Convergent synthesis of the A-J ring system of yessotoxin

Article abstract of DOI:10.1055/s-2008-1078266

A highly convergent synthesis of the A-J ring system of yessotoxin was achieved. A convergent strategy via α-cyano ethers was extensively applied in the assembly of the F and IJ ring fragments to afford the FGHIJ ring unit, followed by coupling with the A

Full text of DOI:10.1055/s-2008-1078266

2368
LETTER
Convergent Synthesis of the A–J Ring System of Yessotoxin
Synthesis of the
A
o
–J
R
ing
S
yst
h
e
m
of
Y
esso
etoxin i Torikai, Koji Watanabe, Hiroaki Minato, Tomoyoshi Imaizumi, Michio Murata, Tohru Oishi*
Department of Chemistry, Graduate School of Science, Osaka University, 1-1 Machikaneyama, Toyonaka, Osaka 560-0043, Japan
Fax +81(6)68505775; E-mail: oishi@chem.sci.osaka-u.ac.jp
Received 24 May 2008
This paper is dedicated to Professor Masahiro Hirama on the occasion of his 60th birthday.
to their scarcity in natural sources. Therefore, chemical
Abstract: A highly convergent synthesis of the A–J ring system of
synthesis9,10 is a practical way of supplying specimens to
allow further investigation of their biological activities.
yessotoxin was achieved. A convergent strategy via a-cyano ethers
was extensively applied in the assembly of the F and IJ ring frag-
During the course of our studies on the total synthesis of
YTX,11 we developed an efficient method11a for the con-
struction of a polycyclic ether system via a-cyano ethers
(a-cyano ether method), which was successfully applied
in the synthesis of model compounds possessing the
CDEF11c and FGHI11b ring systems. Herein, we describe a
highly convergent synthesis of the A–J ring system (2,
Scheme 1), a pivotal intermediate in the synthesis not only
of YTX but also of its congeners.
ments to afford the FGHIJ ring unit, followed by coupling with the
ABC ring unit.
Key words: polyether, convergent synthesis, a-cyano ether, ring-
closing metathesis, reductive etherification
Contamination of bivalve mollusks with yessotoxin
(YTX, 1, Figure 1)1 and its congeners is a worldwide
problem which has resulted in serious damage to shellfish
industries. The toxins are produced by the dinoflagellate
Protoceratium and Lingulodinium species,2 and contami-
nation of shellfish occurs due to filter feeding on the phy-
toplankton blooms in seawater. Although YTX was first
isolated from the digestive glands of scallops in associa-
tion with episodes of diarrhetic shellfish poisoning (DSP),
it has been removed from the category of DSP toxins due
to a lack of diarrheagenicity on oral administration to
mice.3 YTX (1, Figure 1), is known to elicit acute neuro-
toxicity by intraperitoneal administration (LD50 = 286 mg/
kg, mice),4 and a broad spectrum of biological activities
has recently been reported in human cells and tissues, in-
cluding (i) modulation of cytosolic calcium levels of lym-
