Convergent synthesis of the A-E ring segment of ciguatoxin CTX3C

Article abstract of DOI:10.1016/j.tet.2009.07.037

A convergent synthesis of the A-E ring segment of ciguatoxin CTX3C was achieved via the intramolecular allylation of an α-chloroacetoxy ether and subsequent ring-closing metathesis.

Full text of DOI:10.1016/j.tet.2009.07.037

Tetrahedron 65 (2009) 7784–7789
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Convergent synthesis of the A–E ring segment of ciguatoxin CTX3C
,
b
a
a
b
Isao Kadota a , Takashi Abe , Miyuki Uni , Hiroyoshi Takamura , Yoshinori Yamamoto
*
a Department of Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka, Okayama 700-8530, Japan
b Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A convergent synthesis of the A–E ring segment of ciguatoxin CTX3C was achieved via the intramolecular
Received 6 July 2009
Accepted 17 July 2009
Available online 22 July 2009
allylation of an
a
-chloroacetoxy ether and subsequent ring-closing metathesis.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Polycyclic ethers
Ciguatoxin
Intramolecular allylation
Ring-closing metathesis
1. Introduction
followed by ring-closing metathesis.6 The cyclization precursor 3 is
retrosynthetically broken down into two segments, the AB ring 4
and the E ring 5.
Ciguatoxin CTX3C (1),1 one of the causative toxin of ‘ciguatera’
seafood poisoning,2 was isolated from cultured dinoflagellate
Gambierdiscus toxicus (Fig. 1). The potent neurotoxicity and novel
polycyclic ether framework including five- to nine-membered rings
have attracted the attention of synthetic chemists.3 In 2001, the
first total synthesis of 1 was achieved by Hirama and co-workers.4
In this paper, we describe a convergent synthesis of the A–E ring
segment of ciguatoxin CTX3C (1).5
Figure 1. Structure of ciguatoxin CTX3C (1).
2. Results and discussion
Scheme 1.
Scheme 1 outlines our synthetic strategy. The A–E ring segment
2 would be synthesized from 3 via the intramolecular allylation
Synthesis of the carboxylic acid 4 is shown in Scheme 2. Treat-
ment of the known triol 65b with PhCH(OMe)2/p-TsOH gave 7 in 74%
yield. Protection of the remaining secondary alcohol with NAPBr/
NaH followed by deprotection of the benzylidene acetal afforded 8
* Corresponding author. Tel./fax: þ81 86 251 7836.
E-mail address: kadota-i@cc.okayama-u.ac.jp (I. Kadota).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.037

I. Kadota et al. / Tetrahedron 65 (2009) 7784–7789
7785
Scheme 2. Reagents and conditions: (a) PhCH(OMe)2, p-TsOH$H2O, DMF, rt, 74%; (b) (i) NAPBr, NaH, TBAI, THF, 40 ꢀC, (ii) CSA, MeOH, reflux, 95% (two steps); (c) (i) TBSCl, imidazole,
DMF, 70 ꢀC, (ii) CSA, MeOH, 0 ꢀC, 90% (two steps); (d) (i) I2, PPh3, imidazole, benzene/Et2O, 40 ꢀC, (ii) NaCN, DMSO, 70 ꢀC, 94% (two steps); (e) (i) DIBAL-H, CH2Cl2, ꢁ78 ꢀC, (ii) NaClO2,
NaHPO4, 2-methyl-2-butene, t-BuOH/H2O, 0 ꢀC.
in 95% overall yield. Conversion of the diol 8 to the corresponding
bis-TBS ether followed by selective deprotection of the primary TBS
group furnished 9 in 90% overall yield. Treatment of the alcohol 9
with I2/PPh3/imidazole followed by NaCN provided the nitrile 10 in
94% overall yield. Reduction of 10 with DIBAL-H, and subsequent
oxidation of the resulting aldehyde with NaClO2 furnished the
carboxylic acid 4 in quantitative yield.
Preparation of the E ring segment 5 was carried out primarily
based on a Hirama’s procedure (Scheme 3).5b Thus, treatment of 11,
prepared from D-glucose, with NaHMDS followed by 3-butenal gave
12 as an inseparable mixture of diastereoisomers in 95% yield. Ring-
closing metathesis of 12 was carried out using the second
generation Grubbs catalyst 137 to afford a 1:1 mixture of 14 and 15
in 68% yield.8 These stereoisomers were easily separated by
Scheme 3. Reagents and conditions: (a) NaHMDS, THF, ꢁ78 ꢀC, then 3-butenal, 95%; (b) 13, CH2Cl2, 30 ꢀC, 68% (14/15¼1:1); (c) (i) (COCl)2, DMSO, CH2Cl2, ꢁ78 ꢀC, then Et3N, 95%, (ii)
L-Selectride, THF, ꢁ78 ꢀC, 88% (14/15¼2:1); (d) (i) TBSCl, imidazole, DMF, 30 ꢀC, 77%; (ii) DIBAL-H, CH2Cl2, ꢁ78 ꢀC; (iii) Ph3PCHþ3 Brꢁ, NaHMDS, THF, 0 ꢀC to rt; (iv) TBAF, THF, rt, 91%
(three steps).
Scheme 4. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt, then 5, DMAP, toluene, 64% from 10; (b) TBAF, THF, 40 ꢀC, 82%; (c) 18, CSA, CH2Cl2, rt, 87%;
(d) TMSI, HMDS, CH2Cl2, 0 ꢀC, 85%; (e) DIBAL-H, ꢁ78 ꢀC, CH2Cl2, then (CH2ClCO)2O, DMAP, pyridine, ꢁ78 to ꢁ20 ꢀC; (f) BF3$OEt, 4 Å MS, CH3CN/CH2Cl2 (10:1), ꢁ40 ꢀC, 60% (two
steps), 21/22¼4:1); (g) 23, benzene, 70 ꢀC, 74%; (h) CSA, CH2Cl2/MeOH (1:2), 40 ꢀC, 92%.

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I. Kadota et al. / Tetrahedron 65 (2009) 7784–7789
chromatography, and the stereochemistries were confirmed by 1H
NMR analysis and NOE experiments as shown in Scheme 3. The
undesired stereoisomer 15 was subjected to Swern oxidation fol-
lowed by L-Selectride reduction to give a 2:1 mixture of 14 and 15
in 88% overall yield.9 Protection of 14 with TBSCl/imidazole, DIBAL-
H reduction of the ester, Wittig reaction of the resulting aldehyde,
and removal of the TBS group with TBAF furnished the E ring
segment 5.
