Total synthesis of radulanin H and proposed structure of radulanin E

Article abstract of DOI:10.1016/j.tet.2009.05.027

The total synthesis of radulanin H and the proposed structure of radulanin E have been achieved utilizing an intramolecular condensation, sequential regioselective C- and O-allylations, and ring closing metathesis as the key steps.

Full text of DOI:10.1016/j.tet.2009.05.027

Tetrahedron 65 (2009) 5702–5708
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Tetrahedron
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Total synthesis of radulanin H and proposed structure of radulanin E
*
Masahiro Yoshida , Koji Nakatani, 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:
The total synthesis of radulanin H and the proposed structure of radulanin E have been achieved utilizing
an intramolecular condensation, sequential regioselective C- and O-allylations, and ring closing me-
tathesis as the key steps.
Received 19 March 2009
Received in revised form 12 May 2009
Accepted 12 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Available online 18 May 2009
1. Introduction
the seven-membered cyclic ether moiety could be constructed by
the ring closing metathesis of 3 and 4, each of which would be
Radulanins H (1)1 and E (2),2 isolated by Asakawa et al. from the
liverwort Radula perrottetii and Radula variabilis, are 3-methyl-2,5-
dihydro-1-benzoxepin derivatives3 (Fig. 1). It has been reported
that radulanin H (1) exhibits significant calmodulin and cyclo-
oxygenase inhibitory activities,4 and the structures of 1 and 2
containing a highly functionalized benzene ring with a seven-
membered cyclic ether moiety have attracted considerable syn-
thetic interest.5 There have been reports on the total syntheses of 1
and 2 only by Yamaguchi, in which an intramolecular Mitsunobu
cyclization was used for the construction of the seven-membered
ring.6,7 Herein, we describe concise total synthesis of radulanin H
(1) and the proposed structure of radulanin E (2), utilizing an
intramolecular condensation, sequential regioselective allylations,
and ring closing metathesis as the key steps.
prepared from a common synthetic intermediate 5 by sequential
regioselective C- and O-allylations. The substituted resorcinol 5
would be constructed by an intramolecular condensation of the
diketoacetal 6, derived from ethyl acetoacetate and benzyl
bromide.
OH
OH
R1
ring-closing
R1
metathesis
Ph
O
Ph
O
R2
R2
3: R1=CO2Et, R2=H
4: R1=H, R2=CO2Et
1: R1=CO2H, R2=H
2: R1=H, R2=CO2H
sequential
OH
2. Results and discussion
intramolecular
condensation
regioselective
allylation
EtO2C
Ph
Our strategy for the radulanins H (1) and E (2) is embodied in
the retrosynthetic analysis shown in Scheme 1. We anticipated that
OH
5
O
O
× 2
OH
R1
O
O
O
OEt
O
O
+
Ph
OEt
Ph
Br
Ph
6
O
R2
Scheme 1. Retrosynthetic analysis.
radulanin H (1) : R1=CO2H, R2=H
radulanin E (2) : R1=H, R2=CO2H
The preparation of the substituted resorcinol 5 was performed
as shown in Scheme 2. The addition of the dienolate of ethyl ace-
toacetate to benzyl bromide and subsequent protection of the ke-
tone moiety with ethylene glycol in the presence of TsOH furnished
the acetal 7 in 81% yield for the two steps. The diketoacetal 6 was
obtained likewise by addition of the dienolate to the resulting 7.
When 6 was subjected to the reaction with NaClO4 in AcOH,8 the
Figure 1. Structure of radulanins H and E.
* Corresponding author. Tel./fax: þ81 88 6337294.
E-mail address: yoshida@ph.tokushima-u.ac.jp (M. Yoshida).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.027

M. Yoshida et al. / Tetrahedron 65 (2009) 5702–5708
5703
1) NaH; BuLi;
benzyl bromide
THF, 0 °C
OH
OH
Br
EtO2C
, K2CO3 EtO2C
acetone, reflux
O
O
O
O
O
O
O
OEt
OEt
2) ethylene glycol
TsOH, HC(OMe)3
2 steps 81%
OEt
Ph
4
86%
Ph
OH
Ph
O
7
8
3
OH
O
O
O
O
O
NaH; BuLi; 7
1) 20 mol % 10
CH2Cl2
HO2C
Ph
MeI, K2CO3
Ph
OEt
THF, 0 °C, 55%
6
2) KOH, THF-H2O
2 steps 91%
acetone, reflux
quant
O
1
OH
OH
EtO2C
EtO2C
Ph
NaClO4
OMe
N
N
Mes
Cl
Mes
Ph
O
MeO2C
AcOH
48%
Ru
OH
Ph
OH
Cl
PCy3
Ph
O
5
10
11
Scheme 2. Synthesis of resorcinol 5.
Scheme 4. Completion of the synthesis of radulanin H (1).
OH
Our approach toward the synthesis of radulanin H (1) is de-
scribed in Scheme 4. When the allyl resorcinol 8 was treated with
methallyl bromide and K2CO3, the regioselective -methallylation
, base
EtO2C
Ph
Br
3
b
-
toluene, Δ
b
see Table 1
OH
of the C-4 phenolic oxygen proceeded to give the diene 3 in 86%
yield. Finally, ring closing metathesis of 3 using Grubbs second
generation catalyst 10, followed by hydrolysis of the ethyl ester
moiety in aqueous KOH solution produced radulanin H (1) in 91%
yield for the two steps. The structure of the synthesized 1 was
confirmed by preparation of the methyl ester derivative 11.1 Thus,
treatment of 1 with MeI and K2CO3 in acetone produced the methyl
ester 11. The 1H NMR data of synthetic 11 were completely identical
with that of the compound derived from the natural radulanin H.
We next focused on the synthesis of radulanin E (2). To achieve
5
OH
OH
EtO2C
EtO2C
Ph
+
Ph
OH
O
8
9
o-dichlorobenzene, reflux
40%
the synthesis, it is necessary to introduce the b-methallyl moiety on
Scheme 3. Regioselective allylation of 5.
the less reactive C-2 hydroxyl group in 8. We therefore examined
initially the protection of the more reactive C-4 hydroxyl group
(Scheme 5). When the intermediate 8 was subjected to the reaction
desired intramolecular condensation occurred to afford the
substituted resorcinol 5 in 48% yield.
OH
OH
Regioselective C-allylation of 5 was next attempted (Scheme 3).
