Convergent synthesis of the FGHI ring segment of yessotoxin

Article abstract of DOI:10.1016/j.tetlet.2005.10.136

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

Full text of DOI:10.1016/j.tetlet.2005.10.136

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 89–92
Convergent synthesis of the FGHI ring segment of yessotoxin
Isao Kadota,a,* Hirokazu Ueno,b Yuki Satob and Yoshinori Yamamotob
aResearch and Analytical Center for Giant Molecules, Graduate School of Science,
Tohoku University, Sendai 980-8578, Japan
bDepartment of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 16 August 2005; revised 18 October 2005; accepted 26 October 2005
Available online 10 November 2005
Abstract—A convergent synthesis of the FGHI ring segment of yessotoxin was achieved via the intramolecular allylation of an
a-chloroacetoxy ether and subsequent ring-closing metathesis.
Ó 2005 Elsevier Ltd. All rights reserved.
Yessotoxin 1 is a disulfated polycyclic ether isolated
from the digestive glands of the scallops, Patinopecten
yessoensis.1 Due to its novel structural features and bio-
logical activities, yessotoxin has attracted the attention
of synthetic chemists.2 Recently, we developed an effi-
cient method for the convergent synthesis of polycyclic
ethers via the intramolecular allylation of an a-acetoxy
ether and subsequent ring-closing metathesis.3 The
methodology was successfully applied to the stereoselec-
tive synthesis of the A–F ring segment of 1.4 We now
wish to report the further application of this technology
to the synthesis of the FGHI ring system of 1.5
DDQ, acid catalyzed acetal formation with 8, and cleav-
age of the resulting methyl acetal with TMSI/HMDS
furnished the allylic stannane 9 in 78% overall yield.9
Modified Rychnovsky acetylation of 9 via DIBAL-H
reduction followed by treatment with (CH2ClCO)2O/
DMAP/pyridine gave a-chloroacetoxy ether 10 in 94%
yield.10,11 Intramolecular allylation of 10 with
MgBr2ÆOEt2 in CH3CN gave a 78:22 mixture of the
desired product 11 and its stereoisomer 12 in 99% com-
bined yield.
The next task was the construction of the G ring having a
methyl group. Wacker oxidation of 11 provided methyl
ketone 13 in 81% yield (Scheme 3). Desilylation of 13
with TBAF, oxidation of the resulting alcohol, and Wit-
tig olefination gave diene 14 in 90% overall yield. Ring-
closing metathesis of 14 was carried out using the second
generation Grubbs catalyst 15 to give 16 in 88% yield.12
Hydrogenation of 16 under standard conditions afforded
17 as the sole product in 52% yield. However, the stereo-
chemistry of the methyl group of the G ring was opposite
to that required. We attempted other conditions such as
the use of Pd(OH)2 and Crabtreeꢀs catalyst13 in order to
obtain the desired stereochemistry of the Me group, but
all the approaches resulted in failure: the undesired ste-
reochemistry was always obtained.14
Scheme 1 shows the synthesis of the F ring fragment.
The olefin 2, synthesized by the reported procedure,6
was converted to alcohol 3 in 87% overall yield via
MPM protection followed by hydroboration–oxidation.
Protection of 3 with TBDPSCl and selective removal of
the MPM group afforded 4 in 96% overall yield.
The I ring moiety 6 was prepared from diol 57 by several
steps including acetalization with anisaldehyde, DIBAL-
H reduction, Swern oxidation of the resulting primary
alcohol, Wittig reaction, hydroboration–oxidation,
TEMPO oxidation, and NaClO2 oxidation of the result-
ing aldehyde (Scheme 2). Esterification of carboxylic
acid 6 with alcohol 4 was carried out under the Yama-
guchi conditions8 to provide ester 7. A series of reactions
including deprotection of the MPM ether of 7 with
Finally, we found that the following method gave the
desired stereochemistry (Scheme 4). Treatment of 13
15
with KHMDS/PhNTf2 gave the corresponding enol
triflate, which was then subjected to palladium-catalyzed
reaction with CO/MeOH to provide ester 18 in 74%
overall yield.16,17 DIBAL-H reduction of 18 followed
by MPM protection gave 19 in 94% overall yield.
Keywords: Yessotoxin; Polycyclic ethers; Convergent synthesis.
*
Corresponding author. Tel.: +81 227956755; fax: +81 227956784;
e-mail: ikadota@mail.tains.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.10.136