0.25, CHCl3); IR (neat) 3464, 3030, 2979 cmꢁ1
;
1H NMR (400 MHz,
CDCl3) 7.50–7.24 (m, 5H), 5.94–5.88 (m, 1H), 5.84–5.78 (m, 1H),
d
5.54 (s, 1H), 4.34 (dd, J¼15.0, 5.9 Hz, 1H), 4.30 (dd, J¼9.5, 4.8 Hz,
1H), 4.04 (dq, J¼15.0, 2.7 Hz, 1H), 3.84 (t, J¼9.5 Hz, 1H), 3.68 (t,
J¼9.5 Hz, 1H), 3.56 (t, J¼9.5 Hz, 1H), 3.46 (td, J¼9.5, 4.8 Hz, 1H), 3.35
(td, J¼9.5, 3.6 Hz, 1H), 3.29 (t, J¼9.5 Hz, 1H), 2.72 (br s, 1H), 2.63
(ddd, J¼15.9, 8.0, 3.6 Hz,1H), 2.41–2.34 (m,1H); 13C NMR (100 MHz,
CDCl3)
d 131.6, 129.1, 128.2, 127.2, 126.3, 101.8, 87.7, 80.8, 76.4, 73.7,
Scheme 4 describes the key segment coupling. Thus, esterifi-
cation of the carboxylic acid 4 and the alcohol 5 under Yamaguchi
conditions gave the ester 16 in 64% overall yield.10 Removal of the
TBS protective group with TBAF afforded 17 in 82% yield. Acetali-
69.9, 68.9, 68.5, 34.4; HRMS (ESI TOF) calcd for C17H20O5Na
(MþNa)þ 327.1208, found 327.1208.
4.3. Diol 8
zation of 17 with
g-methoxyallylstannane 18 in the presence of
CSA provided the acetal 19 as a mixture of diastereoisomers in 87%
yield. Treatment of 19 with TMSI/HMDS gave allylic stannane 20 in
85% yield.11 Modified Rychnovsky acetylation of the ester 20 pro-
To a suspension of NaH (500 mg, 12.5 mmol, washed with
hexane) in THF (32.0 mL) were added alcohol 7 (1.72 g, 5.66 mmol)
in THF (15.0þ5.0þ5.0 mL), NAPBr (1.88 g, 8.49 mmol), and TBAI
(1.05 g, 2.83 mmol) at 0 ꢀC. After the mixture was stirred for 3 h at
40 ꢀC, the reaction was quenched with MeOH. The mixture was
diluted with EtOAc, washed with H2O and brine, and dried over
Na2SO4. Concentration gave crude naphthylmethyl ether, which
was used for the next step without further purification.
To a solution of naphthylmethyl ether obtained above in MeOH
(57.0 mL) was added CSA (262 mg, 1.13 mmol) at room tempera-
ture. After the mixture was stirred for 2 h at reflux, the reaction was
quenched with Et3N. Concentration and column chromatography
vided the a
-chloroacetoxy ether 3.12,13 Intramolecular allylation of
3 was carried out with BF3$OEt2 to give a 4:1 mixture of the de-
sired product 21 and its stereoisomer 22 in 60% overall yield. The
trans relationship between Ha and Hb of 21 was confirmed by the
large coupling constant, JHa–Hb¼9.0 Hz. The small J value, JHa–
¼2.0 Hz, for 22 clearly indicates the cis relationship of these
Hb
protons. Ring-closing metathesis of 21 with the Grubbs’ catalyst 23
furnished the pentacyclic ether 24 in 74% yield.14 Treatment of 24
with catalytic CSA in MeOH provided the diol 2 in 92% yield. The
spectroscopic data of 2 obtained are identical with those reported
previously.5d
(hexane/EtOAc, 4:1, 2:1, 1:2) gave diol 8 (1.91 g, 95% in two steps):
27
yellow oil; Rf¼0.20 (hexane/EtOAc, 2:1); [
IR (neat) 3434, 3025, 2884, 1602 cmꢁ1
7.84–7.79 (m, 4H), 7.48–7.43 (m, 3H), 5.92–5.87 (m, 1H), 5.82–5.76
a
]
ꢁ28.3 (c 0.21, CHCl3);
D
;
1H NMR (400 MHz, CDCl3)
3. Conclusions
d
(m, 1H), 5.14 (d, J¼12.0 Hz, 1H), 4.87 (d, J¼12.0 Hz, 1H), 4.28 (dd,
J¼15.2, 6.0 Hz, 1H), 4.00 (dd, J¼15.2, 2.6 Hz, 1H), 3.85–3.82 (m, 1H),
3.69–3.66 (m, 1H), 3.56–3.47 (m, 2H), 3.40 (t, J¼8.7 Hz, 1H), 3.35–
3.27 (m, 2H), 2.64 (ddd, J¼16.2, 8.0, 4.0 Hz, 1H), 2.40–2.32 (m, 1H);
We have achieved a convergent synthesis of the A–E ring seg-
ment of ciguatoxin CTX3C via the intramolecular allylation of an a-
chloroacetoxy ether and ring-closing metathesis. Further studies
toward the total synthesis of ciguatoxin CTX3C are in progress in
our laboratories.
13C NMR (100 MHz, CDCl3)
d 136.2, 133.3, 132.9, 131.5, 128.4, 127.8,
127.7,127.1,126.5,126.1,125.9,125.7, 87.8, 84.8, 78.3, 76.0, 75.2, 70.5,
67.9, 63.0, 34.6; HRMS (ESI TOF) calcd for C21H24O5Na (MþNa)þ
379.1521, found 379.1520.
4. Experimental section
4.1. General
4.4. Alcohol 9
Reagents and starting materials were obtained from commercial
suppliers and used without further purification unless otherwise
noted. All other solvents were used as purchased. Reactions re-
quiring anhydrous conditions were performed under an argon at-
mosphere. The NMR spectra were recorded on JEOL JNM-AL400
To a solution of diol 8 (330 mg, 0.930 mmol) in DMF (4.7 mL)
were added imidazole (412 mg, 6.05 mmol) and TBSCl (560 mg,
3.72 mmol) at room temperature. After the mixture was stirred for
5 h at 70 ꢀC, the reaction was quenched with MeOH. The mixture
was diluted with EtOAc, washed with H2O and brine, and dried over
Na2SO4. Concentration and column chromatography (hexane/
EtOAc, 30:1, 10:1) gave crude bis-TBS ether, which was used for the
next step without further purification.