We initially examined the reaction according to Fu¨rstner’s pro-
cedure,9 in which the C-allylation of resorcinols proceeded regio-
selectively. When 5 was treated with allyl bromide and NaH in
toluene at 80 ꢀC, the desired C-3 allylated product 8 was produced
in 38% yield (Table 1, entry 1). Further examination revealed that
the use of Ag2CO3 at 140 ꢀC afforded the O-allylated product 9 as
the major product in 60% yield (entry 2). The ratio of 8 to 9 was
altered depending on the base (entries 2–6), and it was found that
the desired product 8 was obtained in 57% yield along with the
production of 9 (33% yield) when the reaction was carried out in
the presence of K2CO3 (entry 6). The byproduct 9 was able to be
converted to 8 by the Claisen rearrangement in refluxing o-
dichlorobenzene.
2
i
EtO2C
Ph
EtO2C
Ph
MOMCl, Pr2NEt
CH2Cl2
81%
4
OMOM
OH
12
8
O
Br
EtO2C
, NaH, TBAI
acetone, reflux
98%
2 N HCl
MeOH, reflux
97%
Ph
OMOM
13
O
O
20 mol % 10
EtO2C
Ph
EtO2C
Ph
CH2Cl2
84%
Table 1
OH
OH
Examination of the regioselective allylation of 5
4
14
Entry
Base
Temp (ꢀC)
Time (h)
Yields (%)
8
9
O
1
2
3
4
5
6
NaH
80
140
140
140
140
140
13
24
27
18
48
3
38
15
41
33
21
57
d
60
23
37
17
33
HO2C
Ag2CO3
NaOH
K3PO4
Na2CO3
K2CO3
Ph
OH
2
Scheme 5. Attempts toward the synthesis of radulanin E (2).

5704
M. Yoshida et al. / Tetrahedron 65 (2009) 5702–5708
2
3
1
O
1) LAH, THF
reflux
O
O
10
MeO2C
EtO2C
Ph
OHC
4
7
2) CrO3, H2SO4
acetone-H2O, rt
2 steps 84%
OMe9
8H
6
5
OMOM
OMOM
Ph
13
15
Figure 3. Structure of 17.
O
Table 2
Comparison of the 1H NMR data of reported2 and synthesized 17
NaClO2, NaH2PO4
2-methyl-2-butene
1) 2 N HCl
OHC
MeOH, reflux, 83%
t
1H number
Reported (90 MHz)
Synthesized (400 MHz)
Dda
2) 20 mol % 10
CH2Cl2, 85%
THF- BuOH-H2O
Ph
OH
74%
1
2
3
4
4.47 (br s)
1.57 (br s)
5.65 (m)
3.45 (m)
6.77 (s)
4.47 (s)
1.53 (s)
5.56–5.58 (m)
3.40 (d)
6.37 (s)
d
16
þ0.04
þ0.08
þ0.05
þ0.40
þ0.03
þ0.06
þ0.05
þ0.04
O
O
5
MeI, K2CO3
HO2C
MeO2C
Ph
6,7
8
9
2.92 (s)
7.30 (s)
3.78 (s)
2.89 (s)
7.17–7.21 (m), 7.27–7.30 (m)
3.73 (s)
acetone, reflux
73%
Ph
OH
OMe
10
3.95 (s)
3.91 (s)
2
17
a
Chemical shifts in parts per million.
Scheme 6. Completion of the total synthesis of radulanin E (2).
was derived from the natural product (Fig. 3 and Table 2).2 Al-
though most of the signals showed good agreement, the singlet
signal of the aromatic proton was not identical (1H number 5 in
Table 2).13 Based on the structural confirmation of 16 by X-ray
crystallographic analysis, we are confident that the structure of our
synthesized 2 is correct. On the other hand, the assigned structure
of radulanin E is reasonable from the viewpoint of the biosynthesis,
in which both radulanin H and E would be derived from 2-carboxy-
3,5-dihydroxy-4-(3-methyl-2-butenyl)bibenzyl (18)3e (Scheme 7).
From these matters, it is strongly assumed that the signal
(6.77 ppm) in the reported 17 would be the typographical error, and
the assigned structure of radulanin E (2) is correct.
i
with MOMCl and Pr2NEt, the corresponding MOM ether 12 was
regioselectively obtained in 81% yield. The b-methallylation of 12 at
the C-2 hydroxyl group proceeded successfully using NaH and
TBAI10 to produce the diene 13 in 98% yield. Deprotection of the
MOM group under acidic conditions (97% yield) followed by ring
closing metathesis using 10 gave radulanin E ethyl ester (14) (84%
yield). Finally, we examined the hydrolysis or reduction–oxidation
of the ester moiety of 14 under various conditions. However, all
attempts failed presumably because of the steric hindrance around
the ester moiety.
Having been unable to convert the ester 14 to radulanin E, we
chose to adopt the transformation of the ester moiety prior to the
construction of the seven-membered ring (Scheme 6). Thus, the
ester 13 was reduced with LAH, and the resulting primary alcohol
was oxidized using Jones reagent. We expected to obtain the cor-
responding carboxylic acid, but the aldehyde 15 was actually gen-
erated in 84% yield. After cleavage of the MOM group under acidic
conditions (83% yield), the resulting phenolic diene was converted
to 16 by ring closing metathesis with 10 (85% yield). The structure
of 16 was unambiguously confirmed by an X-ray crystallographic
analysis (Fig. 2).11 Although 16 was previously reported as the
synthetic intermediate for radulanin E by Yamaguchi,7 its 1H NMR
spectra showed significant differences from that of the reported
one.12 When oxidation of compound 16 using NaClO2 was carried
out, the synthesis of radulanin E (2) was achieved in 74% yield. The
infrared absorption data of synthetic 2 showed agreement with
that of the compound derived from the natural radulanin E.2 The
synthesized 2 was further converted to the methyl ester derivative
17, whose 1H NMR data were compared to the reported one, which
OH
HO2C
Ph
O
OH
1
HO2C
Ph
OH
O
18
HO2C
Ph
OH
2
Scheme 7. Proposed biosynthetic pathway for radulanin H (1) and E (2).
3. Conclusion
We have completed the total synthesis of radulanin H and the
proposed structure of radulanin E. A part of 1H NMR data of the
methyl ester of synthetic radulanin E was not identical with that of
the compound derived from the natural radulanin E, but it is sug-
gested that the assigned structure of radulanin E (2) is correct.
4. Experimental
4.1. General
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
Figure 2. ORTEP drawing of 16.