phocytes,5 (ii) activation of phosphodiesterases,6 and (iii)
activation of caspases via a mitochondrial signal transduc-
tion pathway to induce apoptosis.7 More than twenty con-
geners of YTX,1b,8 with structural diversity focused on the
K ring system, have been identified to date. However, the
toxicity profiles of these congeners remain unknown due
HO
OBn
H
OBn
Me
O
H
H
J
HO
A
H
H
O
O
H
I
H
O H
B
Me
OH
H
O
H
O
H
C
H
H
H
O
H
H
D
O
H
O
G
F
E
H
H
O
Me
Me Me
6/7-fused
2
convergent method
via α-cyano ethers
Me
H
H
H
H
H
H
O
O
O
TBDPSO
A
B
C
TBSO
O
ONAP
H
3
+
H
OBn
H
H
H
F
HO
H
OBn
O
H
H
J
HO
OH
Me
O
I
O
H
O
H
Me
H
OH
NaO3SO
O
Me
G
O
1
H
Me
K
Me
H
O
H
H
4
Me
J
NaO3SO
A
H
H
O
O
H
I32
H
H
O H
B
O
H
Me
OH
H
O
H
H
8/6-fused
C
H
H
H
O
28
D
O
15
convergent method
via α-cyano ethers
H
O
F
G
E
26
H
Me
H
O
Me Me
H
H
H
H
O
TBSO
OH
O
I
OBn
OBn
Yessotoxin (YTX, 1)
F
J
+
Figure 1 Structure of yessotoxin (YTX, 1)
TBDPSO
O
OH
TESO
O
Me
H
Me
Me
TESO
5
6
SYNLETT 2008, No. 15, pp 2368–2372
1
5
.0
9
.2
0
0
8
Advanced online publication: 21.08.2008
DOI: 10.1055/s-2008-1078266; Art ID: U05408ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Synthetic strategy for the A–J ring system (2) of YTX
based on the convergent method via a-cyano ethers

LETTER
Synthesis of the A–J Ring System of Yessotoxin
2369
H
OBn
OBn
H
H
H
H
H
H
H
H
O
O
I
OBn
OBn
TBSO
O
TBSO
OH
H
J
O
a
I
J
F
28
F
+
O
R1
Me
H
TESO
O
O
TBDPSO
O
OH
Me
OTES
TES
O
Me
Me Me
O
TESO
Me
5
6
7a: α-H28
7b: β-H28
R1 = CH2CH2OTBDPS
H
H
OBn
H
F
TBSO
OBn
OBn
H
H
H
H
H
O
H
H
TBSO
O
H
O
H
O
b
OBn
f
H
J
28
J
O
28
R1
+
I
I
F
28
O
Me
OTES
O
H
R1
Me
R3
Me
O
H
OH
Me
Me
OTES
TES
O
Me
O
O
Me
OH
TES
R2
11b
11a
8: R2 = CH2OH, R3 = CN
9: R2 = CH=CH2, R3 = CN
c,d
e
10: R2 = CH=CH2, R3 = CHO
H
H
OBn
H
OBn
H
NOE
H
H
H
O
H
H
TBSO
TBSO
H
OBn
OBn
O
O
O
O
J
H
H
J
H
H
g, h
k
I
O
G
O
G
25
I
O
Me
OTES
O
Me
OTES
F
R1
Me
22
32
F
28
28
R1
Me
O
Me
O
Me
O
26
Mes
N
N Mes
Ph
24
TES
TES
Cl
Cl
R4
H
Ru
13: unsaturated
14: saturated
i,j
15: R4 = H
PCy3
l
16: R4 = Me
12
H
OBn
H
H
H
HO
H
O
OBn
H
H
J
HO
m,n
17
O
I
F
O
Me
OH
H
31
27
O
Me
G
O
H
26
Me
H
Me
NOE
4
JH26–H27 = 9.5 Hz
JH27–H28 = 9.5 Hz
Scheme 2 Reagents and conditions: a) Sc(OTf)3, benzene, r.t., 2 h, quant., (7a/7b = 1:2.5); b) for 7a: TMSCN, Sc(OTf)3, CH2Cl2, r.t., 1 h,
then K2CO3, MeOH, 1 h, 83%; for 7b: TMSCN, Sc(OTf)3, CH2Cl2, r.t., 6 h, then K2CO3, MeOH, 1 h, 62% (recovery of 7b, 32%); c) DMP,
CH2Cl2, r.t., 4 h, 91%; d) Ph3PMeBr, NaN(TMS)2, THF, 0–2 °C, 2 h, 95%; e) DIBAL-H, CH2Cl2, –78 °C to –54 °C, 1 h, 93%; f) tetravinyltin,
MeLi, THF, –78 °C to –61 °C, 30 min, 11a: 24%, 11b: 66%; g) 12 (8 mol%), toluene, reflux, 45 min, 68%; h) DMP, CH2Cl2, r.t., 2 h, 92%; i)
H2, PtO2, EtOAc, r.t., 1 h; j) DMP, CH2Cl2, r.t., 1 h, 76%; k) DBU, p-xylene, reflux, 12 h, 90%; l) LiN(TMS)2, MeI, THF, –78 °C to –30 °C, 4
h, 73% (recovery of 15, 18%); m) Et3SiH, TMSOTf, CH2Cl2, –75 °C to –52 °C, 50 min; n) TBAF, r.t., 50 min, 74% (2 steps).
