An Ireland-Claisen rearrangement/RCM based approach for the construction of the EF-ring of ciguatoxin 3C

Article abstract of DOI:10.1016/j.tetlet.2012.12.001

The EF-ring of ciguatoxin 3C, a marine toxin from the dinoflagellate Gambierdiscus toxicus, was stereoselectively synthesized by iterative use of a cyclic ether formation process based on chirality-transferring Ireland-Claisen rearrangement and ring-closing olefin metathesis.

Full text of DOI:10.1016/j.tetlet.2012.12.001

Tetrahedron Letters 54 (2013) 676–680
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An Ireland–Claisen rearrangement/RCM based approach for the construction
of the EF-ring of ciguatoxin 3C
⇑
Keisuke Nogoshi, Daisuke Domon, Kenshu Fujiwara , Natsumi Kawamura, Ryo Katoono,
Hidetoshi Kawai , Takanori Suzuki
Department of Chemistry, Faculty of Science, Hokkaido University, Sapporo 060-0810, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The EF-ring of ciguatoxin 3C, a marine toxin from the dinoflagellate Gambierdiscus toxicus, was stereose-
lectively synthesized by iterative use of a cyclic ether formation process based on chirality-transferring
Ireland-Claisen rearrangement and ring-closing olefin metathesis.
Received 23 October 2012
Revised 30 November 2012
Accepted 3 December 2012
Available online 7 December 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Natural product synthesis
Fused cyclic ethers
Ireland-Claisen rearrangement
Ring closing olefin metathesis
Stereoselective synthesis
Ciguatoxin 3C (CTX3C, Fig. 1) was isolated from the dinoflagel-
late Gambierdiscus toxicus as a causative toxin of ciguatera seafood
poisoning, which often occurs in tropical and subtropical areas.1
The strong binding of CTX3C to voltage-gated sodium channels
investigated. We describe here a new synthetic approach to the
key intermediate, EF-ring 1 (Scheme 1), based on chirality-trans-
ferring Ireland-Claisen rearrangement and RCM. It is also reported
that an (E)-iodoalkenyl group, which was previously shown to act
as a connector of the F-ring to the I-ring for the construction of the
FGHI-ring unit,5c was facilely installed at C28 of 1.
Our retrosynthesis of the EF-ring 1, corresponding to the
C14–C28 region of CTX3C, is outlined in Scheme 1. The F-ring of 1
was envisioned to be cyclized by RCM11 of divinyl substrate 2 at
the final stage of the synthesis. The stereoselective formation of
the C26–C27 bond of 2 relies on the Ireland-Claisen rearrangement
of (Z)-3-aryloxyallyl ester 4,12–14 in which the chirality at C24 of 4 is
expected to be transferred efficiently to the C26 and C27 stereocen-
ters of 2 via chair-form transition state 3 after the formation of
(Z)-ketene silyl acetal.12,15 Ester 4 would be prepared from cyclic
(Ki = 0.81 ꢀ 10ꢁ4
l
M)2 results in the activation of the channels
and hence causes the potent toxicity of CTX3C (MLD = 1.3 g/kg,
ip, in mice).1
The structure of CTX3C, which consists of twelve trans-fused
cyclic ethers, a spirocyclic acetal, and thirty stereocenters, is extre-
mely complex in molecular size, topology, and stereochemistry,
and this complexity renders CTX3C an attractive but difficult syn-
thetic target. Therefore, many research groups,3,4 including our
own,5 have long studied the synthesis of CTX3C and its congeners.
However, only the Hirama6–8 and Isobe9 groups have achieved the
total synthesis of them to date.
As a part of our program toward the total synthesis of CTX3C,
we previously reported a method for building the F-ring on the
E-ring based on [2,3]-Wittig rearrangement and ring-closing olefin
metathesis (RCM).5d However, it was found that the resulting
EF-ring could not be used in further synthesis due to difficulty in
transforming the functional groups necessarily obtained in the
method.10 Therefore, the synthesis of the EF-ring which has an only
essential structure for further synthesis was alternatively
ether 5 and chiral (Z)-3-aryloxyallyl alcohol 6. The same
Ireland-Claisen rearrangement/RCM process was planned for the
construction of 5: the eight-membered ring would be obtained by
Me
HO
H
Me
H
O
H28 30
Me
L
I
O H
H
H
H
J
O
G
H
H
H
H
H
H
O
OH
O
H
O
B
E
O
H
K
H
O
H
F
D
C
O
H
A
H
O
O
H
O52
M
14 H
H
O
1
⇑
Corresponding author.
