Synthesis of chiral acetoxy lactones via the Baeyer-Villiger oxidation of cyclic aromatic acetoxy ketones

Article abstract of DOI:10.1016/j.tet.2008.09.035

The α-acetoxylation of indanones and tetralones by using Mn(OAc)₃ followed by the enzyme catalyzed kinetic resolution of acetoxy ketones furnished both of the enantiomers of α-acetoxy ketones in good chemical and optical yields. The Baeyer-Vill

Full text of DOI:10.1016/j.tet.2008.09.035

Tetrahedron 64 (2008) 11256–11261
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Synthesis of chiral acetoxy lactones via the Baeyer–Villiger oxidation
of cyclic aromatic acetoxy ketones
*
Ayhan S. Demir , Asuman Aybey
Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 June 2008
Received in revised form 28 August 2008
Accepted 11 September 2008
Available online 23 September 2008
The
kinetic resolution of acetoxy ketones furnished both of the enantiomers of
chemical and optical yields. The Baeyer–Villiger oxidation of -acetoxy ketones with m-CPBA, CF3SO3H,
and CH2Cl2, at rt gives the corresponding lactones without racemization. The acetoxy ketone moiety
a
-acetoxylation of indanones and tetralones by using Mn(OAc)3 followed by the enzyme catalyzed
a
-acetoxy ketones in good
a
migrates selectively in order to form lactones. The mild hydrolysis of lactones affords phenolic
droxycarboxylic acid derivatives.
a-hy-
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
OH
OH
*
O
OH
R
( )n
The Baeyer–Villiger (BV) oxidation of ketones represents
a powerful methodology in synthesis for cleaving carbon–carbon
bonds in an oxygen-insertion process. BV oxidation has been
widely employed for the transformation of carbonyl compounds
to the corresponding esters or lactones using peracids or hy-
drogen peroxide.1,2 The chiral BV oxidation of cyclic ketones al-
lows for rapid access to chiral lactones, which are valuable
intermediates in organic chemistry. The biocatalytic equivalent
to the above peracids is represented by monooxygenases, which
OAc
R
*
R
( )n
O
( )n
Scheme 1.
2. Results and discussion
In our ongoing work, we have published several papers on the
Mn(OAc)3-mediated direct acetoxylation and acyloxylation (carried
out via metathesis of acetic acid with various carboxylic acids) of
enones and aromatic ketones followed by the enzyme- and fungus-
mediated resolution of acyloxy enones to obtain enantiomerically
are
processes.3
There are several methods for the BV oxidation of simple
a sub-class of the oxygenase enzyme family in green
cycloalkanes, but to our best knowledge, much less attention has
been paid to the synthetic applications of the BV oxidation of
pure a
-hydroxy ketones.5,6
As an initial reaction (Scheme 2), the oxidation of commercially
available tetralone (1a) with Mn(OAc)3 in cyclohexane or benzene
was performed to obtain the desired 2-acetoxytetralone (2a) in 89%
yield after purification of the crude product by column chroma-
tography. Using similar procedures starting from the commercially
functionalized ketones, especially cyclic
could be a straightforward route to the
-hydroxyalkanoic acid derivatives. In the present paper, we report
an effective chemoenzymatic synthetic approach to -acetoxy
ketones, their BV product lactones, and hydroxyalkanoic acid
derivatives by the Mn(OAc)3-mediated acetoxylation of cyclic
aromatic ketones and BV oxidation followed by hydrolysis under
mild conditions as shown in Scheme 1. These BV products and
hydroxyalkanoic acid derivatives are either a precursor of some
important biologically active compounds or they demonstrate
biological activity.4
a
-hydroxy ketones, which
a
-hydroxy lactones and
a
a
available ketones
a-actoxytetralone, indanone, and chromanone
derivatives were synthesized in good to high yields as shown in
Table 1. The direct synthesis of acetoxy enones 2a–g under mild
conditions from 1a–g using Mn(OAc)3 is an attractive alternative to
the other (multistep) procedures for
a
-oxidation.3a,7,17
2.1. Baeyer–Villiger oxidation of -acetoxy ketones
a
A large number of catalysts have been shown to be active in
the oxidation of cycloalkanones to lactones using several oxidants
but none of them describe the BV oxidation of aromatic ketones
* Corresponding author. Fax: þ90 312 210 3200.
E-mail address: asdemir@metu.edu.tr (A.S. Demir).
with electron rich substituents at the
a-position. In most cases,
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.09.035

A.S. Demir, A. Aybey / Tetrahedron 64 (2008) 11256–11261
11257
f
O
O
O
O
OH
O
O
a
b
R
R
+
*
R
*
R
O
O
( )n
( )n
X
( )n
X
( )n
X
X
(R/S)-2
1
rac-2
(R/S)-3
g
e
c
OH
OH
O
O
O
OH
( )n
d
R
R
*
O
( )n
X
O
5
(R/S)-4
Scheme 2. (a) Mn(OAc)3; (b) Enzymatic-kinetic resolution; (c) m-CPBA, CF3SO3H; (d) (K2CO3/MeOH);17 (e) Sc(OTf)3/MeOH/H2O;18c,d (f) acetic anhydride/Cu(OTf)3;18a (g) DBU in
hexane/THF.18b
m-chloroperbenzoic acid is used as an oxidizing agent. In an initial
reaction, the oxidation of 2a was carried out with m-CPBA in CHCl3,
in which the reaction was monitored by TLC and no product for-
mation was observed (48 h). To enhance the reactivity of m-chlor-
operbenzoic acid, the reagent is combined with an appropriate
promoter, such as sulfonic acids, Nafion-H, CF3COOH, hydrotalcite,
SnCl4, Re(OTf)3, as well as trifluoromethanesulfonic acid.8 As shown
in Table 2, m-CPBA was used with various reagents for the BV ox-
idation of the acetoxylated products, in which the reactions were
monitored by TLC: method A:9 m-CPBA, KHCO3, CH2Cl2, reflux (36–
96 h); method B:10 NaBO3$4H2O, HCOOH, 0 ꢀC (3–24 h); method
C:11 m-CPBA, PTSA, CH2Cl2, rt (10–24 h); method D:12 m-CPBA,
Bi(OTf)3, CH2Cl2, 0 ꢀC (48–96 h); method E:13 m-CPBA, CHCl3 (48 h);
and method F:14 m-CPBA, CF3SO3H, CH2Cl2, rt (15–45 min).
