Synthesis of heliannane skeletons. Facile preparation of (±)-heliannuol D

Article abstract of DOI:10.1016/S0040-4020(03)00134-0

Heliannuol D is a natural product with a 7,10-heliannane skeleton, isolated from Helianthus annuus. It has been synthesized in eight steps, in good yield, using a new biomimetic method. Key steps were a Fries rearrangement, a Grignard reaction and, finall

Full text of DOI:10.1016/S0040-4020(03)00134-0

Tetrahedron 59 (2003) 1679–1683
Synthesis of heliannane skeletons. Facile preparation
of (6)-heliannuol Dq
*
Francisco A. Macıas, David Chinchilla, Jose M. G. Molinillo, David Marın, Rosa M. Varela
´
´
and Ascension Torres
´
´
´ ´ ´
Grupo de Alelopatıa, Departamento de Quımica Organica, Universidad de Cadiz, Avda. Republica Saharaui, s/n, Apdo. 40,
´
´
11510 Puerto Real (Cadiz), Spain
´
Received 21 October 2002; revised 19 December 2002; accepted 22 January 2003
Abstract—Heliannuol D is a natural product with a 7,10-heliannane skeleton, isolated from Helianthus annuus. It has been synthesized in
eight steps, in good yield, using a new biomimetic method. Key steps were a Fries rearrangement, a Grignard reaction and, finally, a base
catalyzed cyclization. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
strategies for weed control, makes very interesting their
large scale synthesis, in order to test them in suitable
bioassays, evaluate their modes of action and propose them
as new herbicide models. The synthetic analogs obtained in
their synthesis research are also interesting, since their
bioactivity results can offer hints about the structural
requirements for bioactivity.
Allelochemicals are an important potential source for new
herbicides and agrochemicals, since they offer new modes
of action, more specific interaction with weed and less
environmental damage.2
Between the many organisms from which allelopathic
agents have been isolated (mainly plants and micro-
organisms), Helianthus annuus L. (sunflower), is one of
the most interesting ones, because of its high production
of secondary metabolites, especially terpenes and phenolic
compounds, including sesquiterpene lactones, heli-
espirones, annuionones, helibisabonols, and heliannuols.3
Heliannanes constitute a novel heterocyclic sesquiterpene
structural type isolated from H. annuus4a and from the Indo-
pacific sponge Haliclona fascigera.5 Their skeleton has a
benzenoid moiety fused to a six, seven, or eight-membered
heterocyclic ring (Fig. 1).6
Figure 1. Heliannane skeleton types.
Heliannuols, new compounds isolated from H. annuus, with
the heliannane skeleton, constitute an interesting family of
new compounds belonging to the four structural types
mentioned above. Heliannuols A, D and E7 (Fig. 2), have
special relevance, due to the high phytotoxic activity shown
by them.4b
The fact that these allelochemicals can take part in new
q See Ref. 1.
Keywords: heliannane skeleton; Helianthus annuus; heliannuol;
allelochemicals; synthesis of sesquiterpenes.
*
Corresponding author. Tel.: þ34-956-016-370; fax: þ34-956-016-193;
e-mail: famacias@uca.es
Figure 2. Heliannuols E, A and D.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00134-0

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F. A. Macıas et al. / Tetrahedron 59 (2003) 1679–1683
1680
Scheme 2. Reagents and conditions: (a) KHSO4, N,N-dimethylformamide
(quantitative, 2 h, 908C); (b) m-CPBA, KHCO3 aq (75%, 2 h, room
temperature); (c) H2/Pd/C, N,N-dimethylformamide (quantitative, 2 h,
room temperature).
