Lipase-catalyzed chemo- and enantioselective acetylation of 2-alkyl/aryl-3-hydroxypropiophenones

Article abstract of DOI:10.1016/S0968-0896(01)00184-5

The chemo- and enantioselective capabilities of porcine pancreatic lipase (PPL) in tetrahydrofuran, and Candida rugosa lipase (CRL) in diisopropyl ether have been investigated for the acetylation of racemic 2-alkyl/aryl-3-hydroxypropiophenones, which are

Full text of DOI:10.1016/S0968-0896(01)00184-5

Bioorganic & Medicinal Chemistry 9 (2001) 2643–2652
Lipase-Catalyzed Chemo- and Enantioselective Acetylation of
2-Alkyl/aryl-3-hydroxypropiophenones
Rajesh Kumar,a Abul Azim,a Vijayendra Kumar,a Sunil K. Sharma,a Ashok K. Prasad,a
Oliver W. Howarth,b Carl E. Olsen,c Subhash C. Jaina and Virinder S. Parmara,*
aDepartment of Chemistry, University of Delhi, Delhi-110 007, India
bDepartment of Chemistry, University of Warwick, Coventry CV4 7AL, UK
cChemistry Department, Royal Veterinary and Agricultural University, DK-1871 Frederiksberg C, Copenhagen, Denmark
Received 7 February 2001; accepted 19 May 2001
Abstract—The chemo- and enantioselective capabilities of porcine pancreatic lipase (PPL) in tetrahydrofuran, and Candida rugosa
lipase (CRL) in diisopropyl ether have been investigated for the acetylation of racemic 2-alkyl/aryl-3-hydroxypropiophenones,
which are important precursors in the synthesis of biologically active chromanones and isoflavanones. A highly chemoselective
acetylation of primary hydroxy group in preference to phenolic hydroxy group leading to the formation of enantiomerically
enriched monoacetates has been observed. # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
organic synthesis. This is attributed mainly to their low
cost and wide tolerance towards a variety of mole-
cules.11,12 We have demonstrated earlier the capabilities
of lipases from porcine pancreas (PPL), Candida ant-
arctica (CAL), Candida rugosa (CRL), Aspergillus and
Pseudomonas species for carrying out chemo- and ste-
reoselective acylations/deacylations on polyols and
polyphenolics.13ꢀ18 In this communication, we report
lipase-catalysed chemo- and enantioselective acetylation
of 2-alkyl/aryl-3-hydroxypropiophenones using vinyl
acetate as acyl donor in the presence of PPL and CRL.
As a part of our ongoing research programme towards
the design and synthesis of biologically active natural
polyphenolics and their analogues, polyhydroxy aryl/
alkyl and diaryl ketones, and their a-methylene hydro-
xymethyl derivatives were found to be important pre-
cursors.1ꢀ4 These can be used in the synthesis of
different classes of compounds, for example chalcones,
dihydrochalcones, flavones, flavanones, chromanones,
isoflavanones, and so on.5ꢀ10 As a consequence, the
hydroxymethylation reactions have received consider-
able interest in recent years. Unfortunately, almost all
the chemical methods of hydroxymethylation on an
active methylene group lead to the formation of a race-
mic mixture and thus their cyclised products, that is
chromanones, isoflavanones, and so on are also racemic
and difficult to resolve. Since it is well established that
the enantiomers of a given bioactive compound cause
different biological effects, the synthesis of optically
pure compounds is becoming increasingly desirable. In
this scenario, biocatalytic reactions have played a vital
role in the synthesis of chiral compounds. Amongst
various enzymes, lipases and proteases have found
increasing use for achieving the desired selectivity in
Results and Discussion
We have synthesised 12 differently substituted hydroxy-
methyl ketones; seven aryl/alkyl ketones, namely (ꢁ)-3-
hydroxy-1-(2-hydroxy-4-methoxyphenyl)-2-methylpro-
panone (2a),19 (ꢁ)-2-hydroxymethyl-1-(2-hydroxy-4-
methoxyphenyl)-butan-1-one (2b), (ꢁ)-2-hydroxy-
methyl-1-(2-hydroxy-4-methoxyphenyl)-octan-1-one (2c),
(ꢁ)-2-hydroxymethyl-1-(2-hydroxy-4-methoxyphenyl)-
dodecan-1-one (2d), (ꢁ)-3-hydroxy-1-(2-hydroxy-3,4-
dimethoxyphenyl)-2-methylpropanone (2e),19 (ꢁ)-2-hy-
droxymethyl-1-(2-hydroxy-3,4-dimethoxyphenyl)-butan-
1-one (2f) and (ꢁ)-3-hydroxy-1-(4-methoxyphenyl)-2-
methylpropanone (2g)20 by carrying out hydroxymethyl-
ation of the corresponding ketones, that is 2-hydroxy-4-
methoxypropiophenone (1a),21 2-hydroxy-4-methoxy-
*Corresponding author. Tel.: +91-11-766-6555/7206; fax: +91-11-
766-7206; e-mail: minuashok@now-india.net.in
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(01)00184-5

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R. Kumar et al. / Bioorg. Med. Chem. 9 (2001) 2643–2652
butyrophenone (1b),21 2-hydroxy-4-methoxyphenyl heptyl
ketone (1c),22 2-hydroxy-4-methoxyphenyl undecyl
ketone (1d),22 2-hydroxy-3,4-dimethoxypropiophenone
(1e),21 2-hydroxy-3,4-dimethoxybutyrophenone (1f)21
and 4-methoxypropiophenone (1g), respectively. The
hydroxymethylation of compounds 1a–1g was carried
out with 1.0 equiv of formaldehyde solution (37%) in
0.5N NaOH at room temperature.7
(+)-3-acetoxy-1-(2-hydroxy-4-methoxyphenyl)-2-(4-meth-
oxyphenyl)-propanone (3h), (+)-3-acetoxy-1-(4-benzy-
loxy-2-hydroxyphenyl)-2-phenylpropanone (3i), (+)-3-
acetoxy-1-(4-benzyloxy-2-hydroxyphenyl)-2-(4-methoxy-
phenyl)-propanone (3j), (+)-2-acetoxymethyl-1-(2-
hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-propa-
none (3k) and (ꢀ)-3-acetoxy-1-(2,4-dihydroxyphenyl)-2-
phenylpropanone (3l) were found to be the monoacetyl
derivatives of their respective hydroxymethylated
ketones (ꢁ)-2a–2l. However, no acetylation reaction
was observed when reactions on all these substrates
were carried out under identical conditions but without
the addition of any lipase. All the 12 compounds 2a–2l
(except 2g and 2l) have two hydroxyl groups (one
phenolic and the other alcoholic) which can undergo
acetylation. The formation of monoacetates involving
only the aliphatic hydroxyl group has been seen in all
the compounds, this was clear as the carbinol protons in
all the monoacetates 3a–3l are deshielded (by d 0.35–
0.68 ppm) with respect to the corresponding protons in
the respective hydroxymethylated compounds 2a–2l.
The presence of peak for the chelated phenolic hydroxyl
group (except for 3g) between d12 and 13, and the
absence of any resonance due to the aliphatic hydroxyl
The hydroxymethyl diaryl ketones, namely (ꢁ)-3-
hydroxy-1-(2-hydroxy-4-methoxyphenyl)-2-(4-methoxy-
phenyl)-propanone (2h),23 (ꢁ)-1-(4-benzyloxy-2-hydro-
xyphenyl)-3-hydroxy-2-phenylpropanone (2i), (ꢁ)-1-(4-
benzyloxy-2-hydroxyphenyl)-3-hydroxy-2-(4-methox-
yphenyl)-propanone (2j) and (ꢁ)-2-hydroxymethyl-1-(2
-hydroxyphenyl)-3-(3,4-methylenedioxyphenyl)-propa-
none (2k) were synthesised by the hydroxymethylation
of 1-(2-hydroxy-4-methoxyphenyl)-2-(4-methoxyphenyl)-
ethanone (1h),24 1-(4-benzyloxy-2-hydroxyphenyl)-2-
phenylethanone (1i),25 1-(4-benzyloxy-2-hydroxyphenyl)-
2-(4-methoxyphenyl)-ethanone (1j)25 and 1-(2-hydroxy-
phenyl)-3-(3,4-methylenedioxyphenyl)-propanone (1k),26
respectively using ethoxymethyl chloride and anhydrous
potassium carbonate in refluxing acetone19 and the
ketone (ꢁ)-1-(2,4-dihydroxyphenyl)-3-hydroxy-2-phe-
nylpropanone (2l) was prepared by the debenzylation
of (ꢁ)-2i with palladium-charcoal under hydrogen
atmosphere.
