A stereoselective route towards heliannuol A

Article abstract of DOI:10.1016/j.tet.2008.03.105

Both epimers of Heliannuol A, first heliannane reported in the literature, isolated from Heliannthus annuus, have been prepared individually in a stereoselective route using a ring closing metathesis (RCM) as a key step to obtain the eight-membered ring. Very good overall yield was obtained in both cases.

Full text of DOI:10.1016/j.tet.2008.03.105

Tetrahedron 64 (2008) 5502–5508
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A stereoselective route towards heliannuol A
a
,
a
a
b
c
*
´
Francisco A. Macıas , David Chinchilla , Jose M.G. Molinillo , Frank R. Fronczek , Kozo Shishido
a
´
´
´
´
Grupo de Alelopat´ıa, Departamento de Qu´ımica Organica, Universidad de Cadiz, Avda. Republica Saharahui, s/n, Apdo. 40, 11510 Puerto Real, Cadiz, Spain
b Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA
c Graduate School of Pharmaceutical Sciences, The University of Tokushima, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Both epimers of Heliannuol A, first heliannane reported in the literature, isolated from Heliannthus
annuus, have been prepared individually in a stereoselective route using a ring closing metathesis (RCM)
as a key step to obtain the eight-membered ring. Very good overall yield was obtained in both cases.
Ó 2008 Published by Elsevier Ltd.
Received 24 February 2008
Received in revised form 26 March 2008
Accepted 29 March 2008
Available online 3 April 2008
1. Introduction
heliannane skeleton, or in the synthesis of (ꢀ)-heliannuol D.5
Moreover, several trials to get access to acid-catalyzed cyclization
Heliannuol A is the first heliannane reported in the literature.1 It
was isolated from sunflower leaves and all the following members
of the family have been isolated from the same source, but in
different sunflower varieties. Surprisingly, no heliannuols have
been isolated from other terrestrial sources so far. However, the
basic heliannane skeleton has been isolated lately from a marine
organism, the Indo-Pacific sponge Haliclona fascigera (Fig. 1).2
Later, the remaining members that conform to the family of the
heliannanes have been isolated and they are grouped in function of
their structure in four types of skeletons, 7,11-heliannanes; 7,10-
heliannanes; 8,10-heliannanes and 8,11-heliannanes (Fig. 2).
conditions of Heliannuols did not give satisfactory result. This sit-
uation prompted us to look for an alternative synthetic method-
ology that will give us access to the desired 7,11-heliannuol
backbone that is shown in the retrosynthetic analysis depicted in
Figure 3.
The synthetic procedure presents as key steps the incorporation
of the two side chains into the aromatic core of the molecule, the
intramolecular cyclization using a ruthenium-catalyzed RCM, and
the stereoselective epoxidation of the double bond in the oxepane
ring. This synthetic strategy also allowed us to obtain several
derivatives of the 7,11-heliannanes.
Starting from a previously synthesized 1 by us in the prepara-
tion of (ꢀ)-heliannuol D5 (1) (Scheme 1), selective deprotection of
the benzyl group at C-2 in the aromatic ring was achieved using
MgBr2 in toluene, yielding 2 (78%) as major reaction product and 3
2. Results and discussion
There are some previous reports showing the formation of
heliannuol A3 while base catalyzed cyclization towards heliannuol
D takes place4 that will be in good accordance with the biogenetic
hypothesis proposed by Macias et al.1b However, we have not been
able to detect such a process either in the synthesis of the 7,10-
14
7
14
7
6
3
8
8
1
2
5
9
1
9
2
O
10
10
14
15
O
11
4
11
13
13
7
8
6
3
HO
1
2
12
12
7,10-Heliannane
5
9
7,11-Heliannane
10
11
15
4
OH
O
O
12
14
7
14
7
13
(+)-Heliannane
(-)-Heliannuol A
8
8
9
1
2
9
1
2
10
10
Figure 1. Heliannuol A and heliannane structure.
13
11
O
13
O
11
12
12
8,11-Heliannane
8,10-Heliannane
* Corresponding author. Tel.: þ34 956 016 370; fax: þ34 956 016 193.
´
E-mail address: famacias@uca.es (F.A. Macıas).
Figure 2. Heliannane skeleton types.
0040-4020/$ – see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.03.105

F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 5502–5508
5503
HO
HO
HO
OH
O
O
O
O
O
HO
HO
OH
O
Figure 3. Retrosynthetic analysis.
O
O
6
O
BnO
BnO
7
HO
a
1
2
5
4
8
+
Figure 4. ORTEP diagram of 2.
OBn
OH
OBn
3
2
9
1
3
quinoline in order to avoid overreductions. After 1 h of reaction
a single compound (5) with a slightly higher Rf value could be
isolated with a 92% yield.
b
O
7
6
Treatment of compound 5 with allyl bromide and metallic
magnesium in dry THF (10 min, rt) led to the formation of two
undesired compounds of higher polarity (6 and 7). In order to avoid
these undesired results, the order of the reactions was changed.
Compound 6 obtained could be explained via 1,1-dimethyallyl
bromide formation and subsequent SN20 reaction. Consequently,
using 4 as starting material, the incorporation of the side chain in
the carbonyl system was achieved through a Grignard reaction, as
previously described. After 15 min of reaction two compounds of
higher polarity were formed (8 and 7).
BnO
1
2
5
8
4
11
12
10
O
3
4
9
13
14
d
c
O
BnO
OH
8
9
6
BnO
7
10
13
1
2
5
4
O
12
11
5
O
Once the preparation of both side chains is completed, the route
takes two different paths, depending on the order that we perform
the reactions, but both with the same target, achieving the eight-
membered ring (Scheme 2).