To a solution of bis-TBS ether obtained above in MeOH (9.3 mL)
was added CSA (21.6 mg, 0.09 mmol) at 0 ꢀC. After the mixture was
stirred for 2 h at 0 ꢀC, the reaction was quenched with Et3N. The
mixture was diluted with EtOAc, washed with H2O and brine, and
dried over Na2SO4. Concentration and column chromatography
(1H, 13C NMR). Chemical shifts were reported in delta units (
d)
relative to chloroform (7.24), benzene (7.15). IR spectra were
recorded on a JASCO FT/IR-460 plus. Optical rotations were mea-
sured by a JASCO DIP-1000. Mass spectra were measured by
Micromass LCT (ESI TOF-MS). Thin layer chromatography (TLC) was
performed on Merck silica gel 60F-254 plates. Column chromato-
graphy was performed with Kanto Chemical silica gel 60N (40–100
mesh, spherical, neutral) or Fuji Silysia silica gel BW-300 (200–400
mesh).
(hexane/EtOAc,10:1, 4:1) gave alcohol 9 (396 mg, 90% in two steps):
27
colorless oil; Rf¼0.30 (hexane/EtOAc, 4:1); [
a]
þ0.10 (c 0.22,
D
4.2. Benzylidene acetal 7
CHCl3); IR (neat) 3470, 3024, 2856, 1602 cmꢁ1; 1H NMR (400 MHz,
CDCl3) 7.82–7.78 (m, 4H), 7.50–7.41 (m, 3H), 5.84–5.73 (m, 2H),
d
To a mixture of triol 6 (44.4 mg, 0.210 mmol) and PhCH(OMe)2
5.08 (d, J¼11.7 Hz, 1H), 4.89 (d, J¼11.7 Hz, 1H), 4.12 (dd, J¼15.2,
5.7 Hz, 1H), 3.87–3.82 (m, 2H), 3.64–3.55 (m, 2H), 3.47 (t, J¼8.4 Hz,
1H), 3.37 (t, J¼8.7 Hz, 1H), 3.33–3.27 (m, 2H), 2.64 (ddd, J¼16.4, 7.9,
4.0 Hz, 1H), 2.34–2.28 (m, 1H), 1.90 (t, J¼6.3 Hz, 1H), 0.88 (s, 9H),
(66.0
mL, 0.44 mmol) in DMF (1.0 mL) was added p-TsOH$H2O
(5.0 mg, 26.0
mmol) at room temperature. After the mixture was
stirred for 23 h at room temperature, the reaction was quenched
with saturated aqueous NaHCO3. The mixture was diluted with
EtOAc, washed with H2O and brine, and dried over Na2SO4. Con-
centration and column chromatography (hexane/EtOAc, 4:1, 1:2)
0.06 (s, 3H), 0.03 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 137.0, 133.1,
132.7, 131.4, 127.8, 127.6, 127.6, 126.8, 125.8, 125.7, 125.5, 88.5, 85.6,
79.8, 75.8, 75.2, 70.9, 67.9, 62.5, 34.7, 26.0, 18.2, ꢁ3.7, ꢁ4.8; HRMS
(ESI TOF) calcd for C27H38O5SiNa (MþNa)þ 493.2386, found
493.2382.
gave benzylidene acetal 7 (45.1 mg, 74%): colorless needle; mp
22
176 ꢀC (hexane/EtOAc); Rf¼0.46 (hexane/EtOAc, 1:1); [
a
]
ꢁ7.9 (c
D

I. Kadota et al. / Tetrahedron 65 (2009) 7784–7789
7787
4.5. Nitrile 10
4.25–4.21 (m, 1H), 4.20 (d, J¼2.4 Hz, 1H), 3.80 (t, J¼10.1 Hz, 1H),
3.42 (td, J¼10.1, 5.3 Hz, 1H), 2.55–2.43 (m, 2H), 2.28 (brd, J¼7.3 Hz,
To a solution of alcohol 9 (313 mg, 0.670 mmol) in benzene
(3.4 mL) and Et2O (3.4 mL) were added imidazole (246 mg,
3.62 mmol), PPh3 (703 mg, 2.68 mmol), and I2 (510 mg, 2.01 mmol)
at room temperature. After the mixture was stirred for 1 h at 40 ꢀC,
the reaction was quenched with saturated aqueous Na2S2O3. The
mixture was diluted with EtOAc, washed with H2O and brine, and
dried over Na2SO4. Concentration gave crude iodide, which was
used for the next step without further purification.
To a solution of iodide obtained above in DMSO (6.7 mL) was
added NaCN (49.5 mg, 1.01 mmol) at room temperature. The mix-
ture was stirred for 1 h at 70 ꢀC. The mixture was diluted with
EtOAc, washed with H2O and brine, and dried over Na2SO4. Con-
centration and column chromatography (hexane/EtOAc, 20:1, 4:1)
1H), 1.48 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 170.2, 137.6, 134.2,
129.2, 128.5, 126.7, 126.4, 101.1, 82.6, 81.6, 79.7, 76.2, 73.7, 69.6, 33.7,
28.5; HRMS (ESI TOF) calcd for C20H26O6Na (MþNa)þ 385.1627,
found 385.1667.
