Synthesis and lipase-mediated stereoselective deacetylation of (±)-3-acetoxymethyl-3-alkyl-7-methoxychroman-4-ones

Article abstract of DOI:10.1016/S0040-4020(01)00698-6

Six (±)-3-acetoxymethyl-3-alkyl-7-methoxychroman-4-ones have been synthesized in four steps starting with the coupling of resorcinol with corresponding aliphatic acid leading to the formation of 2,4-dihydroxyphenyl alkyl ketones, which upon monomethylation and hydroxymethylation, followed by acetylation afforded the racemic acetoxymethylated compounds in 17-30% overall yields. Candida rugosa lipase-catalyzed deacetylation of (±)-3-acetoxymethylchromanones in diisopropyl ether exhibited fairly moderate enantioselectivity.

Full text of DOI:10.1016/S0040-4020(01)00698-6

TETRAHEDRON
Pergamon
Tetrahedron 57 +2001) 7395±7402
Synthesis and lipase-mediated stereoselective deacetylation of
ꢀ^)-3-acetoxymethyl-3-alkyl-7-methoxychroman-4-ones
Poonam,a Ashok K. Prasad,a Abul Azim,a Rajesh Kumar,a Subhash C. Jain,a Virinder S. Parmar,a,p
Carl E. Olsenb and William Erringtonc
aDepartment of Chemistry, University of Delhi, Delhi 110 007, India
bDepartment of Chemistry, Royal Veterinary and Agricultural University, DK-1871 Frederiksberg C, Copenhagen, Denmark
cDepartment of Chemistry, University of Warwick, Coventry CV4 7AL, UK
Received 2 October 2000; revised 4 June 2001; accepted 28 June 2001
AbstractÐSix +^)-3-acetoxymethyl-3-alkyl-7-methoxychroman-4-ones have been synthesized in four steps starting with the coupling of
resorcinol with corresponding aliphatic acid leading to the formation of 2,4-dihydroxyphenyl alkyl ketones, which upon monomethylation
and hydroxymethylation, followed by acetylation afforded the racemic acetoxymethylated compounds in 17±30% overall yields. Candida
rugosa lipase-catalyzed deacetylation of +^)-3-acetoxymethylchromanones in diisopropyl ether exhibited fairly moderate enantioselectivity.
q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
quite a few of them are therapeutically useful.11±13,18
However, no ef®cient synthetic methodologies are available
either for the preparation of such chromanones in enantio-
merically pure form or for resolution of their racemic
mixtures.
In the recent past, interest in the preparation of enantio-
merically pure compounds has greatly increased. The
arsenal available to syntheticorganicchemists at present
is rich in chiral building blocks and methods for their
preparation and elaboration. The preparation of necessary
chiral intermediates can usually be achieved either by
asymmetric induction on an achiral compound or by kinetic
resolution of a racemic mixture. Recently, enzymatic
processes have extensively been used for the preparation
of chiral intermediates and target molecules.1 Among the
different enzymatic processes, lipase-catalyzed acylations
and deacylations represent an important class of enzymatic
transformations in organicsynthesis; this is attributed
mainly to the low cost of lipases and their wide tolerance
towards a variety of organicmolecules.
we have successfully used lipases from porcine pancreas;
Candida, Aspergillus and Pseudomonas species for carrying
out regio- and stereo-selective acylations/deacylations on
polyphenolics,4±6 carbohydrates7,8 and polyols.9
We wish to report herein the synthesis of racemic
3-acetoxymethyl-3-alkylchromanones and their resolution
by a lipase-catalyzed deacetylation reaction.
2. Results and discussion
Six racemic hydroxymethylchromanones 6a±6f have been
synthesized in three steps starting from the coupling of
resorcinol +1) with the corresponding aliphatic acids
2a±2f to afford 2,4-dihydroxyphenyl alkyl ketones 3a±3f
in 70±80% yields +Scheme 1).19±22 The partial methylation
of aryl alkyl ketones 3a±3f leads to the formation of
corresponding 2-hydroxy-4-methoxyphenyl alkyl ketones
4a±4f23±26 which on reaction with alkaline formaldehyde
afforded +^)-hydroxymethylchromanones 6a±6f. The
alkaline hydroxymethylation of ketones 4a±4f initially
leads to the formation of geminal dihydroxymethylketones
5a±5f which instantaneously cyclize to +^)-hydroxy-
methylchromanones 6a±6f. The formation of intermediate
geminal dihydroxymethylketones 5a±5f has been
con®rmed by the isolation of 1,1-bis-hydroxymethylethyl
2-hydroxy-4-methoxyphenyl ketone +5a) formed during
the hydroxymethylation of 2-hydroxy-4-methoxyphenyl
ethyl ketone +4a). Acetylation of +^)-3-hydroxymethyl-
chromanones 6a±6f with acetic anhydride and pyridine in
the presence of a catalytic amount of DMAP afforded the
2,3
In recent years,
Chroman-4-ones belong to the class of polyphenolics, and
are widely distributed in the plant kingdom10±13 and possess
a variety of biological activities, viz anticonvulsant,14 anti-
microbial,15 antiin¯ammatory,16 antifungal,17 etc. Several
chiral chromanones, substituted at C-2 and/or C-3
position+s) have been isolated from natural sources and
Keywords: Candida rugosa lipase; 3-hydroxymethylchromanones; stereo-
selective; deacetylation; +S)-+1)-O-acetylmandelic acid.
Corresponding author. Tel.: 191-11-766-6555/7206; fax: 191-11-766-
p
6555; e-mail: minuashok@now-india.net.in
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020+01)00698-6

7396
Poonam et al. / Tetrahedron 57 02001) 7395±7402
Scheme 1. Reagents and conditions: +i) Fused ZnCl2, 140±508C; +ii) +CH3)2SO4, dry acetone, anhyd. K2CO3, re¯uxing; +iii) 37%; HCHO, 0.5M NaOH,
stirring at 25±288C; +iv) Acetic anhydride, pyridine, dimethylaminopyridine, stirring at 25±288C; +v) Candida rugosa lipase, diisopropyl ether, n-butanol,
stirring at 35±388C; +vi) MeOH-HCl, stirring at 25±288C.
corresponding 3-acetoxymethylchromanones 7a±7f in
quantitative yields +Scheme 1). The molecular structure of
+^)-3-ethyl-3-hydroxymethyl-7-methoxychromanone +6b)
deduced on the basis of spectral analysis was further
con®rmed by single crystal X-ray diffraction studies.
