Stereoselective reduction of arteannuin B and its chemical transformations

Article abstract of DOI:10.1016/S0040-4020(03)00330-2

Absolute stereochemistry of dihydroarteannuin B 5 obtained by the reduction of arteannuin B 3 with Ni₂B, NaBH₄ or CdCl₂-Mg-MeOH-H₂O has been established by 2D NMR and single crystal X-ray diffraction studies. Some experiments aimed at the synthesis of dihydrodeoxyarteannuin B [C-4, 5 double bond isomer of 11] are also discussed.

Full text of DOI:10.1016/S0040-4020(03)00330-2

Tetrahedron 59 (2003) 2871–2876
Stereoselective reduction of arteannuin B and its
chemical transformations
a
a
b
b
Asish K. Bhattacharya,a Mahesh Pal, Dharam C. Jain, Bhawani S. Joshi, Raja Roy,
,
*
Urszula Rychlewskac and Ram P. Sharmad
aPhytochemical Technology Division, Central Institute of Medicinal and Aromatic Plants, P.O. CIMAP, Lucknow 226 015, India
bRSIC Division, Central Drug Research Institute, Lucknow 226 001, India
cFaculty of Chemistry, A. Mickiewicz University, 60-780 Poznan, Poland
dDepartment of Chemistry, Lucknow University, Lucknow 226 007, India
Received 1 November 2002; revised 11 February 2003; accepted 28 February 2003
Respectfully dedicated to Professor Richard R. Schmidt on the occasion of his 68th birthday
Abstract—Absolute stereochemistry of dihydroarteannuin B 5 obtained by the reduction of arteannuin B 3 with Ni2B, NaBH4 or CdCl2–
Mg–MeOH–H2O has been established by 2D NMR and single crystal X-ray diffraction studies. Some experiments aimed at the synthesis of
dihydrodeoxyarteannuin B [C-4, 5 double bond isomer of 11] are also discussed. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
The major secondary metabolites of the Chinese anti-
malarial plant Artemisia annua are artemisinin 1,
artemisinic acid 2 and arteannuin B 3 (Fig. 1). Of these
three, only artemisinin 1 is the biologically active
component and has been converted into several other
derivatives, which are more effective and are now under
clinical use.1,2 Artemisinic acid 2 has been chemically
converted into artemisinin 1 in 40% yield in a two-step
synthesis.3 Lansbury et al.4 have reported the chemical
conversion of arteannuin B 3 to artemisinin 1. Our attempts5
for the same conversion led to a novel rearranged product
and during the course of our investigations we carried out
some other reactions which are described herein including
the determination of the relative stereochemistry of the C-13
methyl in dihydroarteannuin B 5.
In an earlier publication, nickel boride reduction of
arteannuin B 3 has been shown to furnish5 the dihydro-
arteannuin B 5. The stereochemistry of the C-13 methyl was
assigned as a mainly on the basis of its chemical shifts in
CDCl3 and C6D6, and also by comparison of coupling
constants.6 Lansbury et al.4 has assigned the b-stereo-
chemistry to the C-13 methyl group of dihydroarteannuin B,
obtained by hydrogenation of arteannuin B 3 with
Wilkinson’s catalyst [Rh(PPh3)3Cl]. Our compound was
different from Lansbury et al.4 in respect of its NMR
behaviour and mp. Reaction of 5 with BF3·Et2O–Ac2O
furnishes the rearranged product 4 whose X-ray analysis5
does confirm the absolute stereochemistry of 5. Never-
theless, in view of the epimerization possible under these
acidic conditions (BF3·Et2O–Ac2O), it was considered
Figure 1. Major secondary metabolites (1–3) of A. annua.
Keywords: Artemisia annua; antimalarial; artemisinin; arteannuin B; chemical transformations.
