The synthesis of heliannuol C, an allelochemical from Helianthus annuus

Article abstract of DOI:10.1016/j.tetlet.2006.04.011

The synthesis of the allelochemical heliannuol C 1 is described by employing a Bargellini condensation and a Claisen rearrangement to install the gem-dimethyl and vinyl functionalities, respectively. A Dieckmann cyclisation of diester 11 enabled the gener

Full text of DOI:10.1016/j.tetlet.2006.04.011

Tetrahedron Letters 47 (2006) 4019–4021
The synthesis of heliannuol C, an allelochemical
from Helianthus annuus
Bidyut Biswas, Prabir K. Sen and Ramanathapuram V. Venkateswaran*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700 032, India
Received 26 January 2006; revised 30 March 2006; accepted 5 April 2006
Available online 2 May 2006
Abstract—The synthesis of the allelochemical heliannuol C 1 is described by employing a Bargellini condensation and a Claisen
rearrangement to install the gem-dimethyl and vinyl functionalities, respectively. A Dieckmann cyclisation of diester 11 enabled
the generation of the benzoxepane ring system enshrined in 1.
Ó 2006 Elsevier Ltd. All rights reserved.
Heliannuol C 1, a novel allelopathic sesquiterpene, was
isolated from the cultiver sunflowers Helianthus annuus.1
Although Macias et al. established the gross structure
and relative stereochemistry of 1, the absolute stereo-
chemistry as (8R,10S) was assigned by Shishido et al.
by synthesis.2 Sesquiterpene 1, along with its congeners
heliannuols A–B and D–E 2–5, have been implicated
in the powerful allelopathic activity displayed by these
sunflowers.1 Subsequently, many oxidised variants of
these compounds have been isolated from these flow-
ers.1e,f Their unique structural features, combined with
their potential agricultural importance as natural and
eco-friendly herbicide models, have rendered them
attractive targets for synthesis.3 We initiated a compre-
hensive programme directed to the synthesis of these
compounds and have reported the synthesis of heliannu-
ols A and D.4 Both heliannuols C 1 and D 4 possess a
benzoxepane ring system. Our previous synthesis of 4
had relied on the regioselective oxidative ring opening
of a benzobicyclo[3.2.1]octanone, and a ring-closing
metathesis, to develop this ring system.4b,c Herein, we
disclose the synthesis of 1 by employing a Claisen rear-
rangement and Bargellini condensation to install the
vinyl and gem-dimethyl groups, respectively, and a
Dieckmann cyclisation to generate the benzoxepane ring
system.
HO
8
10
OH
O
1
HO
HO
HO
O
O
OH
O
O
3
5
2
OH
HO
4
OH
OH
The synthesis began with 6-methoxy-7-methylcoumarin
7, obtained from methylation of the corresponding
6-hydroxycoumarin 65 with methyl iodide under stan-
dard conditions. Low temperature reduction of this
coumarin with LAH in ether at À40 °C furnished the
unsaturated diol 8, in 70% yield, contaminated with ben-
zoxepane ring system the saturated diol in varying pro-
portions (20–25%). Chromatographic separation yielded
the desired unsaturated diol 8 in 50% yield as a colour-
less solid, mp 88–89 °C.6 Diol 8 underwent a selective
Bargellini condensation7 with acetone and chloroform
Keywords: Allelochemical; Heliannuol C; Bargellini condensation;
Claisen orthoester rearrangement; Benzoxepane ring system.
*
Corresponding author. Fax: +91 33 24732805; e-mail: ocrvv@
iacs.res.in
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.04.011

4020
B. Biswas et al. / Tetrahedron Letters 47 (2006) 4019–4021
in the presence of powdered sodium hydroxide to afford
the gem-dimethyl group incorporated carboxylic acid 9
in 65% yield, which was converted to methyl ester 106
by reaction with diazomethane. This allylic alcohol ester
10 was subjected to a Claisen orthoester rearrangement
by refluxing with triethyl orthoacetate in the presence of
a catalytic amount of propionic acid to afford the diester
116 in 70% yield, thereby installing the crucial vinyl
group (Scheme 1).
