Synthesis and absolute configuration of (-)-chettaphanin I and (-)-chettaphanin II

Article abstract of DOI:10.1016/S0040-0(02)01564-8

An efficient synthesis of chettaphanin I and II has been achieved from ent-halimic acid. The absolute configuration of the natural products was established by nOe experiment and by X-ray analysis of chettaphanin II.

Full text of DOI:10.1016/S0040-0(02)01564-8

Tetrahedron 59 (2003) 685–694
Synthesis and absolute configuration of (2)-chettaphanin I
and (2)-chettaphanin II
*
I. S. Marcos, F. A. Hernandez, M. J. Sexmero, D. Dıez, P. Basabe, A. B. Pedrero, N. Garcıa
´
´
and J. G. Urones
´
´ ´ ´
Departamento de Quımica Organica, Facultad de Ciencias Quımicas, Universidad de Salamanca,
´
Plaza de los Caıdos 1-5, 37008 Salamanca, Spain
Received 17 June 2002; revised 2 October 2002; accepted 26 November 2002
Abstract—An efficient synthesis of chettaphanin I and II has been achieved from ent-halimic acid. The absolute configuration of the natural
products was established by nOe experiment and by X-ray analysis of chettaphanin II. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
The ent-halimans constitute a family of bicyclic diterpenes
with a rearranged ent-labdane skeleton. Scarcely a hundred
compounds from this family are known.1 Chettaphanin I
and II, isolated from Adenochlaena siammensis Ridl
(Euphorbiaceae) in 19702 and 1971,3 are the first known
compounds of this class. Both compounds are the main
components of ‘chettaphangki’ a digestive remedy used in
folk medicine in Thailand. The structure of chettaphanin I
and II were determined spectroscopically, chemically
correlated and corroborated by X-ray crystallography of
derivatives, the absolute configuration remaining unknown.
Recently we have reported the synthesis and absolute
2. Results and discussion
configuration of chettaphanin II.4
In order to synthesize chettaphanin I 2 and chettaphanin II 3
from ent-halimic acid 1, it is necessary to functionalize C2
Chettaphanin I and II are furanoditerpenoids that show
and C12 and to introduce a furyl group in the side chain;
functionalization at the same carbons, with the main
furthermore, for the synthesis of 2 it is necessary to
characteristic of chettaphanin II being the double bond
introduce a hydroxyl group on C5.
between C1 and C12 of the ent-haliman skeleton that forms a
third carbon ring.
In this paper, we report the synthesis of chettaphanin I and
II, starting from ent-halimic acid (the main component of
Halimium viscosum (Villarino de los Aires) and a bicyclic
diterpene of known absolute configuration5 with an ent-
halimane skeleton), confirming the structures and establish-
ing the absolute configuration of the natural products. The
ent-halimic acid has been used previously in the synthesis
of ent-halimanolides6 and sesterterpenolide6 analogues of
disidyolide7 with interesting anti-tumour activity.
Keywords: chettaphanin I and II; ent-halimic acid; absolute configuration.
*
Corresponding author. Tel.: þ34-923294474; fax: þ34-923294574;
e-mail: ismarcos@usal.es
Scheme 1.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01564-8

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I. S. Marcos et al. / Tetrahedron 59 (2003) 685–694
Scheme 2. (a) OsO4, NMO, t-BuOH/THF/H2O (7/2/1), 20 h; (b) LTA, C6H6, 20 min; (c) Na2CrO4, Ac2O/AcOH, NaOAc, C6H6, 608C, 15 h; (d) UHP/TFAA,
CH2Cl2, 1 h; (e) ethylene glycol, p-TsOH, C6H6, reflux, 8 h; (f) 3% K2CO3 in MeOH, 2 h; (g) PDC, DMF, 3 h.
Scheme 1 shows the retrosynthesis for 2 and 3 from ent-
halimic acid 1 through intermediate 18. The furan ring of
the side chain was added to a tetranor derivative 12 of ent-
halimic acid 1. The following steps describe the synthesis of
intermediates 12 and 18 and transformation of the latter
compound into 2 and 3.
saponification of 10 with K2CO3 in MeOH gave alcohol 11
in 100% global yield for two steps. Oxidation of 11 with
PDC in DMF12 gave aldehyde 12 in an excellent 98% yield.
2.2. Synthesis of the furan intermediate 18
Treatment of 12 with 3-bromofurane/nBuLi at 2788C led to
different results depending on the stoichiometry of the
reaction for the synthesis of the furyl-lithium species.13
2.1. Degradation of the side chain and functionalization
of A ring
The synthesis of 12 (Scheme 2), starting from 1, requires the
degradation of the side chain by four carbon atoms and
oxidation of ring A at C2. This has been achieved in a high
yield in six steps.
When the reaction is performed with a 3-bromofurane/
nBuLi (2/1) ratio, at 2788C, a mixture of bromohydroxy-
derivatives, epimers at C12 in 13/14, was obtained, and
could be separated by column chromatography (Scheme 3).
TPAP/NMO14 oxidation of 13 and 14 gives the same ketone
15 in quantitative yield.
The first two carbons were eliminated using the sequence of
oxidation by OsO48 followed by treatment with Pb(OAc)4.9
The oxidation of the methyl ester of ent-halimic acid 4 with
OsO4 was totally regioselective, only the side chain double
bond reacting. The resulting triol was oxidized with LTA,
giving ketone 5 in a 94% global yield for the two steps. The
oxidation of 5 with Na2CrO4 in presence of Ac2O/NaOAc10
at 608C gives the a,b-unsaturated ketone 6 (64%) and the
minor products 7 (4%) and 8 (5%). The configuration at C2
of 7 and 8 was established by nOe differential. The NMR 1H
signal of 8 centered at 5.31 ppm, corresponding to the
geminal hydrogen at the secondary acetoxyl group in C2,
shows an nOe with methyls 19 and 20 that are on the a side
of the molecule, so the acetoxyl group of 8 is b and the
configuration of C2 in 8 is R.
The NMR 1H spectra for 13 and 14, are very similar and in
both only signals corresponding to two aromatic hydrogens
appear, so the aromatic fragment should have the bromine in
it. The metalation position was fixed by nOe experiments;
1
on irradiation of the signal at 7.32 ppm in the H NMR
spectrum of 13 a nOe was observed with the signal at
6.36 ppm; so both hydrogens are adjacent, and the
metalation has taken place at C2 in the 3-bromofurane.
The C12 configuration of 13 and 14 was proposed by
comparison with the NMR 1H spectra of hyrtiosal15 and its
epimer at C16. Epimers with S configuration in the carbon
that has the secondary hydroxyl group show signals at
higher field.
The remaining two carbons of the side chain were
eliminated by a Bayer–Villiger reaction of 6 using
trifluoroacetic acid anhydride in presence of urea-hydro-
peroxide11 to give 9 in 61% yield.
When the stoichiocometry of the metalation of 3-bromo-
furane with nBuLi is 1/1, at 2788C, and aldehyde 12 is
added later on, the mixture of the hydroxyderivatives 16/17
is obtained quantitatively (Scheme 3).
1
In order to introduce the furan ring fragment in the side
chain by means of an organometallic reagent, it was
necessary to protect the carbonyl group at C2 as a dioxolane.
This was achieved by reaction of 9 with ethylene glycol in
acidic media, giving a mixture of 10 and 11. Subsequent
The fundamental difference in the NMR H spectra of 16
and 17 with those of 13 and 14 is the presence in this case of
three aromatic hydrogens instead of two. This indicates
that metalation has taken place in position 3 of the furan
ring as expected. The configuration of 16 and 17 at C12 was

I. S. Marcos et al. / Tetrahedron 59 (2003) 685–694
687
Scheme 3. (a) 3-Bromofurane, nBULi, (2/1), 2788C, 30 min; (b) TPAP/NMO; (c) 3-bromofurane, nBULi, (1/1), 2788C, 30 min; (d) TPAP/NMO; (e) p-TsOH,
acetone, 5 h, rt.
proposed as in the above case, by comparison of the NMR
1H spectra of 16 and 17 with hyrtiosal and its epimer.
Oxidation of 16 and 17 with TPAP/NMO gives the same
ketone 18.
formation at C10 and by loss of a proton at C1 to give a
double bond conjugated with the carbonyl on C2. The
opening of the epoxide takes place with retention of the
configuration at C5.