Schematic representation of the molecular structure of
compound 6b is shown in Fig. 1 and some of the crystal-
lographicdata are summarized in the Section 4. The X-ray
crystallographic studies on hydroxymethylchromanone 6b
indicate that the compound exists in a conformation in
which carbonyl group at C-4 position and hydroxymethyl
group at C-3 position are trans +Fig. 1).
pancreas +PPL), Candida rugosa +CRL) and Candida
antarctica +CAL) as the biocatalysts and vinyl acetate as
the acetylating agent were unsuccessful except in the case
of reaction catalyzed by CRL. However, the rate of acetyl-
ation reaction catalyzed by CRL was too slow to be used for
practical purposes. Thus, we undertook the screening of the
enzymes PPL, CRL and CAL in tetrahydrofuran +THF),
diisopropyl ether +DIPE) and dioxane in the presence of
n-butanol +acetyl trap) for the enantioselective deacetylation
of +^)-3-acetoxymethyl-3-alkyl-7-methoxychroman-4-ones
7a±7f. The selection of solvents for the deacetylation reac-
tions catalyzed by PPL, CRL and CAL was based on our
earlier experiences.4,6 While there was no reaction with PPL
in THF and CAL in dioxane, the deacetylation reaction in
the presence of CRL in DIPE proceeded satisfactorily
+Table 1).
Our initial attempts of carrying out enantioselective
acetylation of +^)-3-alkyl-3-hydroxymethyl-7-methoxy-
chroman-4-ones 6a±6f using different lipases from porcine

Poonam et al. / Tetrahedron 57 02001) 7395±7402
7397
Figure 1. X-Ray crystal structure of +^)-6b.
In a typical reaction, the racemic 3-acetoxymethylchroma-
nones 7a±7f were incubated with CRL in DIPE in the
presence of 3±4 equiv. of n-butanol and the reaction was
monitored by HPLC and/or TLC. The reaction was stopped
by ®ltering off the enzyme after about 45±50% conversion
of the starting acetate to the deacetylated hydroxymethyl-
chromanone. The deacetylated 3-hydroxymethylchroma-
nones and the unreacted 3-acetoxymethylchromanones
were separated by column chromatography on silica gel
with a gradient solvent system of petroleum ether±ethyl
acetate and their optical rotations were measured. Both,
deacetylated +1)-3-hydroxymethylchromanones 6a±6f
and unreacted +1)-3-acetoxymethylchromanones 7a±7f
were found to be optically active. Further, the unreacted
+1)-acetoxymethylchromanones 7a±7f recovered from the
deacetylation reaction mediated by CRL were hydrolyzed
chemically by stirring in methanolic-HCl. The chemical
hydrolysis of +1)-7a±7f led to the formation of +2)-3-
hydroxymethylchromanones 6a±6f. The comparison of
optical rotation values of the +1)-hydroxymethylchroma-
nones 6a±6f obtained by enzymaticdeacetylation of + ^)-
3-acetoxymethylchromanones 7a±7f with those of +2)-
hydroxymethylchromanones 6a±6f obtained by chemical
deacetylation of +1)-7a±7f revealed that they are quite
comparable and had opposite signs of rotation +cf. Section
4). All these reactions, when performed under identical
conditions but without addition of the enzyme did not
yield any product.
+chiracel OJ and chiracel OD). However, separation of
enantiomers was not observed. The enantiomericexecss
determination attempted by chiral shift 1H NMR
spectroscopy using +S)-+1)-2,2,2-tri¯uoro-1-+9-anthryl)-
ethanol [+1)-TFAE] shift reagent also failed as the
1
separation of the signals in the H NMR spectra of the
racemic 3-hydroxymethylchromanones 6a±6f was not
observed. Finally, the enantiomericexecss of + 1)-3-
hydroxymethylchromanones 6a±6f were determined by H
1
NMR spectral analysis of their O-acetylmandelic acid esters
+Table 1). The synthesis of O-acetylmandelates was
achieved by the reaction of +1)/+^) alcohols 6a±6f with
d-+2)-O-acetylmandelic acid in dichloromethane according
to the procedure of Whitesell and Reynolds.27
It is noteworthy to mention that the rate of enzymatic
deacetylation of acetoxymethylchromanones depends on
the chain-length of the C-3 alkyl substituent +Table 1).
The rate of the deacetylation reaction increases as the
chain length of the C-3 alkyl group increases from C1±C5,
except in the case of 3-isopropylchromanone 7d. This
may be because of the fact that the alkyl chain is
branched in 7d, which may increase the effective volume
and thus slow its accommodation in the active site of the
enzyme.
3. Conclusion
In order to determine the enantiomericexcess +ee) of + 1)-3-
hydroxymethylchromanones 6a±6f, the separation of two
enantiomers of all the 12 compounds, i.e. +1)-6a±6f and
+1)-7a±7f was attempted using chiral HPLC columns
The present study has revealed fairly moderate enantio-
selective capabilities of CRL for the deacetylation of +^)-
3-acetoxymethylchromanones 7a±7f in diisopropyl ether.
This investigation has also revealed that the rate of
Table 1. Enantioselective deacetylation of +^)-7a±7f catalyzed by Candida rugosa lipase in diisopropyl ether containing n-BuOH as the acyl trap at 35±388C
Entry
Substrate
Reaction time +days)
Products +%yield)a
% ee
1
2
3
4
5
6
+^)-7a
+^)-7b
+^)-7c
+^)-7d
+^)-7e
+^)-7f
8
8
6
10
5
5
+1)-6a +71) and +1)-7a +84)
+1)-6b +78) and +1)-7b +60)
+1)-6c +60) and +1)-7c +70)
+1)-6d +77) and +1)-7d +85)
+1)-6e +65) and +1)-7e +86)
+1)-6f +82) and +1)-7f +87)
+1)-6a:38
+1)-6b:14
+1)-6c:56
+1)-6d:18
+1)-6e:29
+1)-6f:20
All these reactions, when performed under identical conditions, but without adding Candida rugosa lipase, did not yield any product.
Yields are calculated by assuming corresponding single enantiomer as 100% in the starting +^)-3-acetoxymethylchromanones 7a±7f.
a

7398
Poonam et al. / Tetrahedron 57 02001) 7395±7402
deacetylation reaction catalyzed by CRL increases with the
increase in lipophilicity of the substrate, i.e. the chain length
of the C-3 alkyl group in +^)-7a±7f. As it is dif®cult to
synthesize such compounds in enantiomerically enriched
forms by purely chemical methods, the biocatalytic
approach reported herein may ®nd utility in the synthesis
of optically enriched compounds of this class.