1
group in the H NMR spectra of the compounds 3a–3l
further established the exclusive acetylation of aliphatic
hydroxyl group in 2a–2l by the lipase. Furthermore, the
observance of dark brown colouration on spraying
alcoholic FeCl3 solution (2%) over the thin-layer chro-
matograms of the compounds 3a–3l (except in that of
3g) confirmed that the ortho (phenolic) hydroxy func-
tion to the nuclear carbonyl group is not acetylated in
any of these compounds. This clearly indicated that,
both PPL and CRL exhibit outstanding chemoselec-
tivity for the acetylation of aliphatic hydroxyl group
over the phenolic hydroxyl, to give only a monoacetate
involving the primary hydroxy group, though both the
phenolic and alcoholic hydroxy groups can chelate with
the carbonyl group (Fig. 1). This is in confirmation with
our earlier published results on two similar compounds
where enzymatic acetylation took place chemoselec-
tively at the alcoholic hydroxy group in compounds
containing alcoholic hydroxy and non-chelated phenolic
hydroxy groups.15 Further the compound 2l has an
additional non-chelated phenolic hydroxy group at the C-
40 position and enzymatic acetylation is chemoselective in
this case also.
All the hydroxymethyl ketones 2a–2l were obtained in
racemic form and their resolution was attempted by
carrying out lipase-catalysed acetylation reaction using
vinyl acetate as the acyl donor. Both porcine pancreatic
lipase (PPL) in tetrahydrofuran (THF) and Candida
rugosa lipase (CRL) in diisopropyl ether (DIPE) were
screened. For hydroxymethylated aryl alkyl ketones
(ꢁ)-2a–2g, PPL in THF was found to be a better cata-
lyst over CRL as the reaction with CRL was much
slower. However, in the case of hydroxymethylated
diaryl ketones (ꢁ)-2h–2l, CRL in DIPE proved to be a
better catalyst as no significant reaction occurred with
PPL.
The acetylation reaction was carried by incubating the
ketone with the enzyme at 40–42 ꢂCin the presence of
vinyl acetate as acylating agent. The progress of reac-
tion was monitored through periodic checking by TLC
and/or HPLC, the reaction was stopped after about
50% conversion of the ketone to its acetyl derivative by
filtering off the enzyme. The acetate and the recovered,
unreacted hydroxymethylated ketone were separated by
column chromatography over silica gel with a gradient
solvent system of petroleum ether/ethyl acetate. All the
enzymatic reaction products, namely (+)-3-acetoxy-1-
(2-hydroxy-4-methoxyphenyl)-2-methylpropanone (3a),
(ꢀ)-2-acetoxymethyl-1-(2-hydroxy-4-methoxyphenyl)-
butan-1-one (3b), (ꢀ)-2-acetoxymethyl-1-(2-hydroxy-4-
methoxyphenyl)-octan-1-one (3c), (ꢀ)-2-acetoxymethyl-
All the substrates 2a–2l and their corresponding acet-
ates 3a–3l were fully characterized on the basis of their
spectral data. Only the ketones 2a,19 2e,19 2g20 and 2h23
are known earlier in literature, the remaining twenty
compounds have been prepared for the first time. The
ketone 2e has been reported earlier as an oil,19 but our
sample of 2e is a white crystalline solid, we have con-
firmed its structure by X-ray diffraction study (Fig. 1).27
All the enzymatic acetylation products 3a–3l and the
recovered, unreacted ketones 2a–2l were found to be
optically active (Table 1), thus revealing that the che-
moselective acetylation is also accompanied by enantio-
meric resolution of the racemic ketones 2a–2l. The
acetylated products 3a–3l, obtained by enzymatic
1-(2-hydroxy-4-methoxyphenyl)-dodecan-1-one
(+)-3-acetoxy-1-(2-hydroxy-3,4-dimethoxyphenyl)-2-
methylpropanone (3e), (+)-2-acetoxymethyl-1-(2-
(3d),
hydroxy-3,4-dimethoxyphenyl)-butan-1-one (3f), (+)-3-
acetoxy-1-(4-methoxyphenyl)-2-methylpropanone (3g),

R. Kumar et al. / Bioorg. Med. Chem. 9 (2001) 2643–2652
2645
Figure 1. X-ray crystal structure of (ꢁ)-3-hydroxy-1-(2-hydroxy-3,4-dimethoxyphenyl)-2-methylpropanone (2e).
reaction were deacetylated by using either CRL in DIPE
and n-butanol (for 3a–3g), or by using HCl/MeOH (for
3h–3l). It was ascertained in all the cases that the con-
version of acetylated compounds (+)/(ꢀ)-3a–3l into
hydroxy compounds (+)/(ꢀ)-2a–2l is 100%. It is inter-
esting to note that the alcohols 2a–2g are not good
substrates for CRL, but their monoacetates 3a–3g
become better substrates for deacetylation reactions
with CRL in DIPE. The optical rotations of the alco-
hols 2a–2l obtained by deacetylation of the enzymati-
cally acetylated compounds 3a–3l were measured; as
can be seen from Table 1, these were found to be of the
same order (within practical limits), but having opposite
sign to the rotation of the corresponding recovered,
unreacted hydroxy compounds 2a–2l (Scheme 1), thus
showing an efficient enantiomeric resolution.
Since both, the enzymatic acetylated products 3a–3l and
the corresponding recovered, unreacted ketones 2a–2l
were found to be optically active, efforts were made to
determine their enantiomeric excess (ee) values. Our
initial attempts to determine the ee values of these
compounds by using Chiracel OJ HPLC column were
not successful. However, ee values could be determined
1
by H NMR (400 MHz) spectroscopy for compounds
(ꢀ)-2a (ee 60.1) and (+)-2c (ee 43.0) only by using (R)-
(ꢀ)-2,2,2-trifluoro-1-(9-anthryl)ethanol (TFAE) as
chiral shift reagent. Splitting of the chelated hydroxyl
peak as a result of formation of diastereomeric mixture
by the addition of the chiral shift reagent can be seen in
1
Figs 2 and 3 (for 2a) and Fig. 4 (for 2c). All the H
NMR spectra were recorded at 223 K, and deuterated
toluene was used as the solvent. Deuterated chloroform
Table 1. Enantioselective acetylation of hydroxymethylated aryl alkyl ketones 2a–2l mediated by lipases in organic solvent at 40–42 ꢂC
Substrate
Reaction
condition
Reaction
time
[a]2D5 Values of the
acetylated compounds
3a–3l obtained by
[a]2D5 Values of the
recovered, unreacted
hydroxy compounds
2a–2l
[a]2D5 Values of the hydroxy compounds
2a–2l obtained by deacetylation of the
enzymatically acetylated compounds
3a–3l
enzymatic reaction
2a
2b
2c
2d
2e
2f
2g
2h
2i
a
a
a
a
a
a
a
b
b
b
b
b
22 h
48 h
7 days
20 days
52 h
68 h
10 h
10 h
25 h
22 h
9 h
+27.50
ꢀ3.40
ꢀ25.00
+6.80
+6.00
+2.00
ꢀ37.40
+1.40
ꢀ35.00
ꢀ10.00
ꢀ2.80
+20.80 (b)
ꢀ5.40 (b)
ꢀ10.60 (b)
ꢀ4.80 (b)
+32.94 (b)
ꢀ3.20 (b)
+21.80 (b)
+14.30 (c)
+5.20 (c)
+4.80 (c)
+20.20 (c)
ꢀ7.40 (c)
ꢀ3.60
ꢀ5.70
+31.50
+1.80
+11.50
+16.00
+11.70
+6.00
+21.40
ꢀ12.00
2j
2k
2l
ꢀ4.20
ꢀ16.50
+6.20
48 h
a, PPL in tetrahydrofuran (THF); b, CRL in diisopropyl ether (DIPE); c, methanolic-HCl.