M. Yoshida et al. / Tetrahedron 65 (2009) 5702–5708
5705
without further purification except when otherwise noted. Sol-
vents were dried and distilled according to the 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.
stirring was continued for 7 h, the reaction mixture was diluted
with water and extracted with AcOEt. The combined extracts were
washed with water, saturated aqueous NaHCO3 solution and brine.
The residue upon workup was chromatographed on silica gel with
hexane–AcOEt (70:30 v/v) as eluent to give resorcinol 5 (0.40 g,
48%) as colorless crystals; mp: 86.4–87.6 ꢀC (recrystallized from
AcOEt/hexane); IR (KBr) cmꢁ1 3298, 2985, 1647, 1599; 1H NMR
4.2. (2-Phenethyl-[1,3]dioxolan-2-yl)-acetic acid ethyl
ester (7)
(400 MHz, CDCl3)
d
1.39 (3H, t, J¼7.2 Hz), 2.87 (2H, t, J¼7.6 Hz), 3.20
(2H, t, J¼7.6 Hz), 4.43 (2H, q, J¼7.2 Hz), 5.78 (1H, s), 6.18 (1H, d,
J¼2.4 Hz), 6.31 (1H, d, J¼2.4 Hz), 7.16–7.22 (3H, m), 7.25–7.31 (2H,
To a stirred suspension of NaH (0.61 g, 25.2 mmol) in THF
(50 mL) was added dropwise ethyl acetoactate (2.66 mL,
21.0 mmol) at 0 ꢀC. After stirring was continued for 10 min,
a 2.67 M solution of BuLi in hexane (7.9 mL, 21.0 mmol) was added
dropwise at the same temperature. After further stirring was con-
tinued for 20 min, benzyl bromide (2.75 mL, 23.1 mmol) in THF
(3.0 mL) was added dropwise to this mixture and stirring was
continued for 1 h at the same temperature. The reaction mixture
was quenched with aqueous HCl and extracted with Et2O. The
combined extracts were washed with brine and the residue upon
workup was used in the next step without purification. Thus, to
a stirred solution of this crude, trimethylorthoformate (6.90 mL,
63.1 mmol) and ethylene glycol (5.86 mL, 105.2 mmol) was added
p-TsOH (0.40 g, 2.10 mmol) at rt and stirring was continued for 6 h.
The reaction mixture was quenched with aqueous NaH2PO4 solu-
tion and extracted with Et2O. The combined extracts were washed
with brine and the residue upon workup was chromatographed on
silica gel with hexane–AcOEt (80:20 v/v) as eluent to give acetal 7
(4.49 g, 81% in two steps) as a colorless oil. IR (neat) cmꢁ1 2980,
m),11.86 (1H, s); 13C NMR (100 MHz, CDCl3)
d 14.3 (CH3), 38.0 (CH2),
38.3 (CH2), 61.5 (CH2), 101.7 (CH), 105.3 (Cq), 111.0 (CH), 126.0 (CH),
128.2 (CH), 128.4 (CH), 141.7 (Cq), 147.5 (Cq), 160.1 (Cq), 165.4 (Cq),
171.3 (Cq); HRMS (ESI) m/z calcd for C17H18O4Na [MþNa]þ 309.1103,
found 309.1110.
4.5. 3-Allyl-2,4-dihydroxy-6-phenethyl-benzoic acid ethyl
ester (8) and 4-allyloxy-2-hydroxy-6-phenethyl-benzoic acid
ethyl ester (9)
To a stirred suspension of resorcinol 5 (104 mg, 0.36 mmol) and
K2CO3 (60.4 mg, 0.44 mmol) in toluene (6 mL) was added allyl
bromide (0.16 mL, 1.82 mmol) at rt. After stirring was continued for
3 h at 130 ꢀC in sealed tube, the reaction mixture was filtrated
through Celite. The residue upon evaporation of the solvent was
chromatographed on silica gel with hexane–AcOEt (80:20 v/v) as
eluent to give allyl resorcinol 8 (67.5 mg, 57%) and o-allyl ether 9
(39.2 mg, 33%). Compound 8: colorless crystals, mp 88.5–89.6 ꢀC
(recrystallized from AcOEt/hexane); IR (KBr) cmꢁ1 3350, 3074,1618,
2889, 1734, 1045; 1H NMR (400 MHz, CDCl3)
d
1.27 (3H, t, J¼7.2 Hz),
2.13–2.17 (2H, m), 2.70 (2H, s), 2.71–2.76 (2H, m), 3.99–4.07 (4H,
1279; 1H NMR (400 MHz, CDCl3)
d
1.39 (3H, t, J¼7.2 Hz), 2.87 (2H, t,
m), 4.16 (2H, q, J¼7.2 Hz), 7.16–7.22 (3H, m), 7.26–7.29 (2H, m); 13C
J¼5.6 Hz), 3.18 (2H, t, J¼5.6 Hz), 3.48 (2H, d, J¼6.0 Hz), 4.44 (2H, q,
J¼7.2 Hz), 5.11–5.18 (2H, m), 5.38 (1H, s), 6.00 (1H, ddt, J¼16.8, 10.0,
and 6.0 Hz), 6.22 (1H, s), 7.17–7.22 (3H, m), 7.27–7.31 (2H, m), 12.17
NMR (100 MHz, CDCl3)
d 14.1 (CH3), 29.7 (CH2), 39.5 (CH2), 42.7
(CH2), 60.5 (CH2), 65.2 (CH2), 108.9 (Cq), 125.7 (CH), 128.3 (CH),
141.8 (Cq), 169.4 (Cq); HRMS (ESI) m/z calcd for C15H20O4Na
[MþNa]þ 287.1259, found 287.1253.
(1H, s); 13C NMR (100 MHz, CDCl3)
d 14.3 (CH3), 27.2 (CH2), 38.0
(CH2), 38.2 (CH2), 61.5 (CH2), 105.0 (Cq), 110.4 (Cq), 110.8 (CH), 115.8
(CH2), 125.9 (CH), 128.2 (CH), 128.3 (CH), 135.8 (CH), 141.8 (Cq),
144.8 (Cq), 158.9 (Cq), 162.8 (Cq), 171.8 (Cq); HRMS (ESI) m/z calcd
for C20H22O4Na [MþNa]þ 349.1416, found 349.1419. Compound 9:
colorless oil, IR (neat) cmꢁ1 2982, 1650, 1614, 1577, 1254, 1175; 1H
4.3. 3,5-Dioxo-6-(2-phenethyl-[1,3]dioxolan-2-yl)-hexanoic
acid ethyl ester (6)
To a stirred suspension of NaH (7.0 g, 0.29 mol) in THF (800 mL)
was added dropwise ethyl acetoacetate (30.7 mL, 0.24 mol) at 0 ꢀC.