3
9
8
14
15
d
+
OH
16
OH
If we first perform the reduction of compound 8 under the same
conditions as for compound 4, we obtain the desired compound 9
almost quantitatively, starting material of the reaction of metath-
esis. From another point of view, heliannuol A does not have hy-
droxyl group at C-7 in the oxepane ring. Consequently, the hydroxyl
group present in compound 8 should be removed prior to or after
the metathesis cyclization. Using this sequence of reactions, treat-
ment of 8 with BF3$Et2O and Et3SiH (1:0.5:1) at ꢁ78 ꢂC yields
compound 10 (82%) where the hydroxyl group was removed. Re-
duction of the triple bond in 10 under the same conditions men-
tioned for 8 yields the desired compound 11 in a 92%.
The RCM is a synthetic tool that has experienced an extensive
use in the synthesis of natural products containing medium to large
cycles and has been previously used in several heliannane syn-
thesis.10 We have used this reaction to get access effectively to the
oxepane ring using the second generation Grubbs’ catalyst7 and the
two olefins 9 and 11.
Treatment of the diolefin 9 (0.01 M), carrying a hydroxyl group
at C-7 position, with a 10 mol % of the Grubbs’ catalyst8 in degassed
DCM over 1 h gave a more polar compound (12) in a yield of 90%.
When compound 11 was treated under the same conditions,
a compound with a higher polarity (13) than 11 was obtained in 91%
yield.
Direct epoxidation of the 7,11-heliannanes with MCPBA results
in no reaction, probably due to the high steric hindrance caused by
the two methyl groups and the conformation of the molecule.
Looking for small size epoxidizing agents, we selected dioxirane
reagents as a feasible reactant. Their use has been demonstrated to
be more effective if generated in situ from potassium peroxo-
monosulphate and ketones, and specially from methyl(tri-
fluoromethyl)dioxirane buffered with potassium bicarbonate.9
6
3
9
BnO
BnO
7
1
2
10
5
4
8
14
12
13
15
OH
11
O
17
7
6
+
OH
BnO
OH
7
Scheme 1. Reagents and conditions: (a) MgBr2, toluene (2 78%, 3 15%, 12 h, rt then 1 h,
110 ꢂC); (b) 3-chloro-3-methyl-1-butyne, CuCl2, DBU (95%, 5 h, 0 ꢂC); (c) Pd(CO3Ca/Pb)
(40% w/w), quinoline (60% w/w), H2, hexane (5 92%, 1 h, rt); (d) allyl bromide, Mg, I2,
dry THF (6 17%, 7 35% and 8 83%, 7 3%, 10 min, rt).
(15%) as side product. The use of MgBr2 allows selective depro-
tection when a carbonyl group is close to the benzyl derivative
through formation of a chelate between the carbonyl group, the
oxygen of the ether, and the magnesium atom.6 Differentiation
between both structures came from the X-ray analysis of the major
compound 2, which confirmed the expected structure (Fig. 4).
Treatment of 2 with 3-chloro-3-methyl-1-butyne under basic
conditions (DBU) using CuCl2 as catalyst gave 4 with a 95% yield.
Due to the reactive nature of the alkyne protons, several conden-
sation products of unknown nature in the side chain appear when
the catalyst is not present.7
Previous to the incorporation of the second side chain in the
carbonyl group through a Grignard reaction it was necessary to
achieve the reduction of the triple bond to avoid possible in-
terferences of the acidic alkynyl proton. In this case, the method
consisted on the use of the Lindlar catalyst in the presence of

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F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 5502–5508
OH
OH
HO
OH
BnO
BnO
BnO
c
b
d
O
O
O
O
12
14
9
BnO
BnO
g
f
b
O
a
OH
OH
O
O
17
O
16
OH
19
BnO
Global yield: 21.2%
O
BnO
BnO
BnO
e
c
a
8
b
O
O
13
O
11
10
HO
BnO
BnO
g
e
f
O
OH
OH
O
20
O
15
O
18
Global yield: 20.3%
Scheme 2. Reagents and conditions: (a) Pd(CO3Ca/Pb) (40% w/w), quinoline (60% w/w), H2, hexane (9 95%, 11 92%, 1 h, rt); (b) Et3SiH, BF3$Et2O, CH2Cl2 (10 82%, 16 68%, 10 min
at ꢁ78 ꢂC and then 1 h, ꢁ50 ꢂC); (c) Grubbs’ catalyst (10% w/w), CH2Cl2 degassed (12 90%, 13 91%); (d) methyl trifluoromethyl ketone, NaHCO3, OXONEÒ, CH3CN/Na2EDTA (82%,
2 h, ꢁ2 ꢂC); (e) methyl trifluoromethyl ketone, NaHCO3, OXONEÒ, Acetone/Na2EDTA (72%, 2 h, ꢁ2 ꢂC); (f) LiAlH4, dry THF (17 71%, 18 75%, 2 h, rt); (g) Pd/C (50% w/w), H2, CH2Cl2
(19 98%, 20 99%).
Usually, a biphasic solvent system DCM/H2O or Et2O/H2O is adop-
ted, but last reports refer CH3CN/H2O as the most effective solvent
system.10
Reaction of compound 12 with methyl trifluoromethyl ketone
and OXONEÒ (potassium peroxomonosulfate, ALDRICH) in CH3CN/
H2O with NaHCO3 and Na2EDTA gave only one product of higher
polarity in an 82% yield, product 14. Similar treatment of 13 under
the same conditions gave compound 15. However, the yield in this
case was lower (37%). The low polarity of the starting material 13
could be probably the reason for such a low yield due to low sol-
ubility in the biphasic acetonitrile/water solvent system. Best re-
sults were obtained with an acetone/water solvent system (72%).
