Synthesis of heliannuol D, an allelochemical from Helianthus annus

Article abstract of DOI:10.1016/j.tetlet.2003.11.098

A synthesis of heliannuol D 1 is described involving regioselective oxidation of the benzoxabicyclo[3.2.1]octanone 20 followed by hydrogenolysis to generate the benzoxepane ring system of 1.

Full text of DOI:10.1016/j.tetlet.2003.11.098

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 983–985
Synthesis of heliannuol D, an allelochemical from Helianthus annus
Subir K. Sabui and Ramanathapuram V. Venkateswaran*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700-032, India
Received 18 September 2003; revised 10 November 2003; accepted 21 November 2003
Abstract—A synthesis of heliannuol D 1 is described involving regioselective oxidation of the benzoxabicyclo[3.2.1]octanone 20
followed by hydrogenolysis to generate the benzoxepane ring system of 1.
Ó 2003 Elsevier Ltd. All rights reserved.
Heliannuol D 1, along with its siblings heliannuols A–C
and E, 2–5, comprise a new group of phenolic sesqui-
terpenes isolated from the cultivated sun flowers
Helianthus annus.1 These compounds are believed to be
involved in the allelopathic activity displayed by these
flowers. Allelopathy, which is concerned with biochem-
ical plant–plant and plant–microorganism interactions,
including positive and negative effects, has been pro-
posed2 as a possible alternative weed management po-
licy. Due to the increasing concern in recent years
regarding the natural ecological balance and to reduce
further the risk posed by the use of synthetic pesticides,
allelochemicals and their analogues are being looked
upon as useful pest control agents without hazardous
side effects. In this context heliannuols, in view of their
significant bio-activity as natural herbicide models and
the hitherto unknown benzo-fused six-, seven- and
eight-membered cyclic ether skeleta enshrined in them,
have attracted the attention of synthetic chemists from
many laboratories.3 We recently reported4 a synthesis of
heliannuol A. A fragmentation sequence encountered in
the course of this synthesis had resulted in an advanced
intermediate, which had been utilised by others3b for the
synthesis of 1, thus also concluding a formal synthesis of
1. Herein we disclose an alternative synthesis of 1
employing a regioselective oxidation of a benzoxabicy-
clo[3.2.1]octanone to generate the required benzoxepane
ring system present in 1.
the benzoxabicyclo[3.2.1]octanone 6. We envisaged that
if the bridge-locked ketone could be cleaved regioselec-
tively at the site indicated, it would generate the basic
benzoxepane ring system of 1 with the proper func-
tionality for transformation to the isopropanol moiety
present in 1 (Scheme 1). If this strategy were successful,
it could then be applied to an appropriate substrate
containing the additional phenolic functionality at C-5.
A versatile procedure for cleavage of non-enolisable
ketones is the Haller–Bauer reaction.6 However, under
various conditions employed for effecting this cleavage,
the bridged ketone 6 remained obdurately unchanged or
14
6
5
1
7
HO
8
9
4
10
2
15
O
3
13
11
12
1
OH
HO
HO
HO
OH
OH
O
O
3
2
4
OH
HO
O
O
In connection with our synthesis of an A-ring aromatic
trichothecene analogue, we have reported5 a synthesis of
OH
5
O
O
Keywords: Allelochemical; Heliannuol D; Benzobicyclo[3.2.1]octanone
oxidative cleavage; Benzoxepane ring system.
O
H
CO R
7
6
2
* Corresponding author. Tel.: +91-33-2473-4971; fax: +91-33-2473-
2805; e-mail: ocrvv@mahendra.iacs.res.in
Scheme 1.