4.8. Conversion of 15 to 14
To a solution of DMSO (85.2 mL, 1.20 mmol) in CH2Cl2 (4.0 mL)
was added (COCl)2 (68.8
m
L, 0.800 mmol) at ꢁ78 ꢀC. After the
mixture was stirred for 15 min at ꢁ78 ꢀC, to the resulting mixture
was added alcohol 15 (145 mg, 0.400 mmol). After the mixture was
stirred for 30 min at ꢁ78 ꢀC, to the mixture was added Et3N
(0.33 mL, 2.40 mmol), and the mixture was allowed to warm up to
room temperature. The mixture was diluted with EtOAc, washed
with H2O and brine, and dried over Na2SO4. Concentration and
column chromatography (hexane/EtOAc, 2:1) gave ketone and its
corresponding enol as an equilibrated mixture (136 mg, 95%):
Rf¼0.50 (hexane/EtOAc, 4:1); HRMS (ESI TOF) calcd for C20H24O6Na
(MþNa)þ 383.1471, found 383.1485.
gave nitrile 10 (300 mg, 94% in two steps): colorless oil; Rf¼0.34
28
(hexane/EtOAc, 7:1); [
a]
þ23.4 (c 0.22, CHCl3); IR (neat) 3025,
D
2929, 2252 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 7.82–7.77 (m, 4H),
7.50–7.42 (m, 3H), 5.83–5.71 (m, 2H), 5.12 (d, J¼12.0 Hz, 1H), 4.87
(d, J¼12.0 Hz, 1H), 4.08 (d, J¼15.4 Hz, 1H), 3.81 (dd, J¼15.2, 2.6 Hz,
1H), 3.54–3.40 (m, 4H), 3.29 (dt, J¼13.7, 4.7 Hz, 1H), 2.78 (dd,
J¼16.6, 3.4 Hz, 1H), 2.67 (ddd, J¼16.3, 7.4, 4.0 Hz, 1H), 2.56 (dd,
J¼16.6, 6.3 Hz, 1H), 2.37–2.30 (m, 1H), 0.87 (s, 9H), 0.09 (s, 3H), 0.04
To a solution of ketone (23.7 mg, 65.8 mmol) in THF (1.0 mL) was
added L-Selectride (1.0 M in THF, 0.13 mL, 0.130 mmol) at ꢁ78 ꢀC.
After the mixture was stirred for 30 min at the same temperature,
the reaction was quenched with MeOH. Concentration and column
chromatography (hexane/EtOAc, 7:1, 6:1, 3:1) gave alcohol 14
(7.6 mg, 32%, 57% based on recovery), alcohol 15 (4.2 mg, 18%, 31%
based on recovery), and ketone (10.4 mg, 44% recovery).
(s, 3H); 13C NMR (100 MHz, CDCl3)
d 136.8, 133.2, 132.7, 131.1, 127.8,
127.7, 127.6, 126.7, 125.9, 125.5, 125.5, 125.4, 117.1, 88.2, 85.0, 76.1,
75.2, 75.0, 73.4, 67.9, 34.4, 26.0, 21.7, 18.2, ꢁ3.6, ꢁ4.6; HRMS (ESI
TOF) calcd for C28H37NO4SiNa (MþNa)þ 502.2390, found 502.2363.
4.6. Alcohol 12
4.9. Alcohol 5
To a solution of ester 11 (500 mg,1.56 mmol) in THF (7.8 mL) was
added NaHMDS (1.0 M in THF, 2.34 ml, 2.34 mmol) at ꢁ78 ꢀC. After
the mixture was stirred for 15 min at ꢁ78 ꢀC, to the resulting
mixture was added 3-butenal (6.24 mmol) at the same tempera-
ture. After the mixture was stirred for 20 min at ꢁ78 ꢀC, the re-
action was quenched with saturated aqueous NH4Cl/MeOH. The
mixture was diluted with EtOAc, washed with H2O and brine, and
dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc, 10:1, 7:1, 5:1) gave alcohol 12 (384 mg, 95%) as
a diastereomeric mixture.
To a solution of alcohol 14 (534 mg, 1.47 mmol) in DMF
(10.0 mL) were added imidazole (300 mg, 4.41 mmol) and TBSCl
(443 mg, 2.94 mmol) at room temperature. After the mixture was
stirred for 5 h at 30 ꢀC, the reaction was quenched with MeOH. The
mixture was diluted with EtOAc, washed with H2O and brine, and
dried over Na2SO4. Concentration and column chromatography
(hexane/EtOAc, 40:1) gave silyl ether (545 mg, 77%): colorless
22
crystal; mp 113 ꢀC (MeOH); Rf¼0.50 (hexane/EtOAc, 7:1); [
a]
D
ꢁ95.0 (c 0.37, CHCl3); IR (neat) 3068, 2955, 1742 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d 7.49–7.33 (m, 5H), 5.87–5.76 (m, 2H), 5.46 (s,
4.7. Alkene 14
1H), 4.43 (dd, J¼7.9, 4.5 Hz,1H), 4.30 (dt, J¼9.2, 3.0 Hz,1H), 4.24 (dd,
J¼9.8, 4.2 Hz, 1H), 3.73 (d, J¼9.2 Hz, 1H), 3.66–3.55 (m, 2H), 2.63
(ddd, J¼13.3, 9.7, 3.0 Hz, 1H), 2.28 (ddd, J¼13.3, 6.0, 3.0 Hz, 1H), 1.45
(s, 9H), 0.85 (s, 9H), 0.12 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz,
To a solution of alcohol 12 (200 mg, 0.510 mmol) in CH2Cl2
(10.2 mL) was added 13 (21.6 mg, 25.5 mmol) at room temperature.
The mixture was stirred for 4 h at 30 ꢀC. Short column chromato-
graphy (hexane/EtOAc, 2:1) and concentration gave a mixture of
crude products. Purification by column chromatography (hexane/
EtOAc, 7:1, 4:1, 3:1) gave the desired alkene 14 (65.4 mg, 35%) and
its diastereomer alkene 15 (61.6 mg, 33%).
CDCl3) d 170.0,137.7,133.1,129.2, 128.5, 127.3, 126.4, 101.2, 83.1, 81.5,
79.9, 76.7, 72.5, 69.8, 32.9, 28.4, 26.1, 18.3, ꢁ4.2, ꢁ4.6; HRMS (ESI
TOF) calcd for C26H40O6SiNa (MþNa)þ 499.2492, found 499.2484.
To a solution of ester (500 mg, 1.04 mmol) in CH2Cl2 (10.0 mL)
was added DIBAL-H (1.0 M in hexane, 2.2 mL, 2.20 mmol) at ꢁ78 ꢀC.
After the mixture was stirred for 30 min at the same temperature,
the reaction was quenched with saturated aqueous NH4Cl/MeOH.
The mixture was diluted with EtOAc, washed with H2O, saturated
aqueous Rochelle salt and brine, and dried over Na2SO4. Concen-
tration gave crude aldehyde, which was used for the next step
without further purification.
