Efficient and enantioselective total syntheses of heliannuols A and K

Article abstract of DOI:10.1016/j.tet.2011.05.034

The second-generation enantioselective synthesis of heliannuol A and the first enantioselective total synthesis of heliannuol K (via two routes) have both been accomplished efficiently; (heliannuol A, nine steps and 25% yield; heliannuol K, seven steps an

Full text of DOI:10.1016/j.tet.2011.05.034

Tetrahedron 67 (2011) 4758e4766
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Tetrahedron
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Efficient and enantioselective total syntheses of heliannuols A and K
*
Makoto Kanematsu, Kana Soga, Yuki Manabe, Sachie Morimoto, Masahiro Yoshida, Kozo Shishido
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78-1 Sho-machi, Tokushima 770-8505, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 April 2011
Received in revised form 9 May 2011
Accepted 9 May 2011
Available online 14 May 2011
The second-generation enantioselective synthesis of heliannuol A and the first enantioselective total
synthesis of heliannuol K (via two routes) have both been accomplished efficiently; (heliannuol A, nine
steps and 25% yield; heliannuol K, seven steps and 47% yield). Highlights of our synthetic strategy include
a substrate-controlled chirality transfer in the Lewis acid mediated Claisen rearrangement of the allyl
aryl ether for the key construction of a tertiary stereogenic center at the benzylic position followed by, for
heliannuol A, ring-closing metathesis, diastereoselective epoxidation, and regioselective cleavage of the
epoxide; and for heliannuol K, ring-closing metathesis and conjugate reduction of the eight-membered
enone.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
synthesis of the natural enantiomer (ꢀ)-heliannuol A (1),4b which
was completed in seventeen steps from 2,5-dimethoxy-4-methyl-
Heliannuol A (1),1 the first member of a class of bioactive ses-
quiterpenes, and heliannuol K (2)2 were isolated from the moder-
ately polar bioactive fractions of the fresh leaf aqueous extracts of
the cultivar Helianthus annuus L. var. SH-222 in 1993 and in 1999,
respectively, by Macías et al. These natural products have been
reported to exhibit significant allelopathic activity against several
dicotyledon (Lactuca sativa and Lepidium sativum) and mono-
cotyledon species (Hordeum vulgare and Triticum aestivum) at
concentrations of 10ꢀ4e10ꢀ9 M.3 The structure of 1, including the
relative stereochemistry, was determined by single crystal X-ray
diffraction analysis. This intriguing compound contains an aryl ring
fused to the eight-membered oxygen heterocycle with two tertiary
stereogenic centers at the C7 and C10 positions. Its absolute
structure was established to be (7R,10S) by our enantioselective
total synthesis of the unnatural enantiomer of (þ)-heliannuol A,4a
while the structure of heliannuol K (2) was elucidated mainly by
1H NMR and found to have the same carbon framework as heli-
annuol A except for the presence of a C10 carbonyl function.
Although the absolute stereochemistry at C7 has never been
established, it can be deduced to be R based on the biogenetic
parallelism with heliannuol A. Because of the interesting structural
features and phytotoxic properties of these compounds, several
reports on the total synthesis of the heliannuols A (1) and K (2) have
been published.5 During the course of our studies directed toward
the enantioselective synthesis of helianane-type terpenoids with
allelopathic activity,6 we reported the first enantioselective total
iodobenzene with an overall yield of 5%. The obvious challenge was
to improve both the low yield and the many reaction steps. Herein
we describe the efficient and enantioselective total syntheses of
heliannuols A (1) and K (2) (Fig. 1).
HO
Me
HO
Me
7
10
OH
O
O
O
heliannuol K (2)
heliannuol A (1)
Fig. 1. Structures of heliannuols A and K.
2. Results and discussion
2.1. The second-generation synthesis of (L)-heliannuol A (1)
and the first enantioselective synthesis of (L)-heliannuol K (2)
Our retrosynthetic analysis of 1 is shown in Scheme 1. For the
synthesis of 1, we chose the dihydrobenzoxocine 37 with a stereo-
genic center at C7 as the key compound, because it has been con-
verted efficiently to 1 by sequential diastereoselective epoxidation,
regioselective cleavage of the epoxide, and deprotection of the
phenolic hydroxyl function in good overall yield.4b The MOM pro-
tected heliannuol A, the penultimate intermediate of 1, would be
transformed to heliannuol K (2) by a simple two-step sequence;
oxidation followed by deprotection. The eight-membered hetero-
cycle fused to the aryl ring can be assembled by ring-closing
* Corresponding author. Tel.: þ81 88 6337287; fax: þ81 88 6339575; e-mail
address: shishido@ph.tokushima-u.ac.jp (K. Shishido).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.034

M. Kanematsu et al. / Tetrahedron 67 (2011) 4758e4766
4759
metathesis of the diene 4, which would be prepared from the
phenol 5a via Pd-catalyzed dimethylallyl etherification.4b,8 For the
key construction of the tertiary stereogenic center at the benzylic
position, we planned to use a substrate-controlled chirality transfer
in the Claisen rearrangement9,10 of the allyl aryl ether 6a prepared
from the phenol 7a and S-(E)-1-(benzyloxy)pent-3-en-2-ol (8)11 by
the Mitsunobu coupling12 (Scheme 1).
quantitatively. As for the absolute configuration of the stereogenic
center in 10a, it was determined to be S by hydrogenation providing
ent-11 {[
a
]
27 þ18.0 (c 1.48, CHCl3)} in 86% yield. Treatment of 11
D
with the mixed carbonate 12 in the presence of catalytic (Ph3P)4Pd
(1 mol %)8 provided the alkenyl alcohol 13 in 84% yield (Scheme 2).
MOMO
n
ADDP, Bu3P
+
OBn
heliannuol A (1)
benzene, 60 °C, 0.5 h
Me
OH
OH
81% for 6a, 7% for 9a
7a
ref. 4b
heliannuol K (2)
8
three steps
BnO
MOMO
MOMO
Me
MOMO
MOMO
Me
RCM
+
OBn
Me
Me
O
O
O
O
6a
9a
H
3
4
Table 1
MOMO
Me
MOMO
Me
OBn
[3.3]
OBn
MOMO
OBn
OBn
MOMO
Me
O
OH
H
+
6a
5a
Me
OH
OH
5a
10a
MOMO
Me
H2 (5 atm), Pd-C
+
OBn
H2 (5 atm)
Pd-C
EtOH, rt, 12 h, quant.
OH
OH
ent-11
10a
7a
8
EtOH, rt, 8 h
86%
Scheme 1. Retrosynthetic analysis.
MOMO
Me
OH
i
O
O Bu
OR
The Mitsunobu reaction between 4-(methoxymethoxy)-3-
methylphenol (7a), prepared from 3-hydroxy-4-methyl-
acetophenone in two steps, and the allylic alcohol 8, derived from
S-(þ)-benzyl glycidyl ether in two steps, in the presence of
1,1-(azodicarbonyl)dipiperidine (ADDP)13 and nBu3P provided
a chromatographically separable mixture of the requisite ether 6a
(>99% ee; by HPLC analysis using a Chiralcel OD column) and the
regioisomer 9a, which was derived via the SN20 process, in 81% and
7% yield, respectively. The key Claisen rearrangement of 6a
was examined and the results are shown in Table 1. Treatment of
O
12
12, (Ph3P)4Pd (1 mol %)
11: R=H
13: R=C(Me)2CH=CH2
THF, rt, 20 min, 84%
Scheme 2. Preparation of 13.
The alcohol 13 was exposed to the dehydration protocol of
NishizawaeGrieco15 to give the diene 4 (R¼MOM), which was
identical with the authentic material prepared previously, in 76%
yield for the two steps. It was then treated with the Grubbs’ second-
generation catalyst 14 (0.5 mol %)16 in refluxing methylene chloride
to give the dihydrobenzoxocine 3 in 93% yield. Attempts at a sub-
strate-controlled diastereoselective epoxidation of 3 using mCPBA
provided a lower yield (73%) of the product 15. However reaction of
3 with methyl(trifluoromethyl)dioxirane17 generated in situ from
methyl trifluoromethyl ketone and OxoneÒ in the presence of
Na2$EDTA$2H2O and sodium hydrogen carbonate in acetonitrile
provided only the epoxide 15 in 83% yield. The stereochemistry was
confirmed by the observation of a distinct NOE correlation between
Table 1
Claisen rearrangement of 6a
Entry
Conditions
Yield, %
(% ee)a
5a
10a
1
2
3
Eu(fod)3 (8 mol %) ClCH2CH2Cl, 90 ꢁC, 24 h
Et2AlCl (1.5 equiv), hexane 0 ꢁC, 4 h
Me3Al (3 equiv), hexane rt, 0.5 h
92 (90)
27 (>99)
85 (>99)
7
5
4
a
HPLC (Chiralcel AD column).
the Ha (d 3.11) and Hb (d 2.55) protons. LiAlH4 reduction of the
epoxide occurred at the sterically less congested carbon (C9)
regioselectively to give the alcohol 16 in 91% yield as a single
product. Finally, acidic hydrolysis of the MOM ether produced
heliannuol A (1), whose spectroscopic (1H and 13C NMR) properties
9d
a solution of 6a in dichloroethane with 8 mol % of Eu(fod)3 at
90 ꢁC for 24 h gave a separable mixture of R-5a and the Z-isomer
10a with the S configuration in 92% and 7% yield, respectively.
