Enantioselective acylation of 2-hydroxymethyl-2,3-dihydrobenzofurans catalysed by lipase from Pseudomonas cepacia (Amano PS) and total stereoselective synthesis of (-)-(R)-MEM-protected arthrographol

Article abstract of DOI:10.1016/S0957-4166(00)00302-5

Lipase Amano PS catalysed acylation of (±)-2-hydroxymethyl-2,3-dihydrobenzofurans using vinyl acetate as the acyl donor in n-hexane gave (-)-(R)-2-acetoxymethyl-2,3-dihydrobenzofurans and (+)-(S)-2-hydroxymethyl-2,3-dihydrobenzofurans in high enantiomeric excess. (-)-(R)-Acetate 18j is converted to (-)-(R)-MEM-protected arthrographol 22. Copyright (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(00)00302-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 11 (2000) 3375–3393
Enantioselective acylation of
2-hydroxymethyl-2,3-dihydrobenzofurans catalysed by lipase
from Pseudomonas cepacia (Amano PS) and total
stereoselective synthesis of (−)-(R)-MEM-protected
arthrographol
S. Ramadas and G. L. David Krupadanam*
Department of Chemistry, Osmania University, Hyderabad 500 007, India
Received 7 July 2000; accepted 7 August 2000
Abstract
Lipase Amano PS catalysed acylation of ( )-2-hydroxymethyl-2,3-dihydrobenzofurans using vinyl
acetate as the acyl donor in n-hexane gave (−)-(R)-2-acetoxymethyl-2,3-dihydrobenzofurans and (+)-(S)-
2-hydroxymethyl-2,3-dihydrobenzofurans in high enantiomeric excess. (−)-(R)-Acetate 18j is converted to
(−)-(R)-MEM-protected arthrographol 22. © 2000 Published by Elsevier Science Ltd.
1. Introduction
Substituted 2-hydroxymethyl-2,3-dihydrobenzofurans are an important class of naturally
occurring oxygen heterocycles.1–6 Natural dihydrobenzofurans are homochiral.7–10 Enzymes have
simplified the route to homochiral compounds which have value as drugs, synthetic intermedi-
ates and chiral auxiliaries.11 Among the enzymes, lipases have been more extensively investigated
as catalysts for either enantioselective acylation of racemic primary and secondary alcohols or
enantioselective hydrolysis of racemic primary or secondary esters.11
(−)-(R)-Arthrographol 1 was almost simultaneously reported by two research groups, Pfefferle
et al.12 and Ayer et al.,13 from Aspergillus oryzae and Arthographis pinicola, respectively. It was
designated as (−)-(R)-asperfuran by Pfefferle et al., and (−)-(R)-arthrographol by Ayer et al.
Compound 1 is reported to possess antifungal and chitin synthase inhibitor action.12 Its
1
structure was determined by H NMR, 13C NMR and MS spectral data and the absolute
configuration was determined as (R) by CD spectra by correlation with (−)-(R)-tremetone 2,
* Corresponding author. Tel: +91-40-7017336; fax: +91-40-3704926; e-mail: davidkrupa@hotmail.com
0957-4166/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0957-4166(00)00302-5

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S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
whose absolute configuration was determined by its degradation to (−)-(R)-malic acid.14 The
synthesis of ( )-arthrographol has been reported by Fujimoto et al.15 Stereoselective synthesis of
some chiral dihydrobenzofurans has been reported.16–19 There are no reports in the literature of
enzyme mediated resolution of 2-hydroxymethyl-2,3-dihydrobenzofurans.
This paper reports the facile kinetic resolution by enantioselective acylation of unsubstituted
and substituted ( )-2-hydroxymethyl-2,3-dihydrobenzofurans 6a–j with the lipase from Pseu-
domonas cepacia (Amano PS) to give (−)-(R)-2-acetoxymethyl-2,3-dihydrobenzofurans 18a–j and
(+)-(S)-2-hydroxymethyl-2,3-dihydrobenzofurans 19a–j. One of these compounds, (−)-(R)-5,7-
dimethoxyethoxymethyloxy-2-acetoxymethyl-2,3-dihydrobenzofuran 18j, which is obtained by
the resolution of ( )-6j, is converted to (−)-(R)-MEM-protected arthrographol using reactions
that do not affect the C-2 stereogenic centre.
2. Results and discussion
Phenols 3a–i gave the corresponding O-allylethers 4a–i20,21 on reaction with allyl bromide in
acetone–K2CO3. These gave the corresponding O-allylphenols 5a–i21,22 after a Claisen rearrange-
ment in N,N-diethylaniline. Epoxidation of 5a–i with m-CPBA followed by intramolecular
epoxide opening by the phenolic hydroxyl gave the 2-hydroxymethyl-2,3-dihydrobenzofurans
6a–i rather than the isomeric 3-hydroxychromans 7a–i. The structure of the reaction products
6a–i was proved by IBX/DMSO oxidation of 6a to 9 and Jones oxidation of 6a to 10 (Scheme
1).
In the 1H NMR spectrum of 6a the benzylic 3-CH2 protons which are diastereotopic in nature
appeared as an ABq×2. One of these methylene protons (HA) appeared as a double doublet at
l 2.87 (J=16.0, 8.0 Hz) and the other (HB) appeared as a double doublet at l 3.08 (J=16.0,
10.0 Hz). The methylene protons of the CH2OH group are also diastereotopic in nature and
appeared as an ABq×2. One of these methylene protons (HD) appeared as a double doublet at
l 3.60 (J=16.0, 6.0 Hz) and the other (HE) appeared at l 3.70 as a double doublet (J=16.0, 4.0
Hz). The methine proton (HC) at the 2-position appeared as a complex multiplet at l 4.75. The
aromatic protons H-7 appeared at l 6.52 as a doublet (J=10.0 Hz), H-6 at l 6.78 as a double
doublet (J=10.0, 2.0 Hz), and H-4 at l 6.85 as a broad singlet. The CH3 appeared at l 2.20.
The 13C NMR spectrum of 6a supported this structure. The CH2OH appeared at l 64.2, C-2 at
l 82.8 and the C-3 benzylic carbon appeared at l 31.0. The aromatic carbons appeared at l
129.3 (C-3a), 126.1 (C-5), 125.2 (C-4), 127.8 (C-6), 108.5 (C-7), 156.7 (C-7a) and 20.3 (CH3),
respectively. These values are in agreement with the values reported earlier for some natural
dihydrobenzofurans.3,12,23,24 Compound 6a showed M at m/z 164 (85) and a base peak at 133
(100) due to the loss of CH2OH from the molecular ion.

S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
3377
Scheme 1. (a) R1=R2=R4=H, R3=CH3; (b) R1=R2=R3=R4=H; (c) R1=R2=R4=H, R3=Cl; (d) R1=R2=R4=
H, R3=OCH3; (e) R1=R3=R4=H, R2=Cl; (f) R1=R2=R3=H, R4=Br; (g) R1=R2=R3=H, R4=CH3; (h)
R2=R3=R4=H, R1=Cl; (i) R2=R3=R4=H, R1=CH3
Alcohol ( )-6j was prepared from resorcinol 11 in six steps: (1) resorcinol in dry DMF/POCl3
i
in CH3CN gave 13,25 (2) treatment of 2,4-dihydroxybenzaldehyde 13 with MEM-Cl, Pr2NEt
gave 2,4-dimethoxyethoxymethyloxybenzaldehyde 14, (3) Baeyer–Villiger oxidation with m-
CPBA gave the MEM-protected phenol 15, (4) allylation of 15 with allyl bromide in acetone
K2CO3 gave the MEM-protected O-allylether 16, (5) Claisen rearrangement of 16 with DMF at
140°C gave the MEM-protected O-allylphenol 17, and (6) oxidative cyclisation of 17 with
m-CPBA gave ( )-5,7-dimethoxyethoxymethyloxy-2-hydroxymethyl-2,3-dihydrobenzofuran 6j
(Scheme 2).

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S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
Scheme 2.
To monitor the enzyme mediated acylation of ( )-6a–j these compounds were acetylated with
acetic anhydride and pyridine to give ( )-8a–j. Pseudomonas cepacia lipase (Amano PS)
catalysed acylation of racemic 2-hydroxymethyl-2,3-dihydrobenzofurans ( )-6a–j was carried
out with vinyl acetate as the acyl donor in n-hexane at rt and the progress of the reaction was
monitored by TLC (Scheme 3). The reaction was terminated at or close to 50% conversion, the
enzyme filtered off and the product containing 2-hydroxymethyl-2,3-dihydrobenzofuran and its
acetate was separated by column chromatography on silica gel. The ee values of the product
acetates 18a–j and alcohols 19a–j were determined by chiral HPLC (Table 1).
Scheme 3. (a) R1=R2=R4=H, R3=CH3; (b) R1=R2=R3=R4=H; (c) R1=R2=R4=H, R3=Cl; (d) R1=R2=R4=
H, R3=OCH3; (e) R1=R3=R4=H, R2=Cl; (f) R1=R2=R3=H, R4=Br; (g) R1=R2=R3=H, R4=CH3; (h)
R2=R3=R4=H, R1=Cl; (i) R2=R3=R4=H, R1=CH3; (j) R2=R4=H, R1=R3=OMEM
The resolved acetate 18a showed a specific rotation of [h]D=−19.21 (c 1.0, CHCl3). The CD
spectrum of 18a showed a negative Cotton effect with maxima at 237 nm (q=−12.42×10−3 deg
cm2 dmol−1) and 287 nm (q=−5.93×10−3 deg cm2 dmol−1). The resolved alcohol 19a showed a
specific rotation [h]D=+21.00 (c 1.0, CHCl3). The CD spectrum of 19a showed a positive Cotton
effect with maxima at 238 nm (q=+18.52×10−3 deg cm2 dmol−1) and 292 nm (q=+6.74×10−3 deg