Scheme 1. Reagents and conditions: (a) (CH3CO)2O, Py (quantitative,
24 h, room temperature); (b) BF3·Et2O, (quantitative, 3 h, 1208C);
(c) benzyl bromide, K2CO3, dimethoxyethane (quantitative, 12 h, 808C);
(d) 5-Br-2-methyl-2-pentene, Mg, I2, THFdry (81%, 1 h, 658C).
by McEnroe and Fenical,9 and for the obtention of fungal
sesquiterpene sydonic acid.10 Recently, this synthetic path-
way has been adapted for the obtention of (^)-helibisabonol
A,3c a new bisabolenic sesquiterpene from H. annuus
isolated in our laboratory.11
Several synthesis procedures for members of the heli-
annuols have been reported.7 Herein we present an easy and
efficient route to obtain (^)-Heliannuol D. This synthesis
procedure is based on a proposed biosynthetic hypothesis.6
Once the bisabolene skeleton obtained, we introduced an
epoxide moiety between positions C-10 and C-11, being
necessary to eliminate the tertiary hydroxyl group on 5 first
(Scheme 2). The dehydration was carried out with KHSO4
in N,N-dimethylformamide. This elimination procedure has
not been widely used, although KHSO4 has been described
as a useful reagent for dehydration in the synthesis of some
germacrane derivatives.12 This treatment yielded the
mixture of olefins 6 quantitatively. Further treatment of
this mixture with MCPBA in a biphasic system CH2Cl2/
KHCO3 (aq), allowed us obtain compound 7 in 75% yield.
This epoxidation method was chosen to avoid possible
rearrangements in species sensitive to acid.13
2. Results and discussion
The synthesis procedure described here has two main
stages: obtention of the appropriate aromatic bisabolene
skeleton from a benzenoid compound with the desired
substitution pattern, and cyclization to obtain the benz-
oxepane moiety.
The synthesis starts (Scheme 1) with the preparation of the
appropriate aromatic bisabolene skeleton 5, as a first key
step, using 2-methylhydroquinone (1). The desired substi-
tution pattern in the aromatic ring (3) was obtained in
quantitative yield by an ortho-Fries rearrangement8a of the
diacetyl derivative of 2-methyl-hydroquinone (2), carried
out at high temperature (1208C) in order to force an
intramolecular reaction mechanism to give the ortho
regioisomer.
Hydrogenation of 7, catalyzed by Pd/C, provides cleavage
of the benzylic ethers and reduction of the conjugated
double bond. This reduction yielded the pair of diastero-
isomers 8 and 9 in quantitative yield. Finally, cyclization of
epoxides 8 and 9 using NaOH 5% (24 h) led us to obtain the
This reaction have been used in other aromatic 1,4-diesters
with similar results,8b,c involving the cleavage of the non-
rearranged ester to yield 2,5-dihydroxyphenyl-alkyl
ketones.
The hydroxyl groups of 3 were protected to produce the
corresponding benzyl derivative (4) that was linked to the
side-chain by a Grignard reaction that leads to condensation
product 5 in an 81% yield after 1 h. This good yield was not
observed at reaction temperatures below þ658C, probably
due to the high steric hindrance provided by benzyl moiety
in position C-2. A similar procedure for side-chain linkage
has been used in curcuphenol synthesis procedure reported
Scheme 3. Base-catalyzed cyclization to obtain both epimers of
(^)-heliannuol D.

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F. A. Macıas et al. / Tetrahedron 59 (2003) 1679–1683
1681
4.2. Synthesis of compound 5
4.2.1. 2,5-Diacetoxytoluene (2). To 5 g of 2-methylhydro-
quinone (1) in 25 mL of pyridine, an excess (1:5, 21 mL) of
acetic anhydride (CH3CO)2O was added. It was further
stirred at room temperature during 12 h. After this, 30 mL of
AcOEt was added and the mixture was washed with a
saturated solution of CuSO4. The organic phase was dried
over anhydrous Na2SO4 and evaporated to obtain the
acetylated derivative 2 in quantitative yield, with no need
Figure 3. NOEs observed for the most stable conformer of heliannuol D,
using PM3 calculations.