MeO
MeO
i
CO2R
CO2R
O
O
O
7
12 R= H
ii
13 R= Me
iii
MeO
iv
CO2Et
OR
MeO
OH
OH
An alternative, better yielding, method involved the
direct Bargellini condensation of coumarin 7. We
recently reported such direct condensations with couma-
rins to furnish, in good yields, o-carboxyvinylphenoxy
isobutyric acids.8 Following on from this, when couma-
rin 7 was reacted with acetone and chloroform in the
presence of sodium hydroxide, it furnished the expected
diacid 12 in 75% yield, which was quantitatively con-
verted to dimethyl ester 136 with diazomethane. Reduc-
tion of this diester with LAH in ether at À20 °C
delivered diol 146 in excellent yield (90%). The differen-
tial reactivity of diol 14 was suitably exploited to install
the vinyl moiety employing the Claisen orthoester rear-
rangement as before. In the event, refluxing a mixture of
diol 14 in triethyl orthoacetate containing a catalytic
amount of propionic acid furnished the rearranged es-
ter–alcohol 156 in 75% yield. In some runs, acetate 16
was also obtained as a separable minor component.
Mild base treatment of this acetate readily converted it
into alcohol 15. Oxidation of ester–alcohol 15 with
Jones’ reagent at room temperature produced the carb-
oxylic acid 17, which was esterified with diazomethane
to furnish diester 11 (Scheme 2). Although this synthesis
involved an additional oxidative step, the cleaner reac-
tion products and better overall yield made this
approach more suitable for large scale operations as
against the former approach, which necessitated a sepa-
ration in the first step of the reduction process.
O
O
14
15 R= H
16 R= COCH3
v
CO2Et
CO2R
MeO
O
17 R= H
11 R= Me
vi
Scheme 2. Reagents and conditions: (i) NaOH, acetone, CHCl3,
reflux, 6 h, 75%; (ii) CH2N2, Et2O, 0 °C, 98%; (iii) LAH, Et2O, À20 °C,
4 h, 90%; (iv) CH3C(OEt)3, C2H5COOH, reflux, 5 h, 75%; (v) Jones’
oxidation, 70%; (vi) CH2N2, Et2O, 0 °C, 1 h, 99%.
THF achieved the expected cyclisation to deliver the
b-ketoester 18, which was subjected to de-ethoxycarb-
onylation by heating in dimethyl sulfoxide with lithium
chloride and water to furnish benzoxepanone 196 incor-
porating all the structural features as present in 1 in an
overall yield of 61% from 11. Reduction of this ketone
with sodium borohydride in methanol afforded, in 98%
yield, a mixture of O-methyl heliannuol C 20 and its
epimer 21 in a ratio of 1:3 (Scheme 3). Preparative thin
layer chromatography allowed an efficient separation of
Diester 11 now set the stage for the generation of the
benzoxepane ring system through an intramolecular
cyclisation. Treatment of this diester with LDA in
the components and the spectral data (1H NMR and 13
C
NMR) of 20 fully matched those reported previously.3
Since 20 has been demethylated to heliannuol C 1, the
present work concluded the synthesis of this allelochem-
ical. The low yield of the desired product in the reduc-
tion step prompted further experiments. Initial efforts
towards inversion of the hydroxy group in the undesired
epimer 21 through a Mitsunobu reaction were not
encouraging. Alternatively, 21 was oxidised back to
ketone 19 in near quantitative yield employing Jones’
reagent and the ketone reduced with sodium boro-
hydride to yield a mixture of 20 and 21. This sequence
of oxidation and reduction was repeated and after four
such runs, the combined yield of the desired alcohol 20
was improved to 62–65%.
MeO
RO
iii
ii
OH
OH
O
O
6
7
8
R = H
i
R = Me
CO2Et
MeO
MeO
v
OH
CO2Me
CO2R
O
O
11
9
R = H
iv
10 R = Me
In summary, we have developed the synthesis of heli-
annuol C 1 employing a Claisen orthoester rearrange-
ment and a Dieckmann cyclisation to construct the
benzoxepane core of 1, which demonstrates another
application of the Bargellini condensation of coumarins.
Scheme 1. Reagents and conditions: (i) K2CO3, acetone, MeI, reflux,
8 h, 99%; (ii) LAH, Et2O, À40 °C, 2 h, 50%; (iii) NaOH, acetone,
CHCl3, reflux, 6 h, 65%; (iv) CH2N2, Et2O, 1 h, 0 °C, 98%; (v)
CH3C(OEt)3, C2H5COOH, reflux, 8 h, 70%.

B. Biswas et al. / Tetrahedron Letters 47 (2006) 4019–4021
4021
985; (c) Sabui, S. K.; Venkateswaran, R. V. Tetrahedron
Lett. 2004, 45, 2047–2048.