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.098

984
S. K. Sabui, R. V. Venkateswaran / Tetrahedron Letters 45 (2004) 983–985
resulted in decomposition products. Success was finally
achieved through peroxide induced oxidation under
Baeyer–Villiger conditions. Thus, when the ketone 6 was
subjected to oxidation with meta-chloroperbenzoic acid
(m-CPBA) in dichloromethane with added trifluoro-
acetic acid, it furnished the lactone7 8 in 68% yield
through a regioselective migration of the more substi-
tuted bond. The structural assignment of lactone 8 was
based on its 1H NMR spectrum, which showed the lone
bridge-head proton adjacent to the carbonyl group at d
4.75 as it was expected that, in the case of the isomeric
lactone, this proton, sandwiched between two oxygen
atoms would have shifted further downfield. Additional
support for the assigned structure came from further
transformations. This lactone being benzylic in nature,
was expected to undergo ready hydrogenolysis to reveal
the benzoxepane ring system of 1. In anticipation of this,
when a methanolic solution of the lactone 8 containing
perchloric acid was subjected to hydrogenation in
presence of Pd–C, it afforded the bicyclic ester7 9 in 72%
yield after chromatography, encouragingly as a single
isomer. The 1H NMR spectrum of 9 showed the
expected doublet for the secondary methyl group at d
1.23, corroborating the regioselectivity in the oxidation
of the ketone 6. The delivery of hydrogen from the side
opposite to the carboxylic acid function during hydro-
genation was expected to lead to the desired cis dispo-
sition of the two substituents in the bicyclic ester 9.
Reaction of the ester 9 with an excess of methyl mag-
nesium iodide furnished 5-deoxyheliannuol D7 10 in
97% yield (Scheme 2). The stereochemical assignment of
10 was supported by its 1H NMR spectrum where the C-
10 proton appeared as a distinct doublet of doublets at d
3.36 well separated from the C-7 proton, a multiplet at d
3.0, similar to the analogous protons in the spectrum of
5-O-methylheliannuol D 23, which was made available
to us.3b Furthermore, the C-14 secondary methyl dou-
blet at d 1.26 merged with the singlet due to the C-12
and C-13 methyl groups, again in conformity with the
same pattern in the spectrum of 23. In the corresponding
epimer of 23, the C-10 proton does not show any clean
splitting pattern and the multiplet at d 3.25 appears
closer to the C-7 proton multiplet at 3.0. The C-14
methyl doublet is well separated from the singlet due to
the C-12 and C-13 methyl groups.
With the successful synthesis of 5-deoxyheliannuol D,
we turned our attention to the application of the above
procedure on an appropriately C-5 substituted deriva-
tive of 6 for a synthesis of heliannuol D 1. Condensation
of the acetophenone 118 with ethyl formate in the
presence of sodium hydride followed by dehydration of
the resulting chromanol furnished the 6-methoxy-7-me-
thyl chromone 12 in an overall yield of 85%. Reaction of
this chromone with iodobenzene diacetate9 and sub-
sequent acid treatment of the intermediate trimethoxy
chromanol 13 yielded the 3-hydroxychromone 14 in 70%
yield, which was duly methylated to give the 3,6-dime-
thoxy-7-methyl chromone 15 (Scheme 3).
Irradiation of a benzene solution of 15, which was
subjected to a continuous flow of ethylene furnished a
mixture of the adduct7 16 and the oxetanol7 17 in a 4.5:1
ratio in 62% total yield. These were easily separated by
column chromatography. Reaction of the adduct 16
with methyl magnesium iodide afforded the alcohol7 18
in 87% yield. The assignment of stereochemistry to this
alcohol was based on the easier attack from the exo face,
as observed by us on a previous occasion.10 Reduction
of the oxetanol 17 with lithium aluminium hydride
yielded the diol7 19 in excellent yield (90%). Treatment
of a benzene solution of either the alcohol 18 or the diol
19 with a catalytic amount of boron trifluoride etherate
resulted in the expected pinacol–pinacolone rearrange-
ment affording the bridged ketone7 20 in very good yield
(85%) (Scheme 4). The preparation of this appropriately
substituted substrate set the stage for the next sequence
of reactions. Oxidation of 20 with m-CPBA as for 6
furnished the crucial lactone7 21 regioselectively in 71%
yield. Hydrogenolysis of a methanol solution of 21
proceeded as before and delivered the bicyclic ester7 22
in 74% yield (Scheme 2). In the present case, however, it
appeared from 13C NMR that this was contaminated
with some of the trans isomer. Separation at this stage
proved somewhat difficult and hence this mixture was
treated with an excess of methyl magnesium iodide to
furnish the tertiary alcohols in quantitative yield. GC
analysis of the product showed the presence of two
components in a 15.6:1 ratio with close retention times.
