Efficient synthesis and resolution of novel 2-(hydroxymethyl)-7,8-dihydro- 1H-indeno[5,4-b] furan-6(2H)-one by lipase Pseudomonas cepacia

Article abstract of DOI:10.1016/j.tetasy.2014.02.008

Lipase Pseudomonas cepacia catalyzed acylation of (±)-2- (hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one using vinyl acetate as the acyl donor in acetone gave (-)-(R)-2-acetoxy-2-(methyl)-7,8-dihydro-1H- indeno[5,4-b] furan-6(2H)-one and (+)-(S)-2-(hydroxymethyl)-7,8-dihydro-1H- indeno[5,4-b] furan-6(2H)-one with high enantiomeric excess. Enantiomerically pure 2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one are useful intermediates for the preparation of Ramelteon, an FDA approved drug for the treatment of insomnia.

Full text of DOI:10.1016/j.tetasy.2014.02.008

Tetrahedron: Asymmetry 25 (2014± 578–582
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Efficient synthesis and resolution of novel 2-(hydroxymethyl)-
7,8-dihydro-1H-indeno[5,4-b] furan-6(2H)-one by lipase
Pseudomonas cepacia
Lingaiah Nagarapu a, , Hanmanth Reddy Vulupala , Rajashaker Bantu , Yashodakrishna Sajja ,
⇑
a
a
a
b
Jagadeesh Babu Nanubolu
a
Organic Chemistry Division-II, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India
Centre for X-ray Crystallography, Indian Institute of Chemical Technology, CSIR, Tarnaka, Hyderabad 500607, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Accepted 12 February 2014
Available online 15 March 2014
Lipase Pseudomonas cepacia catalyzed acylation of (± ±)2)(hydroxymethyl±)7,8)dihydro)1H)indeno[5,4)b]
furan)6(2H±)one using vinyl acetate as the acyl donor in acetone gave (ꢀ±)(R±)2)acetoxy)2)(methyl±)7,8)
dihydro)1H)indeno[5,4)b] furan)6(2H±)one and (+±)(S±)2)(hydroxymethyl±)7,8)dihydro)1H)indeno[5,4)
b] furan)6(2H±)one with high enantiomeric excess. Enantiomerically pure 2)(hydroxymethyl±)7,8)dihy)
dro)1H)indeno[5,4)b] furan)6(2H±)one are useful intermediates for the preparation of Ramelteon, an
FDA approved drug for the treatment of insomnia.
Ó 2014 Elsevier Ltd. All rights reserved.
1
. Introduction
H
N
OH
O
N
Indanones and their substrates are important building blocks in
O
the synthesis of many biologically active compounds including
indacrinone, ethacrynic acid, indanoyl isoleucine conjugates, ind)
anocines and other medicinally important products.1–6 The indane
skeleton is present in a range of molecules that display significant
and diverse biological activity (Fig. 1±. The indeno[5,4)b] furan
structure is a part of the internal backbone of various important
O
OH
N
N
HN
O
Cl
Cl
O
OH
1
2
melatonin MT
1 2
/MT receptors in the suprachiasmatic nucleus
7
H3C
OH
(
SCN± for the treatment of circadian rhythm sleep disorders. The
protease inhibitor Indinavir 1 (Crixivan± is used as a component
CH3
of highly active retroviral therapy (HART± to treat HIV infection
H3CO
3
8
9,10
and AIDS. Indacrinone 2 is a potent antidiuretic,
while indano)
5
cine 3 has demonstrated significant binding with microtubules.
