiralcel OD-H chiral column
(n-hexane/2-propanol 85:15), 1.0 mL/min flow rate,
254 nm t1 = 14.8 min (minor), t2 = 16.2 min (major).
11. (a) Adam, W.; Diaz, M. T.; Fell, R. T.; Saha-Moller, C. R.
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Acknowledgments
We thank the Turkish Scientific and Technical Research
Council for a Grant [No. TBAG-105T247].
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