*
Corresponding author. Tel.: þ91-522-2342676; fax: þ91-522-2342666; e-mail: asishkb@yahoo.com
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00330-2

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A. K. Bhattacharya et al. / Tetrahedron 59 (2003) 2871–2876
C(1)–C(6) bond, as is an epoxide ring at C(4)–C(5). The
g-lactone ring is trans-fused at C(6)–C(7) and bears an
a-oriented methyl group attached to C(11). The C(10)
methyl group is also a-oriented, while the C(4) methyl
group is b. Due to the fusion with the epoxide ring, the six-
membered A ring is flattened at C(4) and C(5), and its
conformation can be described as an intermediate between
C(1), C(2) half-chair and C(1) sofa. The six-membered B
ring adopts the chair conformation slightly distorted
towards C(7) sofa form. The confirmation of the two rings
closely resembles the conformation found in arteannuin B
3.9–11 The saturated g-lactone ring adopts C(7) envelope
conformation which seems to be characteristic for 11,13-
dihydro derivatives of arteannuin B.12 In arteannuin B 3 and
isoarteannuin B,13 the conformation of a-methylene
g-lactone ring is close to C(7), C(6) half-chair form.
Reduction of arteannuin B 3 with NaBH4 or CdCl2–Mg–
MeOH–H2O14,15 furnished the dihydroarteannuin B 5
(Scheme 1) in almost quantitative yield, which was found
to be identical (mp, mixed mp, TLC, co-TLC, IR and NMR)
with the authentic sample of 5.5
Figure 2. A perspective view of dihydroarteannuin B 5 with numbering
scheme. Thermal ellipsoids were drawn with 40% probability. H-atoms are
represented as spheres of an arbitrary size.
desirable to ascertain the stereochemistry of product 5 by
single crystal X-ray analysis. This would settle the
conflicting reports7,8 appearing in the literature about the
configuration of the C-13 methyl of dihydroarteannuin B 5.
We now describe some experiments (Scheme 1) which were
carried out to synthesize dihydrodeoxyarteannuin B [C-4, 5
double bond isomer of 11] for its eventual transformation to
artemisinin 1 using Lansbury et al.’s method.4 Thus, it was
decided to create a double bond between C-4, C-5 through
bromohydrin formation. However, the reaction of
arteannuin B 3 with HBr in THF at room temperature
A perspective view of the molecule 5 is shown in Figure 2,
which clearly illustrates the relative configuration at all
chiral centers. Two six-membered rings are cis-fused at the
Scheme 1. Reagents and conditions: (i) NaBH4, MeOH, room temperature; (ii) HBr, THF, room temperature; (iii) Ac2O, py, room temperature; (iv) Pd–C
(10%), EtOH, H2, 50 psi; (v) NiCl2·6H2O, NaBH4, diglyme, room temperature (for 9b); (vi) KOH–MeOH (10%) room temperature.

A. K. Bhattacharya et al. / Tetrahedron 59 (2003) 2871–2876
2873
furnished a product, which was identified as 6, mp
186–1878C (EtOAc–hexane) by direct comparison (TLC,
co-TLC, mp, mixed mp and H NMR) with the authentic
oxygen appeared at d 85.8 and 71.8, respectively. The mass
spectrum gave the molecular ion peak at m/z 294.
1
sample.14 The reaction of dihydroarteannuin B 5 with HBr
in THF at room temperature furnished a mixture of three
products, which were separated by preparative TLC (10%
EtOAc–hexane). The less polar minor product was
identified as the ketone 7 (mixture of C-4 epimers) by
spectral data. The more polar major product was found to be
a mixture of two products (<85:15, single spot on TLC) as
indicated by its 1H NMR spectrum. Acetylation of this
mixture with Ac2O–Py led to the isolation of two products
after preparative silica gel TLC (20% EtOAc–hexane,
double run).
