Convergent Synthesis of the ABCDEF-Ring System of Yessotoxin and Adriatoxin

Article abstract of DOI:10.1021/ol026804w

(Matrix Presented) The convergent synthesis of the ABCDEF-ring system of yessotoxin and adriatoxin was accomplished. This efficient convergent strategy was performed on the basis of the coupling of the acetylide of the A-ring and the triflate of the DEF-r

Full text of DOI:10.1021/ol026804w

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3943-3946
Convergent Synthesis of the
ABCDEF-Ring System of Yessotoxin
and Adriatoxin
,†,§
Keisuke Suzuki†,‡ and Tadashi Nakata*
Graduate School of Science and Engineering, Saitama UniVersity, Saitama,
Saitama 338-8570, Japan, and RIKEN (The Institute of Physical and Chemical
Research), Wako, Saitama 351-0198, Japan
nakata@postman.riken.go.jp
Received August 28, 2002
ABSTRACT
The convergent synthesis of the ABCDEF-ring system of yessotoxin and adriatoxin was accomplished. This efficient convergent strategy was
performed on the basis of the coupling of the acetylide of the A-ring and the triflate of the DEF-ring, oxidation of the alkyne to diketone,
intramolecular diacetalization, and stereoselective reduction of the diacetal with Et3SiH−TMSOTf.
Yessotoxin (YTX; 1), isolated from the digestive glands of
DSP (Diarrethic Shellfish Poisoning)-infested scallops,
Patinopecten yessoensis, is a disulfated polycyclic ether toxin
(Figure 1). The relative and absolute configurations have
been elucidated by Yasumoto et al.1 Adriatoxin (ATX; 2), a
new analogue of YTX, was isolated from the digestive glands
of DSP-infested mussels, Mytilus galloproVincialis, and the
structure was determined by Fattorusso et al.2 As they show
potent mouse lethality, contamination of bivalves by these
compounds poses a problem worldwide to human health as
well as to the shellfish industry. The structure of these
compounds features trans-fused polycyclic ether ring systems,
in which six-, seven-, and eight-membered ethers are
involved. The synthetically challenging structure combined
with potent biological activity has attracted the attention of
synthetic organic chemists.3
We have already reported an efficient strategy for con-
vergent synthesis of trans-fused polycyclic ethers.4,5 The
Scheme 1a
† Saitama University.
‡ On leave from Sankyo Co., Ltd.
§ RIKEN.
a Reagents and conditions: (a) TBSOTf, 2,6-lutidine, CH2Cl2,
0 °C; (b) DIBAH, CH2Cl2, 0 °C (85%, two steps); (c) Tf2O, 2,6-
lutidine, CH2Cl2, -78 °C; (d) NaI, acetone, 60 °C (66%, two steps);
(e) Et2NCHMeCN, LDA, THF-HMPA, -78 °C, then SiO2-H2O
(100%); (f) TBAF, THF rt; (g) ethyl propiolate, N-methylmorpho-
line, CH2Cl2, rt (90%, two steps); (h) SmI2, MeOH, THF, rt (84%).
(1) (a) Murata, M.; Kumagai, M.; Lee, J. S.; Yasumoto, T. Tetrahedron
Lett. 1987, 28, 5869. (b) Satake, M.; Terasawa, K.; Kadowaki, Y.;
Yasumoto, T. Tetrahedron Lett. 1996, 37, 5955. (c) Morohashi, A.; Satake,
M.; Oshima, Y.; Yasumoto, T. Biosci. Biotechnol. Biochem. 2000, 64, 1761.
(2) Ciminiello, P.; Fattorusso, E.; Forino, M.; Magno, S.; Poletti, R.;
Viviani, R. Tetrahedron Lett. 1998, 39, 8897.
(3) The convergent synthesis of the BCDE-ring of 1 was reported: Mori,
Y.; Hayashi, H. Tetrahedron 2002, 58, 1789.
10.1021/ol026804w CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/28/2002