1
2.3. Synthesis of chettaphanin I and II
NMR H/13C studies, HMQC and HMBC of 22 make it
possible to assign all the hydrogens in the molecule, the
long-range signals corresponding to H1, H19, H3 with C5
being observed among others.
Treatment of 18 with p-TsOH led to 3 in a 72% yield
(Scheme 3). Physical properties of 3 were coincident with
those described in the literature for chettaphanin II,3 whose
structure has been confirmed by X-ray analysis.4
The configuration at C5 of 22 was established by nOe
1
experiments. In the NMR H of 22 in DMSO the signal
Treatment of 15 with p-TsOH led to 19 in a 72% yield, an
analogue of 3 that was synthesized in order to test its
biological activity.
corresponding to the hydrogen of the hydroxyl group at C5
was observed at 4.77 ppm. A nOe was observed between the
hydrogens of C18 at 3.34 and 3.25 ppm with one of the
hydrogens of C3, H3b. The irradiation of the signal at
4.77 ppm produces an increase in the signal of the other
hydrogen at C3, H3a, and a nOe was observed with Me20,
H7a and H6a. Hence, the hydroxyl group is a and the
configuration of C5 is S. As the opening of the epoxide takes
place with retention of the configuration at C5, the
epoxidation must have been stereoselective on the a side.
The methodology used for the synthesis of 22 will be used
for the synthesis of 2.
The synthesis of the most interesting feature of chettaphanin
I, an hydroxyl group g to an a,b-unsaturated carbonyl in the
bianular system, was tested in a model as 20, previously
obtained from 6, in a parallel study in our laboratory,16 by
the successive reactions of protection of ketone groups,
reduction of the ester and protection of the hydroxyl group
with MOM (Scheme 4). Epoxidation with m-CPBA of 20
stereoselectively gives epoxide 21, which on treatment
under acidic conditions produced the deprotection of both
carbonyl groups and opening of the epoxide to give ketone
22, by protonation of the oxygen of the oxirane, carbocation
Treatment of 18 with m-CPBA (Scheme 5) led to 23 with an
excellent yield. Opening of the epoxide was tested under
Scheme 4. (a) 1. Ethylene glycol, p-TsOH, C6H6, reflux, 8 h; 2. LAH, Et2O, 1.5 h; 3. DMM, BrLi, p-TsOH, 12 h, rt; (b) m-CPBA, Cl2CH2, 30 min, rt;
(c) p-TsOH, acetone, 2 h, rt.

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I. S. Marcos et al. / Tetrahedron 59 (2003) 685–694
Scheme 5. (a) m-CPBA, Cl2CH2, 12 h, rt; (b) p-TsOH, acetone, 5 h, rt or HClO4, 3 h, rt.
different conditions. Reaction of 23 with p-TsOH give
a mixture of 2 (30%), 24 (35%) and 25 (30%) that was
separated by column chromatography. When 23 was treated
with HClO4 (63%) at rt the same mixture was obtained in
similar proportions.
of compound 22 in the nOe studies. By irradiation of the
signal at 5.01 ppm, an increase of the signal at 2.60 ppm was
observed, corresponding to the hydrogen H3a and the Me20
signal at 1.20 ppm. This nOe establishes the position of the
hydroxyl as a and so C5 has the S configuration. Physical
properties of 2 were coincident with those described in
the literature for chettaphanin I,2 so the natural product has
the absolute configuration shown in the figures.
Compound 24 come from deprotection of the carbonyl on
C2 of 23.
Compound 25 shows in its NMR 13C spectrum an
hemiacetalic carbon (d: 105.4 ppm) and in the H NMR,
Opening of the epoxide of 23 takes place with retention
of the configuration at C5, so the epoxidation has been
stereoselective for the a side and epoxide 23 has a 5R,10R
configuration.
1
H16 is shielded with respect to the equivalent proton of 23,
so C12 in 25 is not a carbonyl but a hemiacetal, due to its
participation in the opening of the epoxide. (Fig. 1). The
structure for 25 was corroborated by HMQC and HMBC
experiments. For example H11 is correlated with carbons
C12(105.4), C13(129.1), C9(48.8), C10(90.4) and C8(34.9).
The configuration at C12 corresponds to the more stable one
based on stereoelectronic effects. It was not possible to do
further studies due to instability.
So (2)-chettaphanin I and (2)-chettaphanin II absolute
configuration has been established.
3. Experimental
Unless otherwise stated, all chemicals were purchased as
the highest purity commercially available and were
used without further purification. Melting points were
determined with a Kofler hot stage melting point apparatus
and are uncorrected. IR spectra were recorded on a
Compound 2 shows in its 13C NMR (CDCl3) signals
corresponding to two conjugated carbonyls at (197.6 and
190.8 ppm) and only one tetrasubstituted sp3 carbon bonded
to oxygen (d: 72.7) corresponding to C5, while at 125.6
(d) and 167.4 (s) ppm signals appear corresponding to the
conjugated double bond to the carbonyl at C2. Spectroscopic
data suggest that the opening of the oxirane has taken place
and has produced the desired group of conjugated carbonyl
with an hydroxyl in the g position. The 1H/13C, HMQC and
HMBC experiments corroborate this. The quaternary carbon
at 72.7 ppm of C5, is correlated with the olefinic hydrogen
H1, with the methylene of C3 and with Me19 establishing
the annular functionalization and so the structure of 2.
The absolute configuration of C5 was established by nOe
experiments
1
BOMEM 100 FT IR spectrophotometer. H and 13C NMR
spectra were performed in deuterochloroform and refer-
enced to the residual peak of CHCl3 at 7.26 and 77.0 ppm,
for 1H and 13C, respectively, with a Bruker WP-200 SY or a
BRUKER DRX 400 MHz spectrometer. Chemical shifts are
reported in ppm and coupling constants (J) are given in Hz.
MS were performed with a VG-TS 250 spectrometer with
70 eV ionizing voltage. Mass Spectra are presented as m/z
(% rel. int.). HRMS were recorded at a VG Platform
(Fisons) spectrometer using Chemical Ionization (ammonia
as gas). Optical rotations were determined with a Perkin–
Elmer 241 polarimeter in 1 dm cells. Diethyl ether, THF and
benzene were distilled from sodium, and pyridine and
dichloromethane were distilled from calcium hydride under
an Ar atmosphere.
1
The H NMR spectrum for 2 was done in DMSO and the
signal for the hydrogen of the hydroxyl group observed at
5.01 ppm, this being analogous to the equivalent hydrogen
Figure 1.

I. S. Marcos et al. / Tetrahedron 59 (2003) 685–694
689
3.1. Reaction of 4 with OsO4/LTA: 5
38.3 (C12), 208.1 (C13), 29.8 (C16), 15.6 (C17), 176.6 (C18),
21.9 (C19), 20.6 (C20), 52.2 (–COOMe); EIMS: 320 (Mþ,
13), 219(9), 189(16), 43(18), 153(35), 121(57), 77(100);
EIHRMS: calcd for C19H28O4 (Mþ) 320.1988, found (Mþ)
320.1978; Anal. calcd for C19H28O4: C, 71.21; H, 8.81,
found: C, 71.07; H, 8.92.
To a solution of ent-halimic methyl ester 4 (6.82 g,
20.4 mmol) in t-BuOH/THF/H2O (7/2/1, 200 ml) was
added N-methylmorpholine N-oxide (NMO) (8.27 g,
61.2 mmol) and a solution of OsO4 2.5% (1.1 ml,
0.01 mmol) in t-BuOH. The reaction mixture was stirred
at room temperature for 20 h and a saturated aqueous
solution of Na2SO3 (100 ml) was added. Extraction with
AcOEt, followed by successive washing of the organic layer
with a 10% aqueous Na2S2O3 solution, 2N aqueous HCl
solution, water and brine. The organic layer was dried and
evaporated to yield the expected mixture of hydroxy
derivatives (7.49 g, 99%): IR (film): 3439, 1728 cm21. To
a solution of the hydroxy derivatives (7.19 g, 19.5 mmol) in
benzene (100 ml) was added LTA (19.3 g, 43.6 mmol). The
reaction mixture was stirred at room temperature for 20 min
and then filtered off through celite. The solution was diluted
with AcOEt and washed with a 6% aqueous solution of
NaHCO3, water and brine and then dried and evaporated to
give a crude orange oil which was chromatographed on
silica gel (hexane/AcOEt, 9/1) to give the expected ketone 5
(5.67 g, 94%).