The diastereoselectivity of this reaction is also remarkable as a ra-
cemic diastereoisomer is obtained from each racemic substrate,
thus concluding that epoxidation is produced only by one of the
two faces of each diastereoisomer. The positive NOE effects ob-
served between the methyl group H-14 and the oxirane protons H-
9 and H-10 in 14, and between H-7 and the oxirane protons in 15
clearly demonstrate that there is an asymmetric induction effect
caused by the hydroxyl group at C-7. When the hydroxyl group is
present (compound 14), a relative cis disposition between the
hydroxyl group and the epoxide ring occurs. However, when the
hydroxyl group is not present (compound 15) a relative syn dis-
position is obtained between the methyl group and the oxirane ring
(Fig. 5).
Next step towards the synthesis of (ꢀ)-heliannuol A was to
remove the hydroxyl group of compound 14, prior to the epoxide
ring opening. This was achieved using a similar methodology to
that used for compound 10. Thus, treatment of 14 with Et3SiH (1:1)
and BF3$Et3O (1:0.5) at ꢁ78 ꢂC gave 16 in a 68% yield. Epoxide ring
opening was achieved in both cases (compounds 15 and 16) using
LiAlH4 in good yields, and finally, Pd/C catalyzed hydrogenation of
compounds 17 and 18 gave the corresponding debenzylated com-
pounds 19 and 20 almost quantitatively.
The exact match of chemical shifts and coupling constants for all
proton/carbon resonances between 20 and (þ)-heliannuol
A
Figure 5. NOE in 14 and 15.

F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 5502–5508
5505
isolated from Helianthus annuus allowed to identify this synthetic
4.2.2. 5-Benzyloxy-2-(1,1-dimethylprop-1-yn-1-yl)oxy-4-
methylacetophenone (4)
product as the natural epimer.1
To a solution of 2 (1.5 g, 6.2 mmol) in CH3CN (10 mL) under Ar
and cooled in an ice–salt bath (ꢁ4 ꢂC) were added DBU (3.7 mL,
25 mmol), CuCl2$2H2O (3 mg, 0.3 mol %) and 1,1-dimethyl-
propargyl chloride (3.81 g, 37.2 mmol). The resulting solution was
allowed to stir at 0 ꢂC for 5 h. Then, the mixture was concentrated
at reduced pressure and the residue chromatographed in silica gel
CC using hexane/AcOEt (19:1) as eluent, yielding compound 4
(95%).
3. Conclusion
In summary, it can be concluded that the synthesis of com-
pounds 19 and 20 can be selectively achieved in 11 steps by
changing the order of the deoxygenation and Lindlar reduction
reactions. Using the benzylated hydroquinone 1 as starting mate-
rial, the overall yield for (ꢀ)-epi-heliannuol A (19) and for
(ꢀ)-heliannuol A (20) is 21.2 and 20.3%, respectively.
4.2.2.1. Compound 4. IR (neat, KBr) nmax 3285, 2987, 2834,
1671 cmꢁ1; UV (MeOH) lmax 205, 235, 250 nm; EIMS m/z (rel int.)
322 [M]þ (16), 255 [MꢁC5H7]þ (100). 1H NMR (400 MHz, CDCl3)
4. Experimental
4.1. General
d
7.46 (5H, m, H-30-H-70), 7.34 (2H, s, H-6, H-3), 5.02 (2H, s, H-10),
2.71 (3H, s, H-8), 2.67 (1H, s, H-12), 2.38 (3H, s, H-9), 1.75 (6H, s, H-
13, H-14). 13C NMR (100 MHz, CDCl3)
200.0 (C-7), 152.4 (C-2),
d
148.5 (C-5), 137.1 (C-20), 132.5 (C-4), 131.0 (C-1), 128.4 (C-40, C-70),
127.7 (C-50), 127.2 (C-30,C-60), 124.0 (C-3), 111.5 (C-6), 85.5 (C-11),
74.9 (C-12), 73.8 (C-10), 70.1 (C-10), 31.6 (C-8), 29.6 (C-13,C-14), 16.7
(C-9). HREIMS (Mþ) found 322.1559. C21H22O3 requires 322.1569.
Mp 36–39 ꢂC.
Commercially available chemicals were used as received. Dry
THF was obtained by distillation from sodium benzophenone ketyl.
1H and 13C NMR spectra (400 and 100 MHz, respectively) were
recorded on both Varian Unity Spectrometers with a sample tem-
perature of 25 ꢂC using CDCl3 as solvent and TMS as internal ref-
erence. Mass spectroscopy was carried out using a GC–MS VG1250
apparatus (ion trap detector) in EI mode. FTIR spectra were recor-
ded on a Perkin Elmer Spectrum BX spectrometer and UV–vis
spectra were obtained with a Varian Cary BIO 50 spectrometer. Mps
of crystalline compounds were determined on a Bu¨chi Melting
Point B-545 apparatus and are uncorrected. Purities of synthesized
compounds were determined by NMR and HPLC methods, and
corroborated by HRMS and elemental analysis when appropriate.
The diffraction data were collected to qmax¼32.6ꢂ at T¼105 K on
4.2.3. Lindlar reduction: preparation of 5-benzyloxy-2-
(1,1-dimethylprop-2-en-1-yl)oxy-4-methylacetophenone (5),
5-benzyloxy-2-(1,1-dimethylprop-2-en-1-yl)oxy-4-methyl-1-
(1-methyl-1-hydroxybut-3-en-1-yl)benzene (9), and 5-benzyloxy-
2-(1,1-dimethylprop-2-en-1-yl)oxy-4-methyl-1-(1-methylbut-3-
en-1-yl)benzene (11)
Quinoline (120 mL) and alkyne (500 mg) were dissolved in
hexane (50 mL). Commercially available Lindlar catalyst (200 mg)
was added and the resulting suspension was stirred till complete
conversion under an atmosphere of H2 (1 atm). The catalyst was
filtered off through a pad of Celite, the solvent was evaporated and
the residue was purified by CC (hexane/AcOEt, from 19:1 to 4:1)
affording dienes 5 (92%), 9 (95%) and 11 (92%), respectively.
a KappaCCD diffractometer equipped with Mo K
Oxford Cryosteam sample chiller.
a radiation and an
4.2. Synthetic procedure
4.2.1. 5-Benzyloxy-2-hydroxy-4-methylacetophenone (2)
To a solution of 1 (2 g, 5.77 mmol) in dry toluene, MgBr2 (1.29 g,
7 mmol) was added. The reaction mixture was stirred at room
temperature for 12 h and, then, refluxed for 1 h. Finally, the mixture
was neutralized with diluted HCl aq and extracted (5ꢃ) with ethyl
acetate. The organic layers were combined, the solvent removed
under reduced pressure and chromatographed in silica gel CC using
hexane/AcOEt (19:1) as eluent. This procedure afforded compounds
2 (78%) and 3 (15%).