Me
OH
E-mail address: fjwkn@sci.hokudai.ac.jp (K. Fujiwara).
Present address: Department of Chemistry, Faculty of Science, Tokyo University of
Science, Shinjuku-ku, Tokyo 162-8601, Japan.
Ciguatoxin 3C (CTX3C)
Me
Figure 1. Structure of ciguatoxin 3C (CTX3C).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.001

K. Nogoshi et al. / Tetrahedron Letters 54 (2013) 676–680
677
Ireland-Claisen Rearrangement
Cl
Cl
Cl
OMe
OH
O
BuLi
Cl
OPMP
Cl
OPMP
12
28 OH
OH
OMe
H
H
H
tBu
tBu
O
O
O
27
Et2O
0°C
O
O
Li
NaH, KI
E
OPMP
Si
Si
tBu
26
THF, 60°C
F
11
tBu
O
O
O
O
Me
O
14 H
H
H
24
92%
0°C
Me
Me
Me
1
2
RCM
Me
O
↓
25°C
O
O
H
Me
PMP: 4-methoxyphenyl
PCP: 4-chlorophenyl
O
O
13
O
OPMP
OPMP
66%
H2
Me
O
OH
Z
27
Lindlar cat.
PhH, 23°C
O
O
H
R
10
O
OPMP
48%
H
H
24R
tBu
tBu
O
27
24
O
O
Z
Me +
OTMS
PMPO
Si
Si
tBu
then
PMPO
Me
O
tBu
O
OH
14
O
4
26 Z
O
O
separation
H
3
OH
6 41%
Me
H2, Pd/C
O
Me
O
Me
O
MeOH, 23 °C
92%
O
Me
Me
26
16
RCM
O
O
15
OH OPMP
24 OPMP
OH
18 OPMP
OH
10
H
O
R
PCP
R
PMPO
MeO
6
O
O
16 OPMP
H
Z
O
O
O
5
15O
PCP
18
R
Ireland-Claisen
Rearrangement
O
O
9
ORTEP diagram of 15
18
OPMP
Scheme 2. Synthesis of alcohols 6 and 10.
TMSO
PMPO 16
15 O
O
O
O
R 18
PCP
Z
O
PCP
MeO
O
O
Z
15
O
1) TMSCl (5 equiv)
7
8
THF, –78°C
O
PCP
then
EDCI•HCl
Scheme 1. Retrosynthesis of EF-ring 1.
O
KHMDS (5 equiv), 15 min
DMAP, 10
O
9
CH2Cl2
27°C
87% from 10
then CH2(CO2Et)2 (8 equiv)
–78°C to 0°C
HO2C
RCM of 7, in which
a
,b-dialkoxy ester would be stereoselectively
formed by the Ireland-Claisen rearrangement of ester
2) TMSCHN2
16
9
via
PhH-MeOH, 26°C
94% from 9
(Z)-ketene silyl acetal 8. (Z)-3-Aryloxyallyl alcohol 10, which is a
constituent of 9, is a diastereomer of 6 having the same (4R)-2,2-di-
methyl-1,3-dioxolan-4-yl group but the opposite configuration at
the hydroxy-bearing carbon. Both 6 and 10 would be constructed
simultaneously from the known (R)-2,3-O-isopropylidene glyceral-
dehyde16 in a non-stereoselective manner.