3.2.2. Methyl 2a-acetoxy-13-oxo-14,15-dinor-1(10)-ent-
halimen-18-oate (7). [a]2D2¼þ18.08 (c¼0.1, CHCl3); IR
(film): 1732, 1456, 1375, 1238, 1157, 1119, 1020 cm21; 1H
NMR d: 5.37–5.31 (1H, m, H2), 5.20 (1H, s, H1), 3.63 (3H,
s, –COOMe), 2.85 (1H, dd, J¼12.6, 4.3 Hz, H5), 2.5–1.9
(4H, m), 2.12 (3H, s, Me16), 2.04 (3H, s, MeCOO–),
1.7–1.1 (7H, m), 1.12 (3H, s, Me19), 0.84 (3H, s, Me20),
0.80 (3H, d, J¼7.0 Hz, Me17); 13C NMR d: 120.7 (C1), 69.1
(C2), 33.3 (C3), 44.6 (C4), 38.1 (C5), 23.9 (C6), 28.6 (C7),
39.8 (C8), 43.2 (C9), 146.6 (C10), 32.0 (C11), 38.6 (C12),
209.5 (C13), 29.7 (C16), 15.5 (C17), 177.1 (C18), 21.6
(C19), 21.3 (C20), 51.9 (–COOMe), 21.3 (MeCOO–), 170.7
(MeCOO–); EIMS: 364 (Mþ, 5), 322(7), 262(23), 233(40),
173(100), 105(51); EIHRMS: calcd for C21H32O5 (Mþ)
364.2250, found (Mþ) 364.2261.
3.2.3. Methyl 2b-acetoxy-13-oxo-14,15-dinor-1(10)-ent-
halimen-18-oate (8). Mp: 968C (n-Hexane); [a]2D2¼þ85.48
(c¼0.5, CHCl3); IR (film): 1732, 1456, 1375, 1238, 1130,
1018 cm21; 1H NMR d: 5.34–5.28 (2H, m, H1 and H2), 3.64
(3H, s, –COOMe), 2.70 (1H, dd, J¼12.6, 4.3 Hz, H5), 2.5–
1.8 (4H, m), 2.16 (3H, s, Me16), 2.01 (3H, s, MeCOO–),
1.7–1.1 (7H, m), 1.16 (3H, s, Me19), 0.90 (3H, s, Me20),
0.78 (3H, d, J¼7.0 Hz, Me17); 13C NMR d: 119.4 (C1), 68.1
(C2), 36.4 (C3), 44.1 (C4), 38.3 (C5), 22.9 (C6), 27.9 (C7),
38.5 (C8), 42.8 (C9), 146.6 (C10), 32.6 (C11), 38.7 (C12),
209.3 (C13), 29.9 (C16), 15.5 (C17), 177.0 (C18), 19.6
(C19), 21.3 (C20), 51.8 (–COOMe), 21, 3 (MeCOO–), 170.6
(MeCOO–); EIMS: 364 (Mþ, 2), 233(42), 173(100),
105(51); EIHRMS: calcd for C21H32O5 (Mþ) 364.2250,
found (Mþ) 364.2259.
3.1.1. Methyl 13-oxo-14,15-dinor-1(10)-ent-halimen-18-
oate (5). [a]2D2¼þ101.68 (c¼1.25, CHCl3); IR (film):
1
1726 cm21; H NMR d: 5.33–5.27 (1H, m, H1), 3.61 (3H,
s, –COOMe), 2.61 (1H, dd, J¼12.6, 4.3 Hz, H5), 2.4–1.9
(5H, m), 2.12 (3H, s, Me16), 1.8–1.2 (8H, m), 1.07 (3H, s,
Me19), 0.83 (3H, s, Me20), 0.76 (3H, d, J¼7.0 Hz, Me17);
13C NMR d: 120.2 (C1), 23.1 (C2), 29.8 (C3), 44.9 (C4), 38.2
(C5), 23.3 (C6), 28.6 (C7), 39.0 (C8), 42.7 (C9), 141.3 (C10),
32.6 (C11), 38.9 (C12), 209.5 (C13), 29.8 (C16), 15.6 (C17),
178.1 (C18), 21.0 (C19), 22.1 (C20), 51.5 (–COOMe); EIMS:
306 (Mþ218, 12), 229(42), 213(14), 175(100), 119(28),
105(41), 91(27); EIHRMS: calcd for C19H30O3 (Mþ)
306.2195, found (Mþ) 306.2202.
3.2. Reaction of 5 with Na2CrO4: 6–8
3.3. Reaction of 6 with UHP/TFAA: 9
Na2CrO4 (776 mg, 4.80 mmol), acetic anhydride (7.0 ml),
acetic acid (3.8 ml) and NaOAc (572 mg) was added to a
solution of ketone 5 (844 mg, 2.64 mmol) in benzene (6 ml)
and stirred at 608C for 15 h. The reaction mixture was then
treated with ice, extracted with Et2O and washed with a 10%
aqueous solution of Na2CO3, water and brine. The organic
layer was dried and evaporated to give a crude oil which
was chromatographed on silica gel (hexane/AcOEt,
8/2!7/3!6/4) to give 5 (126 mg, 16%), the acetoxy
derivates 7 (40 mg, 4%) and 8 (50 mg, 5%) and the
expected compound 6 (540 mg, 64%).
To an ice cooled suspension of a,b-unsaturated ketone 6
(123 mg, 0.384 mmol) and UHP (890 mg, 9.45 mmol) in
anhydrous DCM (6 ml), TFAA (0.29 ml, 2.05 mmol) was
added under argon. The reaction mixture was stirred for 1 h,
quenched via a very carefully dropwise addition of a 40%
aqueous solution of NaHSO3 and stirred for 1.5 h.
Extraction with Et2O, washing with a 6% aqueous solution
of NaHCO3 and water followed by drying and evaporation
of the solvent left a crude yellow oil. Purification by
flash chromatography on silica gel (hexane/AcOEt, 8/2!
7/3!6/4) allowed the separation of the expected acetate 9
as a colourless oil (79 mg, 61%) and starting material 6
(32 mg, 26%).
3.2.1. Methyl 2,13-dioxo-14,15-dinor-1(10)-ent-halimen-
18-oate (6). Mp: 838C (n-hexane/Et2O, 99/1); [a]2D2¼
þ186.08 (c¼1.07, CHCl3); UV (EtOH): 238 nm; IR (film):
1726, 1667, 1613, 1462, 1381, 1111 cm21; 1H NMR d: 5.79
(1H, s, H1), 3.62 (3H, s, –COOMe), 2.99 (1H, dd, J¼12.6,
4.3 Hz, H5), 2.70 (1H, d, JAB¼16.1 Hz, H3A), 2.5–2.0 (2H,
m), 2.27 (1H, d, JAB¼16.1 Hz, H3B), 2.12 (3H, s, Me16),
1.9–1.7 (2H, m), 1.6–1.3 (5H, m), 1.21 (3H, s, Me19), 0.94
(3H, s, Me20), 0.79 (3H, d, J¼6.9 Hz, Me17); 13C NMR d:
125.1 (C1), 196.5 (C2), 42.9 (C3), 46.3 (C4), 40.8 (C5), 23.5
(C6), 28.2 (C7), 40.7 (C8), 44.8 (C9), 169.1 (C10), 32.2 (C11),
3.3.1. Methyl 12-acetoxy-2-oxo-13,14,15,16-tetranor-
1(10)-ent-halimen-18-oate (9). [a]2D2¼þ1108 (c¼1.17,
CHCl3); UV (EtOH): 240 nm; IR (film): 1738, 1240,
1
1678 cm21; H NMR d: 5.84 (1H, s, H1), 4.10–3.93 (1H,
m, H12A), 3.89–3.70 (1H, m, H12B), 3.65 (3H, s, –COOMe),
3.10 (1H, dd, J¼12.4, 4.8 Hz, H5), 2.73 (1H, d, JAB
¼
16.1 Hz, H3A), 2.27 (1H, d, JAB¼16.1 Hz, H3B), 2.4–2.1
(2H, m), 2.03 (3H, s, MeCOO–), 1.9–1.7 (2H, m), 1.6–1.3

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I. S. Marcos et al. / Tetrahedron 59 (2003) 685–694
(3H, m), 1.23 (3H, s, Me19), 1.05 (3H, s, Me20), 0.80 (3H, d,
J¼7.5 Hz, Me17); 13C NMR d: 125.0 (C1), 196.7 (C2), 43.3
(C3), 46.4 (C4), 40.8 (C5), 23.4 (C6), 28.2 (C7), 40.4 (C8),
44.1 (C9), 168.1 (C10), 37.3 (C11), 61.2 (C12), 15.2 (C17),
176.6 (C18), 21.6 (C19), 20.9 (C20), 52.5 (–COOMe),
170.8 (MeCOO–), 21.4 (MeCOO–); EIMS: 336 (Mþ,
17), 256(8), 217(59), 189(29), 161(28), 121(34), 91(40),
69(100); EIHRMS: calcd for C19H28O5 (Mþ) 336.1937,
found (Mþ) 336.1928.
water and then dried and evaporated to yield the expected
compound 11 (89 mg, 100%).
