First synthesis and absolute configuration of a β-farnesene-trimethoxystyrene conjugate isolated from Pachypodanthium confine

Full text of DOI:10.1016/j.tet.2009.09.039

Tetrahedron 65 (2009) 9142–9145
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First synthesis and absolute configuration of a
b-farnesene-trimethoxystyrene
conjugate isolated from Pachypodanthium confine
,
Masatsugu Koso a, Takuya Tashiro b, Mitsuru Sasaki a, Hirosato Takikawa a
*
a Department of Agrobioscience, Graduate School of Agricultural Science, Kobe University, Rokkodai 1-1, Nada-ku, Kobe 657-8501, Japan
b Glycosphingolipid Synthesis Group, Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, Hirosawa 2-1, Wako, Saitama 351-0198, Japan
a r t i c l e i n f o
a b s t r a c t
(E)-1-[30-(400,800-Dimethylnona-300,700-dienyl)cyclohex-30-enyl]-2,4,5-trimethoxybenzene (1), a
b-farnesene-
trimethoxystyrene conjugate, was isolated from Pachypodanthium confine. Its first synthesis was accom-
plished, and absolute configuration was determined to be R.
Article history:
Received 26 August 2009
Received in revised form 9 September 2009
Accepted 9 September 2009
Available online 15 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Absolute configuration
Optical resolution
Pachypodanthium confine
1. Introduction
MeO
MeO
2
OMe
1'
4
5
1
4"
8"
3'
In 2007, Mathouet and his co-workers isolated a b-farnesene-
trimethoxystyrene conjugate, (E)-1-[30-(400,800-dimethylnona-
300,700-dienyl)cyclohex-30-enyl]-2,4,5-trimethoxybenzene (1), and
its (Z)-isomer from the bark of Pachypodanthium confine.1 The
structure of 1 is quite unique, because its basic framework has
never been reported in natural products so far, and it appears to
1
Diels-Alder reaction (?)
MeO
MeO
OMe
be synthesized by Diels–Alder reaction between b-farnesene and
+
2,4,5-trimethoxystyrene. To our knowledge, the most structurally
similar natural products may be fissistin2 and its derivatives3
isolated from the Annonaceae and Zingiberaceae families. We can
β-farnesene
trimethoxystyrene
regard these natural products as b-myrcene-chalcone conjugates,
and all these compounds exist as racemic form in nature.
Interestingly, 1, in contrast, is optically active, however, the ab-
solute configuration of 1 has not yet been clarified. Although the
biological activity of 1 has not been studied, fissistin and its
derivatives show various biological and/or physiological activi-
ties. Therefore, 1 may exhibit some biological activities. We were
interested in the unique structure and the expected functional
profile of 1 and undertook a project to synthesize optically active
1. We herein report the first synthesis and absolute configuration
of 1 (Fig. 1).
O
HO
OMe
MeO
OH
Fissistin
OMe
Figure 1. Structures of 1 and related compounds.
2. Results and discussion
Scheme 1 shows our synthetic plan for 1. The crucial point in our
synthesis was the preparation of the optically active form. The
planned route needed to include an asymmetric reaction or an
* Corresponding author. Tel./fax: þ81 78 803 5958.
E-mail address: takikawa@kobe-u.ac.jp (H. Takikawa).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.039

M. Koso et al. / Tetrahedron 65 (2009) 9142–9145
9143
MeO
MeO
OMe
reduction of B. For the synthesis of B, we assigned C and D as ap-
propriate precursors. The enone C was obtainable according to the
reported procedure.5
resolution
1
Scheme 2 shows our synthetic route to both enantiomers of 1.