S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
3379
Table 1
Entry Substrate Reaction (−)-(R)-Acetates 18a–j
(+)-(S)-Alcohols 19a–j
Yield (%) [h]D
time (h)
Yield (%) [h]D
% ee
94.5
59.5
69.1
95.5
% ee
1
2
(9)-6a
(9)-6b
(9)-6c
(9)-6d
(9)-6e
(9)-6f
(9)-6g
(9)-6h
(9)-6i
(9)-6j
4
3
50
50
50
50
50
50
50
50
50
50
−19.2 (c 1.0,
CHCl3)
−15.4 (c 0.5,
CHCl3)
−21.1 (c 1.0,
CHCl3)
−14.6 (c 0.5,
CHCl3)
−20.15 (c 1.0, \99
CHCl3)
−12.45 (c 0.5, \99
CHCl3)
−14.6 (c 0.5,
CHCl3)
−21.2 (c 0.5,
CHCl3)
−22.1 (c 0.5,
CHCl3)
−22.7 (c 1.05,
CHCl3)
50
50
50
50
50
50
50
50
50
50
+21.0 (c 1.0,
CHCl3)
+17.2 (c 0.5,
CHCl3)
+18.45 (c 1.0,
CHCl3)
+16.2 (c 1.0,
CHCl3)
+18.2 (c 1.0,
CHCl3)
+21.3 (c 1.0,
CHCl3)
+16.2 (c 1.0,
CHCl3)
+17.3 (c 0.5,
CHCl3)
93.9
81.8
97.9
67.6
3
4
4
3
5
4
\99
6
3
89.3
25.2
93.8
87.8
81.1
7
5
51.5
\99
59.5
93.4
8
4
9
4
+15.5 (c 0.5,
CHCl3)
+18.0 (c 1.0,
CHCl3)
10
12
cm2 dmol−1). The CD spectra of 18a and 19a are shown in Fig. 1. The acetates 18b–j showed
negative Cotton effect bands similar to those of 18a while the alcohols 19b–j displayed positive
Cotton effects similar to those of 19a (Table 2). The resolved acetates 18a–j are considered to
be (R) while the 2-hydroxymethyl-2,3-dihydrobenzofurans 19a–j are of (S) configuration. In this
reaction the (R)-enantiomer was considered to be reactive and therefore underwent acetylation
while the (S)-enantiomer was less reactive or unreactive.
3. Absolute configuration of the resolved acetates 18a–j and alcohols 19a–j
The active site model for the enantioselective acetylation of chiral primary alcohols without an
oxygen atom attached directly to the asymmetric centre has been proposed by Alexandra et al.26
According to this model the (S)-enantiomer is acylated selectively while the (R)-enantiomer is
unreactive. However there is opposite stereoselectivity in the case of chiral primary alcohols with
an oxygen atom attached directly to the stereogenic centre.27–31 Alexandra et al.,26 Carrea et
al.,27 Xie et al.,28 Schieweek et al.,29 and Kazlauskas30,31 studied the kinetic resolution of chiral
primary alcohols with an oxygen atom attached to the stereogenic centre using Pseudomonas
cepacia lipase and observed that the (R)-enantiomer is selectively acetylated. This reversal was
attributed to the hydrogen bonding between Tyr-29 and the substrate bearing oxygen at the
stereocentre.30,31

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S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
Figure 1. CD spectra of (−)-(R)-18a and (+)-(S)-19a in MeCN
In the case of enantioselective acetylation of chiral 2-hydroxymethyl-2,3-dihydrobenzofurans
6a–j, which have an oxygen atom attached to the stereogenic centre, the (R)-enantiomer is
reactive and the (S)-enantiomer is unreactive or less reactive, the products of the reaction are
(−)-(R)-acetates 18a–j and (+)-(S)-alcohols 19a–j, which is in agreement with literature data.27–31
Further proof that (R) is the reactive enantiomer is also provided by evidence in the following
three sections, i.e. Section 3.1—molecular modelling studies, Section 3.2—comparison of the
specific rotation of 18a–j and 19a–j with structurally similar compounds of known absolute
configuration and a comparison of the CD data and CD curves of 18a–j and 19a–j with
structurally similar compounds of known absolute configuration, and Section 3.3—transforma-
tion of (−)-(R)-5,7-dimethoxyethoxymethyloxy-2-acetoxymethyl-2,3-dihydrobenzofuran 18j to
(−)-(R)-MEM-protected arthrographol using reactions that do not change the configuration at
C-2.
3.1. Molecular modelling studies
Docking studies were carried out on the lipase enzyme (pdb code: 3lip.pdb) with both
enantiomers of 2-hydroxymethyl-2,3-dihydrobenzofuran using the ligand fit module of the
CERIUS2 program suite. Initially, the ligand protein surface was searched for a possible active
,
site with the default values of probe group radius of 1.3 A that generated the grid. This
generated the active site near to the Ser-87 as observed experimentally. This is followed by a
Monto Carlo simulation of the ligand in the most possible active site near the Ser-87. This
simulation generated a number of conformations of the ligand at the active site and this exercise
was necessary because the bioactive conformation differed from the most stable conformation
and there was a need to generate the bioactive conformation. Usually the best of the
conformations generated was regarded as the bioactive conformation as a number of amino acid
residues of the protein interact well with the ligand at the active site. This revealed that the
orientation of the two enantiomers was different at the active site. In the (R)-isomer, the Ser-87
,
hydroxyl group was a distance of 2.64 A from the hydroxyl of the ligand and this distance

S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
3381
Table 2
CD spectral data of 18a–j and 19a–j
Entry Comp. no.
Acetates
q (deg cm2 dmol−1
)
Comp. no.
Alcohols q (deg cm2 dmol−1
)
1
18a
18b
18c
18d
18e
18f
18g
18h
18i
(R)
(−) 237 nm,
19a
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(S)
(+) 238 nm,
(−) 12.42×10−3
(−) 287 nm,
(+) 18.52×10−3
(+) 292 nm,
(−) 5.93×10−3
(−) 227 nm,
(+) 6.74×10−3
(+) 230 nm,
2
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
(R)
19b
19c
19d
19e
19f
19g
19h
19i
(−) 1.53×10−3
(−) 291 nm,
(+) 1.81×10−3
(+) 290 nm,
(−) 0.57×10−3
(−) 230 nm,
(+) 0.35×10−3
(+) 231 nm,
3
(−) 0.39×10−3
(−) 294 nm,
(+) 0.65×10−3
(+) 294 nm,
(−) 0.50×10−3
(−) 230 nm,
(+) 0.31×10−3
(+) 231 nm,
4
(−) 1.95×10−3
(−) 299 nm,
(+) 0.29×10−3
(+) 293 nm,
(−) 0.95×10−3
(−) 233 nm,
(+) 0.20×10−3
(+) 230 nm,
5
(−) 2.53×10−3
(−) 299 nm,
(+) 1.95×10−3
(+) 300 nm,
(−) 2.00×10−3
(−) 235 nm,
(+) 2.14×10−3
(+) 225 nm,
6
(−) 3.21×10−3
(−) 301 nm,
(+) 2.57×10−3
(+) 305 nm,
(−) 1.75×10−3
(−) 235 nm,
(+) 2.32×10−3
(+) 238 nm,
7
(−) 0.25×10−3
(−) 299 nm,
(+) 0.74×10−3
(+) 290 nm,
(−) 0.18×10−3
(−) 235 nm,
(+) 0.25×10−3
(+) 220 nm,
8
(−) 2.35×10−3
(−) 299 nm,
(+) 4.43×10−3
(+) 285 nm,
(−) 1.52×10−3
(−) 231 nm,
(+) 3.26×10−3
(+) 239 nm,
9
(−) 3.25×10−3
(−) 289 nm,
(+) 2.50×10−3
(+) 287 nm,
(−) 2.17×10−3
(−) 229 nm,
(+) 2.20×10−3
(+) 221 nm,
10
18j
19j
(+) 0.29×10−3
(−) 238 nm,
(−) 0.95×10−3
(+) 230 nm,
(−) 0.28×10−3
(+) 280 nm,
(+) 0.97×10−3
(−) 281 nm,
(+) 0.21×10−3
(+) 0.35×10−3
,
increased to 3.15 A in the case of (S)-isomer. As the enzymatic action involved the interaction
of serine at the active site, it was assumed that it played a significant role in the differentiation
of the acylation reactivity between the two isomers and the more readily acylated (R)-isomer
compared with the (S)-isomer. This observation was also in tune with the experimental observation.