4.7.1. Compound 14. Colorless oil; Rf¼0.58 (hexane/EtOAc, 2:1);
22
[
a]
ꢁ51.2 (c 0.40, CHCl3); IR (neat) 3502, 3035, 2976, 1735 cmꢁ1
;
D
1H NMR (400 MHz, CDCl3)
d 7.49–7.34 (m, 5H), 5.92–5.83 (m, 2H),
5.48 (s, 1H), 4.46 (dd, J¼9.9, 3.2 Hz, 1H), 4.34 (dd, J¼9.9, 5.2 Hz, 1H),
4.16–4.13 (m, 1H), 3.86 (d, J¼9.3 Hz, 1H), 3.67 (t, J¼9.9 Hz, 1H), 3.53
(td, J¼9.9, 5.2 Hz, 1H), 3.05 (brs, 1H), 2.69–2.65 (m, 1H), 2.45–2.40
To a suspension of Ph3PþCH3Brꢁ (557 mg, 1.56 mmol) in THF
(5.0 mL) was added NaHMDS (1.0 M in THF, 1.6 mL, 1.60 mmol) at
0 ꢀC. After the mixture was stirred for 30 min at the same tem-
perature, to the resulting mixture was added a solution of aldehyde
obtained above in THF (3.0þ1.0þ1.0 mL) at 0 ꢀC. After the mixture
was stirred for 30 min at room temperature, the reaction was
quenched with H2O. The mixture was diluted with EtOAc, washed
with H2O and brine, and dried over Na2SO4. Concentration gave
crude alkene, which was used for the next step without further
purification.
(m, 1H), 1.49 (s, 9H); 13C NMR (100 MHz, CDCl3)
d 172.1, 137.3, 133.3,
129.0, 128.2, 126.7, 126.0, 100.9, 82.8, 80.8, 79.4, 76.5, 72.3, 69.2,
31.6, 28.1; HRMS (ESI TOF) calcd for C20H26O6Na (MþNa)þ 385.1627,
found 385.1665.
4.7.2. Compound 15. Colorless oil; Rf¼0.31 (hexane/EtOAc, 2:1);
22
[
a]
þ7.0 (c 0.40, CHCl3); IR (neat) 3475, 3033, 2977, 1745 cmꢁ1; 1H
D
NMR (400 MHz, CDCl3) d 7.48–7.33 (m, 5H), 5.83–5.70 (m, 2H), 5.49
(s, 1H), 4.57 (dd, J¼10.1, 4.8 Hz, 1H), 4.42 (dd, J¼10.1, 5.3 Hz, 1H),

7788
I. Kadota et al. / Tetrahedron 65 (2009) 7784–7789
To a solution of crude silyl ether obtained above in THF (10.0 mL)
gave alcohol 17 (91.5 mg, 82%): colorless solid; mp 118 ꢀC (hexane/
24
was added TBAF (1.0 M in THF, 1.9 mL, 1.90 mmol) at room tem-
perature. The mixture was stirred for 1 h at the same temperature.
Concentration and column chromatography (hexane/EtOAc, 7:1,
4:1, 1:1) gave alcohol 5 (274 mg, 91% in three steps): colorless
EtOAc); Rf¼0.43 (hexane/EtOAc, 2:1); [
(neat) 3403, 3052, 2863, 1709, 1645 cmꢁ1
CDCl3) 7.85–7.79 (m, 4H), 7.49–7.44 (m, 5H), 7.38–7.31 (m, 3H),
a
]
ꢁ91.4 (c 0.30, CHCl3); IR
D
;
1H NMR (400 MHz,
d
5.94–5.87 (m, 2H), 5.81–5.65 (m, 3H), 5.47 (s, 1H), 5.24–5.07 (m,
3H), 4.91 (dt, J¼6.5, 3.3 Hz, 1H), 4.86 (d, J¼12.0 Hz, 1H), 4.47–4.44
(m, 1H), 4.32–4.26 (m, 2H), 4.03–3.97 (m, 2H), 3.69–3.58 (m, 2H),
3.48–3.38 (m, 3H), 3.32 (td, J¼9.1, 2.2 Hz,1H), 3.24 (td, J¼9.4, 3.6 Hz,
1H), 2.78 (dd, J¼15.1, 3.4 Hz, 1H), 2.72–2.69 (m, 1H), 2.57 (ddd,
J¼16.0, 8.0, 3.8 Hz, 1H), 2.47–2.30 (m, 3H), 1.51 (brs, 1H); 13C NMR
crystal; mp 90 ꢀC (hexane/EtOAc); Rf¼0.14 (hexane/EtOAc, 4:1);
24
[
a]
ꢁ129.4 (c 0.25, CHCl3); IR (neat) 3531, 3041, 2890 cmꢁ1
;
1H
D
NMR (400 MHz, CDCl3) d 7.50–7.32 (m, 5H), 5.94–5.79 (m, 3H), 5.47
(s, 1H), 5.28 (dt, J¼17.3, 1.5 Hz, 1H), 5.21 (dt, J¼10.5, 1.5 Hz, 1H),
4.47–4.44 (m, 1H), 4.29 (dd, J¼10.8, 5.2 Hz, 1H), 3.80 (dd, J¼9.3,
6.1 Hz, 1H), 3.75–3.70 (m, 1H), 3.64 (t, J¼10.8 Hz, 1H), 3.51–3.45 (m,
1H), 2.76 (ddd, J¼13.6, 10.0, 3.4 Hz, 1H), 2.41 (ddd, J¼13.6, 6.3,
(100 MHz, CDCl3)
d 170.0, 137.4, 136.1, 135.7, 134.2, 133.2, 132.9,
131.5, 128.9, 128.4, 128.2, 127.8, 127.7, 127.5, 126.7, 126.2, 126.1, 126.1,
126.0, 126.0, 125.7, 125.5, 115.8, 101.0, 87.9, 84.5, 80.1, 79.9, 78.8,
76.0, 75.8, 75.4, 75.2, 73.0, 69.5, 67.9, 38.2, 34.5, 29.9; HRMS (ESI
TOF) calcd for C39H42O9Na (MþNa)þ 677.2726, found 677.2718.
2.5 Hz,1H),1.50 (br d,1H); 13C NMR (100 MHz, CDCl3)
d 137.5, 136.9,
133.9, 128.9, 128.2, 126.1, 125.9, 116.7, 100.9, 83.4, 79.9, 75.1, 74.6,
69.9, 32.3; HRMS (ESI TOF) calcd for C17H20O4Na (MþNa)þ 311.1259,
found 311.1279.