R
R
O
O
H
a
O
O
O
O
H
O
MeO
MeO
6 R = H
8
R = H
a,b
20 R = OMe
21 R = OMe
OH
O
12
11
R
R
b
c
O
O
OMe
OMe
MeO
OR1
MeO
c
OH
O
O
d
CO Me
2
OH
O
13
OMe
9 R = H
22 R = OMe
10 R = H
14 R1 = H
23 R = OMe
e
ref. 3b
15 R1 = Me
1
R = OH
Scheme 2. Reagents and conditions: (a) m-CPBA, TFA, CH2Cl2, 6 h,
68% (for 8), 71% (for 21); (b) Pd–C (10%), H2, CH3OH, HClO4, 8 h,
72% (for 9), 74% (for 22); (c) MeMgI, (C2H5)2O, reflux, 5 h, 97% (for
10), 89% (for 23).
Scheme 3. Reagents and conditions: (a) HCO2Et, NaH, THF, rt, 14 h;
(b) PTS, PhH, reflux, 8 h, 85% (two steps); (c) Ph–I(OAc)2, KOH,
CH3OH, 10 h; (d) concd HCl, 5 h, 70% (two steps); (e) MeI, K2CO3,
acetone, reflux, 87%.

S. K. Sabui, R. V. Venkateswaran / Tetrahedron Letters 45 (2004) 983–985
985
(b) Macias, F. A.; Molinillo, J. M. G.; Varela, R. M.;
Torres, A.; Fronzek, F. R. J. Org. Chem. 1994, 59, 8261;
(c) Macias, F. A.; Varela, R. M.; Torres, A.; Molinillo,
J. M. G. Tetrahedron Lett. 1999, 40, 4725.
O
O
HO
O
OMe
H
MeO
MeO
MeO
a
15
+
O
H
2. (a) Einhellig, F. A.; Leather, G. R. J. Chem. Ecol. 1988,
14, 1829; (b) Worsham, A. O. In Phytochemical Ecology:
Allelochemical, Mycotoxins and Insect Pheromones and
Allomons; Chou, G. H., Waller, G. R., Eds.; Monograph
Series No. 9; Institute of Academica Sinica: Taipei,
Taiwan, ROC, 1989, p 275.
16
17
b
c
HO
HO
OMe
OH
MeO
3. (a) Grimm, E. L.; Levac, S.; Trimble, L. A. Tetrahedron
Lett. 1994, 35, 6847; (b) Vyvyan, J. R.; Lopper, R. E.
Tetrahedron Lett. 2000, 41, 1151; (c) Takabatke, K.; Nishi,
I.; Shindo, M.; Shishido, K. J. Chem. Soc., Perkin Trans. 1
2000, 1807; (d) Sato, K.; Yoshimura, T.; Shindo, M.;
Shishido, K. J. Org. Chem. 2001, 66, 309; (e) Kishuku, H.;
Shindo, M.; Shishido, K. Chem. Commun. 2003, 350; (f)
Fuminao, D.; Takahisa, O.; Takeshi, S.; Shigeru, N.
Tetrahedron Lett. 2003, 44, 4877.
O
18
O
19
H
H
d
MeO
O
O
20
4. Tuhina, K.; Bhowmik, D. R.; Venkateswaran, R. V.
Chem. Commun. 2002, 634.
H
5. Mal, J.; Venkateswaran, R. V. J. Org. Chem. 1998, 63,
3855.
6. Mehta, G.; Venkateswaran, R. V. Tetrahedron 2000, 56,
1399.
Scheme 4. Reagents and conditions: (a) hm, CH2@CH2, PhH, 6 h, 62%;
(b) MeMgI, (C2H5)2O, reflux, 5 h, 87%; (c) LAH, THF, reflux, 8 h,
90%; (d) BF3ÆEt2O, PhH, rt, 2 h, 85%.
7. All new compounds reported here gave analytical and
spectral data consistent with the assigned structures.