First, we prepared the dione 3 (quant.) from the known enone 26
according to the reported procedure.5 The dione 3 was converted
into the corresponding enol ether 4 (¼C) by treatment with H2SO4
in MeOH (58% based on 2). A reaction between 4 and homoge-
ranylmagnesium bromide (¼D) afforded the desired adduct 5 (¼B;
59%). As mentioned above, we needed to carry out an optical res-
olution. For the conventional optical resolution, 5 was reduced
under Luche conditions to give cis-allylic alcohol (ꢀ)-6 (¼A) as the
sole diastereomer (91%). We confirmed the cis-relative configura-
tion by observing NOE between 1-H and 5-H. It should be men-
tioned that reduction of 5 with L-SelectrideÒ gave a ca. 1:3 mixture
of (ꢀ)-6 and its trans-isomer. In this case, equatorial attack of hy-
dride was favored, while axial attack was predominant under Luche
conditions. With the key intermediate (ꢀ)-6 in hand, we attempted
the classical resolution using a chiral derivatizing reagent. How-
ever, after discovering that MTPA ester was not suitable for the
optical resolution, we found that Harada’s reagent7 [7, 2-methoxy-
2-(naphthalen-1-yl)propionic acid] achieved successful results as
follows. Condensation of (ꢀ)-6 and (S)-7 was performed with DCC
in the presence of DMAP to give a diastereomeric mixture of 8a and
8b. Flash column chromatography did not easily separate these two
diastereomers, but we did manage to obtain the less polar di-
astereomer 8a (28%) and the more polar 8b (23%). Application of
a modified Mosher’s method8 enabled us to determine the absolute
configurations of 8a and 8b. Figure 2 shows the crucial observed
Dd8a–8b values.
reductive
deoxygenation
OR
A
R = H or derivatizing residue
MeO
MeO
OMe
B
O
MeO
MeO
OMe
XMg
OMe
D
C
O
Scheme 1. Synthetic plan for 1.
optical resolution at the appropriate stage, because it did not begin
with an optically active starting material. For this purpose, we
envisioned adopting the classical optical resolution of A by a di-
astereomer method based on our previous successful experience.4
Another crucial step was the reductive deoxygenation of A to 1. The
intermediate A should be prepared by the diastereoselective
MeO
MeO
OMe
MeO
MeO
OMe
MeO
MeO
OMe
O
c
d
a, b
O
OMe
3
O
e
2
4
O
MeO
MeO
OMe
MeO
MeO
OMe
5
1
O
OH
( )-6
5
OMe
HO2C
f
(S)-7
MeO
OMe
MeO
MeO
OMe
O
5
MeO
6"
1
2
6
OMe
OMe
O
O
O
8a (1st fr.)
8b (2nd fr.)
g
g
MeO
MeO
OMe
1' 3'
MeO
MeO
OMe
(R)-1
(S)-1
Scheme 2. Synthesis of (ꢀ)-1. Reagents and conditions: (a) dimethyl malonate, NaOMe, MeOH, reflux; (b) aq NaOH, reflux; aq HCl, reflux (quant.); (c) conc. H2SO4, MeOH, reflux
(58% based on 2); (d) homogeranylmagnesium bromide, THF, reflux (59%); (e) NaBH4, CeCl3$7H2O, MeOH (91%); (f) 7, DCC, DMAP,CH2Cl2 (28% for 8a, 23% for 8b) (g) Li, t-BuOH, NH3,
THF, [60% for (S)-1, 40% for (R)-1].