(Z)-3-Aryloxy-2-propen-1-ols 6 and 10 were synthesized by a
4-step process: (i) formation of 11 (92%) from 4-methoxyphenol
and 1,1,2-trichloroethylene,17 (ii) in situ generation of acetylide
1218 followed by the reaction with (R)-2,3-O-isopropylidene glyc-
eraldehyde (13)16 to give 14 (66%), (iii) Lindlar hydrogenation of
14, and (iv) separation of diastereomers 6 (41%) and 10 (48%)
(Scheme 2). While the (R)-2,2-dimethyl-1,3-dioxolan-4-yl group
did not influence the stereoselectivity at the addition step (ratio
of diastereomers: ca. 1:1), it acted as a ‘chiral resolving agent’ to
achieve efficient chromatographic separation of homochiral diaste-
reomers 6 and 10. The stereochemistry of 6 and 10 was assigned by
X-ray crystallographic analysis of perhydrogenated derivative 15
derived from 6.19
Me
1) 0.5 M HCl-MeCN
0°C
O
Me
HO
O
2) NaIO4, THF
pH 7 buffer
25°C
PMPO16
O
O
PMPO
PCP
PCP
15
O
O
17
O
O
MeO2C
MeO2C
3) NaBH4
18
CeCl3•7H2O
(17:15-epi-17 > 20:1)
MeOH, –78°C
84% from 17
MesN NMes
IPNBSH
PPh3, DEAD
1-hexene
Cl2Ru
Cy P
Ph
H
H
3 19
16
O
THF, 26°C
PMPO
PCP
7
21
15
then H2O
CF3CH2OH
26°C
O
CH2Cl2
26°C
O
MeO2C H
H
NOE
JH15-H16
5
= 9.5 Hz
81%
97%
Rearrangement of 9,20 prepared by esterification of 1621 with 10
by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) and
DMAP (87%), was performed as shown in Scheme 3. Ester 9 was
treated with potassium bis(trimethylsilyl)amide (KHMDS)
(5 equiv)22 in the presence of TMSCl (5 equiv) in THF at ꢁ78 °C
for 15 min,23 and diethyl malonate (8 equiv) was then added to
the reaction mixture to scavenge unreacted base.24 The resulting
ketene silyl acetal was warmed to 0 °C to complete the rearrange-
ment. After methylation with TMSCHN2,25 15,16-anti diether 17
was obtained exclusively in 94% yield (17:15-epi-17 >20:1).14
Next, rearrangement product 17 was converted into diene 7.
Thus, the isopropylidene acetal of 17 was selectively hydrolyzed
upon treatment with 0.5 M aqueous HCl in MeCN without removal
of the 4-chlorobenzylidene acetal.26 The resulting diol was
subjected to oxidative cleavage followed by reduction to produce
Scheme 3. Synthesis of eight-membered ring ether 5.
18 (84% from 17). Reductive rearrangement of allyl alcohol 18
was performed with N-isopropylidene-N0-2-nitrobenzenesulfonyl
hydrazine (IPNBSH) according to Movassaghi’s procedure27 with
a slight modification, in which an excess amount of 1-hexene
was used as a scavenger of free diimide generated during the reac-
tion,12c to furnish diene 7 successfully (81%).
The ring closure of 7 with Grubbs’ second-generation catalyst
(19) smoothly produced 5 (97%).28 The stereochemistry of 5 was
determined by the presence of an NOE between H15 and H21, a
large JH15–H16 value (9.5 Hz), and absence of an NOE between
H15 and H16, thereby also confirming the stereochemistry of the
major product (17) from the Ireland-Claisen rearrangement step.

678
K. Nogoshi et al. / Tetrahedron Letters 54 (2013) 676–680
1) Tf2O, 2,6-lutidine
1) CAN, DMF-H2O
0°C
CH2Cl2, –78°C
then TESOTf
OH
–78°C to 0°C
2) NaBH4, MeOH
25°C
H
tBu
O
Si
5
3) (tBu)2Si(OTf)2
tBu
2) vinyllithium, CuCN
–78°C to 0°C
O
O
H
pyridine, DMF, 25°C
4) ethanedithiol
Et2O·BF3, CH2Cl2
–40°C
HO
3) PPTS (cat.), EtOH
25°C
20
72% from 20
73% from 5
CO2H
H
t
BrCH2CO2 Bu
Bu4NHSO4
H
tBu
tBu
Figure 2. The ORTEP diagram of compound 26: one of the two crystallographically
independent molecules is shown.