of chromatographic purification; IR (film, cm21) nmax
:
1
3066, 1765, 1211; UV (MeOH, nm) lmax: 208.8; H NMR
(CDCl3, 400 MHz) d 2.15 (s, 3H, Me-7), 2.24p (s, 3H,
Me-90), 2.28p (s, 3H, Me-9), 6.90 (dd, J¼8.5, 2.7 Hz, 1H,
H-4), 6.97 (d, J¼2.7 Hz, 1H, H-6), 6.99 (d, J¼8.5 Hz, 1H,
H-3); 13C NMR (CDCl3, 100 MHz) d 16.12 (C-7), 20.56p
(C-9), 20.88p (C-90), 117.79 (C-1), 119.69 (C-4), 122.52
(C-3), 126.76 (C-6), 0131.34 (C-1), 147.92 (C-2), 169.01p
(C-8), 169.34p (C-8 ); (pvalues may be interchanged);
HRMS calculated for C11H12O4 208.0735, found
208.0740. Analysis calculated for C11H12O4: C, 63.45; H,
5.81. Found: C, 63.52; H, 5.79.
corresponding heliannanes 10 and 11, respectively, in
quantitative yield (Scheme 3).
NOEs observed for 10 are in good agreement with the most
stable conformer found for heliannuol D by PM3 calcu-
lations (Fig. 3), assuming a (7S,10S) relative configuration
(the same as the natural product). Moreover, the exact match
of chemical shifts and coupling constants for all proton/
carbon resonances between 10 and heliannuol D isolated
from H. annuus allowed us to identify this synthetic product
as the natural epimer.4
4.2.2. 2,5-Dihydroxy-4-methylacetophenone (3). 5 g of
2,5-diacetoxytoluene (2) were added to a solution of 21 mL
(excess 1:5) of boron trifluoride dihydrate (BF3·2H2O) and
stirred during 4 h at 1308C. Then, the solution was cooled to
08C by addition of ice and the mixture extracted with AcOEt
(4£30 mL). The organic layers was dried over anhydrous
Na2SO4, evaporated and filtered over silica gel to obtain 3 in
quantitative yield with no need of further purification; IR
We want to note that due to a typographic mistake, the mp
first reported for natural heliannuol D4a was wrong, as
indicated by Vyvyan and Looper.7c We would like to
confirm that the real mp value for the natural product is
159–1618C.
(film, cm21) nmax: 3316, 1610, 1200; UV (MeOH, nm) lmax
:
3. Conclusion
1
232.0; H NMR (CDCl3, 400 MHz) d 2.31 (s, 3H, Me-9),
2.48 (s, 3H, Me-8), 6.79 (s, 1H, H-3), 7.03 (s, 1H, H-6); 13C
NMR (CDCl3, 100 MHz) d 16.87 (C-9), 26.79 (C-8), 112.92
(C-6), 115.07 (C-3), 117.79 (C-1), 126.09 (C-5), 146.26
(C-4), 156.87 (C-2), 203.68 (C-7); HRMS calculated for
C9H10O3 166.0629, found 166.0645. Analysis calculated for
C9H10O3: C, 65.05; H, 6.07. Found: C, 65.18; H, 6.11.
In conclusion, we have developed an efficient route (60.7%
of overall yield) for the synthesis of (^)-heliannuol
D. Further modifications of this procedure would lead us
to 7,10-heliannane and several members of this family, and
to prepare new synthetic analogs of their hypothetical
biogenetic origin.4 Current efforts in our laboratory are
directed toward the development of the asymmetric
synthesis of this family of bioactive compounds.