However, the enantiomeric excess of 5a was 90% (determined by
HPLC analysis using a Chiralcel AD column) (entry 1). When the
reaction was conducted with 1.5 equiv of Et2AlCl in hexane at 0 ꢁC
for 4 h, the enantiomerically pure 5a was obtained in only 27% yield
along with 5% of 10a (entry 2). The optimized reaction conditions
call for 3 equiv of Me3Al14 in hexane at room temperature for 0.5 h;
the requisite 5a was obtained in 85% yield (>99% ee), together with
10a (4%) (entry 3). On exposure of 5a to hydrogenation conditions,
as well as optical rotation, {[
a]
26 ꢀ78.0 (c 2.4, MeOH) {lit.1a
[a]
D
D
ꢀ55.4 (c 0.3, MeOH)}, were identical with those of the natural
product. Thus, the second-generation enantioselective total syn-
thesis of heliannuol A (1) has been accomplished in a longest linear
sequence of nine steps in 25% yield from the phenol 7a. For the
synthesis of heliannuol K (2), the penultimate intermediate 16 was
oxidized with DesseMartin periodinane to give the ketone 17,
which was exposed to the acidic hydrolysis conditions producing 2
in 99% yield for the two steps. The spectroscopic properties (1H and
the phenolic alcohol 11 {[
a
]
27 ꢀ17.3 (c 2.65, CHCl3)} was obtained
D

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M. Kanematsu et al. / Tetrahedron 67 (2011) 4758e4766
13C NMR) of the synthetic 2 were identical with those of the natural
28
D
heliannuol K. However, the optical rotation of the synthetic 2, {[a]
BnO
Me
ref. 5f
ꢀ5.70 (c 0.71, CHCl3), was completely different18 from that reported
2
1
for the natural product {lit.2 {[
a
]
28þ90.0 (c 0.1, CHCl3)}. To confirm
D
O
O
its structure, the synthetic 2 was converted to the crystalline car-
bamate 18 by treatment with 4-bromophenyl isocyanate and Et3N.
X-ray crystallographic analysis of 1819 (Fig. 2) revealed that our
synthetic material was found to possess the structure shown in
Fig. 1. Thus, the first enantioselective total synthesis of heliannuol K
(2) was accomplished in a longest linear sequence of ten steps in
26% yield from 7a (Scheme 3).
19
R
BnO
Me
BnO
Me
R
O
OH
O
5b
20: R=CH2OBn
BnO
[3.3]
Me
O
R
H
6b
Scheme 4. Retrosynthetic analysis.
Heliannuol K (2) would be obtained by the conjugate reduction
of the enone in 19, which could be constructed by ring-closing
metathesis of 20. The diene 20 with the enone and the allyl ether
moieties could be accessed from the phenol 5b, which can be
prepared by the same procedure as for 5a using a Lewis acid me-
diated Claisen rearrangement of 6b. Since the conversion of heli-
annuol K to A by the diastereoselective reduction of 2 with NaBH4
has been reported in the literature,5f the elaboration of 19 to 2
represents a formal synthesis of heliannuol A (Scheme 4).
The Mitsunobu reaction of 7b20 and 8 produced a separable
mixture of 6b, the substrate for the Claisen rearrangement, and the
regioisomer 9b in 78% and 17% yield, respectively. The Claisen
rearrangement was examined using two kinds of Lewis acids,
Eu(fod)3 and Me3Al, and it was revealed that the requisite 5b was
obtained with high enantiomeric excess in both cases. The condi-
tions using a catalytic amount of Eu(fod)3 provided 5b in a higher
yield of 91% (Table 2).
Fig. 2. ORTEP drawing of 18.
NOE
Ha
Hb
O
MOMO
Me
a
b
c
13
4
3
O
15
RO
Me
d
f
RO
Me
16
Table 2
Claisen rearrangement of 6b
OH
O
O
O
Entry
Conditions
Yield, %
(% ee)a
17: R=MOM
2: R=H
g
16: R=MOM
1: R=H
5b
10b
e
1
2
Eu(fod)3 (7 mol %) ClCH2CH2Cl, 90 ꢁC, 12 h
Me3Al (3 equiv), hexane rt, 0.5 h
91 (>99)
81 (>99)
8
7
H
MesN
Cl
NMes
a
HPLC (Chiralcel AD column).
N
O
h
2
Ru
Cl
O
Ph
Br
Me
O
Treatment of 5b with ethyl 2-bromo-2-methylpropanoate and
potassium carbonate provided the ester 21, which was converted to
the Weinreb amide 22 in 95% yield for the two steps. It was then
treated with vinylmagnesium chloride to give quantitatively the
diene 20, which was subjected to the ring-closing metathesis with
the Grubbs’ second-generation catalyst 14 (6 mol %) in the presence
of benzoquinone (10 mol %)21 in refluxing toluene to afford the
eight-membered enone 19 in 80% yield. Catalytic hydrogenation of
19 with Pd/C in EtOH produced heliannuol K (2) quantitatively via
O
PCy3
18
14
Scheme 3. Syntheses of heliannuols A (1) and K (2). Reagents and conditions: (a)
o-NO2C6H4SeCN, nBu3P, THF, rt, 4 h then 30% H2O2 (aq), NaHCO3, THF, rt, 4 h, 91%; (b)
14 (0.5 mol %), CH2Cl2, reflux, 0.5 h, 93%; (c) CF3COCH3, OxoneÒ, Na2$EDTA$2H2O,
NaHCO3, MeCN, 0 ꢁC, 83%; (d) LiAlH4, THF, 50 ꢁC, 4 h, 91%; (e) 6 M HCl (aq), THF, rt, 15 h,
96%; (f) DMP, CH2Cl2, rt, 0.5 h, 99%; (g) 6 M HCl (aq), THF, rt, 3 h, quant.; (h) 4-
bromophenyl isocyanate, Et3N, THF, rt, 0.5 h, quant.
a
chemoselective reduction of the olefin and simultaneous
2.2. An alternative synthesis of (L)-heliannuol K (2)
debenzylation of the phenolic ether. However, the enantiomeric
excess of 2 was only 94%,22 which was determined by HPLC analysis
on Chiralcel OD-H column. Therefore, we searched for a procedure
that would prevent the partial racemization. After numerous at-
tempts, we found that using Raney-nickel (W-2) in EtOH at room
temperature for 0.5 h23 provided heliannuol K (2) in 87% yield
without racemization (>99% ee). The spectroscopic properties as
Although we had achieved an efficient synthesis of heliannuols
A and K, we wanted to find an environmentally benign synthetic
route that avoided the use of an excess amount of the toxic sele-
nium reagent (13/4 in Scheme 3). Our retrosynthetic analysis is
illustrated in Scheme 4.

M. Kanematsu et al. / Tetrahedron 67 (2011) 4758e4766
4761
well as optical rotation {[
a
]
30 ꢀ6.4 (c 1.81, CHCl3)} of the synthetic
completed in a longest linear sequence of nine steps from 4-
(methoxymethoxy)-3-methylphenol with an overall yield of 25%. In
addition, the first enantioselective total synthesis of heliannuol K
(2) was achieved from the penultimate intermediate for 1 via
a two-step sequence. An alternative and efficient total synthesis of
heliannuol K (2) was also accomplished via the Claisen rearrange-
ment, ring-closing metathesis and a conjugate reduction of the
eight-membered enone as the key reaction step in a longest linear
sequence of seven steps from the known 4-benzyloxy-3-
methylphenol with an overall yield of 47%. It has been also
revealed that the optical rotation of the natural heliannuol K was
not identical to that of the compound with the assigned structure 2
by the present total synthesis.
D
material was identical with those of the authentic sample prepared
in 2.1. Thus, a highly efficient and enantioselective total synthesis of
heliannuol K (2) has been accomplished in a longest linear se-
quence of seven steps in a greatly improved yield of 47% from the
phenol 7b.
Since the direct conversion of (ꢂ)-heliannuol K (2) to (ꢂ)-heli-
annuol A (1) has been reported to proceed with complete diaster-
eoselectivity by Venkateswaran, we examined the conversion using
the same reaction conditions. Thus, treatment of 2 with NaBH4 in
MeOH at 0 ꢁC for 0.5 h produced unexpectedly an inseparable 3.8:1
mixture (by 1H NMR) of 10-epi-heliannuol A (23)5d and heliannuol
A (1) quantitatively. Interestingly, on exposure of 19 to Raney-nickel
(W-2) in EtOH under hydrogen atmosphere, a 3.7:1 mixture of 23
and 1 was obtained in 84% yield (Scheme 5).
4. Experimental
4.1. General
BnO
Me
a
+
OBn
All nonaqueous reactions were carried out under a positive at-
mosphere of argon in dried glassware unless otherwise indicated.
Materials were obtained from commercial suppliers and used
without further purification except when otherwise noted. Sol-
vents were dried and distilled according to standard protocols. The
phrase ‘residue upon workup’ refers to the residue obtained when
the organic layer was separated and dried over anhydrous MgSO4
and the solvent was evaporated under reduced pressure. Column
chromatography was performed on silica gel, and flash column
chromatography was performed on silica gel using the indicated
solvent.
OH
OH
H
7b
8
BnO
BnO
BnO
Me
+
OBn
Me
O
O
6b
9b
Table 2
OBn
BnO
Me
OBn BnO
+
4.2. The second-generation synthesis of (L)-heliannuol A (1)
and the first enantioselective synthesis of (L)-heliannuol K (2)
OH
Me
OH
10b
5b
4.2.1. 4-(Methoxymethoxy)-3-methylphenol (7a). To a stirred solu-
tion of 4-hydroxy-3-methylacetophenone (25.0 g, 166 mmol) in
CH2Cl2 (500 mL) were added iPr2NEt (130 mL, 749 mmol) and
MOMCl (28.2 mL, 375 mmol) at 0 ꢁC. After being stirred for 0.5 h at
rt, the reaction mixture was diluted with Et2O and water. The re-
sultant solution was extracted with Et2O. The combined extracts
were washed with brine, and dried over MgSO4, filtered and con-
centrated to give MOM ether as a colorless oil, which was used to
the next reaction without further purification. To a stirred solution
of crude MOM ether in CH2Cl2 (625 mL) was added mCPBA (43.8 g,
70%, 416 mmol) at 0 ꢁC. After being stirred for 20 h at rt, the re-
action mixture was quenched with saturated aqueous NaHCO3 and
extracted with AcOEt. The combined extracts were washed with
brine. To the residue upon workup was added a solution of 10% KOH
in MeOH (pH 9e10) at rt. After being stirred for 30 min at the same
temperature, the reaction mixture was concentrated and added
water. The resultant mixture was acidified with 10% aqueous HCl
and extracted with AcOEt. The combined extracts were washed
with saturated aqueous NaHCO3 and brine. The residue upon
workup was chromatographed on silica gel with hexane/AcOEt
(1:4 v/v) as eluent to give phenol 7a (26.2 g, 93%) as a colorless oil;
b
BnO
Me
OBn
BnO
e
COR
O
Me
O
O
19
21: R=OEt
c
d
22: R=NMe(OMe)
20: R=CH=CH2
HO
Me
f
g
19
2
+
1
OH
O
23
h
23 + 1
19
Scheme 5. Alternative synthesis of heliannuol K (2). Reagents and conditions: (a)
ADDP, nBu3P, benzene, rt, 0.5 h, 78% for 6b, 17% for 9b; (b) ethyl 2-bromo-2-
methylpropanoate, K2CO3, MeCN/DMF¼18/1, 100 ꢁC, 12 h, 95%; (c) LHMDS, (MeO)
MeNH$HCl, THF, rt, 4 h, quant.; (d) vinylmagnesium chloride, THF, rt, 1 h, quant.; (e) 14
(6 mol %), benzoquinone (10 mol %), toluene, reflux, 7 h, 80%; (f) Raney-Ni (W-2), EtOH,
rt, 0.5 h, 87%; (g) NaBH4, MeOH, 0 ꢁC, 0.5 h, quant. (23/1¼3.8/1); (h) H2 (5 atm), Raney-
Ni (W-2), EtOH, rt, 2 h, 84% (23/1¼3.7/1).
