Stereoselective convergent synthesis of a trans-fused polycyclic ether ring system including a 4-hydroxy-5-methyl-tetrahydropyran ring

Article abstract of DOI:10.1021/ol026261q

Stereoselective convergent synthesis of a trans-fused 6-6-6-6-membered tetracyclic ether ring system including 4α-or 4β-hydroxy-5-methyl-tetrahydropyran was achieved. The key reactions involve the acetylide-aldehyde coupling of two tetrahydropyrans, intra

Full text of DOI:10.1021/ol026261q

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2739-2741
Stereoselective Convergent Synthesis of
a trans-Fused Polycyclic Ether Ring
System Including a
4-Hydroxy-5-methyl-tetrahydropyran
Ring
,†,§
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 May 30, 2002
ABSTRACT
Stereoselective convergent synthesis of a trans-fused 6-6-6-6-membered tetracyclic ether ring system including 4r- or 4â-hydroxy-5-methyl-
tetrahydropyran was achieved. The key reactions involve the acetylide-aldehyde coupling of two tetrahydropyrans, intramolecular hetero-
Michael cyclization of enone, stereoselective reduction of enone, hydroboration, intramolecular acetalization, and stereoselective reduction of
the acetal with Et3SiH−TMSOTf.
Marine polycyclic ethers, exemplified by brevetoxins, gam-
bieric acids, yessotoxin, ciguatoxins, maitotoxin, etc., have
attracted the attention of synthetic organic chemists as a result
of their unique and complex structures and potent biological
activities.1 The characteristic structural feature of these
natural products is a trans-fused polycyclic ether ring system.
Among the polycyclic ether rings, several tetrahydropyran
rings have a 4R- or 4â-hydroxyl-5-methyl group (Figure 1).
† Saitama Univeresity.
‡ On leave from Sankyo Co. Ltd.
§ RIKEN.
(1) For reviews, see: (a) Yasumoto, T.; Murata, M. Chem. ReV. 1993,
93, 1897. (b) Shimizu, Y. Chem. ReV. 1993, 93, 1685. (c) Scheuer, P. J.
Tetrahedron 1994, 50, 3.
Figure 1. Partial structure of yessotoxin and gambieric acid
(2) For examples of convergent approaches to fused polycyclic ethers,
see: (a) Nicolaou, K. C.; Hwang, C.-K.; Marron, B. E.; DeFrees, S. A.;
Couladouros, E. A.; Abe, Y.; Carrol, P. J.; Snyder, J. P. J. Am. Chem. Soc.
1990, 112, 3040. (b) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F.
J. Am. Chem. Soc. 1996, 118, 1565. (c) Alvarez, E.; Pe´rez, R.; Rico, M.;
Rodr´ıguez, R. M.; Mart´ın, J. D. J. Org. Chem. 1996, 61, 3003. (d) Oishi,
T.; Nagumo, Y.; Hirama, M. Synlett 1997, 980. (e) Oishi, T.; Nagumo, Y.;
Hirama, M. Chem. Commun. 1998, 1041. (f) Sasaki, M.; Fuwa, H.; Inoue,
M.; Tachibana, K. Tetrahedron Lett. 1998, 39, 9027. (g) Fujiwara, K.; Saka,
K.; Takaoka, D.; Murai, A. Synlett 1999, 1037. (h) Maeda, K.; Oishi, T.;
Oguri, H.; Hirama, M. Chem. Commun. 1999, 1063. (i) Sasaki, M.; Fuwa,
H.; Ishikawa, M.; Tachibana, K. Org. Lett. 1999, 1, 1075. (j) Fujiwara, K.;
Morishita, H.; Saka, K.; Murai, A. Tetrahedron Lett. 2000, 41, 507. (k)
Although several convergent methods for the various ring
systems have been developed,2 convergent synthesis of a
Matsuo, G.; Hinou, H.; Koshino, H.; Suenaga, T.; Nakata, T. Tetrahedron
Lett. 2000, 41, 903. (l) Mori, Y.; Mitsuoka, S.; Furukawa, H. Tetrahedron
Lett. 2000, 41, 4161. (m) Kadowaki, C.; Chan, P. W. H.; Kadota, I.;
Yamamoto, Y. Tetrahedron Lett. 2000, 41, 5769. (n) D´ıaz, M. T.; Pe´rez,
R. L.; Rodr´ıguez, E.; Ravelo, J. L.; Mart´ın, J. D. Synlett 2001, 345. (o)
Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc. 2002,
124, 3562.
10.1021/ol026261q CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/10/2002