4.2. General procedure for the preparation of
2-hydroxy-4-methoxyphenyl alkyl ketones 4a±4f
To a stirred solution of 2,4-dihydroxyphenyl alkyl ketone
3a±3f +0.05 mol) in dry acetone +100 ml) was added freshly
ignited potassium carbonate +3 g), followed by the addition
of dimethyl sulphate +0.055 mol). The reaction mixture was
re¯uxed for 4±6 h and the progress of reaction was moni-
tored by TLC. On completion, the reaction mixture was
cooled, ®ltered and solvent removed under vacuum. Ice
was added to the gummy residue and the resulting solid
®ltered, washed thoroughly with water, dried and puri®ed
by column chromatography on silica gel using a gradient
solvent system of petroleum ether±ethyl acetate to obtain
the pure ketones 4a±4f in 85±90% yields, these were
characterized on the basis of their physical and spectral
data and by comparing them with the data reported in the
literature.20,23±26
4. Experimental
Melting points were determined on a Mettler FP62 instru-
ment and are uncorrected. The IR spectra were recorded
either on a Perkin±Elmer model 2000 FT-IR or RXI
FT-IR spectrophotometer. The UV spectra were recorded
either on a Cary 100 Bio- or on Beckmann DU-64 spectro-
photometer. The optical rotations were measured with
1
Bellingham Stanley AD 220 polarimeter. The H- and 13C
NMR spectra were recorded on Bruker Advance-300
spectrometer at 300 and at 75 MHz, respectively using
TMS as internal standard. The chemical shift values are
on d scale and the coupling constants +J) are in Hz. The
EIMS and HRMS were recorded on a Jeol AX 505 W instru-
ment at 70 eV in FAB +positive or negative ion mode) using
NBA +3-nitrobenzyl alcohol) as matrix. The enzymes,
porcine pancreatic lipase +PPL, Type II) and Candida
rugosa lipase +CRL, Type VII) were purchased from
Sigma Chemical Co. +USA) and used after storing in
vacuo over P2O5 for 24 h. The Candida antarctica lipase
immobilized on accurel was gifted by Novo Nordisk Co.
and used as such. The organic solvents +THF and DIPE)
4.3. General procedure for the preparation of 3-alkyl-3-
hydroxymethyl-7-methoxychroman-4-ones 6a±6f
A solution of 2-hydroxy-4-methoxyphenyl alkyl ketone
4a±4f +0.016 mol) in sodium hydroxide +0.5 M,
4.0 equiv.) and formaldehyde +37%, 4.5 equiv.) was stirred
at 25±288C. The progress of the reaction was followed by
TLC and on completion, was stopped by acidi®cation with
dilute hydrochloric acid. The product was extracted with
ether +3£50 ml), the ethereal layers combined, washed
with brine +3£25 ml), dried over sodium sulfate and the
solvent removed under vacuum to afford a gummy residue,
which was puri®ed by column chromatography on silica gel
using a gradient solvent system of petroleum ether±ethyl
acetate +4:1) to afford pure hydroxymethylated chroma-
nones 6a±6f in 59±69% yields.
Ê
used were distilled over activated molecular sieves +4 A),
while n-butanol was dried and distilled over ignited potas-
sium carbonate. Analytical TLCs were performed on
precoated Merck silica gel 60F254 plates; the spots were
detected either by UV light, charring with 4% alcoholic
H2SO4 or by spraying with 3% alcoholic FeCl3 solution.
Reactions were monitored at l254 nm on a Shimadzu LC-
10AS HPLC instrument with SPD-10A UV±Vis detector
and Shimpack CLC-ODS +4.6£150 mm) reverse phase
column; solvent system used was methanol±water +3:2) at
a ¯ow rate of 0.50 ml min21. +S)-+1)-O-Acetylmandelic
acid +ee 99%) was purchased from Aldrich Chemical Co.
+USA).
In a separate reaction of 2-hydroxy-4-methoxyphenyl ethyl
ketone +4a) with alkaline formaldehyde, the reaction was
stopped when about half of the starting ketone was
consumed. The residue obtained after work-up of the reac-
tion was puri®ed by column chromatography on silica gel
using a gradient solvent system of petroleum ether±ethyl
acetate to afford three products, i.e. the starting ketone 4a,
hydroxymethylchromanone 6a and bis-hydroxymethyl
ketone 5a in 40, 25 and 10% yields, respectively.
4.1. General procedure for the preparation of 2,4-
dihydroxyphenyl alkyl ketones 3a±3f
4.3.1. 1,1-Bis-hydroxymethylethyl 2-hydroxy-4-methoxy-
phenyl ketone ꢀ5a). It was obtained as a white crystalline
solid +0.4 g) in 10% yield. Mp 84±868C; Rf: 0.30 +petroleum
ether±ethyl acetate, 5:3); C12H15O5 +[M2H]1 239.0943,
Calcd 239.0920); IR +Nujol): 3233+OH), 1620+CvO),
Fused ZnCl2 +0.15 mol, 20 g) and fatty acid 2a±2f
+0.15 mol) was heated slowly with stirring until the solution
became homogeneous. Resorcinol 1 +0.1 mol, 11 g) was
added and the reaction mixture stirred for 2 h at 140±
1508C, cooled and poured over crushed ice containing
hydrochloric acid +1:1). The solid that separated was ®ltered
and washed repeatedly with water and sodium bicarbonate
to afford the crude product, which was puri®ed by column
chromatography on silica gel using a gradient solvent
system of petroleum ether±ethyl acetate to obtain the pure
aryl alkyl ketones 3a±3f in 70±80% yield, these were
characterized on the basis of their physical and spectral
data and by comparing them with the data reported in the
literature.19±22
1463, 1274, 1227, 1119, 1033, 935, 809 and 612 cm21
;
1
UV +MeOH): 216, 279 and 316 nm; H NMR +CD3OD) d:
1.42 +3H, s, CH3), 3.85 +3H, s, OCH3), 3.95 +4H, s,
2£OCH2), 6.45 +1H, d, Jˆ2.5 Hz, C-30H), 6.50 +1H, dd,
Jˆ2.5 and 9.0 Hz, C-50H) and 8.04 +1H, d, Jˆ9.0 Hz,
C-60H); 13C NMR +CD3OD) d: 19.08+CH3), 56.00 and
56.30 +2£OCH2 and C-1), 66.93 +OCH3), 102.44 +C-30),
107.39 +C-50), 114.53 +C-10), 133.17 +C-60), 166.53 and
166.84 +C-20 and C-40) and 209.88 +CvO); EIMS, m/z +%
rel. int.): 240 +[M]1, 20), 151 +100), 125 +40), 85 +15) and 73
+14).

Poonam et al. / Tetrahedron 57 02001) 7395±7402
7399
4.3.2. ꢀ^)-3-Hydroxymethyl-7-methoxy-3-methylchro-
man-4-one ꢀ6a). It was obtained as a white amorphous
solid +2.3 g) in 65% yield. Mp 76±778C; Rf: 0.42 +petroleum
ether±ethyl acetate, 7:3); C12H15O4 +[M1H]1 223.0996,
Calcd 223.0970); IR +KBr): 3442 +OH), 2966, 1657
+CvO), 1616, 1441, 1264, 1237, 1106, 1030, 951, 827
and 754 cm21; UV +MeOH): 212, 232, 272 and 311 nm;
1H NMR +CDCl3) d: 1.22 +3H, s, CH3), 2.36 +1H, br t,
Jˆ5.2 Hz, CH2OH), 3.57 +1H, dd, Jˆ5.2 and 11.3 Hz,
C-10Ha), 3.84 +3H, s, OCH3), 3.91 +1H, dd, Jˆ5.2 and
11.3 Hz, C-10Hb), 4.15 +1H, d, Jˆ11.3 Hz, C-2Ha), 4.49
+1H, d, Jˆ11.3 Hz, C-2Hb), 6.40 +1H, d, Jˆ2.0 Hz,
C-8H), 6.59 +1H, dd, Jˆ2.0 and 8.8 Hz, C-6H) and 7.82
+1H, d, Jˆ8.8 Hz, C-5H); 13C NMR +CDCl3) d: 16.55
+CH3), 46.51 +C-3), 55.57 +OCH3), 64.80 +C-10), 73.68
+C-2), 100.50 +C-8), 110.21 +C-6), 113.71 +C-10), 129.18
+C-5), 163.29 +C-9), 166.13 +C-7) and 195.84 +CvO);
EIMS, m/z +% rel. int.): 222 +[M]1,40), 207 +4), 192 +16),
150 +100), 122 +37), 107 +15) and 79 +8).