IR (neat) 3389, 2953, 1505, 1463 cmꢀ1 1H NMR (400 MHz, CDCl3)
;
d
2.21 (3H, s), 3.49 (3H, s), 5.11 (2H, s), 6.59 (1H, dd, J¼3.2 and
8.8 Hz), 6.65 (1H, d, J¼3.2 Hz), 6.92 (1H, d, J¼8.8 Hz); 13C NMR
(100 MHz, CDCl3)
d 16.1 (CH3), 55.8 (CH3), 95.4 (CH2), 113.0 (CH),
116.2 (CH), 117.8 (CH), 129.1 (Cq), 149.1 (Cq), 150.3 (Cq); HRMS (ESI)
m/z calcd for C9H13O3 169.0865 [MþH]þ, found 169.0869.
3. Conclusion
In summary, we have completed the second-generation enan-
tiocontrolled total syntheses of heliannuol A (1) using the chirality
transfer that occurred with high selectivity during the Lewis acid
mediated Claisen rearrangement for the construction of the C7
stereogenic center as the key step. The synthesis was efficiently
4.2.2. (R,E)-4-(1-(Benzyloxy)pent-3-en-2-yloxy)-1-(methox-
ymethoxy)-2-methylbenzene (6a) and (E)-4-(5-(benzyloxy)pent-3-en-
2-yloxy)-1-(methoxymethoxy)-2-methylbenzene (9a). To
solution of phenol 7a (2.02 g, 12.0 mmol), alcohol
a
8
stirred
(3.00 g,
15.6 mmol), and nBu3P (4.49 mL, 18.0 mmol) in benzene (34 mL) was

4762
M. Kanematsu et al. / Tetrahedron 67 (2011) 4758e4766
added 1,1-azodicarbonyldipiperizine (4.54 g, 18.0 mmol) at 0 ꢁC.
After being stirred for 15 min at rt, the reaction mixture was diluted
with hexane and then filtered through a pad of Celite and concen-
trated. The residue was chromatographed on silica gel with hexane/
AcOEt (19:1 v/v) as eluent to afford allyl aryl ether 6a (3.33 g, 81%,
>99% ee) as a colorless oil and the region isomer 9a (281 mg, 7%) as
(5H, m); 13C NMR (100 MHz, CDCl3)
d 15.8 (CH3), 19.8 (CH2), 31.5
(CH), 56.0 (CH2), 65.1 (CH3), 72.8 (CH3), 95.9 (CH3), 113.5 (CH), 118.9
(CH), 122.9 (CH), 127.0 (Cq), 127.0 (Cq), 127.9 (CH), 128.2 (CH), 128.5
(CH), 137.3 (Cq), 140.0 (CH), 148.8 (Cq), 149.5 (Cq); HRMS (ESI) m/z
calcd for C21H27O4 [MþH]þ 343.1909, found 343. 1895.
a colorless oil; 6a; {[
a]
25ꢀ12.99 (c 3.29, CHCl3); IR (neat) 2917, 1498,
4.2.4. (R)-2-(5-Hydroxypentan-2-yl)-4-(methoxymethoxy)-5-
methylphenol (11). To a stirred suspension of Pd/C (7.5 mg, 5 wt %)
in EtOH (0.3 mL), which was preactivated at rt under 1 atm of hy-
drogen gas, was added phenol 5a (75 mg, 0.193 mmol) in EtOH
(1.2 mL) at rt, and the stirring was continued for 12 h at the same
temperature under 5 atm of hydrogen gas. The resulting solution
was filtered and concentrated. The residue was chromatographed
on silica gel with hexane/AcOEt (7:3 v/v) as eluent to afford diol 11
D
1218, 1152, 1011, 737, 698 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
1.69
(3H, d, J¼6.4 Hz), 2.21 (3H, s), 3.49 (3H, s), 3.59 (1H, dd, J¼4.4 and
10.4 Hz), 3.67 (1H, dd, J¼7.2 and 10.8 Hz), 4.59 (1H, d, J¼12.0 Hz),
4.64 (1H, d, J¼12.0 Hz), 4.69 (1H, dt, J¼5.2 and 6.4 Hz), 5.11 (2H, s),
5.45 (1H, ddd, J¼1.6, 6.4 and 15.6 Hz), 5.77 (1H, dq, J¼6.4 and
15.6 Hz), 6.69 (1H, dd, J¼2.8 and 9.2 Hz), 6.76 (1H, d, J¼2.4 Hz), 6.92
(1H, d, J¼8.8 Hz), 7.27e7.31 (5H, m); 13C NMR (100 MHz, CDCl3)
d
16.4 (CH3), 17.9 (CH3), 55.9 (CH3), 72.9 (CH2), 73.4 (CH2), 78.7 (CH),
(52.7 mg, quant.) as a colorless oil; {[
a]
27ꢀ17.25 (c 2.65, CHCl3); IR
D
95.4 (CH2), 113.9 (CH), 115.3 (CH), 119.3 (CH), 127.5 (CH), 127.6 (CH),
128.1 (CH), 128.3 (CH), 128.6 (Cq), 129.3 (CH), 138.3 (Cq), 149.8 (Cq),
152.9 (Cq); HRMS (ESI) m/z calcd for C21H27O4 [MþH]þ 343.1909,
found 343.1904. Enantiomeric excess was determined by HPLC
(neat) 3378, 2954, 1514, 1454, 1190, 1149, 1050, 1007 cmꢀ1; 1H NMR
(400 MHz, CDCl3)
d
1.24 (3H, d, J¼6.8 Hz), 1.49e1.56 (2H, m),
1.59e1.73 (2H, m), 2.18 (3H, s), 3.08 (1H, quint, J¼6.8 Hz), 3.50 (3H,
s), 3.68e3.74 (2H, m), 5.09 (1H, d, J¼8.0 Hz), 5.11 (1H, d, J¼8.0 Hz),
analysis [Chiralcel OD column, 1.0% isopropanol/hexane, 1.0 mL/min,
5.27 (1H, br s, OH, D2O exchangeable), 6.60 (1H, s), 6.83 (1H, s); 13
C
26
D
l
¼254 nm, retention times 22.8 min (S) and 30.6 min (R)]; 9a; {[
a]
NMR (100 MHz, CDCl3) d 15.8 (CH3) 20.9 (CH3), 29.7 (CH2), 31.5
þ26.31 (c 0.68, CHCl3); IR (neat) 2926, 2363, 1498, 1218, 1151, 1075,
(CH), 34.5 (CH2), 56.0 (CH3), 63.3 (CH2), 95.9 (CH2), 114.0 (CH), 118.1
(CH), 126.2 (Cq), 131.1 (Cq), 148.0 (Cq), 149.6 (Cq); HRMS (ESI) m/z
calcd for C14H22O4Na [MþNa]þ 277.1416, found 277.1410.
1010, 738, 698 cmꢀ1 1H NMR (500 MHz, acetone-d6)
;
d
1.36 (3H, d,
J¼6.5 Hz), 2.17 (3H, s), 3.42 (3H, s), 3.99 (1H, dd, J¼5.5 and 12.5 Hz),
4.02 (1H, dd, J¼5.5 and 12.5 Hz), 4.42 (1H, d, J¼12.0 Hz), 4.45 (1H, d,
J¼12.0 Hz), 4.83 (1H, quint, J¼6.0 Hz), 5.10 (2H, s), 5.79 (1H, dd, J¼5.5
and 16.0 Hz), 5.84 (1H, dt, J¼5.0 and 15.5 Hz), 6.70 (1H, dd, J¼3.0 and
9.0 Hz), 6.77 (1H, d, J¼2.5 Hz), 6.93 (1H, d, J¼9.0 Hz), 7.25e7.34 (5H,
4.2.5. (S)-2-(5-Hydroxypentan-2-yl)-4-(methoxymethoxy)-5-
methylphenol (ent-11). By following the same procedure described
27
D
for 11, ent-11 was prepared from 10a: yield 86%; colorless oil; {[a]
m); 13C NMR (125 MHz, CDCl3)
d
16.4 (CH3), 17.9 (CH3), 55.9 (CH3),
þ18.00ꢁ (c 1.48, CHCl3). Other spectral data coincides with those of
the enantiomer ent-11.
72.9 (CH2), 73.4 (CH2), 78.7 (CH), 95.4 (CH2), 113.9 (CH), 115.3 (CH),
119.3 (CH), 127.5 (CH), 127.6 (CH), 128.1 (CH), 128.3 (CH), 128.6 (Cq),
129.3 (CH), 138.3 (Cq), 149.8 (Cq), 152.9 (Cq); HRMS (ESI) m/z calcd
for C21H27O4 [MþH]þ 343.1909, found 343.1904.
4.2.6. (R)-4-(5-(Methoxymethoxy)-4-methyl-2-(2-methylbut-3-en-
2-yloxy)phenyl)pentan-1-ol (13). To a stirred solution of diol 11
(23 mg, 0.090 mmol) in THF (1 mL) were added mixed carbonate 12
4.2.3. (R,E)-2-(5-(Benzyloxy)pent-3-en-2-yl)-4-(methoxymethoxy)-
5-methylphenol (5a) and (S,Z)-2-(5-(benzyloxy)pent-3-en-2-yl)-4-
(methoxymethoxy)-5-methylphenol (10a). To a stirred solution of
allyl aryl ether 6a (1.01 g, 2.95 mmol) in hexane (20 mL) was added
Me3Al (8 mL, 1.10 M solution in hexane, 8.85 mmol) at 0 ꢁC. After
being stirred for 30 min at rt, the reaction mixture was quenched
with water. After being stirred for 1 h at the same temperature, the
resultant mixture was dried over MgSO4 and concentrated. The
residue was chromatographed on silica gel with hexane/AcOEt
(9:1 v/v) as eluent to afford phenol 5a (894 mg, 88%, >99% ee) as
a colorless oil and the Z-isomer 10a (162 mg, 4%) as a colorless oil;
(23 mg, 0.123 mmol) and (Ph3P)4Pd (1.2 mg, 1.02 mmol) at rt. After
being stirred for 20 min at the same temperature, the reaction
mixture was filtered through a pad of silica gel and concentrated.