We envisaged extensive utilization of the a-cyano ether of diastereomers 7a and 7b (7a/7b = 1:2.5) with respect to
method11a to construct the decacyclic A–J ring system (2), the stereogenic center on the acetal carbon.
which was to be derived from the ABC (3) and FGHIJ ring
(4) units via construction of the 6/7-fused DE ring system
Regioselective opening of acetal 7a using TMSCN and
Sc(OTf)3 proceeded smoothly at room temperature (1 h)
as shown in Scheme 1. To prepare 4, we planned to couple
to afford a-cyano ether 8 (83%) as an inseparable mixture
the F (5) and IJ ring (6)11d fragments through formation of
of C2813 diastereomers (5:1). The equivalent reaction of
7b was sluggish (6 h), giving 8 in 62% yield, but recov-
ered 7b (32%) was recycled to give a total yield of 81%
the 8/6-fused GH ring system possessing a b-oriented
methyl group. However, it remained uncertain whether
the a-cyano ether method was applicable to the large mol-
ecule 2 comprising a decacyclic system.
for 8. The resulting primary alcohol 8 was converted to
terminal olefin 9 by a Dess–Martin oxidation14–Wittig
As shown in Scheme 2, synthesis of the FGHIJ ring 4 olefination sequence (86%). Nitrile 9 was reduced with
started with coupling of diol 511c and aldehyde 611d by DIBAL-H at –78 °C to –54 °C to furnish aldehyde 10 as
12
treatment with Sc(OTf)3 in toluene to give a seven- an inseparable mixture of diastereomers (93%, 2.5:1).
membered-ring acetal in the form of a separable mixture Treatment of 10 with vinyllithium resulted in the forma-
tion of a mixture of four diastereomers, which was sepa-
Synlett 2008, No. 15, 2368–2372 © Thieme Stuttgart · New York

2370
K. Torikai et al.
LETTER
TBDPSO
TBSO
rated as two sets of diastereomeric mixtures, 11a (24%)
and 11b (66%). Although the absolute configurations at
C27 and C28 were not identified, the major isomer 11b
was used for subsequent transformations. Ring-closing
metathesis (RCM)15 of the diene 11b by the action of sec-
ond-generation Grubbs catalyst 12 (8 mol%)16 proceeded
smoothly in toluene at reflux for 45 minutes (68%), and
Dess–Martin oxidation of the resulting allylic alcohols
provided the a,b-unsaturated ketone 13 in 92% yield. Hy-
drogenation of the double bond using PtO2 gave a mixture
of saturated ketone 14 and concomitantly formed alcohols
due to overreaction. The mixture was readily oxidized to
give 14 as a single isomer. Although ketone 14 turned out
to be the undesired C28 isomer, epimerization to the de-
sired isomer 15 proceeded by treatment with DBU in p-
xylene under reflux (138 °C) for 12 hours (15/14 = 10:1,
90%). The equivalent reaction in refluxing toluene (110
°C) was too sluggish (20 h, 15/14 = 0.6:1). Stereoselec-
tive methylation of ketone 15 was successfully achieved
under kinetically controlled conditions using LiN(TMS)2
and methyl iodide to afford the desired b-oriented diaste-
reomer 1611b in 73% yield with 18% recovery of 15. Con-
struction of the H ring was achieved in a stereoselective
manner by reductive etherification17,18 of TES ether 16 us-
ing Et3SiH/TMSOTf, and this was followed by removal of
the silyl groups with TBAF to afford the FGHIJ ring unit
4 in 74% yield for two steps. The structure of 4 was deter-
mined by NOE experiments and coupling constants
(JH27–H28 = 9.5 Hz, JH26–H27 = 9.5 Hz).
