First total synthesis of (±)-helibisabonol A

Article abstract of DOI:10.1016/S0040-4039(02)01381-3

Helibisabonol A is a new sesquiterpene with phytotoxic activity isolated from Helianthus annuus leaves. (±)-Helibisabonol A has been synthesized as an approach to the natural product in the search for new herbicide models. Herein, we report the first tota

Full text of DOI:10.1016/S0040-4039(02)01381-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 6417–6420
First total synthesis of ( )-helibisabonol A
Francisco A. Mac´ıas,* David Mar´ın, David Chinchilla and Jose´ M. G. Molinillo
Grupo de Alelopat´ıa, Departamento de Qu´ımica Orga´nica, Facultad de Ciencias, Universidad de Ca´diz, C/Repu´blica Saharaui
s/n, Apdo. 40, 11510-Puerto Real (Ca´diz), Spain
Received 10 May 2002; revised 1 July 2002; accepted 4 July 2002
Abstract—Helibisabonol A is a new sesquiterpene with phytotoxic activity isolated from Helianthus annuus leaves. ( )-Helibis-
abonol A has been synthesized as an approach to the natural product in the search for new herbicide models. Herein, we report
the first total synthesis for this molecule from methylhydroquinone in six steps. The key steps of this synthesis are a Fries
rearrangement, a Grignard reaction and a catalytic hydrogenation. The synthesis was carried out with high yield and in an easy
to scale manner. © 2002 Elsevier Science Ltd. All rights reserved.
Helianthus annuus L. (sunflower) is a plant with a very
high commercial importance and it is known for its
high production of secondary metabolites, specially
terpenes1 and phenolic compounds.2 Recently, a new
phenolic sesquiterpene with the bisabolane skeleton,
helibisabonol A (Fig. 1), has been isolated from H.
annuus L. var. Peredovick©.3
chose that shown in Scheme 1, in which the new CꢀC
bond is formed by nucleophilic addition to the aromatic
ketone 3 using a Grignard reagent.
The low yields obtained in the electrophilic aromatic
substitution reactions enforced us to look for alterna-
tive methods to get access to the starting aromatic
ketone. Thus, a Fries rearrangement6 provides the
desired compound with quantitative yield in short time
and mild conditions.
Allelochemicals are an important potential source for
new agrochemicals, and particularly herbicides, since
they could offer new modes of action, more specific
interactions with weed and less environmental damage.4
These facts make very interesting the large scale synthe-
sis of these products, in order to test them in suitable
bioassays and propose them as new herbicide models.
Firstly, an esterification reaction (Scheme 1) yields the
diacetyl derivative 2 from methylhydroquinone (1) with
a 99% yield. This compound (2,5-diacetoxitoluene) is
heated at 120°C with 2 mol equiv. of aqueous boron
trifluoride (step b) giving the ortho Fries rearrangement
product, in which the ester in positions 2 and 5 are
cleaved. 2,5-Dihydroxy-4-methylacetophenone (3) is
obtained in 6 h (quantitative yield). Temperature con-
trol is extremely important at this point, since a lower
temperature provides the para isomer.
There are no previous reports about the synthesis of
helibisabonol A, but many sesquiterpenes with similar
structures have been synthesized, including curcuphenol
and curcudiol.5 The main difference between the syn-
thetic methods employed for these compounds is the
way to link the side-chain with the aromatic moiety.
Among the different alternatives for this purpose, we
After a double etherification with benzyl bromide in
basic conditions (step c), we were ready to introduce
the side-chain by Grignard reaction (step d). Good
yields were not observed below +65°C, probably due to
the high steric hindrance caused by the benzyl moiety at
position 2.
After 1 h, the observed yield for 5 was 70%. Compound
5 had an unexpected evolution under epoxidation con-
ditions. After reaction with MCPBA and sodium ace-
tate at room temperature, no epoxide derivative could
be isolated. The NMR and HREIMS spectra allowed
Figure 1. ( )-Helibisabonol A.
* Corresponding author. Tel.: +34-956-016370; fax: +34-956-016193;
e-mail: famacias@uca.es
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01381-3