4.12. Mixed acetal 19
4.10. Ester 16
To a solution of alcohol 17 (43.4 mg, 66.3 mmol) in CH2Cl2
To a solution of nitrile 10 (78.2 mg, 0.160 mmol) in CH2Cl2
(3.3 mL) was added DIBAL-H (1.0 M in hexane, 0.32 mL,
0.320 mmol) at ꢁ78 ꢀC. After the mixture was stirred for 30 min at
the same temperature, the reaction was quenched with MeOH. The
mixture was diluted with EtOAc, washed with H2O, saturated
aqueous Rochelle salt and brine, and dried over Na2SO4. Concen-
tration gave crude aldehyde, which was used for the next step
without further purification.
(1.0 mL) were added 18 (62.5
mL, 0.199 mmol) and CSA (3.1 mg,
13.3 mol) at room temperature. After the mixture was stirred for
m
30 min at the same temperature, the reaction was quenched with
Et3N. Concentration and column chromatography (hexane/EtOAc,
20:1, 8:1, 2:1, including 1% Et3N) gave mixed acetal 19 (28.0 mg,
42%, 87% based on recovery) and alcohol 17 (22.7 mg, 52% re-
covery): colorless oil; Rf¼0.47 (hexane/EtOAc, 4:1); IR (neat) 3031,
2925, 1742, 1650 cmꢁ1 1H NMR (400 MHz, C6D6)
; d 7.93 (s, 1H),
To a solution of aldehyde obtained above in t-BuOH (1.6 mL) and
2-methyl-2-butene (1.6 mL) were added 5% aqueous NaH2PO4
(1.6 mL) and NaClO2 (50.6 mg, 0.560 mmol) at 0 ꢀC. The mixture
was stirred for 2 h at the same temperature. The mixture was di-
luted with EtOAc, washed with brine, and dried over Na2SO4.
Concentration gave crude carboxylic acid 4, which was used for the
next step without further purification.
7.78–7.72 (m, 2H), 7.68––7.55 (m, 4H), 7.32–7.11 (m, 5H), 6.02–5.94
(m, 1H), 5.90–5.77 (m, 1H), 5.69–5.46 (m, 3H), 5.33–5.15 (m, 4H),
5.05–4.96 (m, 3H), 4.24––4.15 (m, 2H), 4.03–3.88 (m, 3H), 3.77–
3.69 (m, 2H), 3.66–3.59 (m, 1H), 3.48–3.25 (m, 6H), 3.16 (s, 3H), 2.75
(dd, J¼15.9, 9.8 Hz, 1H), 2.66–2.44 (m, 4H), 2.32–2.22 (m, 1H), 2.07–
1.85 (m, 2H), 1.61–1.47 (m, 6H), 1.46–1.28 (m, 6H), 1.00–0.76 (m,
15H).
To a solution of 4 obtained above in THF (1.6 mL) were added
Et3N (66.9
mL, 0.480 mmol) and 2,4,6-trichlorobenzoyl chloride
4.13. Allylic stannane 20
(37.5 L, 0.240 mmol) at room temperature. The mixture was stir-
m
red for 1 h at the same temperature. After THF was removed under
reduced pressure, toluene (1.2 mL) was added. To the resulting
mixture was added a solution of alcohol 5 (60.6 mg, 0.210 mmol)
and DMAP (35.4 mg, 0.290 mmol) in toluene (1.0þ0.5þ0.5 mL) at
room temperature. After the mixture was stirred for 1 h at the same
temperature, the insoluble material was filtered off through a Celite
pad. Concentration and column chromatography (hexane/EtOAc,
To a solution of mixed acetal 19 (43.4 mg, 42.7
(1.0 mL) were added HMDS (90.0 L, 0.427 mmol) and TMSI
(30.4
L, 0.214 mmol) at 0 ꢀC. After the mixture was stirred for 1 h
at the same temperature, the reaction was quenched with saturated
aqueous NaHCO3. The mixture was diluted with EtOAc, washed
with H2O and brine, and dried over Na2SO4. Concentration and
chromatography (hexane/EtOAc, 12:1, including 1% Et3N) gave
mmol) in CH2Cl2
m
m
15:1, 3:1, 1:1) gave ester 16 (80.4 mg, 64% from 10): colorless oil;
allylic stannane 20 (35.8 mg, 85%): colorless oil; Rf¼0.57 (hexane/
26
27
Rf¼0.46 (hexane/EtOAc, 4:1); [
a]
ꢁ38.6 (c 0.26, CHCl3); IR (neat)
EtOAc, 4:1); [
a
]
ꢁ99.3 (c 0.33, CHCl3); IR (neat) 3033, 2925, 1742,
D
D
2928, 2855, 1742, 1648 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d
7.82–7.77
1651 cmꢁ1 1H NMR (400 MHz, C6D6)
; d 7.97 (s, 1H), 7.78–7.74 (m,
(m, 4H), 7.49–7.41 (m, 5H), 7.37–7.31 (m, 3H), 5.95 (dd, J¼11.0,
5.1 Hz, 1H), 5.82–5.71 (m, 4H), 5.48 (s, 1H), 5.23 (d, J¼17.1 Hz, 1H),
5.12–5.07 (m, 2H), 4.95 (dt, J¼9.6, 2.8 Hz, 1H), 4.88 (d, J¼11.7 Hz,
1H), 4.49–4.46 (m, 1H), 4.31 (dd, J¼10.7, 5.1 Hz, 1H), 4.13–4.08 (m,
1H), 4.02 (dd, J¼9.6, 5.5 Hz,1H), 3.84 (brd, J¼15.3 Hz,1H), 3.70–3.62
(m, 2H), 3.51–3.35 (m, 4H), 3.23 (td, J¼9.6, 3.7 Hz, 1H), 2.81–2.76
(m, 2H), 2.55–2.47 (m, 2H), 2.31–2.25 (m, 2H), 0.87 (s, 9H), 0.04 (s,
2H), 7.70–7.64 (m, 4H), 7.35–7.12 (m, 5H), 6.17–6.10 (m, 1H), 6.00
(dd, J¼10.9, 4.8 Hz, 1H), 5.87 (ddd, J¼17.1, 10.5, 5.3 Hz, 1H), 5.72–
5.65 (m, 1H), 5.55–5.42 (m, 2H), 5.25 (s, 1H), 5.20–5.12 (m, 3H), 5.07
(dt, J¼10.6, 1.6 Hz, 1H), 4.63 (dt, J¼6.0, 9.0 Hz, 1H), 4.23–4.16 (m,
2H), 4.04–3.89 (m, 4H), 3.75–3.64 (m, 2H), 3.56–3.43 (m, 2H), 3.37–
3.24 (m, 3H), 2.96 (dd, J¼15.2, 2.6 Hz, 1H), 2.69–2.46 (m, 4H), 2.29–
2.22 (m, 1H), 1.97–1.85 (m, 2H), 1.67–1.55 (m, 6H), 1.43–1.31 (m,
6H); 13C NMR (100 MHz, CDCl3)
d
170.3, 136.9, 135.7, 134.2, 133.5,
6H), 1.02–0.86 (m, 15H); 13C NMR (100 MHz, C6D6)
d 169.6, 143.2,
133.2, 132.7, 131.4, 131.3, 128.9, 128.1, 127.8, 127.7, 127.6, 127.0, 126.1,
125.8, 125.7, 125.5, 115.9, 88.6, 85.3, 81.3, 80.2, 79.7, 76.0, 75.8, 75.5,
74.0, 69.5, 67.9, 39.1, 38.2, 34.6, 25.8, 18.2, ꢁ3.5, ꢁ4.4; HRMS (ESI
TOF) calcd for C45H56O9SiNa (MþNa)þ 791.3591, found 791.3595.