4.2.3. 2,5-Dibenzyloxy-4-methylacetophenone (4). To a
solution of 3 (2.5 g) in dimethoxyethane (30 mL) was added
K2CO3 (8 g), under nitrogen and the solution was stirred to
808C in N2 atmosphere. Then, 2.2 equiv. (3.8 mL) of benzyl
bromide and 500 mL of dry N,N-dimethylformamide were
added. The reaction was stirred during 12 h in these
conditions and then was quenched with water and extracted
3 times with AcOEt. The organic phases were joined and
dried over anhydrous Na2SO4 and evaporated the solvent to
give crude which was chromatographed (hexane/AcOEt
20%). The desired product 2,5-dibenzyloxy-4-methyl-
acetophenone (4) was obtained in 95% of yield. No
chromatographic procedures for isolation of the pure
product; IR (film, cm21) nmax: 2911, 1606, 1218; UV
4. Experimental
4.1. General
Commercially available chemicals were used as received.
Dry THF was obtained by distillation from sodium
1
benzophenone ketyl. H and 13C NMR spectra (400 and
100 MHz, respectively) were recorded on a Varian Unity
400 NMR Spectrometer with a sample temperature of 258C
using CDCl3 as solvent and TMS as internal reference. Mass
spectroscopy was carried out using a GC-MS VG1250
apparatus (ion trap detector) in EI mode. FTIR spectra were
recorded on a Mattson 5020 spectrometer and UV–VIS
spectra were obtained with a Phillips PU 8710 spectrometer.
Elemental analysis was carried out in a LECO CHNS
apparatus. Mps of both epimers of (^)-heliannuol D were
determined on a Bu¨chi Melting Point B-545 apparatus.
Purities of synthesized compounds were determined by
NMR and HPLC methods, and corroborated by HRMS and
elemental analysis when appropriate.
1
(MeOH, nm) lmax¼206.4; H NMR (CDCl3, 400 MHz)0 d
2.34 (s, 3H, Me-9),0 2.63 (s, 3H, Me-8), 5.09p (s, 2H, H-7 ),
5.13p (s, 2H, H-7 ), 6.91 (s, 1H, H-3), 7.40 (m, 10H,
protecting group), 7.46 (s, 1H, H-6), (pvalues may be
interchanged); 13C NMR (CDCl3, 100 MHz) d 16.83 (C-9),
32.21 (C-8), 112.48 (C-3), 115.97 (C-6), 125.74 (C-1),
152.82 (C-5), 137.10 (C-4), 150.84 (C-2), 20030 .68 (C-7),
0
p
Protecting groups:00 70.26 (C-7 p), 71.21 (C-7 ), 127.15
(C-20), 127.15 (C-2 ), 127.15 (C-60), 127.51 (C-600), 127.69

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F. A. Macıas et al. / Tetrahedron 59 (2003) 1679–1683
1682
(C-400), 127.92 (C-4000), 128.47 (C-300), 128.47 (C-500), 128.53
(C-3 ), 128.53 (C-5 ), 134.08 (C-10), 137.10 (C-100), (pvalues
may be interchanged); HRMS calculated for C11H12O4
346.1569, found 346.1560. Analysis calculated for
C11H12O4: C, 79.74; H, 6.40. Found: C, 79.85; H, 6.43.
found 412.2410. Analysis calculated for C29H32O2: C,
84.43; H, 7.82. Found: C, 84.45; H, 7.89.
4.3.2. D7,14,2-O,5-O-Dibenzyl-10,11-epoxycurcuhydro-
quinone (7). 500 mg of 6 were dissolved in 20 mL of
CH2Cl2, and then 20 mL of KHCO3 aq. were added close to
an excess 1:1.2 of MCPBA. The mixture was stirred during
2 h at room temperature and then washed with NaOH aq.