Depending on the reagents and conditions, most of the reactions
furnished the desired products 4a–g in moderate to high yields
with the same regioselectivity (Scheme 2). According to the spec-
troscopic data, the acetoxy ketone group migrated in order to form
the BV products and no other isomer was detected (GC, NMR, and
GC–MS). Methods A and F work with all the compounds and
method F: (m-CPBA, CF3SO3H (10 mol %), CH2Cl2, rt) gave the best
yields (68–95%) in a short reaction time (15–45 min) compared to
the other conditions. No product formation was observed by using
method E.
Table 1
Mn(OAc)3-mediated acetoxylation of aromatic ketones
Aromatic ketones 1
Acetoxy ketones
2
Yield (%)
895a
O
O
OAc
a
a
O
O
OAc
855a
The enantiomerically pure
a-acetoxy ketones and their re-
spective BV products are interesting and important synthetic pre-
cursors for various compounds.4,5 Therefore, we first attempted to
perform the BV oxidation reaction with biocatalysts. BV oxidations
can also be performed using enzymes (Baeyer–Villigerases). These
biocatalysts enable one to reach very high enantioselectivity, and
several examples demonstrating the possible preparative scale use
of whole cell microorganisms, starting from either racemic or
prochiral substrates, have been described.3,16 The BV oxidation of
2b, 2d, and 2e was carried out with cyclohexanone monooxygenase
Acinetobacter sp. (EC 1.14.13.22) (CHMO, NADPH, DMSO/buffer
(pH¼8–9)) mainly unchanged starting material was isolated to-
gether with a trace amount of the hydrolysis product.
MeO
MeO
b
b
O
O
OAc
80
OMe
c
OMe
c
O
O
OAc
96
d
d
After unsuccessful biocatalytical BV reactions, we attempted the
traditional well proven enzyme catalyzed kinetic resolution of the
O
O
a
-acetoxy ketones. We already published some preliminary results
OAc
755b
for the enzyme catalyzed kinetic resolution of acetoxy ketones.5 In
light of these preliminary results, acetoxy ketones are screened
with enzymes for kinetic resolution.
O
O
e
e
Ester hydrolysis was investigated using commercially available
enzymes: Amano PS, CCL (lipase from Candida cylindracea), PPL
(Porcine pancreatic lipase), HPL (lipase from hog pancreas), WGL
(lipase from wheat germ), MML (lipase from Mucor miehei), PRL
(lipase from Penicillium roqueforti), RAL (Lipase from Rhizopus
arrhizus), RNL (Lipase from Rhizopus niveus), PFL (lipase from
Pseudomonas fluorescens), QLM (lipase from Alcaligenes sp.), AL
(lipase from Aspergillus).
O
O
OAc
83
O
f
O
f
O
O
815a
OAc
In a typical experiment, for enzymatic hydrolysis, the racemic
acetates, 2a–g, were dissolved in an appropriate organic solvent,
g
g

11258
A.S. Demir, A. Aybey / Tetrahedron 64 (2008) 11256–11261
Table 2
The BV oxidation of
a
-acetoxy ketones
Products 4
Acetoxy ketones 2
Method A
Yield (%)
Method B
Yield (%)
Method C
Yield (%)
Method D
Yield (%)
Method E
Yield (%)
Method F
Yield (%)
O
O
OAc
O
a
60
85
d
d
20
30
d
d
d
d
90
95
a
O
OAc
b
c
H3CO
b
O
O
OAc
65
d
40
d
d
90
OCH3
c
O
O
OAc
d
e
80
35
d
d
d
d
d
95
68
d
O
O
OAc
40
45
25
65
O
e
O
O
OAc
f
40
55
30
60
d
d
70
O
O
f
O
g
d
d
d
7015
OAc
g
Table 3
and then phosphate buffer (pH 7.0) (1:10) was added and the
mixture was stirred at rt in the presence of an enzyme. The reaction
was monitored by TLC, HPLC, and LC–MS with a chiral column using
racemic acetate, and alcohol (synthesized from acetate with K2CO3/
MeOH)17 as references. When approximately 50% conversion was
attained, the crude product was separated by flash column chro-
matography to afford acetate 2, and alcohol 3 (Scheme 2).
All the enzymes achieved hydrolysis. Among them, Amano PS
and WGL furnished the best results. All of the other enzymes give
moderate ee (reaction time 48–120 h, ee: 25–52% for acetate 17–
43% for alcohol; solvents: DMSO, toluene, dioxane, THF, acetoni-
trile, and xylene). In case of 2d Amano PS and WGL showed reverse
selectivity.