4
3
+
OBn
OBn
H
Me
O
A
H
H
a
J
H
H
O
O
H
I
H
O H
B
Me
OH
H
H
O
C
H
H
H
15
O
O
H
H
NAPO
O
O
G
E
F
O
H
Me
Me Me
TBDPSO
TBSO
OBn
OBn
H
Me
O
A
17
H
H
J
H
H
O
b
O
H
I32
H
O H
B
O
H
Me
OH
H
H
C
H
H
H
15 O
O
H
O
NAPO
NC
G
F
O
H
Me
R1
c
Me Me
18: R1 = OH
TBDPSO
OBn
OBn
H
19: R1 = SeAr
Me
O
A
H
H
J
TBSO
H
d, e
H
H
O
O
H
I32
H
H
O
H
B
Me
H
O
C
H
H
H
OTES
O
O
H
NAPO
O
R2
G
F
O
H
Me
Me Me
20: R2 = CN
f
21: R2 = CHO
g
22: R2 = CH(OH)CH=CH2
TBDPSO
OBn
H
OBn
Me
O
A
h–j
H
H
H
J
TBSO
H
H
O
O
H
I
H
O H
B
Me
H
H
O
H
C
H
H
With the FGHIJ ring unit 4 in hand, we moved on to cou-
pling with the ABC ring unit 39g,11d and subsequent con-
struction of the DE ring system based on the a-cyano ether
method (Scheme 3). The Sc(OTf)3-catalyzed coupling of
the ABC ring aldehyde 3 with the FGHIJ ring diol 4 pro-
ceeded smoothly irrespective of the molecular size of the
units to furnish seven-membered ring acetal 17 (80%) as
a mixture of C15 diastereomers in a 1:1 ratio. Contrary to
our expectations, attempts to obtain a-cyano ether 18 by
regioselective cleavage under conditions identical to
those used in the successful synthesis of the FGHIJ ring
unit (Scheme 2) failed, and the starting material was re-
covered.
OTES
O
15 O
H
H
NAPO
O
O
G
E
F
O
H
Me
Me Me
23b: β-H15
23a: α-H15
k
HO
OBn
H
OBn
Me
O
A
H
H
O
J
l–n
ROE
HO
H
H
O
H
I
H
O H
B
Me
OH
H
O
H
O
H
C
H
H
H
15 O
H
H
12 D
O
H
O
20
16
H
G
E
F
O
H
Me
Me Me
2
Scheme 3 Reagents and conditions: a) Sc(OTf)3, benzene, r.t., 1.5
h, 80%; b) TMSCN, Sc(OTf)3, MeNO2–CH2Cl2 (7:3), –19 °C to
10 °C, 3.5 h, then PPTS, CH2Cl2–MeOH (1:3), r.t., 1.5 h, 18a: 20%,
18b: 57%; c) ArSeCN, n-Bu3P, MS 4 Å, THF, reflux, 1 h; d) MCPBA,
Cl(CH2)2Cl, r.t., 20 min, then NaHCO3, 60 °C, 1 h; e) TESOTf, 2,6-
lutidine, CH2Cl2, 0 °C, 20 min, 80% (3 steps); f) DIBAL-H, CH2Cl2,
–86 °C to –65 °C, 25 min, 71%; g) tetravinyltin, MeLi, THF, –90 °C
to –65 °C, 30 min, 96%; h) 12 (30 mol%), toluene, reflux, 20 min,
71%; i) DMP, CH2Cl2, r.t., 30 min, 92%; j) H2, PtO2, EtOAc, r.t., 1.5
h, then DMP, CH2Cl2, r.t., 1 h, 85%; k) DBU, p-xylene, reflux, 17 h,
95%; l) DDQ, H2O, CH2Cl2, r.t., 2 h, 73%; m) Et3SiH, BF3·OEt2,
CH2Cl2, –30 °C to –10 °C, 1.5 h; n) TBAF, THF, r.t., 2.5 h, 61% (2
steps). Ar = 2-nitrophenyl.
After considerable experimentation, we found that the use
of MeNO219 as a co-solvent was essential; thus, treatment
of 17 with Sc(OTf)3 and TMSCN in MeNO2–CH2Cl2
(7:3) resulted in the formation of a-cyano ether 18 as a
separable mixture of epimers 18a (20%) and 18b (57%).