+2.4 g) in 59% yield. Mp 74±768C; Rf: 0.40 +petroleum
ether±ethyl acetate, 7:3); C14H19O4 +[M1H]1 251.1268,
Calcd 251.1283); IR +KBr): 3458 +OH), 2970, 1661
+CvO), 1610, 1575, 1437, 1264, 1164, 1026, 921, 823
and 771 cm21; UV +MeOH): 212, 232, 272 and 311 nm;
1H NMR +CDCl3) d: 0.91 and 1.00 +6H, 2d, 3H each,
Jˆ7.0 Hz each, CH +CH3)2), 2.23±2.30 +2H, m, CH+CH3)2
and OH), 3.48 +1H, d, Jˆ11.7 Hz, C-10Ha), 3.83 +3H, s,
OCH3), 4.07 +1H, d, Jˆ11.7 Hz, C-10Hb), 4.48 +2H, br s,
C-2Ha and C-2Hb), 6.37 +1H, d, Jˆ2.3 Hz, C-8H), 6.58 +1H,
dd, Jˆ2.3 and 8.8 Hz, C-6H) and 7.82 +1H, d, Jˆ8.8 Hz,
C-5H); 13C NMR +CDCl3) d: 17.22 and 17.49 +2£CH3),
28.09 +CH+CH3)2), 51.94 +C-3), 55.57 +OCH3), 61.27
+C-10), 70.51 +C-2), 100.37 +C-8), 110.06 +C-6), 114.65
+C-10), 129.06 +C-5), 163.26 +C-9), 166.07 +C-7) and
196.46 +CvO); EIMS m/z +% rel. int.): 250 +[M]1,17),
219 +19), 208 +78), 190 +16), 177 +27), 150 +100), 122
+34), 107 +15) and 79 +9).
4.3.6. ꢀ^)-3-Butyl-3-hydroxymethyl-7-methoxychroman-
4-one ꢀ6e). It was obtained as a colourless viscous oil
+2.9 g) in 68% yield. Rf: 0.52 +petroleum ether±ethyl
acetate, 7:3); C15H21O4 +[M1H]1 265.1419, Calcd
265.1440); IR +thin ®lm): 3456 +OH), 2935, 1670 +CvO),
1608, 1440, 1387, 1257, 1163, 1107, 1030, 940, 837 and
4.3.3. ꢀ^)-3-Ethyl-3-hydroxymethyl-7-methoxychroman-
4-one ꢀ6b). It was obtained as white needles +2.4 g) in
64% yield. Mp 85±888C; Rf: 0.45 +petroleum ether±ethyl
acetate, 7:3); C13H17O4 +[M1H]1 237.1152, Calcd
237.1127); IR +Nujol): 3492 +OH), 2941, 1653 +CvO),
1612, 1437, 1386, 1262, 1199, 1045, 1020, 931, 828 and
758 cm21; UV +MeOH): 286 and 311 nm; 1H NMR +CDCl3)
d: 0.90 +3H, t,Jˆ7.6 Hz, CH3), 1.70 +2H, m, CH2CH3), 2.55
+1H, br s, OH), 3.54 +1H, d, Jˆ13.9 Hz, C-10Ha), 3.81 +3H,
s, OCH3), 3.93 +1H, d, Jˆ13.9 Hz, C-10Hb), 4.29 +1H, d,
Jˆ13.9 Hz, C-2Ha), 4.42 +1H, d, Jˆ13.9 Hz, C-2Hb), 6.36
+1H, d, Jˆ2.4 Hz, C-8H), 6.56 +1H, dd, Jˆ2.4 and 8.8 Hz,
C-6H) and 7.79 +1H, d, Jˆ8.8 Hz, C-5H); 13C NMR
+CDCl3) d: 7.95 +CH3), 22.96 +CH2CH3), 49.32 +C-3),
55.49 +OCH3), 62.61 +C-10), 71.47 +C-2), 100.33 +C-8),
110.07 +C-6), 113.88 +C-10), 129.01 +C-5), 163.17 +C-9),
166.03 +C-7) and 196.12 +CvO); EIMS, m/z +% rel. int.):
236 +[M]1,25), 208 +43), 177 +14), 150 +100), 122 +32), 107
+12) and 79+6).
1
694 cm21; UV +MeOH): 212, 232, 273 and 311 nm; H
NMR +CDCl3) d: 0.87 +3H, t, Jˆ6.7 Hz, CH3), 1.29
+4H, m, C-200H and C-300H), 1.66 +2H, m, C-100H),
2.48 +1H, br s, OH), 3.57 +1H, dd, Jˆ3.6 and
11.5 Hz, C-10Ha), 3.84 +3H, s, OCH3), 3.96 +1H, dd,
Jˆ3.6 and 11.5 Hz, C-10Hb), 4.32 +1H, d, Jˆ11.5 Hz,
C-2Ha), 4.38 +1H, d, Jˆ11.5 Hz, C-2Hb), 6.40 +1H, d,
Jˆ2.3 Hz, C-8H), 6.59 +1H, dd, Jˆ2.3 and 8.8 Hz, C-6H)
and 7.83 +1H, d, Jˆ8.8 Hz, C-5H); 13C NMR +CDCl3)
d: 13.60 +CH3), 23.06, 25.53 and 30.02 +C-100, C-200 and
C-300), 49.36 +C-3), 55.31 +OCH3), 62.75 +C-10), 71.93
+C-2), 100.27 +C-8), 109.86 +C-6), 113.95 +C-10),
128.91 +C-5), 163.11 +C-9), 165.82 +C-7) and 195.50
+CvO); EIMS, m/z +% rel. int.): 264 +[M]1,6), 233
+9), 208 +100), 190 +30), 177 +25), 150 +75), 122 +25),
107 +12) and 79 +6).