O
O
O
OH
Si
Si
tBu O
tBu O
O
50% aq NaOH
PhH, 25°C
O
H
H
22
then MeOH, 25°C
97%
21
Tf2O
TfO
Bu3Sn
Me
28
2,6-lutidine
H
H
tBu
O
CH2Cl2, –78°C
BuLi, THF, 0°C
then 28, 23°C
81% from 1
O
Scheme 4. Synthesis of glycolic acid derivative 22.
OTBS
1
Si
tBu
then TBSOTf
O
O
H
14 H
–78°C to 0°C
27
1) KHMDS (6 equiv)
LiN(CH2)4 (6 equiv)
Me
OTBS
Cp2ZrCl2, DIBALH
THF, 23°C
then 28, 55°C
H
H
tBu
O
O
PhMe-THF, –78°C, 6.5 min
then
EDCI•HCl
Si
tBu
I
O
TMSCl (12 equiv), 15 min
DMAP, 6
O
then I2, 0°C
H
H
4
Me
22
28
87%
then CH2(CO2Et)2 (12 equiv)
–78°C to 0°C
CH2Cl2
24°C
28
H
H
tBu
O
2) TMSCHN2, PhH-MeOH, 24°C
O
OTBS
Si
90% from 22
89% from 4
tBu
O
O
H
14 H
1) ethanedithiol
29
Et2O·BF3, CH2Cl2
CO2Me
H
tBu
O
27 OPMP
–40°C
O
Scheme 6. Installation of an (E)-2-iodoprop-1-en-1-yl group at C28 of 1.
2) NaIO4, THF
Si
26
pH 7 buffer, 25°C tBu
O
O
H
3) NaBH4
of 9, which, unfortunately, gave 23 with low stereoselectivity
(23:27-epi-23 = 1.3:1, 74% combined yield).32 After intensive opti-
mization of reaction conditions, we found that the selectivity of 23
was improved by modification of the procedure for the enolate for-
mation: ester 4 was exposed to the combination of KHMDS
(6 equiv) and lithium pyrrolidinide (6 equiv) as base33 in toluene-
THF (3.4:1) at ꢁ78 °C for 6.5 min,34 and the resulting enolate was
treated with TMSCl (12 equiv). Thus, 26,27-anti diether 23 was
produced in 89% yield stereoselectively (23: 27-epi-23 > 20:1) after
rearrangement and esterification.
The second ring was constructed according to a similar proce-
dure as described above. Acetal 23 was transformed to allyl alcohol
24 (82%) via an acetonide-removal/oxidative diol-cleavage/reduc-
tion sequence. The reductive rearrangement of 24 (88%) followed
by RCM of the resulting triene 2 with Grubbs’ first-generation cat-
alyst (25)35 successfully furnished 26 (87%), the structure of which
was confirmed by X-ray crystallographic analysis (Figure 2).36 The
PMP group of 26 was removed with CAN, and the resulting hydro-
xy ester was reduced with NaBH4 to produce diol 137 (89% from
26).
O
CeCl3·7H2O
Me
MeOH, –78°C
82% from 23
23
(23:27-epi-23 > 20:1)
O
Me
Cy3P
IPNBSH
Cl2Ru
PPh3, DEAD
1-hexene
THF, 24°C
CO2Me
O
H
Ph
Cy3P
tBu
O
25
OPMP
Si
2
tBu
O
O
then H2O
CF3CH2OH
24°C
H
CH2Cl2
reflux
24
HO
88%
87%
CO2Me
1) CAN
H
H
tBu
O
H2O-DMF, 0°C
O
OPMP
1
Si
tBu
O
2) NaBH4
O
H
H
MeOH, 26°C
89% from 26
26
Scheme 5. Synthesis of EF-ring 1.
Toward the second medium ring formation, protected cyclic
ether 5 was transformed to carboxylic acid 22 as follows (Scheme
4). Removal of the PMP group of 5 with CAN29 followed by reduc-
tion of the methyl ester with NaBH4 afforded a diol, which was
subjected to protection as a cyclic silylene and removal of the 4-
Finally, according to the previously established procedure,5c
iodoalkene 29 was constructed from 1 as shown in Scheme 6.