It has been reported16 that the reaction of Ni2B with allylic
acetate furnishes the corresponding olefin by reductive
removal of the acetate, which in certain cases is attended by
double bond migration. Reaction of the acetate 9b with
Ni2B in diglyme furnished a single product, which was
identified as 11 on the basis of spectral data. In the 1H NMR
spectrum, the signals due to the acetate methyl as well as the
proton of the acetate were missing. A multiplet at d 5.35 was
assigned to 3-H and the C-15 methyl appeared as a broad
singlet at d 1.50. The mass spectrum gave the molecular ion
peak at m/z 234. However, in compound 11, the double bond
could not be isomerised to C-4,5-position under various
acidic reaction conditions viz. acidic alumina, oxalic acid in
EtOH/reflux, p-TsOH in benzene etc.
The more polar minor product was identified as 8b, mp
86–878C (EtOAc–hexane) by its spectral analysis. The IR
spectrum gave strong absorption bands at 1780 and
1
1736 cm21. In the H NMR spectrum, a singlet at d 5.85
Alkaline hydrolysis of the acetate 10 with 10% KOH–
MeOH furnished the rearranged alcohol 12 in quantitative
yield. The IR spectrum gave strong absorption bands at
for one proton was assigned to 5-H; the two singlets at d
4.90 and 4.67 each for one proton represented the
exomethylene protons. The mass spectrum gave the
molecular ion peak at m/z 292. The 13C NMR spectrum
gave seventeen peaks in the fully decoupled spectrum as
demanded by structure 8b. In the DEPT edited spectrum,
there were 4£C, 5£CH, 5£CH2, and 3£CH3 which is in full
accord with the assigned structure. The signals at d 179.6
and 169.0 were responsible for the two carbonyl groups of
the lactone and the acetate moieties, respectively. The
signals at d 141.8 and 86.6 were assigned to C-4 and C-6,
respectively. The signal at d 108.4 was assigned to C-15 and
at d 72.6 to C-5.
1
3468 and 1714 cm21. In the H NMR spectrum, a doublet
(J¼7 Hz) at d 4.50 was assigned to 5-H; three doublets
(J¼7 Hz each) at d 1.26, 1.10 and 0.90 were assigned to 13-
CH3, 15-CH3 and 14-CH3, respectively. The mass spectrum
gave the molecular ion peak at m/z 252.
Hydrogenation of the mixture [(8aþ9a) obtained in the
reaction of HBr with 5] over 10% Pd–C in dry EtOH at
50 psi also furnished 12 as the only product.
3. Conclusions
The less polar major product was identified as the acetate 9b
by direct comparison (TLC, co-TLC, mp, mixed mp, NMR
and MS) with its authentic sample.5
Reduction of arteannuin B 3 with Ni2B,5 NaBH4 or CdCl2–
Mg–MeOH–H2O14,15 furnishes the same product, dihydro-
arteannuin B 5 in which the relative stereochemistry of the
C-13 methyl has been established by single crystal X-ray
diffraction studies.
Hydrogenation of 9b over 10% Pd–C in dry EtOH at 50 psi
furnished the dihydro derivative 10, mp 65–678C (EtOAc–
hexane) which was found to be a mixture (vide 1H and 13
C
NMR) of C-4 epimers in the ratio of <1:5. Similarly,
hydrogenation of 8b under the above mentioned conditions
gave the dihydro derivative 10, mp 65–678C (EtOAc–
hexane) which was also found to be a mixture of C-4
epimers in the same ratio (i.e. <1:5) as that obtained from
4. Experimental
4.1. General
1
compound 9b. In the H NMR spectrum, 5-H appeared as
All melting points were determined in open capillaries and
are uncorrected. IR spectra were recorded as thin films
unless otherwise stated on Perkin–Elmer 1710 FT-IR
spectrophotometer. The NMR spectra were recorded on a
Varian FT-80 (80 MHz) or a Bruker WM-400 (400 MHz) or
a Bruker DRX-300 (300 MHz) in CDCl3 unless stated with
TMS as internal standard. Chemical shifts are expressed as d
in ppm. Mass spectra were recorded under electron impact
at 70 eV on JEOL JMS D-100 spectrometer. Fast Atom
Bombardment Mass Spectroscopy (FABMS) were carried
out with JEOL SX 102/DA-6000 mass spectrometer using
m-nitrobenzyl alcohol as matrix at an accelerating voltage
of 10 kV. Optical rotations were recorded on JASCO DIP-
180 digital polarimeter. Elemental analysis was carried out
on HERAEUS CHN-O-RAPID elemental analyzer. For
preparative TLC, Si gel G (E. Merck, India) was used.