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I. Kadota et al. / Tetrahedron Letters 47 (2006) 89–92
Me
HO
H
O
NaO3SO
NaO3SO
H
Me
O
A
K
H
B
H
O
J
H
H
O
Me
OH
H
H
D
O
I
H
H
H
C
O
H
H
H
H
O
O
H
H
O
H
Me
O
H
F
O
E
G
H
Me
Me
yessotoxin 1
H
H
H
H
Ph
O
OH
Ph
a
O
OR1
O
O
O
O
OR2
Me Me
Me Me
3: R1 = MPM, R2 = H
4: R1 = H, R2 = TBDPS
2
b
Scheme 1. Reagents and conditions: (a) (i) MPMCl, KH, THF, 0 °C to rt; (ii) (c-Hex)2BH, THF, 0 °C, then 30% H2O2, 3 N NaOH, 0 °C, 87%; (b) (i)
TBDPSCl, imidazole, DMF, rt; (ii) DDQ, NaHCO3, CH2Cl2–H2O (10:1), rt, 96%.
H
H
H
H
H
H
H
O
O
I
Ph
O
O
O
I
a-c
d
HO
HO
HO2C
MPMO
F
O
O
O
Me Me MPMO
TBDPSO
6
5
7
e-g
H
H
O
H
H
H
H
H
Ph
O
O
Ph
O
O
O
h
O
O
O
RO
O
O
O
O
i
Me Me
TBDPSO
H
Me Me
TBDPSO
10
SnBu3
SnBu3
9
H
O
H O
Ph
H
H
O
H
O
I
H
O
H
O H
H
O
+
G
O
Me
O
H
H
Me
SnBu3
TBDPSO
MeO
11
12
8
Scheme 2. Reagents and conditions: (a) (i) anisaldehyde, PPTS, benzene, reflux; (ii) DIBAL-H, CH2Cl2, rt, 81%; (b) (COCl)2, DMSO, CH2Cl2,
À78 °C, then Et3N; (ii) CH3PPh3+BrÀ, NaHMDS, THF, 0 °C; (iii) 9-BBN, THF, rt, then 3 N NaOH, 30% H2O2, 0 °C, 63%; (c) TEMPO, NaClO,
KBr, NaHCO3, CH2Cl2–H2O, 0 °C, (ii) NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH–THF–H2O, 0 °C, quant; (d) 2,4,6-trichlorobenzoyl
chloride, Et3N, THF, rt, then 4, DMAP, toluene, rt, 88%; (e) DDQ, NaHCO3, CH2Cl2–H2O, rt, 96%; (f) 8, CSA, CH2Cl2, rt, 93%; (g) HMDS,
TMSI, CH2Cl2, 0 °C, 87%; (h) DIBAL-H, CH2Cl2, À78 °C, then (CH2ClCO)2O, pyridine, DMAP, À78 °C, 94%; (i) MgBr2ÆOEt2, CH3CN, 40 °C,
99% (11:12 = 78:22).
Hydroboration of 19 with BH3ÆSMe2 followed by oxida-
tive work-up furnished the corresponding alcohol 20 as
a single stereoisomer in 76% yield.18 Iodination of 20
with I2/PPh3/imidazole followed by lithiation with t-
BuLi and protonation with MeOH gave 21 in 86% over-
all yield.19 Deprotection of the MPM ether, oxidation of
the resulting alcohol, and Wittig reaction afforded 22 in
55% overall yield. Desilylation of 22 with TBAF, treat-
ment of the resulting alcohol with 2-nitrophenyl seleno-
cyanate/PBu3, and oxidative work-up gave diene 23 in

I. Kadota et al. / Tetrahedron Letters 47 (2006) 89–92
91
H
H
H
H
H
O
O
O
Ph
Ph
H
H
O
O
H
H
H
H
O
O
a
O
O
O
O
H
Me
H
H
O
Me
O
Me
Me
Me
O
TBDPSO
TBDPSO
13
11
b
H
O
Ph
Ph
H
O
H
O
H
H
H
H
c
O
O
O
O
O
H
Me
O
H
H
O
Me
O
Me
Me
Me
Me
16
d
14
H
H
O H
H
O
Ph
H
O
H
I
H
O
O
N Mes
Ph
Mes
Cl
Cl
N
G
O
Me
Me
Ru
PCy3
Me
H
15
NOE
17
Scheme 3. Reagents and conditions: (a) PdCl2, CuCl, O2, DMF–H2O, 30 °C, 81%; (b) (i) TBAF, THF, rt; (ii) SO3Æpy, DMSO, Et3N, CH2Cl2, rt; (iii)
CH3PPh3+BrÀ, NaHMDS, THF, 0 °C; 90%; (c) 15, CH2Cl2, rt, 88%; (d) H2, 10% Pd–C, EtOAc, rt, 52%.
H
O
H O
H
H
O
O
a
b
13
O
H
O H
H
c
H
MeO2C
18
19
MPMO
H O
H
O
H
H
O
O
d
O
O
H
H
H
H
Me
OH
MPMO
MPMO
21
20
e-f
H
H
O
O
Ph
Ph
H
O
H
O
H
H
H
H
O
O
g
O
O
O
H
Me
O H
H
Me
H
O
O
Me
Me
Me
Me
TBDPSO
23
22
h
H O
H
H O
Ph
Ph
H
H
O
O
H
H
H
H
I
O
O
i
O
O
F
O
Me
O
O
H
Me
H
H
G
O
Me
Me
Me
H
Me
NOE
25
24
Scheme 4. Reagents and conditions: (a) (i) PhNTf2, KHMDS, DMPU, THF, À78 °C; (ii) CO, MeOH, Pd(PPh3)4, DMF, rt, 74%; (b) (i) DIBAL-H,
CH2Cl2, À78 °C; (ii) MPMCl, KH, THF, rt, 94%; (c) BH3ÆSMe2, THF, 0 °C, then 3 N NaOH, 30% H2O2, 0 °C, 76%; (d) (i) I2, PPh3, imidazole,
benzene, rt; (ii) t-BuLi, THF, À78 °C, then MeOH, 86%; (e) DDQ, NaHCO3, CH2Cl2–H2O, rt, 84%; (f) (i) SO3Æpy, DMSO, Et3N, CH2Cl2, rt; (ii)
CH3PPh3+BrÀ, NaHMDS, THF, 0 °C, 66%; (g) (i) TBAF, THF, rt; (ii) 2-nitrophenyl selenocyanate, PBu3, THF, rt, then, 30% H2O2, 90%; (h) 15,
toluene, 130 °C, sealed tube, 90% ; (i) 5% Pd–C, EtOAc, 98%.