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R. Kumar et al. / Bioorg. Med. Chem. 9 (2001) 2643–2652
was tried first, but no splittings were observed. On the
other hand, toluene, an anisotropic solvent, induced
non-equivalence and hence was useful in making the
chiral separation successful. Other chiral shift reagents,
namely tris (6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-
octanedioate)europium Eu (fod)3, tris (6,6,7,7,8,8,8-
heptafluoro-2,2-dimethyl-3,5-octanedioate) praseody-
mium Pr (fod)3 and tris dipivaloylmethane europium,
Eu (dpm)3, were also tried, but a clear separation of
enantiomers could not be achieved. With Eu (fod)3 and
Eu (dpm)3, a downfield shift was seen with peaks
appearing as humps with no splitting; while with Pr
Scheme 1.
Figure 2. Compound (ꢁ)-2a in toluene-d8 (top); compound (ꢁ)-2a with TFAE in toluene-d8 at 223 K showing splitting of the hydroxyl group
(bottom).

R. Kumar et al. / Bioorg. Med. Chem. 9 (2001) 2643–2652
2647
Figure 3. Compound (ꢀ)-2a in toluene-d8 (top); compound (ꢀ)-2a with TFAE in toluene-d8 at 223 K showing splitting of the hydroxyl group
(bottom).
Successful chiral separation could only be achieved for
the racemic (ꢁ)-2a and (ꢁ)-2c and the corresponding
recovered, unreacted enantiomers in both the cases, that
is the enantiomerically enriched primary alcohols (ꢀ)-2a
and (+)-2c. The ee values for the acetylated products
could not be determined as no splitting was observed
with the acetylated enantiomer in both the cases, it may
be so because no binding site (alcoholic hydroxyl) is left
to bind with TFAE. The ee values were determined by
comparing the chemical shift values of the chelated
hydroxyl group of the sample alone in deuterated tolu-
ene and the sample plus TFAE (1:1 mole ratio) in tolu-
ene-d8. The phenolic hydroxyl group was hydrogen
bonded to the carbonyl and thus resonated downfield.
Chiral splittings were observed for this hydroxyl reso-
nance with a single peak splitting into two signals in the
presence of chiral solvating agent, namely TFAE. The ee
values were calculated from the integration values of these
two signals. The R/S ratio could not be ascertained, since it
was not feasible to assign the absolute configuration to the
Figure 4. Compound (+)-2c in toluene-d8 (top); compound (+)-2c
two enantiomers. Further work is in progress and shall be
with TFAE in toluene-d8 at 223 K showing splitting of the hydroxyl
communicated in a future publication.
group (bottom).
Conclusion
(fod)3, a hump at lower d value was seen without
any clear separation of the peaks. When the tempera-
ture was decreased, the exchange process slowed down
on the NMR time scale and produced further line
broadening.
We have developed a novel, efficient and environmen-
tally benign method for the resolution of racemic
hydroxymethylated aryl alkyl ketones, this biocatalytic
method for the chemo- and enantioselective acetylation
of the racemic hydroxymethylated ketones may find

2648
R. Kumar et al. / Bioorg. Med. Chem. 9 (2001) 2643–2652
applications in the synthesis of optically enriched
bioactive 3-alkylchromanones and isoflavanones.
(MeOH): 230, 277 and 316 nm; nmax (Nujol): 3408
(OH), 2965, 1628 (C¼O), 1509, 1462, 1377, 1159 and
1030 cmꢀ1; dH (300 MHz, CDCl3): 0.96 (3H, t, C-4H),
1.74 (2H, m, C-3H), 2.30 (1H, brs, OH), 3.45–3.49 (1H,
m, C-2H), 3.82 (1H, dd, J=4.0, 11.1 Hz, CHaHbOH),
3.84 (3H, s, OCH3), 3.96 (1H, dd, J=7.0, 11.1 Hz,
CHaHbOH), 6.45 (2H, m, C-30H and C-50H), 7.69 (1H,
d, J=8.8 Hz, C-60H) and 12.92 (1H, s, chelated OH); dC
(75.5 MHz, CDCl3): 11.85 (C-4), 22.90 (C-3), 48.90 (C-
2), 55.62 (OCH3), 62.90 (CH2OH), 101.15 (C-30), 107.89
(C-50), 113.72 (C-10), 131.92 (C-60), 166.11 and 166.45
(C-20 and C-40) and 208.08 (C¼O); m/z EI-MS: 224
[M]+ (10), 177 (4), 151 (100), 97 (8) and 57 (11).
Experimental
Melting points were determined on a Mettler FP62
instrument and are uncorrected. The IR spectra were
recorded on
photometer. The optical rotations were measured with
a Perkin–Elmer RX/FT-IR spectro-
1
Bellingham Stanley AD 220 polarimeter. The H and
13CNMR spectra were recorded on Bruker AC-300
spectrometer at 300 and at 75 MHz, respectively, using
TMS as internal standard. The EI mass spectra were
recorded with a Jeol AX 505 W mass spectrometer at
70eV. The enzymes, porcine pancreatic lipase (PPL,
Type II) and C. rugosa (CRL, Type VII) were purchased
from Sigma Chemical Co. (St. Louis, MO, USA) and
used after keeping in vacuo over P2O5 for 24 h. Analy-
tical TLCs were performed on precoated Merck silica
gel 60F254 plates; the spots were detected either under
UV light or by charring with 5% alcoholic sulphuric
acid. Reactions were monitored on Shimadzu LC-10AS
HPLCinstrument with SPD-10A UV–vis detector and
Shimpack CLC-ODS (4.6 x 150 mm) reverse phase col-
umn; solvent system used was methanol-water at the
flow rate of 1 mL/min. The compound 4-methoxy-
propiophenone (1g) was procured from Aldrich Chemical
Company.
(ꢁ)-2-Hydroxymethyl-1-(2-hydroxy-4-methoxyphenyl)-
octan-1-one (2c). Colourless viscous oil; yield 52%; Rf
0.25 (petroleum ether/ethyl acetate, 19:1); lmax
(MeOH): 230, 277, 316 nm; nmax (Nujol): 3419 (OH),
2928, 1627 (C¼O), 1510, 1463, 1378, 1241, 1161, 1031,
970 cmꢀ1; dH (300 MHz, CDCl3): 0.86 (3H, t, J=6.9
Hz, C-8H), 1.28 (8H, brs, C-4H, C-5H, C-6H and C-
7H), 1.61–1.64 (2H, m, C-3H), 2.20 (1H, brs, CH2OH),
3.49–3.55 (1H, m, C-2H), 3.80–3.85 (4H, m, OCH3 and
CHaHbOH), 3.94 (1H, dd, J=7.3, 10.5 Hz, CHaHbOH),
6.46 (2H, m, C-30H and C-50H), 7.68 (1H, d, J=8.8 Hz,
C-60H), 12.92 (1H, s, chelated OH); dC (75.5 MHz,
CDCl3): 14.04 (C-8), 22.58, 27.42, 29.40, 29.77 and
31.61 (5ÂCH2), 47.48 (C-2), 55.64 (OCH3), 63.27
(CH2OH), 101.19 (C-30), 107.94 (C-50), 113.64 (C-10),
131.86 (C-60), 166.20 and 166.48 (C-20 and C-40), 208.24
(C¼O); m/z, EI-MS: 280 [M]+ (74), 262 (22), 196 (75),
151 (100), 124 (17), 108 (30), 95 (47), 55 (32).
General method of hydroxymethylation
Using formaldehyde and sodium hydroxide.7 A solution
of the ketone (1a–1g, 2.0 g) and formaldehyde (37%,1.0
equiv) in aqueous sodium hydroxide (0.5 N, 1.0 equiv)
was stirred at room temperature. The progress of the
reaction was followed by TLC. On completion, the
reaction mixture was acidified with dilute hydrochloric
acid and the product was extracted with diethyl ether
(2Â50 mL). The organic layer was combined, washed
with brine (2Â50 mL), dried over anhydrous sodium
sulphate and the solvent evaporated. The residue so
obtained was subjected to flash column chromato-
graphy over silica gel to afford the hydroxymethylated
ketones 2a–2g.