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F. A. Mac´ıas et al. / Tetrahedron Letters 43 (2002) 6417–6420
Scheme 1. Reagents and conditions: (a) Ac2O, Py, rt, 12 h, 99%; (b) BF3·2 H2O, 120°C, 5 h, 99%; (c) BnBr, K2CO3, DMF, DME,
80°C, 12 h, 99%; (d) 5-Br-2-methyl-2-pentene, Mg, THF, 65°C, 1 h, 70%; (e) MCPBA, sodium acetate, CHCl3, rt, 1 h, 99%; (f)
H2, Pd/C, AcOEt, rt, 1 h, 99%.
us to identify the main reaction products (85% yield) as
the intramolecular cyclization products 6 and 7. This
couple of diastereomers could be separated easily using
column chromatography (15% Et2O/hexane) and
HPLC methods (8% AcOEt/hexane), in order to con-
tinue the synthesis of both epimers of ( )-helibisabonol
A and complete their activity profile separately.
HREIMS experiment confirm the pyrane ring opening.
The structures were unequivocally confirmed using
spectroscopic data,7,8 and the relative configuration at
the stereogenic centers C-7 and C-10 was proposed by
correlation of bond angles for the most stable conform-
ers (Fig. 2), found by PM3 calculations,9 and experi-
mental coupling constants (Table 1). In conclusion, this
synthesis afforded the desired compound ( )-helibis-
abonol A with a 67% overall yield, in six steps. The
structure of the compounds obtained was unequivocally
determined by using spectral and computational tech-
niques, and structural data for compound 10 match
exactly with the natural compound isolated from H.
annuus var. Peredovick©.3
The final steps illustrate the importance of the solvent
choice to control the evolution of the catalytic hydro-
genation reactions. As shown in Scheme 2, the hydroxyl
groups at C-2 and C-5 are first deprotected, the pyrane
ring opening occurring later. When ethyl acetate is used
as a solvent, the second step proceeds very fast, and
when the solvent used is DMF, products 10 and 11 are
not observed before the complete transformation of 6
and 7 in 8 and 9, respectively. Using both solvents the
transformations are quantitative, so we can get prod-
ucts 10 or 11 as well as 8 and 9 after a simple work-up
with no further purification. These facts allow us to get
large quantities of the desired products in a short time.
Products 8 and 9 were isolated as red oils. Differences
in the [M+] of compounds 8–9 and 10–11 in the
Acknowledgements
This research was supported by the Direccio´n General
de Investigacio´n Cient´ıfica y Te´cnica, Spain (DGICYT,
Project c PB98-0575).