3.6. Oxidation of 11 with PDC: 12
To a solution of alcohol 11 (154 mg, 0.456 mmol) in DMF
(8 ml), pyridinium dichromate (1.82 g, 4.54 mmol) was
added. The reaction mixture was stirred for 3 h and then
water (10 ml) was added. Extraction with Et2O, followed by
washing with water, dried and evaporation of the organic
layer yielded 12 (oil, 68 mg, 98%).
3.4. Reaction of 9 with p-TsOH: 10 and 11
Acetate 9 (635 mg, 1.89 mmol) dissolved in benzene
(35 ml), was refluxed in the presence of p-toluenesulfonic
acid (10 mg, 0.06 mmol) and ethylene glycol (2.1 ml,
excess) at 1388C for 8 h. The solution was diluted with
Et2O and washed with a 6% aqueous solution of NaHCO3
and water. Evaporation of the solvent followed by
chromatography on silica gel (hexane/AcOEt, 7/3!6/4)
yielded the desired compound 10 (oil, 546 mg, 76%) and the
11 (oil, 150 mg, 24%).
3.6.1. Methyl 2-ethylenedioxy-12-oxo-13,14,15,16-tetra-
nor-5(10)-ent-halimen-18-oate (12). [a]2D2¼þ2.18 (c¼
0.95, CHCl3); IR (film): 1734, 1717, 1456, 1375, 1238,
1152, 1078, 1032 cm21; 1H NMR d: 9.63 (1H, s, H12), 4.0–
3.8 (4H, m, –OC2H4O–), 3.60 (3H, s, –COOMe), 2.6–2.2
(5H, m, H11, H1 and H3A), 2.1–1.9 (1H, m), 1.62 (1H, d,
J¼13.2 Hz, H3B), 1.8–1.6 (2H, m), 1.4–1.2 (2H, m), 1.31
(3H, s, Me19), 0.96 (3H, s, Me20), 0.88 (3H, d, J¼6.7 Hz,
Me17); 13C NMR d: 36.4 (C1), 107.2 (C2), 42.2 (C3), 48.8
(C4), 131.3 (C5), 24.5 (C6), 26.2 (C7), 36.4 (C8), 40.1 (C9),
131.7 (C10), 51.2 (C11), 204.3 (C12), 15.7 (C17), 177.0 (C18),
23.9 (C19), 21.1 (C20), 51.9 (–COOMe), 64.3 and 64.1
(–OC2H4O–); EIMS: 336 (Mþ, 6), 259(14), 233(38),
173(29), 153(22), 129(27), 105(45), 77(100); EIHRMS:
calcd for C19H28O5 (Mþ) 336.1937, found (Mþ) 336.1916.
3.4.1. Methyl 12-acetoxy-2-ethylenedioxy-13,14,15,16-
tetranor-5(10)-ent-halimen-18-oate (10). [a]2D2¼219.18
(c¼1.30, CHCl3); IR (film): 1738, 1462, 1371, 1238,
1080, 1032 cm21
;
1H NMR d: 4.2–3.8 (6H, m,
–OC2H4O– and H12), 3.63 (3H, s, COOMe), 2.41 (1H, d,
J¼13.2 Hz, H3A), 2.24 (2H, s, H1), 2.01 (3H, s, MeCOO–),
1.8–1.5 (4H, m), 1.72 (1H, d, J¼13.2 Hz, H3B), 1.5–1.2
(3H, m), 1.33 (3H, s, Me19), 0.88 (3H, s, Me20), 0.87 (3H,
d, J¼6.7 Hz, Me17); 13C NMR d: 35.8 (C1), 107.5 (C2),
42.0 (C3), 48.9 (C4), 130.9 (C5), 24.9 (C6), 26.5 (C7), 34.1
(C8), 39.8 (C9), 132.7 (C10), 35.6 (C11), 61.6 (C12), 15.9
(C17), 177.2 (C18), 23.7 (C19), 20.9 (C20), 51.9 (–COOMe),
170.9 (MeCOO–), 20.8 (MeCOO–), 64.3 and 64.1
(–OC2H4O–); EIMS: 380 (Mþ, 57), 321(11), 293(5),
261(73), 219(22), 153(33), 131(28), 107(48), 77(100);
EIHRMS: calcd for C21H32O6 (Mþ) 380.2199, found
(Mþ) 380.2191.
3.7. Reaction of 12 with 3-bromofuran/nBuLi: 13 and 14
A solution of 3-bromofuran (0.076 ml, 0.500 mmol) in THF
(1.5 ml) was treated dropwise with nBuLi (1.6 M in hexane,
0.16 ml, 0.250 mmol) at 2788C. After the reaction mixture
was stirred for 30 min at this temperature a solution of
aldehyde 12 (70 mg, 0.208 mmol) in dry THF (1.5 ml) was
added. The mixture was stirred for 1 h at 2788C and then
treated with a saturated NH4Cl aqueous solution, extracted
with Et2O and washed with a 6% aqueous solution of
NaHCO3 and water. Evaporation of the solvent followed by
chromatography on silica gel (hexane/AcOEt, 6/4) yielded
13 and 14 (92 mg, 92%).
3.4.2. Methyl 2-ethylenedioxy-12-hydroxy-13,14,15,16-
tetranor-5(10)-ent-halimen-18-oate (11). [a]2D2¼þ0.18
(c¼1.55, CHCl3); IR (film): 3447, 1734, 1458, 1375,
3.7.1. Methyl 14-bromo-13,15-epoxy-2-ethylendioxy-
12S-hydroxy-16-nor-15-homo-5(10),13,15-ent-hali-
matrien-18-oate (13). IR (film): 3470, 3123, 1732, 1464,
1377, 1242, 1078, 1032, 1011, 972, 883 cm21; 1H NMR d:
7.32 (1H, s, H15), 6.36 (1H, s, H15a), 5.04 (1H, dd, J¼9.1,
3.2 Hz, H12), 3.98–3.94 (4H, m, –OC2H4O–), 3.68 (3H, s,
–COOMe), 2.41 (1H, d, J¼13.2 Hz, H3A), 2.3–2.0 (4H, m,
H1 and H11), 1.8–1.6 (3H, m), 1.68 (1H, d, J¼13.2 Hz,
H3B), 1.4–1.2 (2H, m), 1.37 (3H, s, Me19), 0.94 (3H, s,
Me20), 0.92 (3H, d, J¼6.7 Hz, Me17).
1
1236, 1154, 1080, 1032 cm21; H NMR d: 4.0–3.8 (4H,
m, –OC2H4O–), 3.70–3.52 (2H, m, H12), 3.60 (3H, s,
–COOMe), 2.30 (2H, s), 2.28 (1H, d, J¼13.2 Hz, H3A),
2.0–1.8 (2H, m), 1.8–1.6 (4H, m), 1.65 (1H, d, J¼13.2 Hz,
H3B), 1.4–1.2 (1H, m), 1.30 (3H, s, Me19), 0.85 (3H, s,
Me20), 0.85 (3H, d, J¼6.6 Hz, Me17); 13C NMR d: 36.0
(C1), 107.4 (C2), 42.5 (C3), 48.7 (C4), 130.9 (C5), 25.0 (C6),
26.7 (C7), 35.0 (C8), 40.0 (C9), 133.3 (C10), 41.0 (C11), 59.6
(C12), 16.2 (C17), 177.5 (C18), 24.2 (C19), 21.5 (C20), 51.9
(–COOMe), 64.3 and 64.1 (–OC2H4O–); EIMS: 338 (Mþ,
29), 279(20), 219(18), 165(63), 131(22), 107(48), 77(100);
EIHRMS: calcd for C19H30O5 (Mþ) 338.2093, found (Mþ)
338.2086.