polycyclic ether ring system including 4-hydroxy-tetra-
hydropyran has not been reported yet. We now report an
efficient strategy toward stereoselective convergent synthesis
of the trans-fused polycyclic ether system including 4-hy-
droxy-5-methyl-tetrahydropyran.
First, we examined an intramolecular hetero-Michael
addition of the ynone 4a for the construction of enone 6a,
corresponding to the key intermediate iv (Scheme 3). After
Our synthetic strategy for the convergent synthesis is
outlined in Scheme 1. Two tetrahydropyrans i and ii would
Scheme 3a
Scheme 1. Synthetic Strategy
a Reagents and conditions: (a) aq HCl, MeOH, rt; (b) TBAF,
THF, rt (43% from 4a).
deprotection of the TBS group in 4a with aqueous HCl in
MeOH, the cyclization of the ynone 5 was attempted by
treatment with a base (NaH, Et3N, N-methylmorpholine, etc.),
but only the starting material 5 was recovered. On the other
hand, treatment of 4a with TBAF in THF effected depro-
tection of TBS and successive cyclization at room temper-
ature for 1 h, but the yield of 6a was 43%.
Next, we investigated hetero-Michael addition using an
enone 7 having a â-methoxy group, expecting easier access
of the hydroxyl group to the â-position (Scheme 4). The key
intermediate 4b (R ) MPM) toward the enone 7a was
synthesized from 1b3 and 2 by the same procedure as that
for 4a as shown in Scheme 2. The â-methoxy group was
introduced by treatment of 4b with MeONa in MeOH to
give the enone 7a in 92% yield (Scheme 4). After depro-
tecting the TBS group of 7a with TBAF, cyclization of the
resulting alcohol 7b was investigated. As expected, upon
treatment of 7b with p-TsOH in toluene4 at 60 °C, the desired
hetero-Michel reaction took place to give the enone 6b in
63% yield from 7a.
be coupled by addition of the acetylene to the aldehyde. After
conversion to the ynone iii, intramolecular hetero-Michael
cyclization could proceed to give the enone iv. Then, after
conversion of iv into the acetal v, Lewis acid catalyzed silane
reduction would afford the desired polycyclic ether vi.
With this prospect, our convergent synthesis began with
coupling of acetylene 1a3 (R ) Bn) and aldehyde 23 (Scheme
2). The reaction of the lithium acetylide, derived from 1a,
Scheme 2a
With the desired enone 6b in hand, we next investigated
the stereoselective conversion into 12 via the acetal 11.
Reduction of 6b with DIBAH in toluene proceeded smoothly
to give equatorial R-alcohol 8 (94%) as a single product.
Subsequent hydroboration of 8 stereoselectively took place
from the R-side to afford a diol (85%), which was protected
as the di-TES ether 9 in 89% yield. Deprotection of the MPM
group of 9 followed by Swern oxidadion gave ketone 10.
Treatment of 10 with p-TsOH in MeOH-CH2Cl2 at 55 °C
effected the removal of the di-TES groups and cyclization
to give the desired methyl acetal 11 in 74% yield (from 9).
Finally, reduction of the acetal 11 with Et3SiH-TMSOTf
proceeded smoothly to give the desired trans-fused 6-6-6-
6-membered tetracyclic ether 12 as the sole product in 82%
yield.
a Reagents and conditions: (a) 1, t-BuLi, HMPA, THF, -78 °C;
2 in THF (88% for 3a, 76% for 3b); (b) (COCl)2, DMSO, CH2Cl2,
-78 °C; Et3N, -78 °C f rt (99% for 4a, 100% for 4b).
with 2 smoothly proceeded to give the secondary alcohol
3a as a mixture of stereoisomers. The Swern oxidation of
the alcohol 3a quantitatively furnished the required ynone
4a, corresponding to iii.
Having completed the construction of trans-fused 6-6-6-
6-membered tetracyclic ether 12 having an equatorial
R-hydroxyl group, we next turned to the synthesis of the
(4) Ziegler, F. E.; Jaynes, B. H.; Saindane, M. T. J. Am. Chem. Soc.
1987, 109, 8115.
(3) See Supporting Information for the synthetic route of 1a, 1b, and 2.
2740
Org. Lett., Vol. 4, No. 16, 2002