Sodium borohydride used was purchased from Aldrich
Chemical Company Inc., USA. All the solvents were
doublet (J¼5.7 Hz) at d 5.39 for the major compound. For
the minor compound, 5-H appeared as a doublet
(J¼11.1 Hz) at d 5.26. The acetate methyl for the major
compound appeared as a sharp singlet at d 2.04, 13-CH3, 15-
CH3 and 14-CH3 appeared as doublets (J¼6.0–7.0 Hz) at d
1.13, 1.07 and 0.91 respectively, whereas, the corresponding
doublets of these protons for the minor compound were not
clearly discernible. The 13C NMR spectrum also indicated
that it is a mixture of C-4 epimers in the ratio of <1:5 by
displaying seventeen signals for the major product. The
corresponding seventeen signals for the minor compound
were not clearly discernible being partially masked by the
signals of the major isomer. In the DEPT edited spectrum,
there were 3£C, 6£CH, 4£CH2, and 4£CH3 in full accord
with the assigned structure. The two signals at d 179.6 and
169.3 represented the two carbonyl groups of lactone and
acetate, respectively. The carbons of the lactone and acetate

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A. K. Bhattacharya et al. / Tetrahedron 59 (2003) 2871–2876
purified before use. THF was distilled over LiAlH4 before
use. Hexane refers to the fraction bp 65–708C. Work up
reaction mixtures were dried over anhydrous Na2SO4.
s, 5-H), 2.68 (1H, m, 11-H), 1.95 (1H, m, 8-Ha), 1.87 (1H,
m, 9-Ha), 1.85 (2H, m, 3-H), 1.79 (1H, m, 7-H), 1.74 (1H, m,
2-Ha), 1.71 (1H, m, 8-Hb), 1.58 (1H, m, 1-H), 1.52 (1H, m,
10-H), 1.50 (1H, m, 2-Hb), 1.38 (3H, brs, 15-CH3), 1.24
(3H, d, J¼7 Hz, 13-CH3), 1.20 (1H, m, 9-Hb), 0.97 (3H, d,
J¼7 Hz, 14-CH3). Irradiation of signal at d 1.24 (3H, d,
J¼7 Hz, 13-CH3) collapsed the multiplet at d 2.68 into a
doublet (J¼14 Hz); dH (400 MHz, C6D6) 2.45 (1H, s, 5-H),
2.14 (1H, m, 11-H), 1.09 (3H, brs, 15-CH3), 1.02 (3H, d,
J¼7 Hz, 13-CH3), 0.63 (3H, d, J¼7 Hz, 14-CH3); dC (75.5,
CDCl3, assignment by DEPT, HMQC and HMBC NMR
experiments) 178.31 (C-12), 80.81 (C-6), 57.93 (C-5), 57.79
(C-4), 54.69 (C-2), 44.42 (C-1), 32.61 (C-11), 34.51 (C-9),
30.50 (C-10), 24.35 (C-3), 22.76 (C-15), 22.65 (C-8), 18.36
(C-13), 16.14 (C-2), 12.75 (C-14); m/z (EI) 250 (Mþ), 208,
179, 164, 151, 135, 121, 107, 93, 81, 67, 55, 43.