4.3.4. ꢀ^)-3-Hydroxymethyl-7-methoxy-3-propylchro-
man-4-one ꢀ6c). It was obtained as a colourless viscous
oil +2.7 g) in 69% yield. Rf: 0.45 +petroleum ether±ethyl
acetate, 7:3); C14H19O4 +[M1H]1 251.1263, Calcd
251.1283); IR +thin ®lm): 3455+OH), 2960, 1669+CvO),
1608, 1440, 1387, 1245, 1162, 1105, 1029, 947, 837 and
4.3.7. ꢀ^)-3-Hydroxymethyl-7-methoxy-3-pentylchroman-
4-one ꢀ6f). It was obtained as a colourless viscous oil +2.7 g)
in 60% yield. Rf: 0.56 +petroleum ether±ethyl acetate, 7:3);
C16H23O4 +[M1H]1 279.1625, Calcd 279.1596); IR +thin
®lm): 3459 +OH), 2933, 1673 +CvO), 1607, 1441, 1387,
1257, 1163, 1030, 945, 837 and 694 cm21; UV +MeOH):
213, 232, 273 and 311 nm; 1H NMR +CDCl3) d: 0.85 +3H, t,
Jˆ6.7 Hz, CH3), 1.27 +6H, m, C-200H, C-300H and C-400H),
1.64 +2H, m, C-100H), 2.52 +1H, br s, OH), 3.56 +1H, dd,
Jˆ4.3 and 11.5 Hz, C-10Ha), 3.84+3H, s, OCH3), 3.95 +1H,
dd, Jˆ4.3 and 11.5 Hz, C-10Hb), 4.31 +1H, d, Jˆ11.6 Hz,
C-2Ha), 4.44 +1H, d, Jˆ11.6 Hz, C-2Hb), 6.39 +1H, d,
Jˆ2.3 Hz, C-8H), 6.58 +1H, dd, Jˆ2.3 and 8.8 Hz, C-6H)
and 7.81 +1H, d, Jˆ8.8 Hz, C-5H); 13C NMR +CDCl3) d:
14.31 +CH3), 22.78, 23.61, 30.72 and 32.69 +C-100, C-200,
C-300 and C-400), 49.85 +C-3), 55.99 +OCH3), 63.61 +C-10),
72.35 +C-2), 100.91 +C-8), 110.57 +C-6), 114.47 +C-10),
129.56 +C-5), 163.70 +C-9), 166.54 +C-7) and 196.57
+CvO); EIMS, m/z +% rel. int.): 278 +[M]1,4), 247 +6),
208 +100), 190 +32), 177 +24), 150 +65), 122 +25), 107
+10) and 79 +6).
1
772 cm21; UV +MeOH): 212, 232, 272 and 311 nm; H
NMR +CDCl3) d: 0.88 +3H, t, Jˆ6.7 Hz, CH3), 1.32 +2H,
m, C-200H), 1.62 +2H, m, C-100H), 2.51 +1H, br s, OH), 3.56
+1H, d, Jˆ11.5 Hz, C-10Ha), 3.83 +3H, s, OCH3), 3.96 +1H,
d, Jˆ11.5 Hz, C-10Hb), 4.31 +1H, d, Jˆ11.5 Hz, C-2Ha),
4.46 +1H, d, Jˆ11.5 Hz, C-2Hb), 6.39 +1H, d, Jˆ2.0 Hz,
C-8H), 6.57 +1H, dd, Jˆ2.0 and 8.7 Hz, C-6H) and 7.80
+1H, d, Jˆ8.7 Hz, C-5H); 13C NMR +CDCl3) d: 14.97
+CH3), 17.38 +C-200), 33.07 +C-100), 49.94 +C-3), 56.00
+OCH3), 63.57 +C-10), 72.40 +C-2), 100.86 +C-8), 110.58
+C-6), 114.45 +C-10), 129.54 +C-5), 163.70 +C-9), 166.52
+C-7) and 196.50 +CvO); EIMS, m/z +% rel. int.): 250
+[M]1,10), 220 +12), 208 +100), 190 +28), 177 +24), 150
+98), 122 +36), 107 +15) and 79 +8).
4.3.5. ꢀ^)-3-Hydroxymethyl-3-isopropyl-7-methoxy-
chroman-4-one ꢀ6d). It was obtained as white plates

7400
Poonam et al. / Tetrahedron 57 02001) 7395±7402
4.4. General procedure of acetylation of ꢀ^)-hydroxy-
methylchromanones 6a±6f: preparation of ꢀ^)-acetoxy-
methylchromanones 7a±7f
m, C-200H), 1.67 +2H, m, C-100H), 2.03 +3H, s, OCOCH3),
3.83 +3H, s, OCH3), 4.21, 4.33, 4.40 and 4.44 +4H, 4d, 1H
each, Jˆ11.4 Hz each, C-10Ha, C-10Hb, C-2Ha and C-2Hb),
6.40 +1H, d, Jˆ2.3 Hz, C-8H), 6.60 +1H, dd, Jˆ2.3 and
8.8 Hz, C-6H), 7.84 +1H, d, Jˆ8.8 Hz, C-5H); 13C NMR
+CDCl3) d: 14.92 +CH3), 17.36 +C-200), 21.08 +OCOCH3),
33.45 +C-100), 48.31 +C-3), 55.97 +OCH3), 64.45 +C-10),
72.80 +C-2), 100.94 +C-8), 110.60 +C-6), 114.43 +C-10),
129.78 +C-5), 163.42 +C-9), 166.37 +C-7), 171.06
+OCOCH3) and 192.73 +CvO); EIMS, m/z +% rel. int.):
292 +[M]1,5), 250 +44), 190 +100), 150 +96), 122+26), 107
+8) and 43 +9).
To
a solution of hydroxymethylchromanone 6a±6f
+0.01 mol) in acetic anhydride +1.1 equiv.) and pyridine
+2 equiv.), was added a catalytic amount of 4-N,N-dimethyl-
aminopyridine and the reaction mixture stirred at 25±288C
for 18 h. The reaction was worked-up by addition of ice-
cold water and aqueous reaction mixture extracted with
ethyl acetate +3£15 ml). The combined ethyl acetate layers
were washed with sodium bicarbonate and concentrated to
afford the corresponding acetoxymethylchromanones 7a±7f
in 75±99% yields.
4.4.4. ꢀ^)-3-Acetoxymethyl-3-isopropyl-7-methoxychro-
man-4-one ꢀ7d). It was obtained as a white solid +1.1 g) in
96% yield. Mp 65±668C; Rf: 0.65 +petroleum ether±ethyl
acetate, 4:1); C16H21O5 +[M1H]1 293.1365, Calcd
293.1389); IR +KBr): 2970, 1735 +OCOCH3), 1676
+CvO), 1611, 1435, 1386, 1235, 1162, 1019, 927, 834
and 685 cm21; UV +MeOH): 210, 235, 272 and 312 nm;
1H NMR +300 MHz, CDCl3) d: 0.92 and 1.06 +6H, 2d, 3H
each, Jˆ7.0 Hz each, CH+CH3)2), 2.01 +3H, s, OCOCH3),
2.21 +1H, m, CH+CH3)2), 3.82 +3H, s, OCH3), 4.18, 4.42 and
4.52 +4H, 3d of 1H, 1H and 2H, respectively, Jˆ11.3, 11.3
and 11.8 Hz, C-10Ha, C-10Hb, C-2Ha and C-2Hb), 6.39 +1H,
d, Jˆ2.3 Hz, C-8H), 6.59 +1H, dd, Jˆ2.3 and 8.8 Hz, C-6H)
and 7.85 +1H, d, Jˆ8.8 Hz, C-5H); 13C NMR +CDCl3) d:
17.44 and 18.37 +2£CH3), 21.14 +OCOCH3), 28.94
+CH+CH3)2), 50.52 +C-3), 55.98 +OCH3), 62.81 +C-10),
70.97 +C-2), 100.86 +C-8), 110.48 +C-6), 114.83 +C-10),
129.86 +C-5), 163.46 +C-9), 166.26 +C-7), 171.14
+OCOCH3) and 192.85 +CvO); EIMS, m/z +% rel. int.):
292 +[M]1,10), 250 +29), 190 +62), 150 +100), 122 +21),
107 +10) and 43 +12).