4.2.3.1. Compound 5. IR (neat, KBr) nmax 2985, 2954, 1668 cmꢁ1; UV
(MeOH) lmax 215, 235, 295 nm; EIMS m/z (rel int.) 324 [M]þ (16),
257 [MꢁC5H7]þ (100). 1H NMR (400 MHz, CDCl3)
d 7.26 (5H, m, H-
30-H-70), 7.21 (1H, s, H-6), 6.92 (1H, s, H-3), 6.13 (1H, dd, J¼11 and
17.6, H-11), 5.19 (1H, dd, J¼0.8 and 17.6, H-12b), 5.17 (1H, dd, J¼0.8
and 11, H-12a), 5.02 (2H, s, H-70), 2.61 (3H, s, H-8), 2.22 (3H, s, H-9),
1.47 (6H, s, H-14 and H-15). 13C NMR (100 MHz, CDCl3)
d 200.4 (C-
7), 151.6 (C-2), 149.5 (C-5), 144.0 (C-11), 137.2 (C-20), 132.4 (C-4),
130.4 (C-1), 128.4 (C-40, C-60), 127.7 (C-30, C-70), 127.2 (C-50), 123.2
(C-3), 113.8 (C-12), 111.5 (C-6), 80.9 (C-10), 73.8 (C-10), 32.0 (C-8),
27.2 (C-13,-14), 16.8 (C-9). HREIMS (Mþ) found 324.1557. C21H24O3
requires 324.1676.
4.2.1.1. Compound 2. IR (neat, KBr) nmax 3014, 2932, 2845,
1671 cmꢁ1; UV (MeOH) lmax 235, 260, 349 nm; EIMS m/z (rel int.)
256 [M]þ (100), 165 [MꢁC7H7]þ (80). 1H NMR (400 MHz, CDCl3)
d
7.43 (5H, m, H-30-H-70), 7.01 (1H, s, H-6), 6.79 (1H, s, H-3), 5.04
4.2.3.2. Compound 9. IR (neat, KBr) nmax 2985, 2934, 1648 cmꢁ1
;
(2H, s, H-10), 2.53 (3H, s, H-8), 2.29 (3H, s, H-9). 13C NMR (100 MHz,
UV (MeOH) lmax 215, 235, 295 nm; EIMS m/z (rel int.) 366 [M]þ
(35), 348 [MꢁH2O]þ (85), 257 [MꢁH2OꢁC7H7]þ (100). 1H NMR,
see Table 1. 13C NMR, see Table 2. HREIMS (Mþ) found 366.2208.
CDCl3) d 203.3 (C-7), 157.1 (C-2), 149.2 (C-5), 138.9 (C-4), 136.9 (C-6),
128.5 (C-30, C-70),127.9 (C-50),127.2 (C-40, C-60),120.1 (C-1),116.9 (C-
20), 111.8 (C-3), 70.8 (C-10), 26.5 (C-8), 17.0 (C-9). HREIMS (Mþ)
found 256.1104. C16H16O3 requires 256.1099. Mp 60–63 ꢂC.
C24H30O3 requires 366.2150.
4.2.3.3. Compound 11. IR (neat, KBr) nmax 3065, 2957, 2944,
1658 cmꢁ1; UV (MeOH) lmax 209, 230, 285 nm; EIMS m/z (rel int.)
350 [M]þ (10), 382 [MꢁC5H7]þ (55), 241 [MꢁC3H5ꢁC5H7]þ (100). 1H
NMR, see Table 1. 13C NMR, see Table 2. HREIMS (Mþ) found
350.2292. C24H30O2 requires 350.2246.
4.2.1.2. Compound 3. IR (neat, KBr) nmax 3015, 2934, 2835,
1669 cmꢁ1; UV (MeOH) lmax 236, 260, 350 nm; EIMS m/z (rel int.)
256 [M]þ (100), 165 [MꢁC7H7]þ (80). 1H NMR (400 MHz, CDCl3)
d
7.42 (5H, m, H-30-H-70), 7.08 (2H, s, H-6, H-3), 5.04 (2H, s, H-10),
2.56 (3H, s, H-8), 2.25 (3H, s, H-9). 13C NMR (100 MHz, CDCl3)
