Stereocontrolled synthesis of the IJK ring segment of yessotoxin

Article abstract of DOI:10.1016/j.tetlet.2006.07.027

A stereocontrolled synthesis of the IJK ring segment of yessotoxin is described. Cyclization of 11 mediated by SmI₂ gave the IJ ring system 12 as the sole product. Construction of the K ring moiety was performed by the acid catalyzed cyclizatio

Full text of DOI:10.1016/j.tetlet.2006.07.027

Tetrahedron Letters 47 (2006) 6545–6548
Stereocontrolled synthesis of the IJK ring segment of yessotoxin
Isao Kadota,a,* Takashi Abe,b Yuki Sato,b Chizuko Kabutoa 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 2 June 2006; revised 28 June 2006; accepted 7 July 2006
Available online 31 July 2006
Abstract—A stereocontrolled synthesis of the IJK ring segment of yessotoxin is described. Cyclization of 11 mediated by SmI2 gave
the IJ ring system 12 as the sole product. Construction of the K ring moiety was performed by the acid catalyzed cyclization of
epoxy alcohol 20 to afford the IJK ring segment in a highly stereocontrolled manner.
Ó 2006 Elsevier Ltd. All rights reserved.
Yessotoxin 1 is a disulfated polycyclic ether isolated
from the digestive glands of scallops, Patinopecten
yessoensis.1 Due to its novel structural features and bio-
logical activities, yessotoxin has attracted the attention
of synthetic chemists.2 During the course of our syn-
thetic study of 1, we have already reported the synthesis
of the A-F and F-I ring segments.2e,g Herein, we
describe the stereocontrolled synthesis of the IJK ring
segment.
with thexylborane followed by oxidative work-up,
and TBS protection in 86% overall yield. Hydrogeno-
lysis of the benzylidene acetal of 3 followed by protec-
tion with MPMCl/KH afforded bis-MPM ether 4 in
84% overall yield. Selective cleavage of the primary
MPM ether was carried out with TMSI/HMDS to
give primary alcohol 5 in 92% yield.2e Swern oxidation
of 5 followed by treatment with 2-lithio-1,3-dithiane
provided 6 as an inseparable mixture of diastereoiso-
mers in 89% overall yield. Protection of 6 with MOM-
Cl/iPr2NEt gave a 10:1 mixture of the desired 7 and
its stereoisomer 8 in 89% combined yield. These
isomers, 7 and 8, were easily separated by column
chromatography at this stage. Deprotection of the
Scheme 1 describes the synthesis of the IJ ring system.
Alcohol 2,3 prepared from 2-deoxy-D-ribose by a
known procedure,4 was converted to bis-silyl ether 3
via protection with TBSCl/imidazole, hydroboration
Me
HO
H
O
NaO3SO
Me
H
K
H
B
O
A
H
J
H
H
O
NaO3SO
O
Me
OH
H
H
D
O
I
H
H
H
C
O
H
H
H
H
O
O
H
H
O
O
H
F
O
E
G
H
Me
H
Me
Me
yessotoxin (1)
Keywords: Yessotoxin; Polycyclic ethers; Cyclization.
*
Corresponding author. Tel.: +81 22 795 6755; fax: +81 22 795 6784; e-mail: ikadota@mail.tains.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.027