The residue was chromatographed on silica gel with hexane/AcOEt
(6:4 v/v) as eluent to afford alcohol 13 (24.6 mg, 84%) as a colorless
27
oil; {[
a]
ꢀ7.56 (c 3.62, CHCl3); IR (neat) 3419, 2931, 1499, 1391,
D
1190, 1150, 1008, 922, 890 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 1.18
(3H, d, J¼6.8 Hz), 1.30 (1H, br s, OH, D2O exchangeable), 1.41 (3H, s),
1.43 (3H, s),1.46e1.62 (4H, m), 2.15 (3H, s), 3.19 (1H, sext., J¼6.8 Hz),
3.50 (3H, s), 3.60 (2H, t, J¼6.0 Hz), 5.10 (1H, d, J¼11.2 Hz), 5.11 (1H,
d, J¼10.0 Hz), 5.12 (1H, d, J¼11.2 Hz), 5.18 (1H, d, J¼17.6 Hz), 6.13
(1H, dd, J¼10.8 and 17.6 Hz), 6.82 (1H, s), 6.83 (1H, s); 13C NMR
5a; {[
a
]
25 ꢀ3.83 (c 1.20, CHCl3); IR (neat) 3375, 2960, 2928, 1513,
1453, 13D98, 1148, 1004, 740, 698 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
(100 MHz, CDCl3) d 16.1 (CH3) 21.3 (CH3), 26.8 (CH3), 27.4 (CH3),
d
1.38 (3H, d, J¼6.8 Hz), 2.18 (3H, s), 3.49 (3H, s), 3.66 (1H, quint,
30.8 (CH2), 31.7 (CH), 33.9 (CH2), 56.0 (CH3), 63.1 (CH2), 79.3 (Cq),
95.5 (CH2),112.8 (CH2),113.0 (CH),122.6 (CH),124. 6 (Cq),137.7 (Cq),
145.0 (CH),147.9 (Cq),150.7 (Cq); HRMS (ESI) m/z calcd for C19H31O4
[MþH]þ 323.2222, found 323.2220.
J¼7.2 Hz), 4.02 (2H, d, J¼6.0 Hz), 4.50 (2H, s), 4.60 (1H, s, OH, D2O
exchangeable), 5.09 (2H, s), 5.71 (1H, dtd, J¼1.2, 6.0 and 15.6 Hz),
5.94 (1H, dd, J¼6.0 and 15.6 Hz), 6.61 (1H, s), 6.82 (1H, s), 7.26e7.36
(5H, m); 13C NMR (100 MHz, CDCl3)
d 15.8 (CH3), 19.3 (CH3), 36.1
(CH), 56.0 (CH3), 70.6 (CH2), 71.9 (CH2), 95.8 (CH2), 114. 9 (CH), 118.3
(CH), 125.7 (CH), 126.8 (Cq), 127.6 (CH), 127.8 (CH), 128.3 (CH), 128.8
(CH), 138.0 (CH), 138.2 (Cq), 148.1 (Cq), 149.5 (Cq); HRMS (ESI) m/z
calcd for C21H27O4 [MþH]þ 343.1909, found 343. 1902. Enantio-
meric excess was determined by HPLC analysis [Chiralcel AD col-
4.2.7. (R)-1-(Methoxymethoxy)-2-methyl-4-(2-methylbut-3-en-2-
yloxy)-5-(pent-4-en-2-yl)benzene (4). To a stirred solution of alco-
hol 13 (30 mg, 93 mmol) in THF (0.3 mL) were added 2-nitrophenyl
selenocyanate (32 mg, 0.14 mmol) and nBu3P (0.052 mL,
0.21 mmol) at 0 ꢁC. After being stirred for 5 min at rt, and then
cooled to 0 ꢁC. To the reaction mixture was added NaHCO3 (78 mg,
0.93 mmol) and 30% aqueous H2O2 (0.28 mL, 1.03 mmol) at 0 ꢁC.
After being stirred for 4 h at rt, the resultant mixture was diluted
with Et2O and filtered through a pad of Celite and concentrated. The
residue was extracted with Et2O. The combined extracts were
washed with brine. The residue upon workup was chromato-
graphed on silica gel with hexane/AcOEt (19:1 v/v) as eluent to give
umn, 10% isopropanol/hexane, 1.0 mL/min,
l
¼254 nm, retention
times 22.1 min (R) and 25.3 min (S)]; 10a; {[
a
]
25 þ154.1 (c 2.59,
CHCl3); IR (neat) 3365, 2960, 2927, 1513, 1454, D1398, 1190, 1149,
1007, 738, 699 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 1.32 (3H, d,
J¼7.2 Hz), 2.18 (3H, s), 3.50 (3H, s), 3.93 (1H, dd, J¼6.0 and 11.2 Hz),
4.03 (1H, dq, J¼2.8 and 6.8 Hz), 4.23 (1H, dd, J¼4.4 and 11.2 Hz),
4.58 (1H, d, J¼12.0 Hz), 4.62 (1H, d, J¼12.0 Hz), 5.10 (2H, s), 5.55
(1H, dd, J¼8.4 and 10.8 Hz), 5.60 (1H, dt, J¼6.4 and 10.8 Hz), 6.42
(1H, s, OH, D2O exchangeable), 6.64 (1H, s), 6.87 (1H, s), 7.29e7.37
diene 4 (25.8 mg, 91%) as a colorless oil; {[
a
]
27ꢀ6.19 (c 1.49, CHCl3);
IR (neat) 3076, 2976, 1639, 1499, 1151 cmꢀD1
;
1H NMR (400 MHz,

M. Kanematsu et al. / Tetrahedron 67 (2011) 4758e4766
4763
CDCl3)
d
1.16 (3H, d, J¼6.8 Hz), 1.43 (3H, s), 1.43 (3H, s), 2.15 (3H, s),
(2H, m), 1.84 (1H, br s), 1.97 (1H, s, D2O exchangeable, OH), 2.18
(3H, s), 3.50 (3H, s), 3.66 (1H, br s), 3.70 (1H, dd, J¼7.0 and 7.0 Hz),
5.14 (2H, s), 6.71 (1H, s), 6.79 (1H, s); 13C NMR (100 MHz, CDCl3)
2.20(1H, m), 2.35 (1H, m), 3.23 (1H, ddq, J¼6.6, 6.8 and 7.1 Hz), 3.51
(3H, s), 4.94 (1H, ddt, J¼1.0, 2.2, and 10.0 Hz), 5.01 (1H, m), 5.11 (2H,
s), 5.11 (1H, dd, J¼0.8 and 10.8 Hz), 5.19 (1H, dd, J¼1.0 and 17.8 Hz),
5.76 (1H, dddd, J¼6.7, 7.6, 9.5, and 16.9 Hz), 6.13 (1H, dd, J¼10.8 and
d
16.0 (CH3), 19.5 (CH3), 25.0 (CH3), 28.8 (CH3), 30.2 (CH2), 36.2
(CH2), 39.1 (CH), 56.0 (CH3), 78.0 (CH), 94.5 (CH2), 110.2 (CH), 124.2
(Cq), 126.2 (CH), 137.2 (Cq), 146.7 (Cq), 151.8 (Cq); MS (EI) m/z 294
[M]þ; HRMS (EI) m/z calcd for C17H26O4 [M]þ 294.1831, found
294.1837.
17.8 Hz), 6.83 (1H, s), 6.83 (1H, s); 13C NMR (100 MHz, CDCl3)
d 16.2
(CH3), 20.4 (CH3), 27.2 (CH3), 27.3 (CH3), 32.2 (CH), 41.8 (CH2), 56.0
(CH3), 79.1 (Cq), 95.5 (CH2), 112.7 (CH2), 113.3 (CH), 115.4 (CH2),
122.1 (CH), 124.5 (Cq), 137.3 (Cq), 137.6 (CH), 145.0 (CH), 147.8 (Cq),
150.3 (Cq); MS (EI) m/z 304 [M]þ; HRMS (EI) m/z calcd for C19H28O3
[M]þ 304.2038, found 304.2010.
