Chemoenzymatic synthesis and resolution of compounds containing a quaternary stereocenters adjacent to a carbonyl group

Article abstract of DOI:10.1016/j.tetasy.2008.04.024

Racemic compounds containing a quaternary stereocenter (having hydroxymethyl and alkyl group adjacent to keto functionality) based on chromanone, α-tetralone, and indalone scaffolds have been synthesized. An enzymatic irreversible transesterification approach has been applied to generate the pure enantiomers in a stereocontrolled fashion. The pure enantiomers of some α,α-dialkylated carbonyl compounds have been synthesized by this method.

Full text of DOI:10.1016/j.tetasy.2008.04.024

Tetrahedron: Asymmetry 19 (2008) 1224–1232
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: http://www.elsevier.com/locate/tetasy
Chemoenzymatic synthesis and resolution of compounds containing
a quaternary stereocenters adjacent to a carbonyl group
*
Tridib Mahapatra, Nandan Jana, S. Nanda
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 March 2008
Accepted 22 April 2008
Racemic compounds containing a quaternary stereocenter (having hydroxymethyl and alkyl group adja-
cent to keto functionality) based on chromanone, a-tetralone, and indalone scaffolds have been synthe-
sized. An enzymatic irreversible transesterification approach has been applied to generate the pure
enantiomers in a stereocontrolled fashion. The pure enantiomers of some a,a-dialkylated carbonyl com-
pounds have been synthesized by this method.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
reacted with an external electrophile (alkyl halide). Treatment of
the enolate with two different electrophiles in an asymmetric fash-
The generation of carbon containing a quaternary stereocenter
is a challenging task. There exist many well-defined chemical strat-
egies for creating a quaternary stereocenter in a molecule.1 How-
ever, the search for newer methods for the abovementioned
theme still remains. Although there exist many chemical catalyst
based strategies for the generation of quaternary stereocenters,
very few biocatalytic approaches have been known in the litera-
ture.2 Enzymatic kinetic resolution and desymmetrization of meso
or prochiral substrates (EED: enantioselective enzymatic desym-
metrization) are different approaches which can be used success-
fully to create quaternary stereocenters.3 Natural products
provide the inspiration for a variety of strategies used in the diver-
sity oriented synthesis (DOS) of novel small molecule libraries.4
These libraries are mainly based on core scaffolds from individual
natural products or specific substructures found across a class of
natural products or a new chemotype altogether. An increasing
body of evidence supports the effectiveness of these strategies
for identifying new biologically active small organic molecules.
These efforts also have led to significant advances in novel strate-
gies in synthetic organic chemistry.5
ion leads to the generation of new quaternary stereocenters. The
efficiency of this reaction depends on the use of expensive chiral
bases and chiral catalysts.7 We planned to generate an asymmetric
quaternary center via an enzymatic approach. Although hydroxy-
methylation of enolates with formaldehyde provides an efficient
method to introduce a functional group at the a-position of car-
bonyl groups, there have been few, successful examples of catalytic
asymmetric hydroxymethylation that satisfy the synthetic utility
in terms of both yield and selectivity for a wide range of sub-
strates.8 In our case the installation of an alkyl group followed by
a hydroxymethyl group on the carbonyl compounds (chroma-
nones, a-tetralones, and a-indanone) was first achieved to generate
the racemic quaternary stereocenter. The introduction of hydroxy-
methyl functionality served a dual purpose, firstly it allows us to
adopt enzymatic transesterification reaction to fix the quaternary
stereocenter and secondly it opens up the possibility to convert
it to other alkyl groups different from the alkyl group which was
introduced in the initial step (Scheme 1).
2. Results and discussion
In our combinatorial biocatalysis project, we needed to design
and synthesize various small molecular multifunctional scaffolds
which would lead us to a natural product like library after biocata-
lytic modification. We chose chromanone, a-tetralone, and a-inda-
none based scaffolds as there exist many natural products based on
chromanone (flavonoids and homoisoflavonoids) and a-tetralone.6
The asymmetric alkylation of a carbonyl compound is a well-
known strategy for making a new C–C bond, where the enolates
generated from the carbonyl compound and a suitable base were
Commercially available substituted a-tetralones and a-indal-
ones are used whereas different substituted chromanones are pre-
pared as reported elsewhere. When these carbonyl compounds are
treated with LDA and the proper alkyl iodide (1.1 equiv) at ꢀ78 °C,
monoalkylated compounds were obtained in good yield.9 In the
major cases, the first alkyl group introduced was either methyl
or ethyl. The monoalkylation reaction seems to be problematic
for different chromanone substrates as base induced ring opening
of chromanones has been reported in the literature.10 However,
the chemical yields of the monoalkylated chromanones were
good enough (50–60%) to carry out the subsequent steps.
* Corresponding author.
E-mail address: snanda@chem.iitkgp.ernet.in (S. Nanda).
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.04.024

T. Mahapatra et al. / Tetrahedron: Asymmetry 19 (2008) 1224–1232
1225
Y
n
Y
O
Y
O
n
LDA
RI
K2CO3, MeOH
HCHO, H2O
n
OH
R
R
X
X
X
O
Y = C, O
n = 0, 1
Lipase
acyl donor
Y
Y
n
n
Y
O
n
+
R''
R
OH
OCOR'
R
X
R
X
X
O
O
Both enantiomers
Scheme 1. Enzymatic approach for the generation of dialkylated carbonyl compounds.
The hydroxymethyl group was successfully installed by treating
the monoalkylated carbonyl compounds with formalin in mild ba-
sic medium (K2CO3/MeOH).11 By applying the above strategy we
have synthesized 12 carbonyl compounds containing alkyl groups
and hydroxymethyl functionality (Scheme 2). All the mono-
alkylhydroxymethylated compounds 1–12 are well characterized
by standard spectroscopic techniques. We also recorded the HPLC
data for the racemic compounds 1–12 to obtain a clear idea of
the retention time for the individual enantiomers.
The reaction was monitored periodically with TLC. The results
are summarized in Table 1.
It was noticed (from Table 1) that Lipase-PS (Amano) gave the
best result in terms of selectivity (E = 159) with substrate 8.
Although Lipase-AK (Amano) and lipozyme also provided good
enantioselectivities, we applied Lipase-PS for the transesterifica-
tion reaction of compounds 1–7 and 9–12 under similar reaction
conditions. The results are summarized in Table 2.
From Table 2, it was observed that after enzymatic transesteri-
fication the product esters obtained from compounds 1–12 provide
very good enantioselectivities (94–99%), whereas the slow reacting
enantiomeric alcohols 1–12 are not so enantiopure (37–53%). The
enantioselectivities for the product acetates of 1–12 as well as
the parent alcohols are determined by Chiral-HPLC measurement.
In all cases, we synthesized racemic acetates of compounds 1–12
by means of a chemical acylation method and recorded their HPLC
data, which allowed us to assign the retention time for the major
and minor enantiomers. The reaction was monitored by TLC and
was stopped after an appreciable amount of conversion was
achieved (as indicated by TLC; presence of approximately 1:1 ratio
of alcohol and acetate was indicated).
2.1. Enzymatic kinetic resolution of compounds 1–12
After completion of the successful synthesis of compounds 1–
12, the next task was to generate the quaternary stereocenter by
an irreversible enzymatic acylation (transesterification) reaction.
We initially chose substrate 8 for enzyme screening to check the
feasibility and efficiency of the reaction (in terms of enantiomeric
excess) with different lipases in organic solvents with vinyl acetate
as an acyl donor. For this purpose 50 mg of compound 8 was taken
in anhydrous diisopropyl ether (DIPE, 5 mL), followed by the addi-
tion of 50 mg of the required lipase and 8 equiv of vinyl acetate.
OMe
X
Me
R
Me
OH
MeO
OH
OH
O
O
OMe
O
3
X= H, R = Me; 1
X = OMe, R = Et; 2
4
Cl
O
O
Y
O
Ph
R
Me
Me
OH
OH
OH
OH
O
O
7
8
O
R = Me, 5
R = Et, 6
Y = Cl, 9
Y = OMe, 10
O
O
O
O
MeO
O
O
Me
Me
OH
MeO
OH
12
11
Scheme 2. Monoalkylated hydroxymethyl carbonyl compounds.