(ꢁ)-2-Hydroxymethyl-1-(2-hydroxy-4-methoxyphenyl)-
dodecan-1-one (2d). Colourless viscous oil; yield 67%;
Rf 0.35 (petroleum ether/ethyl acetate, 19:1); lmax
(MeOH): 230, 279, 318 nm; nmax (Nujol): 3413 (OH),
2925, 1628 (C¼O), 1509, 1464, 1443, 1378, 1247, 1209,
1161, 1032, 838 cmꢀ1; dH (300 MHz, CDCl3): 0.87 (3H,
t, J=6.5 Hz, C-12H), 1.23 (16H, brs, C-4H, C-5H, C-
6H, C-7H, C-8H, C-9H, C-10H and C-11H), 1.64–1.70
(2H, m, C-3H), 2.31 (1H, brs, OH), 3.51–3.59 (1H, m,
C-2H), 3.79–3.84 (4H, m, OCH3 and CHaHbOH), 3.91–
3.97 (1H, dd, J=7.4, 10.5 Hz, CHaHbOH), 6.42–6.47
(2H, m, C-30H and C-50H), 7.68 (1H, d, J=8.8 Hz, C-
60H), 12.93 (1H, s, chelated OH); dC (75.5 MHz,
CDCl3): 14.39 (C-12), 21.00, 24.36, 28.83, 29.01, 29.17,
33.23 (9ÂCH2), 48.20 (C-2), 55.03 (OCH3), 64.45
(CH2OH), 100.13 (C-30), 106.47 (C-50), 113.14 (C-10),
132.51 (C-60), 165.55 and 165.86 (C-20 and C-40), 207.60
(C¼O); m/z, EI-MS: 336 [M]+ (16), 318 (8), 238 (15),
196 (60), 178 (80), 167 (20), 151 (100), 150 (21), 123 (11),
108 (46), 95 (88), 55 (70).
Using ethoxymethyl chloride.19 To a solution of the
ketone (1h–1k, 5 mmol) in anhydrous acetone (100 mL),
freshly ignited potassium carbonate (3.5 g) and a solu-
tion of ethoxymethyl chloride (5.5 mmol) in anhydrous
acetone (5 mL) were added and the reaction mixture
was refluxed. The progress of reaction was monitored
by TLC(petroleum ether/ethyl acetate, 4:1); on com-
pletion (3–4 h), the reaction mixture was filtered and the
filterate concentrated under reduced pressure. The light
brown residue so obtained was purified by column
chromatography using a gradient system of petroleum
ether and ethyl acetate as eluent to give the hydroxy-
methylated ketones 2h–2k.
(ꢁ)-3-Hydroxy-1-(2-hydroxy-3,4-dimethoxyphenyl)-2-
methylpropanone (2e). White crystalline solid; mp
70 ꢂC; yield 60.0%; Rf 0.30 (petroleum ether/ethyl ace-
tate, 3:1); lmax (MeOH): 218, 284 and 355 nm; nmax
(Nujol): 3516 (OH), 2925, 1625 (C¼O), 1506, 1450,
1378, 1269, 1154 and 1071 cmꢀ1; dH (300 MHz, CDCl3):
1.27 (3H, d, J=7.1 Hz, CH3), 2.32 (1H, brs, OH), 3.61–
3.68 (1H, m, C-2H), 3.77–3.81 (1H, m, C-3Ha), 3.90 and
3.95 (6H, 2s, 3H each, 2ÂOCH3), 3.86–3.99 (1H, m,
(ꢁ)-2-Hydroxymethyl-1-(2-hydroxy-4-methoxyphenyl)-
butan-1-one (2b). Colourless viscous oil; yield 65%; Rf
0.35 (petroleum ether/ethyl acetate, 17:3); lmax

R. Kumar et al. / Bioorg. Med. Chem. 9 (2001) 2643–2652
2649
C-3Hb), 6.53 (1H, d, J=9.1 Hz, C-50H), 7.59 (1H, d,
J=9.1 Hz, C-60H) and 12.64 (1H, s, chelated OH); dC
(75.5 MHz, CDCl3): 15.10 (CH3), 40.92 (C-2), 56.18 and
60.67 (2ÂOCH3), 64.63 (C-3), 103.19 (C-50), 114.36 (C-
10), 126.61 (C-60), 136.83 (C-30), 157.86 and 158.78 (C-20
and C-40) and 208.71 (C¼O); m/z, EI-MS: 240 [M]+
(18), 222 (12), 181 (100), 137 (10), 120 (20), 95 (13) and
55 (12).
4000), 129.3 (C-3000 and C-5000), 130.0 (C-100), 133.0 (C-60),
136.5 (C-10), 159.8 (C-20), 165.9 (C-40), 167.0 (C-400),
205.0 (C¼O).
(ꢁ)-2-Hydroxymethyl-1-(2-hydroxyphenyl)-3-(3,4-me-
thylenedioxyphenyl)- propanone (2k). Thick brownish
oil; yield 45%; Rf 0.42 (petroleum ether/ethyl acetate,
4:1); nmax (CHCl3): 2923, 1633 (C¼O), 1609, 1579, 1488,
1358, 1289, 1245, 1157, 1039, 960 cmꢀ1; dH (300 MHz,
CDCl3): 2.40 (1H, brs, OH), 2.90 and 3.00 (1H each,
2m, C-3Ha and C-3Hb), 3.86–3.89 (3H, m, C-2H and
CH2OH), 5.90 (2H, s, OCH2O), 6.68 (3H, m, C-200H, C-
30H and C-600H), 6.88 (1H, m, C-50H), 6.98 (1H, d,
J=7.5 Hz, C-500H), 7.46 (1H, m, C-40H), 7.73 (1H, d,
J=9.0 Hz, C-60H), 12.25 (1H, s, chelated OH); dC
(75.5 MHz, CDCl3): 31.0 (C-2), 51.0 (C-3), 64.0
(CH2OH), 102.0 (OCH2O), 109.0 (C-30), 110.0 (C-200),
119.6 (C-600), 120.0 (C-500), 120.5 (C-100), 123.0 (C-40),
131.0 (C-60 ), 133.0 (C-50), 137.9 (C-10), 147.5 and 148.5
(ꢁ)-2-Hydroxymethyl-1-(2-hydroxy-3,4-dimethoxyphenyl)-
butan-1-one (2f). Colourless viscous oil; yield 64%; Rf
0.40 (petroleum ether/ethyl acetate, 3:1); lmax (MeOH):
221, 287 and 355 nm; nmax (Nujol): 3429 (OH), 2934,
1628 (C¼O), 1506, 1447, 1379, 1274, 1138, 1068 and
1007 cmꢀ1; dH (400 MHz, CDCl3): 0.95 (3H, t, J=7.7
Hz, CH2CH3), 1.24 (1H, brs, OH), 1.65–1.80 (2H, m,
CH2CH3), 3.40–3.60 (1H, m, C-2H), 3.82 (1H, dd,
J=4.0, 12.0 Hz, CHaHbOH), 3.87 and 3.92 (6H, 2s, 3H
each, 2ÂOCH3), 3.95 (1H, dd, J=12.0, 15.0 Hz,
CHaHbOH), 6.50 (1H, d, J=9.1 Hz, C-50H), 7.56 (1H,
d, J=9.1 Hz, C-60H) and 12.71 (1H, s, chelated OH); dC
(75.5 MHz, CDCl3): 11.74 (CH2CH3), 22.82 (CH2CH3),
48.87 (C-2), 56.02 and 60.55 (2ÂOCH3), 62.79
(CH2OH), 102.95 (C-50), 114.98 (C-10), 126.61 (C-60),
136.56 (C-30), 157.66 and 158.68 (C-20 and C-40) and
208.68 (C¼O); m/z, EI-MS: 254 [M]+ (15), 236 (8), 195
(13), 181 (100), 152 (10), 120 (8), 86 (44), 69 (19) and 55 (8).
00
(C-300, C -4 ),164.0 (C-20), 201.0 (C¼O); m/z, EI-MS: 300
[M]+ (50), 282 (15), 269 (60), 162 (10), 161 (9), 135
(100), 121 (98), 89 (15), 77 (22), 65 (25).