138.6, 137.4, 136.4, 135.0, 134.0, 133.5, 132.5, 131.9, 128.9, 126.7,
126.6, 126.4, 126.2, 125.9, 125.6, 115.7, 105.6, 101.0, 88.1, 85.0, 83.6,
80.5, 79.9, 76.5, 76.4, 76.0, 75.9, 75.5, 69.7, 68.1, 60.1, 38.1, 34.9, 30.3,
29.8, 27.9, 14.1, 10.0; HRMS (ESI TOF) calcd for C54H72O9SnNa
(MþNa)þ 1007.4096, found 1007.4056.
4.11. Alcohol 17
4.14. Tetraene 21
To a solution of silyl ether 16 (130 mg, 0.170 mmol) in THF
(1.7 mL) was added TBAF (1.0 M in THF, 1.7 mL, 1.70 mmol) at room
temperature. The mixture was stirred for 1 h at 40 ꢀC. Concentra-
tion and column chromatography (hexane/EtOAc, 10:1, 4:1, 2:1)
To a solution of ester 20 (13.1 mg, 13.3 mmol) in CH2Cl2 (1.5 mL)
was added DIBAL-H (1.0 M in hexane, 52.2
m
L, 52.2
m
mol) at ꢁ78 ꢀC.
After the mixture was stirred for 10 min at the same temperature, to

I. Kadota et al. / Tetrahedron 65 (2009) 7784–7789
7789
the resulting mixture were added pyridine (17.4
m
L, 0.160 mmol),
4.16. Diol 2
To a solution of benzylidene acetal 24 (2.9 mg, 4.46
MeOH (0.30 mL) and CH2Cl2 (0.15 mL) was added a trace amount of
CSA at room temperature. After the mixture was stirred for 9 h at
40 ꢀC, the reaction was quenched with Et3N. Concentration and
chromatography (hexane/EtOAc, 2:1, 1:2) gave diol 2 (1.9 mg, 76%,
92% based on recovery) and benzylidene acetal 24 (0.5 mg, 17%
recovery). The spectroscopic data of 2 obtained are identical with
those reported previously.5d
DMAP (13.0 mg, 0.106 mmol) in CH2Cl2 (0.6 mL), and (ClCH2CO)2O
(54.5 mg, 0.319 mmol) in CH2Cl2 (0.7 mL) at ꢁ78 ꢀC. After the mix-
ture was allowed to warm up to ꢁ20 ꢀC gradually for 1 h, the re-
actionwas quenched with H2O. The mixture was diluted with EtOAc,
and washed with saturated aqueous Rochelle salt, saturated aque-
ous CuSO4 twice, saturated aqueous NaHCO3, and brine. Dried over
mmol) in
Na2SO4 and concentration gave the crude a-chloroacetoxy ether 3,
which was used for the next step without further purification.
To a mixture of 3 obtained above and molecular sieves 4 Å
(26.0 mg) in CH3CN (2.7 mL) was added BF3$OEt2 (0.40 M in CH2Cl2,
0.26 mL, 0.104 mmol) at ꢁ40 ꢀC. After the mixture was stirred for
1 h at the same temperature, the reaction was quenched with Et3N.
Concentration and chromatography (hexane/EtOAc, 10:1, 8:1, 4:1)
gave the desired product 21 (4.2 mg, 47% in two steps) and its
Acknowledgements
This work was financially supported by the Nagase Science and
Technology Foundation, the Shorai Foundation for Science and
Technology, the Naito Foundation, and the Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan.
diastereomer 22 (1.2 mg, 13% in two steps): colorless solid; mp
29
180 ꢀC (hexane/EtOAc); Rf¼0.37 (hexane/EtOAc, 4:1); [
a
]
ꢁ35.0 (c
D
0.20, CHCl3); IR (neat) 3035, 2864, 1644 cmꢁ1 1H NMR (400 MHz,
;
C6D6)
d 7.96 (s, 1H), 7.74–7.65 (m, 6H), 7.35–7.12 (m, 5H), 6.12–5.93
(m, 3H), 5.63–5.45 (m, 4H), 5.30–5.15 (m, 5H), 5.07 (dt, J¼10.5,
1.6 Hz, 1H), 4.28–4.24 (m, 2H), 4.17 (dd, J¼15.6, 4.9 Hz, 1H), 3.86–
3.80 (m, 2H), 3.71–3.63 (m, 3H), 3.53–3.26 (m, 6H), 2.96 (ddd,
J¼10.8, 9.5, 4.5 Hz, 1H), 2.86 (ddd, J¼11.6, 9.5, 4.5 Hz, 1H), 2.66 (ddd,
J¼16.1, 6.6, 3.8 Hz, 1H), 2.51 (ddd, J¼13.3, 10.6, 2.6 Hz, 1H), 2.41–
2.22 (m, 2H), 2.10 (ddd, J¼13.3, 6.6, 2.6 Hz, 1H); 13C NMR (100 MHz,
References and notes
1. Satake, M.; Murata, M.; Yasumoto, T. Tetrahedron Lett. 1993, 34, 1975–1978.
2. (a) Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93, 1897–1909; (b) Scheuer, P. J.