The BV oxidation of the acetoxy ketone (S)-2 was carried out
under the conditions as described for racemic acetoxy ketones. The
careful monitoring of the ee value of the BV product 4a showed that
no racemization occurred during the oxidation. This procedure was
applied to all of the acetoxy ketones and chiral BV products were
obtained in 69–94% yields (Scheme 2). The results are summarized
in Table 3. Under similar BV conditions as described by the acetate,
the oxidation of chiral alcohol 3a gave a mixture of the products, in
which difficulties were produced by the separation and identifi-
cation of the products. This reaction is under investigation. These
difficulties can be overcome when the alcohols are converted to
their acetate immediately after separation by flash column chro-
matography. Racemization-free acetylation of alcohols was carried
out with acetic anhydride/Cu(OTf)3 according to a procedure
Enzymatic-kinetic resolution and BV oxidation of
a
-acetoxy ketones
Enzymatic-kinetic resolution of -acetoxy ketones
a
Baeyer–Villiger
oxidation
(method F)
a
-Acetoxy
Conditions
Acetatea
2
Alcohola
3
BV product 4
ketone rac-2
ee (%), yield (%) ee (%), yield (%) ee (%), yield(%)
a
Amano PS buffer/ (ꢁ)-(S)-2a5a
(þ)-(R)-3a
81, 36
3b
71, 39
3c
66, 41
3d
81, 41
4a
87, 89
4b
87, 93
4c
83, 90
4d
acetonitrile
89, 45
b
c
Amano PS buffer/ (ꢁ)-2b5a
toluene
90, 35
Amano PS buffer/ (ꢁ)-2c
toluene
84, 40
(þ)-2d
85, 48
d
Lipase from
wheat germ
buffer/DMSO
85, 94
Amano PS buffer/ (ꢁ)-2d
toluene
60, 45
41, 34
58, 91
4e
97, 69
4f
56, 71
4g15
85, 73
e
f
Amano PS buffer/ (ꢁ)-(S)-2e5b
(þ)-(R)-3e
88, 38
3f
toluene
97, 36
Amano PS buffer/ (ꢁ)-2f
toluene
58, 45
61, 41
g
Amano PS buffer/ (þ)-(S)-2g5a
(ꢁ)-(R)-3g
acetonitrile
86, 48
81, 38
a
ee Values are determined via their acetate.
reported in the literature.18a The acetoxy ketone can be epimerized
using DBU in hexane/THF.18b Likewise, racemization-free hydrolysis
of chiral acetoxy ketone was carried out with Sc(OTf)3/MeOH/H2O

A.S. Demir, A. Aybey / Tetrahedron 64 (2008) 11256–11261
11259
(Scheme 2).18c,d With this method, it was possible to obtain both
enantiomers of the lactones.
3.1.3. 3,4-Dihydro-6-methyl-4-oxo-2H-chromen-3-yl acetate (2f)
The crude mixture was purified by column chromatography
The BV product lactones are starting materials for interesting
-hydroxycarboxylic acids with phenolic groups. As a representa-
(hexane/AcOEt 6:1) to give 2f (1.84 g, 83%) as a yellow oil. IR (neat):
a
3443, 1693, 1609, 1060, 762 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d 7.65
tive, examples 4e and 4g are converted to the -hydroxy esters 5a,
a
(s, 1H), 7.29 (d, J¼8.4 Hz, 1H), 6.86 (d, J¼8.4 Hz, 1H), 5.6 (dd, J¼11.3,
5b with K2CO3 in methanol. The reaction works under mild con-
ditions at rt to form the products in 84–88% yield as shown in
Scheme 3.
5.5 Hz,1H), 4.5 (dd, J¼11.0, 5.5 Hz,1H), 4.35 (dd, J¼11.3, 11.0 Hz,1H),
2.33 (s, 3H), 2.20 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 187.7, 169.3,
159.7, 137.6, 131.6, 127.4, 119.9, 117.8, 69.7, 68.6, 20.8, 20.6. Anal.
Calcd for C12H12O4 (220.22): C, 65.45; H, 5.49. Found: C, 65.31; H,
5.62.
O
O
OH
( )n
O
OAc
K2CO3/MeOH
3.2. General procedures for the Baeyer–Villiger oxidation
R
( )n
R
OMe
of
a
-acetoxy ketones
OH
4e n= 1; R=OCH3
4g n= 0; R=H
5a n= 1; R=OCH3
Method A. A solution of
a-acetoxy ketones 2a–g (50 mg,
n= 0; R=H
5b
0.28 mmol) and KHCO3 (35 mg, 0.35 mmol) in 10 mL CH2Cl2 were
stirred, and commercial grade m-CPBA (80% activity, 61 mg,
0.35 mmol) was added to this mixture. The reaction mixture was
stirred under reflux.
Scheme 3.
Method B. A solution of a-acetoxy ketone 2e (50 mg, 0.24 mmol)
The results show that the Mn(OAc)3-mediated acetoxylation of
aromatic ketones followed by BV oxidation selectively furnishes
lactones in good to high yields. By BV reactions, acetoxy ketone
moiety migrates in order to form lactones. The lactones are also
in formic acid (0.5 mL, 98%) was stirred and cooled in an ice bath.
Sodium perborate tetrahydrate (55 mg, 0.36 mmol, 90%) was added
subsequently in small portions over a period of 6 h. Stirring was
continued for another 2 h. The precipitate was filtered off and
washed with ethyl acetate. The filtrate was diluted with water.