One-pot selective triflation/TBS-protection of diol 131 followed by
the reaction with propynyllithium gave 28 (81% from 1), which
was subjected to sequential hydrozirconation and iodination to
furnish 2938 (87%).
In conclusion, fused 8/9-bicyclic ether 1, corresponding to the
EF-ring of ciguatoxin 3C, was stereoselectively synthesized in
12.2% total yield over 26 steps from carboxylic acid 16 by an iter-
ative process based on Ireland-Claisen rearrangement and RCM.
The availability of EF-ring 1 for further synthesis was also demon-
strated by its facile conversion to 29 via the installation of an (E)-
iodoalkenyl group, a key connector of the F-ring to the I-ring for
the construction of the FGHI-ring unit.5c Further work toward the
total synthesis of CTX3C is in progress.
30
chlorobenzylidene acetal group with 1,2-ethanedithiol/BF3ꢂOEt2
to produce 20 (73% from 5). Diol 20 was converted into 21 (72%)
through a process including one-pot selective triflation/TES-pro-
tection of the hydroxy groups,31 vinylation of the triflate ester,
and removal of the TES group. Etherification of 21 with t-butyl
bromoacetate under phase-transfer conditions and subsequent
one-pot hydrolysis by simple addition of methanol as solvent affor-
ded glycolic acid 22 (97%).
At the first stage of the second ring formation (Scheme 5), rear-
rangement of 4,20 prepared from 22 and 6 by condensation using
EDCI (90%), was first examined under the same conditions as that

K. Nogoshi et al. / Tetrahedron Letters 54 (2013) 676–680
16. Schmid, C. R.; Bryant, J. D. Org. Synth. 1995, 72, 6–13.
679
Acknowledgments
17. Geary, L. M.; Hultin, P. G. Org. Lett. 2009, 11, 5478.
18. Kann, N.; Bernardes, V.; Greene, A. E. Org. Synth. 1997, 74, 13.
We thank Dr. Eri Fukushi (GC-MS and NMR Laboratory, Gradu-
ate School of Agriculture, Hokkaido University), Mr. Yusuke Takata,
Ms. Seiko Oka, and Ms. Ai Tokumitsu (Equipment Management
Center, Creative Research Institution, Hokkaido University) for
the measurements of mass spectra. This work was supported by
a Global COE Program (B01: Catalysis as the Basis for Innovation
in Materials Science) and Grants-in-Aid for Scientific Research
from MEXT, Japan.
19. Crystal data for 15: Crystals were obtained by recrystallizing from Et2O/hexane.
C
15H22O5, M = 282.34, colorless platelet, 0.50 ꢀ 0.20 ꢀ 0.05 mm3, monoclinic
P21 (No. 4), a = 8.741(3) Å, b = 5.523(2) Å, c = 15.366(5) Å,
b = 103.967(1)°,
total 1799 unique data (2hmax = 55°) were measured at T = 153 K by Rigaku
a = 90.000(1)°,
c q
= 90.000(1)°, V = 719.9(4) Å3, calcd(Z = 2) = 1.302 g cmꢁ1. A
Mercury CCD apparatus (Mo
absorption correction was applied (
K
a
l
radiation, k = 0.71070 Å). Numerical
= 0.97 cmꢁ1). The structure was solved
by the direct method (SIR92) and refined by the full-matrix least-squares
method of F2 with anisotropic temperature factors for non-hydrogen atoms. All
the hydrogen atoms were located at the calculated positions and refined with
riding. The final wR value is 0.0916 (all data) for 1799 reflections and 182
parameters. Estimated standard deviations are 0.002–0.003 Å for bond lengths
and 0.1–0.2° for bond angles, respectively. CCDC 906654.
References and notes
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with an eluent containing 1–5% Et3N.
21. Glycolic acid 16 was prepared from D-glucose by a four-step process [(i) 4-
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22. KHMDS gave the best result among the bases examined. When 9 was treated
with LDA, significant C-silylation of the enolate was observed. LHMDS was
unreactive to 9.