(0.5 M) and extracted with CH2Cl2. The organic layer was
dried over anhydrous Na2SO4, evaporated and chromato-
graphed (hexane/ethyl ether 20%) to obtained 7 in 74%
yield. IR (film, cm21) nmax 2963, 1609, 1250; UV (MeOH,
nm) 206.4 lmax: 224.2; 1H NMR (CDCl3, 400 MHz) d 1.17p
(s, 3H, Me-13), 1.24p (s, 3H, Me-12), 1.59 (m, 2H, H-9),
2.34 (s, 3H, Me-15), 2.68 (m, 1H, H-8a), 2.68 (dd, J¼7.2,
7.2 Hz, 1H, H-10), 5.06 (s, 2H, H-70), 5.08 (s, 2H, H-700),
5.08 (d, J¼1.4 Hz, 1H, H-14a0), 5.15 (d, J¼1.4 Hz, 1H,
H-14a), 6.73 (s, 1H, H-3), 6.80 (s, 1H, H-6), 7.43 (m, 10H,
protecting group). (pvalues may be interchanged); 13C NMR
(CDCl3, 100 MHz) d 16.31 (C-15), 24.79 (C-13), 24.81
(C-12), 27.62 (C-9), 33.31 (C-08), 58.21 (C-11), 64.01
(C-10), 70.87 (C-700), 71.49 (C-7 ), 114.54 (C-14), 114.61
(C-6), 116.43 (C-3), 138.49 (C-1), 147.63 (C-4), 149.70
(C-5), 151.05 (C-2); HRMS calculated for C29H32O3
428.2351, found 428.2406. Analysis calculated for
C29H32O3: C, 81.27; H, 8.86. Found: C, 80.90; H, 8.82.
4.2.4. 2-O,5-O-Dibenzyl-7-hydroxycurcuhydroquinone
(5). 300 mg of magnesium are stirred overnight in N2
atmosphere with a catalytic amount of I2 at room
temperature. Then, 40 mL of dry THF were added to the
mixture at 658C. 387 mL of 5-bromo-2-methyl-2-pentene
were added and then the color of the reaction changes from
orange to uncolored. After 30 min, it was added 500 mg of
2,5-dibenzyloxy-4-methylacetophenone (4) and the reaction
was stirred during 90 min, then it was filtered and 40 mL of
water was added. The reaction was extracted with AcOEt
(4£). The organic layer was dried over anhydrous Na2SO4
and the solvent evaporated. The mixture was chromato-
graphed (hexane/Ethyl ether 20%). 5 was obtained in 81%
yield.; IR (film, cm21) nmax: 3446, 2960, 2924, 1506, 1198,
1035; UV (MeOH, nm) lmax: 208.8; 1H NMR (CDCl3,
400 MHz) d 1.50p (s, 3H, Me-12), 1.55 (s, 3H, Me-14),
1.65p (s, 3H, Me-13), 1.85 (m, 1H, H-9a), 1.85 (m, 1H,
H-9b), 1.85 (m, 1H, H-8a), 2.02 (m, 1H, H-8b), 2.27 (s, 3H,
Me-15), 5.05p (s, 1H, H-70), 5.07p (s, H, H-700), 6.82 (s, 1H,
H-3), 6.94 (s, 1H, H-6) (pvalues may be interchanged), 7.40
(m, 10H, protecting group); 13C NMR (CDCl3, 100 MHz) d
16.15 (C-12), 17.58 (C-13), 23.29 (C-15), 25.65 (C-9),
27.72 (C-14), 42.07 (C-8), 71.04 (C-70), 71.07 (C-700), 75.10
4.3.3. 10(R p),11-Epoxycurcuphenol (8) and 10(S p),11-
epoxycurcuphenol (9). A catalytic amount of Pd/C was
added a 200 mg of 7 solved in N,N0-dimethylformamide
(DMF) and them a current of H2 was bubbled. After 1 h
stirring in these conditions, reaction was filtering; 25 mL of
AcOEt were added and washed with water (£5) to eliminate
DMF. The organic layer was dried over anhydrous Na2SO4
and the solvent evaporated. The mixture was chromato-
graphed (hexane/AcOEt 10%) and then 8 and 9 were
obtained in 57 and 43% yield, respectively. 10(R p)-
Epoxycurcuphenol (8). IR (film, cm21) nmax: 3394, 2960,
(C-70), 112.08 (C-3), 0 115.44 (C-6), 1020 4.56 (C-1), 127.28
00
p
p
(C-2 p), 127.28 (C-6 p), 127.52 (C-2 ), 127.52 (C-6 ),
0
00
0
127.71 (C-4 p), 128.09 (C-4 ), 128.43 (C-3 p), 128.43
p
0
00
00
(C-5 p), 128.68 (C-3 ), 128.68 (C-5 ), 133.11 (C-4),
p
p
0
00
136.70 (C-1 p), 137.61 (C-1 ), 149.85 (C-5), 150.81
(C-2); HRMS calcd for C29H34O3 430.2508, found
430.2508. Analysis calculated for C29H34O3: C, 80.89; H,
7.96; Found: C, 80.79; H, 7.92.