3.7.2. Methyl 14-bromo-13,15-epoxy-2-ethylendioxy-
12R-hydroxy-16-nor-15-homo-5(10),13,15-ent-hali-
matrien-18-oate (14). IR (film): 3470, 3123, 1732, 1464,
1377, 1242, 1078, 1032, 1011, 972, 883 cm21; 1H NMR d:
7.33 (1H, s, H15), 6.36 (1H, s, H15a), 5.06 (1H, dd, J¼10.1,
3.4 Hz, H12), 3.99–3.95 (4H, m, –OC2H4O–), 3.68 (3H, s,
–COOMe), 2.61 (1H, d, J¼13.2 Hz, H3A), 2.4–2.0 (4H, m,
H1 and H11), 1.82 (1H, d, J¼13.2 Hz, H3B), 1.8–1.7 (3H,
m), 1.4–1.2 (2H, m), 1.37 (3H, s, Me19), 0.92 (3H, s, Me20),
0.84 (3H, d, J¼6.7 Hz, Me17).
3.5. Hydrolysis of 10: 11
To 10 (100 mg, 0.263 mmol) a 3% solution of K2CO3 in
methanol (3 ml) was added. After 2 h the solvent was
evaporated and diluted with Et2O. The organic layer was
successive washed with a 2N aqueous solution of HCl and

I. S. Marcos et al. / Tetrahedron 59 (2003) 685–694
691
3.8. Oxidation of 13 and 14 with TPAP/NMO: 15
3.9.2. Methyl 15,16-epoxy-2-ethylenedioxy-12R-hydroxy-
5(10),13(16),14-ent-halimatrien-18-oate (17). [a]2D2¼
217.28 (c¼0.50, CHCl3); IR (film): 3500, 1730, 1464,
To a mixture of 13/14 (30 mg, 0.062 mmol), N-methylmor-
pholine N-oxide (16 mg, 0.122 mmol) and molecular sieves
(50 mg) in anhydrous DCM (2 ml), under argon, at room
temperature was added TPAP (4 mg, 0.012 mmol). The
reaction mixture was stirred for 30 min and then filtered
on silica gel and celite (EtOAc), the organic layer was
evaporated to yield the expected compound 15 (oil, 29 mg,
97%)
1
1377, 1159, 1089, 1030, 665 cm21; H NMR d: 7.38 (2H,
s, H15 and H16), 6.38 (1H, s, H14), 4.91 (1H, dd, J¼9.4,
2.3 Hz, H12), 4.0–3.8 (4H, m, –OC2H4O–), 3.65 (3H, s,
–COOMe), 2.6–2.0 (5H, m), 1.9–1.6 (3H, m), 1.4–1.2
(3H, m), 1.36 (3H, s, Me19), 0.91 (3H, s, Me20), 0.89 (3H, d,
J¼6.9 Hz, Me17); 13C NMR d: 36.1 (C1), 107.4 (C2), 42.9
(C3), 48.7 (C4), 132.0 (C5), 25.1 (C6), 26.9 (C7), 35.8 (C8),
40.6 (C9), 133.4 (C10), 47.7 (C11), 64.2 (C12), 130.0 (C13),
108.7 (C14), 138.4 (C15), 143.0 (C16), 16.4 (C17), 177.6
(C18), 24.5 (C19), 21.8 (C20), 52.1 (–COOMe), 64.6 and
64.3 (–OC2H4O–); EIMS: 404 (Mþ, 1), 293(12), 233(8),
161(5); EIHRMS: calcd for C23H32O6 (Mþ) 404.2199,
found (Mþ) 404.2193.
3.8.1. Methyl 14-bromo-13,15-epoxy-2-ethylendioxy-12-
oxo-16-nor-15a-homo-5(10),13,15a-ent-halimatrien-18-
oate (15). IR (film): 3123, 1732, 1674, 1549, 1476, 1377,
1
1244, 1155, 1076, 1034, 882, 735 cm21; H NMR d: 7.44
(1H, s, H15), 6.60 (1H, s, H15a), 3.95–3.91 (4H, m,
–OC2H4O–), 3.67 (3H, s, –COOMe), 3.11 and 3.00 (1H,
d, JAB¼15.1 Hz, H11), 2.39 (1H, d, J¼13.2 Hz, H3A), 2.30
(2H, d, J¼6.7 Hz), 2.13–2.10 (1H, m), 1.61 (1H, d, J¼
13.2 Hz, H3A), 1.5–1.2 (4H, m), 1.33 (3H, s, Me19), 1.03
(3H, s, Me20), 0.87 (3H, d, J¼6.9 Hz, Me17); 13C NMR d:
36.2 (C1), 107.4 (C2), 42.1 (C3), 48.5 (C4), 129.6 (C5), 23.2
(C6), 25.7 (C7), 33.3 (C8), 41.4 (C9), 131.9 (C10), 45.5 (C11),
188.9 (C12), 148.7 (C13), 106.2 (C14), 117.5 (C15a), 144.6
(C15), 15.3 (C17), 177.3 (C18), 24.0 (C19), 21.3 (C20),
51.9 (–COOMe), 64.2 and 64.1 (–OC2H4O–); EIHRMS:
calcd for C23H29BrO6 (Mþ) 481.3837, found (Mþ)
481.3830.
3.10. Reaction of 16/17 with TPAP: 18
To a mixture of 16/17 (15 mg, 0.037 mmol), N-methylmor-
pholine N-oxide (8 mg, 0.061 mmol) and molecular sieves
(25 mg) in anhydrous DCM (2 ml), under argon, at room
temperature was added TPAP (2 mg, 0.006 mmol). The
mixture reaction was stirred for 30 min and then filtered on
silica gel (EtOAc), the organic layer was evaporated to yield
the expected compound 18 (oil, 15 mg, 99%).
3.10.1. Methyl 15,16-epoxy-2-ethylenedioxy-12-oxo-
5(10),13(16),14-ent-halimatrien-18-oate (18). [a]2D2¼
269.58 (c¼0.90, CHCl3); UV (EtOH): 252, 215, 204 nm;
IR (film): 3138, 1728, 1669, 1562, 1510, 1462, 1377, 1240,
3.9. Reaction of 12 with 3-bromofuran/nBuLi: 16 and 17
1
A solution of 3-bromofuran (0.038 ml, 0.250 mmol) in THF
(1.5 ml) was treated dropwise with nBuLi (1.6 M in hexane,
0.16 ml, 0.250 mmol) at 2788C. After the reaction mixture
was stirred for 30 min at this temperature a solution of
aldehyde 12 (70 mg, 0.208 mmol) in dry THF (1.5 ml) was
added. The mixture was stirred for 1 h at 2788C and then
treated with a saturated NH4Cl aqueous solution, extracted
with Et2O and washed with a 6% aqueous solution of
NaHCO3 and water. Evaporation of the solvent followed by
chromatography on silica gel (hexane/AcOEt, 6/4) yielded
16 (oil, 38 mg, 54%) and 17 (oil, 25 mg, 36%).
1157, 1076, 999, 874 cm21; H NMR d: 8.04 (1H, s, H16),
7.39 (1H, s, H15), 6.75 (1H, s, H14), 3.95–3.79 (4H, m,
–OC2H4O–), 3.69 (3H, s, –COOMe), 2.95 and 2.79 (1H, d,
JAB¼14.4 Hz, H11), 2.36 (1H, d, J¼12.5 Hz, H3A), 2.30
(1H, d, J¼12.5 Hz, H1A), 2.10 (1H, d, J¼12.5 Hz, H1B),
2.1–1.9 (2H, m), 1.7–1.6 (2H, m), 1.3–1.2 (1H, m), 1.58
(1H, d, J¼12.5 Hz, H3B), 1.33 (3H, s, Me19), 1.05 (3H, s,
Me20), 0.87 (3H, d, J¼6.9 Hz, Me17); 13C NMR d: 36.6
(C1), 107.2 (C2), 42.1 (C3), 48.4 (C4), 131.9 (C5), 23.0 (C6),
25.7 (C7), 34.0 (C8), 41.0 (C9), 129.6 (C10), 48.5 (C11),
194.6 (C12), 129.4 (C13), 108.7 (C14), 143.9 (C15), 147.9
(C16), 15.3 (C17), 177.4 (C18), 24.2 (C19), 21.7 (C20), 51.9
(–COOMe), 64.3 and 64.1 (–OC2H4O–); EIMS: 402 (Mþ,
1), 292(100), 233(76), 173(25), 147(15), 95(62), 69(38);
EIHRMS: calcd for C23H30O6 (Mþ) 402.2042, found (Mþ)
402.2048.