4.2.11. (ꢀ)-Heliannuol A (1). To a stirred solution of MOM ether 16
(35.4 mg, 0.12 mmol) in THF (0.6 mL) was added 6 M aqueous HCl
(0.6 mL) at 0 ꢁC. After being stirred for 15 h at rt, the reaction
mixture was quenched with water and extracted with Et2O. The
combined extracts were washed with saturated aqueous NaHCO3
and brine. The residue upon workup was chromatographed on
silica gel with hexane/AcOEt (8:2 v/v) as eluent to give (ꢀ)-heli-
annuol A (1) (28.7 mg, 96%) as a colorless prism; mp 83.8e85.2
4.2.8. (R,Z)-8-(Methoxymethoxy)-2,2,6,9-tetramethyl-5,6-dihydro-
2H-benzo[b]oxocine (3). To a stirred solution of diene 4 (13 mg,
0.043 mmol) in CH2Cl2 (2.1 mL) was added Grubbs’ second-
generation catalyst 14 (0.18 mg, 0.21 mmol) at rt, and then the
mixture was heated to reflux. After being stirred for 30 min,
the reaction mixture was cooled to rt. After being stirred for 1 h at
the same temperature under air, the resultant mixture was con-
centrated. The residue was chromatographed on silica gel with
(recrystallized from benzene/hexane); {[
a
]
26 ꢀ78.0 (c 2.4, MeOH)
{lit.1a
[
a
]
ꢀ55.4 (c 0.3, MeOH)}; IR (neDat) 3375, 2928, 1507,
1134 cmꢀD1
;
1H NMR (400 MHz, CD3OD, ꢀ30 ꢁC)
d 1.15, 1.31 (3H, s),
hexane/AcOEt (97:3 v/v) as eluent to give oxocine 3 (11.0 mg, 93%)
1.31, 1.44 (3H, s), 1.36 (2H, m), 1.22, 1.27 (3H, d, J¼6.8 Hz), 1.65, 1.88
27
as a colorless oil; {[
a
]
D ꢀ56.5 (c 0.34, CHCl3); IR (neat) 2960, 1652,
(2H, m), 2.08, 2.10 (3H, s), 3.23 (1H, m), 3.47, 3.56 (1H, m), 6.46, 6.51
1503, 1147 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.24 (1H, d, J¼7.1 Hz),
(1H, s), 6.60, 6.65 (1H, s); 13C NMR (100 MHz, CD3OD, ꢀ30 ꢁC)
d 16.1
1.36 (3H, s), 1.57 (3H, s), 2.00e2.10 (1H, br s), 2.16 (3H, s), 2.90 (1H,
br s), 3.26 (1H, br s), 3.49 (3H, s), 5.13 (2H, s), 5.26 (1H, d, J¼11.0 Hz),
5.67 (1H, ddd, J¼8.0, 10.0, and 10.5 Hz), 6.69 (1H, s), 6.72 (1H, s); 13C
(CH3), 16.3 (CH3), 18.2 (CH3), 29.7 (CH3), 30.1 (CH), 31.5 (CH2), 38.5
(CH2), 78.9 (CH), 82.9 (Cq), 114.7 (CH), 122.3 (Cq), 127.5 (CH), 138.2
(Cq), 146.3 (Cq), 153.1 (Cq); MS (EI) m/z 250 [M]þ; HRMS (EI) m/z
calcd for C15H22O3 [M]þ 250.1569, found 250.1587.
NMR (75 MHz, CDCl3)
d 15.9 (CH3), 25.4 (CH3), 28.4 (CH3), 29.4
(CH3), 33.9 (CH2), 40.2 (CH), 56.0 (CH3), 80.9 (Cq), 95.0 (CH2), 116.1
(CH), 124.8 (Cq), 128.7 (CH), 130.0 (CH), 134.8 (CH), 137.9 (Cq), 146.5
(Cq), 152.0 (Cq); MS (EI) m/z 276 [M]þ; HRMS (EI) m/z calcd for
C17H24O3 [M]þ 276.1725, found 276.1725.
4.2.12. (R)-8-(Methoxymethoxy)-2,2,6,9-tetramethyl-5,6-dihydro-
2H-benzo[b]oxocin-3(4H)-one (17). To a stirred solution of alcohol
16 (6.0 mg, 0.020 mmol) in CH2Cl2 was added DesseMartin peri-
odinane (13.0 mg, 0.031 mmol) at 0 ꢁC. After being stirred for 0.5 h
at rt, the reaction mixture was quenched with saturated aqueous
NaHCO3 and saturated aqueous Na2S2O3 and extracted with CH2Cl2.
The combined extracts were washed with brine. The residue upon
workup was chromatographed on silica gel with hexane/AcOEt
(9:1 v/v) as eluent to give ketone (17) (5.8 mg, 99%) as a colorless
4.2.9. (1aS,8R,9aS)-6-(Methoxymethoxy)-2,2,5,8-tetramethyl-
2,8,9,9a-tetrahydro-1aH-benzo[b]oxireno[2,3-f]oxocine
(15). To
a stirred solution of 3 (12.7 mg, 0.046 mmol), Na2$EDTA$2H2O
(0.21 mL), CF3COCH3 (0.05 mL, 0.51 mmol) and NaHCO3 (29.9 mg,
0.357 mmol) in MeCN (0.5 mL) was added OxoneÒ (141.4 mg,
0.23 mmol) over a period of 1 h at 0 ꢁC. After being stirred for 1.5 h
at the same temperature, the reaction mixture was added water
and extracted with CH2Cl2. The combined extracts were washed
with saturated aqueous NaHCO3 and brine. The residue upon
workup was chromatographed on silica gel with hexane/AcOEt
oil; {[
a]
25 ꢀ14.30 (c 0.70, CHCl3); IR (neat) 2931, 1713, 1499, 1187,
D
1147, 1008 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.32 (3H, d, J¼7.2 Hz),
1.45 (3H, s), 1.48 (3H, s), 1.64e1.74 (1H, m), 1.97 (1H, ddt, J¼7.2, 10.0,
and 14.4 Hz), 2.17 (3H, s), 2.45 (1H, ddd, J¼3.2, 8.0 and 11.2 Hz),
2.53e2.59 (1H, m), 3.09 (1H, ddq, J¼3.2, 10.0, and 10.8 Hz), 3.49
(3H, s), 5.14 (2H, s), 6.73 (1H, s), 6.81 (1H, s); 13C NMR (100 MHz,
(95:5 v/v) as eluent to give epoxide 15 (11.1 mg, 83%) as a colorless
26
oil; {[
a
]
ꢀ80.0 (c 0.43, CHCl3); IR (neat) 2925, 1503, 1385,
CDCl3) d 15.9 (CH3), 20.4 (CH3), 23.6 (CH3), 24.4 (CH3), 34.4 (CH2),
D
1147 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d
1.21 (3H, d, J¼6.8 Hz), 1.46
34.7 (CH), 36.1 (CH2), 56.0 (CH3), 86.0 (Cq), 95.1 (CH2), 113.3 (CH),
125.4 (Cq), 127.5 (CH), 137.4 (Cq), 147.2 (Cq), 152.8 (Cq), 212.9 (Cq);
HRMS (ESI) m/z calcd for C17H25O4 [MþH]þ 293.1753, found
293.1743.
(3H, s), 1.56 (3H, s), 2.18 (3H, s), 2.20e2.33 (2H, m), 2.55 (1H, d,
J¼4.0 Hz), 2.96 (1H, dq, J¼6.4 and 6.5 Hz), 3.11 (1H, ddd, J¼3.6, 4.0
and 11.2 Hz), 3.51 (3H, s), 5.15 (2H, dd, J¼6.4 and 10.2 Hz), 6.75 (1H,
s), 6.77 (1H, s); 13C NMR (100 MHz, CDCl3)
d 15.9 (CH3), 25.0 (CH3),
27.4 (CH3), 29.4 (CH3), 34.1 (CH2), 37.2 (CH), 56.1 (CH3), 57.7 (CH),
59.3 (CH), 79.7 (Cq), 95.0 (CH2), 116.2 (CH), 125.4 (Cq), 128.6 (CH),
137.7 (Cq), 146.3 (Cq), 152.2 (Cq); MS (EI) m/z 292 [M]þ; HRMS (EI)
m/z calcd for C17H24O4 [M]þ 292.1675, found 292.1658.
4.2.13. (ꢀ)-Heliannuol K (2). By following the same procedure
described for (ꢀ)-heliannuol A (1), (ꢀ)-heliannuol K (2) was pre-
pared from ketone (17): yield quant.; white solid; mp
125.4e126.3 ꢁC (recrystallized from benzene); {[
a
]
28 ꢀ5.70 (c 0.71,
CHCl3) {lit.2 {[
a
]
25þ90.0 (c 0.1, CHCl3)}; IR (neat) 34D04, 2962, 2932,
4.2.10. (3S,6R)-8-(Methoxymethoxy)-2,2,6,9-tetramethyl-3,4,5,6-
tetrahydro-2H-benzo[b]oxocin-3-ol (16). To a stirred suspension of
LiAlH4 (63.7 mg, 1.68 mmol) in THF (1.5 mL) was added a solution
of epoxide 15 (44.6 mg, 0.152 mmol) in THF (1.0 mL) at 0 ꢁC. After
being stirred for 4 h at 50 ꢁC, the reaction mixture was cooled to
0 ꢁC and then added water. After being stirred for 1 h at the same
temperature, the resultant mixture was filtered through a pad of
Celite and concentrated. The residue was chromatographed on
silica gel with hexane/AcOEt (9:1 v/v) as eluent to give alcohol 16
1710, 1408, 1188D, 1143, 909, 734 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
1.29 (3H, d, J¼7.2 Hz), 1.43 (3H, s), 1.49 (3H, s), 1.58e1.66 (1H, m),
1.93e2.00 (1H, m), 2.18 (3H, s), 2.46e2.49 (2H, m), 3.08 (1H, ddq,
J¼3.6, 10.4, and 10.8 Hz), 4.47 (1H, s, OH, D2O exchangeable), 6.57
(1H, s), 6.72 (1H, s); 13C NMR (100 MHz, CDCl3)
d 15.5 (CH3), 20.4
(CH3), 23.3 (CH3), 24.6 (CH3), 34.0 (CH), 34.6 (CH2), 36.2 (CH2), 86.0
(Cq), 113.5 (CH), 121.5 (Cq), 127.5 (CH), 137.9 (Cq), 146.3 (Cq), 151.0
(Cq), 213.0 (Cq); HRMS (ESI) m/z calcd for C15H20O3Na [MþNa]þ
271.1310, found 271.1301.
