Ent-Hydrohalimic acid transformations: Synthesis of a diterpenic bislactone

Article abstract of DOI:10.1016/j.tetasy.2004.04.001

A new diterpenic lactone has been synthesized starting from ent-hydrohalimic acid and its biological activity has been tested.

Full text of DOI:10.1016/j.tetasy.2004.04.001

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 1793–1799
ent-Hydrohalimic acid transformations: synthesis of a diterpenic
bislactone
a,
a
b
b
*
ꢀ
ꢀ
Jesus M. L. Rodilla, Maria L. A. Silva, David Dıez, Julio G. Urones and
Francisca Sanzc
a
ꢀ
Department of Chemistry, Universidade da Beira Interior, Rua Marqu^es d’Avila e Bolama, 6201-001 Covilh~a, Portugal
b
ꢀ
Department of Organic Chemistry, Universidad of Salamanca, Plaza de los Caıdos 1-5, 37008 Salamanca, Spain
cServicio de Difracciꢀon de Rayos X, Universidad de Salamanca, 37008 Salamanca, Spain
Received 30 March 2004; accepted 1 April 2004
Available online 23 April 2004
Abstract—A new diterpenic lactone has been synthesized starting from ent-hydrohalimic acid and its biological activity has been
tested.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
maintain the a,b-unsaturated lactone moiety, which
could be used to produce a wide range of derivatives.
In the course of our studies on the chemical constitution
of Portuguese Halimium species, we have isolated from
the aerial parts of Halimium viscosum (Wilk) P. da Silva,
several bicyclic diterpenes, with either labdane or ent-
halimane1–5 skeletons along with several tricyclic diter-
penic compounds belonging to the valparane or
valparolane6;7 class. Some minor components possess
rearranged skeletons of the covilanone type.8
O
O
O
O
O
O
OH
1
1
10
10
5
O
5
H
H
H
I
1
II
COOMe
We are involved in the transformation of the main
compounds obtained from the Halimium genus into
biologically active compounds,9 thus providing added
value to areas of our region unsuitable for the produc-
tion of other crops.
O
Figure 1.
2. Results and discussion
Our group has recently reported the transformation of
ent-halimic acid into biologically active compounds such
as, hydroxybutenolide I9 with antifeedant activity, or
biologically active ent-halimanolides such as II.10;11 In
order to do SAR studies on this kind of compound we
decided to synthesize the bislactone 1 (Fig. 1). Our
strategy was threefold: to conformationally constrain
and deactivate the ester moiety of I, to further rigidify
the decalin ring system (which has been shown in similar
system, to have some conformational mobility) and to
The major component of Halimium viscosum (Celorico
da Beira) is ent-hydrohalimic acid (15-hydroxy-ent-
halim-1(10)-en-18-oic acid) 3,1 which has been previ-
ously described and whose stereochemistry was pro-
posed based upon comparison the ½aꢀ values between
D
the methyl ester derivative of 3 and hydrogenated ent-
halimic acid. Now we have established the absolute
stereochemistry of 3 by X-ray diffraction12 studies, as
shown in Figure 2.
The retrosynthetic analysis for the synthesis of com-
pound 1, starting from ent-hydrohalimic acid 3, is shown
in Scheme 1. It requires the use of a Bestman ketene for
the butenolide ring-formation via intermediate 2, that
* Corresponding author. Tel.: +351-275-319700; fax: +351-275-3198-
88; e-mail: rodilla@ubista.ubi.pt
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.04.001

1794
J. M. L. Rodilla et al. / Tetrahedron: Asymmetry 15 (2004) 1793–1799
tion of 3 gave rise to 5 as the major product; since no
iodine was incorporated in the product, we attempted
the acid-mediated cyclization of 3 and found that the
yield improved still further to almost quantitative levels.
The change of stereochemistry at C5 that accompanied
this cyclization was established by X-ray crystallography
as discussed below.
With compound 5 available to us, in gram quantities we
decided to continue our route to bislactone 1. The syn-
thesis was carried out as depicted in Scheme 3. The
transformation of 3 into 7 was carried out with o-
nitrophenylselenocyanate.13 X-ray diffraction studies14
on this compound (Fig. 3) confirmed the b-relationship
between the lactone ring formed by HI treatment and
the a-stereochemistry of H-5, the inverse configuration
with respect to the same hydrogen in ent-hydrohalimic
acid 3.
Figure 2. ORTEP view of ent- hydrohalimic acid 3.
15
Oxidation of 7 with H2O2 gives olefin 8, which after
O
O
Wacker16 oxidation afford methylketone 9. The side-
chain degradation was done by a Baeyer–Williger oxi-
dation17 with m-CPBA leading to the acetyl derivative
10. Subsequent alkaline hydrolysis with Na2CO3 gives
11, which was further oxidized with PCC18 to afford
ketone 2. After treatment with LDA and TMSCl this
ketone gives 12 oxidized in the presence of m-CPBA19 to
obtain hydroxyketone 13. The reaction of the latter with
Bestmann20 ketene gives the desired bislactone 1.
CH2OH
O
O
O
H
H
2
1
H
3
COOH
O
O
Scheme 1.