Although the configuration at C15 had not yet been iden-
tified, the major isomer 18b was used for subsequent
transformations. In contrast to the synthesis of the CDEF
ring model,11c conversion of the primary alcohol 18b into
a terminal olefin was unsuccessful under the standard con-
ditions,20 and modification of the reaction conditions was
required. Tributylphosphine was added to the mixture
of 18b, 2-nitrophenylselenyl cyanide, and MS 4 Å in
THF under reflux to yield 19, which was oxidized with
MCPBA in dichloroethane, and the resulting selenoxide
was heated at 60 °C in the presence of NaHCO3 to afford
the terminal olefin. Protection of the hydroxy group at
C32 as a TES ether gave 20 in 80% yield for three steps.
The reduction of nitrile 20 with DIBAL-H and addition of
Synlett 2008, No. 15, 2368–2372 © Thieme Stuttgart · New York

LETTER
Synthesis of the A–J Ring System of Yessotoxin
2371
(9) Synthetic studies of yessotoxin and its analogues, see:
(a) Suzuki, K.; Nakata, T. Org. Lett. 2002, 4, 3943.
(b) Suzuki, K.; Nakata, T. Org. Lett. 2002, 4, 2739.
vinyllithium to the resulting aldehyde 21 furnished allylic
alcohol 22. Ring-closing metathesis of diene 22 proceed-
ed successfully to form the seven-membered E ring, and
Dess–Martin oxidation of the secondary alcohol and hy-
drogenation of the olefin resulted in the formation of ke-
tone 23b as a single isomer. Although 23b turned out to
be the undesired isomer at C15, epimerization by treat-
ment with DBU in p-xylene under reflux for 17 hours pro-
ceeded to give a mixture of 23a and 23b in a 6:1 ratio in
95% yield. Finally, construction of the D ring was
achieved by oxidative removal of the NAP21 group with
DDQ, reductive etherification of the resulting hydroxy ke-
tone with Et3SiH/BF3·OEt2, and removal of the silyl
groups to afford the A–J ring system 2 in 45% yield for
three steps. The structure of 2 was unambiguously de-
termined by ROE experiments and coupling constants
(JH15–H16 = 9.5 Hz).22
(c) Mori, Y.; Nogami, K.; Hayashi, H.; Noyori, R. J. Org.
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Minato, H.; Murata, M.; Oishi, T. Heterocycles 2007, 72,
207.
In conclusion, a highly convergent synthesis of the A–J
ring system of YTX (2) was achieved by extensive utili-
zation of the a-cyano ether method developed in our lab-
oratory, which proved to be a powerful strategy, not only
for coupling of small fragments, but also for large seg-
ments giving decacyclic ether system. Studies directed to-
wards the total synthesis of YTX and its congeners using
the key intermediate 2 are in progress.
(12) (a) Fukuzawa, S.-I.; Tsuchimoto, T.; Hotaka, T.; Hiyama, T.
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corresponds to that of YTX.
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Acknowledgment
We thank Dr. Nobuaki Matsumori in our laboratory for discussion
and measurement of Mass Spectrometry. This work was supported
by Grant-in-Aid for Scientific Research (B) (Nos. 15350024,
18350021) from JSPS, and Grant-in-Aid for Scientific Research on
Priority Areas (No. 16073211) from MEXT. A research fellowship
to K.W. from the JSPS is acknowledged.
References and Notes
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(4) Terao, K.; Ito, E.; Oarada, M.; Murata, M.; Yasumoto, T.
Toxicon 1990, 28, 1095.
(20) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem.
1976, 41, 1485.
(21) (a) Gaunt, M. J.; Yu, J.; Spencer, J. B. J. Org. Chem. 1998,
63, 4172. (b) Xia, J.; Abbas, S. A.; Locke, R. D.; Piskorz, C.
F.; Alderfer, J. L.; Matta, K. L. Tetrahedron Lett. 2000, 41,
169.
(5) de la Rosa, L. A.; Alfonso, A.; Vilariño, N.; Vieytes, M. R.;
Botana, L. M. Biochem. Pharmacol. 2001, 61, 827.
(6) Alfonso, A.; de la Rosa, L.; Vieytes, M. R.; Yasumoto, T.;
Botana, L. M. Biochem. Pharmacol. 2003, 65, 193.
(7) Korsnes, M. S.; Hetland, D. L.; Espenes, A.; Aune, T.