After stirring was continued for 10 min, a 2.80 M solution of BuLi in
hexane (86.6 mL, 0.24 mol) was added dropwise at the same tem-
perature. After further stirring was continued for 20 min, acetal 7
(15.4 g, 58.1 mmol) in THF (200 mL) and BF3$OEt2 (11.5 mL,
93.0 mmol) were added successively to this mixture at ꢁ78 ꢀC and
stirring was continued for 1 h at 0 ꢀC. The reaction mixture was
quenched with water and extracted with AcOEt. The combined
extracts were washed with saturated aqueous NaHCO3 solution and
brine. The residue upon workup was chromatographed on silica gel
with hexane–AcOEt (70:30 v/v) as eluent to give diketoester 6
(11.1 g, 55%) as a yellow oil; IR (neat) cmꢁ1 2981, 2892, 1738, 1604,
NMR (400 MHz, CDCl3)
d
1.38 (3H, t, J¼7.2 Hz), 2.87 (2H, t,
J¼5.6 Hz), 3.20 (2H, t, J¼5.6 Hz), 4.43 (2H, q, J¼7.2 Hz), 4.50 (2H, d,
J¼5.6 Hz), 5.29 (1H, dd, J¼10.4 and 1.2 Hz), 5.39 (1H, dd, J¼17.2 and
1.2 Hz), 6.00 (1H, ddt, J¼17.2, 10.4, and 5.6 Hz), 6.28 (1H, d,
J¼2.4 Hz), 6.36 (1H, d, J¼2.4 Hz), 7.17–7.22 (3H, m), 7.27–7.31 (2H,
m),11.84 (1H, s); 13C NMR (100 MHz, CDCl3)
d 14.3 (CH3), 38.0 (CH2),
38.4 (CH2), 61.4 (CH2), 68.6 (CH2), 100.0 (CH), 104.9 (Cq), 111.3 (CH),
118.1 (CH2), 125.9 (CH), 128.2 (CH), 128.3 (CH), 132.4 (CH), 141.8
(Cq), 146.7 (Cq), 162.8 (Cq), 165.5 (Cq), 171.4 (Cq); HRMS (ESI) m/z
calcd for C20H22O4Na [MþNa]þ 349.1426, found 349.1423.
4.6. 3-Allyl-2-hydroxy-4-(2-methylallyloxy)-6-phenethyl-
benzoic acid ethyl ester (3)
1033; 1H NMR (400 MHz, CDCl3)
d
1.27 (3H, t, J¼7.2 Hz), 2.03–2.07
(2H, m), 2.66 (2H, s), 2.70–2.75 (2H, m), 2.88 (0.33H, s), 3.35 (2H, s),
3.55 (0.33H, s), 3.83 (0.33H, s), 4.02 (4H, s), 4.19 (2H, q, J¼7.2 Hz),
5.72 (1H, s), 7.16–7.20 (3H, m), 7.26–7.29 (2H, m); 13C NMR
To a stirred suspension of allyl resorcinol 8 (40.0 mg, 0.12 mmol)
and K2CO3 (25.4 mg, 0.18 mmol) in acetone (1 mL) was added b-
methallyl bromide (0.015 mL, 0.15 mmol) at rt. After stirring was
continued for 4 h under reflux condition, the reaction mixture was
filtrated through Celite. The residue upon evaporation of the sol-
vent was chromatographed on silica gel with hexane–AcOEt (97:3
v/v) as eluent to give diene 3 (40.2 mg, 86%) as a colorless oil; IR
(neat) cmꢁ1 2978, 2925, 1649, 1281; 1H NMR (400 MHz, CDCl3)
(100 MHz, CDCl3)
d 14.0 (CH3), 29.6 (CH2), 39.8 (CH2), 45.3 (CH2),
45.8 (CH2), 61.4 (CH2), 65.2 (CH2), 102.0 (CH2), 109.5 (Cq), 125.8
(CH), 128.3 (CH), 128.3 (CH), 141.6 (Cq), 167.3 (Cq), 187.6 (Cq), 187.9
(Cq); HRMS (ESI) m/z calcd for C19H24O6Na [MþNa]þ 371.1471,
found 371.1481.
d
1.39 (3H, t, J¼7.2 Hz), 1.80 (3H, s), 2.88 (2H, t, J¼7.6 Hz), 3.22 (2H, t,
4.4. 2,4-Dihydroxy-6-phenethyl-benzoic acid ethyl ester (5)
J¼7.6 Hz), 3.44 (2H, d, J¼6.4 Hz), 4.34 (2H, s), 4.43 (2H, q, J¼7.2 Hz),
4.94–5.06 (4H, m), 6.00 (1H, ddt, J¼17.2, 10.0, and 6.4 Hz), 6.13 (1H,
s), 7.15–7.21 (3H, m), 7.27–7.30 (2H, m), 11.87 (1H, s); 13C NMR
To a stirred solution of diketoester 6 (1.0 g, 2.87 mmol) in acetic
acid (70 mL) was added NaClO4 (1.76 g, 14.4 mmol) at rt. After
(100 MHz, CDCl3) d 14.3 (CH3), 19.4 (CH3), 27.1 (CH2), 38.1 (CH2),

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M. Yoshida et al. / Tetrahedron 65 (2009) 5702–5708
38.7 (CH2), 61.4 (CH2), 71.5 (CH2), 105.3 (Cq), 107.0 (CH), 112.5 (CH2),
113.6 (Cq), 114.2 (CH2), 125.9 (CH), 128.3 (CH), 128.4 (CH), 136.3
(CH), 140.5 (Cq), 141.8 (Cq), 144.2 (Cq), 160.3 (Cq), 162.1 (Cq), 171.6
(Cq); HRMS (ESI) m/z calcd for C24H28O4Na [MþNa]þ 403.1885,
found 403.1882.
and 6.0 Hz), 6.37 (1H, s), 7.15–7.21 (3H, m), 7.26–7.30 (2H, m), 11.87
(1H, s); 13C NMR (100 MHz, CDCl3)
14.3 (CH3), 27.1 (CH2), 38.1
d
(CH2), 38.6 (CH2), 56.2 (CH3), 61.4 (CH2), 93.7 (CH2), 106.0 (Cq),
108.6 (CH), 114.2 (Cq), 114.2 (CH2), 125.9 (CH), 128.3 (CH), 128.3
(CH), 136.2 (CH), 141.7 (Cq), 144.2 (Cq), 158.9 (Cq), 162.2 (Cq), 171.6
(Cq); HRMS (ESI) m/z calcd for C22H26O5Na [MþNa]þ 393.1678,
found 393.1675.