Compound 1, and intermediates 7 to 14 has been tested
against cytotoxicity in a wide range of biological assays,
including a broad antifungal and antibacterial, antiviral
assays against HIV, RSV, and influenza viruses, recep-
tor based assays against CNS targets such as neuro-
transmitter uptake site Gly-1,VR1, Nac, and GABA-B
receptors, and metabolic targets such as MC-4, and
gastrointestinal targets such as GHSR. Compound 1
was further evaluated a wide range of oncology targets
a2, D2, 5HT, or NPY5, others neurotransmitter uptake
sites, signal transduction protein such as CCR2B or
CRF1, and some enzymes such as BACE (implicated in
Alzheimer’s disease). However in all of these, and in one
in vivo histone acetyl transferase assay, no activity was
observed for any compound. This is in striking contrast
to many similar compounds (e.g., dysidiolide,21 etc.). We
speculate that this may be due to locking of the bute-
nolide side-chain equatorial as it has been previously
suggested that an axial disposition may be required for
the activity of some of these related compounds.
already has a suitably degraded side chain and the
annular lactone ring.
Our initial studies were focused on the preparation of
butenolide 5, which we anticipated would proceed via
acid catalyzed or iodine-mediated oxidative cyclization
of ester 4 or and 3. However, attempted cyclization of 4
under either set of conditions (Scheme 2) gave rise
mainly to isomeric olefin 6. Attempted iodolactoniza-
CH2OH
CH2OH
CH2OH
O
H
H
H
COOR
5
6
COOMe
O
3 R =H
4 R = Me
3. Experimental
Conditions
Starting material
5
6
Unless otherwise stated, all chemicals were purchased as
the highest purity commercially available and were used
without further purification. IR spectra were recorded
on a MATTSON–GENESIS II FT-IR spectrophoto-
meter. 1H and 13C NMR spectra were performed in
deuterochloroform and referenced to the residual peak
of CHCl3 at d 7.26 and 77.0 ppm, for 1H and 13C,
respectively, at a Bruker WP-200 SY and a Bruker DRX
400 MHz. Chemical shifts are reported in d ppm and
I2 / benzene reflux
3
93%
HI (57%) / CHCl3,
reflux
I2 / benzene reflux
3
99%
2%
4
4
90%
HI (57%) / CHCl3,
reflux
19% 72%
Scheme 2.

J. M. L. Rodilla et al. / Tetrahedron: Asymmetry 15 (2004) 1793–1799
1795
CH2SePhNO2
CH2OH
OAc
O
a
b
c
d
O
O
O
O
O
H
H
H
H
H
O
O
9
10
O
O
7
8
O
3
e
O
O
OH
HOH2C
O
OTMS
O
f
i
g
h
O
O
O
O
O
H
H
O
H
H
H
14
13
O
11
O
12
1
O
O
Scheme 3. Reagents and conditions: (a) o-NO2PhSeCN/TBF, 92%; (b) H2O2/THF, 94%; (c) PdCl2/CuCl/O2/DMF, 89%; (d) m-CPBA/CH2Cl2, 79%;
(e) K2CO3/MeOH, 95%; (f) PCC/CH2Cl2; (g) LDA/TMSCl, 63%; (h) m-CPBA/CH2Cl2, 50%; (i) Ph3P@C@C@O/toluene, 75%.
to dryness. The crude product was chromatographed
through silica gel yielding with hexane/EtOAc 8:2,
931 mg (93%) of 5.
3.2. Reaction of 3 with HI: synthesis of 5
To a solution of 3 (1.0 g, 3.11 mmol) in benzene (50 mL)
was added 2 mL a solution (57%) of HI (1.9 g,
15.16 mmol). The reaction mixture was refluxed during
5 h. After cooling the solvent was evaporated and added
water (50 mL). The products reaction was extracted with
ether (3 ꢁ 50 mL) and the organic phase washed with
10% NaHSO3, 6% NaHCO3, water, dried over anhy-
drous Na2SO4, filtered, and evaporated to dryness. The
crude product was chromatographed through silica gel,
to give with hexane/EtOAc 8:2, 1.0 g (99%) of 5.
Figure 3. ORTEP view of compound 7.
coupling constants (J) are given in Hz. MS were per-
formed at a VG-TS 250 spectrometer at 70 eV ionizing
voltage. Mass spectra are presented as m=z (% rel. int.).
HRMS were recorded on a VG Platform (Fisons)
spectrometer using chemical ionization (ammonia as
gas). Optical rotations were determined at a digital ADP
220 polarimeter in 1 dm cells. Crystallographic data
were obtained with Seifert XRD 3000 S diffractometer.
Diethyl ether, THF, and benzene were distilled from
sodium, and pyridine and dichloromethane were dis-
tilled from calcium hydride under an Ar atmosphere.
3.2.1. 5-epi-15-Hydroxy-ent-haliman-18,10b-olide, 5.
22
D
film
max
½aꢀ ¼ ꢂ24:6 (c 0.90, CHCl3). IR m : 3435, 2931,
2875, 1768, 1452, 1382, 1265, 1198, 1165, 1182, 1131,
1
1056, 1026, 942 cmꢂ1. H NMR (CDCl3): 3.67 (2H, m,
H-15), 2.08 (2H, dd, J1 ¼ 11:7 Hz, J2 ¼ 3:1 Hz, H-1),
1.90–1.00 (18H, m), 1,07 (3H, s, Me-19), 0.87 (3H, d,
J ¼ 6:3 Hz, Me-16), 0.82 (3H, d, J ¼ 6:7 Hz, Me-17),
0.73 (3H, s, Me-20). 13C NMR (CDCl3): 29.2 (C-1); 20.1
(C-2); 34.7 (C-3); 49.6 (C-4); 49.4 (C-5); 25.7 (C-6); 27.9
(C-7); 32.4 (C-8); 40.4 (C-9); 89.5 (C-10); 33.3 (C-11);
31.6 (C-12); 30.7 (C-13); 39.8 (C-14); 61.0 (C-15); 19.8
(C-16); 16.2 (C-17); 181.5 (C-18); 16.8 (C-19); 17.0 (C-
20). MS, m=z: 322 ([M]þ, 1), 279 (1), 261 (1), 249 (2), 221
(16), 207 (2), 193 (3), 177 (24), 175 (7), 163 (4), 149 (16),
135 (6), 122 (20), 109 (20), 107 (20), 95 (31), 93 (27), 81
(40), 79 (33), 69 (42), 67 (55), 55 (100), 43 (52), 41 (19).