9144
M. Koso et al. / Tetrahedron 65 (2009) 9142–9145
MeO
MeO
OMe
6"
reaction mixture was concentrated under reduced pressure. The
residue was acidified with 3 M HCl, and extracted with CHCl3. The
organic layer was washed with brine, dried with MgSO4, and con-
centrated under reduced pressure to give the residue (14 g). To this
residue, was added a solution of NaOH (7.5 g, 0.19 mol) in water
(140 mL). After stirring under reflux for 1 h, the reaction mixture
was extracted with Et2O. The aqueous layer was acidified with 3 M
HCl, heated under reflux for 1 h, and extracted with CHCl3. The
organic layer was washed with brine, dried with MgSO4, and con-
centrated under reduced pressure to give 3 (13 g, quant.) as orange
MeO
R
2
6
5
O
O
R
OMe
OMe
MeO
O
O
OMe
8b
8a
R = homogeranyl
Observed Δδ [= δ(8a)-δ(8b)] values in ppm
2-H: +0.27
5-H: -0.04
6-Hax: -0.28
6"-H: -0.15
shielding effect
semi-solid: IR (Nujol) 1630 (m, C]O) cmꢁ1 1H NMR
; d 2.56 (dd,
J¼17.1, 4.5 Hz,1.4H), 2.72 (dd, J¼17.1,11.7 Hz,1.4H), 2.84 (d, J¼7.5 Hz,
1.2H), 3.45 (s, 0.6H), 3.45–3.82 (m, 1H), 3.74 (s, 0.9H), 3.78 (s, 2.1H),
3.80 (s, 3H), 3.86 (s, 3H), 5.61 (s, 0.7H), 6.50 (s, 0.3H), 6.51 (s, 0.7H),
Figure 2. Absolute configurations of 8a and 8b.
6.63 (s, 0.3H), 6.72 (s, 0.7H), 9.82 (br s, 0.7H); 13C NMR
d 31.9, 33.7,
The remaining subject was reductive deoxygenation. For this
purpose, we preliminarily examined Barton–McCombie de-
38.1, 45.5, 55.3, 56.0, 56.1, 56.8, 57.4, 97.6, 97.7, 103.8, 112.0, 112.1,
120.6, 121.7, 142.8, 142.9, 148.5, 148.9, 151.1, 151.5, 192.4, 203.7.
Compound 3 was a mixture of keto and enol forms (ca. 3:7). Thus,
signals due to the minor keto form might not be fully detected.
HRMS (EI) m/z calcd for C15H18O5: 278.1154, found 278.1153.
oxygenation,9 hydrogenolysis via a
p
-allylpalladium complex,10
Zn–AcOH reduction,10 and Birch reduction.10 Our studies sug-
gested that Birch reduction was the best suitable candidate.
Therefore, we subjected the pure 8a to a Birch reduction to furnish
25
20
(S)-1 (60%),11
[
a
]
ꢁ30 (c 0.18 in EtOH), {lit.1
[
a
]
þ5 (c 0.6 in
D
D
4.3. 3-Methoxy-5-(2,4,5-trimethoxyphenyl)cyclohex-
2-en-1-one (4)
EtOH)}. The various spectral data of synthetic (S)-1 are in good
accord with those of the natural product.1 Similarly, the pure 8b
27
was also converted into (R)-1,11
[
a
]
þ30 (c 0.086 in EtOH). Al-
D
A solution of 3 (0.56 g, 2.0 mmol) and H2SO4 (5 drops) in MeOH
(10 mL) was heated under reflux with stirring for 4 h. After removal
of MeOH under reduced pressure, the residue was diluted with
water, neutralized with 10% aq NaOH, and extracted with CHCl3.
The organic layer was washed with brine, dried with MgSO4, and
concentrated under reduced pressure. The residue was purified by
silica gel chromatography to give 4 (7.90 g, 58%) as yellow solid: mp
though there was a considerable difference in the magnitude of
the specific rotation between synthetic and natural 1, we were
able to determine the absolute configuration of the naturally oc-
curring 1 to be R, because synthetic (R)-1 and naturally occurring 1
were both dextrorotatory.