The two-dimensional NMR experiments were carried out
with the sample dissolved in CDCl3 on a Bruker DRX-300
spectrometer (300 MHz). All the 2D NMR experiments
were carried out using standard Bruker software. Assign-
ments of 13C signals have been made on the basis of
comparison with other compounds in this series except
where it has been mentioned by HMQC and HMBC NMR
experiments.
4.2. X-Ray crystallographic study of (5)
C15H22O3, MW¼250.33; orthorhombic; crystal size:
˚
0.55£0.40£0.25 mm;
P212121;
a¼9.451(2) A,
3
˚
˚
˚
b¼10.520(3) A, c¼13.841(3) A; V¼1376.1(5) A ; Z¼4;
4.3. Reaction of (3) with HBr
Dx¼1.208 mg/m3; absorption coefficient: 0.082 mm21
;
F(000)¼544. Single crystals of dihydroarteannuin B 5
were obtained from EtOAc–hexane solution. The reflection
intensities were measured on a four-circle KM-4 (KUMA
Diffraction)17 diffractometer equipped with graphite mono-
chromator using Mo Ka radiation. The cell constants and the
orientation matrix obtained from a least-squares fit of 85
centered reflections with u in the range 8.07 to 18.218. The
reflections were measured using v–2u scan technique for u
from 1 to 278, with the scan rate depending directly on the
net count for rapid pre-scans on each reflections and a scan
range in v of 1.08. Index ranges: 0#h#12, 0#k#13,
0#l#17. Background measurements were estimated from
68-step profile. The intensities were corrected for Lorentz
and polarization effects but not for absorption [m (Mo Ka)
0.082 mm21]. The structure was solved by direct methods
with SHELXS-8618 and refined with SHELXL-93.19 Heavy
atoms (C, O, N) were refined anisotropically. The positions
of the H-atoms attached to the C-atoms were calculated at
To a stirred solution of 3 (100 mg, 0.40 mmol) in freshly
distilled THF (4 mL) at room temperature, 48% HBr
(0.5 mL) was added and the reaction was monitored by
TLC. After 3 h when the reaction was complete, reaction
mixture was quenched with H2O (200 mL) and extracted
with CH2Cl2 (3£100 mL). The organic layer was washed
with H2O, dried (Na2SO4) and evaporated to give a residue
which showed a single spot on TLC and was purified by
preparative TLC (20% EtOAc–hexane) to furnish a solid
(80 mg, 80%) which was identified as 6, mp 186–1878C
(EtOAc–hexane, reported14 mp 182–1848C) on the basis of
TLC, co-TLC, mp, mixed mp and 1H NMR with the
authentic sample.14
4.4. Reaction of (5) with HBr
A solution of 5 (100 mg, 0.40 mmol) in freshly distilled
THF (4 mL) was stirred at room temperature for 5 min and
48% HBr (0.3 mL) was added to it. The reaction mixture
was monitored on TLC and after 7 h when the reaction was
complete the reaction mixture was diluted with H2O
(200 mL) and extracted with CH2Cl2 (3£100 mL). The
CH2Cl2 extract was washed with dilute solution of
NaHCO3, H2O, dried (Na2SO4) and evaporated to give a
yellowish coloured semi-solid which on TLC (10%
EtOAc–hexane) showed two spots. These were isolated
by preparative TLC (10% EtOAc–hexane) to give 18 mg of
the less polar minor product as colourless oil, which was
identified as 7 by spectral data. The more polar major
product showed two spots on TLC moving very close to
each other, which could not be separated on Si gel TLC. The
13C NMR spectrum of this major product indicated that it is
a mixture of two alcohols in the ratio of <85:15. It was
therefore, acetylated as such.