HRMS calcd for C20H34O3: 322.2508; found 322.2520.
The raw material 3 was isolated from a hexane extract of
Halimium viscosum as reported in Ref. 1.
3.1. Reaction of 3 with iodine: synthesis of 5
To a solution of 3 (1.0 g, 3.11 mmol) in benzene (45 mL)
was added I2 (3.5 g, 15.55 mmol). The reaction mixture
was refluxed during 20 h. After cooling the solvent was
evaporated, water added (50 mL) and extracted with
ether (3 ꢁ 50 mL). The organic phase was washed with
10% NaHSO3, 6% NaHCO3, and water (until neutral);
dried over anhydrous Na2SO4, filtered, and evaporated
3.3. Reaction of 4 with iodine: synthesis of 5 and 6
To a solution of 4 (1.0 g, 3.01 mmol) in benzene (45 mL)
was added I2 (3.8 g, 15.05 mmol). The reaction mixture

1796
J. M. L. Rodilla et al. / Tetrahedron: Asymmetry 15 (2004) 1793–1799
was refluxed for 20 h. After cooling the solvent was
evaporated, water added (50 mL), and extracted with
ether (3 ꢁ 50 mL). The organic phase was washed with
10% NaHSO3, 6% NaHCO3, and water (until neutral);
dried over anhydrous Na2SO4, filtered, and evaporated
to dryness. The crude product was chromatographed
with hexane/EtOAc 8:2, to give 19 mg (2%) of 5 and
910 mg (90%) of 6.
19), 0.96 (3H, d, J ¼ 6:4 Hz, Me-16), 0.83 (3H, d,
J ¼ 6:8 Hz, Me-17), 0.75 (3H, s, Me-20). 13C NMR
(CDCl3): 29.0 (C-1); 19.9 (C-2); 34.5 (C-3); 49.3 (C-4);
49.2 (C-5); 25.5 (C-6); 27.8 (C-7); 32.0 (C-8); 40.2 (C-9);
89.2 (C-10); 33.3 (C-11); 31.7 (C-12); 34.6 (C-13); 34.7
(C-14); 23.8 (C-15); 19.3 (C-16); 16.0 (C-17); 181.1 (C-
18); 16.8 (C-19); 16.8 (C-20), 134.0 (C-10), 146.6 (C-20),
126.3 (C-30), 129.1 (C-40), 133.7 (C-50), 125.1 (C-60).
HRMS calcd for C26H37NO4Se: 507.1888; found
507.1892.
3.4. Reaction of 4 with HI: synthesis of 5 and 6
To a solution of 4 (1.0 g, 2.98 mmol) in benzene (50 mL)
was added 2 mL to a solution, 57%, of HI (1.9 g,
15.16 mmol). The reaction mixture was refluxed during
5 h. After cooling the solvent was evaporated, water
added (50 mL) and extracted with ether. The organic
phase was washed with 10% NaHSO3, 6% NaHCO3 and
water, dried over anhydrous Na2SO4, filtered, and
evaporated to dryness. The crude product was chro-
matographed through silica gel, eluted with hexane/
EtOAc 8:2 afforded 189 mg (19%) of 5 and 651 mg (72%)
of 6.
3.6. Oxidation of 7 with H2O2: synthesis of 8
To a solution of 7 (1.0 g, 1.98 mmol) in THF (7 mL) was
added 30% H2O2 (0.40 mL, 134 mg, 3.96 mmol) and
stirred for 12 h. The solvent was evaporated at reduced
pressure and the crude product chromatographed
yielding with hexane/EtOAc 95:5, 566 mg (94%) of 8.