4.4.1. ꢀ^)-3-Acetoxymethyl-7-methoxy-3-methylchroman-
4-one ꢀ7a). It was obtained as a colourless viscous oil +2.4 g)
in 92% yield. Rf: 0.70 +petroleum ether±ethyl acetate, 4:1);
C14H17O5 +[M1H]1 265.1062, Calcd 265.1076); IR +Nujol):
2940, 1744 +OCOCH3), 1681 +CvO), 1611, 1577, 1440,
1394, 1237, 1161, 1040, 952 and 838 cm21; UV +MeOH):
212, 234, 273 and 311 nm; 1H NMR +CDCl3) d: 1.22 +3H, s,
CH3), 2.04 +3H, s, OCOCH3), 3.83 +3H, s, OCH3), 4.15 and
4.19 +2H, 2d, 1H each, Jˆ11.0 and 11.3 Hz, C-10Ha and
C-2Ha), 4.36 and 4.45 +2H, 2d, 1H each, Jˆ11.0 and
11.3 Hz, C-10Hb and C-2Hb), 6.41 +1H, d, Jˆ2.2 Hz,
C-8H), 6.60 +1H, dd, Jˆ2.2 and 8.8 Hz, C-6H) and 7.83
+1H, d, Jˆ8.8 Hz, C-5H); 13C NMR +CDCl3) d: 16.81
+CH3), 21.04 +OCOCH3), 45.29 +C-3), 56.00 +OCH3),
65.56 +C-10), 73.84 +C-2), 100.98 +C-8), 110.73 +C-6),
114.06 +C-10), 129.83 +C-5), 163.54 +C-9), 166.45 +C-7),
171.00 +OCOCH3) and 193.01 +CvO); EIMS, m/z +% rel.
int.): 264 +[M]1, 35), 191 +7), 150 +100), 122 +23), 107 +6)
and 43 +6).
4.4.5. ꢀ^)-3-Acetoxymethyl-3-butyl-7-methoxychroman-
4-one ꢀ7e). It was obtained as a white solid +1.0 g) in 96%
yield. Mp 81±838C; Rf: 0.75 +petroleum ether±ethyl acetate,
4:1); C17H23O5 +[M1H]1 307.1537, Calcd 307.1545); IR
+Nujol): 2937, 1731 +OCOCH3), 1673 +CvO), 1611,
4.4.2. ꢀ^)-3-Acetoxymethyl-3-ethyl-7-methoxychroman-
4-one ꢀ7b). It was obtained as a colourless viscous oil
+2.1 g) in 76% yield. Rf: 0.70 +petroleum ether±ethyl
acetate, 4:1); C15H19O5 +[M1H]1 279.1226, Calcd
279.1232); IR +Nujol): 2923, 1733 +OCOCH3), 1675
+CvO), 1612, 1460, 1384, 1234, 1161, 1092, 1051 and
1442, 1396, 1240, 1107, 1035, 948, 851 and 748 cm21
;
UV +MeOH): 211, 234, 273 and 311 nm; 1H NMR
+CDCl3) d: 0.63 +3H, t, Jˆ6.8 Hz, CH3), 1.07 +4H, m,
C-200H and C-300H), 1.45 +2H, t, Jˆ8.0 Hz, C-100H), 1.80
+3H, s, OCOCH3), 3.60 +3H, s, OCH3), 3.98, 4.10 and
4.20 +4H, 3d of 1H, 1H and 2H, respectively, Jˆ11.4 Hz
each, C-10Ha, C-10Hb, C-2Ha and C-2Hb), 6.17 +1H, d,
Jˆ1.7 Hz, C-8H), 6.36 +1H, dd, Jˆ1.7 and 8.8 Hz, C-6H)
and 7.61 +1H, d, Jˆ8.8 Hz, C-5H); 13C NMR +CDCl3) d:
12.39 +CH3), 19.32 +OCOCH3), 21.82 +C-300), 24.32 and
29.16 +C-100 and C-200), 46.44 +C-3), 54.22 +OCH3), 62.65
+C-10), 71.02 +C-2), 99.19 +C-8), 108.84 +C-6), 112.65
+C-10), 128.01 +C-5), 161.65 +C-9), 164.60 +C-7), 169.26
+OCOCH3) and 190.98 +CvO); EIMS, m/z +% rel. int.): 306
+[M]1, 4), 250 +40), 190 +100), 150 +86), 122 +25), 107 +7)
and 43 +11).
1
926 cm21; UV +MeOH): 219, 231, 273 and 309 nm; H
NMR +CDCl3) d: 0.91 +3H, t, Jˆ7.6 Hz, CH3), 1.76 +2H,
q, Jˆ7.6 Hz, CH2CH3), 2.01 +3H, s, OCOCH3), 3.84 +3H, s,
OCH3), 4.22, 4.34, 4.41 and 4.43 +4H, 4d, 1H each, Jˆ11.4,
11.5, 11.5 and 11.4 Hz, C-10Ha, C-10Hb, C-2Ha and C-2Hb),
6.40 +1H, d, Jˆ2.3 Hz, C-8H), 6.60 +1H, dd, Jˆ2.3 and
8.8 Hz, C-6H) and 7.84 +1H, d, Jˆ8.8 Hz, C-5H); 13C
NMR +CDCl3) d: 6.80 +CH3), 19.42 +OCOCH3), 22.29
+CH2CH3), 46.59 +C-3), 54.30 +OCH3), 62.35 +C-10), 70.88
+C-2), 99.20 +C-8), 108.90 +C-6), 112.68 +C-10), 128.06
+C-5), 161.68 +C-9), 164.65 +C-7), 169.40 +OCOCH3) and
190.99 +CvO); EIMS, m/z +% rel. int.): 278 +[M]1,20), 250
+23), 190 +30), 150 +100), 122 +25), 107 +8) and 43 +10).