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I. Kadota et al. / Tetrahedron Letters 47 (2006) 89–92
90% overall yield.20 Diene 23 was subjected to the ring-
closing metathesis using 15 to furnish 24 in 90% yield.
Finally, hydrogenation of 24 afforded the FGHI ring
segment 25 in 98% yield.21 The stereochemistry of the
methyl group was confirmed by NOE experiments.
9. Kadota, I.; Sakaihara, T.; Yamamoto, Y. Tetrahedron
Lett. 1996, 37, 3195–3198.
10. Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.; Matsuda,
K.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 46–47.
11. 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.
12. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett.
1999, 1, 953–956.
13. Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Chem. Soc.,
Chem. Commun. 1976, 716–717.
In conclusion, we have achieved a convergent and
stereoselective synthesis of the FGHI ring segment of
yessotoxin 1 via the intramolecular allylation of an
a-chloroacetoxy ether and ring-closing metathesis.
Further studies toward the total synthesis of 1 are now
in progress in our laboratories.
14. Stereoselective hydrogenation of the related cyclic ether
using Crabtreeꢀs catalyst has been reported, see: Fujiwara,
K.; Koyama, Y.; Doi, E.; Shimawaki, K.; Ohtaniuchi, Y.;
Takemura, A.; Souma, S.; Murai, A. Synlett 2002, 1496–
1499.
Acknowledgments
This work was financially supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
15. Fujiwara, K.; Tsunashima, M.; Awakura, D.; Murai, A.
Tetrahedron Lett. 1995, 36, 8263–8266.
16. For the palladium-catalyzed carbonylation of enol tri-
flates, see: Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron
Lett. 1985, 26, 1109–1112.
17. Hydroboration–oxidation of the exo-olefin prepared from
12 afforded the undesired stereoisomer as shown below.
References and notes
1) BH3·SMe2
2) H2O2, NaOH
H
H
1. (a) Murata, M.; Kumagai, M.; Lee, J. S.; Yasumoto, T.
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hedron Lett. 2003, 44, 7315–7319; (e) Watanabe, K.;
Suzuki, M.; Murata, M.; Oishi, T. Tetrahedron Lett. 2005,
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H
H
O
O
O
O
O
O
H
Me
H
H
Me
H
HO
18. The hydrogenation of 18 under the standard conditions
gave the corresponding enol ether via olefin migration.
H
H
H
H
O
O
O
O
H2
Pd-C
O
O
H
Me
H
H
H
MPMO
MPMO
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see Ref. 2e.
6. Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang,
C.-K. Tetrahedron 1990, 46, 4517–4552.
7. Nicolaou, K. C.; Hwang, C.-K.; Marron, B. E.; DeFreses,
S. A.; Couladouros, E. A.; Abe, Y.; Carrol, P. J.; Snyder,
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19. Reduction of iodide with metal hydrides such as LiAlH4
resulted in failure.
20. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem.
1976, 41, 1485–1486.
21. A referee pointed out that hydrogenation of the sterically
hindered olefin 24 seems to be problematic, or olefin
migration may occur under the reaction conditions. So we
carried out the hydrogenation of 24 conditions. Although
the reaction was relatively slow, neither olefinic migration
nor epimerization of the methyl group was observed in
this reaction. The desired compound 25 was obtained as
the sole product.