Syntheses of heliannuols G and H; structure revision of the natural products

Article abstract of DOI:10.1016/j.tetlet.2006.08.014

The structures of the natural heliannuols G and H were established by the enantiocontrolled syntheses of the dihydrobenzofurans predicted for the natural products employing the palladium-mediated cyclization and cross metathesis as the key steps.

Full text of DOI:10.1016/j.tetlet.2006.08.014

Tetrahedron Letters 47 (2006) 7353–7356
Syntheses of heliannuols G and H; structure revision
of the natural products
Sachie Morimoto,a Mitsuru Shindo,b Masahiro Yoshidaa and Kozo Shishidoa,*
aGraduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
bInstitute for Materials Chemistry and Engineering, Kyushu University, 6-1 Kasugakoen, Kasuga 816-8580, Japan
Received 6 July 2006; revised 1 August 2006; accepted 4 August 2006
Available online 22 August 2006
Abstract—The structures of the natural heliannuols G and H were established by the enantiocontrolled syntheses of the
dihydrobenzofurans predicted for the natural products employing the palladium-mediated cyclization and cross metathesis as the
key steps.
Ó 2006 Elsevier Ltd. All rights reserved.
The heliannuols G and H, heliannane sesquiterpenes
OH
OH
isolated from the fresh leaf aqueous extracts of Helian-
HO
Me
HO
Me
1
´
thus annuus L. SH-222 and YPP by Macıas et al., were
found to have very interesting phytotoxic allelopathic
activity. In our previous communication,2 we reported
the enantioselective synthesis of compounds 1 and 2
having the proposed structures for the heliannuols G
O
O
1
2
HO
Me
1
and H; however, their H NMR spectra were not iden-
O
tical with those of the natural products. Upon careful
examination of the reported spectral data,1 we noticed
that the coupling constants of the olefinic protons for
the natural heliannuols G and H were 15.7 and
15.5 Hz, respectively, strongly suggesting that the dou-
ble bonds on the eight-membered heterocycle should
be trans instead of cis. In addition, in reviewing the bio-
genetic hypothesis for heliannuol C,3 we predicted that
dihydrobenzofurans 3a and 3b should be the natural
heliannuols G and H. Here we report the syntheses of
3a and 3b, thereby establishing the structures of the
natural heliannuols G and H (Fig. 1).
R
OH
3a: R=β-H
3b: R=α-H
Figure 1.
into the olefin part of 6, which would also be assembled
from 5 via the cyclization of the allyl alcohol or the acyl-
ated substrates 7, employing cross metathesis5 (route b)
(Scheme 1).
First, we examined a direct and convenient synthetic
route, that is, route a in Scheme 1. The alcohol (À)-5,
prepared from the prochiral 2-(2,5-dimethoxy-4-methyl-
phenyl)-propan-1,3-diol via desymmetrization using
PPL,2,6 was oxidized with Dess–Martin periodinane
(DMP) to give alcohol 8 which was reacted with the
dianion generated from 2-methyl-3-butyn-2-ol 9 with
n-BuLi to provide acetylenic diol 10 as an inseparable
mixture of diastereoisomers (dr = 4:1). Reduction with
LiAlH4 produced trans allylic diol 11, which was ex-
posed to acetylation conditions to give monoacetate 12
in a good overall yield. Attempted demethylation of
the 1,4-dimethoxyphenyl moiety in 12 was examined
We thought that dihydrobenzofurans 3a and 3b could be
directly derived via the palladium-mediated cyclization4
from the fully functionalized hydroquinone 4, which in
turn would be prepared from the optically pure alcohol
5 (route a). Alternatively, the target molecules could be
prepared by the introduction of the isopropanol unit
Keywords: Sesquiterpene; Heliannuol; Dihydrobenzofuran; Palladium-
mediated cyclization; Cross metathesis.
*
Corresponding author. Tel.: +81 88 633 7287; fax: +81 88 633
9575; e-mail: shishido@ph.tokushima-u.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.08.014