4.7. 6-Hydroxy-3-methyl-8-phenethyl-2,5-dihydro-
benzo[b]oxepine-7-carboxylic acid (radulanin H) (1)
4.10. 3-Allyl-4-methoxymethoxy-2-(2-methylallyloxy)-6-
phenethyl-benzoic acid ethyl ester (13)
To a stirred solution of diene 3 (9.4 mg, 0.025 mmol) in degassed
CH2Cl2 (2.5 mL) was added second generation Grubbs’ catalyst 10
(4.2 mg, 4.9
mmol) at rt. After stirring was continued for 2 h, the
To a stirred suspension of ether 12 (44.0 mg, 0.12 mmol), NaH
residue upon evaporation of the solvent was quickly chromato-
graphed on silica gel with hexane–AcOEt (95:5 v/v) as eluent to
give radulanin H ethyl ester. To a stirred solution of this radulain H
ethyl ester in THF–water (1:2) (3 mL) was added KOH (12.7 mg,
0.23 mmol) at rt and stirring was continued for 12 h at 50 ꢀC. The
reaction mixture was quenched with aqueous HCl and extracted
with CH2Cl2. The combined extracts were washed with brine and
the residue upon workup was chromatographed on silica gel with
hexane–AcOEt (50:50 v/v) as eluent to give radulanin H (1) (6.7 mg,
91% in two steps) as colorless crystals; mp 125.5–126.4 ꢀC
(recrystallized from AcOEt/hexane); IR (KBr) cmꢁ1 3024, 1635,
(5.7 mg, 0.24 mmol), and
b-methallyl bromide (0.018 mL,
0.18 mmol) in THF (1.5 mL) was added TBAI (87.7 mg, 0.24 mmol) at
0 ꢀC. After stirring was continued for 3 h at rt, the reaction mixture
was quenched with water and extracted with Et2O. The combined
extracts were washed with brine and the residue upon workup was
chromatographed on silica gel with hexane–AcOEt (90:10 v/v) as
eluent to give diene 13 (50.4 mg, 98%) as a colorless oil; IR (neat)
cmꢁ1 2977, 2935, 1721, 1270; 1H NMR (400 MHz, CDCl3)
d 1.35 (3H,
t, J¼7.2 Hz), 1.81 (3H, s), 2.87 (4H, br s), 3.40 (2H, d, J¼6.0 Hz), 3.43
(3H, s), 4.29 (2H, s), 4.35 (2H, q, J¼7.2 Hz), 4.94–5.00 (3H, m), 5.10–
5.14 (3H, m), 5.98 (1H, ddt, J¼17.6, 9.6, and 6.0 Hz), 6.64 (1H, s),
7.16–7.21 (3H, m), 7.26–7.30 (2H, m); 13C NMR (100 MHz, CDCl3)
1254; 1H NMR (400 MHz, CDCl3)
d
1.64 (3H, s), 2.89 (2H, t, J¼7.6 Hz),
3.22 (2H, t, J¼7.6 Hz), 3.52 (2H, d, J¼4.4 Hz), 4.50 (2H, s), 5.72 (1H, t,
d 14.2 (CH3), 19.4 (CH3), 28.1 (CH2), 35.9 (CH2), 37.7 (CH2), 56.1
J¼4.4 Hz), 6.41 (1H, s), 7.18–7.21 (3H, m), 7.27–7.31 (2H, m), 11.70
(CH3), 61.2 (CH2), 78.6 (CH2), 94.2 (CH2), 110.7 (CH), 111.7 (CH2),
114.7 (CH2), 120.6 (Cq), 122.7 (Cq), 125.9 (CH), 128.3 (CH), 128.5
(CH), 136.7 (CH), 139.0 (Cq), 141.3 (Cq), 141.5 (Cq), 155.2 (Cq), 156.8
(Cq), 168.4 (Cq); HRMS (ESI) m/z calcd for C26H32O5Na [MþNa]þ
447.2147, found 447.2154.
(1H, br s); 13C NMR (100 MHz, CDCl3)
d 20.6 (CH3), 21.6 (CH2), 38.1
(CH2), 38.6 (CH2), 72.9 (CH2), 105.6 (Cq), 116.0 (CH), 119.5 (Cq), 122.7
(CH), 126.0 (CH), 128.4 (CH), 128.4 (CH), 134.1 (Cq), 141.8 (Cq), 145.7
(Cq), 162.3 (Cq), 164.2 (Cq), 175.8 (Cq); HRMS (ESI) m/z calcd for
C20H20O4Na [MþNa]þ 347.1259, found 347.1258.
4.11. 3-Allyl-4-hydroxy-2-(2-methylallyloxy)-6-phenethyl-
benzoic acid ethyl ester (4)
4.8. 6-Methoxy-3-methyl-8-phenethyl-2,5-dihydro-
benzo[b]oxepine-7-carboxylic acid methyl ester (radulanin H
methyl ester methyl ether) (11)
To a stirred solution of ether 13 (29.8 mg, 0.070 mmol) in MeOH
(1 mL) was added aqueous HCl at rt. After stirring was continued for
1.5 h under reflux condition, the reaction mixture was diluted with
water and extracted with AcOEt. The combined extracts were
washed with saturated aqueous NaHCO3 solution and brine. The
residue upon workup was chromatographed on silica gel with
hexane–AcOEt (80:20 v/v) as eluent to give phenol 4 (26.0 mg, 97%)
as colorless crystals; mp 57.1–58.0 ꢀC (recrystallized from AcOEt/
hexane); IR (KBr) cmꢁ1 3313, 2978, 2941, 1678; 1H NMR (400 MHz,
To a stirred suspension of radulanin H (1) (24.6 mg, 0.076 mmol)
and K2CO3 (31.4 mg, 0.23 mmol) in acetone (10 mL) was added MeI
(0.24 mL, 3.80 mmol) at rt. After stirring was continued for 18 h
under reflux condition, the reaction mixture was filtrated through
Celite. The residue upon evaporation of the solvent was chroma-
tographed on silica gel with hexane–AcOEt (85:15 v/v) as eluent to
give methyl ester 11 (27.5 mg, quant) as a colorless oil; IR (neat)
cmꢁ1 2942, 1730, 1302, 1268; 1H NMR (400 MHz, CDCl3)
d
1.54 (3H,
CDCl3)
d
1.35 (3H, t, J¼7.2 Hz), 1.81 (3H, s), 2.81–2.90 (4H, m), 3.45
s), 2.79–2.90 (4H, m), 3.40–3.42 (2H, m), 3.74 (3H, s), 3.91 (3H, s),
4.40 (2H, s), 5.59–5.63 (1H, m), 6.70 (1H, s), 7.16–7.21 (3H, m), 7.26–
(2H, d, J¼5.6 Hz), 4.26 (2H, s), 4.35 (2H, q, J¼7.2 Hz), 4.94 (1H, s),
5.10 (1H, s), 5.14–5.18 (2H, m), 5.23 (1H, s), 6.02 (1H, ddt, J¼16.4,
10.8, and 5.6 Hz), 6.49 (1H, s), 7.17–7.21 (3H, m), 7.28–7.30 (2H, m);
7.30 (2H, m); 13C NMR (100 MHz, CDCl3)
d 20.0 (CH3), 22.3 (CH2),
35.6 (CH2), 37.6 (CH2), 52.2 (CH3), 62.9 (CH3), 74.2 (CH2), 118.1 (CH),
120.2 (CH), 124.4 (Cq), 126.1 (CH), 127.9 (Cq), 128.4 (CH), 134.3 (Cq),
139.0 (Cq), 141.5 (Cq), 154.5 (Cq), 160.4 (Cq), 168.7 (Cq); HRMS (ESI)
m/z calcd for C22H24O4Na [MþNa]þ 375.1572, found 375.1571.