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S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
3.2. Comparison of the sign and magnitude of the specific rotations and CD spectra of resolved
acetates and alcohols with compounds of known absolute configuration
It is well known that for compounds which are structurally similar, similarity in sign and
magnitude of the specific rotation and CD curves indicate a similarity in configuration at the
stereogenic centre. (−)-(R)-Arthrographol 112 and (−)-(R)-tremetone 214 are structurally similar
to the 2-hydroxymethyl-2,3-dihydrobenzofurans 6a–j. The resolved acetates 18a–j showed
similar sign and magnitude of specific rotation as well as similar CD curves to those of
(−)-(R)-arthrographol. Therefore the resolved acetates 18a–j are of (R) absolute configuration
by a comparison of their CD spectra and specific rotation with those of (−)-(R)-arthrographol
and (−)-(R)-tremetone. The resolved alcohols 19a–j which showed a (+) sign of specific rotation
and the mirror image CD curve with respect to the resolved acetates 18a–j are therefore of (S)
absolute configuration (Table 3). The CD spectra of 18j and 19j are shown in Fig. 2.
Table 3
Specific rotation values and CD spectral data of resolved (−)-(R)-18a and (+)-(S)-19a compared with (−)-(R)-
arthrographol 1, (−)-(R)-tremetone 2, 18j and 19j (see also Tables 1 and 2 for [h]D and CD data)
Compound
[h]D
CD spectral data (nm)
(−)-(R)-Arthrographol 112
−20.1 (c 0.21, acetone)
(−) 232 nm (q=−18.43×10−3 deg cm2 dmol−1
)
(+) 260 nm (q=+3.02×10−3 deg cm2 dmol−1
(−) 305 nm (q=−0.86×10−3 deg cm2 dmol−1
)
)
(−)-(R)-Tremetone 214
Resolved acetate 18a
−41.0 (c 1.0, CHCl3)
−19.2 (c 1.0, CHCl3)
(−) 237 nm (q=−12.42×10−3 deg cm2 dmol−1
(−) 287 nm (q=−5.93×10−3 deg cm2 dmol−1
(+) 238 nm (q=+18.52×10−3 deg cm2 dmol−1
)
)
Resolved alcohol 19a
Resolved acetate 18j
+21.0 (c 1.0, CHCl3)
−22.7 (c 0.5, CHCl3)
)
(+) 292 nm (q=+ 6.74×10−3 deg cm2 dmol−1
)
(−) 229 nm (q=+0.29×10−3 deg cm2 dmol−1
(−) 238 nm (q=−0.28×10−3 deg cm2 dmol−1
(+) 280 nm (q=+0.21×10−3 deg cm2 dmol−1
(+) 221 nm (q=−0.95×10−3 deg cm2 dmol−1
)
)
)
)
Resolved alcohol 19j
+18.0 (c 1.0, CHCl3)
(+) 230 nm (q=+ 0.97×10−3 deg cm2 dmol−1
(−) 281 nm (q=+ 0.35×10−3 deg cm2 dmol−1
)
)
Figure 2. CD spectra of (−)-(R)-18j and (+)-(S)-19j in CH3CN and the literature CD data of (−)-(R)-arthrographol
1

S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
3383
3.3. Additional proof that the absolute configuration of the resolved acetates is (R) is given by
the conversion of one such resolved acetate, 18j, to (−)-(R)-MEM-protected arthrographol 22
Since the target molecule arthrographol 1 is of (R) configuration and is levorotatory with
[h]D=−20.9 (c 0.21, acetone), acetate 18j which had a specific rotation [h]D=−22.66 (c 0.5,
CHCl3) was used for this synthesis. The (−)-(R)-acetate 18j was hydrolysed with MeOH–K2CO3
and H2O to give (−)-(R)-alcohol 20. Under these alkaline conditions the MEM ethers were not
cleaved. (−)-(R)-Alcohol 20 was oxidised using Swern oxidation to the corresponding aldehyde
21. The aldehyde 21 was used without isolation in the next step, i.e. a Wittig reaction. Crotyl
triphenylphosphonium bromide was prepared by the reaction of crotyl bromide with
triphenylphosphine and was added immediately to the aldehyde 21 in THF to give 22 (Scheme
4).
Scheme 4.
1
In the H NMR spectrum of 22 the olefinic protons H-1%, H-2%, H-3%, H-4% and the H-2
appeared as multiplets in the region l 5.40–6.40. 5%-CH3 appeared as a double doublet (J=6.0,
1.0 Hz) at l 1.80. The benzylic CH2 protons appeared as an ABq×2. One of these methylene
protons (HA) appeared as a double doublet (J=16.0, 8.0 Hz) at l 2.92 and the other (HB)
appeared as a double doublet (J=16.0, 6.0 Hz) at l 3.32. The two OCH2O protons appeared as
singlets at l 5.22 and 5.12 and the two OCH2 protons appeared as multiplets at l 3.52 and 3.80.
The two OCH3 protons appeared as a singlet at l 3.32. The aromatic H-4 appeared at l 6.55
as a doublet (J=2.0 Hz) and H-6 appeared at l 6.65 as a doublet (J=2.0 Hz). In the 13C NMR
spectrum of 22 the olefinic carbons appeared at l 127.5 (C-1%), 105.3 (C-2%), 126.9 (C-3%), 132.9
(C-4%) and the 5%-methyl group appeared at l 18.2. The C-2 appeared at l 79.3 and the C-3
benzylic carbon appeared at l 38.9. The MEM group carbons appeared at l 94.3 (C-5,
OCH2O), 94.9 (C-7, OCH2O), 67.3 (C-5, OCH2), 67.4 (C-7, OCH2), 71.0 (C-5, CH2O), 71.1 (C-7,
CH2O), and 59.2 (C-5, 7, OCH3). The aromatic carbons appeared at l 126.1 (C-3a), 108.1 (C-4),
151.9 (C-5), 132.0 (C-6), 141.2 (C-7) and 133.8 (C-7a). In the MS the molecular ion peak
+
’
appeared at m/z 394 (M ) (30) and the other fragment ions appeared at 89 (100) and 59 (98).
Compound 22 showed a specific rotation [h]D=−14.0 (c 0.5, CHCl3).

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S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
These studies show that in the kinetic resolution of ( )-2-hydroxymethyl-2,3-dihydrobenzo-
furans 6a–j the (R)-enantiomer was acetylated selectively while the (S)-enantiomer was less
reactive or unreactive and the resolved compounds were useful as homochiral synthetic
intermediates.
4. Experimental
1H NMR (200 MHz) and 13C NMR (50.3 MHz, CDCl3) spectra were recorded on a Varian
Gemini 200 spectrometer and the chemical shifts are expressed in l ppm. Optical rotations were
measured on a JASCO J-20 polarimeter (cell size 50 mm) in CHCl3. Mass spectra were recorded
on VG micromass 7070-H and VG AUTOSPEC mass spectrometers. CD spectra were recorded
on a JASCO J-715 spectropolarimeter. Progress of the acylation was monitored by TLC on
silica gel ACME and column chromatography was carried out on finer than 200 mesh silica gel
ACME.
The chiral HPLC of racemic ( )-6a–j was carried out on a Chiracel OD column (25×0.46 cm,
Daicel, Japan) under the following conditions: flow rate 0.5 ml min−1, 10% isopropanol in
n-hexane as the eluent. The retention times (min) are ( )-6a 29.7 and 31.3, ( )-6b 11.8 and 13.1,
( )-6c 14.7 and 16.3, ( )-6d 19.1 and 20.3, ( )-6e 14.4 and 15.2, ( )-6f 24.3 and 26.0, ( )-6g 31.4
and 32.4, ( )-6h 24.6 and 26.1, ( )-6i 18.1 and 18.8, ( )-6j 26.5 and 27.8. The chiral HPLC of
resolved alcohols 19a–j was carried out on a Chiracel OD column (25×0.46 cm, Daicel, Japan)
under the following conditions: flow rate 0.5 ml min−1, 10% isopropanol in n-hexane as the
eluent. The retention times (min) are (+)-19a 29.9 and 31.4, (+)-19b 11.9 and 13.4, (+)-19c 15.0
and 16.4, (+)-19d 19.5 and 20.6, (+)-19e 14.8, (+)-19f 25.0 and 26.1, (+)-19g 31.5 and 32.6,
(+)-19h 24.7 and 26.9, (+)-19i 18.3 and 19.1, (+)-19j 27.2 and 28.5.
The chiral HPLC of racemic ( )-8a–j was carried out on a Chiracel OJ column (25×0.46 cm,
Daicel, Japan) under the following conditions: flow rate 0.8 ml min−1, 5% isopropanol in
n-hexane as the eluent. The retention times (min) are ( )-8a 26 and 27.4, ( )-8b 13.0 and 15.1,
( )-8c 24.5 and 26.2, ( )-8d 21.5 and 22.8, ( )-8e 23.1 and 24.8, ( )-8f 15.2 and 16.4, ( )-8g 25.3
and 26.4, ( )-8h 18.0 and 19.5, ( )-8i 28.1 and 28.8, ( )-8j 18.6 and 19.8. The Chiral HPLC of
resolved acetates 18a–j was carried out on a Chiracel OJ column (25×0.46 cm, Daicel, Japan)
under the following conditions: flow rate 0.8 ml min−1, 5% isopropanol in n-hexane as the
eluent. The retention times (min) are (−)-18a 26.5 and 27.8, (−)-18b 13.2 and 15.3, (−)-18c 25.1
and 26.5, (−)-18d 22.2 and 23.5, (−)-18e 23.4, (−)-18f 15.8, (−)-18g 25.8 and 26.7, (−)-18h 19.2,
(−)-18i 28.5 and 29.2, ( )-18j 19.1 and 20.6.
4.1. General procedure for the synthesis of ( )-2-hydroxymethyl-2,3-dihydrobenzofurans 6a–j
4-Methyl-2-allylphenol 5a (2.0 g, 13 mmol) and m-CPBA (2.2 g, 13 mmol) were dissolved in
CHCl3 (250 ml) and refluxed for 6 h on a water bath. After cooling to room temperature the
separated m-chlorobenzoic acid (mp 157°C) was filtered. The filtrate was washed with aq.
NaHCO3 (2%) to remove traces of m-chlorobenzoic acid and then with water, dried and
concentrated. The residue was chromatographed over silica gel by eluting with petroleum
ether:ethyl acetate (9:1) and gave ( )-5-methyl-2-hydroxymethyl-2,3-dihydrobenzofuran 6a as a
1
colourless oil (1.5 g, 75% yield). UV (MeOH): 231 nm (log m 3.8) and 287 nm (log m 3.6). H
NMR: l 2.20 (s, CH3), 2.87 (dd, J=16.0, 8.0 Hz, CH2-3, HA), 3.08 (dd, J=16.0, 10.0 Hz,