(ꢁ)-1-(2,4-Dihydroxyphenyl)-3-hydroxy-2-phenylpropa-
none (2l). To a solution of 1-(4-benzyloxy-2-hydro-
xyphenyl)-3-hydroxy-2-phenylpropanone (2i, 500 mg) in
ethyl acetate (15 mL), Pd-C(10%, 50 mg) was added
and the reaction mixture was stirred under hydrogen at
atmospheric pressure at 25–30 ꢂC, progress of the reac-
tion was monitored by TLC(petroleum ether/ethyl ace-
tate, 3:2). After completion (3 h), the catalyst was
filtered off, solvent removed under vacuum to afford 2l
as a white solid (320 mg, 86% yield); mp 90–91 ꢂC; Rf
0.32 (petroleum ether/ethyl acetate, 3:2); nmax (CHCl3):
3423, 2939, 1620, 1491, 1439, 1329, 1256, 1160, 1051,
940, 821 and 753 cmꢀ1; dH (300 MHz, CD3OD): 3.30
(1H, brs, OH), 3.72 (1H, dd, J=6.0 Hz and 10.5 Hz, C-
3Ha), 4.30 (1H, dd, J=8.0, 10.5 Hz, C-3Hb), 4.77 (1H,
dd, J=6.0 and 8.0 Hz, C-2H), 6.23 (1H, d, J=3.0 Hz,
C-30H), 6.28 (1H, dd, J=3.0 and 9.0 Hz, C-50H), 7.24–
(ꢁ)-1-(4-Benzyloxy-2-hydroxyphenyl)-3-hydroxy-2-phe-
nylpropanone (2i). Colourless viscous oil; yield 58%; Rf
0.52 (petroleum ether/ethyl acetate, 4:1); nmax (CHCl3):
3441 (OH), 2934, 1627 (C¼O), 1580, 1455, 1303, 1250,
1147, 1035 cmꢀ1; dH (300 MHz, CDCl3): 2.50 (1H, brs,
OH), 3.84 (1H, dd, J=4.5, 12.0 Hz, C-3Ha), 4.25 (1H,
dd, J=7.5, 12.0 Hz, C-3Hb), 4.74 (1H, dd, J=4.5 and
9.0 Hz, C-2H), 5.04 (2H, s, OCH2Ph), 6.40 (1H, dd,
J=3.0 and 7.5 Hz, C-50H), 6.49 (1H, d, J=3.0 Hz, C-
30H), 7.22–7.24 (10H, m, C-200H, C-300H, C-400H, C-500H,
C-600H and CH2C6H5), 7.64 (1H, d, J=9.0Hz, C-60H),
12.70 (1H, s, chelated OH); dC (75.5 MHz, CDCl3): 56.0
(C-2), 65.0 (C-3), 71.0 (OCH2Ph), 102.5 (C-30), 109.0
00
7.32 (5H, m, C-200H, C-300H, C-400H, C-500H and C -6 H),
00
000
(C-50), 114.0 (C-400), 128.0 (C-200, C -6, C -2 and C-6000),
7.78 (1H, d, J=9.0 Hz, C-60H), 12.70 (1H, s, chelated
OH); dC (75.5 MHz, CD3OD): 56.5 (C-2), 65.0 (C-3),
103.5 (C-50), 109.0 (C-30), 114.0 (C-400), 129.4 (C-300 and
C-500), 129.7 (C-100), 130.2 (C-200 and C-600), 134.2 (C-60),
138.6 (C-10), 166.5 (C-40), 167.5 (C-20) and 204.0 (C¼O).
128.7 (C-4000), 129.0 (C-1000), 129.3 (C-300, C -5 , C -3 and
C-5000), 129.7 (C-100), 136.0 (C-60), 137.0 (C-10), 165.6 (C-
20), 166.4 (C-40), 204.0 (C¼O).
00
000
(ꢁ)-1-(4-Benzyloxy-2-hydroxyphenyl)-3-hydroxy-2-(4-
methoxyphenyl)- propanone (2j). Thick brownish oil;
yield 66%; Rf 0.50 (petroleum ether/ethyl acetate, 4:1);
nmax (CHCl3): 3441 (OH), 3032, 1627 (C¼O), 1612,
1580, 1455, 1369, 1303, 1250, 1183, 1071 cmꢀ1; dH
(300 MHz, CDCl3): 2.95 (1H, brs, OH), 3.65 (3H, s,
OCH3), 3.83 (1H, dd, J=4.5, 12.0 Hz, C-3Ha), 4.23
(1H, dd,J=9.0, 12.0 Hz, C-3Hb), 4.67 (1H, dd, J=4.5
and 9.0 Hz, C-2H), 5.10 (2H, s, OCH2C6H5), 6.42 (1H,
dd, J=3.4 and 8.4 Hz, C-30H), 6.51 (1H, d, J=3.4 Hz,
General method of lipase-catalysed acetylation of
hydroxymethylated aryl alkyl ketones
To a solution of the hydroxymethylated ketone (ꢁ)-2a–
2l (2.0 mmol) in anhydrous THF/DIPE (20 mL) was
added vinyl acetate (4.4 mmol) as the acylating agent
and the lipase (half the weight of the ketone). The reac-
tion mixture was incubated at 40 ꢂCand the progress of
the reaction was monitored periodically by HPLC/TLC
examination. After 50% conversion, the reaction was
quenched by filtering off the enzyme and the filterate
concentrated under vacuo; the thick oil so obtained was
column chromatographed over silica gel using a gra-
dient system of petroleum ether/ethyl acetate as eluent
to afford the corresponding acetates and the unreacted
hydroxy compounds.
00
C-50H), 6.87 (2H, d, J=9.0 Hz, C-3 H and C-500H), 7.24
00
(2H, d, J=9.0 Hz, C-200H and C -6H), 7.34–7.38 (5H,
m, OCH2C6H5), 7.70 (1H, d, J=9.0Hz, C-60H), 12.85
(1H, s, chelated OH); dC (75.5 MHz, CDCl3): 55.5 (C-2),
57.0 (OCH3), 65.5 (C-3), 71.0 (OCH2C6H5), 102.5 (C-
000
30), 109.0 (C-50), 114.1 and 115.4 (C-2000, C -6 and C-300,
C-500), 128.2 (C-200 and C-600), 129.0 (C-1000), 129.2 (C-

2650
R. Kumar et al. / Bioorg. Med. Chem. 9 (2001) 2643–2652
(+)-3-Acetoxy-1-(2-hydroxy-4-methoxyphenyl)-2-methyl-
propanone (3a). Colourless viscous oil; yield 48%; Rf
0.40 (petroleum ether/ethyl acetate, 17:3); lmax
(MeOH): 217, 234, 281, 318 nm; nmax (Nujol): 2937,
1745 (OCOCH3), 1632 (C¼O), 1510, 1463, 1376, 1220,
1163, 1124, 1036, 983 cmꢀ1; dH (300 MHz, CHCl3): 1.25
(3H, d, J=6.9 Hz, CH3), 1.99 (3H, s, OCOCH3), 3.75–
3.85 (4H, m, OCH3 and C-2H), 4.17 (1H, dd, J=5.8,
10.8 Hz, C-3Ha), 4.40 (1H, dd, J=8.2, 10.8 Hz, C-3Hb),
6.45–6.48 (2H, m, C-30H and C-50H), 7.69 (1H, d,
J=8.6 Hz, C-60H), 12.82 (1H, s, chelated OH); dC
(100.6 MHz, CDCl3): 15.10 (CH3), 20.86 (OCOCH3),
39.21 (C-2), 55.65 (OCH3), 65.72 (C-3), 101.15 and
107.92 (C-30 and C-50), 112.87 (C-10), 131.49 (C-60),
166.15 and 166.39 (C-20 and C-40), 170.95 (OCOCH3),
205.27 (C¼O); m/z EI-MS: 252 [M]+ (42), 238 (7), 210
(22), 192 (80), 177 (33), 151 (100), 108 (35), 95 (40), 71
(71), 57 (65), 43 (85).