5. Sethna, S.; Phadke, R. In The Pechmann Reaction, Blatt,
A. H., Cope, A. C., McGrew, F. C., Niemann, C., Snyder,
H. R., Eds.; Org. React.; 1953; Vol. VII, p 46.
CO2Et
O
CO2Et
MeO
MeO
i
CO2Me
O
O
18
11
6. All new compounds reported here gave analytical and
spectral data consistent with the assigned structures.
ii
1
Selected spectral data: For 8: H NMR (300 MHz, CDCl3)
d 2.18 (s, 3H), 3.76 (s, 3H), 4.23 (d, J = 7.1 Hz, 2H), 5.99–
6.07 (m, 1H), 6.52 (s, 1H), 6.55 (d, J = 11.4, 1H), 6.69 (s,
1H); 13C NMR (75 MHz, DMSO-d6) d 16.2, 56.0, 58.7,
112.4, 117.9, 121.3, 125.4, 126.5, 131.4, 148.6, 150.1; HRMS
(ES +ve) calcd for C11H14O3Na [M+Na]+ 217.0841, found
217.0841. For 10: IR (neat) 1738, 3450 (br) cmÀ1; 1H NMR
(300 MHz, CDCl3) d 1.48 (s, 6H), 2.16 (s, 3H), 3.78 (s, 3H),
3.79 (s, 3H), 4.25 (d, J = 7.2 Hz, 2H), 5.85–5.94 (m, 1H),
6.59 (s, 1H), 6.64 (d, J = 11.7 Hz, 1H), 6.66 (s, 1H); 13C
NMR (75 MHz, CDCl3) d 16.2, 25.0, 25.1, 52.5, 55.6, 59.9,
80.4, 111.5, 122.3, 122.9, 126.5, 127.9, 130.6, 145.6, 153.1,
MeO
O
O
19
iii
MeO
RO
OH
OH
1
174.9. For 11: IR (neat) 1735 cmÀ1; H NMR (300 MHz,
O
O
CDCl3) d 1.21 (t, J = 7.2 Hz, 3H), 1.53 (s, 3H), 1.56 (s, 3H),
2.11 (s, 3H), 2.69 (d, J = 7.5 Hz, 2H), 3.76 (s, 3H), 3.79 (s,
3H), 4.10 (q, J = 7.2 Hz, 2H), 4.25–4.28 (m, 1H), 5.05–5.12
(m, 2H), 5.95–6.06 (m, 1H), 6.49 (s, 1H), 6.59 (s, 1H); 13C
NMR (75 MHz, CDCl3) d 14.1, 16.0, 25.0, 25.5, 39.2, 39.4,
52.3, 55.6, 60.2, 79.2, 110.0, 114.7, 120.2, 125.0, 131.7,
139.6, 145.9, 152.7, 172.0, 175.3; HRMS (ES +ve) calcd for
C20H29O6 [M+H]+ 365.1965, found 365.1959. For 13: IR
(neat) 1716, 1738 cmÀ1; 1H NMR (300 MHz, CDCl3) d 1.51
(s, 6H), 2.16 (s, 3H), 3.69 (s, 3H), 3.78 (s, 3H), 3.79 (s, 3H),
5.92 (d, J = 12.7 Hz, 1H), 6.61 (s, 1H), 7.19 (d, J = 12.7 Hz,
1H), 7.32 (s, 1H); 13C NMR (75 MHz, CDCl3) d 16.4, 25.0,
25.0, 51.1, 52.2, 55.4, 80.2, 111.8, 118.3, 121.2, 125.9, 128.9,
139.4, 146.8, 152.3, 166.6, 174.6. For 14: 1H NMR
(300 MHz, CDCl3) d 1.20 (s, 6H), 2.18 (s, 3H), 3.53 (s,
2H), 3.78 (s, 3H), 4.18 (d, J = 6.9 Hz, 2H), 5.89–5.92 (m,
21
20
1
R = Me
R = H
Ref. 3
Scheme 3. Reagents and conditions: (i) LDA, THF, À10 to 0 °C, then
rt, 12 h, 72%; (ii) LiCl, DMSO, H2O, 160 °C, 5 h, 85%; (iii) NaBH4,
MeOH, 0 °C, 0.5 h, 98%.
Acknowledgements
We sincerely thank Professor J. R. Vyvyan, Department
of Chemistry, Western Washington University, Belling-
ham WA, for providing us with copies of the spectra (1H
NMR and 13C NMR) of their synthetic O-methyl heli-
annuol C and its epimer. We also gratefully acknowl-
edge financial support from the Department of Science
and Technology, Government of India, New Delhi.