3.9.1. Methyl 15,16-epoxy-2-ethylenedioxy-12S-hydroxy-
5(10),13(16),14-ent-halimatrien-18-oate (16). [a]2D2¼
þ4.68 (c¼0.80, CHCl3); IR (film): 3500, 1724, 1458,
1375, 1262, 1157, 1078, 1030, 665 cm21; 1H NMR d: 7.34
(2H, s, H15 and H16), 6.39 (1H, s, H14), 4.85 (1H, dd, J¼9.0
and 2.2 Hz, H12), 4.0–3.8 (4H, m, –OC2H4O–), 3.67 (3H,
s, –COOMe), 2.38 (1H, d, J¼12.5 Hz, H3A), 2.35 (1H, d,
J¼10.5 Hz, H1A), 2.15 (1H, d, J¼10.5 Hz, H1B), 2.00 (1H,
dd, J¼15.0, 9.4 Hz, H11A), 1.72 (1H, d, J¼15.0, 2.2 Hz,
H11B), 1.70 (1H, d, J¼12.5 Hz, H3B), 1.7–1.5 (2H, m),
1.4–1.2 (3H, m), 1.35 (3H, s, Me19), 0.93 (3H, s, Me20),
0.93 (3H, d, J¼6.8 Hz, Me17); 13C NMR d: 36.7 (C1),
107.3 (C2), 42.7 (C3), 48.6 (C4), 131.7 (C5), 25.2 (C6), 26.8
(C7), 35.3 (C8), 40.6 (C9), 133.2 (C10), 46.5 (C11), 64.4
(C12), 130.8 (C13), 108.6 (C14), 138.3 (C15), 143.0
(C16), 16.1 (C17), 177.6 (C18), 24.5 (C19), 21.3 (C20),
52.0 (–COOMe), 64.4 and 64.2 (–OC2H4O–); EIMS: 404
(Mþ, 2), 292(37), 233(22), 189(10), 161(13), 91(46);
EIHRMS: calcd for C23H32O6 (Mþ) 404.2199, found
(Mþ) 404.2191.
3.11. Reaction of 15 with p-TsOH: 19
Ketone 15 (24 mg, 0.050 mmol) in acetone (2 ml) was
stirred at room temperature in the presence of p-toluene-
sulfonic acid (6 mg, 0.036 mmol) for 5 h. The mixture
reaction was diluted with Et2O and washed successively
with a 6% aqueous solution of NaHCO3 and water. The
organic layer was dried and evaporated to give a crude
which was chromatographed on silica gel (hexane/AcOEt,
8/2) to yield 19 (oil, 16 mg, 72%).
3.11.1. Methyl 15-bromo-13,15-epoxy-2-oxo-16-nor-15-
homo-1(12),5(10),13,15-ent-halimatetraen-18-oate (19).
UV (EtOH): 356, 264, 208 nm; IR (film): 3148, 1732,
1699, 1464, 1431, 1377, 1327, 1269, 1161, 1107, 868,

692
I. S. Marcos et al. / Tetrahedron 59 (2003) 685–694
737 cm21; 1H NMR d: 7.46 (1H, s, H15), 6.52 (1H, s, H14),
3.59 (3H, s, –COOMe), 2.90 and 2.84 (1H, d, J¼13.2 Hz,
H11), 2.82 and 2.48 (1H, d, J¼15.2 Hz, H3), 2.36 (1H, ddd,
J¼18.0, 6.2, 1.0 Hz, H6A), 2.20 (1H, ddd, J¼18.0, 9.2,
1.0 Hz, H6B), 1.7–1.5 (3H, m), 1.39 (3H, s, Me19), 1.01
(3H, s, Me20), 0.96 (3H, d, J¼6.3 Hz, Me17); 13C NMR d:
130.6 (C1), 193.4 (C2), 52.1 (C3), 49.4 (C4), 128.1 (C5),
23.9 (C6), 27.0 (C7), 37.0 (C8), 43.6 (C9), 149.7 (C10),
49.5 (C11), 132.9 (C12), 147.3 (C13), 103.7 (C14), 116.4
(C15a), 143.5 (C15), 16.3 (C17), 174.4 (C18), 22.5 (C19), 20.2
(C20), 52.3 (–COOMe); EIMS: 420 (Mþ, 6), 418(6),
339(87), 279(100), 189(82), 69(52), 55(81); EIHRMS:
calcd for C21H23BrO4 (Mþ) 418.0780, found (Mþ)
418.0788.
p-toluenesulfonic acid (1 mg, 0.005 mmol) and was stirred
for 12 h at room temperature. The reaction mixture was then
treated with NaCl sat., extracted with Et2O and washed with
a 6% aqueous solution of NaHCO3 and water. Evaporation
followed by chromatography on silica gel yielded the
desired compound 20 (oil, 200 mg, 97%).
3.13.1. 2,13-Diethylendioxy-18-methoxymethylenoxy-
14,15-dinor-5(10)-ent-halimene
(20).
[a]2D2¼þ34.98
(c¼1.37, CHCl3); IR (film): 1466, 1381, 1148, 1107,
1078, 1047 cm21; 1H NMR d: 4.57–4.56 (2H, m, MeOCH2-
O–), 3.95–3.91 (8H, m, –OC2H4O–), 3.44 and 3.17 (1H, d,
JAB¼9.0 Hz, H18), 3.33 (3H, s, MeOCH2O–), 2.20 (2H, s,
H1), 2.18–2.04 (3H, m), 2.00 and 1.51 (1H, d, JAB
¼
13.4 Hz, H3), 1.8–1.7 (2H, m), 1.6–1.3 (4H, m), 1.29 (3H,
s, Me16), 1.09 (3H, s, Me19), 0.85 (3H, s, Me20), 0.84 (3H, d,
J¼6.2 Hz, Me17); 13C NMR d: 35.2 (C1), 108.9 (C2), 40.1
(C3), 41.5 (C4), 133.0 (C5), 25.0 (C6), 33.1 (C7), 33.6 (C8),
40.5 (C9), 132.5 (C10), 29.9 (C11), 27.0 (C12), 110.4 (C13),
23.7 (C16), 16.1 (C17), 74.8 (C18), 23.2 (C19), 20.7 (C20),
55.2 (MeOCH2O–), 96.7 (MeOCH2O–), 64.5 and 63.9
(–OC2H4O–); EIMS: 424 (Mþ, 20), 287(48), 243(33),
165(25), 115(26), 87 (100); EIHRMS: calcd for C24H40O6
(Mþ) 424.2825, found (Mþ) 424.2829.
3.12. Reaction of 18 with p-TsOH: chettaphanin II (3)
Ketone 18 (5 mg, 0.012 mmol) in acetone (1.5 ml) was
stirred at room temperature in the presence of p-toluene-
sulfonic acid (2 mg, 0.01 mmol) for 5 h. The mixture
reaction was diluted with Et2O and washed successively
with a 6% aqueous solution of NaHCO3 and water.
The organic layer was dried and evaporated to give a
crude orange oil which was chromatographed on silica
gel (hexane/AcOEt, 9/1) to yield chettaphanin II 3 (3 mg,
72%).
3.14. Reaction of 20 with m-CPBA: 21
3.12.1. Chettaphanin II: methyl 15,16-epoxy-2-oxo-
1(12),5(10),13(16),14-ent-halimatetraen-18-oate (3). Mp:
1278C (Et2O); [a]2D2¼2435.08 (c¼0.81, Me2CO); UV
(EtOH): 356, 264, 208 nm; IR (film): 3163, 1728, 1682,
1574, 1464, 1433, 1377, 1265, 1167, 1109, 1017 cm21; 1H
NMR d: 8.57 (1H, s, H16), 7.43 (1H, s, H15), 7.00 (1H, s,
H14), 3.57 (3H, s, COOMe), 2.81 and 2.45 (1H, d,
J¼15.7 Hz, H3), 2.71 and 2.66 (1H, d, J¼16.9 Hz, H11),
2.37 (1H, ddd, J¼18.0, 6.2, 1.0 Hz, H6A), 2.25 (1H, ddd,
J¼18.0, 9.2, 1.0 Hz, H6B), 1.66–1.58 (2H, m, H7), 1.59–
1.56 (1H, m, H8), 1.38 (3H, s, Me19), 0.99 (3H, s, Me20),
0.97 (3H, d, J¼6.2 Hz, Me17); 13C NMR d: 127.9 (C1),
195.1 (C2), 52.1 (C3), 48.4 (C4), 125.1 (C5), 23.7 (C6),
27.0 (C7), 37.1 (C8), 42.4 (C9), 150.3 (C10), 50.3
(C11), 139.7 (C12), 121.8 (C13), 111.0 (C14), 142.7
(C15), 146.3 (C16), 16.4 (C17), 174.6 (C18), 22.3 (C19),
20.3 (C20), 52.3 (–COOMe); EIMS: 340 (Mþ, 35),
281(100), 256(18), 205(17), 152(10), 105(18), 91(19),
69(32); EIHRMS: calcd for C21H24O4 (Mþ) 340.1674,
found (Mþ) 340.1668.