23. When TMSCl was reacted with an enolate pre-generated from 9 with KHMDS,
the yield of 17 was decreased with increasing enolate-generating time (2 min:
65%; 10 min: 32%) due to decomposition of the enolate.
24. Diethyl malonate was used as
a scavenger of the excess base to avoid
elimination of the 4-methoxyphenoxy group from the rearrangement
products.
25. Hashimoto, N.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1981, 29, 1457.
26. When a benzylidene acetal was employed instead of the 4-chlorobenzylidene
acetal, the hydrolysis of the isopropylidene acetal was accompanied by partial
removal of the benzylidene acetal.
27. (a) Movassaghi, M.; Ahmad, O. K. J. Org. Chem. 2007, 72, 1838; (b) Movassaghi,
M.; Piizzi, G.; Siegel, D. S.; Piersanti, G. Angew. Chem., Int. Ed. 2006, 45, 5859; (c)
Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62, 7507.
28. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953.
29. (a) Corey, E. J.; Link, J. O. Tetrahedron Lett. 1992, 33, 3431; (b) Fukuyama, T.;
Laud, A. A.; Hotchkiss, L. M. Tetrahedron Lett. 1985, 26, 6291.
30. Konosu, T.; Oida, S. Chem. Pharm. Bull. 1991, 39, 2212.
31. Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1996, 118, 8158.
32. The rearrangement products 23 and 27-epi-23 were separable by HPLC (silica
5. (a) Fujiwara, K.; Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka, H.; Murai, A.; Kawai,
H.; Suzuki, T. Tetrahedron Lett. 2004, 45, 7011; (b) Domon, D.; Fujiwara, K.;
Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005, 46, 8285; (c) Takizawa,
A.; Fujiwara, K.; Doi, E.; Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron 2006, 62,
7408; (d) Goto, A.; Fujiwara, K.; Kawai, A.; Kawai, H.; Suzuki, T. Org. Lett. 2007,
9, 5373.
gel 60,
5 lm, 250 mm ꢀ 20 mm, hexane/EtOH = 20). The (26S,27S)-
configuration of 23 was confirmed by X-ray crystallographic analysis of
bicyclic ether 26 derived from 23 (Fig. 2). The configurations at C26 and C27 of
27-epi-23 were determined as follows. The absolute stereochemistry at C26 of
27-epi-23 was determined by the application of modified Mosher’s method to
an alcohol derived from 27-epi-23 by the removal of the PMP group [CAN,
H2O–DMF, 0 °C, 78%]. After the conversion of the alcohol into a 26,28-O-
isopropylidene acetal derivative by reduction with NaBH4 (78%) followed by
acetalization with 2,2-dimethoxypropane and p-TsOHꢂH2O (42%), the cis-
relationship between H26 and H27 of the 6-membered ring isopropylidene
acetal was confirmed by the small JH26–H27 value (<2 Hz) and the presence of
NOE between H27 and H26, of which the axial orientation was verified by the
presence of NOE between H26 and the protons of an isopropylidene methyl
group. Thus, the (26S,27R)-stereochemistry of 27-epi-23 was determined. For
modified Mosher’s method: Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092.
6. Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.; Oguri, H.; Satake,
M. Science 2001, 294, 1904.
7. Inoue, M.; Miyazaki, K.; Ishihara, Y.; Tatami, A.; Ohnuma, Y.; Kawada, Y.;
Komano, K.; Yamashita, S.; Lee, N.; Hirama, M. J. Am. Chem. Soc. 2006, 128, 9352.
8. (a) Inoue, M.; Uehara, H.; Maruyama, M.; Hirama, M. Org. Lett. 2002, 4, 4551;
(b) Inoue, M.; Miyazaki, K.; Uehara, H.; Maruyama, M.; Hirama, M. Proc. Natl.
Acad. Sci. U.S.A. 2004, 101, 12013; (c) Inoue, M.; Hirama, M. Acc. Chem. Res. 2004,
37, 961; (d) Yamashita, S.; Ishihara, Y.; Morita, H.; Uchiyama, J.; Takeuchi, K.;
Inoue, M.; Hirama, M. J. Nat. Prod. 2011, 74, 357.