d
204.2 (C-7), 155.6 (C-2), 150.0 (C-5), 136.8 (C-4), 128.7 (C-6), 128.6
4.2.4. Grignard reaction: preparation of 5-benzyloxy-4-methyl-
2-(3-methylbut-2-en-1-yl)oxy-1-(1-methyl-1-hydroxybut-3-en-
1-yl)benzene (6), 5-benzyloxy-4-methyl-1-(1-methyl-1-
(C-70, C-30), 128.0 (C-50), 127.5 (C-60,C-40), 126.1 (C-1), 116.9 (C-20),
112.2 (C-3), 70.9 (C-10), 26.8 (C-8), 15.6 (C-9). HREIMS (Mþ) found
256.1103. C16H16O3 requires 256.1099.
hydroxybut-3-en-1-yl)-2-hydroxybencene (7), and 5-benzyloxy-

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F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 5502–5508
Table 1
1H NMR data for compounds 6, 8–19 (400 MHz in CDCl3, signal of residual CHCl3 centred at
d
7.25 ppm)
6
8
9
10
11
12
13
14
15
16
17
18
19
3
6
7
8
6.80 s
6.80 s
6.80 s
7.25 s
6.80 s
6.93 s
6.68 s
7.21 s
3.23 ddq
2.32 m
6.67 s
6.82 s
3.23 ddq
2.32 m
6.73 s
7.22 s
6.56 s
6.71 s
2.91 m
3.30 m
2.15 m
5.67 ddd
6.78 s
7.23 s
6.60 s
6.77 s
2.93 ddq
2.29 dd
2.25 dd
3.03 ddd
6.65 s
6.68 s
3.23 ddq
2.50 ddd
6.66 s
6.70 s
3.19 ddq
2.04 m
6.65 s
6.74 s
3.19 ddq
6.52 s
6.69 s
3.08 ddq
2.06 m
2.77 dd
2.48 dd
5.70 dddd
6.88 dd
6.80 dd
5.52 dddd
2.77 dd
2.58 dd
5.60 dddd
3.82 ddd
2.24 ddd
5.73 ddd
2.67 dd
2.42 dd
3.31 ddd
9
5.71 dddd
5.71 dddd
3.13 ddd
2.68 d
2.05 m
3.43 d
2.05 m
1.91 dddd
3.38 d
10
5.17 dd
5.14 dd
3.35 d
5.06 dd
5.00 dd
5.05 dd
4.97 dd
4.94 dd
4.92 dd
4.89 dd
5.41 dd
5.41 dd
2.59 d
2.52 d
3.65 br d
11
12
13
5.01 dd
6.18 dd
5.25 dd
5.21 dd
5.10 ddd
6.12 dd
5.19 dd
5.10 dd
1.40 s
1.40 s
1.12 d
2.17 s
1.58a
1.45a
s
s
1.57a
1.37a
s
s
1.44a
1.40a
s
s
1.53a
1.41a
s
s
1.52a
1.41a
s
s
1.44a
1.39a
s
s
1.44a
1.38a
s
s
1.40a
1.35a
s
s
2.64 s
2.50 s
14
15
16
1.58a
1.52a
1.47 s
2.17 s
s
s
1.73a
s
1.58a
1.52a
1.47 s
2.17 s
s
s
1.64 s
1.62 s
1.15 d
2.19 s
5.02 s
7.36 m
1.37 s
2.22 s
1.26 d
2.19 s
1.56 s
2.23 s
1.17 d
2.18 s
1.30 d
2.20 s
1.25 d
2.22 s
1.25 d
2.22 s
1.15 d
2.14 s
1.72 s
1.44 s
2.22 s
5.02 s
7.36 m
17
10
5.02 s
7.36 m
5.02 s
7.36 m
5.02 s
7.36 m
5.06 s
7.40 m
5.01 s
7.40 m
5.06 s
7.40 m
5.04 s
7.35 m
5.02 s
7.36 m
5.05 s
7.35 m
5.03 s
7.35 m
30–70
J (Hz): (6) 9,10a¼18; 9,10b¼10.2; 9,8a¼9,8b¼7.3; 8a,8b¼13.6; 11a,12¼11b,12¼6.2; 12,13¼1.3; 10a,10b¼0.9; 12,13a¼10.7; 12,13b¼17.9; 13a,13b¼0.54. (8) 9,10a¼17.1; 9,10b¼10;
9,8a¼9,8b¼6.5; 8a,8b¼13.6; 10a,10b¼0.9. (9) 9,10a¼18; 9,10b¼10.2; 9,8a¼9,8b¼7.3; 8a,8b¼13.6; 10a,10b¼0.9; 12,13a¼10.7; 12,13b¼17.9; 13a,13b¼0.54. (10) 9,10a¼17.2;
9,10b¼10.3; 9,8a¼9,8b¼7.3; 7,14¼7,8a¼7,8b¼6.6, 10a,10b¼0.8. (11) 9,10a¼17.3; 9,10b¼10.3; 9,8a¼9,8b¼7.3; 7,14¼7,8a¼7,8b¼7.1, 10a,10b¼1.0; 12,13a¼10.9; 12,13b¼17.6;
13a,13b¼0.98. (12) 8a,10¼1.2; 8a,9¼10; 8a,8b¼12.8; 9,10¼10.7. (13) 7,14¼6.9; 9,10¼10.6. (14) 8a,9¼3.9; 8a,8b¼13.6; 8b,9¼11; 9,10¼3.9. (15) 8a,8b¼6.9; 8a,9¼8b,9¼3.9;
7,14¼6.9; 9,10¼4.2. (16) 9,10¼4.2; 9,8a¼4.2; 9,8b¼8.7; 7,14¼7,8a¼7,8b¼7.4. (17) 7,8a¼7.5; 7,8b¼15.6; 7,14¼6.9; 9a,10¼9.1. (18) 7,14¼6.9; 10,9a¼7. (19) 7,8a¼7.4; 7,8b¼14.8;
7,14¼7.2; 9b,10¼9.1; 9b,9a¼13.8; 9b,8a¼9b,8b¼3.1.
a
Signals may be interchanged.
4-methyl-2-(1,1-dimethylprop-2-yn-1-yl)oxy-1-(1-methyl-
1-hydroxybut-3-en-1-yl)benzene (8)
The treatment of
(22.3 mg, 930 mol) and allyl bromide (78
(5 mL) afforded 8 (83%) and 7 (3%).
4
(100 mg, 310
m
mol) with magnesium
m
m
L, 930 mol) in THF
m
A catalytic amount of I2 was added to 23 mg (924 mmol) of
magnesium in 1 mL of dry THF in Ar atmosphere at room temper-
ature. The mixture was stirred and 0.5 mL of a solution of 5
(100 mg, 308 mmol) and allyl bromide (77 mL, 924 mmol) in THF
4.2.4.1. Compound 6. IR (neat, KBr) nmax 3055, 2897, 2844,
1612 cmꢁ1; UV (MeOH) lmax 205, 235, 250 nm; EIMS m/z (rel int.)