Over the last few decades, the development of chiral organic
compound in non)racemic forms and stereoselective synthesis
has dramatically increased as a method for preparing enantiomeri)
cally pure compounds in the pharmaceutical industry. These facts
occur because chirality plays an important role on both the effi)
ciency and safety of many drugs. Lipases are the most widely ap)
plied enzymes for regio) and enantioselective biotransformations,
because they are inexpensive, stable, and easy to recycle. They also
direct the asymmetric course of many chemical transformations to
H CO
O
NH2
3
Figure 1.
produce chiral compounds in enantiomerically pure form. Lipase)
catalyzed reactions have been applied to solve a number of syn)
thetic problems, one of which is the kinetic resolution of diastereo)
meric and enantiomeric mixtures of primary and secondary
Among the various types of lipases, Pseudomonas
cepacia (PC± is one of the most versatile and widely used enzymes
1
1
alcohols.
⇑
Corresponding author. Tel.: +91 40 27191509/10/11; fax: +91 40 27193382.
E-mail addresses: lnagarapuiict@yahoo.com, nagarapu@iict.res.in (L. Nagarapu±.
http://dx.doi.org/10.1016/j.tetasy.2014.02.008
957)4166/Ó 2014 Elsevier Ltd. All rights reserved.
0

L. Nagarapu et al. / Tetrahedron: Asymmetry 25 (2014) 578–582
579
for the resolution of esters and alcohols in both aqueous and or)
ganic media. In addition to stereoselective ester conversions, PC
can be used to perform regioselective and chemoselective acyla)
tions and deacylations and simple hydrolysis of esters under mild
1
2
reaction conditions.
2
. Results and discussions
Herein we report an enzymatic approach for the preparation of
optically active indeno[5,4)b] furan)6(2H±)one via enzymatic reso)
lution of racemic (± ±)2)(hydroxymethyl±)7,8)dihydro)1H)inde)
no[5,4)b] furan)6(2H±)one using Pseudomonas cepacia (Scheme 1±.
The enantiomerically pure 2)(hydroxymethyl±)7,8)dihydro)1H)
indeno[5,4)b] furan)6(2H±)ones are useful intermediates for the
preparation of Ramelteon, an FDA approved drug for the treatment
Figure 2. The molecular structure of (RS±)9 with the atom numbering scheme.
Displacement ellipsoids are drawn at the 30% probability level and H atoms are
shown as small spheres of arbitrary radius. Only the major component of the
disordered groups is shown for clarity.
1
3
of insomnia.
In view of our research14–19 to synthesize the target molecules,
racemic 2)(hydroxymethyl±)7,8)dihydro)1H)indeno[5,4)b] furan)
Crystal data for AR98: C12
H
12
O
3
, M = 204.22, pale yellow needle,
.36 ꢁ 0.12 ꢁ 0.09 mm , racemic, crystallizes in the centrosym)
metric triclinic space group P)1 (No. 2±, a = 7.6508(12±,
6
2
(2H±)one was prepared by the condensation of 4)allyl)5)hydroxy
,3)dihydro)1H)inde)1one with meta-chloroperbenzoic acid in the
3
0
presence of chloroform in excellent yield. The formation of com)
o
+
b = 7.7669(12±, c = 8.5129(13± Å,
a = 92.234(2± , b = 94.884(3±,
pound (RS±)9 was evident from the appearance of the [M+H] peak
3
3
a
= 101.602(2±°,
000 = 216, CCD area detector, MoK
T = 293(2±K, 2Ømax = 50.0°, 4777 reflections collected, 1732 unique
int = 0.0208±, Final GooF = 1.048, R1 = 0.0542, wR2 = 0.1545, R
V = 492.91(13± Å ,
Z = 2,
c
D = 1.376 g/cm ,
at m/z 205 in the mass spectrum (ESI±, AC@O stretching at
ꢀ1
F
a radiation, k = 0.71073 Å,
1
673 cm in the IR; the appearance of the dihydrofuran CH proton
as a multiplet at d 5.11–5.05; the furan attached CH OH protons as
2
(R
two doublet of doublets at d 3.94, 3.79 and the characteristic
proton of furan as two multiplets at d 3.28–3.21 and 3.08–3.01 in
indices based on 1459 reflections with I > 2
F ±, 186 parameters, 15 restraints and
83305 contains the supplementary crystallographic data for this pa)
r
(I± (refinement on
2
ꢀ1
1
l
= 0.099 mm . CCDC
H NMR. The X)ray analysis of (RS±)9 confirms the structure
9
(Fig. 2±.
per. These data can be obtained free of charge at www.ccdc.cam.
ac.uk/conts/retrieving.html [or from the Cambridge Crystallo)
graphic Data Centre (CCDC±, 12 Union Road, Cambridge CB2 1EZ,
UK; fax: +44 (0± 1223 336 033; email: deposit@ccdc.cam.ac.uk].