1H), 6.56 (s, 1H), 6.57 (d, J = 9.9 Hz, 1H), 6.81 (s, 1H); 13
C
NMR (75 MHz, CDCl3) d 15.9, 22.9, 22.9, 55.4, 59.6, 70.0,
81.7, 111.1, 126.0, 126.3, 128.2, 129.2, 131.0, 144.9, 153.4;
HRMS (ES +ve) calcd for C15H22O4Na [M+Na]+
289.1416, found 289.1416. For 15: IR (neat) 1735, 3450
(br) cmÀ1 1H NMR (300 MHz, CDCl3)
d 1.20 (t,
References and notes
J = 7.2 Hz, 3H), 1.27 (s, 3H), 1.34 (s, 3H), 2.16 (s, 3H),
2.59 (dd, A of ABX, JAB = 14.4 Hz, JAX = 6.5 Hz, 1H),
2.65 (dd, B of ABX, JBA = 14.4 Hz, JBX = 8.5 Hz, 1H),
3.57 (dd, J = 11.5, 4.8 Hz, 1H), 3.70 (d, J = 11.5 Hz, 1H),
3.77 (s, 3H), 4.11 (q, J = 7.2 Hz, 2H), 4.35–4.42 (m, X of
ABX, 1H), 5.08–5.15 (m, 2H), 5.93–6.05 (m, 1H), 6.58 (s,
1H), 6.83 (s, 1H); 13C NMR (75 MHz, CDCl3) d 13.9, 15.9,
22.3, 23.8, 38.5, 39.8, 55.4, 60.5, 70.8, 80.8, 109.1, 114.8,
124.2, 125.0, 133.6, 139.4, 145.4, 153.3, 172.6; HRMS (ES
+ve) calcd for C19H28O5Na [M+Na]+ 359.1835, found
1. (a) Macias, F. A.; Varela, R. M.; Torres, A.; Molinillo, J.
M. G.; Fronczek, F. R. Tetrahedron Lett. 1993, 34, 1999–
2002; (b) Macias, F. A.; Molinillo, J. M. G.; Varela, R.
M.; Torres, A.; Fronczek, F. R. J. Org. Chem. 1994, 59,
8261–8266; (c) Macias, F. A.; Varela, R. M.; Torres, A.;
Molinillo, J. M. G. Tetrahedron Lett. 1999, 40, 4725–
4728; (d) Macias, F. A.; Varela, R. M.; Torres, A.;
Molinillo, J. M. G. J. Nat. Prod. 1999, 62, 1636–1639; (e)
Macias, F. A.; Varela, R. M.; Torres, A.; Molinillo, J.
M. G. J. Chem. Ecol. 2000, 26, 2173–2186; (f) Macias, F.
A.; Torres, A.; Galindo, J. L. G.; Varela, R. M.; Alvarez,
J. A.; Molinillo, J. M. G. Phytochemistry 2002, 61, 687–
692.
359.1834. For 19: IR (neat) 1720 cmÀ1
;
1H NMR
(300 MHz, CDCl3) d 1.27 (s, 3H), 1.40 (s, 3H), 2.14 (s,
3H), 2.85 (dd, J = 10.8, 5.8 Hz, 1H), 3.42 (t, J = 10.8 Hz,
1H), 3.63–3.75 (m, 1H), 3.75 (s, 3H), 5.08 (d, J = 10.0 Hz,
1H), 5.13 (d, J = 17.0 Hz, 1H), 5.83–5.95 (m, 1H), 6.50
(s, 1H), 6.74 (s, 1H); 13C NMR (75 MHz, CDCl3) d 15.7,
22.6, 25.1, 42.7, 43.9, 55.5, 87.9, 111.9, 114.9, 126.4, 126.6,
129.0, 141.3, 146.7, 154.4, 214.1; HRMS (ES +ve) calcd
for C16H21O3 [M+H]+ 261.1491, found 261.1485.
2. Kamei, T.; Shindo, M.; Shishido, K. Tetrahedron Lett.
2003, 44, 8505–8507.
3. Vyvyan, J. R.; Oaksmith, J. M.; Parks, B. W.; Peterson, E.
M. Tetrahedron Lett. 2005, 46, 2457–2460, and references
cited therein.
7. Bargellini, G. Gazz. Chim. Ital. 1906, 36, 329–339.
8. Sen, P. K.; Biswas, B.; Venkateswaran, R. V. Tetrahedron
Lett. 2005, 46, 8741–8743.
4. (a) Tuhina, K.; Bhowmik, D. R.; Venkateswaran, R. V.
Chem. Commun. 2002, 634–635; (b) Sabui, S. K.;
Venkateswaran, R. V. Tetrahedron Lett. 2004, 45, 983–