(5 mL) was added. The reaction mixture colour changes from or-
ange to colourless. When the colour turns to grey, the remaining
solution of 5 and allyl bromide was added and stirred for 10–30 min
till a polar compound was observed in TLC. NH4Cl saturated solu-
tion (50 mL) in water was added and the mixture extracted with
EtOAc (5ꢃ). The organic layer was dried over anhydrous Na2SO4
and the solvent evaporated. The mixture was chromatographed
(hexane/AcOEt 9:1), yielding compounds 6 (17%) and 7 (35%).
366 [M]þ (14), 333 [MꢁH2OꢁCH3]þ (100). 1H NMR, see Table 1. 13
C
NMR, see Table 2. HREIMS (Mþ) found 366.2024. C24H30O3 requires
366.2195.
4.2.4.2. Compound 7. IR (neat, KBr) nmax 3255, 3027, 2977,
2954 cmꢁ1; UV (MeOH) lmax 235, 260, 349 nm; EIMS m/z (rel int.)
298 [M]þ (18), 280 [MꢁH2O]þ (75). 1H NMR (400 MHz, CDCl3)
d 7.40
(5H, m, H-30-H-70), 6.70 (1H, s, H-6), 6.56 (1H, s, H-3), 5.70 (1H,
Table 2
13C NMR data for compounds 6, 8–19 (100 MHz in CDCl3, signal CDCl3 centred at
d 77.0 ppm)
6
8
9
10
11
12
13
14
15
16
17
18
19
1
2
3
4
5
6
7
8
125.0
149.8
118.0
124.7
149.2
115.1
64.0
125.5
150.5
117.5
125.5
147.2
111.6
60.9
125.5
150.5
117.5
125.5
147.2
111.6
70.7
137.3
152.4
115.5
124.4
146.4
110.4
32.1
127.3
151.8
115.4
124.2
146.8
110.6
32.1
126.2
153.6
126.7
127.6
151.4
110.6
70.0
128.9
153.4
127.4
127.1
145.6
124.4
33.8
126.2
153.7
128.5
127.6
151.4
110.6
70.1
42.0
55.9
59.6
127.5
150.7
122.0
127.2
145.6
117.0
29.8
37.2
58.0
59.6
127.4
153.6
111.5
126.3
148.2
109.1
25.4
43.7
56.9
62.6
71.1
124.9
153.7
126.9
124.4
146.0
109.4
31.7
25.7
35.9
75.7
124.9
153.6
126.6
124.3
146.7
109.1
31.8
25.3
35.6
76.7
121.4
150.9
127.1
112.4
145.8
127.0
32.1
36.2
23.2
82.9
48.4
46.9
47.0
41.9
41.9
40.5
40.0
9
134.5
119.0
64.5
119.6
137.9
22.8
20.5
32.2
16.6
73.4
134.4
117.9
71.7
86.1
74.1
29.7
29.6
27.6
16.2
134.9
120.1
80.1
144.8
113.4
27.7
27.7
27.4
16.1
74.2
137.4
122.7
70.5
86.9
73.2
29.9
29.9
20.5
16.3
137.6
122.8
79.1
145.0
122.8
27.8
27.8
20.5
16.2
70.6
128.8
137.2
77.1
134.9
137.5
70.0
10
11
12
13
14
15
16
17
10
74.1
70.6
82.6
82.5
75.9
29.5a
27.9a
33.0
29.3a
28.3a
33.7
29.3a
27.4a
34.2
27.6a
27.5a
34.2
26.7a
25.4
27.3
23.1a
20.9
23.2a
20.5a
25.5
23.2a
21.1a
25.8
25.6
16.0
16.0
15.83
16.0
15.7
16.1
16.0
15.8
74.0
72.3
81.7
143.2
127.2
128.3
128.6
80.7
143.2
127.2
128.3
128.6
79.9
143.2
127.2
128.3
127.6
80.7
142.1
127.3
128.1
127.7
70.5
137.8
127.9
128.7
127.4
70.4
137.6
127.3
128.4
127.7
70.6
137.1
127.3
128.4
127.7
20
134.6
127.6
127.8
127.6
137.6
128.3
127.3
127.6
137.2
127.7
128.4
127.2
137.6
127.2
128.3
127.3
137.6
127.2
128.3
127.3
30,70
40,60
50
a
Signals may be interchanged.

F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 5502–5508
5507
dddd, J¼18, 10, 7.5, and 7.5, H-9), 5.17 (1H, d, J¼18, H-10a), 5.14 (1H,
d, J¼10, H-10b), 5.02 (2H, s, H-10), 2.75 (1H, dd, J¼13.5, and 7.5, H-
8a), 2.48 (1H, dd, J¼13.5, and 7.5, H-8b), 2.23 (3H, s, H-12), 1.58 (3H,
[MꢁC7H7]þ (85), 177 (100). 1H NMR, see Table 1. 13C NMR, see Table
2. HREIMS (Mþ) found 322.1922. C22H26O2 requires 322.1933.
s, H-11). 13C NMR (100 MHz, CDCl3)
d 149.7 (C-2), 149.5 (C-5), 133.6
4.2.7. Stereoselective epoxidation: preparation of 5-benzyloxy-7-
(C-20), 133.0 (C-9), 128.0 (C-1), 127.7 (C-40,C-60), 127.5 (C-50), 127.4
(C-30,C-70), 126.6 (C-4), 119.8 (C-10), 119.6 (C-3), 111.2 (C-6), 71.3 (C-
7), 71.3 (C-10), 46.5 (C-8), 28.3 (C-11), 15.8 (C-12). HREIMS (Mþ)
found 298.1595. C19H22O3 requires 298.1569.