1226
T. Mahapatra et al. / Tetrahedron: Asymmetry 19 (2008) 1224–1232
0.5, MeOH)} and compared with those of known compounds13
Table 1
24
Lipase catalyzed transesterification of compound 8
{reported value for (S)-1; ½aꢁD ¼ ꢀ1:4 (c 1.3, CHCl3) and for (R)-5
21
a
a
Entry
Lipase
Conversion (c)
ees (%)
eep (%)
Eb
½aꢁD ¼ þ1:6 (c 0.95, CHCl3)} and satisfactory results were found
which further established the usefulness of such an empirical mod-
el in the lipase catalyzed transesterification reaction. A simplified
and modified version of the above rule has already been proposed
by two different research groups14 to predict the enantioprefer-
ence of lipases from Pseudomonas fluorescens toward primary alco-
hols having quaternary stereocenters. Our substrates 1–12 fit
perfectly in that model too. It was also observed in the HPLC chro-
matogram that (R)-acetates 13–24 were eluted first compared to
their corresponding (S)-isomers. A similar trend was observed in
a previous report13 for an enantiomeric mixture of compounds 1
and 5 in HPLC chromatogram.
1
2
3
4
5
6
7
8
9
Lipase AK-Amano
Lipase PS-Amano
Lipase A (Aamno-6)
Lipase F (AP 15)
Lipase PS-D
Novozyme-435
Lipozyme
Rhizopus arrhizus
Candida lipolytica
37
34
36.5
26.8
25
38
35
31.2
39.6
55
50
46
22
20
33
52
10
21
94
98
80
60
60
54
96
22
32
57
159
15.5
4.8
4
4.6
92
1.7
2.4
a
Ees were calculated by chiral HPLC (Diacel, Chiral OD-H, and OJ-H column,
hexane/isopropanol, 9/1).
b
Enantioselectivities of the reactions (E) were determined from the following
equation: E = ln[1 ꢀ c(1 + eep)]/ln[1 ꢀ c(1 ꢀ eep)], where eep = product ee,
ees = substrate ee; c = ees/(ees + eep)%. Enantioselectivities of the reaction (E) were
determined using the ‘SELECTIVITY’ program developed by K. Faber, H. Hönig, and A.
Kleewein (http://www.cis.TUGraz.at/orgc/).
2.3. Asymmetric synthesis of dialkylated carbonyl compounds
After successful installation of the quaternary stereocenters
adjacent to the carbonyl groups of compounds 1–12, we extended
our synthetic strategy to the general synthesis of a,a-dialkylated
carbonyl compounds. We chose compounds 3 and 6 for this meth-
od. After successful enzymatic transesterification of compounds 3
and 6 with lipase PS followed by deacetylation with K2CO3/MeOH
yielded the corresponding (S) alcohols. The carbonyl group was
protected with ethyleneglycol as the corresponding ketals. The free
alcohol group was converted to respective methanesulfonate ester.
Reductive deoxygenation of mesylates with LAH in refluxing THF
followed by acid induced deketalyzation afforded the dialkylated
compound in good yield (Scheme 4).
Table 2
Lipase-PS catalyzed transesterification of compounds 1–7 and 9–12
Eb
a
a
Entry
Substrate
Conversion (c)
ees (%)
eep (%)
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
9
32.2
28.9
33.3
34.8
31.7
30.7
35.1
28
47
40
49
52
46
44
51
37
42
53
44
99
98
98
97
99
99
94
95
98
98
96
316
146
161
110
314
307
54
57
10
11
12
30
35
31.4
150
168
75.6
10
11
3. Conclusion
a
Ees were calculated by chiral HPLC (Diacel, Chiral OD-H, and OJ-H column,
hexane/isopropanol, 9/1).
In conclusion, we have developed an efficient, chemoenzymatic
strategy for the synthesis of several alcohols having quaternary
stereocenters based on 4-chromanone, a-tetralone, and a-inda-
none scaffolds. Further synthetic manipulation of the enantiopure
alcohols yielded dialkylated carbonyl compounds in good overall
yields with high enantioselectivities. Elaboration of the above syn-
thetic strategy is currently ongoing in our laboratory to access
enantiopure novel chemical intermediates based on multifunc-
tional scaffolds.
b
Enantioselectivities of the reactions (E) were determined from the following
equation: E = ln[1 ꢀ c(1 + eep)]/ln[1 ꢀ c(1 ꢀ eep)], where eep = product ee,
ees = substrate ee; c = ees/(ees + eep)%. Enantioselectivities of the reaction (E) were
determined using the ‘SELECTIVITY’ program developed by K. Faber, H. Hönig, and A.
Kleewein (http://www.cis.TUGraz.at/orgc/).
2.2. Determination of the absolute configuration of product
acetate
An empirical rule as predicted by Weissfloch and Kazlauskas12
was applied to determine the enantiopreference of lipases from
Pseudomonas species toward primary alcohols. The rule is based
on the size of the substituents at the stereocenter (Scheme 3). Sub-
strates 1–12 follow this empirical model perfectly and in each case,
the (R)-enantiomer was acylated faster with the enzyme, whereas
the (S)-enantiomer was the slow reacting enantiomer remaining
unreacted in the mixture. We assumed that an alkyl group (e.g.,
Me, Et) attached to the quaternary stereocenter would be the med-
ium group (M) as depicted in the model, whereas the compact ring
structure of a-tetralone, a-indalone, and 4-chromanone would be
the large group (L). In the case of substrate 7, a little ambiguity
may arise as the stereocenter contains a benzyl group (–CH2Ph)
and the cyclic ring structure of a-indalone (with a Cl atom in the
5 position). Although their steric nature seems to be similar mainly
due to the similar size of both the groups, we assume that the com-
pactness of the rigid a-indalone ring as well as presence of an extra
‘Cl’ group made the rigid indalone ring the large group (L). It was
also noticed that substrate 7 provided a little less enantioselection
To gain further proof for the enantiopreference of Lipase-PS with
our substrates 1–12, we deacetylated the enantiopure (R)-acetate
obtained from substrates 1 and 5 with K2CO3/MeOH. The specific
rotations for enantiopure (R)-alcohol 1 and 5 were recorded {for
4. Experimental
4.1. General
Unless otherwise stated, materials were obtained from com-
mercial suppliers and used without further purification. THF and
diethylether were distilled from sodiumbenzophenone ketyl.
Dimethylformamide (DMF) and dimethylsulfoxide (DMSO) were
distilled from calcium hydride. Lipase AK (P. fluorescens), LipasePS
(Burkholderia cepacia), Lipase A (Aspergillus niger), and Lipase F
(Rhizopus oryzae) were purchased from AMANO, Japan. Novo-
zyme-435, Lipozyme and other lipases (Porcine pancreatic, Mucor
javanicus, Rhizopus arrhizus, Candida lipolytica, Penicillum roqueforti)
were purchased from FLUKA, USA. Reactions were monitored by
thin-layer chromatography (TLC) carried out on 0.25 mm silica
gel plates (Merck) with UV light, ethanolic anisaldehyde, and phos-
phomolybdic acid/heat as developing agents. Silicagel 100–
200 mesh was used for column chromatography. Yields refer to
chromatographically and spectroscopically homogeneous materi-
als unless otherwise stated. NMR spectra were recorded on Bruker
400 MHz spectrometers at 25 °C in CDCl3 using TMS as the internal
standard. Chemical shifts are shown in d. 13C NMR spectra were
28
28
recorded with
a complete proton decoupling environment.
(R)-1; ½aꢁD ¼ þ1:8 (c 2.04, MeOH) and for (R)-5 ½aꢁD ¼ þ4:1 (c

T. Mahapatra et al. / Tetrahedron: Asymmetry 19 (2008) 1224–1232
1227
OH
M
L
The fast reacting enantiomer of primary alchols
OAc
O
OH
O
OH
Lipase-PS
OAc
n
O
+
n
n
(R)-acetate
(S)-alcohol
K2CO3/MeOH
OH
O
n
Scheme 3. Emperical rule showing the enantiopreference of lipase toward the primary alcohol (no ‘O’ at stereocenter).
n
a) Lipase-PS
n
(CH2OH)2
PTSA
n
OH
OH
OH
X
Et
OAc
b) K2CO3/MeOH
X
Et
X
Et
O
O
O
O
X = H, n = 0; 6
X = OMe, n = 1; 3
MsCl
Et3N, DMAP
n
LiAlH4/THF
H3O+
n
OMs
X
Et
X
Et
O
O
O
Scheme 4. Asymmetric synthesis of dialkylated carbonyl compounds.
The chemical shift values are listed as dH and dC for 1H and 13C,
respectively. Optical rotations were measured on a JASCO Dip
360 digital polarimeter. Chiral HPLC was performed using Chiral
OJ-H and OD-H column (0.46 ꢂ 25 cm, Daicel industries) with Shi-
madzu Prominence LC-20AT chromatograph coupled with UV–vis
detector (254 nm). Eluting solvent used was different ratio of hex-
ane and 2-propanol. Mass spectra were recorded at CRF (Central
Research Facility), IIT, Kharagpur.
onic acid (1 equiv) in DMF was added and the mixture was then
stirred for 14 h. The reaction mixture was diluted with methanol
(10 mL), acidified with dilute HCl, and extracted with ethyl acetate
(2 ꢂ 100 mL). The combined ethyl acetate layer was washed with
water (50 mL) and brine (30 mL), and dried over sodium sulfate.