F. A. Mac´ıas et al. / Tetrahedron Letters 43 (2002) 6417–6420
6419
Scheme 2. Reagents and conditions: (a) H2, 10% Pd/C, DMF, rt, 1 h, 99%; (b) H2, 10% Pd/C, AcOEt, rt, 1 h, 99%.
(e) Duke, S. O.; Dayan, F. E.; Hernandez, A. In Proceed-
ings of Weeds. The 1997 Brighton Crop Protection Confer-
ence; Pallett, K. E., Ed.; British Crop Protection Council:
Farnham, UK, 1997; Vol. 2, pp. 579–586; (f) Rice, E. L.
Biological Control of Weeds and Plant Diseases; University
of Oklahoma Press: Norman, USA, 1995; (g) Waller, G.
R.; Yamasaki, K. Advances in Experimental Medicine and
Biology; Saponins Used in Food and Agriculture. Plenum
Press: New York, 1996; Vol. 405.
Figure 2. Most stable conformer for compound 10.
5. (a) Ono, M.; Ogura, Y.; Hatogai, K.; Akita, H. Tetra-
hedron: Asymmetry 1995, 6, 1829–1832; (b) Fuganti, C.;
Serra, S. Synlett 1998, 1252–1254; (c) Sugahara, T.;
Ogasawara, K. Tetrahedron: Asymmetry 1998, 9, 2215–
2217.
Table 1. Observed coupling constants versus b obtained
for the most stable conformer of 10
Protons
Calculated b
Observed J
H9a-10
H9b-10
73.8
41.5
1.38
4.9
6. Trost, B. M.; Fleming, I. Comprehensive Organic Synthe-
sis; Pergamon: Oxford; Vol. 2, 745–747, 1991.
7. Analytical data for ( )-6-[2,5-dihydroxy-4-methylphenil]-
2,2,6-trimethyltetrahydropyran-3-ol (8): 1H NMR (C3D6O,
400 MHz) l (ppm): 6.58 (1H, s, H-3), 6.72, (1H, s, H-6),
2.46 (1H, ddd, H-8a), 2.13 (1H, m, H-8b), 2.03 (1H, dddd,
H-9a), 1.86, (1H, dddd, H-9b), 3.87 (1H, dd, H-10), 1.23*
(3H, s, H-12), 1.29* (3H, s, H-13), 1.56 (3H, s, H-14), 2.18
(3H, s, H-15); J (Hz): 8a,8b=8b,8a=12.3; 10,9a=9a,10=
7.7; 10,9b=9b,10=7.1; 9a,9b=9b,9a=12.3; 13C NMR
(C3D6O, 100 MHz) l (ppm): 129.51 (C-1), 148.53 (C-2),
112.86 (C-3), 124.26 (C-4), 148.15 (C-5), 119.23 (C-6),
86.92 (C-7), 38.70 (C-8), 25.74 (C-9), 86.82 (C-10), 70.69
(C-11), 25.74* (C-12), 28.94* (C-13), 28.45 (C-14), 15.63
(C-15) (* interchangeable values); HREIMS, m/z calcd for
C15H22O4 266.1518, found 266.1524; umax (MeOH)=201.6
References
1. Mac´ıas, F. A.; Molinillo, J. M. G.; Torres, A.; Varela, R.
M.; Castellano, D. Phytochemistry 1997, 45, 683–687.
2. Mac´ıas, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M.
G. In Allelopathy in Pests Management for Sustainable
Agriculture; Narwal, S. S.; Tauro, P., Eds.; Scientific Pub-
lishers: Jodhpur, India, 1996; Chapter 4, pp. 77–92.
3. Mac´ıas, F. A.; Varela, R. M.; Galindo, J. L. G.; Torres,
A.; Molinillo, J. M. G. Phytochemistry 2002, 60.
4. (a) Vyvyan, J. R. Tetrahedron 2002, 58, 1631–1646; (b)
Duke, S. O. Rev. Weed Sci. 1986, 2, 15–44; (c) Mac´ıas, F.
A. In Allelopathy: Organisms, Processes, and Applications;
Inderjit; Dakshini, K. M. M.; Einhellig, F. A., Eds.; ACS
Symposium Series, 582: Washington, DC, USA, 1995;
Chapter 23, pp. 310–329; (d) Duke, S. O. In The Science of
Allelopathy; Putnam, A. R.; Tang, C. S., Eds.; John Wiley
& Sons: New York, USA, 1986; Chapter 17, pp. 287–304;
nm; FTIR 3386 cm−1 (intense), 1020 cm−1
.
8. Analytical data for ( )-helibisabonol A (10): 1H NMR
(C3D6O, 400 MHz) l (ppm): 6.51 (1H, s, H-3), 6.59, (1H,
s, H-6), 3.06 (1H, ddq, H-7), 1.74 (1H, dddd, H-8a), 1.55
(1H, m, H-8b), 1.45 (1H, dddd, H-9a), 1.23 (1H, m, H-9b),
3.66 (1H, dd, H-10), 1.03* (3H, s, H-12), 1.04* (3H, s,

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F. A. Mac´ıas et al. / Tetrahedron Letters 43 (2002) 6417–6420
H-13), 1.09 (3H, s, H-14), 2.04 (3H, s, H-15); J (Hz):
7,8a=8a,7=7.1; 7,8b=8b,7=7.5; 7,14=14,7=5.1;
(* interchangeable values); HREIMS, m/z calcd for
C15H24O4 268.1674, found 268.1678; umax (MeOH)=201.6
nm; FTIR 3364 cm−1 (very intense). These data are in
good agreement with the previous reported for the natural
product.3
8a,8b=8b,8a=12.4; 8a,9a=9a,8a=5.5; 8a,9b=9b,8a=
9.8; 8b,9a=9a,8b=8.7; 8b,9b=9b,8b=5.8; 9a,9b=
9b,9a=13.1; 10,9a=9a,10=1.38; 10,9b=9b,10=4.9; 13C
NMR (C3D6O, 100 MHz) l (ppm): 132.0 (C-1), 148.8*
(C-2), 117.9 (C-3), 121.9 (C-4), 147.5* (C-5), 113.3 (C-6),
29.7 (C-7), 35.4 (C-8), 24.4 (C-9), 79.2 (C-10), 72.4 (C-11),
25.4* (C-12), 28.9* (C-13), 21.5 (C-14), 15.4 (C-15)
9. Stewart, J. J. P. J. Comput. Chem. 1989, 10, 209. Molecu-
lar orbital calculations were carried out using PM3 Hamil-
tonian as implemented in MOPAC 6.0. Geometries were
fully optimized using the PRECISE keyword.