9. Hamajima, A.; Isobe, M. Angew. Chem., Int. Ed. 2009, 48, 2941.
10. The previously synthesized EF-ring possessed a 2,2-dimethyl-1,3-dioxolan-4-
yl group at C28, which was used as a stereocontrolling auxiliary in the [2,3]-
Wittig rearrangement for the construction of C26 and C27 stereocenters.5d
However, the conversion of the group to an (E)-2-iodoprop-1-en-1-yl group for
the next segment connection5c could not be achieved. Therefore, the synthesis
of EF-ring 1 was newly designed.
33. The use of LDA and LiNEt2 instead of lithium pyrrolidinide decreased the
selectivity of 23 [23:27-epi-23 = 1.7:1 (LDA), 13:1 (LiNEt2)]. When tBuOK was
used in place of KHMDS, the rearranged products were scarcely obtained
owing to a significant and rapid decomposition of 4.
34. The enolate generated from 4 under these conditions was fairly stable in
contrast to the above mentioned enolate of 9.
11. Handbook of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003.
12. (a) Fujiwara, K.; Goto, A.; Sato, D.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2005,
46, 3465; (b) Sato, D.; Fujiwara, K.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2008,
49, 1514; (c) Fujiwara, K.; Kawamura, N.; Kawai, H.; Suzuki, T. Tetrahedron Lett.
2009, 50, 1236.
13. (a) Ireland, R. E.; Muller, R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868; (b)
McFarland, C. M.; McIntosh, M. C. In The Claisen Rearrangement; Hiersemann,
M., Nubbemeyer, U., Eds.; Wiley-VCH: Weinheim, 2007; p 117.
35. Schwab, P.; Grubbs, R. H.; Ziller, J. W. J. Am. Chem. Soc. 1996, 118, 100–110.
36. Crystal data of 26: Crystals were obtained by recrystallizing from Et2O/hexane.
C
31H46O8Si, M = 574.79, colorless platelet, 0.70 ꢀ 0.20 ꢀ 0.01 mm3, triclinic P1
(No. 1), a = 8.808(3) Å, b = 9.111(3) Å, c = 19.458(6) Å,
b = 89.474(9)°,
total 6463 unique data (2hmax = 55°) were measured at T = 150 K by Rigaku
a = 83.231(6)°,
c q
= 89.004(10)°, V = 1550.4(8) Å3, calcd(Z = 2) = 1.231 g cmꢁ1. A
Mercury CCD apparatus (Mo
absorption correction was applied (
K
a
l
radiation, k = 0.71070 Å). Numerical
= 1.23 cmꢁ1). The structure was solved
14. Previously, we reported the development of the similar Ireland-Claisen
by the direct method (SIR92) and refined by the full-matrix least-squares
method of F2 with anisotropic temperature factors for non-hydrogen atoms. All
the hydrogen atoms were located at the calculated positions and refined with
riding. The final wR value is 0.2161 (all data) for 6448 reflections and 718
parameters. Estimated standard deviations are 0.004–0.010 Å for bond lengths
and 0.2–0.7° for bond angles, respectively. CCDC 906653.
rearrangement using
a (Z)-3-(N,N,-diisopropylcarbamoyloxy)allyl glycolate
ester as a substrate.12c However, the low stereoselectivity (at most 3.4:1)
remained as a problem. During the improvement of the stereoselectivity, we
found that (Z)-3-(4-methoxyphenoxy)allyl glycolate esters produced the
rearrangement products in excellent yield and higher stereoselectivity
(unpublished results). The details of the findings will be described elsewhere.
15. For the selective generation of (Z)-ketene silyl acetals from glycolate esters,
see: Denmark, S. E.; Chung, W. J. Org. Chem. 2008, 73, 4582.