22
D
3.6.1. 5-epi-ent-Halim-14-en-18,10b-olide, 8. ½aꢀ
¼
film
max
ꢂ27:5 (c 0.80, CHCl3). IR m : 3076, 2955, 2936, 2875,
1771, 1640, 1452, 1382, 1263, 1196, 1165, 1125, 1025,
1
996, 941, 923 cmꢂ1. H NMR (CDCl3): 5.68 (1H, ddd,
3.4.1. Methyl 15-hydroxy-ent-halim-5(10)-en-18-oate, 6.
J1 ¼ 17:3 Hz, J2 ¼ 10:3 Hz, J3 ¼ 7:7 Hz, H-14), 4.97
(1H, ddd, J1 ¼ 17:3 Hz, J2 ¼ 2:1 Hz, J3 ¼ 0:9 Hz, H-
15a), 4.87 (1H, ddd, J1 ¼ 10:3 Hz, J2 ¼ 2:1 Hz,
J3 ¼ 1:0 Hz, H-15b), 2.07 (2H, dd, J1 ¼ 11:7 Hz,
J2 ¼ 3:1 Hz, H-1), 2.00–1.04 (15H, m), 1.06 (3H, s, Me-
19), 0.98 (3H, d, J ¼ 6:7 Hz, Me-16), 0.80 (3H, d,
J ¼ 6:8 Hz, Me-17), 0.73 (3H, s, Me-20). 13C NMR
(CDCl3): 29.2 (C-1); 20.1 (C-2); 34.7 (C-3); 49.6 (C-4);
49.4 (C-5); 25.8 (C-6); 28.0 (C-7); 32.5 (C-8); 40.4 (C-9);
89.5 (C-10); 33.6 (C-11); 31.4 (C-12); 39.3 (C-13); 145.0
(C-14); 112.7 (C-15); 20.6 (C-16); 16.2 (C-17); 181.4 (C-
18); 16.8 (C-19); 17.1 (C-20). MS, m=z: 304 ([M]þ, <1),
289 (0.8), 276 (0.9), 261 (2), 249 (3), 243 (3), 222 (86),
221 (46), 207 (11), 193 (8), 177 (83), 161 (8), 149 (25), 135
(14), 122 (35), 109 (52), 95 (75), 93 (43), 81 (68), 79 (41),
69 (62), 67 (72), 55 (100). HRMS calcd for C20H32O2:
304.2402; found 304.2413.
22
D
film
max
½aꢀ ¼ ꢂ32:2 (c 0.25, CHCl3). IR m : 3430, 2931, 2875,
1732, 1460, 1433, 1377, 1250, 1188, 1081, 1057,
1
1007 cmꢂ1. H NMR (CDCl3): 3.66 (2H, m, H-15), 3.63
(3H, s, COOMe), 2.10–1.20 (17H, m), 1,26 (3H, s, Me-
19), 1.17–0.91 (2H, m), 0.88 (3H, d, J ¼ 6:3 Hz, Me-16),
0.80 (3H, d, J ¼ 7:3 Hz, Me-17), 0.79 (3H, s, Me-20).
13C NMR (CDCl3): 25.0 (C-1); 19.4 (C-2); 35.2 (C-3);
47.4 (C-4); 131.0 (C-5); 25.9 (C-6); 26.7 (C-7); 33.2 (C-8);
40.6 (C-9); 135.9 (C-10); 33.5 (C-11); 30.5 (C-12); 30.8
(C-13); 40.1 (C-14); 60.9 (C-15); 19.6 (C-16); 15.9 (C-17);
178.5 (C-18); 22.9 (C-19); 20.8 (C-20), 51.7 (COOCH3).
MS, m=z: 336 ([M]þ, 1), 277 (3), 235 (42), 203 (2), 175
(100), 161 (9), 147 (7), 133 (11), 119 (19), 105 (18), 91
(10), 81 (7), 69 (9), 55 (40), 41 (33). HRMS calcd for
C21H38O3: 338.2821; found 338.2832.
3.5. Reaction of 5: synthesis of 7
3.7. WACKER oxidation of 8: synthesis of 9
To a solution of 5 (1.0 g, 3.14 mmol) in dry THF (10 mL)
was
added
o-nitrophenylselenocyanate
(8.9 g,
To a solution of PdCl2 (128 mg, 0.72 mmol) and CuCl
(3.6 g, 3.60 mmol) in DMF (10 mL) and H2O (1 mL) was
activated for 30 min with O2. A solution of 8 (1.1 g,
3.62 mmol) in DMF (8 mL) was added and stirred with
O2 atmosphere at room temperature for 36 h. Then was
added a cool solution of 3 N HCl, extracted with
CH2Cl2 (3 ꢁ 30 mL), and washed successively with 10%
NaHCO3 and water, dried, filtered, evaporated, and
chromatographed gave (hexane/EtOAc 9:1) 1.0 g (89%)
of 9.
3.77 mmol) and stirred under inert atmosphere for
20 min at 48 °C. TBF (760 mg, 3.77 mmol) was added to
reactional mixture, stirred for 48 min, the solvent was
removed at reduced pressure and the residue chroma-
tographed yielding with hexane/EtOAc 9:1, 1.46 g (92%)
of 7.
3.5.1. 5-epi-15-o-Nitrophenylseleno-ent-haliman-18,10b-
22
D
olide, 7. Mp 127–128 °C. ½aꢀ ¼ ꢂ20:3 (c 1.48, CHCl3).
film
max
IR m : 3512, 3072, 2979, 1590, 1566, 1198, 1127, 1048,
22
3.7.1. 5-epi-14-Oxo-ent-haliman-18,10b-olide, 9. ½aꢀ ¼
1026, 972, 943, 921, 850, 789, 737 cmꢂ1
.