106–108 ꢂC; IR (Nujol) 1650 (m, C]O), 1600 (m, C]C) cmꢁ1
NMR 2.48–2.71 (m, 4H), 3.53–3.67 (m, 1H), 3.68 (s, 3H), 3.77 (s,
3H), 3.79 (s, 3H), 3.84 (s, 3H), 5.39 (s, 1H), 6.50 (s, 1H), 6.68 (s, 1H);
13C NMR
33.3, 37.8, 42.4, 55.6, 55.9, 56.0, 56.7, 97.6, 101.7, 111.6,
;
1H
3. Conclusion
d
In conclusion, we accomplished the first synthesis of both en-
antiomers of (E)-1-[30-(400,800-dimethylnona-300,700-dienyl)cyclohex-
30-enyl]-2,4,5-trimethoxybenzene (1) by employing an optical
resolution using Harada’s reagent as the key step. We were con-
sequently able to determine the absolute configuration of naturally
occurring 1 to be R. Bioassays employing our synthetic samples are
now in preparation.
d
121.9, 142.7, 148.3, 151.3, 178.3, 199.3; HRMS (EI) m/z calcd for
C16H20O5: 292.1311, found 292.1306.
4.4. (30E)-3-(40,80-Dimethylnona-30,70-dienyl)-5-(200,400,500-
trimethoxyphenyl)cyclohex-2-en-1-one (5)
4. Experimental
4.1. General
To a stirred solution of homogeranylmagnesium bromide, pre-
pared from homogeranyl bromide (1.8 g, 7.8 mmol) and Mg (0.19 g,
7.8 mmol) in THF (20 mL), a solution of 4 (2.20 g, 7.53 mmol) in THF
(20 mL) was added at room temperature. After stirring under gentle
reflux for 2 h, the reaction mixture was quenched with satd aq
NH4Cl and extracted with CHCl3. The organic layer was washed
with brine, dried with MgSO4, and concentrated under reduced
pressure. The residue was purified by silica gel chromatography to
give 5 (1.83 g, 59%) as a slightly orange oil: IR (film) 1660 (s, C]O),
Melting points were measured with YANAKO MP-S9 micro-
melting point apparatus. IR spectra were recorded with a Shimadzu
IR-408 spectrophotometer. 1H NMR spectra were recorded at
300 MHz on a JEOL JNM-AL300 spectrometer. The peak for CHCl3 in
CDCl3
are reported in ppm on the
NMR spectra were recorded at 75 MHz on a JEOL JNM-AL300
spectrometer. The peak for CDCl3 ( 77.0) was used for the internal
(
d
7.26) was used for the internal standard. Chemical shifts
1620 (m, C]C) cmꢁ1; 1H NMR
d 1.58 (s, 3H),1.60 (s, 3H),1.66 (s, 3H),
d
scale and J-values are given in Hz. 13
C
1.94–2.10 (m, 4H), 2.17–2.39 (m, 4H), 2.40–2.66 (m, 4H), 3.52–3.64
(m, 1H), 3.79 (s, 3H), 3.82 (s, 3H), 3.87 (s, 3H), 5.02–5.12 (m, 2H),
d
5.94 (s, 1H), 6.53 (s, 1H), 6.71 (s, 1H); 13C NMR
d 16.0, 17.6, 25.4, 25.6,
standard. Optical rotations were taken with a HORIBA SEPA-300
polarimeter. Mass spectra were measured with a JEOL JMS-SX102A.
Flash chromatography was carried out on Kanto Chemical Co., Inc.
Silica Gel 60 N (spherical, neutral, 40–50
tography was carried out on Kanto Chemical Co., Inc. Silica Gel 60 N
26.6, 34.7, 36.2, 38.0, 39.6, 43.0, 56.09, 56.14, 56.8, 97.8, 111.7, 122.5,
122.9, 124.0, 125.3, 131.4, 136.4, 142.9, 148.4, 151.4, 165.8, 200.0;
HRMS (EI) m/z calcd for C26H36O4: 412.2614, found 412.2601.
mm). Column chroma-
4.5. (1S*,5S*,30E)-3-(40,80-Dimethylnona-30,70-dienyl)-5-
(200,400,500-trimethoxyphenyl)cyclohex-2-en-1-ol (6)
(spherical, neutral, 63–210
Merck silica gel plates 60 F254
m
m). TLC analyses were performed on
.