The residue obtained after evaporation of the solvent was chro-
matographed over a silica gel column using a mixture of petroleum
ether and ethyl acetate (75:25) as eluent to give the coupled acids
in 35–40% yield in all cases.
4.2. General method for chroman-4-one synthesis
4.2.2. Intramolecular Friedel–Crafts acylation reaction for
substituted chromanone synthesis
A catalytic amount of dry DMF was added to a suspension of dif-
ferent 3-aryloxy-propionic acid (0.5 g, 1 equiv) in 50 mL of dry
benzene. Oxalyl chloride (2 equiv) was then added, and the result-
ing solution was stirred at rt for 4 h. The organic solvent was
4.2.1. Coupling of substituted phenols with 3-bromopropionic
acid
To a mixture of sodium hydride (1 equiv) in DMF (15 mL/g) was
added 3-methoxyphenol (1 equiv) in DMF (10 mL) at 10–15 °C and
the mixture was stirred at rt for 1 h. A solution of 3-bromo propi-

1228
T. Mahapatra et al. / Tetrahedron: Asymmetry 19 (2008) 1224–1232
removed under reduced pressure, and the resulting oil was
dissolved in 30 mL of dry DCM. After the solution was cooled to
0 °C, SnCl4 (1.4 equiv) was added and the solution was stirred for
further 1 h while allowing it to attain rt. Next the reaction mixture
was poured into ice (20 g) and after dilution with water (30 mL),
the aqueous layer was extracted with DCM. The organic extracts
were dried over sodium sulfate, filtered, and concentrated under
vacuum. The residue was chromatographed over silica gel column
using mixture of petroleum ether and ethyl acetate (80:20) as
eluent to give the chromanones in 90% yield in all the cases.
4.6. 2-Hydroxymethyl-2-methyl-3,4-dihydro-2H-naphthalen-1-
one 1
dH: 8.0 (d, J = 8.0 Hz, 1H, ArH), 7.5 (t, J = 8.0 Hz, 1H, ArH), 7.32 (d,
J = 8.0 Hz, 1H, ArH), 7.24 (d, J = 8.0 Hz, 1H, ArH), 3.73 (d, J = 10.8 Hz,
1H, –CH2OH), 3.65 (d, J = 10.8 Hz, 1H, –CH2OH), 3.18 (dt, J = 16.0,
5.2 Hz, 1H, –C–CH2), 2.95 (td, J = 16.0, 4.0 Hz, 1H, –C–CH2), 2.25
(dt, J = 16.0, 5.2 Hz, 1H, –CH2–CH2), 1.75 (td, J = 16.0, 4.0 Hz, 1H,
–CH2–CH2), 1.24 (s, 3H, –Me). dC: 204.04 (C@O), 143.41, 133.61,
131.36, 128.74, 127.66, 126.67, 68.96 (–CH2O), 46.25 (–C2), 31.3
(–C4), 24.9 (–C3), 18.2 (–CH3). IR (neat): 3442, 1657 cmꢀ1. ES+MS
(TOF): 191 (M+1). HPLC (Daicel Chiralcel OJ-H, hexane/i-
PrOH = 9/1, flow rate = 0.75 mL/min) tR = 11.87 min (major, as-
sumed R), tR = 13.24 min (minor, assumed S).
4.2.2.1. 7-Chloro-chroman-4-one. dH: 7.7 (d, J = 8.8 Hz, 1H), 7.0
(m, 2H), 4.5 (t, J = 6.0 Hz, 2H), 2.8 (t, J = 6.0 Hz, 2H).
4.2.2.2. 7-Methoxy-chroman-4-one. dH: 7.8 (d, J = 8.8 Hz, 1H),
6.6 (dd, J = 8.8, 2.4 Hz, 1H), 6.4 (d, J = 2.4 Hz, 1H), 4.5 (t, J = 6.2 Hz,
2H), 3.8 (s, 3H), 2.75 (t, J = 6.2 Hz, 2H).
4.7. 2-Ethyl-2-hydroxymethyl-6-methoxy-3,4-dihydro-2H-
naphthalen-1-one 2
4.2.2.3. 6,7-Dimethoxy-chroman-4-one. dH: 7.4 (s, 1H), 6.4 (s,
1H), 4.5 (t, J = 6.2 Hz, 2H), 3.9 (s, 3H), 3.87 (s, 3H), 2.7 (t,
J = 6.2 Hz, 2H).
dH: 7.96 (d, J = 8.8 Hz, 1H, ArH), 6.82 (dd, J = 8.8, 1.6 Hz, 1H,
ArH), 6.65 (d, J = 1.6 Hz, 1H, ArH), 3.84 (s, 3H, –OMe), 3.72 (d,
J = 12.0 Hz, 1H, –CH2OH), 3.62 (d, J = 12.0 Hz, 1H, –CH2OH), 3.1
(m, 1H, -C–CH2), 2.85 (m, 1H, –C–CH2), 2.03 (m, 1H, –CH2–CH2),
1.98 (m, 1H, –CH2–CH2), 1.75 (m, 1H, –CH2–Me), 1.55 (m, 1H,
–CH2–Me), 0.93 (t, J = 7.6 Hz, 3H, –Me). dC: 203.5 (C@O), 163.73,
145.94, 130.1, 125.05, 113.37, 112.32, 66.5 (–CH2O), 55.4 (–OMe),
48.59 (–C2), 28.6 (–C4), 25.43 (–C3), 22.67 (–CH2–Me), 8.1
(–CH2–Me). IR (neat): 3448, 1635, 1456, 1250 cmꢀ1. ES+MS (TOF):
235 (M+1). HPLC (Daicel Chiralcel OJ-H, hexane/i-PrOH = 9/1, flow
rate = 0.5 mL/min) tR = 28.97 min (major, assumed R), tR =
38.18 min (minor, assumed S).
4.2.2.4. 6,7-Dihydro-[1,3]dioxolo[4,5-g]chromen-8-one. dH: 7.4
(s, 1H), 6.45 (s, 1H), 6.0 (s, 2H), 4.5 (t, J = 6.2 Hz, 2H), 2.75 (t,
J = 6.2 Hz, 2H).
4.3. Monomethylation of substituted chromanones
Substituted chromanones (0.5 g) were slowly added to a stirred
solution of LDA (1 equiv, 1.5 M in THF) in THF (8 mL) at ꢀ78 °C and
stirred for 20 min. Methyliodide (1 equiv) was then added and this
solution was stirred for 6 h at room temperature. A solution of sat-
urated NH4Cl (2 mL) was added and mixture was extracted with
ether. The combined organic layers were dried over Na2SO4 and
the solvents were evaporated under reduced pressure. The residue
was purified by flash column chromatography on silica gel eluting
with petroleum ether/ethyl acetate (10:1) to give the desired prod-
uct in 70% yield.
4.8. 2-Hydroxymethyl-7-methoxy-2-methyl-3,4-dihydro-2H-
naphthalen-1-one 3
dH: 7.45 (d, J = 2.8 Hz, 1H, ArH), 7.2 (d, J = 8.0 Hz, 1H, ArH), 7.0
(dd, J = 8.0, 2.8 Hz, 1H, ArH), 3.8 (s, 3H, –OMe), 3.72 (d,
J = 11.2 Hz, 1H, –CH2OH), 3.62 (d, J = 11.2 Hz, 1H, –CH2OH), 3.05
(m, 1H, –C–CH2), 2.88 (m, 1H, –C–CH2), 2.2 (m, 1H, –CH2–CH2),
1.75 (m, 1H, –CH2–CH2), 1.12 (s, 3H, –Me). dC: 203.9 (C@O),
158.3, 136.1, 132.09, 129.94, 122.08, 109.6, 68.94 (–CH2O), 55.4
(–OMe), 46.1 (–C2), 31.7 (–C4), 24.38 (–C3), 19.4 (–Me). IR (neat):
3445, 1634, 1460, 1250 cmꢀ1. ES+MS (TOF): 221 (M+1). HPLC
(Daicel Chiralcel OJ-H, hexane/i-PrOH = 9/1, flow rate = 1.0 mL/
min) tR = 16.72 min (major, assumed R), tR = 21.06 min (minor,
assumed S).
4.4. Monomethylation of 1-tetralone and 1-indalones
Substituted 1-tetralone/1-indalone (2.0 g) was slowly added
dropwise to a stirred solution of LDA (1.2 equiv, 1.5 M in THF) at
ꢀ78 °C and stirred for 20 min. Methyliodide (1.2 equiv) was then
added and this solution was stirred for 14 h. A solution of saturated
NH4Cl (10 mL) was added and the mixture was extracted with
ether (3 ꢂ 50). The combined organic layers were dried over
Na2SO4 and the solvent was evaporated under reduced pressure.