Sodium metabisulphite was slowly added in order to quench the
remaining peroxides. The aqueous layer was extracted with ethyl
acetate. The combined organic layers were dried over CaSO4 and
concentrated in vacuo to dryness.
formed from the chiral a-acetoxy ketones without racemization.
The chiral acetoxy ketones are synthesized via enzymatic-kinetic
resolution. Enzyme-mediated hydrolysis of the acetoxy group
provides hydroxy enone 4 and acetoxy enone 3 up to 97% enan-
tiomeric excesses and in good chemical yields. In a representative
example, lactones are converted to phenolic a-hydroxy esters 5a,b
Method C. Baeyer–Villiger oxidation of 2c (50 mg) with m-CPBA
(217 mg) and p-toluenesulfonic acid (27 mg) in dichloromethane
(5 mL) for 5 h gave a crude product.
in 84–88% yields. This method gives a simple new entry to the
synthesis of lactones in order to form acetoxy ketones and their
conversion to phenolic hydroxy esters, which are interesting in-
termediates for the synthesis of amino acids and other interesting
compounds.
Method D. To a mixture of an appropriate ketone (0.2 mmol) and
Bi(OTf)3 (5 mol %) in 10 mL of anhydrous dichloromethane at 0 ꢀC
commercial grade m-CPBA (80% activity, 69 mg, 0.4 mmol) was
added, and the reaction mixture was stirred at rt. After the com-
pletion of the reaction, the catalyst was separated by simple fil-
tration and the unreacted m-CPBA was decomposed by the addition
of an aq Na2S2O3 solution. The product was extracted using ethyl
acetate, and all of the organic extracts were combined, dried over
anhydrous Na2SO4, and concentrated to yield a crude product.
3. Experimental
3.1. General procedure for Mn(OAc)3 oxidation
General procedures have been described previously.5
Method E. To a solution of a-acetoxy ketones (0.2 mmol) in 5 mL
3.1.1. 1,2,3,4-Tetrahydro-5-methoxy-1-oxonaphthalen-2-yl
acetate (2c)
dry CHCl3 commercial grade m-CPBA (80% activity, 69 mg,
0.4 mmol) was added, and the reaction mixture was stirred under
reflux. Then, it was cooled to rt and extracted using ethyl acetate,
and all the organic extracts were combined, dried over anhydrous
Na2SO4, and concentrated to yield a crude product.
Method F. To a mixture of the starting material (0.2 mmol) and
TfOH (3 mg, 0.02 mmol) in 10 mL of anhydrous CH2Cl2 at 0 ꢀC,
commercial grade m-CPBA (80% activity, 69 mg, 0.4 mmol) was
added, and the mixture was stirred at rt. After the completion of the
reaction, the excess of the reagent was decomposed by the addition
of an aq Na2S2O3 solution. Conventional workup and purification by
silica gel column chromatography gave the desired esters or
lactones.
The crude mixture was purified by column chromatography
(hexane/AcOEt 6:1) to give 2c (1.78 g, 80%) as a yellow solid. Mp
94–95 ꢀC. IR (KBr): 3049, 2953, 1750, 1673, 1590, 1240, 1104,
940 cmꢁ1
.
1H NMR (400 MHz, CDCl3):
d
7.6 (d, J¼8.0 Hz, 1H), 7.27
(t, J¼8.0 Hz, 1H), 7.0 (d, J¼8.0 Hz, 1H), 5.48 (dd, J¼13.7, 5.0 Hz,
1H), 3.87 (s, 3H), 3.24 (m, 1H), 2.84 (m, 1H), 2.07–2.30 (m, 2H),
2.21 (s, 3H). 13C NMR (100 MHz, CDCl3):
d 192.4, 169.6, 156.6,
132.7, 131.8, 127.4, 119.4, 114.4, 74.2, 55.5, 28.3, 21.8, 20.7. Anal.
Calcd for C13H14O4 (234.25): C, 66.66; H, 6.02. Found: C, 66.36; H,
5.87.
3.1.2. 1,2,3,4-Tetrahydro-5,7-dimethyl-1-oxonaphthalen-2-yl
acetate (2d)
3.2.1. 2,3,4,5-Tetrahydro-2-oxobenzooxepin-3-yl acetate (4a)
The crude mixture was purified by column chromatography
(hexane/AcOEt 5:1) to give 4a (40 mg, 90%) as a colorless solid. Mp
67–68 ꢀC. IR (KBr): 3461, 2953, 1782, 1738, 1450, 1384, 1169,
The crude mixture was purified by column chromatography
(hexane/AcOEt 6:1) to give 2d (1.67 g, 96%) as a yellow solid. Mp
101–103 ꢀC. IR (CHCl3): 3447, 1693, 1608, 763 cmꢁ1 1H NMR
.
(400 MHz, CDCl3):
1H), 2.80–3.0 (m, 2H), 2.34 (m, 1H), 2.27 (s, 3H), 2.21 (s,3H), 2.15 (s,
3H), 2.12 (m, 1H). 13C NMR (100 MHz, CDCl3):
192.9, 169.9, 138.2,
d
7.6 (s, 1H), 7.1 (s, 1H), 5.4 (dd, J¼13.7, 5.0 Hz,
766 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d 7.16–7.33 (m, 4H), 5.08 (dd,
J¼10.4, 8.7 Hz, 1H), 3.05 (dt, J¼13.6, 7.9 Hz, 1H), 2.71 (dt, J¼14.0,
d
7.9 Hz, 1H), 2.28–2.48 (m, 2H), 2.10 (s, 3H). 13C NMR (100 MHz,
136.3, 136.2, 135.9, 131.7, 125.8, 74.2, 28.4, 25.0, 20.9, 19.3. Anal.