(MeOH): 213, 228, 277 nm; nmax (Nujol): 2927, 2854,
1745 (OCOCH3), 1628 (C¼O), 1509, 1464, 1444, 1376,
1241, 1163, 1126, 1033, 980 cmꢀ1; dH (300 MHz,
CDCl3): 0.87 (3H, t, J=6.4 Hz, C-12H), 1.22 (16H, brs,
C-4H, C-5H, C-6H, C-7H, C-8H, C-9H, C-10H and C-
11H), 1.49–1.57 (1H, m, C-3Ha), 1.69–1.78 (1H, m, C-
3Hb), 1.95 (3H, s, OCOCH3), 3.68–3.78 (1H, m, C-2H),
3.85 (3H, s, OCH3), 4.23–4.37 (2H, m, CH2OAc), 6.45–
6.48 (2H, m, C-30H and C-50H), 7.68 (1H, d, J=8.7 Hz,
C-60H), 12.98 (1H, s, chelated OH); dC (75.5 MHz,
CDCl3): 14.12 (C-12), 19.84 (OCOCH3), 20.83, 22.69,
27.17, 28.73, 29.32, 29.54, 29.67, 29.91, 31.89 (9ÂCH2),
44.37 (C-2), 55.62 (OCH3), 65.12 (CH2OAc), 101.08 (C-
30), 107.86 (C-50), 113.95 (C-10), 131.59 (C-60), 166.05
and 166.40 (C-20 and C-40), 170.92 (OCOCH3), 205.48
(C¼O); m/z, EI-MS: 378 [M]+ (2), 318 (10), 178 (40),
151 (100), 95 (5), 43 (4).
(+)-3-Acetoxy-1-(2-hydroxy-3,4-dimethoxyphenyl)-2-
methylpropanone (3e). Colourless viscous oil; yield
56%; Rf 0.45 (petroleum ether/ethyl acetate, 3:1); lmax
(MeOH): 221, 286 nm; nmax (Nujol): 2935, 1744
(OCOCH3), 1631 (C¼O), 1507, 1462, 1423, 1376, 1270,
1183, 1067, 1035 cmꢀ1; dH (300 MHz, CDCl3): 1.26 (3H,
d, J=7.0 Hz, CH3), 2.00 (3H, s, OCOCH3), 3.76–3.86
(1H, m, C-2H), 3.90 and 3.99 (6H, 2s, 3H each,
2ÂOCH3), 4.17 (1H, dd, J=5.8, 10.8 Hz, C-3Ha), 4.41
(1H, dd, J=8.1, 10.8 Hz, C-3Hb), 6.54 (1H, d, J=9.1
Hz, C-50H), 7.58 (1H, d, J=9.1 Hz, C-60H), 12.63 (1H,
s, chelated OH); dC (75.5 MHz, CDCl3): 14.95 (CH3),
20.73 (COCH3), 39.33 (C-2), 56.10 and 60.57
(2ÂOCH3), 65.62 (C-3), 102.67 (C-50), 114.22 (C-10),
126.23 (C-60), 136.72 (C-30), 157.74 and 158.72 (C-20 and
C-40), 170.79 (OCOCH3), 205.92 (C¼O); m/z, EI-MS:
282 [M]+ (50), 240 (3), 222 (80), 207 (51), 181 (100), 166
(45), 148 (55), 120 (47), 95 (26), 55 (21), 43 (95).
(ꢀ)-2-Acetoxymethyl-1-(2-hydroxy-4-methoxyphenyl)-
butan-1-one (3b). Colourless viscous oil; yield 66%; Rf
0.45 (petroleum ether/ethyl acetate, 11:2); lmax
(MeOH): 214, 230, 278, 317 nm; nmax (Nujol): 2929,
2853, 1747 (OCOCH3), 1631 (C¼O), 1510, 1462, 1376,
1220, 1162, 1124, 1038 cmꢀ1; dH (300 MHz, CDCl3):
0.93 (3H, t, J=7.5 Hz, C-4H), 1.56–1.70 (1H, m, C-
3Ha), 1.73–1.88 (1H, m, C-3Hb), 1.96 (3H, s, OCOCH3),
3.64–3.75 (1H, m, C-2H), 3.85 (3H, s, OCH3), 4.27 (1H,
dd, J=5.4, 10.7 Hz, CHaHbOAc), 4.36 (1H, dd, J=8.7,
10.7 Hz, CHaHbOAc), 6.45–6.48 (2H, m, C-30H and C-
50H), 7.69 (1H, d, J=8.6 Hz, C-60H), 12.95 (1H, s, che-
lated OH); dC (75.5 MHz, CDCl3): 11.12 (C-4), 20.36
(C-3), 22.65 (COCH3), 45.36 (C-2), 55.18 (OCH3), 64.40
(CH2OAc), 101.44 and 107.39 (C-30 and C-50), 113.58
(C-10), 131.23 (C-60), 165.62 and 166.00 (C-20 and C-40),
174.85 (OCOCH3), 204.89 (C¼O); m/z, EI-MS: 266
[M]+ (70), 206 (80), 177 (54), 151 (100), 122 (12), 108
(41), 65 (17), 52 (26), 43 (85).
(+)-2-Acetoxymethyl-1-(2-hydroxy-3,4-dimethoxyphenyl)-
butan-1-one (3f). Colourless viscous oil; yield 62%; Rf
0.35 (petroleum ether/ethyl acetate, 4:1); lmax (MeOH):
219, 286 nm; nmax (Nujol): 2934, 1744 (OCOCH3), 1630
(C¼O), 1506, 1448, 1423, 1377, 1276, 1120, 1067, 1041
cmꢀ1; dH (250 MHz, CDCl3): 0.86 (3H, t, J=8.4 Hz, C-
4H), 1.56–1.62 (1H, m, C-3Ha), 1.64–1.70 (1H, m, C-
3Hb), 1.95 (3H, s, OCOCH3), 3.65–3.71 (1H, m, C-2H),
3.89 and 4.23 (6H, 2s, 3H each, 2ÂOCH3), 4.25–4.39
(2H, m, CH2OAc), 6.50 (1H, d, J=9.0 Hz, C-50H), 7.55
(1H, d, J=9.0 Hz, C-60H), 12.73 (1H, s, chelated OH);
dC (62.5 MHz, CDCl3): 11.44 (C-4), 20.71 (C-3), 23.01
(COCH3), 45.77 (C-2), 56.02 and 60.55 (2ÂOCH3),
64.66 (CH2OAc), 102.88 (C-50), 115.24 (C-10), 126.30
(C-60), 136.55 (C-30), 158.66 and 157.60 (C-20 and C-40),
170.82 (OCOCH3), 205.90 (C¼O); m/z, EI-MS: 296
[M]+ (55), 236 (95), 221 (32), 207 (34), 181 (100), 166
(18), 86 (78), 74 (31), 73 (30), 69 (64), 55 (42).
(ꢀ)-2-Acetoxymethyl-1-(2-hydroxy-4-methoxyphenyl)-oc-
tan-1-one (3c). Colourless viscous oil; yield 70%; Rf 0.35
(petroleum ether/ethyl acetate, 19:1); lmax (MeOH):
214, 230, 278 nm; nmax (Nujol): 2929, 2857, 1745
(OCOCH3), 1632 (C¼O), 1509, 1464, 1444, 1376, 1238,
1162, 1125, 1033, 982 cmꢀ1; dH (300 MHz, CDCl3): 0.85
(3H, t, J=6.8 Hz, C-8H), 1.24–1.26 (8H, m, C-4H, C-
5H, C-6H and C-7H), 1.53–1.58 (1H, m, C-3Ha), 1.74–
1.78 (1H, m, C-3Hb), 1.95 (3H, s, OCOCH3), 3.68–3.78
(1H, m, C-2H), 3.85 (3H, s, OCH3), 4.23–4.37 (2H, m,
CH2OAc), 6.45–6.48 (2H, m, C-30H and C-50H), 7.68
(1H, d, J=8.6 Hz, C-60H), 12.98 (1H, s, chelated OH);
dC (100 MHz, CDCl3): 13.87 (C-8), 20.71 (OCOCH3),
22.40, 26.98, 29.20, 29.76 and 31.37 (5ÂCH2), 44.22 (C-
2), 55.49 (OCH3), 65.01 (CH2OAc), 100.93 (C-30),
107.73 (C-50), 113.79 (C-10), 131.43 (C-60), 165.88 and
166.25 (C-20 and C-40), 170.81 (OCOCH3), 205.32
(C¼O); m/z, EI-MS: 322 [M]+ (20), 284 (5), 262 (42),
178 (80), 177 (37), 151 (100), 150 (18), 149 (14), 123 (7),
111 (12), 108 (22), 95 (27), 74 (4), 73 (37), 57 (55).