˚
standardized distances of 0.96 A. All H-atoms were refined
using a riding model with isotropic temperature factors 30%
higher than the isotropic equivalent for the atom to which
the H-atom was bonded. The function minimized was
P
[w(F2o2F2c)2] with w¼1/[s 2(Fo)2þ(aP)2þbP] where
P¼(F2oþ2F2c)/3, a¼0.083 and b¼0. Convergence was
attained at R¼0.042 for 899 observed reflections
[Fo$4s(Fo)] and wR2¼0.148 for all 1740 reflections and
164 refined parameters. The final difference map showed
23
˚
minima and maxima ranging from 20.16 to 0.19 eA
.
Siemens Stereochemical Workstation was used to prepare
drawings.20,21
4.2.1. Dihydroarteannuin B (5). To a stirred solution of 3
(100 mg, 0.40 mmol) in dry MeOH (4 mL) at room
temperature, NaBH4 (100 mg, 2.65 mmol) was added
slowly over a period of 15 min and monitored the reaction
on TLC. After 1 h when reaction was complete, H2O
(200 mL) was added and extracted with CH2Cl2
(3£100 mL), dried (Na2SO4) and evaporated to dryness to
give dihydroarteannuin B 5 (90 mg, 89%) as colourless
orthorhombic crystals, mp 179–1818C (EtOAc–hexane);
[Found: C, 71.92; H, 8.80. C15H22O3 (250.33) requires C,
71.97; H, 8.86%]; Rf (20% EtOAc–n-hexane) 0.55;
[a]2D5¼258.58 (c, 0.4, CHCl3); nmax(KBr) 1768 cm21; dH
(300 MHz, CDCl3, assignment by 1H–1H COSY) 2.85 (1H,
4.5. Acetylation
To a solution of 100 mg of the major product (mixture of
two alcohols) in dry pyridine (1.0 mL), Ac2O (2.0 mL) was
added and the reaction mixture was left at room temperature
for overnight. The reaction mixture was diluted with H2O
(100 mL) and extracted with CH2Cl2 (3£150 mL), dried
(Na2SO4) and evaporated under vacuum. The traces of
pyridine were removed by co-distillation with toluene to

A. K. Bhattacharya et al. / Tetrahedron 59 (2003) 2871–2876
2875
afford a residue, which on TLC (20% EtOAc–hexane)
4.6. Hydrogenation of (8b)
showed two spots and these were isolated by preparative
TLC (20% EtOAc–hexane, double run). The less polar
major product was obtained as a solid (83 mg), mp 120–
1228C (EtOAc–hexane) and was identified as the acetate 9b
A solution of 8b (50 mg, 0.17 mmol) in dry EtOH (25 mL)
and 10% Pd–C (200 mg) was hydrogenated as discussed
above. After 3 h when no starting material was left, the
reaction was worked up as given above to furnish 10
(48 mg, 96%).
1
by direct comparison (TLC, co-TLC, mp, mixed mp, H
NMR and MS) with its authentic sample.5 The more polar
minor product 8b was also obtained as a colourless solid
(10 mg), mp 86–878C (EtOAc–hexane).
4.7. Reaction of (9b) with Ni2B
4.5.1. Ketone (7). Colourless oil; [Found: C, 71.92; H, 8.82.
C15H22O3 (250.33) requires C, 71.97; H, 8.86%]; Rf (10%
To solution of 9b (100 mg, 0.34 mmol) in dry diglyme
(3 mL), NiCl2·6H2O (400 mg, 1.69 mmol) was added and
the reaction mixture was stirred at room temperature. After
5 min, NaBH4 (200 mg, 5.26 mmol) was added in portions
over a period of 30 min and the reaction was monitored by
TLC. After 2 h of addition of NaBH4, reaction mixture was
diluted with H2O (100 mL) and extracted with CH2Cl2
(3£100 mL), dried (Na2SO4) and evaporated to dryness.
The residue after preparative TLC (10% EtOAc–hexane)
furnished 11 (12 mg, 15%) as gum and 9b (86 mg) was
obtained as unreacted starting material.