The key intermediate 4)allyl)5)hydroxy 2,3)dihydro)1H)inde)
2
.1. Crystallographic data for AR98
X)ray data for the compound were collected at room tempera)
ture using a Bruker Smart Apex CCD diffractometer with graphite
monochromated MoK radiation (k = 0.71073ű with an )scan
method. Preliminary lattice parameters and orientation matrices
were obtained from four sets of frames. Unit cell dimensions were
determined using 2046 reflections for AR98 data. Integration and
scaling of intensity data were accomplished using SAINT pro)
1
one was prepared from readily available 3)hydroxy benzalde)
a
x
2
0
hyde. Accordingly, the treatment of 3)hydroxy benzaldehyde with
dimethyl sulfate in the presence of potassium carbonate and ace)
tone resulted in the formation of 3)methoxybenzaldehyde in excel)
lent yields (Scheme 2±. Knoevenagel condensation of the aldehydes
with active methylene compounds is an important method for CAC
bond construction in organic synthesis. Knoevenagel condensation
of 3)methoxy benzaldehyde 2 and malonic acid in basic media at
2
0
gram.
The structures were solved by direct methods using
2
1
SHELXS97 and refinement was carried out by full)matrix least)
21
squares technique using SHELXL97. Anisotropic displacement
parameters were included for all non)hydrogen atoms. All of the
H atoms were positioned geometrically and treated as riding on
their parent C atoms, with CAH distances of 0.93–0.97 Å, and with
8
0 °C resulted in the formation of (E±)3)3methoxyphenyl±acrylic
acid 3. Subsequent Claisen rearrangement of 5)(allyloxy±)2,3)dihy)
dro)1H)inden)1)one 7 via [3.3] sigmatropic rearrangement gave
4
)allyl)5)hydroxy)2,3)dihydro)1H)inden)1)one 8 in 56% yield.
U
iso(H± = 1.2Ueq (C± or 1.5Ueq for methyl atoms. The O bonded H
Epoxidation of compound 8 with m)chloroperbenzoic acid gave
compound 9 in 89% yield. The epoxide formation and opening of
the epoxide with a free hydroxyl group takes place in a single step.
The subsequent resolution of the racemic 2)(hydroxymethyl±)
atom was located from the difference Fourier map. The C10, C11,
and O2 atoms of furan ring, C12 atom of the hydroxymethyl group
and O1 atom of furan)6)one ring were disordered over two sites—
6
6.8% site occupancy for the major component and 32.8% site
7
,8)dihydro)1H)indeno[5,4)b] furan)6(2H±)one 9 via lipase)medi)
occupancy for the minor component. PART and FVAR instructions
were used for modeling the disorder and DFIX was used for
restraining the CAC, CAO and OAH bond distances to the expected
ated transesterification gave the (2R,4S±)2)(hydroxymethyl±)7,8)
dihydro)1H)indeno[5,4)b] furan)6(2H±)one 9a and 2)acetoxy2)
2
2
(
methyl±)7,8)dihydro)1H)indeno[5,4)b]
furan)6(2H±)one
9b
values.
O
O
O
Pseudomonas Cepacia lipase
vinyl acetate, acetone, -20°C
8h
+
O
O
O
4
HO
HO
AcO
H
H
H
(
RS)-9
9a
S)-9a (44%, e.e.>30%)
9b
(R)-9b (46%, e.e.>99%)
(
Scheme 1. Resolution of (± ±)2)(hydroxymethyl±)7,8)dihydro)1H)indeno[5,4)b] furan)6(2H±)one using Pseudomonas cepacia lipase.