S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
3385
CH2-3, HB), 3.60 (dd, J=16.0, 6.0 Hz, 2-CH2ꢀOH, HD), 3.70 (dd, J=16.0, 4.0 Hz, 2-CH2ꢀOH,
HE), 4.75 (m, H-2, HC), 6.52 (d, J=10.0 Hz, H-7), 6.78 (dd, J=10.0, 2.0 Hz, H-6), and 6.85 (bs,
H-4). 13C NMR: l 20.3 (CH3), 31.0 (C-3), 64.2 (CH2OH), 82.8 (C-2), 108.5 (C-7), 125.2 (C-4),
126.1 (C-5), 127.8 (C-6), 129.3 (C-3a) and 156.7 (C-7a). FABMS: m/z (relative intensity) 164
+
’
(M , 85), 145 (45), 133 (100), 121 (25), 105 (70), 91 (45), 77 (40), 53 (15) and 43 (40).
+
’
FABHRMS: Calc. C10H12O2 (M ) 164.083730, found: 164.083753.
4.1.1. ( )-2-Hydroxymethyl-2,3-dihydrobenzofuran 6b
1
UV (MeOH): 230 nm (log m 3.7) and 280 nm (log m 3.8). H NMR: l 2.55 (bs, OH), 2.98 (dd,
J=16.0, 8.0 Hz, CH2-3, HA), 3.20 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 3.70 (dd, J=16.0, 6.0 Hz,
2-CH2ꢀOH, HD), 3.80 (dd, J=16.0, 4.0 Hz, 2-CH2ꢀOH, HE), 4.85 (m, H-2, HC), 6.78 (m, 2H,
H-4, 7) and 7.10 (m, 2H, H-5, 6). 13C NMR: l 30.9 (C-3), 64.2 (CH2OH), 82.8 (C-2), 109.0
(C-7), 120.2 (C-5), 124.6 (C-4), 126.2 (C-6), 127.6 (C-3a) and 158.8 (C-7a). FABMS: m/z
+
’
(relative intensity) 150 (M , 40), 131 (40), 119 (50), 107 (20), 91 (100), 70 (20), 65 (20) and 39
+
’
(40). FABHRMS: Calc. C9H10O2 (M ) 150.068080, found: 150.068912.
4.1.2. ( )-5-Chloro-2-hydroxymethyl-2,3-dihydrobenzofuran 6c
1
UV (MeOH): 233 nm (log m 3.6) and 284 nm (log m 3.5). H NMR: l 2.13 (bs, OH), 3.04 (dd,
J=16.0, 8.0 Hz, CH2-3, HA), 3.22 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 3.72 (dd, J=16.0, 6.0 Hz,
2-CH2ꢀOH, HD), 3.83 (dd, J=16.0, 4.0 Hz, 2-CH2ꢀOH, HE), 4.92 (m, H-2, HC), 6.68 (d, J=10.0
Hz, H-7), 7.05 (dd, J=10.0, 2.0 Hz, H-6) and 7.12 (d, J=2.0 Hz, H-4). 13C NMR: l 31.1 (C-3),
64.6 (CH2OH), 82.9 (C-2), 109.2 (C-7), 120.5 (C-5), 124.9 (C-4), 126.4 (C-6), 127.9 (C-3a) and
+
’
159.0 (C-7a). MS: m/z (relative intensity) 184 (M , 80), 186 (M+2) (40), 165 (50), 153 (70), 141
+
’
(30), 125 (100), 89 (60), 77 (50), 63 (50), 51 (45) and 39 (40). FABHRMS: Calc. C9H9ClO2 (M )
186.026157, found: 186.026253.
4.1.3. ( )-5-Methoxy-2-hydroxymethyl-2,3-dihydrobenzofuran 6d
1
UV (MeOH): 231 nm (log m 3.5) and 299 nm (log m 3.7). H NMR: l 2.05 (bs, OH), 2.98 (dd,
J=16.0, 8.0 Hz, CH2-3, HA), 3.32 (dd, J=16.0, 10.0 Hz, CH2-3, HB, 3.73 (s, OCH3), 3.75 (m,
2H, 2-CH2ꢀOH, HD, HE), 4.88 (m, H-2, HC) and 6.70 (m, 3H, H-4, 6, 7). 13C NMR: l 31.1
(C-3), 54.3 (OCH3), 64.6 (CH2OH), 82.9 (C-2), 108.7 (C-7), 125.4 (C-5), 127.3 (C-6), 128.1 (C-4),
+
’
129.6 (C-3a) and 156.8 (C-7a). FABMS: m/z (relative intensity) 180 (M , 100), 149 (70), 136
+
’
(60), 121 (70), 91 (98). FABHRMS: Calc. C10H12O3 (M ) 180.078644, found: 180.079041.
4.1.4. ( )-6-Chloro-2-hydroxymethyl-2,3-dihydrobenzofuran 6e
1
UV (MeOH): 231 nm (log m 3.6) and 278 nm (log m 3.8). H NMR: l 2.36 (bs, OH), 2.97 (dd,
J=16.0, 8.0 Hz, CH2-3, HA), 3.18 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 3.78 (dd, J=16.0, 6.0 Hz,
2-CH2ꢀOH, HD), 3.80 (dd, J=16.0, 4.0 Hz, 2-CH2ꢀOH, HE), 4.90 (m, H-2, HC), 6.72 (d, J=2.0
Hz, H-7), 6.78 (dd, J=10.0, 2.0 Hz, H-5) and 7.04 (d, J=10.0 Hz, H-4). 13NMR: l 30.7 (C-3),
64.4 (CH2OH), 84.2 (C-2), 110.0 (C-7), 120.6 (C-5), 125.3 (C-4), 125.4 (C-6), 133.1 (C-3a) and
+
’
160.0 (C-7a). MS: m/z (relative intensity) 184 (M , 100), 186 (M+2) (40), 165 (50), 153 (70), 141
+
’
(40), 125 (80) and 89 (30). FABHRMS: Calc. C9H9ClO2 (M ) 186.035248, found: 186.035245.
4.1.5. ( )-4-Bromo-2-hydroxymethyl-2,3-dihydrobenzofuran 6f
1
UV (MeOH): 222 nm (log m 3.7) and 285 nm (log m 3.6). H NMR: l 1.95 (bs, OH), 3.04 (dd,
J=16.0, 8.0 Hz, CH2-3, HA), 3.25 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 3.73 (dd, J=16.0, 6.0 Hz,