37. Selected physical and spectral data of 1: a colorless oil; ½a D25
ꢁ100 (c 1.37,
ꢃ
CHCl3); IR (neat) m 3396, 3020, 2960, 2932, 2893, 2860, 1474, 1463, 1450, 1443,
1386, 1364, 1214, 1199, 1145, 1123, 1099, 1067, 1056, 1011, 941, 825, 795,

680
K. Nogoshi et al. / Tetrahedron Letters 54 (2013) 676–680
1H NMR (300 MHz, CDCl3) d 0.94 (9H, s), 1.02 (9H, s), 2.08– 1294, 1257, 1213, 1195, 1121, 1097, 1054, 1027, 1007, 941, 826, 775 cmꢁ1 1H
;
777, 755, 652 cmꢁ1
;
2.22 (3H, m), 2.29–2.42 (2H, m), 2.62 (1H, ddd, J = 4.0, 8.2, 13.3 Hz), 2.72–2.90
(2H, m), 3.14 (1H, ddd, J = 3.7, 4.9, 8.6 Hz), 3.45 (1H, ddd, J = 5.1, 9.2, 10.5 Hz),
3.53 (1H, br d, J = 3.5, 8.7 Hz), 3.64–3.82 (2H, m), 3.76 (1H, br t, J = 10.4 Hz),
3.90 (1H, dd, J = 3.8, 8.7 Hz), 3.98–4.05 (1H, m), 4.02 (1H, dd, J = 5.1, 10.1 Hz),
4.09 (1H, ddd, J = 2.3, 4.0, 9.2 Hz), 5.71–5.90 (4H, m); 13C NMR (75 MHz, CDCl3)
d 20.1 (C), 22.5 (C), 27.1 (CH3 ꢀ 3), 27.4 (CH3 ꢀ 3), 32.3 (CH2 ꢀ 2), 32.7 (CH2),
63.7 (CH2), 67.4 (CH2), 71.6 (CH), 77.7 (CH), 78.0 (CH), 84.0 (CH), 84.7 (CH), 86.8
(CH), 126.8 (CH), 127.6 (CH), 128.5 (CH), 136.7 (CH); ESI-HRMS calcd for
NMR (400 MHz, CDCl3) d 0.03 (3H, s), 0.09 (3H, s), 0.88 (9H, s), 0.95 (9H, s), 1.01
(9H, s), 1.96–2.14 (2H, m), 2.16–2.25 (1H, m), 2.35 (3H, s), 2.28–2.41 (2H, m),
2.61 (1H, ddd, J = 4.2, 9.0, 13.4 Hz), 2.66–2.77 (1H, m), 2.77–2.89 (1H, m), 3.10–
3.18 (1H, m), 3.43–3.52 (2H, m), 3.70–3.77 (1H, m), 3.75 (1H, br t, J = 10.4 Hz),
3.87 (1H, dd, J = 4.5, 8.6 Hz), 4.01 (1H, dd, J = 5.1, 10.1 Hz), 4.05–4.10 (1H, m),
5.67–5.82 (4H, m), 6.20–6.26 (1H, m); 13C NMR (100 MHz, CDCl3) d ꢁ4.9 (CH3),
ꢁ4.2 (CH3), 17.9 (C), 20.2 (C), 22.5 (C), 25.8 (CH3 ꢀ 3), 27.1 (CH3 ꢀ 3), 27.5
(CH3 ꢀ 3), 27.9 (CH3), 31.9 (CH2), 32.2 (CH2), 32.7 (CH2), 33.7 (CH2), 67.5 (CH2),
73.5 (CH), 77.8 (CH), 78.0 (CH), 83.1 (CH), 85.0 (CH), 86.3 (CH), 94.9 (C), 125.5
(CH), 127.6 (CH), 128.2 (CH), 137.5 (CH), 137.6 (CH); APCI-HRMS calcd for
C
23H41O6Si [M+H]+: 441.2667, found: 441.2667.
38. Selected physical and spectral data of 29: a colorless oil; ½a D25
ꢁ78 (c 0.20,
ꢃ
CHCl3); IR (neat)
m
3022, 2957, 2930, 2894, 2858, 1470, 1445, 1386, 1364, 1308,
C
32H58O5Si2I [M+H]+: 705.2862, found: 705.2872.