1H NMR
D
(CDCl3): 8.26 (1H, d, J ¼ 8:2 Hz, H-30), 7.55 (2H, m, H-
40 and H-50), 7.28 (1H, m, H-60), 2.98 (1H, m, H-15a),
2.91 (1H, m, H-15b), 2.07 (2H, dd, J1 ¼ 11:7 Hz,
J2 ¼ 3:1 Hz, H-1), 1.90–1.05 (17H, m), 1.06 (3H, s, Me-
ꢂ26:4 (c 0.76, CHCl3). IR m : 2960, 2939, 1762, 1711,
film
max
1458, 1379, 1358, 1265, 1248, 1198, 1167, 1026,
941 cmꢂ1. H NMR (CDCl3): 2.35 (1H, sex, J ¼ 7:1 Hz,
1
H-13), 2.12 (3H, s, H-15), 2.09–1.12 (16H, m), 1.07 (3H,

J. M. L. Rodilla et al. / Tetrahedron: Asymmetry 15 (2004) 1793–1799
1797
d, J ¼ 6:8 Hz, Me-16), 1.05 (3H, s, Me-19), 0.81 (3H, d,
J ¼ 6:8 Hz, Me-17), 0.72 (3H, s, Me-20). 13C NMR
(CDCl3): 29.0 (C-1); 19.9 (C-2); 34.5 (C-3); 49.3 (C-4);
49.2 (C-5); 25.5 (C-6); 27.7 (C-7); 32.0 (C-8); 40.2 (C-9);
89.1 (C-10); 33.1 (C-11); 28.0 (C-12); 48.4 (C-13); 213.3
(C-14); 27.3 (C-15); 16.0 (C-16); 16.2 (C-17); 181.0 (C-
18); 16.8 (C-19); 16.2 (C-20). MS, m=z: 320 ([M]þ, 1), 292
(2), 277 (4), 259 (3), 249 (69), 231 (9), 221 (30), 203 (29),
193 (12), 177 (49), 161 (13), 149 (30), 135 (12), 122 (20),
121 (26), 119 (27), 109 (34), 99 (47), 95 (54), 93 (48), 81
(59), 79 (55), 69 (52), 67 (73), 55 (100). HRMS calcd for
C20H32O3: 320.2351; found 320.2362.
(C-12); 69.2 (C-13); 23.2 (C-16); 15.9 (C-17); 181.3 (C-
18); 16.8 (C-19); 16.8 (C-20). MS, m=z: 294 ([M]þ, <1),
276 (0.8), 261 (0.6), 248 (1), 221 (12), 205 (1), 193 (3),
177 (32), 163 (8), 149 (17), 133 (8), 122 (30), 107 (31), 95
(39), 81 (52), 67 (73), 55 (100), 45 (90), 41 (88). HRMS
calcd for C18H30O3: 294.2145; found 294.2156.
3.10. Oxidation of 11 with PCC: synthesis of 12
To a stirred suspension of powdered molecular sieves
ꢁ
(4 A) and PCC (1.7 g, 7.74 mmol) in dry CH2Cl2 (30 mL)
was added 11 (758 mg, 2.58 mmol). The reaction mixture
was stirred at 40 °C for 1 h. The reaction mixture was
cooled to room temperature, was added ether (250 mL),
the mixture was filtered through a pad of Florisil, and
concentrated. It was obtained 640 mg (85%) of 12.
3.8. Treatment of 9 with m-CPBA: synthesis of 10
Compound 9 (500 mg, 1.49 mmol) was dissolved in
CH2Cl2 (10 mL) and m-CPBA (935 mg, 2.98 mmol) was
added. The mixture was stirred at 40 °C and monitored
by TLC. After 24 h the reaction was complete and the
solvent evaporated. Work-up afforded 480 mg of crude
product that after chromatography on silica gel gave
470 mg (79%) of 10 in the hexane/EtOAc 9:1 fractions.
3.10.1.
5-epi-14,15-Di-nor-13-oxo-ent-haliman-18,10b-
22
D
film
max
olide, 12. ½aꢀ ¼ ꢂ18:4 (c 0.76, CHCl3). IR m : 2935,
2878, 2863, 1770, 1716, 1450, 1419, 1378, 1262, 1197,
1168, 1026, 940 cmꢂ1. 1H NMR (CDCl3): 2.91 (1H, ddd,
J1 ¼ 15:5 Hz, J2 ¼ 11:0 Hz, J3 ¼ 5:4 Hz, H-12a), 2.35
(1H, ddd, J1 ¼ 15:5 Hz, J2 ¼ 8:9 Hz, J3 ¼ 7:5 Hz, H-
12b), 2.13 (3H, s, Me-16), 2.00–1.05 (14H, m), 1.04 (3H,
s, Me-19), 0.78 (3H, d, J ¼ 6:7 Hz, Me-17), 0.76 (3H, s,
Me-20). 13C NMR (CDCl3): 28.9 (C-1); 20.0 (C-2); 34.7
(C-3); 49.5 (C-4); 49.3 (C-5); 25.7 (C-6); 27.8 (C-7); 31.2
(C-8); 40.1 (C-9); 89.3 (C-10); 28.3 (C-11); 39.1 (C-12);
209.8 (C-13); 30.5 (C-16); 15.8 (C-17); 181.1 (C-18); 17.5
(C-19); 17.0 (C-20). MS, m=z: 292 ([M]þ, 6), 274 (11),
259 (5), 249 (28), 231 (36), 222 (56), 221 (48), 213 (11),
204 (18), 193 (15), 189 (17), 177 (83), 161 (17), 149 (50),
133 (21), 121 (54), 107 (51), 95 (65), 93 (57), 81 (56), 79
(50), 69 (39), 67 (58), 55 (76), 43 (100), 41 (77). HRMS
calcd for C18H28O3: 292.2038; found 292.2050.