4.4.3. ꢀ^)-3-Acetoxymethyl-7-methoxy-3-propylchroman-
4-one ꢀ7c). It was obtained as an off-white viscous oil
+2.2 g) in 75% yield. Rf: 0.72 +petroleum ether±ethyl
acetate, 4:1); C16H21O5 +[M1H]1 293.1363, Calcd
4.4.6. ꢀ^)-3-Acetoxymethyl-7-methoxy-3-pentylchroman-
4-one ꢀ7f). It was obtained as a colourless viscous oil +3.2 g)
in 99% yield. Rf: 0.75 +petroleum ether±ethyl acetate, 4:1);
C18H25O5 +[M1H]1 321.1712, Calcd 321.1702); IR +KBr):
2932, 1744 +OCOCH3), 1678 +CvO), 1611, 1441, 1238,
1107, 1038, 948 and 837 cm21; UV +MeOH): 232 and
293.1389);
1681+CvO), 1610, 1464, 1236, 1161, 1039, 946 and
IR
+Nujol):
2959,
1745+OCOCH3),
1
736 cm21; UV +MeOH): 213, 230, 269 and 309 nm; H
NMR +CDCl3) d: 0.88 +3H, t, Jˆ7.2 Hz, CH3), 1.32 +2H,

Poonam et al. / Tetrahedron 57 02001) 7395±7402
7401
267 nm; 1H NMR +CDCl3) d: 0.84 +3H, t, Jˆ6.9 Hz, CH3),
1.25 +6H, m, C-200H, C-300H and C-400H), 1.67 +2H, m, C-
100H), 2.03 +3H, s, OCOCH3), 3.84 +3H, s, OCH3), 4.20, 4.33
and 4.43 +4H, 3d of 1H, 1H and 2H, respectively, Jˆ11.4 Hz
each, C-10Ha, C-10Hb, C-2Ha and C-2Hb), 6.40 +1H, d,
Jˆ2.3 Hz, C-8H), 6.60 +1H, dd, Jˆ2.3 and 8.8 Hz, C-6H)
and 7.84 +1H, d, Jˆ8.8 Hz, C-5H); 13C NMR +CDCl3) d:
14.29 +CH3), 21.11 +OCOCH3), 22.71, 23.59, 31.12 and
32.63 +C-100, C-200, C-300 and C-400), 48.21 +C-3), 55.99
+OCH3), 64.39 +C-10), 72.75 +C-2), 100.9 +C-8), 110.60
+C-6), 114.38 +C-10), 129.78 +C-5), 163.39 +C-9), 166.33
+C-7), 171.08 +OCOCH3) and 192.76 +CvO); EIMS, m/z +%
rel. int.): 320 +[M]1,4), 250 +35), 190 +100), 150 +67), 122
+20), 107 +11) and 43 +12).
4-ones 6a±6f in 86±95 yields. The +2)-hydroxymethyl-
chromanones 6a±6f were identi®ed on the basis of their
spectroscopic data, which were found identical with the
spectroscopic data of corresponding +1)- and +^)-hydroxy-
methylchromanones reported above. The optical rotation
values of +2)-3-hydroxymethylchromanones 6a±6f were
found to be: +2)-6a 210.68 +CHCl3), +2)-6b 225.38
+CHCl3), +2)-6c 212.98 +CHCl3), +2)-6d 29.58 +CHCl3),
+2)-6e 213.08 +CHCl3) and +2)-6f 216.48 +CHCl3).
4.7. General procedure for the preparation of O-acetyl-
mandelates of ꢀ1)/ꢀ^)-3-alkyl-3-hydroxymethyl-
chromanones 6a±6f
To a solution of +1)/+^)-3-hydroxymethylchromanone
6a±6f +0.25 mmol), catalytic amount of 4-+N,N-dimethyl-
4.5. General procedure of enzymatic deacetylation of
ꢀ^)-3-acetoxymethyl-3-alkyl-7-methoxychroman-4-ones
7a±7f
amino)pyridine
and
d-+2)-O-acetylmandelic
acid
+0.25 mmol) in CH2Cl2 +5 ml) at 08C, dicyclohexylcarbodi-
imide +0.25 mmol in 1 ml CH2Cl2) was added with the help
of a syringe in 35±40 min. The reaction was then allowed to
proceed at 258C for an additional 15±20 h. The N,N-
dicyclohexyl urea formed during the reaction was removed
by ®lteration and the resulting solution was washed succes-
sively with 0.5N HCl +5 ml), 2N Na2CO3 +5 ml) and brine
+10 ml). The organiclayer was dried over Na 2SO4, concen-
trated and the product isolated after puri®cation by column
To a solution of +^)-acetoxymethylchromanone +7a±7f,
1.0 mmol) in anhydrous diisopropyl ether +15 ml),
n-butanol +3±4 equiv.) was added, followed by the addition
of Candida rugosa lipase +200 mg). The suspension was
stirred at 35±388C in an incubator and progress of the reac-
tion was monitored periodically by HPLC and/or TLC.
After about 45±50% conversion of the starting material
into the product, the reaction was quenched by ®ltering
off the enzyme and the solvent evaporated to dryness in
vacuo to afford a gummy residue, which was puri®ed by
column chromatography on silica gel using a gradient
solvent system of petroleum ether±ethyl acetate to afford
optically enriched +1)-3-alkyl-3-hydroxymethyl-7-methoxy-
chroman-4-ones 6a±6f and +1)-3-acetoxymethyl-3-alkyl-7-
methoxychroman-4-ones 7a±7f in 60±82 and 60±87%
yields +yields were calculated by assuming single enantio-
mer as 100% in starting +^)-7a±7f), respectively. The +1)-
hydroxymethylchromanones 6a±6f and +1)-acetoxy-
methylchromanones 7a±7f were identi®ed on the basis of
their spectral data, which were found identical with the
spectral data of the corresponding racemic compounds,
i.e. +^)-6a±6f and +^)-7a±7f, respectively as reported
above. The optical rotation values of +1)-3-hydroxymethyl-
chromanones 6a±6f and +1)-3-acetoxymethylchromanones
7a±7f were found to be: +1)-6a 19.08 +c 0.66, CHCl3), +1)-
6b 123.48 +c 0.68, CHCl3), +1)-6c 112.08 +c 0.66, CHCl3),
+1)-6d 112.28 +c 0.81, CHCl3), +1)-6e 112.08 +c 0.66,
CHCl3), +1)-6f 113.08 +c 0.66, CHCl3), +1)-7a 118.08 +c
0.66, CHCl3), +1)-7b 122.88 +c 0.70, CHCl3), +1)-7c
127.08 +c 0.66, CHCl3), +1)-7d 118.08 +c 0.66, CHCl3),
+1)-7e112.08 +c 0.66, CHCl3) and +1)-7f 121.08 +c 0.66,
CHCl3).
1
chromatography or PTLC in quantitative yields. The H
NMR spectra of O-acetylmandelates of +^)-alcohols
6a±6f exhibited baseline resolution of the signals of
diastereomericprotons of the O-acetylmandelic acid
moiety, which resonated between d 5.80 and 5.90. The
1
integration of these signals in the H NMR spectra of the
O-acetylmandelates of +1)-6a±6f gives a measure of their
diastereomeric compositions, which are directly related to
the enantiomericocmpositions of the enzymataiclly
deacetylated +1)-3-hydroxymethylchromanones +Table 1).