hydroxy-9
,10 -epoxy-7
To an acetonitrile solution (6 mL) of 12 (217 mg, 0.64 mmol) was
a,10a-epoxy-7,11-heliannane (14) and 5-benzyloxy-
9a
a
bH,11-heliannane (15)
added an aqueous Na2$EDTA solution (3.2 mL, 4ꢃ10ꢁ4 M). The
homogeneous solution was cooled to ꢁ2 ꢂC, followed by addition of
methyl trifluoromethyl ketone (0.7 mL) via a precooled syringe. To
this solution was added a mixture of NaHCO3 (554 mg, 6.6 mmol)
and OXONEÒ (2.478 g, 4.03 mmol) in five portions during an hour,
and, then, water was added and extraction with dichloromethane
was carried out (3ꢃ). The combined extracts were dried over an-
hydrous sodium sulfate and concentrated under reduced pressure.
The residue was purified by column chromatography using hexane/
EtOAc (4:1), yielding 14 (82%).
4.2.4.3. Compound 8. IR (neat, KBr) nmax, 3478, 3275, 3034, 2987,
2934 cmꢁ1; UV (MeOH) lmax 209, 235, 285 nm; EIMS m/z (rel int.)
364 [M]þ (18), 323 [MꢁC3H5]þ (65), 257 [MꢁC3H5ꢁC5H8]þ (100).
1H NMR, see Table 1. 13C NMR, see Table 2. HREIMS (Mþ) found
298.1595. C24H28O3 requires 298.1569.
4.2.5. Reductive deoxygenation: 5-benzyloxy-4-methyl-2-
(1,1-dimethylprop-2-yn-1-yl)oxy-1-(1-methylbut-3-en-
When this procedure was carried out on 13 it afforded
15 (72%).
1-yl)benzene (10) and 5-benzyloxy-9
heliannane (16)
a,10a-epoxy-7b-11-
A solution of 8 (100 mg, 274
m
mol) and triethylsilane (22 mL,
4.2.7.1. Compound 14. IR (neat, KBr) nmax 3465, 2981, 2924 cmꢁ1
;
137 mmol) in dry dichloromethane (3 mL) was cooled down to
ꢁ78 ꢂC and treated dropwise with freshly distilled boron trifluoride
UV (MeOH) lmax 209, 220, 280 nm; EIMS m/z (rel int.) 354 [M]þ
(40), 336 [MꢁH2O]þ (8). 1H NMR, see Table 1. 13C NMR, see Table 2.
HREIMS (Mþ) found 354.1829. C22H26O4 requires 354.1831.
etherate (34 mL, 274 mmol). The reaction mixture was stirred for
10 min at ꢁ78 ꢂC and 30 min at ꢁ50 ꢂC. Then, the reaction mixture
was quenched by the addition of 3 mL of saturated solution of
NaHCO3, allowed to warm up to 5 ꢂC, diluted with H2O (5 mL), and
thoroughly extracted with CH2Cl2 (4ꢃ). The combined extracts
were washed (brine), dried (Na2SO4), and evaporated. The oily
residue was purified by column chromatography (hexane/EtOAc
95:5) to furnish 10 (82%) as colourless oil.
4.2.7.2. Compound 15. IR (neat, KBr) nmax 2925, 2914, 1500 cmꢁ1
;
UV (MeOH) lmax 205, 215, 280 nm; EIMS m/z (rel int.) 338 [M]þ
(35), 267 (100). 1H NMR, see Table 1. 13C NMR, see Table 2. HREIMS
(Mþ) found 338.1891. C22H26O3 requires 338.1882. Mp 126–129 ꢂC.
Analogous treatment of 14 yielded 16 (62%).
4.2.8. Reductive opening of oxirane ring: preparation of
5-benzyloxy-10
5-benzyloxy-10
a
-hydroxy-7
a
H,11-heliannane (17) and
H,11-heliannane (18)
4.2.5.1. Compound 10. IR (neat, KBr) nmax 3277, 3104, 2954,
2924 cmꢁ1; UV (MeOH) lmax 209, 285 nm; EIMS m/z (rel int.) 348
[M]þ (42), 282 [MꢁC5H8]þ (100). 1H NMR, see Table 1. 13C NMR,
see Table 2. HREIMS (Mþ) found 348.2082. C24H28O2 requires
348.2089.
a-hydroxy-7
b
To a stirred suspension of LiAlH4 (123 mg, 3.25 mmol) in THF
(3 mL) at 0 ꢂC, a solution of 16 (100 mg, 295
mmol) in THF (1 mL)
was added. The reaction mixture was stirred for 5 h and a mixture
of water and diethylether (1:1) was then added and stirred for an
hour. The reaction mixture was filtered through Celite, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by column chromatography
using hexane/EtOAc (9:1), yielding 17 (71%).
4.2.5.2. Compound 16. IR (neat, KBr) nmax 2972, 2927 cmꢁ1; UV
(MeOH) lmax 205, 225, 285 nm; EIMS m/z (rel int.) 338 [M]þ (30),
267 (100). 1H NMR, see Table 1. 13C NMR, see Table 2. HREIMS (Mþ)
found 338.1880, C22H26O3 requires 338.1882.
When this procedure was carried out on 15 it afforded
18 (75%).
4.2.6. Ring closing metathesis reaction: preparation of 5-benzyloxy-
7-hydroxy-7,11-heliann-9(10)-ene (12) and 5-benzyloxy-7,11-
heliann-9(10)-ene (13)
The diene 9 (855 mg, 2.33 mmol) was dissolved in 233 mL of
gas free dichloromethane under Ar atmosphere. (Tricyclohexyl)-
phosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-
4.2.8.1. Compound 17. IR (neat, KBr) nmax 3464, 2933, 2924,
1499 cmꢁ1; UV (MeOH) lmax 205, 280 nm; EIMS m/z (rel int.) 340
[M]þ (36), 151 (100). 1H NMR, see Table 1. 13C NMR, see Table 2.