p
1
4.3. Synthesis of (6)-heliannuol D
2855, 1704, 1618; UV (MeOH, nm) lmax: 223.9; H NMR
(CDCl3, 400 MHz) d 1.16 (m, 1H, H-9a), 1.21p (s, 3H,
Me-12), 1.21 (d, J¼6.8 Hz, 3H, Me-14), 1.32p (s, 3H,
Me-13), 1.69 (m, 1H, H-9b), 1.72 (m, 1H, H-8a), 1.84 (m,
1H, H-8b), 2.27 (s, 3H, Me-15), 2.84 (dd, J¼9.2, 3.2 Hz,
1H, H-10), 3.17 (ddq, J¼6.8, 6.8, 4.4 Hz, 1H, H-7), 6.56 (s,
1H, H-3), 6.62 (s, 1H, H-6) (pvalues may be interchanged);
13C NMR (CDCl3, 100 MHz) d 15.01 (C-12), 18.58 (C-15),
20.89 (C-14), 24.75 (C-13), 25.85 (C-9), 31.12 (C-7), 32.98
(C-8), 58.88 (C-11), 66.01 (C-10), 113.54 (C-3), 117.92
(C-6), 121.57 (C-1), 132.02 (C-4), 146.23 (C-5), 148.03 (C-
2); HRMS calcd for C15H22O3 250.1568, found 250.1562;
10(S p)-Epoxycurcuphenol (9). IR (film, cm21) nmax: 3413,
4.3.1. D7,14-2-O,5-O-Dibenzyl-curcuhydroquinone (6a)
and D7,8,2-O,5-O-dibenzyl-curcuhydroquinone (6b).
500 mg of 5 were dissolved in 10 mL of N,N-dimethyl-
formamide, 174 mg of KHSO4 were added and the mixture
was stirred during 1 h at 808C. Then, 25 mL of AcOEt were
added and washed 6 times with water to eliminate the
solvent. After low pressure evaporation, the residue was
chromatographed (2% AcOEt/hexane) to obtain the desired
products 6 were obtained quantitatively; UV (MeOH, nm)
1
n
max: 212.0; H NMR (CDCl3, 400 MHz) d 1.66p (s, 3H,
Me-12), 1.80p (s, 3H, Me-13), 2.20 (m, 2H, H-8a), 2.40 (s,
6H, Me-14b, Me-15), 2.70 (m, 2H, H-9a), 3.01 (m, 2H,
H-9b), 5.08 (s, 2H, H-14a), 5.12 (s, 2H, H-140a0), 5.21p (s, H,
H-700), 5.25 (m, 1H, H-10a), 5.28p (s, 1H, H-7 ), 5.36 (m, 1H,
H-10b), 5.61 (m, 1H, H-8b), 6.89 (s, 1H, H-3), 6.91 (s, 1H,
H-6) (pvalues may be interchanged), 7.50 (m, 10H,
protecting group). 13C NMR (CDCl3, 400 MHz) d 16.19
(C-15a), 16.25 (C-15b), 17.71 (C-13), 25.62 (C-14b), 26.73
(C-12), 27.46 (C-9b), 36.47 (C-9a), 113.90 (C-14a) 114.40
(C-8b), 122.70 (C-3a), 124.22 (C-3b), 126.62 (C-10b),
128.27 (C-10a), 130.50 (C-8b), 131.13 (C-6a), 131.58
(C-6b), 149.65 (C-5b), 150.03 (C-2b), 150.89 (C-5a),
150.89 (C-2a). HRMS calculated for C29H32O2 412.2402,
1
2959, 2853, 1692, 1614; UV (MeOH, nm) lmax: 224.2; H
NMR (CDCl3, 400 MHz) d 1.17 (d, J¼6.9 Hz, 3H, Me-14),
1.20p (s, 3H, Me-12), 1.28p (s, 3H, Me-13), 1.47 (m, 2H,
H-9), 1.60 (m, 1H, H-8a), 1.75 (m, 1H, H-8b), 2.13 (s, 3H,
Me-15), 2.75 (dd, J¼6.2, 6.2 Hz, 1H, H-10), 3.05 (ddq,
J¼6.9, 6.9, 6.4 Hz, 1H, H-7), 6.52 (s, 1H, H-3), 6.55 (s, 1H,
H-6) (pvalues may be interchanged); 13C NMR (CDCl3,
100 MHz) d 15.34 (C-12), 18.58 (C-15), 20.92 (C-14),