7354
S. Morimoto et al. / Tetrahedron Letters 47 (2006) 7353–7356
OH
HO
Me
MeO
Me
OH
route a
3a,b
OCOR
OH
OMe
OR
4
5
route b
HO
Me
HO
Me
O
OH
H
6
7: R=H or COR'
Scheme 1. Retrosynthetic analysis for 3a,b.
employing the procedure reported previously;7 however,
oxidation with cerium ammonium nitrate (CAN) did
not furnish the benzoquinone but a complex mixture in-
stead. After several attempts, oxidation using diacet-
oxyiodobenzene8 gave the benzoquinone, which was
then reduced with sodium hydrosulfite to give the requi-
site hydroquinone 13, a substrate for the cyclization. In-
stead of the desired 3a and 3b, palladium-mediated
cyclization4 of 13 gave only recovered starting material
or the formation of a mixture of unidentified products
(Scheme 2).
tion occurred to afford the benzofuran 17 (dr = 6:1) in
87% yield (Scheme 3).
Thus, although we successfully prepared the key com-
pound for the synthesis of 3a and 3b, there were two
drawbacks with the present route: (i) low overall yield
and (ii) reproducibility of the cyclization step. To over-
come these problems, we came up with another synthetic
route, starting with treatment of aldehyde 8 with vinyl-
magnesium chloride in the presence of cerium trichlo-
ride10 to produce a diastereomeric mixture (4:1) of
allylic alcohol 19 without racemization. This was con-
firmed by HPLC analysis using a Chiralcel OD column.
It should be noted that in the absence of cerium trichlo-
ride, partial racemization occurred. Mixed carbonate
formation followed by sequential treatment with CAN
and sodium hydrosulfite provided the hydroquinone
20, which was reacted with catalytic tetrakis(triphenyl-
phosphine)palladium4 at room temperature for 3 h to
give dihydrobenzofuran 17 in 83% yield. This product
was identical to the material prepared in Scheme 3.
Elaboration of the side chain was achieved by the cross
metathesis5 of 17 with 2-methyl-3-buten-2-ol (21) in the
presence of 10 mol % of (tricyclohexyl)phosphine[1,
3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-yl-
idene][benzylidene]-ruthenium(IV) dichloride (22) in
CH2Cl2 at room temperature to furnish the desired 3a
Since the direct cyclization to the fully functionalized
dihydrobenzofuran proved unsuccessful, we turned our
attention to route b, proceeding with a stepwise assem-
bly of the side chain. Aldehyde 8 was oxidized with so-
dium chlorite in the presence of 2-methyl-2-butene to
provide carboxylic acid 14, whose dimethyl ether was
cleaved with boron tribromide to give the c-lactone via
simultaneous lactonization. The resulting phenolic
hydroxyl group was protected as the t-butyldimethylsilyl
(TBS) ether to give 15, which was transformed into phe-
nolic allyl alcohol 16 (dr = 5:1) by reduction with di-
isobutylaluminum hydride followed by treatment of
the resulting hemiacetal with vinylmagnesium chloride.
Upon exposure of 16 to acidic conditions, sulfuric acid
in methanol9 at room temperature, the cationic cycliza-
OH
Dess-Martin
periodinane
OH
MeO
MeO
CH2Cl2, rt
9
CHO
(–)-5
OH
OMe
nBuLi, THF
HMPA, –30 °C-rt
Me
Me
OMe
10
8
(74% from 5)
Ac2O
pyridine, rt
OH
OH
LiAlH4
MeO
Me
MeO
Me
Et2O, 0 °C-rt
OH
OMe
OAc
OMe
(quant.)
(75%)
11
12
OH
1) PhI(OAc)2
HO
Me
Pd(0)
MeOH, H2O, rt
3a,b
OAc
OH
2) Na2S2O4
THF, H2O, rt
13
(42%)
Scheme 2. Attempted preparation of 3a and 3b.