Figure 1. Structures of yessotoxin (1) and adriatoxin (2).
Scheme 2a
a Reagents and conditions: (a) DIBAH, toluene, -78 °C (100%); (b) Ph3PdCH(Me)CO2Et, toluene, 100 °C (100%); (c) TBSOTf, 2,6-
lutidine, CH2Cl2, 0 °C (100%); (d) DIBAH, toluene, -78 °C (89%); (e) (-)-DET, Ti(Oi-Pr)4, TBHP, 4 Å MS, CH2Cl2, -35 °C (96%); (f)
SO3‚pyridine, Et3N, DMSO, CH2Cl2, rt; (g) Ph3P+CH3Br-, NaHMDS, THF, 0 °C (96%, 2 steps); (h) TBAF, THF, rt (74%); (i) PPTS,
CH2Cl2, 0 °C (68%); (j) 9-BBN, THF, 0 °C; then 30% H2O2,, 3 N NaOH, 0 °C (82%); (k) BnBr, NaH, Bu4NI, THF, 0 °C (87%); (l) CSA,
MeOH, rt (85%); (m) Tf2O, 2,6-lutidine, CH2Cl2, -78 °C, then TBSOTf, -78 °C (100%).
strategy involves only four steps: (1) the acelylide-triflate
coupling of two cyclic ethers, (2) oxidation of the alkyne to
the R-diketone, (3) intramolecular diacetalization, and (4)
stereoselective Lewis acid-catalyzed silane reduction. As an
application of this strategy toward the total synthesis of
marine polycyclic ethers, we now report the convergent
synthesis of the ABCDEF-ring system of YTX (1) and ATX
(2).
reduction of the ester, the resultant alcohol was transformed
into the iodide 5 in 56% yield (four steps). Treatment of 5
with the lithium anion of diethylaminopropionitrile8 followed
by hydrolysis with wet silica gel effectively afforded ketone
6 in quantitative yield. After removal of the TBS group in
Scheme 3a
Synthesis of the lactone 8, corresponding to the DE- ring
of 1 and 2, is shown in Scheme 1. The synthesis started with
cyclic ether 4,6 corresponding to the D-ring, which was
stereoselectively synthesized by our developed SmI2-induced
cyclization7 of 3, prepared from 2-deoxy-D-ribose. After
protection of the secondary alcohol of 4 with TBSOTf and
(4) Matsuo, G.; Hinou, H.; Koshino, H.; Suenaga, T.; Nakata, T.
Tetrahedron Lett. 2000, 41, 903.
(5) The same strategy was reported independently by the groups of Murai
and Mori at almost the same time: (a) Fujiwara, K.; Morishita, H.; Saka,
K.; Murai, A. Tetrahedron Lett. 2000, 41, 507. (b) Mori, Y.; Mitsuoka, S.;
Furukawa, H. Tetrahedron Lett. 2000, 41, 4161.
(6) The synthesis of 4 will be described in detail elsewhere. See
Supporting Information for the synthetic scheme of 4.
(7) (a) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron
Lett. 1999, 40, 2811. (b) Hori, N.; Matsukura, H.; Nakata, T. Org. Lett.
1999, 1, 1099. (c) Matsuo, G.; Hori, N.; Nakata, T. Tetrahedron Lett. 1999,
40, 8859. (d) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron
2002, 58, 1853.
a Reagents and conditions: (a) Me2C(OMe)2, CSA, DMF, rt
(94%); (b) H2, Pd(OH)2, EtOAc, rt (99%); (c) Tf2O, 2,6-lutidine,
CH2Cl2, -78 °C, then TBSOTf, -78 °C; (d) (trimethylsilyl)acet-
ylene, n-BuLi, THF, -78 °C (99%, two steps); (e) K2CO3, MeOH,
rt (83%).
3944
Org. Lett., Vol. 4, No. 22, 2002