Calcd for C14H16O3 (232.28): C, 72.39; H, 6.94. Found: C, 72.33; H,
6.82.
CDCl3): d 169.8, 168.1, 150.5, 129.5, 129.0, 128.9, 126.4, 119.7, 69.1,
32.3, 25.7, 20.5. Anal. Calcd for C12H12O4 (220.22): C, 65.45; H, 5.49.
Found: C, 65.36; H, 5.64.

11260
A.S. Demir, A. Aybey / Tetrahedron 64 (2008) 11256–11261
3.2.2. 2,3,4,5-Tetrahydro-7-methoxy-2-oxobenzooxepin-3-yl
acetate (4b)
3.3.1. (ꢁ)-(S) 1,2,3,4-Tetrahydro-1-oxonaphthalen-2-yl acetate (2a)
HPLC (Chiralcel OBH column, flow rate of 0.8 mL/min, hexane/
The crude mixture was purified by column chromatography
(hexane/AcOEt 6:1) to give 4b (48 mg, 95%) as a semisolid. IR (KBr):
i-propanol 9:1): tR 26.1 for (ꢁ)-2a, 31.7 for (þ)-2a. [
a]
ꢁ63.3 (c
D
0.57, CH2Cl2).
3445, 2949, 1769, 1738, 1494, 1380, 1163, 835 cmꢁ1 1H NMR
.
(400 MHz, CDCl3):
d
7.04 (d, J¼8.8 Hz, 1H), 6.71 (dd, J¼8.8, 2.9 Hz,
3.3.2. (ꢁ)-1,2,3,4-Tetrahydro-6-methoxy-1-oxonaphthalen-2-yl
acetate (2b)
1H), 6.63 (d, J¼2.9 Hz, 1H), 4.99 (dd, J¼10.5, 8.7 Hz, 1H), 3.73 (s, 3H),
2.96 (m, 1H), 2.57 (m, 1H), 2.19–2.37 (m, 2H), 2.05 (s, 3H). 13C NMR
HPLC (Chiralcel OBH column, flow rate of 0.8 mL/min, hexane/
(100 MHz, CDCl3):
112.8, 69.2, 55.7, 32.3, 26.4, 20.8. Anal. Calcd for C13H14O5 (250.25):
C, 62.39; H, 5.34. Found: C, 62.43; H, 5.41.
d
169.6, 168.3, 157.8, 144.4, 130.7, 120.9, 115.3,
i-propanol 9:1): tR 45.6 for (ꢁ)-2b, tR 66.8 for (þ)-2b. [ D ꢁ200 (c
a
]
0.074, CH2Cl2).
3.3.3. (ꢁ)-1,2,3,4-Tetrahydro-5-methoxy-1-oxonaphthalen-2-yl
acetate (2c)
3.2.3. 2,3,4,5-Tetrahydro-6-methoxy-2-oxobenzooxepin-3-yl
acetate (4c)
HPLC (Chiralcel OBH column, flow rate of 0.8 mL/min, hexane/
The crude mixture was purified by column chromatography
(hexane/AcOEt 6:1) to give 4c (45 mg, 90%) as a yellow solid. Mp
122–123 ꢀC. IR (KBr): 3450, 2948, 1772, 1736, 1485, 1379, 1157,
i-propanol 9:1): tR 29.4 for (ꢁ)-2c, tR 41.7 for (þ)-2c. [
a
]
ꢁ61 (c
D
0.32, CHCl3).
784 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
7.20 (t, J¼8.3 Hz, 1H), 6.81
3.3.4. (þ)-1,2,3,4-Tetrahydro-5,7-dimethyl-1-oxonaphthalen-2-yl
acetate (2d)
(d, J¼8.1 Hz, 1H), 6.74 (d, J¼8.3 Hz, 1H), 5.03 (t, J¼8.7 Hz, 1H), 3.85
(s, 3H), 3.26 (dd, J¼13.9, 6.5 Hz, 1H), 2.60 (dt, J¼13.9, 7.5 Hz, 1H),
HPLC (Chiralcel OBH column, flow rate of 0.5 mL/min, hexane/
2.21–2.43 (m, 2H), 2.1 (s, 3H). 13C NMR (100 MHz, CDCl3):
d
169.3,
i-propanol 9:1): tR 27.6 for (ꢁ)-2d, tR 41.9 for (þ)-2d. [
a]D 8.9 (c 0.36,
167.6, 156.9, 151.5, 128.3, 117.9, 112.2, 108.2, 69.3, 55.8, 31.6, 20.4,
17.4. Anal. Calcd for C13H14O5 (250.25): C, 62.39; H, 5.34. Found: C,
62.33; H, 5.43.
CH2Cl2).
3.3.5. (ꢁ)-1,2,3,4-Tetrahydro-5,7-dimethyl-1-oxonaphthalen-2-yl
acetate (2d)
3.2.4. 2,3,4,5-Tetrahydro-6,8-dimethyl-2-oxobenzooxepin-3-yl
acetate (4d)
The crude mixture was purified by column chromatography
(hexane/AcOEt 6:1) to give 4d (36 mg, 95%) as an oily compound. IR
(neat): 3441, 2940, 1768, 1743, 1448, 1376, 1076, 838 cmꢁ1. 1H NMR
HPLC (Chiralcel OBH column, flow rate of 0.5 mL/min, hexane/
i-propanol 9:1): tR 27.6. [
a
]
D
ꢁ49.1 (c 0.81, CH2Cl2).