4.2. 5-(2,4,5-Trimethoxyphenyl)cyclohexane-1,3-dione (3)
To a stirred and ice-cooled solution of 5 (0.45 g, 1.1 mmol) in
MeOH (7 mL), CeCl3$7H2O (0.82 g, 2.2 mmol) and NaBH4 (84 mg,
2.2 mmol) were added portionwise. After stirring for 10 min with
warming to room temperature, the reaction mixture was quenched
with satd aq NH4Cl and extracted with CHCl3. The organic layer was
To a solution of Na (4.8 g, 0.21 mol) in MeOH (60 mL), dimethyl
malonate (9.2 g, 70 mmol) and 2 (11.0 g, 46.6 mmol) were added at
room temperature under Ar. After stirring under reflux for 4 h, the

M. Koso et al. / Tetrahedron 65 (2009) 9142–9145
9145
washed with brine, dried with MgSO4, and concentrated under
reduced pressure. The residue was purified by silica gel chroma-
tography to give 6 (0.41 g, 91%) as a pale yellow oil: IR (film) 3350 (s,
125.3, 125.6, 126.2, 128.7, 129.3, 131.3, 134.1, 135.3, 135.4, 142.4,
143.0, 147.8, 151.0, 174.0; HRMS (EI) m/z calcd for C40H50O6:
626.3607, found 626.3612.
O–H) cmꢁ1 1H NMR
; d 1.60 (s, 6H), 1.60–1.68 (m, 2H), 1.67 (s, 3H),
4.7. (10S, 300E)-1-[30-(400,800-Dimethylnona-300,700-dienyl)-
cyclohex-30-enyl]-2,4,5-trimethoxybenzene [(S)-1]
1.93–2.21 (m, 11H), 3.24 (br t-like, J¼10.8, 1H), 3.80 (s, 3H), 3.83 (s,
3H), 3.88 (s, 3H), 4.46 (m, 1H), 5.05–5.16 (m, 2H), 5.47 (s, 1H), 6.53
(s, 1H), 6.73 (s, 1H); 13C NMR
d 16.0, 17.6, 25.6, 26.1, 26.7, 32.0, 35.9,
37.0, 38.7, 39.7, 56.2, 56.4, 56.7, 68.9, 97.9, 111.2, 123.8, 124.3, 124.8,
125.5, 131.3, 135.3, 140.8, 143.1, 147.7, 151.1; HRMS (EI) m/z calcd for
C26H38O4: 414.2770, found 414.2777.
To a solution of Li (20 mg, 2.9 mmol) in liq. NH3 (2 mL), 8a
(24 mg, 38 mmol) and t-BuOH (0.10 g, 1.3 mmol) in dry THF (2 mL)
was added at ꢁ78 ꢂC under Ar. After stirring for 10 min, the reaction
mixture was carefully poured into satd aq NH4Cl and extracted with
CHCl3. The organic layer was washed with brine, dried with MgSO4,
and concentrated under reduced pressure. The residue was purified
4.6. (1R,5R,30E)-3-(40,80-Dimethylnona-30,70-dienyl)-5-
(200,400,500-trimethoxyphenyl)cyclohex-2-enyl (S)-2-
methoxy-2-(naphthalen-1-yl)propionate (8a) and
(1S,5S,30E)-3-(40,80-dimethylnona-30,70-dienyl)-
5-(200,400,500-trimethoxyphenyl)-cyclohex-2-enyl
(S)-2-methoxy-2-(naphthalen-1-yl)-
by silica gel chromatography to give (S)-1 (9.1 mg, 60%) as a color-
25
less oil: [
a
]
ꢁ30 (c 0.18, EtOH); 1H NMR
d 1.60 (s, 6H), 1.62–1.83
D
(m, 2H), 1.68 (s, 3H), 1.94–2.21 (m, 12H), 3.18 (m, 1H), 3.80 (s, 3H),
3.84 (s, 3H), 3.88 (s, 3H), 5.06–5.17 (m, 2H), 5.46 (s, 1H), 6.53 (s, 1H),
6.76 (s, 1H); 13C NMR
d 16.0, 17.7, 25.7, 25.9, 26.4, 26.7, 28.7, 32.8,
propionate (8b)
35.7, 37.8, 39.7, 56.2, 56.6, 56.7, 98.0, 111.4, 120.4, 124.3, 124.4, 127.4,
131.3, 135.0, 137.8, 143.1, 147.4, 151.0; HRMS (FAB) m/z calcd for
C26H38O3: 398.2821, found 398.2829.