(40.6 mg, 91%) as a colorless oil; {[
a
;
]
26 ꢀ67.0 (c 0.36, CHCl3); IR
D
(neat) 3446, 2930, 1499, 1010 cmꢀ1
1H NMR (400 MHz, CDCl3)
4.2.14. (R)-2,2,6,9-Tetramethyl-3-oxo-3,4,5,6-tetrahydro-2H-benzo
d
1.25 (3H, s), 1.26 (3H, s), 1.26 (3H, d, J¼6.8 Hz), 1.46 (2H, br s), 1.69
[b]oxocin-8-yl 4-bromophenyl carbamate (18). To a stirred solution

4764
M. Kanematsu et al. / Tetrahedron 67 (2011) 4758e4766
of (ꢀ)-heliannuol K (2) (3.3 mg, 13
m
mol) in THF (0.5 mL) were
(3H, s), 3.59 (1H, dd, J¼4.0 and 10.4 Hz), 3.67 (1H, dd, J¼6.8 and
10.4 Hz), 4.59 (1H, d, J¼12.0 Hz), 4.64 (1H, d, J¼12.0 Hz), 4.68 (1H,
dt, J¼5.2 and 6.0 Hz), 5.01 (2H, s), 5.50 (1H, dd, J¼1.6 and 15.6 Hz),
5.77 (1H, dq, J¼6.4 and 15.2 Hz), 6.69 (1H, dd, J¼2.8 and 8.8 Hz),
6.76 (1H, d, J¼8.8 Hz), 6.79 (1H, d, J¼2.4 Hz), 7.27e7.74 (10H, m);
added Et3N (4.0
mL, 26 mmol) and 4-bromophenyl isocyanate
(3.2 mg, 16 m
mol) at 0 ꢁC. After being stirred for 0.5 h at rt, the re-
action mixture was concentrated. The residue was chromato-
graphed on silica gel with hexane/AcOEt (4:1 v/v) as eluent to give
carbamate (18) (7.5 mg, quant.) as a white solid; mp 155.2e156.4 ꢁC
13C NMR (100 MHz, CDCl3)
d 16.5 (CH3), 17.9 (CH3), 70.6 (CH2), 72.9
(recrystallized from benzene); {[
a
]
25ꢀ7.48 (c 0.48, CHCl3); IR (neat)
(CH2), 73.3 (CH2), 78.8 (CH), 112.5 (CH), 113.8 (CH), 119.6 (CH), 127.1
(CH), 127.5 (CH), 127.6 (CH), 128.1 (CH), 128.2 (Cq), 128.3 (CH), 128.4
(CH), 129.3 (CH), 137.7 (Cq), 138.3 (Cq), 151.4 (Cq), 152.1 (Cq); HRMS
(ESI) m/z calcd for C26H29O3 [MþH]þ 389.2117, found 389.2105:
3316, 2929, 1715, 1538, 1492, 1395, D1211, 1169, 1008, 826, 732 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
1.31 (3H, d, J¼7.2 Hz), 1.46 (3H, s), 1.52
(3H, s), 1.55e1.64 (1H, m), 1.95e2.05 (1H, m), 2.19 (3H, s), 2.46e2.50
(2H, m), 3.12 (1H, ddq, J¼3.8, 10.4, and 10.8 Hz), 6.83 (1H, s), 6.92
(1H, s), 7.35 (1H, d, J¼6.0 Hz), 7.45 (1H, d, J¼8.8 Hz); 13C NMR
yield 17% for 9b; colorless oil; {[
a
]
25þ31.78 (c 2.71, CHCl3); IR (neat)
D
2856, 1498, 1454, 1216, 1027, 968, 737, 696 cmꢀ1
;
1H NMR
(100 MHz, CDCl3)
d
15.9 (CH3), 20.2 (CH3), 23.2 (CH3), 24.6 (CH3),
(400 MHz, acetone-d6)
d
1.35 (3H, d, J¼6.4 Hz), 2.19 (3H, s), 3.97
33.7 (CH), 34.5 (CH2), 36.0 (CH2), 86.4 (Cq), 120.3 (CH), 120.8 (CH),
127.6 (CH), 128.5 (Cq), 128.5 (Cq), 132.1 (CH), 136.6 (Cq), 138.3 (Cq),
145.0 (Cq), 150.7 (Cq), 151.3 (Cq), 212.3 (Cq); HRMS (ESI) m/z calcd
for C22H25NO4Br [MþH]þ 446.0967, found 446.0984.
(1H, dd, J¼4.8 and 12.4 Hz), 4.01 (1H, dd, J¼5.2 and 12.4 Hz), 4.42
(2H, s), 4.81 (1H, quint, J¼6.0 Hz), 5.03 (2H, s), 5.77 (1H, dd, J¼4.8
and 15.6 Hz), 5.83 (1H, dt, J¼4.8 and 15.6 Hz), 6.70 (1H, dd, J¼3.2
and 8.8 Hz), 6.78 (1H, d, J¼2.8 Hz), 6.86 (1H, d, J¼8.8 Hz), 7.23e7.47
(10H, m); 13C NMR (100 MHz, CDCl3)
d 16.5 (CH3), 21.4 (CH3), 70.0
4.3. An alternative synthesis of (L)-heliannuol K (2)
(CH2), 70.6 (CH2), 71.9 (CH2), 74.6 (CH), 112.6 (CH), 113.8 (CH), 119.6
(CH), 127.1 (CH), 127.6 (CH), 127.7 (CH), 127.7 (CH), 127.8 (CH), 128.3
(CH), 128.3 (CH), 128.3 (CH), 128.4 (CH), 137.7 (Cq), 138.2 (Cq), 151.4
(Cq), 151.8 (Cq); HRMS (ESI) m/z calcd for C26H29O3 [MþH]þ
389.2117, found 389.2121.
4.3.1. 4-(Benzyloxy)-3-methylphenol (7b). To a stirred solution of 4-
hydroxy-3-methylacetophenone (3.0 g, 19.98 mmol) in acetone
(60 mL) were added K2CO3 (13.8 g, 99.89 mmol) and BnBr (8.3 mL,
69.92 mmol) at 0 ꢁC. After being stirred for 1 h under reflux con-
dition, the reaction mixture was cooled to rt, and then added water.
The resultant solution was extracted with AcOEt. The combined
extracts were washed with brine. The residue upon workup was
chromatographed on silica gel with hexane/AcOEt (1:4 v/v) as el-
uent to give benzyl ether (5.01 g, quant.) as a white solid; mp
75.8 ꢁC (recrystallized from benzene); IR (neat) 1675, 1601, 1502,
4.3.3. (R,E)-4-(Benzyloxy)-2-(5-(benzyloxy)pent-3-en-2-yl)-5-
methylphenol(5b)and(S,Z)-4-(benzyloxy)-2-(5-(benzyloxy)pent-3-en-
2-yl)-5-methylphenol(10b). To a stirred solution of allyl aryl ether 6b
(3.52 g, 9.06 mmol) in 1,2-dichloroethane (70 mL) was added
tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionaic) euro-
pium (700 mg, 0.67 mol) at rt. After being stirred at 100 ꢁC for 12 h,
the reaction mixture was filtered through a pad of silica gel and
concentrated. The residue was chromatographed on silica gel with
hexane/AcOEt (17:3 v/v) as eluent to afford phenol 5b (3.19 g, 91%,
1263, 1143, 737 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 2.32 (3H, s), 2.55
(3H, s), 5.16 (2H, s), 6.90 (1H, d, J¼8.4 Hz), 7.32e7.44 (5H, m), 7.79
(1H, d, J¼2.4 and 8.8 Hz), 7.80 (1H, s); 13C NMR (100 MHz, CDCl3)
d
16.4 (CH3), 26.3 (CH3), 69.9 (CH2), 110.5 (CH), 127.0 (CH), 127.1
>99% ee) as a colorless oil and the Z-isomer 10b (292 mg, 8%) as
25
(Cq), 127.9 (CH), 128.3 (CH), 128.6 (CH), 130.1 (Cq), 131.0 (CH), 136.6
(Cq), 160.8 (Cq), 197.0 (Cq); HRMS (ESI) m/z calcd for C16H16O2Na
[MþNa]þ 263.1048, found 263.1053; To a stirred solution of benzyl
ether (4.91 g, 20.43 mmol) in CH2Cl2 (100 mL) were added NaHCO3
(3.43 g, 40.86 mmol) and mCPBA (5.88 g, 70%, 24.52 mmol) at 0 ꢁC.
After being stirred for 6 h at rt, the reaction mixture was quenched
with saturated aqueous NaHCO3 and extracted with AcOEt. The
combined extracts were washed with brine. To the residue upon
workup was added a solution of 10% KOH in MeOH (pH 9e10) at rt.
After being stirred for 30 min at the same temperature, the reaction
mixture was concentrated and added water. The resultant mixture
was acidified with 10% aqueous HCl and extracted with AcOEt. The
combined extracts were washed with saturated aqueous NaHCO3
and brine. The residue upon workup was chromatographed on
silica gel with hexane/AcOEt (7:3 v/v) as eluent to give phenol 7b
(4.57 g, quant.) as a white solid; mp 58.1 ꢁC (recrystallized from
benzene); IR (neat) 3311, 1697, 1505, 1454, 1217, 1020, 742 cmꢀ1; 1H
a white solid; 5b; {[
a
]
ꢀ6.15 (c 2.44, CHCl3); IR (neat) 3363,
2926, 2863, 1508, 1453,D1414, 1377, 1192, 974, 737, 697 cmꢀ1
;
1H
NMR (400 MHz, CDCl3)
d
1.36 (3H, d, J¼6.8 Hz), 2.21 (3H, s), 3.69
(1H, quint, J¼6.8 Hz), 4.02 (2H, d, J¼5.6 Hz), 4.51 (2H, s), 4.51 (1H,
br s, OH, D2O exchangeable), 4.99 (2H, s), 5.69 (1H, dt, J¼6.4 and
15.2 Hz), 5.92 (1H, dd, J¼6.0 and 15.6 Hz), 6.62 (1H, s), 6.66 (1H,
s), 7.28e7.43 (10H, m); 13C NMR (100 MHz, CDCl3)
d 15.9 (CH3),
19.4 (CH3), 36.1 (CH), 70.6 (CH2), 71.1 (CH2), 72.1 (CH2), 112.4 (CH),
118. 6 (CH), 125.9 (CH), 126.5 (Cq), 127.3 (CH), 127.6 (CH), 127.7
(CH), 127.8 (CH), 128.3 (Cq), 128.4 (CH), 128.4 (CH), 137.7 (CH),
138.3 (Cq), 138.8 (Cq), 147.1 (Cq), 151.1 (Cq); HRMS (ESI) m/z calcd
for C26H29O3 [MþH]þ 389.2117, found 389.2125. Enantiomeric
excess was determined by HPLC analysis [Chiralcel AD column,
5.0% isopropanol/hexane, 1.0 mL/min,
l
¼254 nm, retention times
44.7 min (R) and 51.0 min (S)]; 10b; mp 70.2 ꢁC; {[
a
]
25 ꢀ128.06
D
(c 0.87, CHCl3); IR (neat) 3361, 2866, 1507, 1455, 1417, 1192, 1066,
1026, 736, 697 cmꢀ1 1H NMR (400 MHz, CDCl3)
; d 1.29 (3H, d,
NMR (400 MHz, CDCl3)
d
2.24 (3H, s), 4.30 (1H, br s, D2O ex-
J¼7.2 Hz), 2.21 (3H, s), 3.93 (1H, dd, J¼6.0 and 11.6 Hz), 4.03 (1H,
dq, J¼6.8 and 9.2 Hz), 4.21 (1H, ddd, J¼1.2, 4.8, and 10.8 Hz), 4.57
(1H, d, J¼12.0 Hz), 4.61 (1H, d, J¼12.0 Hz), 5.00 (2H, s), 5.53 (1H,
ddd, J¼1.2, 10.0, and 10.8 Hz), 5.59 (1H, dt, J¼6.0 and 10.8 Hz),
6.25 (1H, s, OH, D2O exchangeable), 6.66 (1H, s), 6.70 (1H, s),
changeable, OH), 5.01 (2H, s), 6.59 (1H, dd, J¼2.8 and 8.4 Hz), 6.67
(1H, d, J¼3.2 Hz), 6.75 (1H, d, J¼8.4 Hz), 7.29e7.44 (5H, m); 13C NMR
(100 MHz, CDCl3)
d 16.4 (CH3), 70.9 (CH2), 112.6 (CH), 113.3 (CH),
118.0 (CH), 127.2 (CH), 127.7 (CH), 128.4 (CH), 128.8 (Cq), 137.7 (Cq),
149.3 (Cq), 151.1 (Cq); HRMS (ESI) m/z calcd for C14H14O2Na
[MþNa]þ 237.0891, found 237.0882.