13C NMR (100 MHz, CDCl3)
d 14.2 (CH3), 19.4 (CH3), 28.1 (CH2), 35.5
(CH2), 37.5 (CH2), 61.3 (CH2), 78.8 (CH2), 112.0 (CH2), 112.8 (CH),
116.4 (CH2), 116.8 (Cq), 121.7 (Cq), 126.0 (CH), 128.3 (CH), 128.4 (CH),
136.0 (CH), 139.7 (Cq), 141.1 (Cq), 141.5 (Cq), 155.5 (Cq), 156.4 (Cq),
168.5 (Cq); HRMS (ESI) m/z calcd for C24H28O4Na [MþNa]þ
403.1885, found 403.1884.
4.9. 3-Allyl-2-hydroxy-4-methoxymethoxy-6-phenethyl-
benzoic acid ethyl ester (12)
4.12. 6-Hydroxy-3-methyl-8-phenethyl-2,5-dihydro-
To a stirred solution of allyl resorcinol 8 (0.37 g, 1.14 mmol) and
iPr2NEt (0.40 mL, 2.27 mmol) in CH2Cl2 (12 mL) was added MOMCl
(0.13 mL,1.70 mmol) at rt. After stirring was continued for 8 h at the
same temperature, the reaction mixture was diluted with water
and extracted with AcOEt. The combined extracts were washed
with brine and the residue upon workup was chromatographed on
silica gel with hexane–AcOEt (90:10 v/v) as eluent to give ether 12
(0.34 g, 81%) as a colorless oil; IR (neat) cmꢁ1 2979, 1650, 1274; 1H
benzo[b]oxepine-9-carboxylic acid ethyl ester (14)
To a stirred solution of phenol 4 (19.1 mg, 0.050 mmol) in
degassed CH2Cl2 (3 mL) was added second generation Grubbs’
catalyst 10 (8.5 mg, 0.010 mmol) at rt. After stirring was continued
for 3 h, the residue upon evaporation of the solvent was chroma-
tographed on silica gel with hexane–AcOEt (90:10 v/v) as eluent to
give radulanin E ethyl ester (14) (14.9 mg, 84%) as a colorless oil; IR
(neat) cmꢁ1 3378, 2978, 2929, 1696, 1609; 1H NMR (400 MHz,
NMR (400 MHz, CDCl3)
d
1.38 (3H, t, J¼7.2 Hz), 2.88 (2H, t, J¼7.2 Hz),
3.22 (2H, t, J¼7.2 Hz), 3.43 (2H, d, J¼6.0 Hz), 3.43 (3H, s), 4.44 (2H, q,
J¼7.2 Hz), 4.94–5.02 (2H, m), 5.12 (2H, s), 5.97 (1H, ddt, J¼17.2, 10.0,
CDCl3)
d
1.38 (3H, t, J¼7.2 Hz), 1.53 (3H, d, J¼0.8 Hz), 2.82–2.87 (4H,
m), 3.38 (2H, d, J¼4.0 Hz), 4.39 (2H, q, J¼7.2 Hz), 4.47 (2H, s), 5.16

M. Yoshida et al. / Tetrahedron 65 (2009) 5702–5708
5707
(1H, s), 5.56–5.59 (1H, m), 6.34 (1H, s), 7.15–7.21 (3H, m), 7.28–7.29
(2H, m); 13C NMR (100 MHz, CDCl3)
14.4 (CH3), 19.9 (CH3), 21.5
as colorless crystals; mp: 169.7–170.3 ꢀC (recrystallized from
AcOEt/hexane); IR (KBr) cmꢁ1 3147, 2924, 1658, 1577, 1309; 1H NMR
d
(CH2), 35.4 (CH2), 37.6 (CH2), 61.1 (CH2), 74.2 (CH2), 112.3 (CH), 119.8
(CH), 120.4 (Cq), 121.9 (Cq), 126.0 (CH), 128.4 (CH), 134.1 (Cq), 138.9
(Cq), 141.5 (Cq), 153.2 (Cq), 156.9 (Cq), 168.2 (Cq); HRMS (ESI) m/z
calcd for C22H24O4Na [MþNa]þ 375.1572, found 375.1572.
(400 MHz, CDCl3)
d
1.57 (3H, d, J¼1.2 Hz), 2.82 (2H, t, J¼7.6 Hz), 3.20
(2H, t, J¼7.6 Hz), 3.43 (2H, d, J¼4.0 Hz), 4.53 (2H, d, J¼1.2 Hz), 5.62–
5.66 (1H, m), 5.87 (1H, s), 6.36 (1H, s), 7.15–7.20 (2H, m), 7.24–7.29
(3H, m), 10.46 (1H, s); 13C NMR (100 MHz, CDCl3)
d 19.8 (CH3), 21.2
(CH2), 36.3 (CH2), 37.3 (CH2), 74.7 (CH2),114.4 (CH),120.0 (Cq),120.4
(CH), 122.0 (Cq), 125.9 (CH), 128.3 (CH), 128.6 (CH), 133.6 (Cq), 141.9
(Cq), 144.9 (Cq), 157.3 (Cq), 165.5 (Cq), 191.1 (Cq); HRMS (ESI) m/z
calcd for C20H20O3Na [MþNa]þ 331.1310, found 331.1313.