3.3.6. (ꢁ)-(S)-3,4-Dihydro-4-oxo-2H-chromen-3-yl acetate (2e)
HPLC (Chiralcel OD column, flow rate of 0.8 mL/min, hexane/
(400 MHz, CDCl3):
(m, 2H), 2.24 (s, 3H), 2.23 (s, 3H), 2.12–2.31 (m, 2H), 2.04 (s, 3H). 13C
NMR (100 MHz, CDCl3): 169.6, 168.2, 151.1, 138.2, 136.3, 129.1,
d
6.77 (s, 2H), 4.91 (t, J¼9.1 Hz, 1H), 2.65–2.84
i-propanol 9:1): tR 12.1 for (ꢁ)-2e, tR 13.2 for (þ)-2e. [ D ꢁ63 (c 0.5,
a
]
CHCl3).
d
125.0, 118.3, 69.5, 30.1, 21.4, 21.3, 20.7, 19.6. Anal. Calcd for C14H16O4
(248.27): C, 67.73; H, 6.50. Found: C, 67.56; H, 6.33.
3.3.7. (ꢁ)-3,4-Dihydro-6-methyl-4-oxo-2H-chromen-3-yl
acetate (2f)
HPLC (Chiralpak IA column, flow rate of 0.5 mL/min, hexane/
3.2.5. 3,4-Dihydro-2-oxo-2H-benzo[1,4]dioxepin-3-yl acetate (4e)
The crude mixture was purified by column chromatography
(hexane/AcOEt 3:1) to give 4e (30 mg, 68%) as a colorless solid. Mp
125–126 ꢀC. IR (KBr): 3433, 2956, 1772, 1735, 1491, 1252, 1091,
i-propanol 9:1): tR 15.9 for (þ)-2f, tR 18.9 for (ꢁ)-2f. [
a
]
ꢁ19.5 (c
D
0.6, CH2Cl2).
3.3.8. (þ)-(S)-2,3-Dihydro-1-oxo-1H-inden-2-yl acetate (2g)
832 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
7.1 (m, 4H), 5.4 (t, J¼8.5 Hz,
HPLC (Chiralcel OD column, flow rate of 0.8 mL/min, hexane/
1H), 4.5 (d, J¼8.0 Hz, 2H), 2.1 (s, 3H). 13C NMR (100 MHz, CDCl3):
i-propanol 95:5): tR 21.1 for (ꢁ)-2g, tR 23.3 for (þ)-2g. [
a] 16.2 (c
D
d
167.5, 164.2, 145.7, 143.4, 126.5, 125.2, 121.5, 119.4, 72.9, 66.7, 19.4.
0.81, CH2Cl2).
Anal. Calcd for C11H10O5 (222.19): C, 59.46; H, 4.54. Found: C, 59.52;
H, 4.63.
3.2.6. 3,4-Dihydro-8-methyl-2-oxo-2H-benzo[1,4]dioxepin-3-yl
acetate (4f)
3.4. General procedure for the hydrolysis of lactones
The crude mixture was purified by column chromatography
(hexane/AcOEt 3:1) to give 4f (33 mg, 70%) as a yellow solid. Mp
107–108 ꢀC. IR (KBr): 3447, 2944, 1792, 1751, 1403, 1274, 1091,
To 50 mg of starting compound in 10 mL MeOH, anhydrous
K2CO3 (1:2 equivalent) was added. The mixture was stirred for 2 h
at rt and monitored by TLC.
832 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
6.96 (d, J¼7.8 Hz, 2H), 6.88
(d, J¼8.0 Hz, 1H), 5.36 (t, J¼8.7 Hz, 1H), 4.40 (d, J¼8.6 Hz, 2H), 2.28
(s, 3H), 2.06 (s, 3H). 13C NMR (100 MHz, CDCl3):
168.6, 165.5,
3.4.1. Methyl 2-hydroxy-4-(2-hydroxy-5-methoxyphenyl)-
butanoate (5a)
d
144.4, 144.0, 136.4, 127.0, 122.0, 120.8, 73.9, 67.8, 20.8, 20.0. Anal.
Calcd for C12H12O5 (236.07): C, 61.01; H, 5.12. Found: C, 61.33; H,
5.24.
Colorless semisolid (39 mg, 84%). 1H NMR (400 MHz, CDCl3):
d
1.67–1.87 (m, 2H), 2.5 (m, 2H), 3.20 (s, 3H), 3.37 (s, 3H), 3.87
(dd, J¼4.1 Hz, J¼7.7 Hz, 1H), 6.60 (m, 2H), 6.69 (d, J¼2.5 Hz,
1H). 13C NMR (100 MHz, CDCl3þCCl4):
d 181.5, 151.7, 150.2,
3.3. General procedure for the lipase-catalyzed kinetic
resolution of a-acetoxy ketones
130.3, 129.5, 117.2, 111.6, 71.9, 56.3, 50.8, 34.7, 25.7. Anal. Calcd
for C12H16O5 (240.25): C, 59.99; H, 6.71. Found: C, 60.21; H,
6.55.