To a solution of 20 (188 mg, 0.44 mmol) in DCM (0.8 ml) at
08C, was added m-CPBA (150 mg, 0.88 mmol) dissolved in
DCM (2.2 ml). The reaction mixture was stirred for 30 min
at room temperature and then treated with a 6% aqueous
solution of Na2SO3. Extraction with AcOEt, followed by
successive washing of the organic layer with a 10% aqueous
Na2SO3 solution, 6% aqueous NaHCO3 solution and water.
The organic layer was dried and evaporated. Purification by
chromatography on silica gel yielded desired compound 21
(171 mg, 86%).
3.14.1. 5a,10a-Epoxy-2,13-diethylendioxy-18-methoxy-
methylenoxy-14,15-dinor-ent-halimane (21). [a]2D2¼
þ9.38 (c¼1.29, CHCl3); IR (film): 1466, 1373, 1213,
1148, 1111, 1047, 949, 858 cm21; 1H NMR d: 4.64 and 4.60
(1H, d, JAB¼6.7 Hz, MeOCH2O–), 4.66 and 3.93 (8H, m,
–OC2H4O–), 3.60 and 3.28 (1H, d, J¼9.2 Hz, H18), 3.37
(3H, s, MeOCH2O–), 2.25 and 2.09 (1H, d, JAB¼15 Hz,
H1), 1.98–1.95 (1H, m, H6), 1.85 and 1.38 (1H, d, JAB
¼
13.6 Hz, H3), 1.8–1.2 (8H, m), 1.30 (3H, s, Me16), 1.04 (3H,
s, Me19), 0.86 (3H, s, Me20), 0.76 (3H, d, J¼6.2 Hz, Me17);
13C NMR d: 35.4 (C1), 108.1 (C2), 38.2 (C3), 39.3 (C4), 67.9
(C5), 25.9 (C6), 24.7 (C7), 34.0 (C8), 38.9 (C9), 68.8 (C10),
31.2 (C11), 33.1 (C12), 110.2 (C13), 24.0 (C16), 16.4 (C17),
73.5 (C18), 20.9 (C19), 18.1 (C20), 55.4 (MeOCH2O–), 96.9
(MeOCH2O–), 64.7, 64.5 and 63.4 (–OC2H4O–); EIMS:
440 (Mþ, 1), 187(20), 126(15), 87(100).
3.13. Successive reactions of protection, reduction and
protection starting from 6: 20
To a solution of 6 (175 mg, 0.55 mmol) in ethylene glycol
(0.5 ml), was added benzene (5 ml) and was refluxed in the
presence of p-toluenesulfonic acid (5 mg, 0.02 mmol) for
8 h. The mixture was extracted with Et2O and washed with a
6% aqueous solution of NaHCO3 and water. Evaporation of
the solvent yielded a crude (200 mg, 0.49 mmol, 90%)
which was dissolved in Et2O (4 ml) and was added LAH
(20 mg, 0.40 mmol). The mixture was stirred for 1.5 h at
room temperature and quenched by addition of AcOEt sat.
Evaporation of the solvent yielded a crude (185 mg,
0.48 mmol, 97%), which was dissolved in DMM (1 ml).
To the solution was added BrLi (0.1 mg, 1.20 mmol) and
3.15. Reaction of 21 with p-TsOH: 22
To a solution of 21 (132 mg, 0.30 mmol) in distilled acetone
over KMnO4 (4 ml), was added p-toluenesulfonic acid
(5 mg). The reaction mixture was stirred for 2 h and was
extracted with AcOEt followed by successive washing of
the organic layer with 6% aqueous NaHCO3 solution and
water. The organic layer was dried and evaporated to give a

I. S. Marcos et al. / Tetrahedron 59 (2003) 685–694
693
crude mixture which was chromatographed on silica gel to
yield the expected compound 22 (oil, 68 mg, 64%).
3.17. Reaction of 23 with HClO4: 24, 25 and
chettaphanin I (2)
3.15.1. 5a-Hydroxy-18-methoxymethylenoxy-14,15-
dinor-1(10)-ent-halimen-2,13-dione (22). [a]2D2¼29.68
(c¼0.5, CHCl3); IR (film): 3474, 1717, 1669, 1464, 1370,
1150, 1107, 1044, 918. cm21; 1H NMR d: 5.90 (1H, s, H1),
4.53 and 4.50 (1H, d, JAB¼6.6 Hz, MeOCH2O–), 3.39 and
3.38 (1H, d, JAB¼9.6 Hz, H18), 3.29 (3H, s, MeOCH2O–),
2.56 and 2.37 (1H, d, JAB¼16.6 Hz, H3), 2.35–2.30 (2H, m,
H12), 2.12 (3H, s, Me16), 2.0–1.8 (5H, m), 1.6–1.4 (2H, m),
1.18 (3H, s, Me20), 1.10 (3H, s, Me19), 0.91 (3H, d, J¼
To a solution of 23 (41 mg, 0.098 mmol) in DMF (1.5 ml)
HClO4 63% (0.025 ml) was added. The mixture reaction
was stirred for 3 h and then water was added. Extraction
with Et2O followed by washing with water. The organic
layer was dried and evaporated to give a crude oil which
was chromatographed on silica gel to yield 24 (13 mg,
35%), 25 (11 mg, 30%) and chettaphanin I 2 (11 mg,
30%).
1
6.6 Hz, Me17); H NMR (DMSO) d: 5.71 (1H, s, H1), 4.77
3.17.1. Methyl 5a,10a-epoxy-2,12-dioxo-13(16),14-ent-
halimandien-18-oate (24). [a]2D2¼235.28 (c¼0.5, CHCl3);
IR (film): 1728, 1680, 1561, 1508, 1458, 1285, 1155, 1045,
(1H, s, –OH), 4.47 and 4.45 (1H, d, JAB¼6.6 Hz,
MeOCH2O–), 3.34 and 3.25 (1H, d, JAB¼9.6 Hz, H18),
1
3.16 (3H, s, MeOCH2O), 2.62 and 2.13 (1H, d, JAB
¼
874, 667 cm21; H NMR d: 7.98 (1H, s, H16), 7.42 (1H, s,
16.6 Hz, H3), 2.36 and 2.20 (1H, m, H12), 2.05 (3H, s,
Me16), 1.75 and 1.37 (1H, m, H6), 1.66 (2H, m, H11), 1.48
(1H, m, H8), 1.23 (2H, m, H7), 1.10 (3H, s, Me20), 0.95 (3H,
s, Me19), 0.84 (3H, d, J¼6.3 Hz, Me17); 13C NMR d: 126.9
(C1), 199.7 (C2), 44.5 (C3), 45.6 (C4), 74.4 (C5), 31.3 (C6),
26.0 (C7), 37.0 (C8), 44.3 (C9), 167.9 (C10), 32.8 (C11), 39.2
(C12), 208.9 (C13), 31.0 (C16), 17.0 (C17), 73.7 (C18), 20.2
(C19), 26.5 (C20), 56.4 (MeOCH2O–), 97.6 (MeOCH2O–);
13C NMR (DMSO) d: 124.9 (C1), 192.2 (C2), 42.9 (C3), 44.3
(C4), 71.3 (C5), 30.6 (C6), 24.7 (C7), 34.6 (C8), 42.6 (C9),
166.7 (C10), 29.8 (C11), 37.8 (C12), 208.0 (C13), 19.8 (C16),
16.1 (C17), 72.13 (C18), 19.2 (C19), 26.1 (C20), 95.9
(MeOCH2O–), 54.6 (MeOCH2O); EIMS: 352 (Mþ, 5),
307(10), 282(11), 235(20), 189(13), 165(100), 137(28);
EIHRMS: calcd for C20H32O5 (M)þ 352.2250, found (Mþ)
352.2258.