3386
S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
2-CH2ꢀOH, HD), 3.85 (dd, J=16.0, 4.0 Hz, 2-CH2ꢀOH, HE), 4.93 (m, H-2, HC), 6.45 (dd,
J=10.0, 10.0 Hz, H-6), 7.13 (dd, J=10.0, 2.0 Hz, H-5), and 7.21 (dd, J=10.0, 2.0 Hz, H-7). 13C
NMR: l 32.5 (C-3), 64.0 (CH2OH), 82.4 (C-2), 107.8 (C-7), 118.8 (C-5), 123.1 (C-4), 127.5 (C-6),
+
’
129.1 (C-3a) and 159.2 (C-7a). MS: m/z (relative intensity) 228 (M , 40), 230 (M+2) (10), 209
(30), 197 (50), 118 (100), 89 (40), 77 (40), 51 (30) and 39 (25). FABHRMS: Calc. C9H9BrO2
+
’
(M ) 230.052019, found: 230.052015.
4.1.6. ( )-4-Methyl-2-hydroxymethyl-2,3-dihydrobenzofuran 6g
1
UV (MeOH): 228 nm (log m 3.7) and 284 nm (log m 3.6). H NMR: l 2.20 (s, CH3), 2.86 (dd,
J=16.0, 8.0 Hz, CH2-3, HA), 3.08 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 3.65 (dd, J=16.0, 6.0 Hz,
2-CH2ꢀOH, HD), 3.78 (dd, J=16.0, 4.0 Hz, 2-CH2ꢀOH, HE), 4.81 (m, H-2, HC), 6.50 (dd,
J=10.0, 2.0 Hz, H-7), 6.58 (dd, J=10.0, 2.0 Hz, H-5) and 6.95 (dd, J=10.0, 10.0 Hz, H-6). 13C
NMR: l 20.2 (CH3), 31.9 (C-3), 64.2 (CH2OH), 82.7 (C-2), 106.1 (C-7), 124.1 (C-5), 125.3 (C-4),
+
’
127.4 (C-6), 128.2 (C-3a) and 158.9 (C-7a). MS: m/z (relative intensity) 164 (M , 50), 145 (40),
+
’
133 (60), 121 (30), 105 (100) and 91 (70). FABHRMS: Calc. C10H12O2 (M ) 164.043723, found:
164.043763.
4.1.7. ( )-7-Chloro-2-hydroxymethyl-2,3-dihydrobenzofuran 6h
1
UV (MeOH): 225 nm (log m 3.6) and 280 nm (log m 3.8). H NMR: l 2.65 (bs, OH), 3.07 (dd,
J=16.0, 8.0 Hz, CH2-3, HA), 3.22 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 3.65 (dd, J=16.0, 6.0 Hz,
2-CH2ꢀOH, HD), 3.82 (dd, J=16.0, 4.0 Hz, 2-CH2ꢀOH, HE), 4.90 (m, H-2, HC), 6.70 (m, H-5)
and 6.97 (m, 2H, H-4, 6). 13C NMR: l 31.5 (C-3), 64.0 (CH2OH), 83.8 (C-2), 114.4 (C-7), 123.0
(C-5), 127.9 (C-6), 128.3 (C-4), 128.4 (C-3a) and 154.9 (C-7a). FABMS: m/z (relative intensity)
184 M, 30 186 (M+2) (50), 184 (50), 165 (45), 153 (50), 141 (30), 125 (100), 112 (20), 105 (30)
+
’
and 89 (70). FABHRMS: Calc. C9H9ClO2 (M ) 186.05 2430, found: 186.052453.
4.1.8. ( )-7-Methyl-2-hydroxymethyl-2,3-dihydrobenzofuran 6i
1
UV (MeOH): 223 nm (log m 3.7) and 279 nm (log m 3.6). H NMR: l 2.20 (s, CH3), 3.03 (dd,
J=16.0, 8.0 Hz, CH2-3, HA), 3.22 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 3.73 (dd, J=16.0, 6.0 Hz,
2-CH2ꢀOH, HD), 3.85 (dd, J=16.0, 4.0 Hz, 2-CH2ꢀOH, HE), 4.87 (m, H-2, HC), 6.73 (dd,
J=10.0, 10.0 Hz, H-5), 6.90 (dd, J=10.0, 2.0 Hz, H-4) and 6.96 (dd, J=10.0, 2.0 Hz, H-6). 13C
NMR: l 15.1 (CH3), 31.5 (C-3), 64.7 (CH2OH), 82.6 (C-2), 119.4 (C-7), 122.2 (C-5), 125.6 (C-4),
+
’
128.5 (C-6), 129.1 (C-3a) and 157.4 (C-7a). MS: m/z (relative intensity) 164 (M , 50), 145 (30),
+
’
133 (70), 121 (20), 105 (100) and 91 (50). FABHRMS: Calc. C10H12O2 (M ) 164.078762, found:
164.078793.
4.2. 5-Methyl-2,3-dihydrobenzofuran-2-carbaldehyde 9
THF (10 ml) was added to a solution of 2-iodoxybenzoic acid (0.50 g, 3 mmol) in dry DMSO
(4 ml) 6a (0.59 g, 3 mmol) and this solution was stirred for 1 h. The reaction was quenched by
the addition of water, the precipitated solid was filtered, the filtrate was extracted with ethyl
acetate and the combined extracts were dried over anhydrous MgSO4. Evaporation of the
solvent and purification of the crude product by column chromatography over silica gel by
eluting with petroleum ether:ethyl acetate (8:2) afforded aldehyde 9 (0.4 g, 80% yield) as a
1
colourless solid, mp 156°C. H NMR: l 2.30 (s, CH3), 3.32 (dd, J=16.0, 8.0 Hz, CH2-3, HA),
3.45 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 4.98 (m, H-2, HC), 6.82 (d, J=10.0 Hz, H-7), 6.95 (m,

S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
3387
+
’
2H, H-4, 6) and 9.86 (s, CHO). EIMS: m/z (relative intensity) 162 (M ) (40), 145 (18), 133 (75),
105 (100), 79 (30), 77 (40), 51 (30) and 39 (25).
4.3. 5-Methyl-2,3-dihydrobenzofuron-2-carboxylic acid 10
A solution of chromium trioxide (1.5 g, 15 mmol) in water (5 ml) containing conc. H2SO4 (0.5
ml) was added over a 2 h period to a stirred solution of 5-methyl-2-hydroxymethyl-2,3-dihy-
drobenzofuran 6a (1.0 g, 6 mmol) in acetone (5 ml) and this solution was then kept at 0°C for
a further hour. The excess reagent was quenched with isopropanol, filtered and the filtrate was
evaporated. The residue was dissolved in aq. NaHCO3 solution, washed with ether and the
aqueous layer was neutralised with dil. HCl, and then extracted with ethyl acetate. The organic
layer was dried with MgSO4 and concentrated. The residue was purified by chromatography
over silica gel by eluting with petroleum ether:ethyl acetate (6:4) furnishing acid 10 (0.6 g, 60%
1
yield), mp 176°C. H NMR: l 2.22 (s, CH3), 3.32 (dd, J=16.0, 7.0 Hz, CH2-3, HA), 3.52 (dd,
J=16.0, 10.0 Hz, CH2-3, HB), 5.15 (dd, J=10.0, 7.0 Hz, H-2, HC), 6.72 (d, J=10.0 Hz, H-7),
+
’
6.90 (m, 2H, H-4, 6) and 8.20 (bs, COOH). EIMS: m/z (relative intensity) 178 (M , 75), 133
(85), 105 (100), 77 (45) and 39 (45).
4.4. Synthesis of ( )-5,7-dimethoxyethoxymethyloxy-2-hydroxymethyl-2,3-dihydrobenzofuran 6j
4.4.1. 2,4-Dihydroxybenzaldehyde 1325
To a well cooled (0–5°C) solution of resorcinol 11 (22 g, 64 mmol) in acetonitrile (75 ml), dry
DMF (6.3 g, 64 mmol) and freshly distilled dry POCl3 (11.3 g, 73 mmol) were added with
constant stirring at 0–5°C. The salt 12 that separated was filtered and was washed with cold
acetonitrile. To this salt 12, water (100 ml) was added and heated at 50°C for 0.5 h and then
cooled. The solid that separated was filtered, washed with cold water, dried and chro-
matographed over silica gel by eluting with petroleum ether:ethyl acetate (1:1) to give 2,4-dihy-
droxybenzaldehyde 13 (21.5 g, 80% yield) as a white solid, mp 134°C (lit.25 mp 134°C). UV
1
(MeOH): 230 nm (log m 3.5), 278 nm (log m 3.7), 340 nm (log m 3.4) and 347 nm (log m 3.8). H
NMR (DMSO-d6): l 6.35 (d, J=2.0 Hz, H-2), 6.51 (dd, J=8.0, 2.0 Hz, H-5), 7.42 (d, J=8.0
Hz, H-6), 9.97 (s, CHO) and 10.44 and 11.28 (bs, OH-2, 4). 13C NMR: l 103.0 (C-3), 109.0
+
’
(C-5), 135.4 (C-6), 136.0 (C-1), 163.9 (C-2), 164.4 (C-4) and 194.6 (CHO). EIMS: m/z 138 (M )
(80), 137 (98), 89 (10), 81 (15), 69 (18), 68 (5), 59 (30), 53 (10) and 38 (100).
4.4.2. 2,4-Dimethoxyethoxymethyloxybenzaldehyde 14
N,N%-Diisopropylethylamine (23.0 g, 176.5 mmol) was added to a stirred solution of 13 (10.0
g, 72 mmol) in dry THF (100 ml), cooled to 0°C and methoxyethoxymethyl chloride (MEM-
chloride) (22.0 g, 176.5 mmol) was added slowly and the solution was allowed to attain room
temperature. After 2 h the reaction mixture was diluted with water and extracted with ethyl
acetate. The organic layer was washed with water followed by brine, dried over anhydrous
MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (eluted with petroleum ether:ethyl acetate 6:4) to give the MEM-protected
derivative 14 (9.0 g, 90% yield) as a colourless oil. UV (MeOH): 209 nm (log m 3.6), 225 nm (log m
1
3.7), 273 nm (log m 3.5) and 311 nm (log m 3.6). H NMR: l 3.34 (s, OCH3×2), 3.65 (m,
OCH2×2), 3.82 (m, CH2O×2), 5.30 (s, OCH2O-4), 5.35 (s, OCH2O-2), 6.75 (dd, J=10.0, 2.0 Hz,
H-5), 6.85 (d, J=2.0 Hz, H-3), 7.78 (d, J=10.0 Hz, H-6) and 10.30 (s, CHO). 13C NMR: l 58.8