7.29e7.45 (10H, m); 13C NMR (100 MHz, CDCl3)
d 15.8 (CH3), 19.9
(CH3), 31.6 (CH), 65.2 (CH2), 71.3 (CH2), 72.8 (CH2), 111.1 (CH),
119.2 (CH), 123.0 (CH), 126.6 (Cq), 127.3 (CH), 127.7 (CH), 127.9
(CH), 128.1 (CH), 128.4 (CH), 128.5 (CH), 137.4 (Cq), 137.8 (Cq),
139.9 (CH), 147.8 (Cq), 147.1 (Cq), 151.0 (Cq); HRMS (ESI) m/z calcd
for C26H29O3 [MþH]þ 389.2117, found 389.2136.
4.3.2. (R,E)-1-(Benzyloxy)-4-(1-(benzyloxy)pent-3-en-2-yloxy)-
2-methylbenzene (6b) and (E)-1-(benzyloxy)-4-(5-(benzyloxy)pent-
3-en-2-yloxy)-2-methylbenzene (9b). By following the same
procedure described for 6a and 9a, 6b and 9b were prepared from
7b and 8: yield 78% for 6b; colorless oil; {[
a]
25 ꢀ13.34 (c 2.26,
4.3.4. (E)-1-(Benzyloxy)-4-(5-(benzyloxy)pent-3-en-2-yloxy)-2-
methylbenzene (21). To a stirred solution of phenol 5b (1.67 g,
4.29 mmol) and ethyl 2-bromo-2-methylpropanoate (5.0 g,
CHCl3); IR (neat) 1499, 1454, 1379, 1215, 1100D, 1026, 966, 736,
697 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
1.70 (3H, d, J¼6.4 Hz), 2.24

M. Kanematsu et al. / Tetrahedron 67 (2011) 4758e4766
4765
25.71 mmol) in MeCN/DMF (18 mL, 18/1 v/v) was added K2CO3
(3.6 g, 25.71 mmol) at rt. After being stirred for 12 h at 107 ꢁC, the
reaction mixture was cooled to 0 ꢁC, and then diluted with E2O and
1 M aqueous HCl. The resultant mixture was extracted with E2O.
The combined extracts were washed with brine. The residue upon
workup was chromatographed on silica gel with hexane/AcOEt
(4:1 v/v) as eluent to give ester 18 (2.04 g, 95%) as a colorless oil;
(CH), 129.8 (CH2), 130.4 (CH), 134.2 (Cq), 137.6 (Cq), 137.6 (Cq), 138.5
(CH), 146.0 (Cq), 151.8 (Cq), 202.6 (Cq); HRMS (ESI) m/z calcd for
C32H36O4Na [MþNa]þ 507.2511, found 507.2526.
4.3.7. (R,Z)-8-(Benzyloxy)-2,2,6,9-tetramethyl-2H-benzo[b]oxocin-
3(6H)-one (19). To
a stirred solution of diene 20 (20 mg,
0.041 mmol) in toluene (2 mL) were added benzoquinone (1.0 mg,
{[a
]
25 ꢀ5.55 (c 3.14, CHCl3); IR (neat) 2932, 1733, 1500, 1454, 1382,
4.1
2.5
m
mol) and Grubbs’ second-generation catalyst 14 (3.0 mg,
D
1197, 1176, 1138, 1019, 972, 737, 697 cmꢀ1
;
1H NMR (400 MHz,
mmol) at rt, and then the mixture was heated to reflux. After
CDCl3)
d
1.27 (3H, t, J¼7.2 Hz), 1.29 (3H, d, J¼8.4 Hz), 1.53 (3H, s),
being stirred for 7 h, the reaction mixture was cooled to rt. After
being stirred for 1 h at the same temperature under air, the re-
sultant mixture was concentrated. The residue was chromato-
graphed on silica gel with benzene as eluent to give eight-
membered enone 19 (11.1 mg, 80%, >99% ee) as a white solid;
1.56 (3H, s), 2.17 (3H, s), 3.96 (1H, quint, J¼6.8 Hz), 4.00 (2H, d,
J¼6.0 Hz), 4.26 (2H, q, J¼6.8 Hz), 4.50 (2H, s), 4.98 (2H, s), 5.62 (1H,
dt, J¼6.4 and 15.6 Hz), 5.86 (1H, dd, J¼5.6 and 15.6 Hz), 6.57 (1H, s),
6.67 (1H, s), 7.24e7.41 (10H, m); 13C NMR (100 MHz, CDCl3)
d 14.1
(CH3), 16.2 (CH3), 20.1 (CH3), 25.1 (CH3), 25.7 (CH3), 34.5 (CH), 61.3
(CH2), 70.5 (CH2), 71.9 (CH2), 79.3 (Cq), 111.6 (CH), 120.5 (CH), 124.8
(CH), 125.1 (Cq), 127.3 (CH), 127.5 (CH), 127.6 (CH), 127.7 (CH), 128.3
(CH), 128.4 (CH), 135.0 (Cq), 137.6 (Cq), 138.5 (Cq), 138.5 (Cq), 138.7
(CH), 146.1 (Cq), 152.0 (Cq), 174.7 (Cq); HRMS (ESI) m/z calcd for
C32H38O5Na [MþNa]þ 525.2617, found 525.2625.
mp 131.4 ꢁC; {[
a
]
25 ꢀ83.29 (c 1.46, CHCl3); IR (neat) 2984, 1685,
D
1503, 1456, 1377, 1197, 1152, 1016, 737, 697 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
1.47 (3H, d, J¼7.6 Hz), 1.53 (3H, s), 1.54 (3H, s),
2.20 (3H, s), 3.85 (1H, br m), 4.99 (2H, s), 5.76 (1H, dd, J¼1.6 and
12.8 Hz), 6.22 (1H, dd, J¼4.8 and 12.8 Hz), 6.61 (1H, s), 6.87 (1H, s),
7.29e7.42 (5H, m); 13C NMR (125 MHz, CDCl3)
d 16.1 (CH3), 19.5
(CH3), 24.6 (CH3), 25.5 (CH), 70.4 (CH2), 87.4 (Cq), 110.9 (CH), 126.0
(Cq), 126.1 (CH), 126.8 (CH), 127.2 (CH), 127.8 (CH), 128.5 (CH),
135.5 (Cq), 137.4 (Cq), 144.4 (CH), 147.6 (Cq), 153.9 (Cq), 206.3 (Cq);
HRMS (ESI) m/z calcd for C22H24O3Na [MþNa]þ 356.1623, found
359.1624. Enantiomeric excess was determined by HPLC analysis
[Chiralcel OD-H column, 1.0% isopropanol/hexane, 1.0 mL/min,
4.3.5. (R,E)-2-(4-(Benzyloxy)-2-(5-(benzyloxy)pent-3-en-2-yl)-5-
methylphenoxy)-N-methoxy-N,2-dimethylpropanamide (22). To
a
stirred solution of ester 18 (1.99 g, 3.96 mmol) and (MeO)
MeNH$HCl (1.16 g, 11.87 mmol) in THF (26 mL) was added LHMDS
(12 mL, 1.0 M solution in THF, 34.4 mmol) at 0 ꢁC. After being
stirred for 4 h at rt, the reaction mixture was quenched with
saturated aqueous NH4Cl and extracted with Et2O. The combined
extracts were washed with brine. The residue upon workup was
chromatographed on silica gel with hexane/AcOEt (4:1 v/v) as
eluent to give Weinreb amide 22 (2.84 g, 98%) as a colorless oil;
l¼254 nm, retention times 46.3 min (S) and 62.6 min (R)].
4.3.8. (ꢀ)-Heliannuol
K
(2). To stirred solution of eight-
a
membered enone 19 (11.2 mg, 0.033 mmol) in EtOH (0.5 mL) was
added Raney-Ni (W-2) (10 mg) at rt. After being stirred for 30 min
at the same temperature, the reaction mixture was filtered and
concentrated. The residue was chromatographed on silica gel with
hexane/AcOEt (4:1 v/v) as eluent to give (ꢀ)-Heliannuol K (2)
{[a
]
25ꢀ8.71 (c 3.56, CHCl3); IR (neat) 2932, 1655, 1500, 1454, 1382,
D
1198, 1151, 1017, 738, 698 cmꢀ1
;
1H NMR (400 MHz, CDCl3)
d
1.31
(3H, d, J¼6.8 Hz), 1.56 (3H, s), 1.58 (3H, s), 2.17 (3H, s), 3.33 (3H, s),
3.63 (3H, s), 3.89 (1H, quint, J¼6.8 Hz), 4.00 (2H, d, J¼6.4 Hz), 4.50
(2H, s), 4.98 (2H, s), 5.62 (1H, dt, J¼6.4 and 15.2 Hz), 5.87 (1H, dd,
J¼6.0 and 15.6 Hz), 6.57 (1H, s), 6.69 (1H, s), 7.27e7.42 (10H, m);
(7.1 mg, 87%, >99% ee) as a white solid; {[
a]
30 ꢀ6.4 (c 1.81, CHCl3);
Other spectral data matched with those of Dthe authentic sample
prepared in Section 4.2.13. Enantiomeric excess was determined
by HPLC analysis [Chiralcel AS-H column, 5.0% isopropanol/
13C NMR (125 MHz, CDCl3)
d 16.2 (CH3), 20.1 (CH3), 25.2 (CH3),
25.2 (CH3), 35.1 (CH), 60.5 (CH3), 70.5 (CH2), 70.9 (CH2), 72.0 (CH2),
77.2 (CH3), 79.9 (Cq), 111.7 (CH), 119.3 (CH), 124.9 (CH), 125.3 (Cq),
127.3 (CH), 127.5 (CH), 127.7 (CH), 127.7 (CH), 128.3 (CH), 128.4
(CH), 134.1 (Cq), 137.6 (Cq), 138.4 (Cq), 138.5 (CH), 146.1 (Cq), 151.7
(Cq), 173.6 (Cq); HRMS (ESI) m/z calcd for C32H39NO5Na [MþNa]þ
540.2726, found 540.2744.