H15), 6.68 (1H, s, H14), 3.87 (3H, s, –COOMe), 3.00 and
2.69 (1H, d, JAB¼18.6 Hz, H11), 2.73 and 2.70 (1H, d, JAB
¼
17.6 Hz, H1), 2.46 and 2.27 (1H, d, J¼17.6 Hz, H3), 1.8–1.2
(5H, m), 1.40 (3H, s, Me19), 0.92 (3H, s, Me20), 0.86 (3H, d,
J¼5.2 Hz, Me17); EIMS: 375 (Mþþ1, 5), 265(63), 233 (11),
164 (43), 95 (100).
3.17.2. Methyl (10S,12S)-10,12-15,16-diepoxy-5a,12-
hydroxy-2-oxo-13(16),14-ent-halimandien-18-oate (25).
IR (film): 3400, 1726, 1464, 1196, 1127, 1053, 1009, 972,
665 cm21; 1H NMR d: 7.34 (2H, s, H15 and H16), 6.23 (1H,
s, H14), 3.57 (3H, s, –COOMe), 2.99 and 2.94 (1H, d, J¼
12.5 Hz, H1), 2.8–2.7 (1H, m, H6), 2.69 and 2.63 (1H, d,
J¼12.4 Hz, H3), 2.30 and 2.13 (1H, d, JAB¼13.5 Hz, H11),
1.85–1.75 (1H, m, H6), 1.97–1.85 (1H, m, H7), 1.70–1.63
(1H, m, H7), 1.60–1.50 (1H, m, H8), 1.29 (3H, s, Me19),
0.95 (3H, s, Me20), 0.72 (3H, d, J¼6.7 Hz, Me17); 13C NMR
d: 45.9 (C1), 208.5 (C2), 47.0 (C3), 52.8 (C4), 75.3 (C5), 29.8
(C6), 25.0 (C7), 34.9 (C8), 48.8 (C9), 90.4 (C10), 51.7 (C11),
105.4 (C12), 129.1 (C13), 108.6 (C14), 141.0 (C15), 143.4
(C16), 16.7 (C17), 175.1 (C18), 21.9 (C19), 15.0 (C20), 52.1
(–COOMe); EIMS: 375 (Mþþ1, 10), 256(8), 149(38);
EIHRMS: calcd for C21H28O7 (Mþ) 392.1835, found (Mþ)
392.1841.
3.16. Reaction of 18 with m-CPBA: 23
To a solution of 18 (31 mg, 0.077 mmol) in DCM (0.1 ml) at
08C, was added m-CPBA (15.9 mg, 0.092 mmol) dissolved
in DCM (0.18 ml). The reaction mixture was stirred for 12 h
at room temperature and then treated with a 6% aqueous
solution of Na2SO3. Extraction with AcOEt, followed by
successive washing of the organic layer with a 10% aqueous
Na2SO3 solution, 6% aqueous NaHCO3 solution and water.
The organic layer was dried and evaporated to yield the
expected compound 23 (29 mg, 92%).
3.17.3. Chettaphanin I: methyl 15,16-epoxy-5a-hydroxy-
2,12-dioxo-1(10),13(16),14-ent-halimantrien-18-oate (2).
[a]2D2¼231.78 (c¼0.3, CHCl3); UV (EtOH): 245 nm; IR
(film): 3400, 1728, 1682, 1458, 1377, 1277, 1155, 1121,
1044, 999 cm21; 1H NMR d: 7.98 (1H, s, H16), 7.41 (1H, s,
H15), 6.64 (1H, s, H14), 5.84 (1H, s, H1), 3.71 (3H, s,
–COOMe), 3.25 and 3.14 (1H, d, JAB¼18.0 Hz, H11), 2.69
and 2.57 (1H, d, JAB¼17.4 Hz, H3), 2.40 (1H, ddd, J¼14.0,
14.0, 3.6 Hz, H6A), 2.00 (1H, ddd, J¼14.0, 3.0, 3.0 Hz,
H6B), 1.8–1.5 (2H, m), 1.3–1.2 (1H, m), 1.38 (3H, s, Me19),
1.20 (3H, s, Me20), 0.89 (3H, d, J¼6.8 Hz, Me17); 1H NMR
(DMSO) d: 8.57 (1H, s, H16), 7.73 (1H, s, H15), 6.68 (1H, s,
H14), 5.75 (1H, s, H1), 5.01 (1H, s, –OH), 3.54 (3H, s,
–COOMe), 3.50 and 3.11 (1H, d, JAB¼18.0 Hz, H11), 2.60
and 2.21 (1H, d, JAB¼17.4 Hz, H3), 2.2–1.9 (2H, m),
1.7–1.5 (2H, m), 1.3–1.2 (1H, m), 1.20 (3H, s, Me19), 1.10
(3H, s, Me20), 0.82 (3H, d, J¼6.8 Hz, Me17); 13C NMR d:
125.6 (C1), 197.6 (C2), 43.2 (C3), 52.9 (C4), 72.7 (C5), 31.8
(C6), 25.0 (C7), 35.2 (C8), 41.2 (C9), 167.4 (C10), 47.8 (C11),
190.8 (C12), 127.6 (C13), 108.3 (C14), 144.1 (C15), 146.3
(C16), 16.7 (C17), 174.5 (C18), 19.4 (C19), 25.9 (C20), 52.4
(–COOMe); EIMS: 374 (Mþ, 1), 149 (10), 99(35), 71(52),
3.16.1. Methyl 5a,10a-15,16-diepoxy-2-ethylendioxy-12-
oxo-13(16),14-ent-halimandien-18-oate (23). [a]2D2¼
223.68 (c¼0.5, CHCl3); IR (film): 1732, 1670, 1561,
1508, 1458, 1375, 1157, 1123, 1044, 874 cm21; 1H NMR d:
8.08 (1H, t, J¼1.0 Hz, H16), 7.42 (1H, t, J¼1.0 Hz, H15),
6.77 (1H, t, J¼1.0 Hz, H14), 3.88–3.84 (4H, m, –OC2H4O–),
3.78 (3H, s, –COOMe), 3.21 and 2.77 (1H, d, JAB¼15.7 Hz,
H11), 2.14 (2H, s, H1), 2.01 and 1.68 (1H, d, JAB¼13.6 Hz,
H3), 2.0–1.9 (2H, m), 1.6–1.5 (2H, m), 1.4–1.3 (1H, m),
1.31 (3H, s, Me19), 1.18 (3H, s, Me20), 0.96 (3H, d, J¼7 Hz,
Me17); 13C NMR d: 36.6 (C1), 106.4 (C2), 40.0 (C3), 47.4
(C4), 66.2 (C5), 24.3 (C6), 24.0 (C7), 33.5 (C8), 39.6 (C9),
68.9 (C10), 46.61 (C11), 194.1 (C12), 129.3 (C13), 108.7
(C14), 144.1 (C15), 147.3 (C16), 15.9 (C17), 176.0 (C18), 20.8
(C19), 19.3 (C20), 51.8 (–COOMe), 64.1–64.1 (–OC2H4O–);
EIMS: 418 (Mþ, 4), 292(30), 233(18), 146(48), 95(62),
95(50); EIHRMS: calcd for C23H30O7 (M)þ 418.1991,
found (Mþ) 418.1998.

694
I. S. Marcos et al. / Tetrahedron 59 (2003) 685–694
57(100); EIHRMS: calcd for C21H26O6 (Mþ) 374.1729,
found (Mþ) 374.1734.
7. (a) Gunasekera, G. P.; McCarthy, P. J.; Kelly-Borges, M.;
Lobkovsky, E.; Clardy, J. J. Am. Chem. Soc. 1996, 118, 8759.
(b) Corey, E. J.; Roberts, B. E. J. Am. Chem. Soc. 1997, 119,
12425. (c) Jung, M. E.; Nishimura, N. Org. Lett. 2001, 3, 2113.
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Waldmann, H. Angew. Chem., Int. Ed. Engl. 2002, 41, 307.
and references cited therein.
The authors thank the CICYT for financial support (PB98-
0257).
8. Marcos, I. S.; Moro, R. F.; Carballares, S.; Urones, J. G.
Synlett 2000, 541.
9. Rabjohn, N. Organic Synthesis; Wiley: New York, 1967;
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