3.8.1. 5-epi-13-Acetoxy-14,15-di-nor-ent-haliman-18,10b-
22
D
film
max
olide, 10. ½aꢀ ¼ ꢂ25:0 (c 0.48, CHCl3). IR m : 2973,
2938, 2878, 1768, 1736, 1452, 1374, 1246, 1198, 1127,
1054, 1016, 952 cmꢂ1. H NMR (CDCl3): 4.73 (1H, sex,
1
J ¼ 6:1 Hz, H-13), 1.97 (3H, s, Me-15), 1.88–1.00 (16H,
m), 1.14 (3H, d, J ¼ 6:1 Hz, Me-16), 1.01 (3H, s, Me-
19), 0.70 (3H, s, Me-20). 13C NMR (CDCl3): 28.9 (C-1);
19.9 (C-2); 34.6 (C-3); 49.4 (C-4); 49.2 (C-5); 25.6 (C-6);
27.8 (C-7); 31.8 (C-8); 40.1 (C-9); 89.1 (C-10); 30.8 (C-
11); 31.2 (C-12); 72.1 (C-13); 19.8 (C-16); 15.8 (C-17);
181.1 (C-18); 16.9 (C-19); 16.9 (C-20); 170.9 (OOCMe),
21.4 (OOCCH3). MS, m=z: 334 ([M]þ, <0.8), 302 (2), 263
(5), 211 (8), 179 (37), 124 (32), 109 (100), 105 (20), 95
(16), 93 (16), 91 (32), 81 (26), 79 (32), 77 (17), 69 (26), 67
(17), 59 (12), 55 (30). HRMS calcd for C20H32O4:
336.2301; found 336.2313.
3.11. Reaction of 12 with LDA/TMSCl: synthesis of 13
A mixture of LDA (0.8 mL, 5.68 mmol), 2 mL of dry
THF, 1.8 mL of BuLi (1.36 mmol) and 0.5 mL of 2,20-
dipyridine, under argon atmosphere and at ꢂ75 °C was
stirred during 5 min. The mixture was warmed till room
temperature and 10 min later the solution become pink.
It was then cooled to ꢂ78 °C again and it was added
1.8 mL of TMSCl (6.9 mmol) and the compound 12
(621 mg, 213 mmol). The reaction mixture was stirred
for 1 h and it was warmed to ꢂ20 °C and 4 mL of tri-
ethylamine was added and reacted during 2 h. After was
added 5 mL of a solution 6% NaHCO3, extracted with
EtOAc (3 ꢁ 15 mL), the organic phase was washed with
a saturated solution of NaCl and water; dried over
anhydrous Na2SO4, filtered, and the solvent evaporated.
The crude product was chromatographed through silica
gel yielding with hexane/EtOAc 9:1, 488 mg (63%) of
13.
3.9. Alkaline hydrolysis of 10: synthesis 11
To a solution of 10 (455 mg, 1.35 mmol) in methanol
(45 mL) was added K2CO3 (43 mg). The reaction mix-
ture was stirred at room temperature for 3 h, water was
added, and the mixture extracted with ether washed with
2 N HCl and H2O, dried, filtered, and evaporated
yielding 375 mg (95%) of 11.
3.9.1. 5-epi-14,15-Di-nor-13-hydroxy-ent-haliman-18,10b-
22
D
film
max
olide, 11. ½aꢀ ¼ ꢂ13:4 (c 0.89, CHCl3). IR m : 3419,
2960, 2878, 1764, 1453, 1381, 1283, 1264, 1198, 1166,
1
1131, 943, 755 cmꢂ1. H NMR (CDCl3): 3.63 (1H, sext,
J ¼ 6:1 Hz, H-13), 2.09 (2H, d, J ¼ 11:8 Hz, H-1), 1.90–
1.00 (15H, m), 1.19 (3H, d, J ¼ 6:1 Hz, Me-16), 1.07
(3H, s, Me-19), 0.83 (3H, d, J ¼ 6:7 Hz, Me-17), 0.76
(3H, s, Me-20). 13C NMR (CDCl3): 28.9 (C-1); 19.8 (C-
2); 34.4 (C-3); 49.3 (C-4); 49.2 (C-5); 25.5 (C-6); 27.7 (C-
7); 31.9 (C-8); 40.0 (C-9); 89.3 (C-10); 31.6 (C-11); 34.1
3.11.1. 5-epi-14,15-Di-nor-13-trimethylsililoxy-ent-halim-
22
D
13(16)-en-18,10b-olide, 13. ½aꢀ ¼ ꢂ21:4 (c 0.80,
film
max
CHCl3). IR m : 3109, 2956, 2938, 2879, 1774, 1635,

1798
J. M. L. Rodilla et al. / Tetrahedron: Asymmetry 15 (2004) 1793–1799
1450, 1384, 1296, 1262, 1122, 1029, 1012, 942, 848 cmꢂ1
.
1124, 1026, 941, 887, 848 cmꢂ1. UV (EtOH) kmax: 209 nm
ðe ¼ 10; 687Þ. 1H NMR (CDCl3): 5.79 (1H, s, H-14),
4.79 (1H, d, J ¼ 17:3 Hz, H-16a), 4.71 (1H, d,
J ¼ 17:3 Hz, H-16b), 2.83 (1H, m, H-12a), 2.35 (1H, m,
H-12b), 1.99–1.05 (14H, m), 1.07 (3H, s, Me-19), 0.83
(3H, d, J ¼ 6:7 Hz, Me-17), 0.82 (3H, s, Me-20). 13C
NMR (CDCl3): 29.1 (C-1); 19.9 (C-2); 34.6 (C-3); 49.4
(C-4); 49.3 (C-5); 25.6 (C-6); 27.7 (C-7); 31.2 (C-8); 40.4
(C-9); 89.0 (C-10); 32.7 (C-11); 24.1 (C-12); 171.9 (C-13);
114.4 (C-14); 174.3 (C-15); 73.4 (C-16); 15.8 (C-17);
180.9 (C-18); 17.4 (C-19); 16.9 (C-20). HRMS calcd for
C20H28O4: 332.1988; found 332.2009.
