Iterative synthesis of the ABCDEF-ring system of yessotoxin and adriatoxin

Article abstract of DOI:10.1016/S0040-4039(03)00252-1

A stereocontrolled linear synthesis of the ABCDEF-ring system of yessotoxin and adriatoxin, diarrhetic shellfish toxins, is described. Iterative application of a tetrahydropyran synthesis by reaction of the alkylation of a sulfonyl-stabilized oxiranyl ani

Full text of DOI:10.1016/S0040-4039(03)00252-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2319–2322
Iterative synthesis of the ABCDEF-ring system of yessotoxin
and adriatoxin
Yuji Mori,a,* Toyohisa Takasea and Ryoji Noyorib,†
aFaculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503, Japan
bDepartment of Chemistry, Graduate School of Science, Nagoya University, Chikusa-ku, Nagoya 464-8602, Japan
Received 26 December 2002; revised 20 January 2003; accepted 24 January 2003
Abstract—A stereocontrolled linear synthesis of the ABCDEF-ring system of yessotoxin and adriatoxin, diarrhetic shellfish toxins,
is described. Iterative application of a tetrahydropyran synthesis by reaction of the alkylation of a sulfonyl-stabilized oxiranyl
anion followed by 6-endo cyclization of a 4,5-epoxy alcohol led to the synthesis of the trans-fused hexacyclic ether system, and
the seven-membered E ring was constructed by ring expansion reaction. © 2003 Elsevier Science Ltd. All rights reserved.
Polycyclic ether marine toxins produced by marine
dinoflagellates consist of bioactive agents, the skeletons
of which incorporate regular oxygenated heterocycles.1
A few of them are known as causative toxins of
diarrhetic shellfish poisoning. Yessotoxin (1) was iso-
lated as a diarrhetic toxin from the digestive glands of
scallops, Patinopecten yessoensis, infested by toxic
dinoflagellates in Japan.2 More recently, adriatoxin (2),
a new analog of yessotoxin, was also isolated from the
digestive glands of toxic mussels, Mytilus galloprovin-
cialis, in Italy.3 These two molecules contain the same
ring system from ring A to ring J, and yessotoxin has
an extra K-ring with a side chain containing three
olefinic bonds. Both toxins are an interesting synthetic
target from the viewpoints of their unique structural
frameworks and biological activity, and an initial syn-
thetic approach has been documented by us.4 The
recent synthesis of the ABCDEF-ring system of the
toxins by Nakata’s group5 prompted us to publish our
own results that utilize the alkylation of a sulfonyl-sta-
bilized oxiranyl anion and 6-endo cyclization in the key
steps. Our method allows for a linear, iterative synthesis
of the ABCDEF-ring system 3 of yessotoxin.
E rings are the same epoxy sulfone, fragment 3 can be
constructed from only four building blocks 5–8.
Synthesis of the A ring started from the coupling
reaction of the oxiranyl anion generated from epoxy
sulfone 56 and triflate 6 prepared from 1,3-O-di-t-
butylsilylene-
-erythritol (9)7 (Scheme 2). A mixture of
D
5 and 6 in THF–HMPA at −100°C was treated with
n-BuLi to give epoxy sulfone 10 in 85% yield. Treat-
ment of 10 with TsOH·H2O in CHCl3 at 0°C led to
detriethylsilylation and the subsequent stereospecific 6-
endo cyclization of the 4,5-epoxy alcohol afforded
ketone 11 in 89% yield.
The reaction temperature was critical for the 6-endo
cyclization of 10; reaction at 25°C induced a 1,2-shift of
the sulfonyl group rather than 6-endo cyclization to give
a-sulfonyl ketone 14 in 52% yield. Stereoselective reduc-
tion with NaBH4 followed by O-benzylation and
deprotection of the silylene group gave the A ring diol
12. The diol was transformed into triflate 13 by regiose-
lective O-triflation followed by triethylsilylation in one
pot.
Retrosynthetic analysis based on the oxiranyl anion
strategy led to disconnection of the ABCDEF-ring
fragment 3 into seven building blocks (Scheme 1). As
the building blocks for construction of the B, C, D, and
Construction of rings B, C, and D on the A ring was
accomplished sequentially in a five-step iterative man-
ner (Scheme 3). Reaction of triflate 13 and oxiranyl-
lithium of 78 by an in situ quenching method afforded
epoxy sulfone 15 (step 1). The 6-endo cyclization of 15
was achieved by heating at 55°C with TsOH·H2O in
CHCl3 to give bicyclic ketone 16 (step 2). Reduction
with NaBH4 (step 3), desilylation with n-Bu4NF (step
4), and O-triflation and -silylation in one pot (step 5)
Keywords: polycyclic ethers; marine toxins; oxiranyllithiums; 6-endo
cyclization.
* Corresponding author. Tel.: +81-52-832-1781; fax: +81-52-834-8090;
e-mail: mori@ccmfs.meijo-u.ac.jp
† Visiting Professor of Meijo University.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00252-1