To a stirred solution of 6 (200 mg, 0.482 mmol) in dry CH2Cl2
(2 mL), (S)-7 (0.55 g, 2.4 mmol), DCC (0.99 g, 4.8 mmol) and DMAP
(59 mg, 0.48 mmol) were added successively under Ar. After stir-
ring at room temperature for 4 d, the reaction mixture was
quenched with satd aq NH4Cl and filtered through Celite. The fil-
trate was extracted with CHCl3. The organic layer was washed with
brine, dried with MgSO4, and concentrated under reduced pressure.
The residue was purified by silica gel flash chromatography to give
the less polar 8a (86 mg, 28%), the more polar 8b (69 mg, 23%), and
4.8. (10R, 300E)-1-[30-(400,800-Dimethylnona-300,700-dienyl)-
cyclohex-30-enyl]-2,4,5-trimethoxybenzene [(R)-1]
In the same manner as described above, 8b (39 mg, 62 mmol)
27
was converted to (R)-1 (10 mg, 40%): [
a]
þ30 (c 0.086, EtOH);
D
HRMS (FAB) m/z calcd for C26H38O3: 398.2821, found 398.2820.
NMR spectra of (R)-1 were identical to those of (S)-1.
a mixture of 8a and 8b (47 mg, 16%).
25
8a: [
a
]
ꢁ11.9 (c 1.18, CHCl3); IR (film) 1730 (s, C]O) cmꢁ1; 1H
D
NMR
d
1.37 (q-like, J¼11.7 Hz, 1H, 6-Hax), 1.56 (s, 3H, C]C–Me), 1.59
References and notes
(s, 3H, C]C–Me), 1.67 (s, 3H, C]C–Me), 1.81–2.13 (m, 11H), 2.01 (s,
3H, 3-H3), 3.10 (s, 3H, 2-OMe), 3.20 (m, 1H, 5-H), 3.73 (s, 3H, Ar-
OMe), 3.77 (s, 3H, Ar-OMe), 3.86 (s, 3H, Ar-OMe), 5.01–5.13 (m, 2H,
30- and 70-H), 5.27 (s, 1H, 2-H), 5.61 (m, 1H, 10-H), 6.47 (s, 1H, 300-H),
6.48 (s, 1H, 600-H), 7.41–7.45 (m, 3H, Np-H), 7.62 (d, J¼6.6 Hz, 1H,
Np-H), 7.80–7.87 (m, 2H, Np-H), 8.34–8.46 (m, 1H, Np-H); 13C NMR
1. Mathouet, H.; Elomri, A.; Lameiras, P.; Da¨ıch, A.; Ve´rite´, P. Phytochemistry 2007,
68, 1813–1818.
2. Alias, Y.; Awang, K.; Hadi, A. H. A. J. Nat. Prod. 1995, 58, 1160–1166.
3. (a) Shibata, K.; Tatsukawa, A.; Umeoka, K.; Lee, H. S.; Ochi, M. Tetrahedron 2000,
56, 8821–8824; (b) Gu, J.-Q.; Park, E. J.; Vigo, J. S.; Graham, J. G.; Fong, H. H. S.;
Pezzuto, J. M.; Kinghorn, A. D. J. Nat. Prod. 2002, 65, 1616–1620; (c) Morikawa, T.;
Funakoshi, K.; Ninomiya, K.; Yasuda, D.; Miyagawa, K.; Matsuda, H.; Yoshikawa, M.