4.13. 3-Allyl-4-methoxymethoxy-2-(2-methylallyloxy)-6-
phenethyl-benzaldehyde (15)
To a stirred suspension of LAH (0.11 g, 3.0 mmol) in THF (3 mL)
was added dropwise diene 13 (25.5 mg, 0.060 mmol) in THF
(0.5 mL) at rt. After stirring was continued for 1 h under reflux
condition, and the reaction mixture was quenched with water and
extracted with AcOEt. The combined extracts were washed with
brine and the residue upon workup was used in the next step
without purification. Thus, to a stirred solution of this crude in
acetone (1 mL) was added Jones reagent (prepared from 2.7 g of
CrO3 and 2.3 mL of concentrated H2SO4 in 7.7 mL of water) at rt and
stirring was continued for 1 min. The reaction mixture was filtrated
through Celite and the residue upon evaporation of the solvent was
chromatographed on silica gel with hexane–AcOEt (80:20 v/v) as
eluent to give aldehyde 15 (22.9 mg, 84% in two steps) as a colorless
oil; IR (neat) cmꢁ1 2922, 2861, 1681, 1595, 1562, 1060; 1H NMR
4.16. X-ray crystallographic analysis of compound 1611
A colorless block crystal having approximate dimensions of
0.70ꢂ0.50ꢂ0.30 mm was mounted on a glass fiber. All measure-
ments were made on a Rigaku RAXIS RAPID imaging plate area
detector with graphite monochromated Mo Ka radiation. The
structure was solved by direct methods (SIR97) and expanded using
Fourier techniques (DIRDIF99). The non-hydrogen atoms were re-
fined anisotropically. Hydrogen atoms were refined using the riding
model. The final cycle of full-matrix least-squares refinement on F
was based on 31,136 observed reflections (I>0.00s(I)) and 912
variable parameters and converged (largest parameter shift was
8.20 times its esd) with unweighted and weighted agreement fac-
tors of R¼0.064 and Rw¼0.199. Crystal data for 16: C20H20O3,
M¼308.38, monoclinic, space group P21, a¼7.2514(3) Å,
b¼15.3163(8) Å, c¼29.364(1) Å, b¼90.0000ꢀ, V¼3261.3(3) Å3, Z¼8,
(400 MHz, CDCl3)
d
1.87 (3H, s), 2.85 (2H, t, J¼7.6 Hz), 3.25 (2H, t,
J¼7.6 Hz), 3.42–3.43 (2H, m), 3.44 (3H, s), 4.29 (2H, s), 4.96–5.02
(3H, m), 5.15 (2H, s), 5.18 (1H, s), 5.98 (1H, ddt, J¼16.4, 10.4, and
7.6 Hz), 6.62 (1H, s), 7.16–7.20 (2H, m), 7.24–7.30 (3H, m), 10.41 (1H,
Dc¼1.256 g/cm3, F(000)¼1312.00,
m(Mo K
a
)¼0.83 cmꢁ3
.
s); 13C NMR (100 MHz, CDCl3)
d 19.5 (CH3), 27.7 (CH2), 36.7 (CH2),
37.4 (CH2), 56.3 (CH3), 80.5 (CH2), 93.9 (CH2), 112.4 (CH), 112.8
(CH2), 114.8 (CH2), 120.6 (Cq), 121.7 (Cq), 125.7 (CH), 128.2 (CH),
128.7 (CH), 136.3 (CH), 140.4 (Cq), 141.9 (Cq), 145.4 (Cq), 160.0 (Cq),
163.4 (Cq), 191.2 (Cq); HRMS (ESI) m/z calcd for C24H28O4Na
[MþNa]þ 403.1885, found 403.1885.
4.17. 6-Hydroxy-3-methyl-8-phenethyl-2,5-dihydro-
benzo[b]oxepine-9-carboxylic acid (proposed structure of
radulanin E) (2)
To a stirred solution of 16 (29.8 mg, 0.10 mmol), NaH2PO4
(92.8 mg, 0.77 mmol), and 2-methyl-2-butene (0.56 mL, 5.3 mmol)
in THF–tBuOH–water (1:3:5) (5 mL) was added NaClO2 (61.2 mg,
0.68 mmol) at rt and stirring was continued for 15 h. The reaction
mixture was quenched with aqueous HCl and extracted with CH2Cl2.
The combined extracts were washed with brine and the residue
upon workup was chromatographed on silica gel with hexane–
AcOEt (50:50 v/v) as eluent to give the proposed structure of radu-
lanin E (2) (23.2 mg, 74%) as colorless crystals; mp 150.6–151.2 ꢀC
(recrystallized from AcOEt/hexane); IR (CHCl3) cmꢁ1 3170, 1716,
4.14. 3-Allyl-4-hydroxy-2-(2-methylallyloxy)-6-phenethyl-
benzaldehyde
To a stirred solution of aldehyde 15 (22.9 mg, 0.060 mmol) in
MeOH (1 mL) was added aqueous HCl at rt. After stirring was
continued for 2 h at under reflux condition, the reaction mixture
was diluted with water and extracted with AcOEt. The combined
extracts were washed with saturated aqueous NaHCO3 solution and
brine. The residue upon workup was chromatographed on silica gel
with hexane–AcOEt (80:20 v/v) as eluent to give phenol (16.9 g,
83%) as colorless crystals; mp: 112.8–113.0 ꢀC (recrystallized from
AcOEt/hexane); IR (KBr) cmꢁ1 3070, 2924,1657,1593,1427; 1H NMR
1603, 1583, 1504, 874, 744; 1H NMR (400 MHz, CDCl3)
d 1.56 (3H, s),
2.89 (2H, t, J¼7.2 Hz), 3.16 (2H, t, J¼7.2 Hz), 3.43 (2H, d, J¼4.0 Hz),
4.60 (2H, s), 5.50 (1H, br s), 5.62–5.65 (1H,m), 6.45 (1H, s), 7.16–7.29
(5H, m),10.73 (1H, br s); 13C NMR (100 MHz, CDCl3)
d 19.7 (CH3), 21.4
(400 MHz, CDCl3)
d
1.87 (3H, s), 2.83 (2H, t, J¼7.6 Hz), 3.22 (2H, t,
(CH2), 37.0 (CH2), 37.7 (CH2), 74.8 (CH2), 114.7 (CH), 115.0 (Cq), 120.3
(CH), 121.9 (Cq), 125.9 (CH), 128.3 (CH), 128.6 (CH), 132.9 (Cq), 141.8
(Cq), 144.1 (Cq), 154.7 (Cq), 158.8 (Cq), 167.5 (Cq); HRMS (ESI) m/z
calcd for C20H20O4Na [MþNa]þ 347.1259, found 347.1256.