(+)-3-Acetoxy-1-(4-methoxyphenyl)-2-methylpropanone
(3g). Colourless viscous oil; yield 77%; Rf 0.40 (petro-
leum ether/ethyl acetate, 9:1); lmax (MeOH): 220, 276
nm; nmax (Nujol): 2938, 2846, 1744 (OCOCH3), 1625
(C¼O), 1601, 1574, 1511, 1462, 1421, 1375, 1309, 1238,
1175, 1035, 975 cmꢀ1; dH (300 MHz, CDCl3): 1.22 (3H,
d, J=7.0 Hz, CH3), 1.96 (3H, s, OCOCH3), 3.76–3.85
(ꢀ)-2-Acetoxymethyl-1-(2-hydroxy-4-methoxyphenyl)-
dodecan-1-one (3d). Colourless viscous oil; yield 50%;
Rf 0.45 (petroleum ether/ethyl acetate, 19:1); lmax

R. Kumar et al. / Bioorg. Med. Chem. 9 (2001) 2643–2652
2651
(1H, m, C-2H), 3.88 (3H, s, OCH3), 4.17 (1H, dd,
J=5.9, 10.7 Hz, C-3Ha), 4.42 (1H, dd, J=7.9, 010.7 Hz,
C-3Hb), 6.96 (2H, d, J=8.5 Hz, C-30H and C -5H), 7.96
(2H, d, J=8.5 Hz, C-20H and C-60H); dC (75.5 MHz,
CDCl3): 14.78 (CH3), 20.84 (OCOCH3), 39.56 (C-2),
55.51 (OCH3), 66.14 (C-3), 113.92 (C-30 and C-50),
129.20 (C-10), 130.70 (C-20 and C-60), 164.00 (C-40),
171.00 (OCOCH3), 200.00 (C¼O); m/z, EI-MS: 236
[M]+ (20), 194 (17), 176 (53), 135 (100), 121 (10), 107
(44), 92 (73), 77 (82), 64 (30), 43 (85).
128.0 (C-4000), 128.5 (C-3000 and C-5000 ), 130.0 (C-200 and
C-600), 132.5 (C-60), 137.0 (C-10), 159.5 (C-400), 166.5 (C-
20), 168.5 (C-40), 171.0 (OCO), 201.0 (C¼O).
(+)-2-Acetoxymethyl-1-(2-hydroxyphenyl)-3-(3,4-methy-
lenedioxyphenyl)- propanone (3k). Brown coloured oil;
nmax (CHCl3): 2922, 1741 (OCOCH3),1635 (C¼O),
1489, 1245, 1207, 1100, 1039 cmꢀ1; dH (300 MHz,
CDCl3): 1.92 (3H, s, OCOCH3), 2.78 (1H, dd, J=7.5,
13.5 Hz, C-3Ha), 3.02 (1H, dd, J=7.5, 13.5 Hz, C-
3Hb), 4.08 (1H, m, C-2H), 4.24 (1H, dd, J=6.0, 12.0
Hz, CHaHbOAc), 4.38 (1H, dd, J=7.5, 12.0 Hz,
CHaHbOAc), 5.86 (2H, s, OCH2O), 6.58 (1H, dd,
J=3.0 and 9.0 Hz, C-30H), 6.63 (1H, d, J=2.5 Hz, C-
200H), 6.66 (1H, d,J=9.0 Hz, C-500H), 6.86 (1H, m, C-
50H), 6.96 (1H, dd, J=2.5 and 9.0 Hz, C-600H), 7.45
(1H, m, C-40H), 7.70 (1H, dd, J=3.0, 9.0 Hz, C-60H),
12.30 (1H, s, chelated OH); dC (75.5 MHz, CDCl3): 22.0
(OCOCH3), 36.0 (C-3), 47.5 (C-2), 65.0 (CH2OAc),
101.0 (OCH2O), 109.0 (C-30), 110.0 (C-200), 119.0 (C-600),
119.5 (C-500), 120.0 (C-100), 123.0 (C-40), 130.5 (C-60),
132.5 (C-50), 137.5 (C-10), 146.5 (C-400), 148.0 (C-300),
164.0 (C-20), 171.0 (OCO), 201.0 (C¼O); m/z, EI-MS:
342 [M]+ (10), 282 (30), 162 (3), 161 (10), 135 (65), 121
(100), 905 (7), 93 (10), 77 (30), 43 (30).
(+)-3-Acetoxy-1-(2-hydroxy-4-methoxyphenyl)-2-(4-
methoxyphenyl)-propanone (3h). Colourless oil; nmax
(CHCl3): 2956, 1739 (OCOCH3), 1628 (C¼O), 1579,
1459, 1304, 1249, 1218, 1180, 1151, 1133 cmꢀ1; dH
(300 MHz, CDCl3): 2.00 (3H, s, OCOCH3), 3.75 (3H, s,
OCH3), 3.79 (3H, s, OCH3), 4.34 (1H, dd, J=6.0 and
10.5, C-3Ha), 4.73 (1H, dd, J=9.0, 10.5 Hz, C-3Hb),
4.83 (1H, dd, J=6.0 and 9.0 Hz, C-2H), 6.36 (1H, dd,
J=3.0 and 9.0 Hz, C-50H), 6.39 (1H, d, J=3.0 Hz, C-
30H), 6.84 (2H, d, J=8.4 Hz, C-300H and C-500H), 7.24
(2H, d, J=8.4 Hz, C-200H and C-600H), 7.64 (1H, d,
J=9.0 Hz, C-60H), 12.70 (1H, s, chelated OH); dC
(75.5 MHz, CDCl3): 22.5 (OCOCH3), 52.0 (C-2), 56.0
(OCH3), 56.5 (OCH3), 66.0 (C-3), 102.0 (C-30), 109.0 (C-
100), 114.0 (C-50), 116.0 (C-300 and C-500), 128.5 (C-60),
130.5 (C-200 and C-600), 133.0 (C-10), 161.0 (C-20), 167.0
(C-40 and C-400), 172.0 (OCO), 202.5 (C¼O).
(ꢀ)-3-Acetoxy-1-(2,4-dihydroxyphenyl)-2-phenylpropanone
(3l). White solid; mp 115–116 ꢂC; yield 58%; nmax: 2956,
1739, 1628, 1579, 1459, 1368, 1304, 1218, 1151, 1133
and 945 cmꢀ1; dH (300 MHz, CD3OD): 1.96 (3H, s,
OCOCH3), 4.30 (1H, dd, J=4.5, 12.0 Hz, CHaHbOAc),
4.72 (1H, dd, J=9.0, 12.0 Hz, CHaHbOAc), 4.97 (1H,
dd, J=4.5 and 9.0 Hz, C-2H), 6.24 (1H, d, J=2.5 Hz,
C-30H), 6.28 (1H, dd, J=3.0 and 8.0 Hz, C-50H), 7.25–
(+)-3-Acetoxy-1-(2-hydroxy-4-benzyloxyphenyl)-2-phenyl-
propanone (3i). Colourless oil; nmax (CHCl3): 3031, 1739
(OCOCH3), 1628 (C¼O), 1575, 1454, 1368, 1232, 1215,
1147, 1075, 1023 cmꢀ1; dH (300 MHz, CDCl3): 2.00 (3H,
s, OCOCH3), 4.38 (1H, dd, J=6.0 and 12.0, C-3Ha),
4.77 (1H, dd, J=9.0, 12.0 Hz, C-3Hb), 4.88 (1H, dd,
J=6.0 and 9.0 Hz, C-2H), 5.06 (2H, s, OCH2C6H5),
6.44 (1H, dd, J=3.0 and 9.0 Hz, C-50H), 6.49 (1H, d,
J=3.0 Hz, C-30H), 7.34–7.37 (10H, m, C-200H, C-300H,
C-400H, C-500H, C-600H, OCH2C6H5), 7.66 (1H, d, J=9.0
Hz, C-60H), 12.70 (1H, s, chelated OH); dC (75.5 MHz,
CDCl3): 21.5 (OCOCH3), 52.5 (C-2), 66.0 (C-3), 71.0
(OCH2C6H5), 103.0 (C-30), 109.0 (C-50), 114.0 (C-100),
128.3 (C-300 and C-500), 128.8 (C-400) 129.0 (C-200 and C-
600), 129.2 (C-1000), 129.5 (C-3000 and C-5000), 130.1 (C-2000
and C-6000), 132.8 (C-4000), 136.4 (C-60), 136.6 (C-10),
166.0 (C-20), 167.0 (C-40), 172.0 (OCO), 201.0 (C¼O).