Chem. Pharm. Bull. 2008, 56, 956–962.
d
16.0, 17.6, 21.8, 25.6, 25.9, 26.7, 31.6, 33.4, 35.7, 37.0, 39.7, 51.0, 56.1,
56.4, 56.7, 72.9, 81.6, 97.8, 111.0, 120.1, 123.6, 124.3, 124.7, 124.9,
125.3, 125.6, 125.7, 126.2, 128.6, 129.3, 131.3, 134.1, 135.3, 135.4,
142.6, 143.0, 147.7, 151.0, 174.0; HRMS (EI) m/z calcd for C40H50O6:
4. (a) Imamura, Y.; Takikawa, H.; Sasaki, M.; Mori, K. Org. Biomol. Chem. 2004, 2,
2236–2244; (b) Takikawa, H.; Tobe, M.; Isono, K.; Sasaki, M. Tetrahedron 2005,
61, 8830–8835.
5. (a) Gudriniece, E.; Kurgan, D. K.; Vanags, G. Zh. Org. Khim. 1957, 27, 3087–3092;
(b) Itoh, Y.; Brossi, A.; Hamel, E.; Lin, C. M. Helv. Chim. Acta 1988, 71, 1199–1209.
6. (a) Sanchez-Viesca, F.; Mainero, R. M. Ciencia (Mexico City) 1966, 25, 61–66; (b)
Hidaka, H.; Ishikawa, T.; Arakawa, E.; Kato, T.; Takamura, T. Jpn. Kokai Tokkyo
Koho 1992, JP 04342579 A 19921130.
626.3607, found 626.3599.
22
8b: [
a
]
D
ꢁ43.2 (c 0.806, CHCl3); IR (film) 1730 (s, C]O) cmꢁ1
;
1H NMR
d
1.53 (s, 3H, C]C–Me), 1.60 (s, 3H, C]C–Me), 1.60–1.73
(m, 1H, 6-Hax), 1.68 (s, 3H, C]C–Me), 1.79–2.13 (m, 11H), 1.98 (s, 3H,
3-H3), 3.12 (s, 3H, 2-OMe), 3.24 (m, 1H, 5-H), 3.77 (s, 3H, Ar-OMe),
3.80 (s, 3H, Ar-OMe), 3.87 (s, 3H, Ar-OMe), 5.00 (br s, 1H, 2-H), 5.08
(m, 2H, 30- and 70-H), 5.60 (m, 1H, 10-H), 6.50 (s, 1H, 300-H), 6.63 (s,
1H, 600-H, 600-H), 7.41–7.51 (m, 3H, Np-H), 7.61 (d, J¼6.6 Hz, 1H, Np-
H), 7.80–7.88 (m, 2H, Np-H), 8.39–8.46 (m, 1H, Np-H); 13C NMR
7. (a) Ichikawa, A.; Hiradate, S.; Sugio, A.; Kuwahara, S.; Watanabe, M.; Harada, N.
Tetrahedron: Asymmetry 1999, 10, 4075–4078; (b) Harada, N.; Watanabe, M.;
Kuwahara, S.; Sugio, A.; Kasai, Y.; Ichikawa, A. Tetrahedron: Asymmetry 2000, 11,
1249–1253.
8. Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J. Am. Chem. Soc. 1991, 113,
4092–4096.
9. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1 1975, 1574–1585.
10. The O-acetylated (ꢀ)-6 was employed as a substrate for these reactions.
d
15.9, 17.7, 21.9, 25.7, 25.8, 26.7, 31.6, 33.8, 35.6, 36.8, 39.6, 51.0,
11. Synthetic
1 contained a small amount of inseparable impurity. The most
probable structure of it was
0
56.2, 56.4, 56.7, 72.9, 81.7, 97.8,111.2,120.0, 123.7,124.3,124.7,125.0,
D
4 -isomer.