EtOAc–n-hexane) 0.75;
nmax(CHCl3) 2928, 1778,
1723 cm21; dH (400 MHz, CDCl3) 2.95 (1H, m, 4-H),
2.83 (1H, m, 11-H), 1.16 (3H, d, J¼7 Hz, 13-CH3), 0.98
(3H, d, J¼7 Hz, 15-CH3), 0.90 (3H, d, J¼7 Hz, 14-CH3).
Irradiation of signal at d 1.16 (3H, d, J¼7 Hz, 13-CH3)
collapsed the multiplet at d 2.83 (11-H) into a doublet
(J¼13.4 Hz); dH (200 MHz, C6D6) 2.81 (1H, m, 11-H or
4-H), 2.04 (1H, m, 11-H or 4-H), 1.06 (3H, d, J¼7 Hz,
13-CH3), 0.95 (3H, d, J¼7 Hz, 15-CH3), 0.62 (3H, d,
J¼7 Hz, 14-CH3); m/z (EI) 250 (Mþ), 222, 207, 192, 179,
165 (100), 151, 137, 123, 109, 95, 81, 69, 55, 42.
4.7.1. Compound (11). Gum; [Found: C, 76.84; H, 9.43.
C15H22O2 (234.34) requires C, 76.88, H, 9.46%]; Rf (20%
EtOAc–n-hexane) 0.45; nmax(CHCl3) 1747 cm21; dH
(80 MHz, CDCl3) 5.35 (1H, brs, 3-H), 1.50 (3H, brs, 15-
CH3), 1.20 (3H, d, J¼7 Hz, 13-CH3), 0.90 (3H, d, J¼7 Hz,
14-CH3); m/z(EI) 234 (Mþ), 219, 206 and 204.
4.5.2. Acetate (8b). Colourless crystals, mp 86–878C
(EtOAc–hexane); [Found: C, 69.80; H, 8.24. C17H24O4
(292.37) requires C, 69.84; H, 8.27%]; Rf (20% EtOAc–n-
hexane) 0.30; nmax (KBr) 1780 (CO of lactone), 1736 cm21
(CO of acetate); dH (400 MHz, CDCl3) 5.85 (1H, s, 5-H),
4.90 (1H, s, 15-Ha), 4.67 (1H, s, 15-Hb), 2.60 (1H, m, 11-H),
2.15 (3H, s, OCOCH3), 1.18 (3H, d, J¼7 Hz, 13-CH3), 0.98
(3H, d, J¼7 Hz, 14-CH3); dC (100.6 MHz, CDCl3, assign-
ment by DEPT NMR experiment) 179.6 (s, C-12), 169.0 (s,
OCOCH3), 141.8 (s, C-4), 108.4 (t, C-15), 86.6 (s, C-6),
72.6 (d, C-5), 56.2 (d), 50.8 (d), 38.9 (d), 35.5 (t), 30.8 (d),
28.9 (t), 23.8 (t), 22.9 (t), 21.1 (q, OCOCH3), 19.9 (q), 15.2
(q); m/z (EI) 292 (Mþ), 250, 233, 232, 204, 177, 176, 151
and 69.
4.7.2. Alkaline hydrolysis of (10). To a solution of 10
(100 mg, 0.34 mmol) in MeOH (5 mL), 10% KOH–MeOH
(0.5 mL) was added and the reaction mixture was stirred at
room temperature monitoring on TLC. After 7 h when no
starting material was left, it was diluted with 3% HCl
(3 mL). The aqueous layer was extracted with CH2Cl2
(3£100 mL), washed with dilute solution of NaHCO3, H2O,
dried (Na2SO4) and evaporated to furnish a residue which
on purification by preparative TLC (20% EtOAc–hexane)
furnished 12 (84 mg, 98%) as colourless oil; [Found: C,
71.34; H, 9.56. C15H24O3 (252.35) requires C, 71.39; H,
9.59%]; Rf (20% EtOAc–n-hexane) 0.35; nmax(CHCl3)
3468, 1714 cm21; dH (80 MHz, CDCl3) 4.50 (1H, d,
J¼8 Hz, 5-H), 1.26 (3H, d, J¼7 Hz, 13-CH3), 1.10 (3H, d,
J¼7 Hz, 15-CH3), 0.90 (3H, d, J¼7 Hz, 14-CH3); m/z (EI)
252 (Mþ), 234, 223, 195, 177, 160, 124, 109, 96, 84, 69, 55,
42.