The residue was purified by flash column chromatography on silica
gel eluting with light petroleum ether/ethyl acetate (7:1) to give
the desired 2-methyl 1-tetralone/1-indalones in 65% yield.
4.9. 2-Hydroxymethyl-5,8-dimethoxy-2-methyl-3,4-dihydro-
2H-naphthalen-1-one 4
dH: 7.0 (d, J = 8.8 Hz, 1H, ArH), 6.8 (d, J = 8.8 Hz, 1H, ArH), 3.85 (s,
3H, –OMe), 3.82 (s, 3H, OMe), 3.67 (s, 2H, –CH2OH), 3.1 (m, 1H, –C–
CH2), 2.8 (m, 1H, –C–CH2), 2.15 (m, 1H, –CH2–CH2), 1.75 (m, 1H,
–CH2–CH2), 1.2 (s, 3H, –Me). dC: 204.4 (C@O), 154.42, 150.06,
134.08, 121.49, 115.38, 109.88, 69.28 (–CH2O), 56.2 (–OMe), 55.84
(–OMe), 46.95 (–C2), 30.23 (–C4), 19.54 (–C3), 18.04 (–Me). IR (neat):
3442, 1630, 1461, 1254 cmꢀ1. ES+MS (TOF): 251 (M+1). HPLC (Daicel
Chiralcel OJ-H, hexane/i-PrOH = 9/1, flow rate = 1.0 mL/min) tR =
22.92 min (major, assumed R), tR = 34.06 min (minor, assumed S).
4.5. Hydroxymethylation of 2-methyl-1-tetralone/1-indanone
and substituted 3-methyl-chroman-4-one
A mixture of 2-methyl 1-tetralone/1-indanone/chroman-4-one
(0.25 g), and K2CO3 (0.5 equiv)/in 40 mL of water/ethanol (10:1)
was stirred vigorously at 40 °C while formaldehyde (19 mL,
0.230 mmol, 1.9 equiv, 37% aqueous solution) was added for
0.5 h. Stirring was continued for 1 h at the same temperature, the
reaction mixture was cooled and extracted with ether, and the or-
ganic layer was dried over Na2SO4 and concentrated. The residue
was purified by flash column chromatography on silica gel eluting
with light petroleum ether/ethyl acetate (3:1) to give 2-(hydroxy-
methyl)-2-methyl-1-tetralone/1-indanone and the chromanones
in 80% yield in almost all cases.
4.10. 2-Hydroxymethyl-2-methyl-indan-1-one 5
dH: 7.72 (d, J = 7.6 Hz, 1H, ArH), 7.6 (d, J = 7.6 Hz, 1H, ArH), 7.4
(d, J = 7.6 Hz, 1H, ArH), 7.33 (d, J = 7.6 Hz, 1H, ArH), 3.85 (d,
J = 10.8 Hz, 1H, –CH2OH), 3.6 (d, J = 10.8 Hz, 1H, –CH2OH), 3.25 (d,
J = 17.2 Hz, 1H, –C–CH2), 2.88 (d, J = 17.2 Hz, 1H, –C–CH2), 1.23 (s,
3H, –Me). dC: 211.17 (C@O), 153.3, 135.72, 135.15, 127.43,

T. Mahapatra et al. / Tetrahedron: Asymmetry 19 (2008) 1224–1232
1229
126.63, 124.15, 67.7 (–CH2O), 50.85 (–C2), 37.88 (–C3), 20.6
(–Me). IR (neat): 3440, 1668 cmꢀ1. ES+MS (TOF): 177 (M+1). HPLC
(Daicel Chiralcel OJ-H, hexane/i-PrOH = 9/1, flow rate = 1.0 mL/
min) tR = 8.64 min (major, assumed R), tR = 9.43 min (minor,
assumed S).
110.53, 100.25, 73.64 (–O-CH2), 64.87 (–CH2O), 55.6 (–OMe),
46.44 (–C3), 16.64 (–Me). IR (neat): 3428, 1624, 1462, 1265 cmꢀ1
.
ES+MS (TOF): 223 (M+1). HPLC (Daicel Chiralcel OD-H, hexane/
i-PrOH = 9/1, flow rate = 1.0 mL/min) tR = 7.21 min (major, as-
sumed R), tR = 8.75 min (minor, assumed S).
4.11. 2-Hydroxymethyl-2-ethyl-indan-1-one 6
4.16. 3-Hydroxymethyl-6,7-dimethoxy-3-methyl-chroman-4-
one 11
dH: 7.72 (d, J = 7.6 Hz, 1H, ArH), 7.6 (d, J = 7.6 Hz, 1H, ArH), 7.4
(d, J = 7.6 Hz, 1H, ArH), 7.33 (d, J = 7.6 Hz, 1H, ArH), 3.85 (d,
J = 10.8 Hz, 1H, –CH2OH), 3.6 (d, J = 10.8 Hz, 1H, –CH2OH), 3.0 (s,
2H, –C–CH2), 1.75 (m, 2H, –CH2–Me), 0.84 (t, J = 7.6 Hz, 3H, –Me).
dC: 211.56 (C@O), 153.91, 136.76, 130.83, 127.15, 126.72, 124.16,
67.23 (–CH2O), 54.83 (–C2), 34.24 (–C3), 25.6 (–CH2–Me), 10.1
(–Me). IR (neat): 3444, 1664 cmꢀ1. ES+MS (TOF): 191 (M+1). HPLC
(Daicel Chiralcel OJ-H, hexane/i-PrOH = 9/1, flow rate = 0.8 mL/
min) tR = 10.41 min (major, assumed R), tR = 13.59 min (minor, as-
sumed S).
dH: 7.22 (s, 1H, ArH), 6.4 (s, 1H, ArH), 4.36 (d, J = 11.2 Hz, 1H,
–O–CH2–), 4.1 (d, J = 11.2 Hz, 1H, –O–CH2–), 3.88 (s, 3H, –OMe),
3.85 (d, J = 11.6 Hz, 1H, –CH2OH), 3.83 (s, 3H, –OMe), 3.54 (d,
J = 11.6 Hz, 1H, –CH2OH), 1.18 (s, 3H, –Me). dC: 195.85 (C@O),
157.8, 156.26, 144.6, 111.98, 106.83, 99.79, 73.82 (–O–CH2),
64.83 (–CH2O), 56.2 (–OMe), 56.0 (–OMe), 46.36 (–C3), 16.58
(–Me). IR (neat): 3438, 1631, 1460, 1262 cmꢀ1. ES+MS (TOF):
253 (M+1). HPLC (Daicel Chiralcel OD-H, hexane/i-PrOH = 9/1,
flow rate = 1.0 mL/min) tR = 11.01 min (major, assumed R), tR =
12.91 min (minor, assumed S).
4.12. 2-Benzyl-5-chloro-2-hydroxymethyl-indan-1-one 7
4.17. 7-Hydroxymethyl-7-methyl-6,7-dihydro-[1,3]dioxolo[4,5-g]-
dH: 7.62 (d, J = 8.0 Hz, 1H, ArH), 7.33 (s, 1H, ArH), 7.27 (d,
J = 8.0 Hz, 1H, ArH), 7.17–7.12 (m, 5H, ArH), 3.85 (d, J = 11.2 Hz,
1H, –CH2OH), 3.62 (d, J = 11.2 Hz, 1H, –CH2OH), 3.1 (d,
J = 17.6 Hz, 1H, –C–CH2), 3.0 (d, J = 3.6 Hz, 2H, –CH2Ph), 2.84 (d,
J = 17.6 Hz, 1H, –C–CH2). dC: 209.51 (C@O), 154.98, 141.71,
136.28, 134.65, 130.04, 129.96, 128.24, 127.9, 126.46, 124.87,
66.58 (–CH2O), 55.65 (–C2), 39.85 (–CH2–Ph), 34.18 (–C3).
chromen-8-one 12
dH: 7.24 (s, 1H, ArH), 6.41 (s, 1H, ArH), 5.98 (s, 2H, –O–CH2–O–),
4.44 (d, J = 11.2 Hz, 1H, –O–CH2–), 4.1 (d, J = 11.2 Hz, 1H, –O–CH2–),
3.8 (d, J = 10.0 Hz, 1H, –CH2OH), 3.56 (d, J = 10.0 Hz, 1H, –CH2OH),
1.19 (s, 3H, –Me). dC: 195.61 (C@O), 159.38, 154.45, 143.23,
113.33, 104.45, 102.0, 98.1 (–O–CH2–O), 73.8 (–O–CH2), 64.8
(–CH2O), 46.22 (–C3), 16.63 (–Me). IR (KBr): 3449, 1620, 1480,
1258 cmꢀ1. ES+MS (TOF): 237 (M+1). HPLC (Daicel Chiralcel OD-
H, hexane/i-PrOH = 19/1, flow rate = 0.5 mL/min) tR = 31.67 min
(major, assumed R), tR = 33.9 min (minor, assumed S).