24.78 (C-13), 26.67 (C-9), 31.76 (C-7), 33.59 (C-8), 58.81
(C-11), 64.69 (C-10), 113.48 (C-3), 117.90 (C-6), 121.94
(C-1), 131.31 (C-4), 146.89 (C-5), 148.02 (C-2); HRMS
calculated for C15H22O3 250.1568, found 250.1572.

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F. A. Macıas et al. / Tetrahedron 59 (2003) 1679–1683
1683
´
part 13 see: Macıas, F. A.; Galindo, J. C. G.; Castellano, D.;
Velasco, R. F. J. Agric. Food Chem. 2000, 48, 5288–5296.
2. (a) Vyvyan, J. R. Tetrahedron 2002, 58, 1631–1646. (b) Duke,
Analysis calculated for C15H22O3: C, 71.97; H, 8.86. Found:
C, 71.85; H, 8.76.
4.3.4. 10(S p)-Heliannuol D (10) and 10(R p)-heliannuol D
(11). Stirring during 24 h at room temperature 200 mg of 8
in 10 mL of NaOH 1 M, permits to obtain after neutrali-
zation with HCl 1 M, extraction with AcOEt (£4) and low
pressure evaporation, the heliannuol 10, pure and in
quantitative yield. The same procedure for 9 permits to
obtain 11 in the same yield. Colorless crystals were obtained
´
S. O. Rev. Weed Sci. 1986, 2, 15–44. (c) Macıas, F. A. In
Allelopathy: Organisms, Processes, and Applications. ACS
Symposium Series, 582; Inderjit, Dakshini, K. M. M.,
Einhellig, F. A., Eds.; ACS: Washington, DC, 1995; pp
310–329, Chapter 23. (d) Duke, S. O. In The Science of
Allelopathy; Putnam, A. R., Tang, C. S., Eds.; Wiley: New
York, 1986; pp 287–304, Chapter 17. (e) Duke, S. O.; Dayan,
F. E.; Hernandez, A. Proceedings of Weeds. The 1997
Brighton Crop Protection Conference; Pallett, K. E., Ed.;
British Crop Protection Council: Farnham, UK, 1997; Vol. 2,
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in both cases. 10(S p)-Heliannuol D (10). IR (film, cm21
max: 3360, 2955, 2930, 1614, 1256; UV (MeOH, nm) lmax
)
n
:
1
208.5, 276.7; H NMR (CDCl3, 400 MHz) d 1.20 (d, 3H,
Me-14), 1.21p (s, 3H, Me-12), 1.21p (s, 3H, Me-13), 1.74
(m, 1H, H-8b), 1.74 (m, 1H, H-9a), 1.82 (m, 1H, H-8a), 1.96
(m, 1H, H-9b), 2.21 (s, 3H, Me-15), 2.91 (ddq, J¼9.8, 9.8,
7.2 Hz, 1H, H-7), 3.25 (dd, J¼5.3, 3.5 Hz, 1H, H-10), 6.50
(s, 1H, H-3), 6.65 (s, 1H, H-6) (pvalues may be inter-
changed); 13C NMR (CDCl3, 100 MHz) d 15.31 (C-12),
18.52 (C-15), 24.37 (C-14), 25.41 (C-13), 25.80 (C-9),
31.74 (C-7), 38.45 (C-8), 72.56 (C-11), 90.31 (C-10),
115.47 (C-3), 122.48 (C-6), 123.34 (C-1), 137.76 (C-4),
150.154 (C-5), 151.11 (C-2); HRMS calculated for
C15H22O3 250.1568, found 250.1553. Analysis calculated
for C15H22O3: C, 71.97; H, 8.86. Found: C, 71.99; H, 8.95.