HREIMS (Mþ) found 340.2055. C22H28O3 requires 340.2038.
ylidene][benzylidene]ruthenium(IV) dichloride (197 mg, 233 mmol)
4.2.8.2. Compound 18. IR (neat, KBr) nmax 3450, 2926, 2914,
1500 cmꢁ1; UV (MeOH) lmax 205, 280 nm; EIMS m/z (rel int.) 340
[M]þ (36), 151 (100). 1H NMR, see Table 1. 13C NMR, see Table 2.
HREIMS (Mþ) found 340.2054. C22H28O3 requires 340.2038.
Mp 65–68 ꢂC.
was added and the resulting mixture was stirred for 1 h at room
temperature. The reaction flask was opened to deactivate Grubbs’
catalyst and stirred for an additional hour. The solvent was removed
by evaporation and chromatographed (hexane/AcOEt, 19:1), yielding
compound 12 (90%).
This procedure using 11 as starting material afforded 13 (91%).
4.2.9. Deprotection of hydroxyl group: preparation of
4.2.6.1. Compound 12. IR (neat, KBr) nmax 3469, 2976, 2926 cmꢁ1
;
5-hydroxy-10
(ꢀ)-heliannuol A (20)
Pd/C catalyst (50 mg) was added to a solution of 17 (100 mg,
293 mol) in dichloromethane (10 mL) and stirred for 3 h under
a-hydroxy-7aH,11-heliannane (19) and
UV (MeOH) lmax 209, 220, 280 nm; EIMS m/z (rel int.) 338 [M]þ
(15), 320 [MꢁC5H8]þ (35), 229 [MꢁC7H7]þ (100). 1H NMR, see Table 1.
13C NMR, see Table 2. HREIMS (Mþ) found 338.1869. C22H26O3
requires 338.1882.
m
hydrogen atmosphere (1 atm). The reaction mixture was filtered
through Celite and concentrated under reduced pressure. The
residue was purified by column chromatography using hexane/
EtOAc (4:1), yielding 19 (98%).
4.2.6.2. Compound 13. IR (neat, KBr) nmax 2961, 2926, 1499 cmꢁ1
UV (MeOH) lmax 215, 280 nm; EIMS m/z (rel int.) 322 [M]þ (70), 231
;

5508
F.A. Mac´ıas et al. / Tetrahedron 64 (2008) 5502–5508
When this procedure was carried out on 18 it afforded
References and notes
20 (99%).
1. (a) Macı´as, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G. Tetrahedron Lett.
´
1993, 34, 1999–2002; (b) Macıas, F. A.; Molinillo, J. M. G.; Varela, R. M.; Torres, A.
4.2.9.1. Compound 19. IR (neat, KBr) nmax 3390, 2927, 2914,
1500 cmꢁ1; UV (MeOH) lmax 205, 275, 290 nm; EIMS m/z (rel
int.) 250 [M]þ (27), 151 (100). 1H NMR, see Table 1. 13C NMR,
seeTable 2.HREIMS(Mþ)found250.1581. C15H22O3 requires250.1569.
J. Org. Chem. 1994, 59, 8261–8266.
2. Harrison, B.; Crews, P. J. Org. Chem. 1997, 62, 2646–2648.
3. (a) Grimm, E. L.; Levac, S.; Trimble, L. A. Tetrahedron Lett. 1994, 35, 6847–6850;
(b) Tuhina, K.; Bhowmik, D. R.; Venkateswaran, R. V. Chem. Commun. 2002,
´
634–635; (c) Lecornue, F.; Ollivier, J. Synlett 2004, 1613–1615.
4. Takabatake, K.; Nishi, I.; Shindo, M.; Shishido, K. J. Chem. Soc., Perkin Trans. 1
2000, 1807–1808.
5. Supplementary data
5. Macı´as, F. A.; Chinchilla, D.; Molinillo, J. M. G.; Marı´n, D.; Varela, R. M.; Torres, A.
Tetrahedron 2003, 59, 1679–1683.
6. Haraldsson, G. G.; Baldwin, J. E. Tetrahedron 1997, 53, 215–224.
7. Godfrey, J. D., Jr.; Mueller, R. H.; Sedergran, T. C.; Soundararajan, N.; Colandrea,
V. J. Tetrahedron Lett. 1994, 35, 6405–6408.
CCDC 676889 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2
1EZ, UK; fax: þ44(0)1223 336033; email: deposit@ccdc.cam.ac.uk].
8. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956.
9. Yang, D.; Wong, M.-.K.; Yip, Y.-.C. J. Org. Chem. 1995, 60, 3887–3889.
10. (a) Stefinovic, M.; Snieckus, V. J. Org. Chem.1998, 63, 2808–2809; (b) Kishuku, H.;
Shindo, M.; Shishido, K. Chem. Commun. 2003, 350–351; (c) Kamei, T.; Shindo,
M.; Shishido, K. Tetrahedron Lett. 2003, 44, 8505–8507; (d) Sabui, S. K.;
Venkateswaran, R. V. Tetrahedron Lett. 2004, 45, 3979–3982; (e) Biswas, B.;
Sen, P. K.; Venkateswaran, R. V. Tetrahedron 2007, 63, 12026–12036; (f) Zhang, J.;
Wang, X.; Wang, W.; Quan, W.; She, X.; Pan, X. Tetrahedron 2007, 63, 6990–6995;
(g) Roy, A.; Biswas, B.; Sen, P. K.; Venkateswaran, R. V. Tetrahedron Lett. 2007,
48, 6933–6936.
Acknowledgements
´
This research was supported by the Ministerio de Educacion y
Ciencia, Spain (MEC; AGL2005-05190/AGR).