IR (neat): 3448, 1674 cmꢀ1 ES+MS (TOF): 287 (M+1). HPLC
.
(Daicel Chiralcel OJ-H, hexane/i-PrOH = 9/1, flow rate = 1.0 mL/
min) tR = 16.77 min (major, assumed R), tR = 25.61 min (minor,
assumed S).
4.13. 3-Hydroxymethyl-3-methyl-chroman-4-one 8
4.18. Enzymatic transesterification of Compounds 1–12
dH: 7.87 (d, J = 8.0 Hz, 1H, ArH), 7.5 (t, J = 8.0 Hz, 1H, ArH), 7.05
(d, J = 8.0 Hz, 1H, ArH), 6.9 (d, J = 8.0 Hz, 1H, ArH), 4.5 (d,
J = 12.0 Hz, 1H, –O–CH2–), 4.16 (d, J = 12.0 Hz, 1H, –O–CH2–), 3.92
(d, J = 11.6 Hz, 1H, –CH2OH), 3.57 (d, J = 11.6 Hz, 1H, –CH2OH),
1.2 (s, 3H, –Me). dC: 197.15 (C@O), 161.25, 136.08, 127.64,
121.46, 119.8, 117.75, 73.37 (–O–CH2), 64.6 (–CH2O), 46.98 (–C3),
16.35 (–Me). IR (neat): 3436, 1620, 1462 cmꢀ1. ES+MS (TOF): 193
(M+1). HPLC (Daicel Chiralcel OD-H, hexane/i-PrOH = 9/1, flow
rate = 1.0 mL/min) tR = 4.73 min (major, assumed R), tR = 5.4 min
(minor, assumed S).
In a typical resolution experiment, a solution of 1–12 (50 mg) in
anhydrous diisopropylether (5 mL) was stirred with vinyl acetate
(8 equiv) and powdered molecular sieves (25 mg, 4 Å) followed
by the addition of Lipase (50 mg). The reaction mixture was stirred
in an orbit shaker (250 rpm) at room temperature for 12 h. After
50% conversion (by TLC analysis) the reaction mixture was filtered
through a pad of Celite and evaporated to dryness. The alcohols
1–12 and their acetates were isolated by flash chromatography.
4.19. Acetic acid 2-methyl-1-oxo-1,2,3,4-tetrahydro-
naphthalen-2-ylmethyl ester 13
4.14. 7-Chloro-3-hydroxymethyl-3-methyl-chroman-4-one 9
dH: 8.0 (d, J = 8.0 Hz, 1H, ArH), 7.5 (t, J = 8.0 Hz, 1H, ArH), 7.32 (d,
J = 8.0 Hz, 1H, ArH), 7.24 (d, J = 8.0 Hz, 1H, ArH), 4.47 (d, J = 10.8 Hz,
1H, –CH2OAc), 4.11 (d, J = 10.8 Hz, 1H, –CH2OAc), 3.18 (dt, J = 16.0,
5.2 Hz, 1H, –C–CH2), 2.95 (td, J = 16.0, 4.0 Hz, 1H, –C–CH2), 2.25 (dt,
J = 16.0, 5.2 Hz, 1H, –CH2–CH2), 2.0 (s, 3H, –OCOCH3), 1.75 (td,
J = 16.0, 4.0 Hz, 1H, –CH2–CH2), 1.24 (s, 3H, –Me). dC: 199.55
(C@O), 170.89 (–OCOMe), 143.41, 133.61, 131.36, 128.74, 127.66,
126.67, 68.56 (–CH2OAc), 45.25 (–C2), 31.3 (–C4), 24.9 (–C3),
dH: 7.7 (d, J = 8.0 Hz, 1H, ArH), 7.0 (m, 2H, ArH), 4.5 (d,
J = 12.0 Hz, 1H, –O–CH2–), 4.2 (d, J = 12.0 Hz, 1H, –O–CH2–), 3.88
(d, J = 11.6 Hz, 1H, –CH2OH), 3.65 (d, J = 11.6 Hz, 1H, –CH2OH),
1.2 (s, 3H, –Me). dC: 193.8 (C@O), 161.86, 142.2, 134.94, 128.52,
122.35, 117.9, 72.31 (–O–CH2), 65.3 (–CH2O), 48.72 (–C3), 15.32
(–Me). IR (neat): 3439, 1622, 1460 cmꢀ1 ES+MS (TOF): 227
.
(M+1). HPLC (Daicel Chiralcel OD-H, hexane/i-PrOH = 9/1, flow
rate = 1.0 mL/min) tR = 7.55 min (major, assumed R), tR = 9.25 min
(minor, assumed S).
28
20.78 (–OCOCH3), 19.08 (–Me). ½aꢁD ¼ ꢀ11:1 (c 1.0, MeOH). ES+MS
(TOF): 233 (M+1). HRMS m/z [M+H]+ found 233.1178 calculated
233.1173 for C14H17O3. HPLC (Daicel Chiralcel OJ-H, hexane/
i-PrOH = 9/1, flow rate = 1.0 mL/min) tR = 9.5 min (major, assumed
R), tR = 9.9 min (minor, assumed S).
4.15. 7-Methoxy-3-hydroxymethyl-3-methyl-chroman-4-one
10
dH: 7.81 (d, J = 8.8 Hz, 1H, ArH), 6.58 (dd, J = 2.4 Hz, 8.8 Hz, 1H,
ArH), 6.4 (d, J = 2.0 Hz, 1H, ArH), 4.5 (d, J = 11.2 Hz, 1H, –O–CH2–),
4.15 (d, J = 11.2 Hz, 1H, –O–CH2–), 3.88 (d, J = 11.2 Hz, 1H,
–CH2OH), 3.83 (s, 3H, –OMe), 3.57 (d, J = 11.2 Hz, 1H, –CH2OH),
1.2 (s, 3H, –Me). dC: 208.3 (C@O), 166.22, 163.25, 129.16, 113.62,
4.20. Acetic acid 2-ethyl-6-methoxy-1-oxo-1,2,3,4-tetrahydro-
naphthalen-2-ylmethyl ester 14
dH: 7.96 (d, J = 8.8 Hz, 1H, ArH), 6.82 (dd, J = 8.8, 1.6 Hz, 1H,
ArH), 6.65 (d, J = 1.6 Hz, 1H, ArH), 4.5 (d, J = 12.0 Hz, 1H, –CH2OAc),

1230
T. Mahapatra et al. / Tetrahedron: Asymmetry 19 (2008) 1224–1232
4.12 (d, J = 12.0 Hz, 1H, –CH2OAc), 3.84 (s, 3H, –OMe), 3.1 (m, 1H,
–C–CH2), 2.85 (m, 1H, –C–CH2), 2.1 (s, 3H, –OCOCH3), 2.03 (m,
1H, –CH2–CH2), 1.98 (m, 1H, –CH2–CH2), 1.75–1.55 (m, 2H, –CH2–
Me), 0.93 (t, J = 7.6 Hz, 3H, –Me). dC: 201.5 (C@O), 172.25
(–OCOMe), 163.73, 145.94, 130.1, 125.05, 113.37, 112.32, 68.5
(–CH2OAc), 55.4 (–OMe), 48.59 (–C2), 28.6 (–C4), 25.43 (–C3),
(–C2), 34.24 (–C3), 25.6 (–CH2–Me), 21.25 (–OCOCH3), 10.1
28
(–Me). ½aꢁD ¼ ꢀ18:8 (c 0.6, MeOH). ES+MS (TOF): 233 (M+1). HRMS
m/z [M+H]+ found 233.0658 calculated 233.0663 for C14H17O3.
HPLC (Daicel Chiralcel OJ-H, hexane/i-PrOH = 9/1, flow rate =
1.0 mL/min) tR = 8.3 min (major, assumed R), tR = 9.4 min (minor,
assumed S).
28
22.67 (–OCOCH3), 20.48 (–CH2–Me), 8.1 (–Me). ½aꢁD ¼ ꢀ18:5 (c
0.7, MeOH) ES+MS (TOF): 277 (M+1). HRMS m/z [M+H]+ found
277.1429 calculated 277.1434 for C16H21O4. HPLC (Daicel Chiralcel
OJ-H, hexane/i-PrOH = 9/1, flow rate = 1.0 mL/min) tR = 14.55 min
(major, assumed R), tR = 17.25 min (minor, assumed S).