Mp 161–1628C (these data match exactly with those for
natural heliannuol D). 10(R p)-Heliannuol D (11). IR (film,
cm21) nmax: 3369, 2964, 2935, 1617, 1228; UV (MeOH,
´
3. (a) Macıas, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G.
´
Tetrahedron Lett. 1998, 39, 427–430. (b) Macıas, F. A.; Oliva,
R. M.; Varela, R. M.; Torres, A.; Molinillo, J. M. G.
´
Phytochemistry 1999, 52, 613–621. (c) Macıas, F. A.; Torres,
´
A.; Galindo, J. L. G.; Varela, R. M.; Alvarez, J. A.; Molinillo,
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4. (a) Macıas, F. A.; Molinillo, J. M. G.; Varela, R. M.; Torres, A.
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J. Org. Chem. 1994, 59, 8261–8266. (b) Macıas, F. A.; Varela,
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5. Harrison, B.; Crews, P. J. Org. Chem. 1997, 62, 2646–2648.
1
nm) lmax: 208.0, 276.0; H NMR (CDCl3, 400 MHz) d
1.29p (s, 3H, Me-12), 1.30p (s, 3H, Me-13), 1.34 (d,
J¼7.2 Hz, 3H, Me-14), 1.30 (m, 1H, H-8b), 1.93 (m, 1H,
H-9a), 1.93 (m, 1H, H-8a), 1.93 (m, 1H, H-9b), 2.26 (s, 3H,
Me-15), 3.03 (ddq, J¼7.2, 7.2, 2.8 Hz, 1H, H-7), 3.30 (dd,
J¼11.2, 1.3 Hz, 1H, H-10), 6.55 (s, 1H, H-3), 6.61 (s, 1H,
H-6) (pvalues may be interchanged); 13C NMR (CDCl3,
100 MHz) d 15.25 (C-12), 18.42 (C-15), 23.97 (C-14),
25.40 (C-13), 25.75 (C-9), 31.33 (C-7), 39.45 (C-8), 72.46
(C-11), 90.12 (C-10), 115.57 (C-3), 122.48 (C-6), 123.24
(C-1), 137.85 (C-4), 150.13 (C-5), 150.56 (C-2); HRMS
calculated for C15H22O3 250.1568, found 250.1551. Analy-
sis calculated for C15H22O3: C, 71.97; H, 8.86. Found: C,
71.85; H, 8.92. Mp 158–1598C.
´
6. Macıas, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G.
J. Chem. Ecol. 2000, 26, 2173–2186.
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Acknowledgements
9. McEnroe, F. J.; Fenical, W. Tetrahedron 1978, 34,
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´
This research was supported by the Comision Inter-
ministerial de Ciencia y Tecnologıa (C.I.C.Y.T; Project
PB98-0575) Spain.
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References
1. Part 14 in the series Natural products as Allelochemicals. For