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Y. Mori et al. / Tetrahedron Letters 44 (2003) 2319–2322
Scheme 1.
Scheme 2. Reagents and conditions: (a) Tf2O, 2,6-lutidine, CH2Cl2, −78°C, 30 min, then TESOTf, 95%; (b) 5, n-BuLi, THF,
HMPA, −100°C, 85%; (c) TsOH·H2O, CHCl3, 0°C, 89%; (d) (i) NaBH4, MeOH–CH2Cl2, −78°C, 97%; (ii) KH, BnBr, THF, rt,
96%; (iii) TBAF, THF, 100%; (e) Tf2O, 2,6-lutidine, CH2Cl2, −78°C, 30 min, then TESOTf, 86%.
yielded the AB-ring triflate 17. Construction of the C
ring on 17 was performed by iteration of the five-step
reaction sequence described above, and the tricyclic
triflate 20 was obtained in 55% overall yield. Reiterative
application of the tetrahydropyran synthesis with 20 led
to the tetracyclic triflate 23 in 49% overall yield, which
was then converted into pentacyclic ketone 25 by apply-
ing the steps 1–3 of the iterative process.
hydropyran.8 Thus, reaction of 25 with trimethylsilyl-
diazomethane in the presence of BF3·OEt2 in CH2Cl2 at
−78°C gave the seven-membered ketone 26 in 56% yield
along with 5% of its isomeric ketone.
In order to construct a tertiary alcohol on the E ring,
direct methylation of 26 with MeMgBr, MeLi, and
Me3Al was examined. However, the major product was
a compound methylated undesirably from the less-hin-
dered a-side. Then, a methyl group was introduced in a
stepwise manner (Scheme 4). Methylenation of the keto
The oxepane (E ring) formation was accomplished sim-
ply by using a ring-expansion reaction of a keto tetra-

Y. Mori et al. / Tetrahedron Letters 44 (2003) 2319–2322
2321
Scheme 3. Reagents and conditions: (a) 7, n-BuLi, THF, HMPA, −100°C, 15: 91%, 18: 89%, 21: 95%, 24: 89%; (b) TsOH·H2O,
CHCl3, 55°C, 16: 74%, 19: 74%, 22: 73%, 25: 73%; (c) NaBH4, MeOH–CH2Cl2, −78°C, 95% (1st), 96% (2nd), 93% (3rd); (d)
TBAF, THF, rt, 89% (1st), 96% (2nd), 86% (3rd); (e) Tf2O, 2,6-lutidine, CH2Cl2, −78°C, 30 min, then TESOTf, 92% (1st), 91%
(2nd), 84% (3rd); (f) Me3SiCHN2, BF3·OEt2, CH2Cl2, −78°C; PPTS, MeOH, rt, 56% (isomeric ketone: 5%).
function with the Tebbe reagent and epoxidation with
m-CPBA gave a mixture of epoxides (a:b=4:1), from
which a-epoxide 28 was isolated in 56% yield. Reduc-
tion with lithium triethylborohydride yielded the
desired tertiary alcohol 29 after desilylation with n-
Bu4NF. Synthesis of the F ring on 29 includes the
construction of sterically congested 1,3-diaxial dimethyl
groups. Our oxiranyl anion strategy also provides an
effective method to construct such methyl-substituted
tetrahydropyans.9 One-pot triflation of the primary
alcohol and trimethylsilylation of the tertiary alcohol of
29 gave 30. Coupling reaction of the triflate 30 with the
oxiranyllithium generated from 86 afforded epoxy sul-
fone 31 in 90% yield. The crucial 6-endo cyclization was
performed by exposure of 31 to BF3·OEt2 to give the
hexacyclic ketone 32 in 72% yield.
In summary, we have completed a linear synthesis of
the ABCDEF hexacyclic system of yessotoxin and adri-
atoxin based on the oxiranyl anion strategy. Reiterative
application of the tetrahydropyran synthesis via a five-
step sequence of triflation-silylation of a diol, reaction
with oxiranyl anion, 6-endo cyclization of a 4,5-epoxy
alcohol, carbonyl reduction, and O-deprotection pro-
vided a useful method for the construction of a trans-
fused polycyclic ethers system containing sterically
congested methyl-substituted and 1,3-diaxial dimethyl-
substituted tetrahydropyrans. Further efforts directed
toward total synthesis of natural products are in
progress.
Acknowledgements
The 1,3-diaxial stereochemistry of the two methyl
groups in the F ring was established by NOE experi-
ments. Finally, reduction of the ketone with NaBH4
followed by desilylation afforded the target ABCDEF-
ring system 3 of yessotoxin and adriatoxin.
This work was aided by Grant-in-Aid for Creative
Scientific Research (No. 14GS0214) from the Ministry
of Education, Culture, Sports, Science and Technology,
Japan.

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Y. Mori et al. / Tetrahedron Letters 44 (2003) 2319–2322
Scheme 4. Reagents and conditions: (a) Tebbe, THF, rt, 80%; (b) m-CPBA, CH2Cl2, rt, 56% (b-epoxide: 13%); (c) LiBHEt3, THF,
0°C, 92%; (d) TBAF, THF, rt, 89%; (e) Tf2O, 2,6-lutidine, CH2Cl2, −78°C, 30 min, then TMSOTf, 85%; (f) 8, n-BuLi, THF,
HMPA, −100°C, 90%; (g) BF3·OEt2, CH2Cl2, 0°C, 72%; (h) NaBH4, MeOH–CH2Cl2, 0°C, 95%; (i) TBAF, THF, rt, 90%.
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