5
80
L. Nagarapu et al. / Tetrahedron: Asymmetry 25 (2014) 578–582
O
O
O
O
O
H
H
OH
OH
ii
iii
i
iv
OH
O
O
O
2
1
3
4
O
O
O
O
v
vi
vii
+
O
HO
O
7
5a
5b
6
O
O
O
O
HO
O
HO
viii
OH
8
9
Scheme 2. Reagents and conditions: (i± K
2
CO
3
,(CH
3
±
2
SO
4
, acetone, reflux, 2 h, 92%; (ii± malonic acid, pyridine, piperidine (cat± 80 °C,12 h, 78%; (iii± Pd/C, H
2
gas, methanol,
0
97%; (iv± PPA, 80 °C, 4 h, 66%; (v± 48% HBr in H
6%; (viii± m)CPBA, dryDCM, 6 h, 89%.
2
O, glacial acetic acid, 110 °C, 2 h 60%; (vi± allylbromide, K
2
CO
3
acetone, reflux, 5 h, 86%; (vii± N,N )dimethyl aniline, 200 °C, 2 h,
5
Table 1
furan)6(2H±)one via an enzymatic resolution of racemic 1H)inde)
no[5,4)b] furan)6(2H±)one using Pseudomonas cepacia lipase. This
is the first report for the preparation of chiral 2)(hydroxy)
methyl±)7,8)dihydro)1H)indeno[5,4)b] furan)6(2H±)one by enzy)
matic resolution. First synthesis of racemic 2)(hydroxymethyl±)
Enzymatic resolution of racemic 2)(hydroxyl methyl±)7,8)dihydro)1H)indeno[5,4)b]
furan)6(2H±)one using various lipases
S. No Lipase
Solvent
Time (h± Temp (°C±
eea%
OAc OH
05
1
2
3
4
5
6
7
8
Amino PS Acetonitrile
Lipozyme Di)isopropyl ether
48
24
72
48
24
24
36
04
rt 10
0
rt 14
rt 84
rt 15
rt 13
7
,8)dihydro)1H)indeno[5,4)b] furan)6(2H±)one is reported in good
06
02
07
12
48
06
57
16
yields. A new method to synthesize chiral 2)(hydroxymethyl±)7,8)
dihydro)1H)indeno[5,4)b] furan)6(2H±)one has been achieved.
Porcine
PCL
CAL)B
Rugusa
CAL)B
Di)methylcarbonate
Acetone
Methanol
Hexane
Vinayl acetate
Acetonitrile
4
4
. Experimental
0
23
L)proline
80 24
.1. General
9
1
1
1
Amino PS Acetone
72
48
72
48
rt 16
0
06
58
21
30
0
1
2
CAL)B
PCL
PCL
Acetone
Di)isopropyl ether
Acetone
23
ꢀ20 60
All reactions requiring anhydrous conditions were performed
ꢀ20 99
in an oven)dried glassware under nitrogen atmosphere (all except
those involving water in the reaction medium± The solvents used
were purified by distillation over the drying agents indicated and
a
ee% is calculated based on Chiral HPLC.
were transferred under nitrogen atmosphere: CH
KOH±, THF were dried by distillation from sodium using sodium
benzophenone ketyl as indicator. All organic extracts were dried
over anhydrous Na SO , All crude reaction products were purified
2 2 2 3
Cl (CaH ±, Et N
(
(
Scheme 1±. The treatment of 9 with Pseudomonas cepacia lipase in
the presence of vinyl acetate and acetone at ꢀ20 °C for 48 h affor)
ded 9a and 9b in a 1:1 ratio. Vinyl acetate was used as the acyl do)
nor in the reaction. Among the lipases Amino PS, Porcine, CAL-B and
Rugusa, Pseudomonas cepacia lipase was found to be most effective
in terms of conversion and enantioselectivity (Table 1±. The enan)
tiomeric excesses of the resulting acetates and unreacted alcohols
were higher than 88% ee. Thus, the lipase Pseudomonas cepacia
proved to be the optimal biocatalyst in the resolution of
2
4
by column chromatography silica gel (60–120 mesh and 100–
200 mesh± by using distilled ethyl acetate and petroleum ether.