Selected spectral data: For 8: IR 1760 cmÀ1 1H NMR
;
Careful preparative thin layer chromatography allowed
separation of the less polar major component and fur-
nished ( )-5-O-methylheliannuol D 23 in 89% yield
(Scheme 2), whose spectral data (1H NMR and 13C
NMR) fully matched the data recorded previously.3b
Since this has been demethylated3b to ( )-heliannuol D
1, the present efforts concluded a formal synthesis of
racemic 1.
(300 MHz, CDCl3) dH 1.82 (3H, s), 2.28 (3H, s), 4.75 (1H,
dd, J 0.9, 6 Hz). For 9: IR 1750 cmÀ1; 1H NMR (300 MHz,
CDCl3) dH 1.23 (3H, d, J 7.1 Hz), 2.21 (3H, s), 2.99 (1H,
1
m), 3.74 (3H, s), 4.12 (1H, dd, J 1.9, 11.3 Hz). For 10: H
NMR (300 MHz, CDCl3) dH 2.27 (3H, s), 3.0 (1H, m), 3.36
(1H, dd, J 1.1, 11.0 Hz); 13C (CDCl3, 75 MHz) dC 19.2,
21.1, 24.8, 25.8, 25.9, 32.2, 38.7, 72.9, 90.7, 122.4, 124.8,
129.8, 136.9, 137.7, 158.4. For 20: IR 1765 cmÀ1; 1H NMR
(300 MHz, CDCl3) dH 1.32 (3H, s), 2.06 (3H, s), 3.69 (3H,
s), 4.09 (1H, d, J 5.7 Hz); 13C (CDCl3, 75 MHz) dC 14.5,
16.2, 26.1, 37.9, 48.0, 56.4, 76.9, 106.6, 118.6, 128.0, 129.4,
In summary, we have developed an efficient synthesis of
heliannuol D 1, employing a regioselective oxidative
cleavage of a benzoxabicyclo[3.2.1]octanone to generate
the benzoxepane ring system present in 1, affording the
final compound in good overall yield.
145.3, 153.1, 214.2. For 21: IR 1761 cmÀ1 1H NMR
;
(300 MHz, CDCl3) dH 1.83 (3H, s), 2.15 (3H, s), 3.77 (3H,
s), 4.72 (1H, d, J 5.1 Hz); 13C (CDCl3, 75 MHz) dC 16.9,
26.4, 27.8, 37.5, 57.3, 74.2, 84.0, 108.9, 122.5, 124.8, 131.0,
;
148.1, 153.2, 169.8. For 22: IR 1749 cmÀ1 1H NMR
(300 MHz, CDCl3) dH 1.32 (3H, d, J 7.1 Hz), 2.13 (3H, s),
2.99 (1H, m), 3.79 (3H, s), 3.80 (3H, s), 4.11 (1H, d, J
10.1 Hz); 13C (CDCl3, 75 MHz) dC 15.4, 18.5, 28.8, 31.3,
38.2, 52.1, 55.5, 81.1, 110.5, 124.3, 136.7, 150.0, 154.0,
171.8, 194.5. For 23: 1H NMR (300 MHz, CDCl3) dH 1.23
(3H, d, J 7.2 Hz,), 2.06 (3H, s), 2.88 (1H, m), 3.22 (1H, dd,
J 1.2, 11.1 Hz), 3.71 (3H, s); 13C (CDCl3, 75 MHz) dC 15.5,
18.5, 24.4, 25.5, 26.0, 31.7, 39.0, 55.6, 72.4, 90.4, 111.2,
123.5, 125.0, 137.3, 151.3, 153.5.
Acknowledgements
We sincerely thank Prof. 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 5-O-methyl-
heliannuol D and its epimer. We also gratefully
acknowledge financial support from the Department of
Science and Technology, Govt. of India, New Delhi.
8. Sabui, S. K.; Venkateswaran, R. V. Tetrahedron 2003, 59,
8375.
References and notes
9. Moriarty, R. M.; Prakash, O. J. Heterocycl. Chem. 1985,
22, 583.
1. (a) Macias, F. A.; Varela, R. M.; Torres, A.; Molinillo, J.
M. G.; Fronzek, F. R. Tetrahedron Lett. 1993, 34, 1999;
10. Sengupta, D.; Venkateswaran, R. V. Chem. Commun.
1986, 1638.