Tetrahedron 1994, 50, 3–18; (c) Lewis, R. J. Toxicon 2001, 39, 97–106; (d) Yasu-
moto, T. Chem. Rec. 2001, 1, 228–242.
C6D6)
d 138.9, 137.9, 137.8, 136.4, 134.4, 134.2, 133.8, 132.0, 129.2,
3. For recent reviews on syntheses of polycyclic ethers, see: (a) Nakata, T. Chem.
Rev. 2005, 105, 4314–4347; (b) Inoue, M. Chem. Rev. 2005, 105, 4379–4405.
4. (a) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.; Oguri, H.; Satake,
M. Science 2001, 294, 1904–1907; (b) Inoue, M.; Uehara, H.; Maruyama, M.;
Hirama, M. Org. Lett. 2002, 4, 4551–4554; (c) Inoue, M.; Miyazaki, K.; Uehara, H.;
Maruyama, M.; Hirama, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 12013–12018.
5. For the previous synthesis of the A–E ring segment of 1, see: (a) Maruyama, M.;
Maeda, K.; Oishi, T.; Oguri, H.; Hirama, M. Heterocycles 2001, 54, 93–99; (b)
Maruyama, M.; Inoue, M.; Oishi, T.; Oguri, H.; Ogasawara, Y.; Shindo, Y.; Hirama,
M. Tetrahedron 2002, 58, 1835–1851; (c) Fuwa, H.; Fujikawa, S.; Tachibana, K.;
Takakura, H.; Sasaki, M. Tetrahedron Lett. 2004, 45, 4795–4799; (d) Kobayashi,
S.; Takahashi, Y.; Komano, K.; Alizadeh, B. H.; Kawada, Y.; Oishi, T.; Tanaka, S.;
Ogasawara, Y.; Sasaki, S.; Hirama, M. Tetrahedron 2004, 60, 8375–8396;
(e) Fujiwara, K.; Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka, H.; Murai, A.; Kawai,
H.; Suzuki, T. Tetrahedron Lett. 2004, 45, 7011–7014; (f) Inoue, M.; Yamashita, S.;
Ishihara, Y.; Hirama, M. Org. Lett. 2006, 8, 5805–5808; (g) Clark, J. S.; Conroy, J.;
Blake, A. J. Org. Lett. 2007, 9, 2091–2094.
128.4, 128.3, 128.1, 127.0, 126.9, 126.9, 126.4, 126.3, 126.0, 116.9,
115.0, 101.4, 88.1, 83.6, 82.7, 82.1, 81.7, 81.2, 80.5, 77.7, 77.6, 76.2,
75.5, 73.5, 70.1, 69.0, 38.3, 35.6, 31.3; HRMS (ESI TOF) calcd for
C42H46O8Na (MþNa)þ 701.3090, found 701.3187.
4.15. Triene 24
To a solution of tetraene 21 (4.1 mg, 6.04
mmol) in benzene
(0.7 mL) was added 23 (15.0 mg, 18.1 mol) at room temperature.
m
After the mixture was stirred for 5 h at 70 ꢀC, the reaction was
quenched with Et3N. Short column chromatography (hexane/EtOAc,
2:1) and concentration gave crude triene. Purification by column
chromatography (hexane/EtOAc, 8:1) gave triene 24 (2.9 mg, 74%):
6. Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002, 124,
3562–3566.
7. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956.
8. Compounds 14 and 15 were the products isolated in reasonable yields, and the
other stereoisomer was not detected.
colorless solid; mp 195 ꢀC (hexane/EtOAc); Rf¼0.36 (hexane/EtOAc,
28
4:1); [
a
]
D
ꢁ49.0 (c 0.22, CHCl3); IR (neat) 3023, 2864,1604 cmꢁ1; 1H
NMR (400 MHz, CDCl3) d 7.82–7.78 (m, 4H), 7.53–7.41 (m, 5H), 7.35–
7.30 (m, 3H), 5.87–5.71 (m, 5H), 5.62 (dt, J¼12.6, 2.3 Hz, 1H), 5.45 (s,
1H), 5.03–4.95 (m, 2H), 4.42 (dd, J¼8.7, 3.0 Hz, 1H), 4.32–4.27 (m,
2H), 4.18 (dd, J¼8.5, 2.0 Hz, 1H), 4.04–4.00 (m, 1H), 3.81 (dd, J¼9.0,
1.7 Hz, 1H), 3.65–3.60 (m, 2H), 3.52–3.46 (m, 2H), 3.36 (t, J¼8.8 Hz,
1H), 3.30–3.20 (m, 2H), 3.11–3.08 (m, 2H), 2.74–2.68 (m, 1H), 2.63
(ddd, J¼16.2, 7.6, 3.9 Hz,1H), 2.36–2.25 (m, 4H); 13C NMR (100 MHz,
9. Other conditions such as NaBH4 in MeOH afforded the undesired isomer 15 as
a major product.
10. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn.
1979, 52, 1989–1993.
11. Kadota, I.; Sakaihara, T.; Yamamoto, Y. Tetrahedron Lett. 1996, 37, 3195–3198.
12. Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am.
Chem. Soc. 2003, 125, 46–47.
13. For the original conditions, see: (a) Dahanukar, V. H.; Rychnovsky, S. D. J. Org.
Chem. 1996, 61, 8317–8320; (b) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem.
2000, 65, 191–198; (c) Kopecky, D. J.; Rychnovsky, S. D. Org. Synth. 2003, 80,
177–183.
C6D6)
d 136.6, 134.9, 133.2, 132.9, 131.3, 130.9, 128.9, 128.2, 127.8,
127.8, 127.6, 126.8, 126.7, 126.2, 126.1, 125.8, 125.6, 100.8, 89.2, 87.4,
85.0, 82.1, 81.0, 80.9, 80.5, 79.8, 78.1, 77.2, 76.9, 76.0, 73.2, 68.4, 37.0,
34.7, 32.7; HRMS (ESI TOF) calcd for C40H42O8Na (MþNa)þ 673.2777,
found 673.2753.
14. (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed.
Engl. 1995, 34, 2039–2041; (b) Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem.
Soc. 1996, 118, 100–110.