S. Morimoto et al. / Tetrahedron Letters 47 (2006) 7353–7356
NaClO2, NaH2PO4
7355
2-methyl-2-butene
1) BBr3
CH2Cl2
TBSO
MeO
Me
tBuOH, H2O
CO2H
OMe
8
(83% from 5)
2) TBSCl, imidazole
4-DMAP, CH2Cl2
Me
O
O
14
15
(35%)
1) iBu2AlH
CH2Cl2
H2SO4
HO
TBSO
Me
MeOH, rt
OH
OH
MgCl
THF
2)
(87%)
Me
O
H
16 (dr=5:1)
17 (dr=6:1)
(40%)
Scheme 3. Synthesis of dihydrobenzofurans 17.
and 3b in 32% yield. To improve the yield, the phenolic
hydroxyl moiety was protected as a TBS ether and
compound 18 was subjected to the cross metathesis in
refluxing CH2Cl2 producing 23 in 98% yield. Finally,
desilylation with tetra-n-butylammonium fluoride affor-
ded a mixture of 3a and 3b in 93% yield (Scheme 4). The
diastereoisomers were separated by HPLC11 affording
3a {colorless oil; [a]D À13.7 (c 0.4, CHCl3); lit. [a]D
À6.2 (c 0.1, CHCl3)} and 3b {plate, mp 142–144 °C;
[a]D +166.3 (c 0.2, CHCl3); lit. [a]D À16.1 (c 0.2,
CHCl3)},12 whose 1H NMR data were identical with
those of the natural heliannuols G and H. The structure
of 3b was confirmed by an X-ray crystallographic anal-
ysis13 as shown in Figure 2.
In summary, we have completed the enantioselective
syntheses of the predicted structures for the heliannuols
G and H and established the real structures of the natu-
ral products. The key steps include palladium-mediated
cyclization for the construction of the dihydrobenzo-
furan skeleton and highly efficient cross metathesis for
assembling the dimethylallyl alcohol moiety. The syn-
thetic route developed here is general and efficient and
would be applicable to other related molecules. It should
also be pointed out that the existence of the novel
carbon framework of the heliannane sesquiterpenes in
nature was clarified by the present work.
Acknowledgements
´
We thank Professor Francisco Macıas of the University
of Cadiz (Spain) for providing us with the spectral data
of the natural heliannuols G and H. This work was
supported financially by a Grant-in-Aid for Scientific
Figure 2. The molecular structure of 3b.
1) ClCO2Et, 4-DMAP
CH2Cl2
2) (NH4)2Ce(NO3)6
CH3CN, H2O
MgCl
OH
OCO2Et
MeO
HO
Me
CeCl3, THF
8
(77% from 5)
3) Na2S2O4
THF, H2O
Me
OMe
19 (dr=4:1)
OH
20
(97%)
OH
21
Pd(Ph3P)4 (5 mol%)
THF, rt, 3 h
RO
Me
HO
Me
CH2Cl2, 40°C
17
(83%)
O
O
NMes
Ph
MesN
Cl
H
R
OH
17: R=H (dr=2:1)
18: R=TBS
TBSCl, imidazole
4-DMAP, CH2Cl2
3a: R=β-H
3b: R=α-H
Ru
22
Cl
(95%)
PCy3
(32%)
nBu4NF
THF, rt
(93%)
TBSO
21, 22 (10 mol%)
3a,b
18
CH2Cl2, reflux
Me
O
H
OH
20 h
23
(98%)
Scheme 4. Syntheses of heliannuols G (3a) and H (3b).

7356
S. Morimoto et al. / Tetrahedron Letters 47 (2006) 7353–7356
7. Takabatake, K.; Nishi, I.; Shindo, M.; Shishido, K. J.
Chem. Soc., Perkin Trans. 1 2000, 1807–1808.
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Research (A) (No. 16209001) from the Japan Society for
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11. Conditions of HPLC separation: Column, Mightysil Si 60
250-20 (5 lm); eluent, hexane/AcOEt = 7/3; flow rate
10 ml/min; detect, UV detection 254 nm; retention time
for 3a = 38.8 min, for 3b = 35.6 min.
12. Because of the inaccessibility of the natural heliannuol H,
the discrepancy of the optical rotations between the
synthetic 3b and the natural product1 cannot be explained
at this stage.
13. Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 613441. Copies of the
data can be obtained, free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
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