6546
I. Kadota et al. / Tetrahedron Letters 47 (2006) 6545–6548
H
H
H
H
H
H
H
Ph
O
OH
Ph
O
OTBS
OTBS
MPMO
MPMO
OTBS
OTBS
b
a
O
O
O
O
O
Me
Me
H
Me
H
c
4
2
3
MPMO
H
MPMO
S
H
H
H
H
OTBS
OTBS
OTBS
MPMO
HO
OTBS
e
d
S
S
O
OTBS
f
S
O
O
OTBS
Me
H
Me
Me
H
MOMO
HO
7
6
5
+
EtO2C
HO
H
H
O
H
S
OTBS
OTBS
OTBS
g
S
S
S
S
O
OTBS
S
O
MOMO
Me
Me
H
MOMO
MOMO
9
8
10
h
H
H
O
H
H
H
H
H
OTBS
OTBS
O
OTBS
OTBS
EtO2C
HO
i
EtO2C
I
J
O
OHC
O
H
Me
Me
MOMO
MOMO
12
11
Scheme 1. Reagents and conditions: (a) (i) TBSCl, imidazole, DMF, rt, 98%; (ii) thexylborane, THF, 0 °C, then 3 N NaOH, 30% H2O2, 89%; (iii)
TBSCl, imidazole, DMF, 0 °C, 99%; (b) (i) H2, Pd(OH)2-C, rt, quant; (ii) MPMCl, KH, THF, 0 °C to rt, 84%; (c) TMSI, HMDS, CH2Cl2, 0 °C, then
K2CO3, MeOH, rt, 92%; (d) (i) (COCl)2, DMSO, CH2Cl2, À78 °C, then Et3N, À78 °C to rt; (ii) 1,3-dithiane, n-BuLi, THF, À78 °C, 89% (2 steps); (e)
i
MOMCl, Pr2NEt, CH2Cl2, reflux; 89% (7:8 = 10:1); (f) DDQ, saturated NaHCO3, CH2Cl2, rt; (g) ethyl propiolate, N-methylmorpholine, CH2Cl2,
rt, 86% (2 steps); (h) MeI, saturated NaHCO3, CH2Cl2, reflux, 82%; (i) SmI2, MeOH, THF, À78 °C, 79%.
MPM ether 7 with DDQ followed by treatment with
ethyl propiolate/NMM gave acrylate 10 in 86% over-
all yield. Hydrolysis of the dithio acetal 10 was carried
out with MeI to give aldehyde 11 in 82% yield. The
cyclization precursor 11 was then subjected to the
Nakata protocol. Thus, treatment of 11 with SmI2
in the presence of MeOH furnished 12 as a single ste-
reoisomer in 79% yield.5,6
the corresponding diol, which was converted to bis-ben-
zyl ether 14 in 97% overall yield. Selective removal of the
primary TBS group with CSA, iodination of the result-
ing primary alcohol, and treatment with NaCN afforded
15 in 87% yield. Reduction of the nitrile 15 with DI-
BAL-H gave aldehyde 16 in 81% yield. Treatment of
16 with Eschenmoser’s salt afforded a-vinyl aldehyde
17,8 which was then subjected to Wittig reaction to
provide 18 in 93% overall yield. Reduction of the dienyl
ester 18 with DIBAL-H afforded 19 in 96% yield. Regio-
and stereoselective epoxidation of the diene 19 was
performed under Sharpless conditions to give 20 as a
single stereoisomer in quantitative yield. Removal of
the TBS protection with TBAF afforded diol 21 in quan-
titative yield. Regio- and stereoselective exo-cyclization
of the epoxy alcohol 21 was carried out with CSA to fur-
nish the IJK ring segment 22 as a single stereoisomer in
84% yield.9 The stereochemistry of 22 was unambigu-
ously determined by X-ray crystallographic analysis of
a crystalline derivative 23, Figure 2, prepared by
esterification with p-Br-BzCl/pyridine followed by
removal of the MOM protection with CSA in 77% over-
all yield.10
1
The stereochemistry of 12 was confirmed by H NMR
analysis of the acetate derivative 13, prepared from 12
with Ac2O/pyridine, as shown in Figure 1.7 Coupling
constants, JHa–Hb = 10.5 Hz and JHb–Hc = 2.4 Hz ob-
served clearly indicated the ax–ax and ax–eq relation-
ship of these protons, respectively.
Construction of the K ring moiety is illustrated in
Scheme 2. Reduction of the ester 12 with LiAlH4 gave
2.4 Hz
H
Me OR
OR
10.5 Hz
EtO2C
Hb
In conclusion, we have achieved the synthesis of the IJK
ring segment of yessotoxin 1 via SmI2 mediated cycliza-
tion and acid catalyzed cyclization as key ring-closure
processes in highly stereocontrolled manner. Further
studies towards the total synthesis of 1 are now in
progress in our laboratories.
O
O
H
Hc
AcO
H
Ha
OMOM
Figure 1. 1H NMR analysis of 13.