3388
S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
(C-2, 4, OCH3), 68.0 (C-2, OCH2), 68.1 (C-4, OCH2), 71.3 (C-2, 4, CH2O), 92.1 (C-2, 4,
OCH2O), 103.3 (C-3), 109.4 (C-5), 115.8 (C-1), 135.2 (C-6), 163.9 (C-4), 164.1 (C-2) and 188.1
+
’
(CHO). EIMS: m/z (relative intensity) 314 (M , 15), 225 (20), 165 (10) and 151 (12). Analysis
found: C, 57.30; H, 7.03. C15H22O7 requires: C, 57.32; H, 7.05%.
4.4.3. 2,4-Dimethoxyethoxymethyloxyphenol 15
Compound 14 (5.0 g, 16.5 mmol) was dissolved in dry ethyl acetate (50 ml) and m-CPBA (2.8
g, 16.5 mmol) was added and stirred for 24 h at rt and kept overnight. The separated
m-chlorobenzoic acid (mp 157°C) was filtered. The filtrate was washed with aq. NaHCO3 (2%)
to remove traces of m-chlorobenzoic acid and then washed with water. The organic layer was
dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluted with petroleum ether:ethyl acetate 1:1) to
give phenol 15 (4.0 g, 80% yield) as a colourless oil. UV (MeOH): 201 nm (log m 3.5), 224 nm
1
(log m 3.7) and 256 nm (log m 3.6). H NMR: l 3.35 (s, OCH3×2), 3.55 (m, OCH2×2), 3.80 (m,
CH2O×2), 5.12 (s, OCH2O-4), 5.22 (s, OCH2O-2), 6.58 (dd, J=10.0, 2.0 Hz, H-5), 6.80 (d,
J=2.0 Hz, H-3), 6.77 (d, J=10.0 Hz, H-6) and 7.90 (s, OH). 13C NMR: l 58.3 (C-2, 4, OCH3),
67.0 (C-2, OCH2), 67.1 (C-4, OCH2), 67.6 (C-2, CH2O), 71.1 (C-4, CH2O), 94.0 (C-4, OCH2O),
94.7 (C-2, OCH2O), 106.7 (C-3), 110.3 (C-5), 115.5 (C-6), 142.1 (C-1, OH), 144.8 (C-2) and 150.0
+
’
(C-4). EIMS: m/z (relative intensity) 302 (M , 10), 89 (80), 59 (100) and 45 (15). Analysis found:
C, 55.60; H, 7.31. C14H22O7 requires: C, 55.62; H, 7.33%.
4.4.4. 1-Allyloxy-2,4-dimethoxyethoxymethyloxybenzene 16
Compound 15 (3.75 g, 12 mmol) and allyl bromide (1.5 g, 12 mmol) were dissolved in dry
acetone (150 ml) and refluxed over anhydrous K2CO3 (3.0 g) for 6 h on a water bath. The
acetone was removed under reduced pressure and crushed ice was added to the residue. The
resulting product was extracted with ether. The organic layer was washed with water, dried over
anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by silica
gel column chromatography (eluted with petroleum ether:ethyl acetate 8:2) to give MEM-pro-
tected-1-allyoxybenzene 16 (3.15 g, 85% yield) as a colourless oil. UV (MeOH): 207 nm (log m
1
3.6) and 282 nm (log m 3.5). H NMR: l 3.32 (s, OCH3×2), 3.50 (m, OCH2×2), 3.80 (m,
CH2O×2), 4.50 (d, J=6.0 Hz, OCH2-1%), 5.12 (s, OCH2O-4), 5.22 (s, OCH2O-2), 5.25 (m,
CH2-3%), 6.00 (m, H-2%), 6.60 (dd, J=10.0, 2.0 Hz, H-5), 6.75 (d, J=10.0 Hz, H-6) and 6.84 (d,
J=2.0 Hz, H-3). 13C NMR: l 58.4 (C-2, 4 OCH3×2), 67.1 (C-4, OCH2), 67.2 (C-2, OCH2), 69.5
(C-1%), 70.3 (C-2, 4, CH2O), 94.3 (C-2, OCH2O), 107.2 (C-3), 109.2 (C-5), 115.0 (C-6), 117.0
(C-3%), 133.3 (C-2%), 143.8 (C-1), 147.3 (C-2) and 151.6 (C-4). EIMS: m/z (relative intensity) 342
+
’
(M , 10), 89 (90) and 59 (100). Analysis found: C, 59.62; H, 7.63. C17H26O7 requires: C, 59.64;
H, 7.65%.
4.4.5. 2-Allyl-4,6-dimethoxyethoxymethyloxyphenol 17
Compound 16 (3.0 g, 8.5 mmol) was dissolved in N,N%-dimethylformamide (DMF, 6 ml) and
refluxed for 10 h at 140°C in an oil bath. After cooling to room temperature the solution was
poured onto crushed ice. The product was extracted with ethyl acetate, washed with water, dried
over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (eluted with petroleum ether:ethyl acetate 7:3) to give phenol
derivative 17 (2.25 g, 75% yield) as a colourless oil. UV (MeOH): 204 nm (log m 3.7) and 283 nm
(log m 3.6). 1H NMR: l 3.32 (s, OCH3-6), 3.32 (d, J=6.0 Hz, CH2-1%), 3.35 (s, OCH3-4), 3.52 (m,

S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
3389
OCH2×2), 3.80 (m, CH2O×2), 5.00 (m, CH2-3%), 5.10 (s, OCH2O-6), 5.20 (s, OCH2O-4), 5.95 (m,
H-2%), 6.50 (d, J=2.0 Hz, H-5) and 6.65 (d, J=2.0 Hz, H-3). 13C NMR: l 34.1 (C-1%), 58.8 (C-4,
6, OCH3), 67.4 (C-6, OCH2), 68.5 (C-4, OCH2), 71.5 (C-4, 6, CH2O), 94.4 (C-6, OCH2O), 95.7
(C-4, OCH2O), 104.4 (C-5), 112.0 (C-3), 115.5 (C-3%), 127.0 (C-1), 136.3 (C-2%), 138.7 (C-2), 144.8
(C-6) and 150.1 (C-4). Analysis found: C, 59.60; H, 7.62. C17H26O7 requires: C, 59.64; H, 7.65%.
4.4.6. ( )-5,7-Dimethoxyethoxymethyloxy-2-hydroxymethyl-2,3-dihydrobenzofuran 6j
Compound 17 (2.0 g, 5.5 mmol) and m-CPBA (1.0 g, 5.5 mmol) were dissolved in CHCl3 (150
ml) and refluxed for 5 h on a water bath. After cooling to room temperature the separated
m-chlorobenzoic acid was filtered. The filtrate was washed with aq. NaHCO3 (2%) to remove
traces of m-chlorobenzoic acid, then with water, dried over anhydrous MgSO4 and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography (eluted
with petroleum ether:ethyl acetate 7:3) to give ( )-5,7-dimethoxyethoxymethyloxy-2-hydroxy-
methyl-2,3-dihydrobenzofuran 6j (1.5 g, 75% yield). UV (MeOH): 218 nm (log m 3.6), 232 nm
1
(log m 3.7) and 287 nm (log m 3.5). H NMR: l 3.00 (dd, J=16.0, 6.0 Hz, CH2-3, HA), 3.20 (dd,
J=16.0, 8.0 Hz, CH2-3, HB), 3.20 (m, 2-CH2OH, HD), 3.32 (s, OCH3-7), 3.36 (s, OCH3-5), 3.38
(m, 2-CH2OH, HE), 3.53 (m, OCH2-5), 3.80 (m, 2H, OCH2-7), 4.88 (m, H-2, HC), 5.12 (s,
CH2O×2, OCH2O-5), 5.25 (ABq×2, OCH2O-7), 6.58 (d, J=2.0 Hz, H-4) and 6.62 (d, J=2.0 Hz,
H-6). 13C NMR: l 38.3 (C-3), 61.5 (C-5, 7, OCH3), 65.3 (C-2, OH), 72.6 (C-5, 7 CH2O×2), 73.5
(C-5, 7 OCH2), 83.7 (C-2), 94.1 (C-7, OCH2O), 94.5 (C-5, OCH2O), 125.7 (C-6), 126.0 (C-4),
+
’
131.4 (C-3a), 138.2 (C-7), 141.5 (C-7a) and 154.2 (C-5). EIMS: m/z (relative intensity 358 (M ,
5), 130 (10), 89 (100) and 59 (98). Analysis found: C, 56.95; H, 7.30. C17H26O8 requires: C, 56.97;
H, 7.31%.
4.5. Acetylation of 6a–j
6a–j were acetylated with acetic anhydride/pyridine at rt for 6 h, the reaction mixture was
poured into ice cold water, the compound was extracted with ethyl acetate, dried and
concentrated to give 8a–j
4.5.1. ( )-5-Methyl-2-acetoxymethyl-2,3-dihydrobenzofuran 8a
1
UV (MeOH): 226 nm (log m 3.5) and 285 nm (log m 3.4). H NMR: l 2.08 (s, OCOCH3), 2.25
(s, CH3), 2.98 (dd, J=16.0, 7.0 Hz, CH2-3, HA), 3.25 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 4.18
(dd, J=16.0, 6.0 Hz, CH2O, HD), 4.28 (dd, J=16.0, 4.0 Hz, CH2O, HE), 4.93 (m, H-2, HC), 6.65
(d, J=10.0 Hz, H-7), 6.88 (dd, J=10.0, 2.0 Hz, H-6) and 6.92 (d, J=2.0 Hz, H-4). 13C NMR:
l 20.6 (OCOCH3, 5-CH3), 32.1 (C-3), 65.8 (CH2O), 79.9 (C-2), 109.0 (C-7), 130.0 (C-4), 128.4
(C-6), 129.9 (C-3a, C-5), 157.1 (C-7a) and 170.6 (CꢁO). FABMS: m/z (relative intensity) 206
+
’
(M , 30), 145 (100), 133 (30), 121 (15), 91 (15), 77 (20) and 43 (48). FABHRMS: Calc. C12H14O3
+
’
(M ) 206.094294, found: 206.095246.
4.5.2. ( )-2-Acetoxymethyl-2,3-dihydrobenzofuran 8b
1
UV (MeOH): 228 nm (log m 3.5) and 279 nm (log m 3.6). H NMR: l 2.08 (s, OCOCH3), 2.95
(dd, J=16.0, 8.0 Hz, CH2-3, HA), 3.30 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 4.18 (dd, J=16.0, 6.0
Hz, CH2O, HD), 4.30 (dd, J=16.0, 4.0 Hz, CH2O, HE), 4.95 (m, H-2, HC), 6.80 (m, 2H, H-4,
7) and 7.10 (m, 2H, H-5, 6). 13C NMR: l 20.3 (OCOCH3), 31.8 (C-3), 65.5 (CH2O), 79.5 (C-2),
109.3 (C-7), 120.3 (C-5), 124.5 (C-4), 125.4 (C-6), 127.9 (C-3a, C-5), 159.0 (C-7a) and 169.9