1
13
Nuclear Magnetic Resonance ( H and C NMR± spectra were re)
corded on Varian Gemini 200, 400 or Bruker WH 300 MHz spec)
trometers, using tetramethylsilane (TMS± as the internal
standard. Chemical shifts were expressed in (ppm± down field
from TMS. IR spectra were recorded on PerkinElmer model 683
or 1310 spectrometers with sodium chloride optics or KBr pellets.
EI Mass spectra were recorded on a VG Micromass)7070 Hz 70 eV
using a direct inlet system. ESI MS were recorded on Thermo Finn)
igan LCQ ion trap mass spectrometer equipped with an electron
spray ionization. High Resolution Mass spectra were recorded on
QSTAR mass spectrometer (Applied Biosystems USA± at 5 or 7 K
resolution using polyethylene glycol as an internal reference com)
pound. Optical rotations were recorded on JASCO DIP 370 digital
polarimeter. The enantiomeric purity was determined by HPLC
analysis on Chiralcel OD)H column (250 ꢁ 5 mm±, Mobile phase,
(
± ±)2)(hydroxymethyl±)7,8)dihydro)1H)indeno[5,4)b] furan)6(2H±)
one 9. Acetone, when used as the solvent, appeared to give the best
results. The acyl compound 9b was hydrolyzed by treatment with
methanolic K CO at room temperature to afford the (R±)alcohol
2 3
2
D
8
with a specific rotation of ½
aꢂ
¼ ꢀ15:3 (c 0.26, CHCl
3
±. All of the
1
13
products were characterized by H NMR, C NMR, IR, and mass
spectroscopy.
3
. Conclusion
1
5% 2)propanol in hexane. Flow rate, 1.0 mL/min. Detection wave)
In conclusion, we have developed a novel strategy to prepare
length, 220 nm.
optically active 2)(hydroxymethyl±)7,8)dihydro)1H)indeno[5,4)b]

L. Nagarapu et al. / Tetrahedron: Asymmetry 25 (2014) 578–582
581
4
.2. 3-Methoxy benzaldehyde 2
J = 5.8, 5.4 Hz±. 13C NMR (75 MHz, CDCl
3
+DMSO)d
6
±: d 204, 163.1,
1
57.4, 128, 124.3, 115.1, 111.3, 35.4, 24.6. MS (ESI±: m/z =149
+
3
)Hydroxy benzaldehyde (1.0 g, 0.082 mol±, anhydrous potas)
sium carbonate (1.7 g, 0.123 mol±, and dimethyl sulfate (1.24 g,
.098 mol± were heated at reflux with stirring in acetone (50 mL±
(M+H± ; HRMS: Calcd for C
4.7. 5-(Allyloxy)-2,3-dihydro-1H-inden-1-one 7
To suspension of 5)hydroxy)2,3)dihydro)1H)inden)1)one
9 9 2
H O : 149.05945. Found: 149.05971.