4.25. Acetic acid 2-benzyl-5-chloro-1-oxo-indan-2-ylmethyl
ester 19
dH: 7.62 (d, J = 8.0 Hz, 1H, ArH), 7.33 (s, 1H, ArH), 7.27 (d,
J = 8.0 Hz, 1H, ArH), 7.17–7.12 (m, 5H, ArH), 4.27 (d, J = 5.2 Hz,
2H, –CH2OAc), 3.1 (d, J = 17.6 Hz, 1H, C–CH2–), 3.0 (d, J = 3.6 Hz,
2H, –CH2Ph), 2.84 (d, J = 17.6 Hz, 1H, C–CH2–), 1.94 (s, 3H,
–OCOCH3). dC: 201.34 (C@O), 173.24 (–OCOMe), 154.98, 141.71,
136.28, 134.65, 130.04, 129.96, 128.24, 127.9, 126.46, 124.87,
66.58 (–CH2OAc), 55.65 (–C2), 39.85 (–CH2Ph), 34.18 (–C3), 22.54
4.21. Acetic acid 7-methoxy-2-methyl-1-oxo-1,2,3,4-
tetrahydro-naphthalen-2-ylmethyl ester 15
dH: 7.55 (d, J = 2.8 Hz, 1H, ArH), 7.2 (d, J = 8.0 Hz, 1H, ArH), 7.0
(dd, J = 8.0, 2.8 Hz, 1H, ArH), 4.52 (d, J = 11.2 Hz, 1H, –CH2OAc),
4.13 (d, J = 11.2 Hz, 1H, –CH2OAc), 3.8 (s, 3H, –OMe), 3.05 (m, 1H,
–C–CH2), 2.88 (m, 1H, –C–CH2), 2.2 (m, 1H, –CH2–CH2), 2.1 (s, 3H,
–OCOCH3), 1.75 (m, 1H, –CH2–CH2), 1.12 (s, 3H, –Me). dC: 199.65
(C@O), 171.05 (–OCOMe), 158.3, 136.1, 132.09, 129.94, 122.08,
109.6, 68.64 (–CH2OAc), 55.4 (–OMe), 45.1 (–C2), 31.7 (–C4),
28
(–OCOCH3). ½aꢁD ¼ ꢀ12:6(c 0.5, MeOH). ES+MS (TOF): 329 (M+1).
HRMS m/z [M+H]+ found 329.5769 calculated 329.5778 for
C19H18ClO3. HPLC (Daicel Chiralcel OJ-H, hexane/i-PrOH = 9/1, flow
rate = 1.0 mL/min) tR = 17.42 min (major, assumed R), tR = 19.2 min
(minor, assumed S).
28
24.38 (–C3), 20.89 (–OCOCH3), 19.4 (–Me). ½aꢁD ¼ ꢀ7:6 (c 0.9,
MeOH). ES+MS (TOF): 263 (M+1). HRMS m/z [M+H]+ found
263.1285 calculated 263.1278 for C15H19O4. HPLC (Daicel Chiralcel
OJ-H, hexane/i-PrOH = 9/1, flow rate = 1.0 mL/min) tR = 13.27 min
(major, assumed R), tR = 15.98 min (minor, assumed S).
4.26. Acetic acid 3-methyl-4-oxo-chroman-3-ylmethyl ester 20
dH: 7.87 (d, J = 8.0 Hz, 1H, ArH), 7.5 (t, J = 8.0 Hz, 1H, ArH), 7.05
(d, J = 8.0 Hz, 1H, ArH), 6.9 (d, J = 8.0 Hz, 1H, ArH), 4.5 (d,
J = 12.0 Hz, 2H, –O–CH2–), 4.36 (d, J = 12.0 Hz, 1H, –CH2OAc), 4.18
(d, J = 12.0 Hz, 1H, –CH2OAc), 2.0 (s, 3H, –OCOCH3), 1.2 (s, 3H,
–Me). dC: 193.45 (C@O), 170.98 (–OCOMe), 161.25, 136.08,
127.64, 121.46, 119.8, 117.75, 73.37 (–OCH2), 64.6 (–CH2OAc),
4.22. Acetic acid 5,8-dimethoxy-2-methyl-1-oxo-1,2,3,4-
tetrahydro-naphthalen-2-ylmethyl ester 16
dH: 7.0 (d, J = 8.8 Hz, 1Hm ArH), 6.8 (d, J = 8.8 Hz, 1H, ArH), 4.45
(d, J = 11.2 Hz, 1H, –CH2OAc), 4.15 (d, J = 11.2 Hz, 1H, –CH2OAc),
3.85 (s, 3H, –OMe), 3.82 (s, 3H, –OMe), 3.1 (m, 1H, –C–CH2), 2.8
(m, 1H, –C–CH2), 2.15 (m, 1H, –CH2–CH2), 2.1 (s, 3H, –OCOCH3),
1.75 (m, 1H, –CH2–CH2), 1.2 (s, 3H, –Me). dC: 200.4 (C@O), 172.38
(–OCOMe), 154.42, 150.06, 134.08, 121.49, 115.38, 109.88, 68.28
(–CH2OAc), 56.2 (–OMe), 55.84 (–OMe), 46.95 (–C2), 31.23 (–C4),
28
46.98 (–C3), 20.67 (–OCOCH3), 16.35 (–Me). ½aꢁD ¼ ꢀ2:0 (c 0.5,
MeOH). ES+MS (TOF): 235 (M+1); HRMS m/z [M+H]+ found
235.0958 calculated 235.0966 for C13H15O4. HPLC (Daicel Chiralcel
OJ-H, hexane/i-PrOH = 9/1, flow rate = 1.0 mL/min) tR = 11.1 min
(major, assumed R), tR = 12.88 min (minor, assumed S).
28
4.27. Acetic acid 7-chloro-3-methyl-4-oxo-chroman-3-ylmethyl
ester 21
20.98 (–C3), 19.24 (–OCOCH3), 18.04 (–Me). ½aꢁD ¼ ꢀ2:3 (c 0.4,
MeOH). ES+MS (TOF): 293 (M+1). HRMS m/z [M+H]+ found
293.1376 calculated 293.1383 for C16H21O5. HPLC (Daicel Chiralcel
OJ-H, hexane/i-PrOH = 9/1, flow rate = 1.0 mL/min) tR = 25.85 min
(major, assumed R), tR = 31.24 min (minor, assumed S).
dH: 7.7 (d, J = 8.0 Hz, 1H, ArH), 7.0 (m, 2H, ArH), 4.5 (d,
J = 12.0 Hz, 2H, –O–CH2–), 4.4 (d, J = 11.6 Hz, 1H, –CH2OAc), 4.28
(d, J = 11.6 Hz, 1H, –CH2OAc), 1.98 (s, 3H, –OCOCH3), 1.2 (s, 3H,
–Me). dC: 193.48 (C@O), 171.23 (–OCOMe), 161.86, 142.26,
134.94, 128.82, 122.38, 117.9, 72.31 (–OCH2), 65.3 (–CH2OAc),
4.23. Acetic acid 2-methyl-1-oxo-indan-2-ylmethyl ester 17
28
48.72 (–C3), 21.46 (–OCOCH3), 15.62 (–Me). ½aꢁD ¼ ꢀ17:5 (c 1.0,
dH: 7.72 (d, J = 7.6 Hz, 1H, ArH), 7.6 (d, J = 7.6 Hz, 1H, ArH), 7.4
(d, J = 7.6 Hz, 1H, ArH), 7.33 (d, J = 7.6 Hz, 1H, ArH), 4.21 (s, 2H,
–CH2OAc), 3.31 (d, J = 17.2 Hz, 1H, –C–CH2–), 2.95 (d, J = 17.2 Hz,
1H, C–CH2–), 1.91 (s, 3H, –OCOCH3), 1.23 (s, 3H, –Me). dC: 204.17
(C@O), 178.92 (–OCOMe), 153.3, 135.72, 135.15, 127.43, 126.63,
124.15, 67.7 (–CH2OAc), 50.85 (–C2), 37.88 (–C3), 22.52
MeOH). ES+MS (TOF): 269 (M+1). HRMS m/z [M+H]+ found
269.5422 calculated 269.5415 for
C13H14ClO4. HPLC (Daicel
Chiralcel OJ-H, hexane/i-PrOH = 9/1, flow rate = 1.0 mL/min) tR =
19.55 min (major, assumed R), tR = 22.25 min (minor, assumed S).