hexane, 1.0 mL/min,
60.0 min (R)].
l
¼254 nm, retention times 50.2 min (S) and
4.3.9. (ꢀ)-Heliannuol A (1) and 10-epi-heliannuol A (23). 4.3.9.1. Re-
duction of (ꢀ)-heliannuol K (2). To a stirred solution of (ꢀ)-heli-
annuol K (2) (34.2 mg, 0.138 mmol) in MeOH (0.5 mL) was added
NaBH4 (10.4 mg, 0.275 mmol) at 0 ꢁC. After being stirred for 10 min
at the same temperature, the reaction mixture was added water and
extracted with AcOEt. The combined extracts were washed with
brine. The residue upon workup was chromatographed on silica gel
with hexane/AcOEt (17:8 v/v) as eluent to give (ꢀ)-heliannuol A (1)
and 10-epi-heliannuol A (23) (35.0 mg, quant. as a 1:3.8 mixture) as
a white solid; IR (neat) 3396, 2935, 1507, 1459, 1407, 1189, 1135,
4.3.6. (R,E)-4-(4-(Benzyloxy)-2-(5-(benzyloxy)pent-3-en-2-yl)-5-
methylphenoxy)-4-methylpent-1-en-3-one (20). To a stirred solu-
tion of amide 22 (30 mg, 0.058 mmol) in THF (0.6 mL) was added
vinylmagnesium chloride (0.13 mL, 1.36 M solution in THF,
34.4 mmol) at 0 ꢁC. After being stirred for 1 h at the same tem-
perature, the reaction mixture was quenched with 1 M aqueous HCl
and extracted with AcOEt. The combined extracts were washed
with saturated aqueous NaHCO3 and brine. The residue upon
workup was chromatographed on silica gel with hexane/AcOEt
(9:1 v/v) as eluent to give diene 20 (31.8 mg, quant.) as a colorless
1035 cmꢀ1 1H NMR (500 MHz, CDCl3)
; d 1.14e1.37 (0.42H, m),
1.22e1.58 (0.79H, br m),1.23 (3H, d, J¼7.5 Hz),1.28,1.47 (0.63H, br s),
1.37e1.55 (0.21H, br m), 1.38 (2.37H, s), 1.43 (2.37H, s), 1.47, 1.63
(0.63H, br s), 1.56e1.61 (0.79H, br m), 1.84 (0.21H, br m), 1.98 (0.79H,
ddt, J¼3.0, 8.0 and 14.0 Hz), 2.06e2.15 (0.79H, m), 2.18 (3H, s), 2.82,
3.26 (0.21H, br m), 3.11e3.20 (0.79H, m), 3.42 (0.79H, dd, J¼6.5 and
8.5 Hz), 3.66 (0.21H, br s), 4.61e4.68 (1H, br m, OH, D2O exchange-
able), 6.56 (0.21H, s), 6.59 (0.79H, s), 6.70 (0.21H, s), 6.73 (0.79H, s);
oil; {[
a
]
25 ꢀ9.17 (c 2.45, CHCl3); IR (neat) 2937, 2857, 1700, 1609,
D
1500, 1455, 1401, 1379, 1196, 1154, 1066, 736, 697 cmꢀ1
;
1H NMR
(400 MHz, CDCl3)
d
1.32 (3H, d, J¼6.8 Hz), 1.45 (3H, s), 1.47 (3H, s),
2.12 (3H, s), 3.93 (1H, quint, J¼6.4 Hz), 4.01 (2H, d, J¼6.0 Hz), 4.51
(2H, s), 4.97 (2H, s), 5.63 (1H, dt, J¼6.0 and 15.6 Hz), 5.74 (1H, dd,
J¼1.6 and 10.4 Hz), 5.89 (1H, dd, J¼6.0 and 15.6 Hz), 6.31 (1H, s),
6.51 (1H, dd, J¼2.0 and 17.2 Hz), 6.69 (1H, s), 7.04 (1H, dd, J¼10 and
13C NMR (125 MHz, CDCl3)
d 15.5 (CH3), 18.8 (CH3), 19.7 (CH3), 20.9
(CH3), 23.1 (CH3), 25.6 (CH3), 29.0 (CH3), 29.8 (CH), 30.7 (CH2), 31.9
(CH), 32.4 (CH2), 36.0 (CH2), 36.8 (CH2), 75.7 (CH), 78.5 (CH), 82.1
(Cq), 82.6 (Cq), 111.8 (CH), 112.1 (CH), 120.8 (Cq), 121.1 (Cq), 126.8
(CH), 138.5 (Cq), 139.5 (Cq), 145.9 (Cq), 146.8 (Cq), 150.4 (Cq), 150.5
(Cq); HRMS (ESI) m/z calcd for C15H23O3 [MþH]þ 251.1647, found
251.1641.
17.2 Hz), 7.28e7.41 (10H, m); 13C NMR (125 MHz, CDCl3)
d 16.1
(CH3), 20.0 (CH3), 23.8 (CH3), 23.9 (CH3), 35.0 (CH), 70.6 (CH2), 71.0
(CH2), 72.0 (CH2), 83.3 (Cq), 111.9 (CH), 119.4 (CH), 125.0 (CH), 125.2
(Cq), 127.3 (CH), 127.5 (CH), 127.7 (CH), 127.7 (CH), 128.3 (CH), 128.4

4766
M. Kanematsu et al. / Tetrahedron 67 (2011) 4758e4766
Fronczek, F. R.; Shishido, K. Tetrahedron 2008, 64, 5502e5508; (e) Heliannuols A
and K: for racemic syntheses, see: Lecornue, F.; Ollivier, J. Synlett 2004,
4.3.9.2. Reduction of eight-membered enone (19). To a stirred
solution of eight-membered enone 19 (9.0 mg, 27 mol) in EtOH
ꢀ
m
1613e1615; (f) Ghosh, S.; Tuhina, K.; Bhowmik, D. R.; Venkateswaran, R. V.
Tetrahedron 2007, 63, 644e651; (g) Biswas, B.; Sen, P. K.; Venkateswaran, R. V.
Tetrahedron 2007, 63, 12026e12036.
6. For a review, see: Kamei, T.; Morimoto, S.; Shishido, K. J. Synth. Org. Chem. Jpn.
2006, 64, 1021e1031.
(0.5 mL) was added Raney-Ni (W-2) (10 mg) at rt. After being stir-
red for 2 h at the same temperature under 5 atm of hydrogen gas,
the reaction mixture was filtered and concentrated. The residue
was chromatographed on silica gel with hexane/AcOEt (4:1 v/v) as
eluent to give (ꢀ)-heliannuol A (1) and 10-epi-heliannuol A (23)
(5.7 mg, 84% as a 1:3.7 mixture) as a white solid; The spectral data
matched with those of the sample prepared in Section 4.3.9.1.
7. Soga, K.; Kanematsu, M.; Yoshida, M.; Shishido, K. Synlett 2011, 1171e1173.
8. (a) Kaiho, T.; Yokoyama, T.; Mori, H.; Fujiwara, J.; Nobori, T.; Okada, H.; Kamiya,
J.; Maruyama, M.; Sugawara, T. JP06128238, 1994; [C. A., 1995, 123, 55900]. (b)
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8505e8507; (d) Morimoto, S.; Shindo, M.; Shishido, K. Heterocycles 2005, 66,
69e73.
9. For examples of the construction of a tertiary stereogenic center at the benzylic
position by chirality transfer during the aromatic Claisen rearrangement, see:
(a) Goerring, H. L.; Kimoto, W. I. J. Am. Chem. Soc. 1965, 87, 1748e1753; (b)
Borgulya, von J.; Madeja, R.; Fahrni, P.; Hansen, H.-J.; Schmid, H.; Barner, R. Helv.
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Acknowledgements
We thank SANYO FINE Co. Ltd. for providing S-(þ)-benzyl gly-
cidyl ether. We also thank Dr. Takashi Ooi of the University of
Tokushima for X-ray analysis. This work was supported financially
by a Grant-in-Aid for the Program for Promotion of Basic and Ap-
plied Research for Innovation in the Bio-oriented Industry (BRAIN).
10. For reviews, see: (a) Castro, A. M. M. Chem. Rev. 2004, 104, 2939e3002; (b) The
Claisen Rearrangement; Hiersemann, M., Nubbemeyer, U., Eds.; Wiley-VCH:
Weinheim, 2007; (c) Majumdar, K. C.; Almam, S.; Chattopadhyay, B. Tetrahedron
2008, 64, 597e643.
Supplementary data
11. Takano, S.; Sekiguchi, Y.; Sato, N.; Ogasawara, K. Synthesis 1987, 139e141.
12. For reviews, see: (a) Mitsunobu, O. Synthesis 1981, 1e28; (b) Hughes, D. L. Org.
React. 1992, 42, 335e656; (c) Hughes, D. L. Org. Prep. Proced. Int. 1996, 28,
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Yamamiya, Y.; Ito, S. Tetrahedron Lett. 1993, 34, 1639e1642.
14. Chan, T. H.; Osanai, K.; Milacic, V.; Dou, Q. P. Heterocycles 2008, 76, 485e505.
15. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485e1486.
16. For a review, see: Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18e29.
17. Yang, D.; Wong, M. K.; Yip, Y. C. J. Org. Chem. 1995, 60, 3887e3889.
18. Since we were not able to obtain the sample of natural heliannuol K, the dis-
crepancy with the optical rotation of synthetic product with that reported for
the natural product could not be explained.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.05.034. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
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