1H NMR (CDCl3): 4.04 (1H, s, H-16a), 3.98 (1H, s, H-
16b), 2.42–1.20 (16H, m), 1.06 (3H, s, Me-19), 0.84 (3H,
d, J ¼ 6:8 Hz, Me-17), 0.76 (3H, s, Me-20), 0.14 (9H, s,
OSi(CH3)3). 13C NMR (CDCl3): 29.0 (C-1); 20.0 (C-2);
34.7 (C-3); 49.5 (C-4); 49.3 (C-5); 25.7 (C-6); 28.0 (C-7);
31.8 (C-8); 40.4 (C-9); 89.3 (C-10); 32.2 (C-11); 33.3 (C-
12); 160.6 (C-13); 89.8 (C-16); 15.8 (C-17); 181.2 (C-18);
17.1 (C-19); 17.0 (C-20); 1.0 and 0.3 (OSi(CH3)3). MS,
m=z: 364 ([M]þ, 2), 355 (0.7), 294 (33), 279 (8), 251 (2),
229 (2), 222 (2), 204 (23), 176 (50), 161 (10), 143 (80), 136
(8), 119 (12), 105 (10), 91 (13), 73 (100), 67 (23), 55 (30),
45 (24), 43 (47), 41 (33). HRMS calcd for C21H36O3Si:
364.2434; found 364.2445.
Acknowledgements
3.12. Treatment of 13 with m-CPBA: 14
The authors are grateful to A. Lithgow, Servicio Gen-
Compound 13 (448 mg, 1.34 mmol) was dissolved in dry
CH2Cl2 (10 mL), stirred at 0 °C and m-CPBA (230 mg,
1.34 mmol) was added. The mixture was stirred at room
temperature and monitored by TLC. After 15 h the
reaction was complete and the solvent evaporated.
Work-up afforded 410 mg of crude product that after
chromatography on silica gel gave 205 mg (50%) of 14 in
the hexane/EtOAc 1:1 fractions.
ꢀ
eral de Resonancia Magnetica Nuclear, Facultad de
Ciencias Quımicas, Universidad de Salamanca for the
ꢀ
NMR spectra, and Jansen-Cilag for the biological
activities.
References and notes
1. Rodilla, J. M. L.; Mendonßca, D. I.; Lithgow, A.; Marcos,
I. S. Phytochemistry 1997, 49, 1301.
2. Urones, J. G.; Marcos, I. S.; Diez, D.; Brito Palma, F. M.
S.; Rodilla, J. S. Phytochemistry 1987, 26, 3037.
3. Urones, J. G.; Marcos, I. S.; Basabe, P.; Garrido, N. M.
Phytochemistry 1990, 29, 2927.
3.12.1. 5-epi-14,15-Di-nor-16-hydroxy-13-oxo-ent-hali-
22
D
: 3481, 2935, 2879, 1766, 1720, 1450, 1378, 1280,
man-18,10b-olide, 14. ½aꢀ ¼ ꢂ19:5 (c 0.72, CHCl3). IR
film
max
m
1244, 1198, 1124, 1078, 1018, 939 cmꢂ1
.
1H NMR
(CDCl3): 4.28 (1H, d, J ¼ 17:5 Hz, H-16a), 4.16 (1H, d,
J ¼ 17:5 Hz, H-16b), 3.20 (1H, br s, 16-OH), 2.88 (1H,
m, H-12a), 2.26 (1H, m, H-12b), 2.22–1.91 (2H, m),
1.89–1.10 (12H, m), 1.02 (3H, s, Me-19), 0.77 (3H, d,
J ¼ 7:9 Hz, Me-17), 0.76 (3H, s, Me-20). 13C NMR
(CDCl3): 28.9 (C-1); 19.9 (C-2); 34.5 (C-3); 49.4 (C-4);
49.3 (C-5); 25.6 (C-6); 27.8 (C-7); 31.0 (C-8); 40.1 (C-9);
89.1 (C-10); 27.6 (C-11); 33.6 (C-12); 210.6 (C-13); 68.3
(C-16); 15.7 (C-17); 180.9 (C-18); 17.4 (C-19); 16.8 (C-
20). MS, m=z: 308 ([M]þ, 1), 277 (9), 260 (5), 250 (59),
249 (68), 231 (7), 222 (100), 221 (40), 204 (7), 189 (7), 177
(42), 167 (18), 153 (9), 149 (27), 135 (26), 121 (79), 107
(98), 95 (82), 93 (62), 91 (47), 81 (76), 79 (57), 69 (52), 67
(47), 55 (88), 43 (31), 41 (64). HRMS calcd for
C18H28O4: 308.1988; found 308.1996.
ꢀ
4. Urones, J. G.; de Pascual Teresa, J.; Marcos, I. S.; Dıez,
D.; Garrido, N. M.; Alfayate, R. Phytochemistry 1987, 26,
1077.
5. Urones, J. G.; Marcos, I. S.; Martın, D. D.; Alonso, M. C.
ꢀ
A.; Brito Palma, F. M. S.; Rodilla, J. M. Phytochemistry
1989, 28, 557.
6. (a) Urones, J. G.; Marcos, I. S.; Alonso, C. A.; Moro, R.
F.; Rodilla, J. M. L. Phytochemistry 1993, 34, 569; (b)
Rodilla, J. M. L.; Mendonßca, D. I.; Urones, J. G.; Moro,
R. Phytochemistry 1998, 49, 817; (c) Urones, J. G.;
Marcos, I. S.; Alonso, C. A.; Moro, R. F.; Willians, D.
J. Phytochemistry 1998, 49, 1545; (d) Rodilla, J. M. L.;
Mendonßca, D. I.; Ismael, I. G.; Figueiredo, A.; Silva, L.;
Lopes, E. Nat. Prod. Lett. 2001, 15, 401.