28
(–OCOCH3), 20.6 (–Me). ½aꢁD ¼ ꢀ5:6 (c 1.1, MeOH). ES+MS (TOF):
4.28. Acetic acid 7-methoxy-3-methyl-4-oxo-chroman-3-
ylmethyl ester 22
219 (M+1). HRMS m/z [M+H]+ found 219.1024 calculated
219.1017 for C13H15O3. HPLC (Daicel Chiralcel OJ-H, hexane/
i-PrOH = 9/1, flow rate = 1.0 mL/min) tR = 9.7 min (major, assumed
R), tR = 10.25 min (minor, assumed S).
dH: 7.81 (d, J = 8.8 Hz, 1H, ArH), 6.58 (dd, J = 2.4 Hz, 8.8 Hz, 1H,
ArH), 6.4 (d, J = 2.0 Hz, 1H, ArH), 4.5 (d, J = 11.2 Hz, 2H, –O–CH2–),
4.35 (d, J = 11.2 Hz, 1H, –CH2OAc), 4.12 (d, J = 11.2 Hz, 1H,
–CH2OAc), 3.83 (s, 3H, –OMe), 2.0 (s, 3H, –OCOCH3), 1.2 (s, 3H,
–Me). dC: 204.53 (C@O), 172.25 (–OCOMe), 166.28, 163.46,
4.24. Acetic acid 2-ethyl-1-oxo-indan-2-ylmethyl ester 18
129.34, 113.62, 110.53, 100.25, 73.64 (–OCH2), 64.57 (–CH2OAc),
dH: 7.72 (d, J = 7.6 Hz, 1H, ArH), 7.6 (d, J = 7.6 Hz, 1H, ArH), 7.4
(d, J = 7.6 Hz, 1H, ArH), 7.33 (d, J = 7.6 Hz, 1H, ArH), 4.24 (s, 2H,
–CH2OAc), 3.20 (d, J = 17.4, 1H, C–CH2–), 3.06 (d, J = 17.4, 1H, C–
CH2–), 1.96 (s, 3H, –OCOCH3), 1.75 (m, 2H, –CH2–Me), 0.84 (t,
J = 7.6 Hz, 3H, –Me). dC: 203.56 (C@O), 174.32 (–OCOMe), 153.91,
136.76, 130.83, 127.15, 126.72, 124.16, 67.23 (–CH2OAc), 54.83
28
55.6 (–OMe), 46.44 (–C3), 22.45 (–OCOCH3), 16.64 (–Me). ½aꢁD
¼
ꢀ7:1 (c 0.5, MeOH). ES+MS (TOF): 265 (M+1). HRMS m/z [M+H]+
found 265.1078 calculated 265.1071 for C14H17O5. HPLC (Daicel
Chiralcel OJ-H, hexane/i-PrOH = 9/1, flow rate = 1.0 mL/min) tR =
21.81 min (major, assumed R), tR = 25.3 min (minor, assumed S).

T. Mahapatra et al. / Tetrahedron: Asymmetry 19 (2008) 1224–1232
1231
4.29. Acetic acid 6,7-dimethoxy-3-methyl-4-oxo-chroman-3-
ylmethyl ester 23
3.44 (d, J = 12.0 Hz, 1H, –CH2–O–SO2–Me), 3.1–2.9 (m, 2H, –C–
CH2), 2.85 (s, 3H, –CH2–O–SO2–Me), 2.1–1.9 (m, 2H, –CH2–CH2–),
1.76–1.64 (m, 2H, –CH2–Me), 0.92 (t, J = 7.6 Hz, 3H, –Me). dC:
164.66, 146.46, 131.85, 123.96, 117.75, 112.87, 111.88, 73.41,
72.65, 60.46, 55.86, 48.89 (–C2), 39.46 (–CH2–O–SO2–Me), 27.22
(–C4), 24.86 (–C3), 20.97 (CH2–Me), 10.42 (–CH2–Me). ES+MS
(TOF): 357 (M+1).
dH: 7.28 (s, 1H, ArH), 6.4 (s, 1H, ArH), 4.44 (d, J = 6.2 Hz, 1H, –O–
CH2–), 4.38 (d, J = 6.2 Hz, 1H, –O–CH2–), 4.19 (d, J = 4.4 Hz, 1H,
–CH2OAc), 4.12 (d, J = 4.4 Hz, 1H, –CH2OAc), 3.91 (s, 3H, –OMe),
3.87 (s, 3H, –OMe), 2.0 (s, 3H, –OCOCH3), 1.18 (s, 3H, –Me). dC:
194.50 (C@O), 171.26 (–OCOMe), 157.8, 156.26, 144.6, 111.98,
106.83, 99.79, 73.82 (–OCH2), 64.53 (–CH2OAc), 56.2 (–OMe), 56.0
4.33. (R)-2-Ethyl-6-methoxy-2-methyl-3,4-dihydro-2H-
naphthalen-1-one 27
28
(–OMe), 46.67 (–C3), 23.14 (–OCOCH3), 16.78 (–Me). ½aꢁD ¼ ꢀ4:27
(c 0.6, MeOH). ES+MS (TOF): 295 (M+1). HRMS m/z [M+H]+ found
295.1169 calculated 295.1176 for C15H19O6. HPLC (Daicel Chiralcel
OJ-H, hexane/i-PrOH = 9/1, flow rate = 1.0 mL/min) tR = 55.0 min
(major, assumed R), tR = 60.2 min (minor, assumed S).
The mesylate ester (60 mg, 0.17 mmol) obtained in the previous
step was taken in THF followed by addition of LiAlH4 (15 mg,
0.34 mmol). The reaction mixture was refluxed for 8 h, after which
time TLC indicates presence of no starting material. The reaction
mixture was quenched with careful addition of saturated aqueous
Na2SO4 solution at 0 °C. The reaction mixture was filtered upon a
pad of Celite, and the filtrate was evaporated. The crude demesy-
lated product (30 mg) was dissolved in THF/1M HCl (2 mL) and
stirred for 24 h at room temperature. The solvent was evaporated
in vacuo and the product purified by flash chromatography to
afford (12 mg) the parent keto compound in 60% yield. dH: 8.0 (d,
J = 8.8 Hz, 1H, ArH), 6.81 (dd, J = 8.8, 2.6 Hz, 1H, ArH), 6.64 (d,
J = 2.6 Hz, 1H, ArH), 3.84 (s, 3H, OMe), 3.0 (m, 2H, –C–CH2), 2.0
(m, 2H, –CH2–CH2–), 1.6 (m, 2H, –CH2–Me), 1.2 (s, 3H, –Me), 0.85
(t, J = 7.4 Hz, 3H, CH2–Me). dC: 201.59 (C@O), 163.24, 145.72,
130.36, 125.47, 113.16, 112.31, 55.39 (–OMe), 44.52 (–C2), 33.29
(–C4), 29.71 (–C3), 25.84 (–CH2–Me), 21.78 (–Me), 8.36 (–CH2–
4.30. Acetic acid 7-methyl-8-oxo-7,8-dihydro-6H-
[1,3]dioxolo[4,5-g]chromen-7-ylmethyl ester 24
dH: 7.25 (s, 1H, ArH), 6.42 (s, 1H, ArH), 5.99 (s, 2H, –O–H2–O),
4.40 (d, J = 7.4 Hz, 1H, –O–CH2–), 4.35 (d, J = 7.4 Hz, 1H, –O–CH2–),
4.15 (d, J = 11.2 Hz, 2H, –CH2OAc), 2.1 (s, 3H, –OCOCH3), 1.19
(s, 3H, –Me). dC: 194.87 (C@O), 172.68 (–OCOMe), 159.38, 154.45,
143.23, 113.33, 104.45, 102.67, 98.16 (–O–CH2–O), 73.48
(–OCH2), 64.85 (–CH2OAc), 46.22 (–C3), 21.67 (–OCOCH3), 16.63
28
(–Me). ½aꢁD ¼ ꢀ7:3 (c 0.8, MeOH). ES+MS (TOF): 279 (M+1). HRMS
m/z [M+H]+ found 279.0868 calculated 279.0864 for C14H15O6.
HPLC (Daicel Chiralcel OJ-H, hexane/i-PrOH = 9/1, flow rate =
1.0 mL/min) tR = 22.8 min (major, assumed R), tR = 29.4 min (minor,
assumed S).
28
Me). ½aꢁD ¼ ꢀ21:1 (c 1.2, MeOH). ES+MS (TOF): 219 (M+1).