Toxicol. in Vitro 2006, 20, 1419.
(8) (a) Ciminiello, P.; Fattorusso, E.; Forino, M.; Magno, S.;
Poletti, R.; Viviani, R. Tetrahedron Lett. 1998, 39, 8897.
(b) Suzuki, T.; Horie, Y.; Koike, K.; Satake, M.; Oshima, Y.;
Iwataki, M.; Yoshimatsu, S. J. Chromatogr. A 2007, 1142,
172.
(22) Physical Data of 2
[a]D30 –10.8 (c 0.04, CHCl3). 1H NMR (500 MHz, C6D6):
d = 7.30–6.99 (10 H, m, Ph), 4.41 (1 H, d, J = 12.0 Hz, Bn),
4.37 (1 H, d, J = 12.0 Hz, Bn), 4.33 (1 H, d, J = 12.0 Hz, Bn),
4.18 (1 H, d, J = 12.0 Hz, Bn), 4.00 (1 H, d, J = 2.5 Hz, H32),
3.88 (1 H, ddd, J = 11.5, 10.0, 4.5 Hz, H30), 3.82 (1 H, dd,
J = 13.5, 4.0 Hz, H34), 3.72 (1 H, m, H37), 3.65 (1 H, dd,
Synlett 2008, No. 15, 2368–2372 © Thieme Stuttgart · New York

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J = 11.0, 4.0 Hz, H38), 3.60 (1 H, dd, J = 11.0, 2.0 Hz, H38),
3.49 (4 H, m, H1, H1, H4, H36), 3.31 (1 H, ddd, J = 10.5,
9.5, 4.0 Hz, H15), 3.27–3.19 (3 H, m, H7, H20, H22), 3.15
(1 H, ddd, J = 9.5, 9.0, 5.5 Hz, H16), 3.12–3.07 (2 H, m,
H13, H28), 3.05–3.00 (3 H, m, H9, H10, H31), 2.94–2.88 (2
H, m, H6, H12), 2.64 (1 H, dd, J = 9.5, 9.0 Hz, H27), 2.59 (1
H, ddd, J = 12.0, 4.5, 4.0 Hz, H14), 2.52 (1 H, ddd, J = 10.5,
4.5, 4.0 Hz, H11), 2.42 (1 H, ddd, J = 10.5, 4.5, 4.0 Hz,
H29), 2.36–2.29 (2 H, m, H8, H35), 2.20 (1 H, ddd, J = 10.5,
4.0, 4.0 Hz, H5), 2.05–1.98 (2 H, m, H17, H17), 1.91–1.81
(5 H, m, H18, H18, H21, H24, H25), 1.76–1.62 (9 H, m, H2,
H2, H5, H11, H14, H21, H26, H29, H35), 1.60–1.53 (2 H,
m, H8, H24), 1.41 (1 H, dddd, J = 10.0, 9.0, 9.0, 2.5 Hz,
H25), 1.27 (3 H, s, Me), 1.26 (3 H, s, Me), 1.16 (3 H, d,
J = 6.0 Hz, 26-Me), 1.11 (3 H, s, Me), 1.00 (3 H, s, Me). 13
C
NMR (150 MHz, C6D6): d = 139.95, 138.84, 88.61, 86.22,
82.89, 81.83, 81.22, 80.45, 78.97, 78.67, 78.04, 77.82, 77.56
(2 ×), 77.24, 76.86, 75.81, 74.93, 73.43 (3 ×), 73.15, 72.26,
71.62, 71.45, 70.96, 69.80, 69.74, 58.75, 46.50, 43.76,
40.46, 39.87, 39.49, 37.70, 36.21, 35.95, 34.53, 32.74,
32.07, 30.15, 29.78, 23.56, 22.11, 20.59, 14.84, 14.30
(signals of aromatic region are overlapped with solvent). IR
(film): n = 3437, 2928, 2874, 1453, 1378, 1340, 1286, 1204,
1068, 1025, 738, 698 cm–1. HRMS (ESI-TOF): m/z calcd for
C57H80O15Na: 1027.5395 [M + Na]+; found: 1027.5398.
Synlett 2008, No. 15, 2368–2372 © Thieme Stuttgart · New York

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