7. Urones, J. G.; Marcos, I. S.; Basabe, P.; Sexmero, M. J.;
Carrillo, H.; Melchor, M. Phytochemistry 1994, 37, 1359.
8. Rodilla, J. M.; Ismael, M. I.; Silva, L. A.; Serrano, J. P. C.;
Urones, J. G.; Sanz, F. Tetrahedron Lett. 2002, 43, 4605.
3.13. Reaction of 14 with Bestmann ketene: synthesis of 1
ꢀ
ꢀ
9. Urones, J. G.; Dıez, D.; Gomez, P. M.; Marcos, I. S.;
Basabe, P.; Moro, R. F. J. Chem. Soc., Perkin Trans. 1
1997, 1815.
To a solution of 14 (189 mg, 0.61 mmol) in toluene
temperature
ꢀ
10. Marcos, I. S.; Gonzalez, J. L.; Sexmero, M. J.; Dıez, D.;
Basabe, P.; Williams, D. J.; Simmonds, M. S. J.; Urones,
(15 mL)
was
added
at
room
Ph3P@C@C@O (422 mg, 1.40 mmol) and stirred for 3 h
at 85 °C. After the solution was filtered with ether under
celite. The solvent was removed at reduced pressure and
the residue chromatographed yielding with hexane/
EtOAc 7:3, 153 mg (75%) of 1.
J. G. Tetrahedron Lett. 2000, 41, 2553.
11. Marcos, I. S.; Pedrero, A. B.; Sexmero, M. J.; Dıez, D.;
ꢀ
Basabe, P.; Hernandez, F. A.; Urones, J. G. Tetrahedron
ꢀ
Lett. 2003, 44, 369.
12. Crystal data for 3: C20H34O3, M ¼ 322:47, orthorhombic,
space group P212121 (no 19). a ¼ 6:5835ð6Þ, b ¼
3
ꢁ
ꢁ
11:9462ð5Þ, c ¼ 24:931ð2Þ A, V ¼ 1960:8ð3Þ A , Z ¼ 4,
Dc ¼ 1:092 Mg/m3, m ¼ (Cu-Ka) ¼ 0.557, F ð000Þ ¼ 712.
Data (1946 collected reflections and 1262 observed reflec-
tions [I > 2rðIÞ]) were measured on a Seifert 3003 SC
3.13.1. 5-epi-ent-Halim-13-en-18,10b;15,16-diolide, 1.
22
D
film
max
½aꢀ ¼ ꢂ15:4 (c 0.26, CHCl3). IR m : 3103, 2937,
2878, 1768, 1747, 1637, 1448, 1377, 1263, 1244, 1197,

J. M. L. Rodilla et al. / Tetrahedron: Asymmetry 15 (2004) 1793–1799
1799
rotating anode diffractometer with (Cu-Ka) radiation
(graphite monochromator) using 2h ꢂ x scans at
293(2) K. The structure was solved by direct methods
and the nonhydrogen atoms were refined anisotropically
by full-matrix least squares based on F 2 to give the
agreement factors R1 ¼ 0:0352, wR2 ¼ 0:0629. Full crys-
tallographic details for the structures reported in this
paper has been deposited at the Cambridge Crystallo-
graphic Data Centre as supplementary material no
CCDC-203161.
performed using CRYSOM software for data collection,
XRAY8O for data reduction, SHELXTLTM to resolve and
refine the structure. Full crystallographic details for the
structures reported in this paper has been deposited at the
Cambridge Crystallographic Data Centre as supplemen-
tary material no CCDC-203162.
15. (a) Sharpless, K. B.; Yong, M. W. J. Org. Chem. 1975, 40,
7947; (b) Back, T. G.; McPhee, D. J. J. Org. Chem. 1984,
49, 3842.
16. Poli, G. Tetrahedron 2000, 56, 5959.
17. Krow, G. R. In Organic Reactions; John Wiley and Sons:
New York, 1993; 43, p 251.
18. Piacatelli, G.; Scentti, A.; D’Auria, M. Synthesis 1982,
245.
19. Brownbridge, P. Synthesis 1983, 1–28.
13. Grieco, P. A.; Jaw, J. Y. J. Org. Chem. 1981, 46, 1215.
14. Crystal data for 7: C26H37O4Se, M ¼ 506:53, monoclinic,
space group P21 (no 4). a ¼ 10:681ð2Þ, b ¼ 10:032ð2Þ,
ꢁ
c ¼ 11:815ð2Þ A, a ¼ d ¼ 90°, b ¼ 101:39ð3Þ°, V ¼
3
3
ꢁ
1241:0ð4Þ A , Z ¼ 2, Dc ¼ 1:356 Mg/m , m ¼ (Cu-Ka) ¼
1.544, F ð000Þ ¼ 532. (3567 collected reflections and 3218
observed reflections [I > 2rðIÞ]). The structure was solved
by direct methods and the nonhydrogen atoms were
placed in calculated positions. Final agreement factors
were R1 ¼ 0:0556, wR2 ¼ 0:0692. All calculations were
20. Bestmann, H. J. Angew. Chem., Int. Engl. 1977, 16, 349.
ꢀ
21. Marcos, I. S.; Pedrero, A. B.; Sexmero, M. J.; Dıez, D.;
Basabe, P.; Garcia, N.; Moro, R. F.; Broughton, H. B.;
Mollinedo, H. B.; Urones, J. G. J. Org. Chem. 2003, 68,
7496.