3390
S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
+
’
(CꢁO). FABMS: m/z (relative intensity) 190 (M , 15), 131 (50), 119 (10), 91 (75), 65 (20), 51 (30)
+
’
and 43 (100). FABHRMS: Calc. C11H12O3 (M ) 190.037222, found: 190.037236.
4.5.3. ( )-5-Chloro-2-acetoxymethyl-2,3-dihydrobenzofuran 8c
1
UV (MeOH): 232 nm (log m 3.7) and 288 nm (log m 3.5). H NMR: l 2.07 (s, OCOCH3), 2.94
(dd, J=16.0, 8.0 Hz, CH2-3, HA), 3.25 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 4.18 (dd, J=16.0, 6.0
Hz, CH2O, HD), 4.27 (dd, J=16.0, 4.0 Hz, CH2O, HE), 4.97 (m, H-2, HC), 6.65 (d, J=10.0 Hz,
H-7) and 7.05 (m, 2H, H-4, 6). 13C NMR: l 20.0 (OCOCH3), 31.3 (C-3), 65.0 (CH2O), 80.2 (C-2),
109.8 (C-7), 123.0 (C-5), 124.4 (C-4), 127.1 (C-6), 127.4 (C-3a), 157.4 (C-7a) and 170.0 (CꢁO).
+
’
FABMS: m/z (relative intensity) 226 (M , 20), 228 (M+2) (10), 184 (15), 116 (100), 152 (15), 125
+
’
(50), 102 (10), 88 (50), 77 (30), 63 (45), and 44 (98). FABHRMS: Calc. C11H11ClO3 (M )
226.039672, found: 226.039572.
4.5.4. ( )-5-Methoxy-2-acetoxymethyl-2,3-dihydrobenzofuran 8d
1
UV (MeOH): 225 nm (log m 3.7) and 286 nm (log m 3.6). H NMR: l 2.09 (s, OCOCH3), 2.95
(dd, J=16.0, 8.0 Hz, CH2-3, HA), 3.25 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 3.62 (m, 2H, CH2O,
HD, HE), 3.75 (s, OCH3), 4.82 (m, H-2, HC), 6.67 (m, 3H, H-4, 6, 7). 13C NMR: l 20.3 (OCOCH3),
31.9 (C-3), 55.2 (OCH3-5), 65.5 (C-CH2O), 79.5 (C-2), 108.8 (C-7), 125.1 (C-4), 128.2 (C-3a, C-5),
+
’
128.7 (C-6), 156.9 (C-7a) and 169.8 (CꢁO). FABMS: m/z (relative intensity) 222 (M , 10), 207
(10), 146 (80), 131 (40), 115 (10), 106 (100), 91 (50), 77 (75) and 51 (40). FABHRMS: Calc. C12H14O4
+
’
(M ) 222.084337, found: 222.084351.
4.5.5. ( )-6-Chloro-2-acetoxymethyl-2,3-dihydrobenzofuran 8e
1
UV (MeOH): 220 nm (log m 3.6) and 284 nm (log m 3.5). H NMR: l 2.10 (s, OCOCH3), 3.02
(dd, J=16.0, 8.0 Hz, CH2-3, HA), 3.35 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 4.20 (dd, J=16.0, 6.0
Hz, CH2O, HD), 4.32 (dd, J=10.0, 4.0 Hz, CH2O, HE), 5.03 (m, H-2, HC), 6.65 (d, J=2.0 Hz,
H-7), 6.82 (dd, J=10.0, 2.0 Hz, H-5) and 7.03 (d, J=10.0 Hz, H-4). 13C NMR: l 20.5 (OCOCH3),
32.6 (C-3), 65.2 (CH2O), 80.5 (C-2), 115.1 (C-7), 121.4 (C-4), 122.9 (C-5), 127.5 (C-6), 128.5 (C-3a),
+
’
155.2 (C-7a) and 169.9 (CꢁO). FABMS: m/z (relative intensity) 226 (M , 10), 228 (M+2) (10),
166 (75), 165 (80), 153 (30), 131 (50), 125 (90), 102 (40), 88 (70), 77 (39), 63 (75), 44 (100) and
+
’
43 (50). FABHRMS: Calc. C11H11ClO3 (M ) 228.056136, found: 228.056124.
4.5.6. ( )-4-Bromo-2-acetoxymethyl-2,3-dihydrobenzofuran 8f
1
UV (MeOH): 249 nm (log m 3.7) and 285 nm (log m 3.6). H NMR: l 2.10 (s, OCOCH3), 2.98
(dd, J=16.0, 8.0 Hz, CH2-3, HA), 3.32 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 4.21 (dd, J=16.0, 6.0
Hz, CH2O, HD), 4.32 (dd, J=16.0, 4.0 Hz, CH2O, HE), 5.01 (m, H-2, HC), 6.51 (dd, J=10.0, 10.0
Hz, H-6), 7.16 (dd, J=10.0, 2.0 Hz, H-5) and 7.32 (dd, J=10.0, 2.0 Hz, H-7). 13C NMR: l 20.2
(OCOCH3), 33.1 (C-3), 65.1 (CH2O), 79.2 (C-2), 108.0 (C-7), 118.6 (C-4), 123.1 (C-5), 126.9 (C-6),
+
’
129.3 (C-3a), 159.3 (C-7a) and 169.6 (CꢁO). FABMS: m/z (relative intensity) 270 (M , 10), 272
(M+2) (4), 211 (95), 131 (50), 118 (70), 102 (15), 88 (70), 77 (50), 63 (80) and 44 (100). FABHRMS:
+
’
Calc. C11H11BrO3 (M ) 272.027145, found: 272.027136.
4.5.7. ( )-4-Methyl-2-acetoxymethyl-2,3-dihydrobenzofuran 8g
1
UV (MeOH): 229 nm (log m 3.6) and 282 nm (log m 3.5). H NMR: l 2.15 (s, OCOCH3), 2.25
(s, CH3), 2.85 (dd, J=16.0, 8.0 Hz, 1H, CH2-3, HA), 3.10 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 3.75
(dd, J=16.0, 6.0 Hz, CH2O, HD), 4.81 (dd, J=16.0, 4.0 Hz, CH2O, HE), 4.85 (m, H-2, HC), 6.64
(dd, J=10.0, 2.0 Hz, H-7), 6.72 (dd, J=10.0, 2.0 Hz, H-5) and 6.85 (dd, J=10.0, 10.0 Hz,