00
7.32 (5H, m, C-200H, C-300H, C-400H, C-500H and C -6 H),
7.71 (1H, d, J=9.0 Hz, C-60H), 12.60 (1H, s, chelated
OH); dC (75.5 MHz, CD3OD): 21.0 (OCOCH3), 52.5 (C-
3), 66.0 (C-2), 104.0 (C-30),00109.5 (C-50), 113.5 (C-60),
00
00
129.0-134.0 (C-200, C -3, C -4, C -5 and C-600),134.0 (C-
100),137.5 (C-10), 166.5 (C-40), 167.0 (C-20), 172.5 (OCO)
and 201.0 (C¼O).
General procedure for the enzymatic deacetylation of the
acetates 3a–3g
To a solution of the acetylated ketones 3a–3g (100 mg)
in diisopropyl ether (10–15 mL) containing n-butanol (5
mmol), C. rugosa lipase (100 mg) was added and the
reaction mixture was stirred at 40–42 ꢂC. On completion
of deacetylation (checked upto 100% in all cases by
TLC/HPLC), the reaction mixture was filtered and the
filterate concentrated in vacuo to get the deacetylated
hydroxymethylated ketones 2a–2g.
(+)-3-Acetoxy-1-(4-benzyloxy-2-hydroxyphenyl)-2-(4-
methoxyphenyl)- propanone (3j). Thick brown oil; nmax
(CHCl3): 2956, 1739 (OCOCH3), 1628 (C¼O), 1511,
1459, 1368, 1249, 1180, 1151 cmꢀ1; dH (300 MHz,
CDCl3): 2.00 (3H, s, OCOCH3), 3.75 (3H, s, OCH3),
4.34 (1H, dd, J=6.0 and 12.0, C-3Ha), 4.72 (1H, dd,
J=9.0, 12.0 Hz, C-3Hb), 4.82 (1H, dd, J=6.0 and 9.0
Hz, C-2H), 5.06 (2H, s, OCH2C6H5), 6.34 (1H, dd,
J=3.0 and 9.0 Hz, C-50H), 6.47 (1H, d, J=3.0 Hz, C-
30H), 6.85 (2H, d, J=9.0 Hz, C-300H and C-500H), 7.23
(2H, d, J=9.0 Hz, C-200H and C-600H), 7.36–7.38 (5H,
m, OCH2C6H5), 7.65 (1H, d, J=9.0 Hz, C-60H), 12.70
(1H, s, chelated OH); dC (75.5 MHz, CDCl3): 21.5
(OCOCH3), 51.5 (C-2), 56.0 (OCH3), 66.0 (C-3), 71.0
(OCH2Ph), 102.5 (C-50), 108.5 (C-30), 113.0 (C-100 and
C-1000), 115.0 (C-300 and C-500), 127.5 (C-2000 and C-6000),
General procedure for the chemical hydrolysis of
acetates 3h–3l
To a solution of the acetylated ketones 3h–3l (50 mg) in
analytical grade MeOH (3.0 mL), 2–3 drops of analy-
tical grade HCl were added and the mixture was stirred
till deacetylation was complete (4–5 h) at 28–30 ꢂC. The
reaction was quenched with water, and extracted with
dichloromethane (4Â10 mL). The organic phases were

2652
R. Kumar et al. / Bioorg. Med. Chem. 9 (2001) 2643–2652
combined and washed with brine and dried. Evapora-
tion of the solvent afforded the crude product, which
was purified by column chromatography over silica gel
using petroleum ether/ethyl acetate mixture as eluent to
give the desired alcohols 2h–2l.
7. Barlocco, D.; Cignarella, G.; Curzu, M. M. Synthesis 1985,
876.
8. Pinkey Jain, P. K.; Grover, S. K. Indian J. Chem. 1986,
25B, 365.
9. Pinkey Jain, P. K.; Makrandi, J. K.; Grover, S. K. Indian J.
Chem. 1985, 24B, 51.
10. Jain, A. C.; Sharma, A. Indian J. Chem. 1984, 23B, 45.
11. Waldmann, H.; Sebastian, D. Chem. Rev. 1994, 94, 911.
12. Roberts, S. M. Perkin Trans 1 1999, 1.
13. Parmar, V. S.; Kumar, A.; Bisht, K. S.; Mukherjee, S.;
Prasad, A. K.; Sharma, S. K.; Wengel, J.; Olsen, C. E. Tetra-
hedron 1997, 53, 2163.
14. Parmar, V. S.; Kumar, A.; Poonam; Pati, H. N.; Saxena,
R. K.; Davidson, W. S.; Gupta, R. Biochim. Biophys. Acta
1998, 1387, 325.
Acknowledgements
Financial assistance from Danish International Devel-
opment Agency (DANIDA, Denmark) and Council for
Scientific and Industrial Research (CSIR, India) is
highly acknowledged.
15. Parmar, V. S.; Prasad, A. K.; Pati, H. N.; Kumar, R.;
Azim, A.; Roy, S.; Errington, W. Bioorg. Chem. 1999, 27, 119.
16. Prasad, A. K.; Sorensen, M. D.; Parmar, V. S.; Wengel, J.
Tetrahedron Lett. 1995, 36, 6163. Sharma, S. K.; Roy, S.;
Kumar, R.; Parmar, V. S. Tetrahedron Lett. 1999, 40, 9145.
17. Parmar, V. S.; Sinha, R.; Bisht, K. S.; Gupta, S.; Prasad,
A. K.; Taneja, P. Tetrahedron 1993, 49, 4107.
18. Bisht, K. S.; Parmar, V. S.; Crout, D. H. G. Tetrahedron:
Asymmetry 1993, 4, 957.
19. Jain, A. C.; Tyagi, O. D.; Saksena, R. Indian J. Chem.
1989, 28B, 15.
20. Curzu, M. M.; Pinna, G. A.; Barlocco, D.; Bugatti, C.;
Cignarella, G. Synthesis 1984, 339.
21. Ahluwalia, V. K.; Prakash, C.; Jolly, R. S. Gazz. Chim.
Italiana 1979, 109, 641.
22. Berger, J.; Binte, H. J.; Brunne, L.; Neuman, R. J. Prakt.
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130886.
23. Jain, A. C.; Mehta, A. Perkin Trans. 1 1986, 215.
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References and Notes
1. Parmar, V. S.; Jain, S. C.; Bisht, K. S.; Sharma, N. K.;
Himanshu; Gupta, S.; Prasad, A. K.; Jha, A.; Poonam;
Malhotra, S.; Sharma, S. K.; Bracke, M. E.; Errington, W.;
Olsen, C. E.; Wengel, J. Indian J. Chem. 1998, 37B, 628.
2. Parmar, V. S.; Bracke, M. E.; Philippe, J.; Wengel, J.; Jain,
S. C.; Vennekens, K.; Marck, V. V.; Singh, S. K.; Kumar, N.;
Kumar, A.; Malhotra, S.; Kumar, R.; Rajwanshi, V. K.; Jain,
R.; Mareel, M. M. Bioorg. Med. Chem. 1997, 5, 1609.
3. Parmar, V. S.; Bisht, K. S.; Jain, R.; Singh, S.; Sharma,
S. K.; Gupta, S.; Malhotra, S.; Tyagi, O. D.; Vardhan, A.;
Pati, H. N.; Vanden Berghe, D.; Vlietinck, A. J. Indian J.
Chem. 1996, 35B, 220.
4. Parmar, V. S.; Jain, R.; Sharma, S. K.; Vardhan, A.;
Jha, A.; Taneja, P.; Singh, S.; Vyncke, B. M.; Bracke, M. E.;
Mareel, M. M. J. Pharm. Sci. 1994, 83, 1217.
5. Harborne, J. B. The Flavonoids; Chapman and Hall:
London, 1988.
26. Dhawan, D.; Grover, S. K. Synth. Commun. 1992, 16,
2405.
6. Dean, F. M. Naturally Occurring Oxygen Ring Compounds;
Butterworths: London, 1963.
27. Azim, A.; Errington, W.; Parmar, V. S. Acta Cryst. 2001,
E57, o266.