Synthesis of bioactive sesquiterpene heliannuol E involving a ring-expansion reaction of spirodienones

Article abstract of DOI:10.1055/s-2003-37124

A heliannane-type sesquiterpene, heliannuol E (1), has been successfully synthesized. The key step was conversion of the electrochemically produced spiro compounds (8, and 18) into the corresponding dihydrobenzopyrans (11, 12, 19, and 20) by a selective r

Full text of DOI:10.1055/s-2003-37124

LETTER
411
Synthesis of Bioactive Sesquiterpene Heliannuol E Involving a Ring-
Expansion Reaction of Spirodienones
Synthesis of
B
u
ioactive Sesq
m
uiterpene
H
eliannu
i
ol
E
nao Doi, Takahisa Ogamino, Takeshi Sugai, Shigeru Nishiyama*
Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi 3-14-1, Kohoku-ku, Yokohama 223-8522, Japan
Fax +81(45)5661717; E-mail: nisiyama@chem.keio.ac.jp
Received 7 December 2002
D was 2:3 at the most in the case of R = H, such bulky
Abstract: A heliannane-type sesquiterpene, heliannuol E (1), has
substituents as Fmoc-amino, i-Pr, i-Bu, gem-dimethyl
groups, provided the type-D products in 70–77% yields.
been successfully synthesized. The key step was conversion of the
electrochemically produced spiro compounds (8, and 18) into the
To expand the utility of this rearrangement into natural
products synthesis, we demonstrate herein the synthesis of
1. According to a fundamental retrosynthetic analysis
(Scheme 2), the target molecule would be produced by the
regioselective conversion of 3 into 2, which might be ob-
tained by the two-electron oxidation of 4. To accomplish
this purpose, the effect of a methyl group in the aromatic
ring, should be confirmed in the anodic oxidation leading
to the spiro compound 3, as well as in the ring expansion
reaction to 2.
corresponding dihydrobenzopyrans (11, 12, 19, and 20) by a selec-
tive ring expansion process.
Key words: heliannuol E, anodic oxidation, sesquiterpene, dihy-
drobenzopyran, two-electron oxidation
Heliannuol E 1, isolated from the aqueous extracts of
Helianthus annuus L. cv. SH-222, might contribute to the
allelopathogenic action of cultivar sunflowers,1 which
would open up the possibility of new-type agricultural
chemicals. This sesquiterpene in an optically active form,
was ingeniously synthesized by Shishido et al.,2 employ-
ing a similar route to its proposed biogenesis.3
R
HO
Heliannuol E (1)
Me
Me
O
OH
2
Me
Me
HO
OH
Me
O
R
HO
HO
Me
OH
Me
Heliannuol E (1)
O
Me
O
Me
Me
OH
Me
OH
3
4
R
Me
O
to D
HO
Br
Scheme 2
[O]
O
Br
R
B
A
to C
R
At the outset, anodic oxidation of 5, synthesized in the
usual way from ortho-cresol in 7 steps, was carried out as
a model study to understand the chemical profile of the
phenol derivatives carrying methyl groups in the oxida-
tion. When 5 was oxidized under CCE conditions (anode:
glassy carbon beaker, cathode: platinum wire, LiClO4 as a
supporting salt, MeOH or dioxane with/without 60% aq
HClO4 as a solvent), the spiro compound 6 was produced
in very low yield under a wide range of reaction condi-
tions attempted. After synthetic elaboration of the spiro-
structure, we noticed an introduction of a halogen atom to
the ortho-moiety of the phenol group to control the oxida-
tion potential and the reaction mode.4–6,9 Thus, compound
5 was treated with bromine to give 7 in 90% yield, which
was submitted to the anodic oxidation by employing es-
sentially the same procedure as described above (Table 1,
Figure 1).