I. Kadota et al. / Tetrahedron Letters 47 (2006) 6545–6548
6547
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
BnO
O
OTBS
CHO
BnO
O
OTBS
OTBS
BnO
O
OTBS
CN
c
b
a
12
BnO
BnO
O
BnO
O
BnO
O
Me
OMOM
Me
OMOM
Me
OMOM
16
15
14
d
H
H
O
H
H
H
H
O
H
H
H
H
BnO
OTBS
BnO
OTBS
BnO
O
OTBS
f
e
Me
Me
OH
BnO
O
CO2Et
O
CHO
BnO
BnO
BnO
O
H
Me
H
H
Me
OMOM
H
H
Me
H
OMOM
OMOM
18
19
17
g
H
H
H
O
H
H
O
H
BnO
BnO
OTBS
BnO
OH
h
Me
O
Me
O
OH
OH
O
BnO
O
Me
H
H
Me
H
OMOM
OMOM
20
i
21
Br
Me
Me
OH
OH
H
H
H
O
H
H
H
O
H
H
H
H
BnO
O
O
K
j
O
OH
I
J
O
O
BnO
O
Me
H
Me
H
OH
OMOM
23
22
Scheme 2. Reagents and conditions: (a) (i) LiAlH4, ether, 0 °C; (ii) BnBr, NaH, THF, reflux, 97% (2 steps); (b) (i) CSA, MeOH, 0 °C, 90%; (ii) I2,
PPh3, imidazole, benzene–ether, quant; (iii) NaCN, DMF, 50 °C, 97%; (c) DIBAL-H, CH2Cl2, À78 °C, 81%; (d) Me2N+@CH2IÀ, Et3N, CH2Cl2, rt;
i
˚
(e) Ph3P@C(Me)CO2Et, CH2Cl2, rt, 93% (2 steps); (f) DIBAL-H, CH2Cl2, À78 °C, 96%; (g) (À)-DET, Ti(O Pr)4, TBHP, 4 A MS, CH2Cl2, À20 °C,
quant; (h) TBAF, THF, rt, quant; (i) CSA, CH2Cl2, 0 °C, 84%; (j) (i) p-Br-BzCl, pyridine, CH2Cl2, 77%; (ii) CSA, MeOH, rt, quant.
T. Org. Lett. 2002, 4, 3943–3946; (c) Mori, Y.; Takase, T.;
Noyori, R. Tetrahedron Lett. 2003, 44, 2319–2322; (d)
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89–92; (h) Oishi, T.; Suzuki, M.; Watanabe, K.; Murata,
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3. Kadota, I.; Kadowaki, C.; Park, C.-H.; Takamura, H.;
Sato, K.; Chan, P. W. H.; Thorand, S.; Yamamoto, Y.
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4. Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang,
C.-K. Tetrahedron 1990, 46, 4517–4552.
5. (a) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T.
Figure 2. ORTEP drawing of 23.
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Acknowledgements
6. The SmI2 mediated reaction of 11 at 0 °C gave a cyclized
product which had no MOMO group on the I ring.
Elimination of the MOMO group from the ketyl interme-
diate would be faster than the cyclization at higher
temperature.
This work was financially supported by the Novartis
Foundation for the Promotion of Science, the Kurata
Memorial Hitachi Science and Technology Foundation,
the Grant-in-Aid for Scientific Research from the
Ministry of Education, Culture, Sports, Science and
Technology, Japan.
H
H
O
O
EtO2C
EtO2C
References and notes
LnSm O
LnSm O
Me
Me
H
MOMO
1. (a) Murata, M.; Kumagai, M.; Lee, J. S.; Yasumoto, T.
Tetrahedron Lett. 1987, 28, 5869–5872; (b) Satake, M.;
Terasawa, K.; Kadowaki, Y.; Yasumoto, T. Tetrahedron
Lett. 1996, 37, 5955–5958.
2. For synthetic studies of 1, see: (a) Mori, Y.; Hayashi, H.
Tetrahedron 2002, 58, 1789–1797; (b) Suzuki, K.; Nakata,
MeOH
H
H
O
O
SmI2
EtO2C
EtO2C
HO
OHC
Me
H
Me