The maximum ee of 56% was observed for +1)-3-hydroxy-
methyl-7-methoxy-3-propylchroman-4-one +6c).
4.8. X-Ray crystallography
The crystallographic measurements on +^)-3-ethyl-3-
hydroxymethyl-7-methoxychroman-4-one +6b) were made
using a Siemens SMART area-detector diffractometer.
Graphite monochromated MoKa radiation was used for
data collection. The structure was solved using
SHELXTL-PLUS28 and re®ned with SHELXL-96.29
Crystal data of compound 6b. C13H16O4, Mˆ236.26,
Ê
Tˆ180+2) K, lˆ0.71073 A, orthorhombic aˆ7.7656 +4),
Ê
Ê 3
bˆ7.0204+3), cˆ21.0668+11) A, bˆ908, Vˆ1148.51+10) A ,
space group pnma, Zˆ4, Dxˆ1.366 Mg m23, mˆ
0.101 mm21, F+000)ˆ504. Crystal size 0.48£0.44£
0.22 mm; u range for data collection 1.93±25.508; index
range 29 , h , 10; 26 , k , 9; 227 , l , 28; re¯ec-
tions collected 5899; independent re¯ections 1166
[R+int)ˆ0.0430]; re®nement method full-matrix least squares
on F2; data/restraints/parameters 1166:0:125; goodness-of-®t
on F2 1.045; R+F) ‰I . 2ꢀI†Š ˆ 0:0616; wR2ˆ0.1462 +for 846
re¯ections); largest diff. peak and hole 0.357 and
4.6. General procedure for chemical deacetylation of
unreacted, recovered acetates ꢀ1)-7a±7f
The +1)-acetoxymethylchroman-4-one 7a±7f +100 mg) was
dissolved in MeOH +5 ml) containing 2±3 drops of hydro-
chloric acid. The reaction mixture was stirred for 4 h at
25±288C and quenched by the addition of ice-cold water
+5 ml). The reaction mixture was extracted with ethyl
acetate +2£10 ml), combined ethyl acetate layer was washed
with brine, dried over anhydrous Na2SO4 and evaporated at
reduced pressure to afford the +2)-hydroxymethylchroman-
Ê 23
20.358 eA .

7402
Poonam et al. / Tetrahedron 57 02001) 7395±7402
12. Calmarini, O. L.; Stodola, F. H. J. Org. Chem. 1965, 30, 112.
Acknowledgements
13. Tamm, C.; Boehner, P.; Zuencher, W. Helv. Chim. Acta 1972,
55, 510.
We thank the Council of Scienti®c and Industrial Research
+CSIR, India) and Danish International Development
Agency +DANIDA, Denmark) for ®nancial assistance.
14. Mehta, A. C.; Razdan, R. Ger Offen 2,209,854, 1972; Chem.
Abstr., 1972, 77, 151933.
15. Schering, A. -G. Brit. Patent 1250, 340, 1971; Chem. Abstr.,
1972, 76, 3684.
References
16. Barlocco, D.; Cignarella, G.; Curzu, M. M. Synthesis 1980,
825.
1. Drauz, K., Waldmann, H., Eds.; Enzyme Catalysis in Organic
Synthesis; VCH: Weinheim, 1994; Vols. 1 and 2, p. 23.
2. Waldmann, H.; Sebastian, D. Chem. Rev. 1994, 94, 911.
3. Roberts, S. M. J. Chem. Soc., Perkin Trans 1 1999, 1.
4. Parmar, V. S.; Kumar, A.; Bisht, K. S.; Mukherjee, S.; Prasad,
A. K.; Sharma, S. K.; Wengel, J.; Olsen, C. E. Tetrahedron
1997, 53, 2163.
17. Alnakib, T.; Bezjak, V.; Meegan, M. J.; Chandy, R. Eur. J.
Med. Chem. 1990, 25, 455.
18. McGahren, W. J.; Ellestad, G. A.; Morton, G. O.; Kunstmann,
M. P. J. Org. Chem. 1972, 37, 1636.
19. Johnson, T. B.; Lahe, F. W. J. Am. Chem. Soc. 1921, 43, 348.
20. Sangwan, N. K.; Verma, B. S.; Malik, O. P.; Dhindsa, K. S.
Indian J. Chem. 1990, 29B, 294.
5. Parmar, V. S.; Kumar, A.; Poonam; Pati, H. N.; Saxena, R. K.;
Davidson, W. S.; Gupta, R. Biochim. Biophys. Acta 1998,
1387, 325.
21. Dohme, A. R. L.; Edward, H. C.; Miller, E. J. Am. Chem. Soc.
1926, 48, 1688.
22. Karrer, P.; Rosenfeld, S. Helv. Chim. Acta 1921, 4, 707.
23. Ahluwalia, V. K.; Prakash, C.; Jolly, R. S. Gazz. Chim. Ital.
1979, 109, 641.
6. Parmar, V. S.; Prasad, A. K.; Pati, H. N.; Kumar, R.; Azim, A.;
Roy, S.; Errington, W. Bioorg. Chem. 1999, 27, 119.
7. Prasad, A. K.; Sorensen, M. D.; Parmar, V. S.; Wengel, J.
Tetrahedron Lett. 1995, 36, 6163.
24. Wiley, P. F. US Patent 2,621, 189, 1952; Chem. Abstr., 1953,
47, 10011.
8. +a) Sharma, S. K.; Roy, S.; Kumar, R.; Parmar, V. S.
Tetrahedron Lett. 1999, 40, 9145. +b) Roy, S.; Kumar, R.;
Wengel, J.; Olsen, C. E.; Parmar, V. S.; Prasad, A. K. Bioorg.
Med. Chem. Lett. 2001 +in press).
25. Reichstein, T.; Oppenauer, R.; Grussner, A.; Hirt, R.; Rhyner,
L.; Glatthaar, C. Helv. Chim. Acta 1935, 18, 816.
26. Berger, J.; Binte, H. J.; Brunne, L.; Neuman, R. J. Prakt.
Chem./Chem.-Ztg. 1992, 334, 269; Chem. Abstr., 1992, 117,
130886.
9. +a) Bisht, K. S.; Parmar, V. S.; Crout, D. H. G. Tetrahedron:
Asymmetry 1993, 4, 957. +b) Parmar, V. S.; Sinha, R.; Bisht,
K. S.; Gupta, S.; Prasad, A. K.; Taneja, P. Tetrahedron 1993,
49, 4107.
27. Whitesell, J. K.; Reynolds, D. J. Org. Chem. 1983, 48, 3548.
28. Sheldrick, G. M. SHELXTL-PLUS; Siemens Analytical X-ray
Instrument Inc., Madison, Wisconsin, USA, 1990.
29. Sheldrick, G. M. SHELXL-96; Program for Crystal Structure
10. Chromenes, Chromanones and Chromones, Ellis, G. P., Ed.;
Wiley: New York, 1977.
11. Boehner, P.; Tamm, C. Tetrahedron Lett. 1967, 3479.
È
Re®nement, University of Gottingen, Germany, 1996.