0
for 2 h. After cooling, the solution was filtered and evaporated to
dryness under reduced pressure to give 3)methoxy benzaldehyde
a
ꢀ
1
(
1
(
93%±. IR (KBr,
v
cm ±: 2955, 2838, 1701, 1592, 1483, 1262,
040, 784. H NMR (CDCl , 300 MHz±: d 9.94 (s, 1H, CHO±, 7.41
d, 2H, Ar)H, J = 5.2 Hz±, 7.34 (s, 1H, Ar)H±, 7.16–7.10 (m, 1H, Ar)
(1.0 g, 0.013 mol± in acetone (50 mL± were added potassium car)
bonate (1.4 g, 0.02 mol± and allylbromide (0.98 g, 0.016 mol± at
room temperature and heated at reflux for 5 h. After completion
of the reaction, the inorganic salts were filtered after which was
added water and extracted into ethyl acetate (3 ꢁ 50 mL±. The
combined organic layers were dried over anhydrous sodium sul)
fate and concentrated in vacuo. The residue obtained was purified
using silica)gel column chromatography (n)hexane/ethyl acetate
9:1± to give 5)(allyloxy±)2,3)dihydro)1H)inden)1)one (86%± as a
1
3
+
H±, 3.85 (s, 3H, OCH
3
±, EI)MS: m/z = 135 [MꢀH] .
4
.3. (E)-3-(3-Methoxyphenyl)acrylic acid 3
3
)Methoxy benzaldehyde (1.0 g, 0.034 mol± was condensed
with malonic acid (1.5 g, 0.06 mol± in pyridine (30 mL± and piper)
idine (5 drops± at 80 °C for 12 h to give (E±)3)(3)methoxy)
phenyl±acrylic acid (80% and light yellow± mp 105–110 °C, IR
KBr, v cm ±: 3436, 2965, 1679, 1579, 1489, 1422, 1323, 1244,
157, 1049, 944, 781, H NMR (CDCl
CH, J = 16.0 Hz±, 7.26 (d, 1H, Ar)H, J = 10.0 Hz±, 7.12 (d, 1H, Ar)
H, J = 7.5 Hz±, 7.03 (s,1H, Ar)H±, 6.91 (d,1H, Ar)H, J = 10.0 Hz±, 6.41
d, 1H, @CH, J = 15.8 Hz±, 3.84 (s, 3H,OCH
CDCl ± : d 172.5, 159.8, 147, 135.3, 129.9, 121, 117.5, 116.6, 113,
ꢀ1
colorless oil. IR (KBr,
1333, 1257, 1143, 1089, 998, 928, 835, H NMR (300 MHz, CDCl
d 7.64 (d, 1H, Ar)H, J = 8.3 Hz±, 6.88 (d, 2H, Ar)H, J = 9.6 Hz±, 6.1–
5.96 (m, 1H, @CH±, 5.41 (dd, 1H, @CH , J = 15.8, 1.3 Hz±, 5.31 (dd,
1H, @CH , J = 9.2, 1.3 Hz±, 4.59 (d, 2H, OCH , J = 5.2 Hz±, 3.06 (t,
2H, CH , J = 6.0, 5.6 Hz±, 2.63 (t, 2H, CH , J = 6.0, 5.8 Hz± , C NMR
(CDCl , 75 MHz±: d 205.1, 164.1, 158, 132.3, 130.4, 125.3, 118.1,
115.7, 110.5, 68.9, 36.3, 25.8. MS (ESI±: m/z = 189 (M+H± ; HRMS:
Calcd for C12 : 189.09058. Found: 189.09101.
v cm ±: 3084, 2924, 1694, 1606, 1487,
1
3
±:
ꢀ1
(
1
@
1
3
, 300 MHz±: d 7.73 (d, 1H,
2
2
2
13
2
2
13
(
3
±, C NMR (75 MHz,
3
+
3
+
5
5.2; MS (ESI±: m/z = 179 (M+H± ; HRMS: Calcd for C10
H
11
O
3
:
13 2
H O
1
79.07020. Found: 179.07027.
4
.8. 4-Allyl-5-hydroxy-2,3-dihydro-1H-inden-1-one 8
4
.4. 3-(3-Methoxyphenyl)propanoic acid 4
A
solution of 5)(allyloxy±)2,3)dihydro)1H)inden)1)one in
N,N)dimethylaniline (20 mL± was heated at 200 °C for 2 h. After
cooling to room temperature, the mixture was diluted with H
and 6 M HCl was slowly added and extracted with EtOAC. The com)
bined organic layers were washed with brine, dried over anhy)
Hydrogenation of 3)(3)methoxyphenyl±acrylic acid (1.0 g± over
0% Pd/C (catalytic amount± in methanol (20 mL± gave 3)methoxy
1
2
O
ꢀ1
phenyl propanoic acid in 97% yield, mp 43–46 °C, IR (KBr,
v
cm ±:
1
2
920, 1708, 1593, 1436, 1313, 1208, 1156, 929, 686; H NMR
CDCl , 300 MHz±; d 7.13 (t, 1H, Ar)H, J = 7.9, 7.7 Hz±, 6.7 (m, 3H,
Ar)H±, 3.76 (s, 3H, OCH ±, 2.86 (t, 2H, CH , J = 7.9, 7.5 Hz±, 2.52 (t,
, 75 MHz±: d 179.3, 159.6,
41.7, 129.5, 120.5, 113.9, 111.6, 55, 35.5, 30.5. MS (ESI±: m/
(
3
4
drous NaSO , and concentrated under reduced pressure. The
residue was further purified by chromatography on silica gel (7:1
3
2
13
2
1
H, CH
2
, J = 7.9, 7.5 Hz±, C NMR (CDCl
3
hexane/EtOAc± to afford 4)allyl)5)hydroxy)2,3)dihydro)1H)inden)
ꢀ1
1)one (55%±. IR (KBr,
1350, 1261, 1050, 999, 970, 898, 817, H NMR (300 MHz, CDCl
d 7.59 (d, 1H, Ar)H, J = 8.3 Hz±, 6.85 (d, 1H, Ar)H, J = 8.3 Hz±, 6.06–
v cm ±: 3452, 2921, 1686, 1603, 1473,
+
1
z = 181 (M+H± ; HRMS: Calcd for C10
H
13
O
3
: 181.08553. Found:
3
±:
1
81.08592.
.5. 5-Methoxy-2,3-dihydro-1H-inden-1-one 5
)(3)Methoxy phenyl±propanoic acid (1.0 g± was reacted with
5
.92 (m, 1H, @CH±, 5.19–5.11 (m, 2H, @CH
J = 6.0 Hz±, 3.03 (t, 2H, CH , J = 6.0, 5.6 Hz±, 2.69 (t, 2H, CH
J = 6.0, 5.6 Hz±. MS (ESI±: m/z = 189 (M+H± .
2
±, 3.47 (d, 2H, CH
2
,
,
4
2
2
+
3
polyphosphoric acid (4.0 g± at 80 °C for 4 h and then poured onto
ice cold water stirred for 30 min. and extracted into ethyl acetate
4.9. Racemic 2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b]
furan-6(2H)one 9
(
3 ꢁ 50 mL±. The combined organic layers were dried over anhy)
drous sodium sulfate and concentrated under reduced pressure
4)Allyl)5)hydroxy)2,3)dihydro)1H)inden)1)one (1.0 g, 0.026 mol±
was reacted with meta)chloroperbenzoic acid (1.36 g, 0.039 mol± in
dry dichloromethane at room temperature for 5 h to get 2)
(hydroxymethyl±)7,8)dihydro)1H)indeno[5,4)b] furan)6(2H±)one
as a light yellow compound in 89% yield, mp 151–154 °C; IR
to yield 5)methoxy)2,3)dihydro)1H)inden)1)one and 7)methoxy)
1
2
,3)dihydro)1H)inden)1)one in a 4:1 in 80:20% yield. H NMR
(
CDCl
Ar)H, J = 7.9 Hz±, 6.79 (d, 1H, Ar)H, J = 7.8 Hz±, 3.95 (s, 3H, OCH
.09 (t, 2H, CH , J = 6.2, 5.9 Hz±, 2.68 (t, 2H, CH , J = 6.1, 5.9 Hz±.
: 163.07498.