Lipase was dissolved in potassium phosphate buffer (pH 7,
25 mL) and added to a solution of the pure substrate (200 mg) in
organic solvent (5 mL) and the reaction mixture was stirred at rt.
The reaction was monitored by TLC and HPLC and when 50% con-
version was reached, the reaction was terminated by filtration.
3.4.2. Methyl 2-hydroxy-3-(2-hydroxyphenyl)propanoate (5b)19
Colorless semisolid (42 mg, 88%). 1H NMR (400 MHz, CDCl3):
d
2.84 (m, 1H), 3.06 (d, J¼13.9 Hz, 1H), 3.50 (s, 3H), 4.23 (d,
J¼5.7 Hz, 1H), 6.75 (m, 2H), 7.15 (m, 2H). 13C NMR (100 MHz,

A.S. Demir, A. Aybey / Tetrahedron 64 (2008) 11256–11261
11261
Gray, T. J. B.; Evans, J. G.; Lewis, D. F. V.; Beamand, J. A.; Hue, K. L. Toxicol. Appl.
Pharmacol. 1989, 97, 311.
CDCl3þCCl4):
d 180.7, 160.4, 131.6, 128.3, 125.3, 120.6, 113.5, 72.8,
35.4, 23.5.
5. (a) Demir, A. S.; Reis, O.; Igdir, A. C. Tetrahedron 2004, 60, 3427; (b) Demir, A. S.;
Aybey, A.; Sesenoglu, O.; Polat, F. Tetrahedron: Asymmetry 2003, 14, 1489; (c)
Demir, A. S.; Emrullahoglu, M. Curr. Org. Synth. 2007, 4, 321; (d) Demir, A. S.;
Findik, H. Tetrahedron 2008, 64, 6196; (e) Beshara, C. S.; Hall, A.; Jenkins, R. L.;
Jones, K. L.; Jones, T. C.; Killeen, N. M.; Taylor, P. H.; Thomas, S. P.; Tomkinson, N.
C. O. Org. Lett. 2005, 7, 5729.
Acknowledgements
The financial support from the Scientific and Technical
Research Council of Turkey (TUBITAK) for A.A., the Turkish
Academy of Sciences (TUBA), the Turkish State Planning Orga-
nization, and the Middle East Technical University is gratefully
acknowledged.
6. (a) Demir, A. S.; Jeganathan, A. Synthesis 1992, 235; (b) Demir, A. S.; Gross, R. S.;
Dunlap, N. K.; Hashemi, A. B.; Watt, D. S. Tetrahedron Lett. 1986, 27, 5567; (c)
Dunlap, N. K.; Sabol, M. R.; Watt, D. S. Tetrahedron Lett. 1984, 25, 5839.
7. (a) Demir, A. S.; Saatcioglu, A. Synth. Commun. 1993, 23, 571; (b) Demir, A. S.;
Gercek, Z.; Reis, O.; Duygu, A. N.; Arikan, E. Tetrahedron 1999, 55, 2441; (c)
Demir, A. S.; Camkerten, N.; Akgun, H.; Tanyeli, C.; Mahasneh, A. S.; Watt, D. S.
Synth. Commun. 1990, 20, 2279; (d) de Klein, W. J. In Organic Syntheses by Ox-
idation with Metal Compounds; Mijs, W. J., DE Jonge, C. R. H. I., Eds.; Plenum:
NewYork, NY, 1986.
8. Hao, X.; Yamazaki, O.; Yoshida, A.; Nishikido, J. Tetrahedron Lett. 2003, 44, 4977.
9. Whitesell, J. K.; Matthews, R. S.; Helbling, A. M. J. Org. Chem. 1978, 43, 784.
10. Espiritu, M.; Handley, P. N.; Neumann, R. Adv. Synth. Catal. 2003, 345, 325.
11. Suginome, H.; Yamada, S. J. Org. Chem. 1985, 50, 2489.
12. Alam, M. M.; Varala, R.; Adapa, S. R. Synth. Commun. 2003, 33, 3035.
13. Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R.. Vogel’s Textbook of
Practical Organic Chemistry, 5th ed.; John Wiley & Sons: NewYork, NY, 1996.
14. Kotsuki, H.; Arimura, K.; Araki, T.; Shinohara, T. Synlett 1999, 462.
15. Rubottom, G. M.; Gruber, J. M.; Marrero, R.; Juve, H. D.; Kim, C. W. J. Org. Chem.
1983, 48, 4940.
16. (a) Mihovilovic, M. D.; Mu¨ller, B.; Stanetty, P. Eur. J. Org. Chem. 2002, 3711; (b)
Stewart, J. D. Curr. Org. Chem. 1998, 2, 195; (c) Flitsch, S.; Grogan, G. In Enzyme
Catalysis in Organic Synthesis; Drauz, K., Waldmann, H., Eds.; Wiley-VCH:
Weinheim, 2002; p 1202; (d) Roberts, S. M.; Wan, P. W. H. J. Mol. Catal. B: En-
zym. 1998, 4, 111; (e) Willetts, A. J. Trends Biotechnol. 1997, 15, 55; (f) Kelly, D. R.;
Wan, P. W. H.; Tang, J. In Biotechnology; Rehm, H. J., Reed, G., Eds.; Wiley-VCH:
Weinheim, 1998; Vol. 8a, p 535; (g) Alphand, V.; Furstoss, R. In Asymmetric
Oxidation Reactions: A Practical Approach; Katsuki, T., Ed.; Oxford University
Press: New York, NY, 2001; p 214; (h) Mihalovilovic, M. D. Eur. J. Org. Chem.