6548
I. Kadota et al. / Tetrahedron Letters 47 (2006) 6545–6548
7. Compound 13: 1H NMR (400 MHz, C6D6) d 5.05 (dd,
3.35 (s, 3H), 2.53–2.51 (m, 2H), 2.19 (dddd, J = 14.4, 7.6,
7.2, 2.8 Hz, 1H), 2.09–2.02 (m, 2H), 1.70–1.41 (m, 3H),
1.28 (s, 3H), 1.07 (s, 3H).
J = 10.5, 2.4 Hz, 1H), 4.89 (d, J = 6.6 Hz, 1H), 4.70 (d,
J = 6.6;Hz, 1H), 4.57 (m, 1H), 4.14 (d, J = 2.4 Hz, 1H),
3.98–3.90 (m, 3H), 3.76–3.73 (m, 2H), 3.61–3.56 (m, 1H),
3.30–3.25 (m, 4H), 2.55 (dd, J = 15.6, 3.6 Hz, 1H), 2.46
(dd, J = 15.6, 8.0 Hz, 1H), 2.23–2.10 (m, 2H), 1.71 (s, 3H),
1.69–1.48 (m, 2H), 1.16 (s, 3H), 0.98 (s, 9H), 0.93 (t,
J = 7.3 Hz, 3H), 0.90 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H),
À0.03 (s, 3H), À0.09 (s, 3H).
10. Crystal data for 23: 4(C39H45O9Br)Æ(CH3CO2C2H5);
MW = 3024.8, monoclinic, space group P21 (#4); a =
˚
13.427(3), b = 46.89(1), c = 13.452(3) A, b = 92.953(1)°,
3
3
˚
V = 8459(3) A ; Z = 2, Dc = 1.188 g/cm , F(000) = 3168,
l(Mo-Ka) = 1.024 cmÀ1, Rigaku/MSC CCD diffracto-
meter, T = 173 K, 95,659 reflections measured, 34,323
unique (Rint = 0.059), final R1 = 0.155 and wR (all
data) = 0.423. The relatively high R values are due
to the fact that four independent molecules are included
in the asymmetric unit as well as the crystals being of poor
quality. Each four independent molecule adopts a different
conformation of the terminal benzyl groups. Complete
crystallographic data, as a CIF file, have been deposited
with Cambridge Crystallographic Data Centre (CCDC
No. 612577). Copies can be obtained free of charge from:
The Director, CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (e-mail: deposit@ccdc.cam.ac.uk).
8. (a) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser,
A. Angew. Chem., Int. Ed. Engl. 1971, 10, 330–331; (b)
Takano, S.; Inomata, K.; Samizu, K.; Tomita, S.; Yanase,
M.; Suzuki, M.; Iwabuchi, Y.; Sugihara, T.; Ogasawara,
K. Chem. Lett. 1989, 1283–1284.
1
9. Compound 22: H NMR (400 MHz, CDCl3) d 7.60–7.33
(m, 10H), 5.08 (s, 1H), 4.89 (s, 1H), 4.83 (d, J = 6.4 Hz,
1H), 4.69 (d, J = 7.6 Hz, 1H), 4.68 (d, J = 6.4 Hz, 1H),
4.52 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.45
(d, J = 7.6 Hz, 1H), 3.95 (d, J = 2.8 Hz, 1H), 3.91 (s, 1H),
3.83–3.74 (m, 3H), 3.63–3.57 (m, 3H), 3.39–3.32 (m, 3H),