Scheme 4a
Scheme 5a
a Reagents and conditions: (a) (COCl)2, DMSO, CH2Cl2, -78
°C; Et3N, -78 °C f rt; (b) L-Selectride, THF, -78 °C (91% from
12).
In conclusion, we have developed an efficient convergent
synthesis of a trans-fused 6-6-6-6-membered tetracyclic ether
ring system including 4R- or 4â-hydroxy-5-methyl-tetra-
hydropyran in a stereoselective manner. This strategy would
be widely applicable to efficient and stereoselective synthesis
of natural polycyclic ethers. Further studies along these lines
are currently in progress in our laboratory.
a Reagents and conditions: (a) MeONa, MeOH, rt (92%); (b)
TBAF, THF, rt (83%); (c) p-TsOH‚H2O, toluene, 60 °C (76%);
(d) DIBAH, toluene, -78 °C (94%); (e) BH3‚THF, THF, 0 °C; 3
N NaOH, 30% H2O2, 0 °C (85%); (f) TESOTf, 2,6-lutidine, CH2Cl2,
0 °C (89%); (g) DDQ, CH2Cl2-H2O (10:1), 0 °C; (h) (COCl)2,
DMSO, CH2Cl2, -78 °C; Et3N, -78 °C f rt; (i) p-TsOH‚H2O,
MeOH, CH2Cl2, 55 °C (74% from 9); (j) Et3SiH, TMSOTf, CH2Cl2,
0 °C (82%).
Figure 2. NOE and J value of 15 and 16.
Acknowledgment. This work was supported in part
Special Project Funding for Basic Science (Essential reaction)
from RIKEN. The authors thank Ms. K. Harata for the mass
spectral measurement and Ms. T. Chijimatsu for the NOE
measurement.
axial â-hydroxy isomer (Scheme 5). After the Swern
oxidation of 12, reduction of the ketone 13 with L-Selectride
in THF at -78 °C proceeded smoothly to give only the
desired â-alcohol 14 in 91% yield from 12.5 The stereo-
structure of both tetracyclic ethers, 12 and 14, was confirmed
1
by the H and 13C NMR and NOE analysis of the corre-
Supporting Information Available: Synthetic scheme
for compounds 1 and 2, experimental procedures and spectral
data for 3b-14, and 1H NMR spectra of 4b, 6b, 7b, 12, and
14. This material is available free of charge via the Internet
at http://pubs.acs.org.
sponding acetates 15 and 16, prepared from 12 and 14,
respectively, by acetylation (Figure 2).
(5) (a) Matsukura, H.; Hori, N.; Matsuo, G.; Nakata, T. Tetrahedron
Lett. 2000, 41, 7681. (b) Matsukura, H.; Morimoto, M.; Nakata, T. Chem.
Lett. 1996, 487.
OL026261Q
Org. Lett., Vol. 4, No. 16, 2002
2741