4.31. (R)-3,4-Dihydrospiro[1,3-dioxolane-2-ethyl-2-
hydroxymethyl-6-methoxy-10(2H)-napthalene] 25
4.34. (R)-2-Ethyl-2-methyl-indan-1-one 28
dH: 7.6 (d, J = 6.2 Hz, 1H, ArH), 7.45 (m, 1H, ArH), 7.40 (m, 2H,
ArH), 3.1 (d, J = 17.4 Hz, 1H, –C–CH2), 2.85 (d, J = 17.4 Hz, 1H, –C–
CH2), 1.65 (m, 2H, –CH2–Me), 1.60 (s, 3H,-CH2–Me), 0.85 (t,
J = 7.4 Hz, 3H, –Me). dC: 211.66 (C@O), 152.84, 136.27, 134.76,
127.35, 126.54, 124.16, 49.72 (–C2), 31.28 (–C3), 25.8 (–CH2–Me),
(R)-2-Hydroxymethyl-2-methyl-3,4-dihydro-2H-naphthalen-1-
one (100 mg, 0.42 mmol) was taken in 5 mL benzene. Ethylenegly-
col (200 mg, 2.5 mmol) was then added followed by the addition of
catalytic PPTS. The reaction mixture was refluxed in a Dean–Stark
apparatus for 2 days. Next benzene was evaporated and the mix-
ture purified by flash chromatography to give the required com-
pound in 60% yield. dH: 7.16 (d, J = 8.8 Hz, 1H, ArH), 6.62 (dd,
J = 8.8, 1.6 Hz, 1H, ArH), 6.45 (d, J = 1.6 Hz, 1H, ArH), 3.88–3.8 (m,
4H, –O–CH2–CH2–O–), 3.85 (s, 3H, –OMe), 3.72 (d, J = 12.0 Hz, 1H,
–CH2OH), 3.65 (d, J = 12.0 Hz, 1H, –CH2OH), 3.1–2.85 (m, 2H,
–C–CH2), 2.06–1.9 (m, 2H, –CH2–CH2–), 1.75–1.60 (m, 2H,
–CH2–Me), 0.93 (t, J = 7.6 Hz, 3H, –Me). dC: 162.76 (C@O), 144.24,
132.35, 124.16, 116.45, 113.87, 111.32, 72.45 (–O–CH2–CH2–O–),
71.68 (–O–CH2–CH2–O–), 66.56 (–CH2OH), 56.47 (–OMe), 48.79
(–C2), 28.66 (–C4), 25.43 (–C3), 22.67 (–CH2–Me), 9.32 (–Me).
ES+MS (TOF): 279 (M+1).
28
21.78 (–Me), 8.46 (–CH2–Me). ½aꢁD ¼ ꢀ10:4 (c 1.0, MeOH). ES+MS
(TOF): 175 (M+1).
Acknowledgments
We are thankful to DST (New Delhi, India) for providing finan-
cial support (DST Fast track scheme and IPHRA). T.M. and N.J. are
thankful to CSIR (New Delhi, India) for a research fellowship.
References
1. New Frontiers in Asymmetric Catalysis; Mikami, K., Lautens, M., Eds.; Wiley-
Interscience: New Jersey, 2007.
2. Enzyme Catalysis in Organic Synthesis; Drauz, K., Waldmann, H., Eds.; Wiley-
VCH: Weinheim, 2002; Vols. 1–3.
4.32. (R)-Methanesulfonic acid-3,4-dihydrospiro[1,3-
dioxolane-2-ethyl-6-methoxy-10(2H)-napthalene]-2-
ylmethylester 26
3. Garcia-Urdiales, E.; Alfonso, I.; Gotor, V. Chem. Rev. 2005, 105, 313–354.
4. (a) Shang, S.; Tan, D. Curr. Opin. Chem. Biol. 2005, 9, 245–258; (b) Reayi, A.; Arya,
P. Curr. Opin. Chem. Biol. 2005, 9, 240–247; (c) Breinbauer, R.; Vetter, I. R.;
Waldmann, H. Angew. Chem., Int. Ed. 2002, 41, 2879–2890; (d) Ecker, D. J.;
Crooke, S. T. Biotechnology 1995, 13, 351–360.
5. (a) Rich, J. O.; Michels, P. C.; Khmelnitsky, Y. L. Curr. Opin. Chem. Biol. 2002, 6,
161–167; (b) Altreuter, D. H.; Clark, D. S. Curr. Opin. Biotechnol. 1999, 10, 130–
136; (c) Michels, P. C.; Khmelnitsky, Y. L.; Dordick, J. S.; Clark, D. S. Trends
Biotechnol. 1998, 16, 210–215; (d) Goodnow, R. A.; Guba, W.; Haap, W. Comb.
Chem. High Throughput Screening 2003, 6, 649–690; (e) Ramstrom, O.; Lehn, J.
M. Nat. Rev. Drug Disc. 2002, 1, 26–36; (f) Krstenansky, J. L.; Khmelnitsky, Y. L.
Biorg. Med. Chem. 1999, 7, 2157–2162.
6. (a) Kesavan, S.; Panek, J. S.; Porko, J. A., Jr. Org. Lett. 2007, 9, 5203–5206; (b) Gu,
W.; Ge, H. M.; Song, Y. C.; Ding, H.; Zhu, H. L.; Zhao, X. A.; Tan, R. X. J. Nat. Prod.
2007, 70(1), 114–117; (c) Beugelmans, Rene; Chastanet, Jacqueline; Ginsburg,
Helene; Quintero-Cortes, Leticia; Roussi, Georges J. Org. Chem. 1985, 50, 4933–
4938.
The compound obtained in the previous step was dissolved in
anhydrous DCM (64 mg, 0.23 mmol) at 0 °C. Triethylamine
(45 mg, 0.46 mmol) was added to it at the same temperature, fol-
lowed by the dropwise addition of methanesulfonyl chloride
(39 mg, 35 mmol). The reaction mixture was allowed to attain
room temperature and stirred overnight. Next it was quenched
with water, washed successively with 5% NaHCO3 and brine. Evap-
oration of the organic layer followed by chromatographic separa-
tion provided the desired methanesulfonate ester in 65% yield.
dH: 7.19 (d, J = 8.8 Hz, 1H, ArH), 6.68 (dd, J = 8.8, 1.6 Hz, 1H, ArH),
6.51 (d, J = 1.6 Hz, 1H, ArH), 3.88–3.8 (m, 4H, –O–CH2–CH2–O–),
3.85 (s, 3H, –OMe), 3.56 (d, J = 12.0 Hz, 1H, –CH2–O–SO2–Me),
7. (a) Heathcock, C. H.; Flippin, L. A. J. Am. Chem. Soc. 1983, 105, 1667–1668; (b)
Lodge, E. P.; Heathcock, C. H. J. Am. Chem. Soc. 1987, 109, 2819–2820; (c)

1232
T. Mahapatra et al. / Tetrahedron: Asymmetry 19 (2008) 1224–1232
Hashimoto, S.; Yamada, S.; Koga, K. Chem. Pharm. Bull. 1979, 27, 771–782; (d)
10. (a) Yamashita, A.; Norton, E.; Hanna, C.; Shim, J.; Salaski, E.; Zhou, D.; Mansour,
T. Synth. Commun. 2006, 36, 465–472; (b) Davis, F.; Weismiller, M. C. J. Org.
Chem. 1990, 55, 3715–3717.
Kogen, H.; Tomioka, K.; Hashimoto, S.; Koga, K. Tetrahedron 1981, 37, 3951–
3956; (e) Meyers, A. I.; Lutomski, K. A. J. Am. Chem. Soc. 1982, 104, 879–881; (f)
Meyers, A. I.; Himmelsbach, R. J. J. Am. Chem. Soc. 1985, 107, 682–685; (g)
Meyers, A. I.; Meier, A.; Rawson, D. J. Tetrahedron Lett. 1992, 33, 853–856.
8. (a) Hayashi, Y.; Sumiya, T.; Takahashi, J.; Gotoh, H.; Urushima, T.; Shoji, M.
Angew. Chem., Int. Ed. 2006, 45, 958–961; (b) Casas, J.; Sunden, H.; Cordova, A.
Tetrahedron Lett. 2004, 45, 6117–6119.
11. Wipf, P.; Aslan, D. C. J. Org. Chem. 2001, 66, 337–343.
12. Weissfloch, A. N. E.; Kazlauskas, R. J. J. Org. Chem. 1995, 60, 6959–6969.
13. (a) Kobayashi, S.; Ogino, T.; Shimizu, H.; Ishikawa, S.; Hamada, T.; Manabe, K.
Org. Lett. 2005, 7, 4729–4731; (b) Ishikawa, S.; Hamada, T.; Manabe, K.;
Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 12236–12237.
9. Eames, J.; Weerasooriya, N.; Coumbarides, G. S. Eur. J. Org. Chem. 2002, 181–
187.
14. (a) Hof, R. P.; Kellogg, R. M. J. Chem. Soc., Perkin Trans. 1 1996, 2051–2060; (b)
Chen, S. T.; Fang, G. M. J. Org. Chem. 1997, 62, 4349–4357.