Br
HO
Br
HO
R
R
O
O
C
D
Scheme 1
From our extensive electrochemical investigation towards
the total synthesis of natural products,4–6 it was observed
that the spiro derivative B generated by anodic oxidation
of the corresponding monobromophenol A,7 was convert-
ed under Lewis acid conditions into dihydrobenzopyrans
C and D (Scheme 1). The regioselectivity in the ring ex-
pansion reaction (B to C and/or D) was controlled by
steric hindrance between a bromine and substituents R of
the 3-hydroxypropyl side-chain.8 While the ratio of C and
Synlett 2003, No. 3, Print: 19 02 2003.
Art Id.1437-2096,E;2002,0,02,0411,0413,ftx,en;U11902ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

412
F. Doi et al.
LETTER
Table 1 Anodic Oxidation of Bromophenol 7 under CCE Condi-
8) proceeded to the Br side. One reason for this selectivity
might be directed by the electron-withdrawing property of
the bromine atom, along with the donating property of a
methyl group.
tionsa
Entry Condition
V vs SCE(Fmol–1)
Solvent
Products, yield (%)
8
9
10
Me
Me
1
2
3
4
0.85–1.30
(1.7)
MeOH
MeOH
21
32
5
BnO
BnO
BnO
d
b
a
CO2Me
CO2Me
CO2Me
1.20–1.30
(2.0)
43
29
–
13
30
–
14
13
Me
1.20–1.30
(2.0)
MeOH–60% aq 24
HClO4 (5:1)
Me
BnO
c
Me
O
1.60–1.80
(8.2)
Dioxane–60% aq 50
HClO4 (5:1)
–
Me
15
O
16
(CH2)2OAc
Br
a Concentration of the substrate 7: 1.2 mM. Supporting salt: 0.1 M
concentration LiClO4.
Me
HO
Br
O
(CH2)2OAc
e
Me
OH
Me
HO
Me
X
O
X
17
18
(CH2)2OAc
O
Me
OH
HO
Me
O
OH
Me
f
Me
5: X= H
7: X= Br
Me
(CH2)2OR'
X
(CH2)2OR'
6: X= H
8: X= Br
RO
X
RO
Br
O
O
Me
OR''
Me
O
O
Me
O
OR''
OMe
Me
Me
Me
Me
Me
20: R= R''= H, R'= Ac, X= Br
22: R= R''= MOM, R'= X= H
OH
19: R= R''= H, R'= Ac, X= Br
21: R= R''= MOM, R'= X= H
g
g
O
O
9
10
NOE
Br
H
Me
H
O
HO
Me
HO
Me
h
Heliannuol E
(1)
HO
Br
22
Me
O
O
OH
23
Me
12
NOE
11
Scheme 3 Reagents: a. i) Dimethyl malonate, DBU/MeOH, reflux;
ii) DMSO, NaCl/reflux, 84% in two steps; b. i) KOH (98%); ii)
(PhO)2P(O)Cl, Et3N, then MeOH, pyridine; iii) BH3⋅THF; CSA/PhH
(87% in four steps); c. i) DIBALH; ii) i-PrPh3PI, n-BuLi; iii) Ac2O,
pyridine (74% in three steps); d. i) OsO4; ii) H2, Pd-C; iii) pyridi-
ne⋅HBr3 (90% in three steps); e. Table 2; f. BF3⋅OEt2 75% as a mixture
of 19 and 20); g. i) H2, Pd-C (quant.); ii) MOMCl, i-Pr2NEt (67%);
iii) K2CO3/MeOH (95%); h. i) MsCl, pyridine (quant.); ii)
O2NC6H4SeCN, NaBH4, then 35% H2O2 (45%); iii) 6 M HCl (1: 56%,
23: 36%).
Figure 1
While the expected spirodienone 813 was obtained in all of
the entries,10 entries 1–3 involved the undesired radical
coupling product 9 and the dienone 10 involving a MeO
group derived from the solvent. Ultimately, despite the
low current efficiency, acidic conditions in dioxane–60%
aq HClO4 (entry 4) effectively induced the two-electron
oxidation to generate a cation, which was captured by the
terminal hydroxyl group to give 8 as the sole product. In
the next stage, the spiro derivative 8 was submitted to the
Lewis acid-promoted rearrangement (BF3⋅OEt2/CH2Cl2,
r.t.). Although the reaction conditions were not optimized,
two rearranged products 1113 and 1213 were obtained in 6
and 33% yields, respectively. The NOE experiments indi-
cated that the expected 12 was preferentially produced. In
the preceding paper using ortho-bromo phenol deriva-
tives, steric repulsion of substituents controlled the direc-
tion of the rearrangement: the benzylic carbon was shifted
to the opposite side of the Br group. In contrast, the rear-
rangement of ortho,ortho-bromomethyl derivatives (ex.