J¼7.6 Hz), 3.48 (2H, d, J¼5.6 Hz), 4.27 (2H, s), 5.02 (1H, s), 5.13–5.18
(3H, m), 5.92 (1H, br s), 6.03 (1H, ddt, J¼17.2, 10.4, and 7.6 Hz), 6.48
(1H, s), 7.16–7.20 (2H, m), 7.25–7.30 (3H, m), 10.37 (1H, s); 13C NMR
(100 MHz, CDCl3)
d 19.5 (CH3), 27.7 (CH2), 36.4 (CH2), 37.3 (CH2),
80.6 (CH2),113.0 (CH2),114.8 (CH),116.0 (CH2),117.6 (Cq),120.6 (Cq),
125.8 (CH), 128.2 (CH), 128.5 (CH), 135.8 (CH), 140.3 (Cq), 141.8 (Cq),
146.1 (Cq), 160.8 (Cq), 164.5 (Cq), 191.8 (Cq); HRMS (ESI) m/z calcd
for C22H24O3Na [MþNa]þ 359.1623, found 359.1620.
4.18. 6-Methoxy-3-methyl-8-phenethyl-2,5-dihydro-
benzo[b]oxepine-9-carboxylic acid methyl ester (17)
To a stirred suspension of (2) (12.8 mg, 0.039 mmol) and K2CO3
(16.4 mg, 0.12 mmol) in acetone (4 mL) was added MeI (0.12 mL,
1.97 mmol) at rt. After stirring was continued for 1 h under reflux
condition, the reaction mixture was filtrated through Celite. The
residue upon evaporation of the solvent was chromatographed on
silica gel with hexane–AcOEt (90:10 v/v) as eluent to give methyl
ester 17 (10.2 g, 73%) as a colorless oil; IR (neat) cmꢁ1 2947, 1731,
4.15. 6-Hydroxy-3-methyl-8-phenethyl-2,5-dihydro-
benzo[b]oxepine-9-carbaldehyde (16)
To a stirred solution of phenol (18.8 mg, 0.056 mmol) in
degassed CH2Cl2 (3 mL) was added second generation Grubbs’
catalyst 10 (9.5 mg, 0.011 mmol) at rt. After stirring was continued
for 2 h at the same temperature, the reaction mixture was evapo-
rated and residual oil was directly chromatographed on silica gel
with hexane–AcOEt (90:10 v/v) as eluent to give 16 (14.6 mg, 85%)
1604, 1577, 1452; 1H NMR (400 MHz, CDCl3)
d 1.53 (3H, s), 2.89 (4H,
s), 3.40 (2H, d, J¼4.0 Hz), 3.73 (3H, s), 3.91 (3H, s), 4.47 (2H, s), 5.56–
5.58 (1H, m), 6.37 (1H, s), 7.17–7.21 (3H, m), 7.27–7.30 (2H, m); 13C
NMR (100 MHz, CDCl3)
d 19.9 (CH3), 21.1 (CH2), 36.2 (CH2), 37.9

5708
M. Yoshida et al. / Tetrahedron 65 (2009) 5702–5708
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(CH2), 52.0 (CH3), 55.7 (CH3), 74.1 (CH2), 107.8 (CH), 120.0 (CH),
120.1 (Cq), 123.6 (Cq), 126.0 (CH), 128.4 (CH), 128.5 (CH), 134.1 (Cq),
138.9 (Cq), 141.6 (Cq), 156.4 (Cq), 156.8 (Cq), 168.5 (Cq); HRMS (ESI)
m/z calcd for C22H24O4Na [MþNa]þ 375.1572, found 375.1572.
Acknowledgements
We thank Prof. Asakawa and Prof. Hashimoto for providing 1H
NMR spectra of radulanin H methyl ester and helpful suggestion
about the structure of radulanin E. We are also indebted to Prof.
Yamaguchi for providing 1H NMR spectra of 16. This study was
supported in part by a Grant-in-Aid for the Encouragement of
Young Scientists (B) from the Japan Society for the Promotion of
Science (JSPS) and the Program for Promotion of Basic and Applied
Researches for Innovations in Bio-oriented Industry (BRAIN).
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6. Yamaguchi, S. Heterocycles 2009, 79, 243.
7. Yamaguchi, S.; Tsuchida, N.; Miyazawa, M.; Hirai, Y. J. Org. Chem. 2005, 70, 7505.
8. Yamaguchi, M.; Shibato, K.; Nakashima, H.; Minami, T. Tetrahedron 1988, 44,
4767.
Supplementary data
9. Fu¨rstner, A.; Gastner, T. Org. Lett. 2000, 2, 2467.
1H and 13C spectra for all compounds can be found in the Sup-
plementary data. Supplementary data associated with this article
can be found in the online version, at doi:10.1016/j.tet.2009.05.027.
10. Nguyen, V. T. H.; Bellur, E.; Langer, P. Tetrahedron Lett. 2006, 47, 113.
11. Crystallographic data (excluding structure factors) for the structures in this
paper have been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication number CCDC 724435. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB2
1EZ, UK [fax: þ44(0) 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
12. We checked the Yamaguchi’s NMR chart of 16, which was provided by Prof.
Yamaguchi, and it was found that his sample contained many impurities. It is
assumed that the Yamaguchi’s data have been misassigned because of the
impurity peaks.
References and notes
1. Asakawa, Y.; Takikawa, K.; Toyota, M.; Takemoto, T. Phytochemistry 1982, 21,
2481.
2. Asakawa, Y.; Kusube, E.; Takemoto, T.; Suire, C. Phytochemistry 1978, 17, 2005.
3. (a) Dean, F. M.; Taylor, D. A. H. J. Chem. Soc. C 1966, 114; (b) MacCabe, P. H.;
McCrindle, R.; Murray, D. H. J. Chem. Soc. C 1967, 145; (c) Dean, F. M.; Parton, B.;
13. A NMR chart of 17, which was prepared by Asakawa could not be obtained
because the data were measured more than 30 years ago.