4.5.3. Hydrogenation of (9b). A solution of 9b (100 mg,
0.34 mmol) in dry EtOH (25 mL) was hydrogenated in the
presence of 10% Pd–C (300 mg) in a Parr shaker type
hydrogenator with H2 pressure at 50 psi for 5 h and the
reaction was monitored on TLC. After 5 h when no starting
material was left in the reaction mixture, catalyst was
filtered out and the solvent evaporated to furnish 10 (98 mg,
97%) as colourless crystals, mp 65–678C (EtOAc–hexane);
[Found: C, 69.32; H, 8.86. C17H26O4 (294.39) requires C,
69.36; H, 8.90%]; Rf (20% EtOAc–n-hexane) 0.40;
4.8. Hydrogenation of the mixture of (8a) and (9a)
n
max(KBr) 1780 (CO of lactone), 1739 cm21 (CO of
A solution of 8a and 9a (100 mg, mixture of two alcohols)
in dry EtOH (25 mL) was hydrogenated in the presence of
10% Pd–C (200 mg) with H2 pressure set at 50 psi as
discussed above. After 7 h when no starting material was
left, catalyst was filtered out and the solvent evaporated to
furnish 12 (98 mg, 97%) as colourless oil, which was
identified on the basis of comparison with the authentic
sample (TLC, co-TLC, IR, NMR and MS).
acetate); dH (300 MHz, CDCl3) 5.39 (1H, d, J¼5.7 Hz, 5-
H of major), 5.26 (1H, d, J¼11.1 Hz, 5-H of minor), 2.52
(1H, m, 4-H or 11-H), 2.26 (1H, m, 4-H or 11-H), 2.04
(3H, s, OCOCH3), 1.13 (3H, d, J¼6.9 Hz, 13-CH3), 1.07
(3H, d, J¼7.2 Hz, 15-CH3), 0.91 (3H, d, J¼6.0 Hz, 14-
CH3); dC (75.5 MHz, CDCl3, assignment by DEPT NMR
experiment) 179.6 (s, C-12), 169.3 (s, OCOCH3), 85.8 (s,
C-6), 71.8 (d, C-5), 57.3 (d), 50.5 (d), 38.9 (d), 35.5 (t),
32.0 (d), 30.4 (d), 24.7 (t), 22.6 (t), 21.4 (q, OCOCH3),
19.8 (q), 17.9 (t), 15.4 (q), 14.0 (q); m/z (EI) 294 (Mþ),
266, 252, 238, 234, 220, 219, 206, 192 (100), 178, 165,
161, 109, 103, 83, 69, 54, 43; m/z (FAB) 295 [M þ H]þ,
251, 235.
Acknowledgements
The authors are grateful to the Director, CIMAP, Lucknow

2876
A. K. Bhattacharya et al. / Tetrahedron 59 (2003) 2871–2876
12. Lin, X.; Zhang, S.; Wu, S. Huaxue Xuebao (Acta Chim.
Sinica.) 1984, 42, 105–107.
for providing the necessary facilities for this work. The
authors are thankful to the referees for valuable suggestions.
13. Fan, Z. Youji Huaxue (J. Org. Chem.) 1984, 25–27.
14. Bhattacharya, A. K.; Jain, D. C.; Sharma, R. P. J. Chem. Res.
(S) 1998, 768–769, and references cited therein.
15. Bhattacharya, A. K.; Sharma, R. P. J. Ind. Chem. Soc. 1998,
75, 568–574.
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