Based on the observation mentioned above, a synthetic
approach towards (+/–)-1 was commenced with the
Michael addition of dimethyl malonate to the cinnamic
acid derivative 13, followed by decarboxylation to give
diester 14 (Scheme 3). After hydrolysis, compound 14
was converted in three steps into δ-lactone 15 in good
yield. Compound 15 was treated with DIBALH, followed
by Wittig reaction with isopropylidenetriphenylphos-
phorane and acylation to yield 16. Successive three-step
procedure produced the phenol 17, which was submitted
to the anodic oxidation (Table 2).
Synlett 2003, No. 3, 411–413 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Bioactive Sesquiterpene Heliannuol E
413
Table 2 Anodic Oxidation of 17 under CCE Conditionsa
Acknowledgment
Entry Condition
V vs SCE (F mol–1)
Solvent
MeOH
Yield of 18 (%)
The authors are grateful to FY 2002 The 21st Century COE Program
for the financial support of this work.
1
2
3
4
5
1.10–1.20
(4.0)
39
6
References
(1) Macías, F. A.; Varela, R. M.; Torres, A.; Molinillo, J. M. G.
Tetrahedron Lett. 1999, 40, 4725.
(2) Sato, K.; Yoshimura, T.; Shindo, M.; Shishido, K. J. Org.
Chem. 2001, 66, 309.
(3) Macías, F. A.; Molinillo, J. M. G.; Varela, R. M.; Torres, A.
J. Org. Chem. 1994, 59, 8261.
(4) Yamamura, S.; Nishiyama, S. In Studies in Natural
Products Chemistry, Vol. 10F; Atta-ur-Rahman, Ed.;
Elsevier Science publishers: Amsterdam, 1992, 629.
(5) Yamamura, S.; Nishiyama, S. J. Synth. Org. Chem., Jpn.
1997, 55, 1029.
(6) Yamamura, S.; Nishiyama, S. Synlett 2002, 533.
(7) Mori, K.; Yamamura, S.; Nishiyama, S. Tetrahedron 2001,
57, 5527.
1.20–1.30
(2.0)
MeOH/60% aq
HClO4 (5/1)
1.55–1.75
(12.0)
Dioxane/60% aq 35
HClO4 (5/1)
1.50–1.60
(2.0)
MeCN
32
1.30–1.50
(2.0)
Acetone
61
a Substrate concentration: 1.5–2.0 mM. Supporting salt: entries 1–4
LiClO4 (0.1 M), entry 5 Bu4NClO4 (0.1 M).
(8) Mori, K.; Yamamura, S.; Nishiyama, S. Tetrahedron 2001,
57, 5533. After this article was published, Plourde reported
a similar oxidation of ortho-methoxyphenol 5 using such
oxidants as Pb(OAc)4, PIDA, or PIFA:Plourde, G. L.
Tetrahedron Lett. 2002, 43, 3597.
(9) The ortho-bromophenol derivative without methyl groups,
might be available: the bromo substituent would be
converted into the appropriate alkyl group. Although this
method would require a rather longer synthetic process, the
feasibility of the method is under consideration.
(10) Despite similar CV curves (first peak: ca. 1.05 V vs SCE), 5
and 7 provided different oxidation reactions.