3
, 300 MHz±: d 7.52 (t, 1H, Ar)H, J = 8.0, 7.6 Hz±, 7.02 (d, 1H,
3
±,
ꢀ1
3
2
2
(KBr,
998, 820, H NMR (CDCl
J = 7.6 Hz±, 6.8 (d, 1H, Ar)H, J = 7.6 Hz±, 5.11–5.05 (m, 1H, CH±,
.94 (dd, 1H, CH , J = 8.6, 3.8, 2.8 Hz±, 3.79 (dd, 1H, CH , J = 6.7,
5.7 Hz±, 3.28–3.21 (m, 1H, CH ±, 3.08–3.01 (m, 1H, CH ±, 2.97 (t,
H, CH , J = 5.7 Hz±, 2.68 (t, 2H, CH , J = 5.7 Hz±, C NMR (CDCl
v cm ±: 3430, 2925, 1673, 1602, 1471, 1367, 1259, 1056,
+
1
MS (ESI±: m/z 163 (M+H± ; HRMS: Calcd for C10
H
11
O
2
3
, 300 MHz±: d 7.61 (d, 1H, Ar)H,
Found: 163.07536.
3
2
2
4
.6. 5-Hydroxy-2,3-dihydro-1H-inden-1-one 6
2
2
1
3
2
2
2
3
,
5
)Methoxy)2,3)dihydro)1H)inden)1)one (1.0 g± in glacial acetic
acid (20 mL± was flushed with nitrogen, heated until it became
homogeneous and then diluted with 48% HBr in H O (80 mL±.
The mixture was heated at reflux (110 °C± for 2 h, to give 5)hydro)
75 MHz±: d 204.9, 165.1, 152.5, 130.8, 125, 123.4, 109.5, 84.9,
52.9, 36.4, 28.7, 24.2. MS (ESI±: m/z = 205 (M+H± ; HRMS: Calcd
for C12H O : 205.08553. Found: 205.08592.
13 3
+
2
ꢀ1
xy)2,3)dihydro)1H)inden)1)one in 60% yield. IR (KBr,
435, 2925, 1694, 1601, 1492, 1307, 1253, 1095, 1037, 841; H
v
cm ±:
4.10. General procedure for the lipase-catalyzed kinetic resolution
1
3
NMR (300 MHz, CDCl
J = 7.9, 7.7 HZ±, 6.95 (d, 1H, Ar)H, J = 7.5 Hz±, 6.77 (d, 1H, Ar)H,
J = 8.3 Hz±, 3.12 (t, 2H, CH , J = 5.8, 5.2 Hz±, 2.72 (t, 2H, CH
3
±: d 9.08 (s,1H, OH±, 7.48 (t, 1H, Ar)H,
Racemic alcohol (0.5 g, 0.2 mol± was placed in round bottom
flask (10 mL± and dissolved in acetone (3.0 mL±, after which were
added vinyl acetate (0.84 g, 0.8 mol±, Pseudomonas cepacia from
2
2
,

5
82
L. Nagarapu et al. / Tetrahedron: Asymmetry 25 (2014) 578–582
lipase (0.5 g± and 4–5 drops of phosphate buffer solution (PH = 7.9±.
Scientific and Industrial Research (CSIR±, New Delhi for the award
of a fellowship to V.H.R. and Y.K.
The resulting mixture was incubated at ꢀ20 °C on a rotary shaker
(
350 rpm± for 48 h. The progress of the reaction was assessed
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2
1
2
.
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8
3
.95 (dd, 1H, CH
2
, J = 9.0, 3.0 Hz±, 3.79 (dd, 1H, CH
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, J = 6.0 Hz±,
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2
3
+
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3
1
28
12
H
13
O
3
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(
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,
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3
15 4
H O
2
D
8
lid ½
a
ꢂ
3
Acknowledgements
The authors gratefully acknowledge DST)SERB/EMEQ)078/2013
and DENOVA (ESC 0205±, New Delhi, India and the Council of