2002, 1, 3711; (i) Alphand, V.; Carrea, G.; Wohlgemuth, R.; Furstoss, R.;
Woodley, J. M. Trends Biotechnol. 2003, 21, 318; (j) Chen, G.; Kayser, M. M.;
Mihovilovic, M. D.; Mrstik, M. E.; Martinez, C. A.; Stewart, J. D. New J. Chem.
1999, 23, 827; (k) Doig, S. D.; O’Sullivan, L. M.; Patel, S.; Ward, J. M.; Woodley, J.
M. Enzymol. Microb. Technol. 2001, 28, 265; (l) Walton, A. Z.; Stewart, J. D. Bio-
technol. Prog. 2002, 18, 1039.
17. Floresca, R.; Kurihara, M.; Watt, D. S.; Demir, A. S. J. Org. Chem. 1993, 58, 2196.
18. (a) Chandra, K. L.; Saravanan, P.; Singh, R. K.; Singh, V. K. Tetrahedron 2002, 58,
1369; (b) Demir, A. S.; Hamamcl, H.; Sesenoglu, O.; Aydogan, F.; Capanoglu, D.;
Neslihanoglu, R. Tetrahedron: Asymmetry 2001, 12,1953; (c) Kajiro, H.; Mitamura,
S.; Mori, A.; Hiyama, T. Synlett 1998, 51; (d) Kobayashi, S. Synlett 1994, 689.
19. Nair, M. G.; Wang, H.; Strasburg, G. M.; Booren, A. M.; Gray, J. I. Method for
inhibiting cyclooxygenase and inflammation using cherry bioflavonoids. PCT
Int. Appl. CODEN: PIXXD2 WO 2000033824, 2000, 33 pp.
References and notes
1. (a) Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625; (b) ten Brink,
G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Chem. Rev. 2004, 104, 4105; (c) Krow, G. R.
Org. React. 1993, 43, 251; (d) Renz, M.; Meunier, B. Eur. J. Org. Chem. 1999, 4, 737;
(e) Strukul, G. Angew. Chem., Int. Ed. 1998, 37, 1198; (f) Bolm, C. In Advances in
Catalytic Processes; Doyle, M. P., Ed.; JAI: Greenwich, 1997; Vol. 2, p 43.
2. (a) Hassall, C. H. Org. React. 1957, 9, 73; (b) Le Paith, J.; Frison, J. C.; Bolm, C. In
Modern Oxidation Methods; Ba¨ckvall, J. E., Ed.; Wiley-VCH: Weinheim, Germany,
2004; p 267; (c) Bolm, C.; Palazzi, C.; Beckmann, O. In Transition Metals for
Organic Synthesis, 2nd ed.; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; Vol. 2, p 267.
3. (a) Kamerbeek, N. M.; Janssen, D. B.; van Berkel, W. J. H.; Fraaije, M. W. Adv.
Synth. Catal. 2003, 345, 667; (b) Anastas, P. T.; Bartlett, L. B.; Kirchhoff, M. M.;
Williamson, T. C. Catal. Today 2000, 55, 11; (c) Murahashi, S.-I.; Ono, S.; Imada, Y.
Angew. Chem., Int. Ed. 2002, 41, 2366; (d) Mazzini, C.; Lebreton, J.; Furstoss, R.
J. Org. Chem. 1996, 61, 8; (e) Fukuda, O.; Sakaguchi, S.; Ishii, Y. Tetrahedron Lett.
2001, 42, 3; (f) Bolm, C.; Palazzi, C.; Francio, G.; Leitner, W. Chem. Commun.
´
2002, 1588; (g) Gutierrez, M. C.; Alphand, V.; Furstoss, R. J. Mol. Catal. B: Enzym.
2003, 21, 231.
4. (a) Mitsunori, H.; Morikazu, A.; Yasutomo, O. Preparation of arylhydroxy-
alkanoic acid derivatives as intermediates for pharmaceuticals. Jpn. Kokai
Tokkyo Koho JP 62212329 A 19870918, 1987, 9 pp; (b) Popp, K. F.; Clark, K. L.
Alpha hydroxy acid compositions for treatment of skin disorders (USA). U.S.
Patent 20060269495 A1, 2006; (c) Shaw, K. N. F.; McMillan, A.; Armstrong, M.
D. J. Org. Chem. 1956, 21, 601; (d) Li, C.-Y.; Wu, T.-S. Chem. Pharm. Bull. 2002, 50,
1305; (e) Lake, B. G.; Evans, J. G.; Chapuis, F.; Walters, D. G.; Price, R. J. Food
Chem. Toxicol. 2002, 40, 809; (f) Lovell, D. P.; Van Iersel, M. L. P. S.; Walters, D. G.;
Price, R. J.; Lake, B. G. Pharmacogenetics 1999, 9, 239; (g) Goodwin, B. L.;
Ruthven, C. R. J.; Sandler, M. Gen. Pharmacol. 1998, 31, 437; (h) Van Iersel, M. L.
P. S.; Henderson, C. J.; Walters, D. G.; Price, R. J.; Wolf, C. R.; Lake, B. G. Xen-
obiotica 1994, 24, 795; (i) Huwer, T.; Altmann, H. J.; Grunow, W.; Lenhardt, S.;
Przybylski, M.; Eisenbrand, G. Chem. Res. Toxicol. 1991, 4, 586; (j) Lake, B. G.;