A crucial factor in the anodic oxidation was the selection
of the reaction solvents: acetone effected oxidation lead-
ing to the spiro compound 18 (61% yield, entry 5),11 rather
than dioxane–HClO4 conditions which provided good re-
sults in the case of 8. The relatively low yields under the
acidic conditions, might be owing to the acid-labile char-
acter of the tertiary hydroxyl group in the side-chain moi-
ety. The Lewis acid treatment of the spirodienone 18 in
hand, effected the desired rearrangement to give a mixture
of the branched dihydrobenzopyrans 19 and 20 in 75%
total yield. Unfortunately, diastereomers of both com-
pounds could not be separated, and they were submitted to
the following reactions without further separation. The
mixture was hydrogenolized, followed by protection with
MOM groups and solvolysis provided a chromatographi-
cally separable mixture of 21 and 22 (1:5). In spite of the
diastereomeric mixtures of the aliphatic parts, their struc-
tures were spectroscopically confirmed by the ortho-cou-
pling of the aryl protons (21), as well as the NOE effects
of the benzylic protons with the aryl-methyl group (21)
and the aryl protons (22). Finally, according to the report-
ed procedure involving the selenium-supported dehydra-
tion by the Grieco protocol,2,12 the major isomer 22 was
successfully converted into the target molecule 1,13 along
with the cis-isomer 2313 (1/23 = 1.6:1).
(11) Several unknown by-products were observed. Upon
employing acetone as a solvent, anodic oxidation of 7
provided 8 (40%), along with several by-products.
(12) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem.
1976, 41, 1485.
(13) Selected Spectroscopic Data. Compound 8: 1H NMR
(CDCl3): δ = 2.01 (3 H, d, J = 1.5 Hz), 2.1 (4 H, complex),
4.15 (2 H, t, J = 6.6 Hz), 6.67 (1 H, dd, J = 3, 1.5 Hz), 7.29
(1 H, d, J = 3 Hz).
Compound 11: 1H NMR (CDCl3): δ = 2.00 (2 H, complex),
2.16 (3 H, s), 2.61 (t, J = 6.6 Hz), 4.06 (2 H, t, J = 5 Hz), 6.82
(1 H, s).
Compound 12: 1H NMR (CDCl3): δ = 2.00 (2 H, complex),
2.20 (3 H, s), 2.69 (2 H, t, J = 6.6 Hz), 4.06 (2 H, t, J = 5 Hz),
6.59 (1 H, s).
Compound 1: 1H NMR(CDCl3): δ = 1.24 (3 H, s), 1.30 (3
H, s), 1.9 (2 H, complex), 2.20 (3 H, s), 3.46 (1 H, m), 3.74
(1 H, dd, J = 3.6, 10 Hz), 4.91 (1 H, dd, J = 17, 1.5 Hz), 5.11
(1 H, dd, J = 10.4, 1.5 Hz), 5.97 (1 H, ddd, J = 17, 10.4, 6.4
Hz), 6.49 (1 H, s), 6.66 (1 H, s). The spectroscopy was
superimposable to the reported one. Found: m/z = 248.1428.
Calcd for C15H20O3 (M): 248.1412.
In conclusion, the synthesis of the bioactive sesquiterpene
(+/–)-heliannuol E 1 was accomplished by using conver-
sion of spirodienone 18 electrochemically obtained into
the dihydrobenzopyran 19, 20 as the key step. The direc-
tion of the rearrangement was controlled by the bromine
substituent at the ortho-position of a phenol group. Fur-
ther synthesis of optically active 1 is under way.
Compound 23: 1H NMR(CDCl3): δ = 1.26 (3 H, s), 1.31 (3
H, s), 1.65 (1 H, q, J = 12 Hz), 2.01 (1 H, br dd. J = 11.7, 12
Hz), 2.19 (3 H, s), 3.48 (1 H, m), 3.80 (1 H, br d, J = 17 Hz),
5.20 (1 H, br d, J = 10 Hz), 5.24 (1 H, br d, J = 17 Hz), 5.68
(1 H, ddd, J = 17, 10, 9.8 Hz), 6.60 (1 H, s), 6.64 (1 H, s).
Found: m/z = 248.1416. Calcd for C15H20O3 (M): 248.1412.
Synlett 2003, No. 3, 411–413 ISSN 0936-5214 © Thieme Stuttgart · New York