S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
3391
H-6). 13C NMR: l 20.1 (OCOCH3), 21.1 (CH3), 31.7 (C-3), 64.2 (CH2O), 77.6 (C-2), 109.6 (C-7),
123.0 (C-5), 124.5 (C-4), 126.1 (C-6), 129.2 (C-3a), 158.9 (C-7a) and 169.8 (CꢁO). FABMS: m/z
+
’
(relative intensity) 206 (M , 10), 164 (70), 145 (50), 133 (70), 104 (100), 90 (40), 77 (50), 52 (15)
+
’
and 40 (20). FABHRMS: Calc. C12H14O3 (M ) 206.065731, found: 206.065742.
4.5.8. ( )-7-Chloro-2-acetoxymethyl-2,3-dihydrobenzofuran 8h
1
UV (MeOH): 226 nm (log m 3.5) and 280 nm (log m 3.7). H NMR: l 2.08 (s, OCOCH3), 3.05
(dd, J=16.0, 8.0 Hz, CH2-3, HA), 3.35 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 4.24 (dd, J=16.0, 6.0
Hz, CH2O, HD), 4.31 (dd, J=16.0, 4.0 Hz, CH2O, HE), 5.05 (m, H-2, HC), 6.75 (dd, J=10.0, 10.0
Hz, H-5), 7.00 (dd, J=10.0, 2.0 Hz, H-4) and 7.08 (dd, J=10.0, 2.0 Hz, H-6). 13C NMR: l 20.5
(OCOCH3), 32.6 (C-3), 65.2 (CH2O), 80.4 (C-2), 115.2 (C-7), 121.4 (C-4), 122.9 (C-5), 127.4 (C-6),
+
’
128.5 (C-3a), 155.2 (C-7a) and 170.0 (CꢁO). FABMS: m/z 226 (relative intensity) (M , 10), 228
(M+2) (5), 166 (95), 153 (20), 125 (80), 103 (50), 89 (70), 77 (40), 63 (70) and 43 (100). FABHRMS:
+
’
Calc. C11H11ClO3 (M ) 228.082615, found: 228.082631.
4.5.9. ( )-7-Methyl-2-acetoxymethyl-2,3-dihydrobenzofuran 8i
1
UV (MeOH): 227 nm (log m 3.6) and 278 nm (log m 3.6). H NMR: l 2.20 (s, OCOCH3), 2.40
(s, CH3), 3.00 (dd, J=16.0, 8.0 Hz, CH2-3, HA), 3.20 (dd, J=16.0, 10.0 Hz, CH2-3, HB), 3.70 (dd,
J=10.0, 6.0 Hz, CH2O, HD), 3.82 (dd, J=16.0, 4.0 Hz, CH2O, HE), 4.85 (m, H-2, HC), 6.88 (dd,
J=10.0, 2.0 Hz, H-4), 6.72 (dd, J=10.0, 10.0 Hz, H-5), and 6.95 (dd, J=10.0, 2.0 Hz, H-6). 13C
NMR: l 20.1 (CH3), 20.8 (OCOCH3), 31.4 (C-3), 64.5 (CH2O), 82.5 (C-2), 119.2 (C-7), 120.2 (C-4),
122.1 (C-5), 126.6 (C-6), 129.0 (C-3a), 157.4 (C-7a) and 170.2 (CꢁO). FABMS: m/z (relative
+
’
intensity) 206 (M , 10), 164 (50), 145 (45), 133 (50), 104 (100), 90 (40), 77 (45), 52 (10) and 40
+
’
(15). FABHRMS: Calc. C12H14O3 (M ) 206.074171, found: 206.074152.
4.5.10. ( )-5,7-Dimethoxyethoxymethyloxy-2-acetoxymethyl-2,3-dihydrobenzofuran 8j
1
UV (MeOH): 226 nm (log m 3.6), 240 nm (log m 3.8) and 285 nm (log m 3.6). H NMR: l 2.06
(s, OCOCH3), 2.95 (dd, J=16.0, 7.0 Hz, CH2-3, HA), 3.28 (dd, J=16.0, 10.0 Hz, CH2-3, HB),
3.40 (s, OCH3×2), 3.55 (m, OCH2×2), 3.80 (m, CH2O×2), 4.25 (m, 2H, 2-CH2O, HD, HE), 4.98
(m, H-2, HC), 5.14 (s, OCH2O-5), 5.25 (s, OCH2O-7), 6.60 (d, J=2.0 Hz, H-4), and 6.70 (d, J=2.0
Hz, H-6). 13C NMR: l 20.3 (OCOCH3), 33.0 (C-3), 58.9 (OCH3×2), 65.6 (CH2O), 67.5 (OCH2-5),
67.8 (OCH2-7), 71.5 (CH2O-5), 71.6 (CH2O-7), 80.5 (C-2), 94.4 (OCH2O-5), 94.6 (OCH2O-7), 104.7
(C-6), 106.9 (C-4), 131.1 (C-3a), 141.3 (C-7a), 152.2 (C-5) and 170.0 (CꢁO). EIMS: m/z (relative
+
’
intensity) 400 (M , 5), 156 (10), 139 (12), 89 (75) and 59 (100). Analysis found: C, 56.97; H, 7.03.
C19H28O9 requires: C, 56.99; H, 7.05%.
4.6. General procedure for the lipase mediated enantioselective acylation of 2-hydroxymethyl-
2,3-dihydrobenzofurans 6a–j
( )-5-Methyl-2-hydroxymethyl-2,3-dihydrobenzofuran 6a (0.5 g, 3 mmol) was dissolved in
n-hexane (50 ml). Lipase Amano PS (500 mg) was added to this solution and the suspension was
thermostated at rt. After a few minutes vinyl acetate (5 ml) was added and the reaction mixture
was stirred using a magnetic stirrer and the progress of the reaction was monitored by TLC by
comparing the amount of ( )-6a present with the amount of ( )-8a. After 50% conversion, the
lipase was filtered off, the hexane was evaporated and the resulting gum was chromatographed
on silica gel by eluting with petroleum ether:ethyl acetate (7:3, v/v) to give acetate 18a and alcohol
19a. Similarly, ( )-6b–j gave (−)-(R)-acetates 18b–j and (+)-(S)-alcohols 19b–j after lipase mediated

3392
S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
kinetic resolution. The chemical yield, [h]D and % ee of 18a–j and 19a–j are given in Table 1. The
CD spectral data are given in Table 2.
4.7. Synthesis of (−)-(R)-MEM-protected arthrographol 22 from (−)-18j
4.7.1. (−)-(R)-5,7-Dimethoxyethoxymethyloxy-2-hydroxymethyl-2,3-dihydrobenzofuran 20
Acetate 18j (1.5 g, 4 mmol) in methanol (10 ml) was hydrolysed by K2CO3–MeOH (0.42 g, 3.0
mmol) in water (three drops) and stirring at rt for 30 min. The reaction mixture was extracted
with ethyl acetate dried over anhydrous MgSO4 and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography by eluting with petroleum ether:ethyl
acetate (8:2) to give (−)-(R)-alcohol 20 as a colourless oil (1.3 g, 90% yield). UV (MeOH): 205
1
nm (log m 3.6) and 283 nm (log m 3.6). H NMR: l 2.50 (s, bs, OH), 3.00 (dd, J=16.0, 6.0 Hz,
CH2-3, HA), 3.60 (m, 2-CH2ꢀOH, HD), 3.30 (dd, J=16.0, 8.0 Hz, CH2-3, HB), 3.32 (s, OCH3-7),
3.36 (s, OCH3-5), 3.70 (m, 2-CH2ꢀOH, HE), 3.53 (m, OCH2-5), 3.80 (m, OCH2-7), 4.88 (m, H-2,
HC), 5.14 (ABq, OCH2O-5), 5.12 (s, CH2O×2), 5.25 (ABq, OCH2O-7), 6.58 (d, J=2.0 Hz, H-4)
and 6.62 (d, J=2.0 Hz, H-6). [h]D=−20.83 (c 1.31, CHCl3).
4.7.2. Oxidation of 20: formation of (−)-(R)-5,7-dimethoxyethoxymethyloxy-2,3-dihydro-
benzofuran-2-carbaldehyde 21
A solution of oxalyl chloride (0.53 g, 4 mmol) in dry DCM (20 ml) was cooled at −78°C under
nitrogen atmosphere and then anhydrous DMSO (0.32 g, 4 mmol) was added dropwise. After
stirring for 10 min at −78°C, a solution of (−)-(R)-20 (1.35 g, 4 mmol) in dry DCM (5 ml) was
introduced to the reaction mixture via a syringe. The resultant white suspension was stirred at
−78°C for 1 h and then quenched with triethylamine (0.42 g, 4 mmol) at the same temperature,
then allowed to attain room temperature, poured over crushed ice, and the organic layer was
separated and the aqueous layer was extracted with DCM. The combined extracts were washed
with water, brine and dried over anhydrous MgSO4 and concentrated under reduced pressure to
afford (−)-(R)-21 as a syrup in 85% yield. The compound was used immediately in the next step
without further characterisation.
4.7.3. Synthesis of (−)-(R)-MEM-protected arthrographol 22
n-Butyllithium (0.11 ml of a 2.5 M solution of hexane) was added to a suspension of crotyl
triphenylphosphonium bromide (0.5 g, 2 mmol) in dry THF (10 ml) at 0°C to give an orange-red
solution of the phosphonyl anion. The solution was cooled to −78°C and a solution of the aldehyde
21 (0.5 g, 2 mmol) in THF (2 ml) was added dropwise. The mixture was stirred at −78°C for 2
h, then warmed to room temperature and quenched with water. The solution was transferred to
a separatory funnel, diluted with water and extracted with DCM. The combined extracts were
dried over anhydrous MgSO4 and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (eluted with petroleum ether:ethyl acetate 7:3) to give
(−)-(R)-MEM-protected arthrographol 22 (0.44 g, 89% yield). UV (MeOH): 226 nm (log m 4.0)
1
and 292 nm (log m 3.5). H NMR: l 1.80 (dd, J=6.0, 1.0 Hz, CH3-5%), 2.92 (dd, J=16.0, 8.0 Hz,
H-3, HA), 3.32 (dd, J=16.0, 6.0 Hz, H-3, HB), 3.32 (s, H-5, 7, OCH3), 3.52 (m, OCH2-5), 3.80
(m, OCH2-7), 5.12 (s, OCH2O-5), 5.22 (s, OCH2O-7), 5.40–6.40 (m, fourolefinic protons, H-1%,
2%, 3%, 4% and H-2), 6.55 (d, J=2.0 Hz, H-4), 6.65 (d, J=2.0 Hz, H-6). 13C NMR: l 18.2 (C-5%,
CH3), l 38.9 (C-3), l 59.2 (C-5, 7 OCH3×2), 67.3 (C-5, OCH2), 67.4 (C-7, CH2O), 71.0 (C-5, CH2O),
71.1 (C-7, CH2O), 79.3 (C-2), 94.3 (C-5, OCH2O), 94.9 (C-7, OCH2O), 105.3 (C-2%), 108.1 (C-4),

S. Ramadas, G. L. D. Krupadanam / Tetrahedron: Asymmetry 11 (2000) 3375–3393
3393
126.9 (C-3%), 127.5 (C-1%), 126.1 (C-3a), 133.8 (C-7a), 131.0 (C-4%), 132.0 (C-6), 141.2 (C-7) and
+
’
151.9 (C-5). EIMS: m/z (relative intensity) 394 (M , 30) 89 (100) and 59 (98). HREIMS: Calc.
+
’
C21H30O7 (M ) 394.199154, found: 394.199124. [h]D=−14.0 (c 0.5, CHCl3).
Acknowledgements
The authors would like to thank the Amano Pharmaceutical Co. Ltd., Japan for a generous
gift of lipase. They would also like to thank the CSIR, New Delhi for financial support and a
grant of Senior Research Fellowship to Sathunuru Ramadas. The authors are indebted to J.A.R.P.
Sarma and D. Ravinder, Molecular Modelling Division, IICT for the molecular modelling studies.
References
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2. Benevides, P. J. C.; Sartorelli, P.; Kato, M. J. Phytochemistry 1999, 52, 339.
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