Scheme 4a
a Reagents and conditions: (a) t-BuLi, THF, HMPA, -78 °C (100%); (b) CSA, MeOH, rt; (c) TBSOTf, 2,6-lutidine, CH2Cl2, 0 °C
(100%, two steps); (d) RuO2, NaIO4, MeCN-CCl4-H2O, rt (83%); (e) CH(OMe)3, CSA, MeOH, 80 °C (67%); (f) TMSOTf, Et3SiH,
CH2Cl2, 0 °C (57%).
6, the hetero-Michael reaction with ethyl propiolate gave
ketone 7 in 90% yield. Treatment of 7 with SmI2 in THF in
the presence of MeOH effected the reductive cyclization,
accompanied by formation of γ-lactone, to give the desired
trans-fused 6,7-membered ether 8, corresponding to the DE-
ring, in 84% yield with complete stereoselection.
Synthesis of acetylene 17 as the other coupling partner,
corresponding to the A-ring, started with diol 14,13 which
was prepared from 2-deoxy-L-ribose (Scheme 3). Protection
of the diol in 14 as an acetonide followed by removal of the
benzylidene group afforded diol 15 in 93% yield. After
triflation and silylation in one pot,12 reaction of the resultant
product 16 with lithium (trimethysilyl)acetylide followed by
removal of the TMS group afforded 17 in 82% yield from
15.
We next investigated the construction of the F-ring from
the lactone 8 (Scheme 2). DIBAH reduction of 8 followed
by the Wittig reaction with Ph3PdCH(Me)CO2Et gave R,â-
unsaturated ester (100%), which was converted into allyl
alcohol 9 in 89% yield by successive treatments with
TBSOTf and DIBAH. The Sharpless asymmetric epoxida-
tion9 of 9 using (-)-DET stereoselectively gave the â-
epoxide (96%), which was subjected to oxidation with
SO3‚pyridine and Wittig reaction with Ph3PdCH2 to afford
vinylepoxide 10 in 96% yield. After removal of the TBS
group of 10 with TBAF, treatment of the resultant alcohol
with PPTS10 in CH2Cl2 effected 6-endo-cyclization11 to
stereoselectively give 6,7,6-membered ether 11, correspond-
ing to the DEF-ring. Then, conversion of 11 to triflate 13,
the coupling partner of the A-ring acetylide, was carried out.
Hydroboration of the double bond in 11 gave a diol (82%),
which was protected by treatment with BnBr to give dibenzyl
ether 12 in 87% yield. Deprotection of the benzylidene in
12 with CSA in MeOH and selective triflation and silylation
in one pot12 gave the desired triflate 13 in 85% yield.
After having established suitable coupling conditions in a
model study,14 we turned to the coupling of 13 and 17 toward
the convergent synthesis of the ABCDEF-ring system
(Scheme 4). Upon treatment of 17 with t-BuLi in THF-
HMPA followed by addition of 13, coupling reaction
proceeded smoothly to give acetylene 18 in quantitative yield.
Deprotection of the acetonide 18 and subsequent protection
of the resultant diol with TBSOTf quantitatively gave tetra-
15
TBS ether 19. Oxidation of alkyne 19 with RuO2-NaIO4
gave diketone 20 (83%), which was treated with CSA in
CH(OMe)3-MeOH to effect simultaneous TBS deprotection
and methylacetalization to give hexacyclic diacetal 21 in 67%
yield. Reduction of 21 with Et3SiH-TMSOTf at 0 °C
smoothly proceeded to give the desired trans-fused 6,6,6,6,7,6-
membered hexacyclic ether 22, corresponding to the
ABCDEF-ring of YTX (1) and ATX (2), in 57% yield. The
(12) Mori, Y.; Yaegashi, K.; Furusawa, H. J. Am. Chem. Soc. 1996, 118,
8158.
(13) (a) Sakamoto, Y.; Matsuo, G.; Matsukura, H.; Hori, N.; Nakata, T.
Org. Lett. 2001, 3, 2749. (b) Matsuo, G.; Matsukura, H.; Hori, N.; Nakata,
T.; Tetrahedron Lett. 2000, 41, 7673.
(14) In a model study, we found that acetonide 17 was a more suitable
coupling partner than the corresponding benzylidene and di-tert-butyl
silylene derivatives and that use of t-BuLi gave the best result in generating
acetylide. See Supporting Information for the model study.
(15) (a) Carling, R. W.; Holmes, A. B. Tetrahedron Lett. 1986, 27, 6133.
(b) Zibuck, R.; Seebach, D. HelV. Chim. Acta 1988, 71, 237.
(8) Stork, G.; Jacobsen, R. M.; Levitz, R. Tetrahedron Lett. 1979, 20,
771.
(9) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5976.
(10) Miyashita, M.; Yoshikoshi, A.; Grieco, P. A. J. Org. Chem. 1977,
42, 3772.
(11) (a) Nicolaou, K. C.; Duggan, M. E.; Hwang, C.-K.; Somers, P. K.
J. Chem. Soc., Chem. Commun. 1985, 1359. (b) Nicolaou, K. C.; Prasad,
C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am. Chem. Soc. 1989, 111, 5330.
(c) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J. Am.
Chem. Soc. 1989, 111, 5335.
Org. Lett., Vol. 4, No. 22, 2002
3945

1
structure of hexacyclic ether 22 was confirmed by H and
from RIKEN. The authors thank Dr. H. Koshino and Ms. T.
Chijimatsu for the NOE and HMBC measurement and Ms.
K. Harata for the mass spectral measurement.
13C NMR, PFG-NOESY, and PFG-HMBC analysis.16
In summary, we have accomplished a convergent synthesis
of the ABCDEF-ring system of YTX (1) and ATX (2).
Progress toward the completion of the total synthesis of 1
and 2 is under way in this laboratory.
Supporting Information Available: Synthetic scheme
for compound 4, a model study for the coupling reaction,
and characterization data for compounds 8, 11, 17, and 22.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported in part by
Special Project Funding for Basic Science (Essential reaction)
(16) See Supporting Information for stereochemical confirmation of 22
by extensive NMR analysis.
OL026804W
3946
Org. Lett., Vol. 4, No. 22, 2002