A convergent strategy for the synthesis of polycyclic ethers by using oxiranyl anions

Article abstract of DOI:10.1021/ol202467z

A new [X+2+Y]-type for the convergent synthesis of polycyclic ethers based on an oxiranyl anion strategy was developed. The sequence involves nucleophilic substitution of a triflate with an oxiranyl anion followed by 6-endo cyclization, ring expansion, an

Full text of DOI:10.1021/ol202467z

ORGANIC
LETTERS
2011
Vol. 13, No. 21
5850–5853
A Convergent Strategy for the Synthesis of
Polycyclic Ethers by Using Oxiranyl Anions
Takeo Sakai, Ai Sugimoto, and Yuji Mori*
Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, Nagoya 468-8503,
Japan
mori@meijo-u.ac.jp
Received September 12, 2011
ABSTRACT
A new [Xþ2þY]-type for the convergent synthesis of polycyclic ethers based on an oxiranyl anion strategy was developed. The sequence
involves nucleophilic substitution of a triflate with an oxiranyl anion followed by 6-endo cyclization, ring expansion, and reductive etherification.
The protocol features a flexible approach toward trans-fused polycyclic arrays consisting of six- and seven-membered ether rings from the same
starting materials.
An ocean is a mine of natural products with potent
physiological properties.1 Among such products, ladder-
shaped polyether marine toxins produced by the red tide
and epiphytic dinoflagellates are known to have diverse
biological activities such as neurotoxicity, cytotoxicity,
and antifungal activity.2 These biotoxins persist and
accumulate in fish and shellfish throughout the food
chain and ultimately can reach dangerous concentra-
tions. Hence, humans are also at risk if they consume
contaminated seafood. In addition to their interesting
biological activities, massive and distinct structures of
trans-fused cyclic ethers with sizes ranging from five- to
nine-membered rings have attracted the attention of a
number of synthetic chemists. The construction of their
complex architectures necessitates a highly efficient syn-
thetic methodology, and over the past two decades, a
great deal of effort has been devoted to developing a new
convergent methodology3 to complete total synthesis for
several of these marine toxins.4
We previously established a linear methodology for the
synthesis of polycyclic ethers by using oxiranyl anions.5,6
(4) For reviews, see: (a) Nakata, T. Chem. Rev. 2005, 105, 4314–4347.
(b) Nicolaou, K. C.; Frederick, M. O.; Aversa, R. J. Angew. Chem., Int.
Ed. 2008, 47, 7182–7225. (c) Sasaki, M.; Fuwa, H. Nat. Prod. Rep. 2008,
25, 401–426. For recent examples, see: (d) Inoue, M.; Miyazaki, K.;
Ishihara, Y.; Tatami, A.; Ohnuma, Y.; Kawada, Y.; Komano, K.;
Yamashita, S.; Lee, N.; Hirama, M. J. Am. Chem. Soc. 2006, 128,
9352–9354. (e) Crimmins, M. T.; Zuccarello, J. L.; Ellis, J. M.; McDou-
gall, P. J.; Haile, P. A.; Parrish, J. D.; Emmitte, K. A. Org. Lett. 2009, 11,
489–492. (f) Ebine, M.; Fuwa, H.; Sasaki, M. Org. Lett. 2008, 10, 2275–
2278. (g) Takamura, H.; Kikuchi, S.; Nakamura, Y.; Yamagami, Y.;
Kishi, T.; Kadota, I.; Yamamoto, Y. Org. Lett. 2009, 11, 2531–2534.
(h) Hamajima, A.; Isobe, M. Angew. Chem., Int. Ed. 2009, 48, 2941–2945.
(i) Yamashita, S.; Ishihara, Y.; Morita, H.; Uchiyama, J.; Takeuchi, K.;
Inoue, M.; Hirama, M. J. Nat. Prod. 2011, 74, 357–364.
(5) For reviews on oxiranyl anions, see: (a) Satoh, T. Chem. Rev.
1996, 96, 3303–3325. (b) Mori, Y. In Reviews on Heteroatom Chemistry;
Oae, S., Ed.; MYU: Tokyo, 1997; Vol. 17, pp 183ꢀ211. (c) Hodgson,
D. M.; Gras, E. Synthesis 2002, 1625–1642.
(6) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1996,
118, 8158–8159.
(1) Kornprobst, J.-M. Encyclopedia of Marine Natural Products;
Wiley-Blackwell: Weihein, Germany, 2010; Vols. 1ꢀ3.
(2) (a) Shimizu, Y. Marine Natural Products; Academic Press: New York,
1978; Vol. 1. (b) Shimizu, Y. Chem. Rev. 1993,93, 1685–1698. (c) Yasumoto,
T.; Murata, M. Chem. Rev. 1993, 93, 1897–1909. (d) Murata, M.;
Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293–314. (e) Yasumoto, T.
Chem. Rec. 2001, 1, 228–242.
(3) For reviews, see: (a) Inoue, M. Chem. Rev. 2005, 105, 4379–4405.
(b) Isobe, M.; Hamajima, A. Nat. Prod. Rep. 2010, 27, 1204–1226. For
recent examples, see: (c) Takizawa, A.; Fujiwara, K.; Doi, E.; Murai, A.;
Kawai, H.; Suzuki, T. Tetrahedron Lett. 2006, 47, 747–751. (d) Clark,
J. S.; Grainger, D. M.; Ehkirch, A. A.-C.; Blake, A. J.; Wilson, C. Org.
Lett. 2007, 9, 1033–1036. (e) Oishi, T.; Hasegawa, F.; Torikai, K.;
Konoki, K.; Matsumori, N.; Murata, M. Org. Lett. 2008, 10, 3599–
3602. (f) Kadota, I.; Abe, T.; Uni, M.; Takamura, H.; Yamamoto, Y.
Tetrahedron 2009, 65, 7784–7789. (g) Zhang, Y.; Rainier, J. D. Org. Lett.
2009, 11, 237–239. (h) Tsubone, K.; Hashizume, K.; Fuwa, H.; Sasaki,
M. Tetrahedron 2011, 67, 6600–6615. (i) Nicolaou, K. C.; Baker, T. M.;
Nakamura, T. J. Am. Chem. Soc. 2011, 133, 220–226.
r
10.1021/ol202467z
Published on Web 10/06/2011
2011 American Chemical Society

The initial coupling reaction was performed with cis-
epoxy sulfone 1 and trans-epoxy sulfone 2, each consisting
of a mixture of two diastereomers at the oxirane ring
(Scheme 2). Lithiation of cis-1 and trans-2 with n-BuLi in
the presence of triflate 3 in THF/HMPA at ꢀ100 °C
afforded, respectively, the coupling products 4a,b and 5a,
b in good yield. The diastereomeric ratios of the products
were unchanged before and after the coupling reactions.
Figure 1. Structure of gymnocin-A.
Scheme 2. Synthesis of the Tetrahydropyranyl Ketone 6
This iterative procedure was applied to the synthesis of
gambierol7 and the ABCDEF ring fragment of yessotoxin
and adriatoxin.8 However, the stepwise synthesis of com-
pounds with more than ten fused rings such as gymnocins9
(Figure 1) is practically impossible owing to the large
number of transformations required. It is therefore impor-
tant to develop an efficient method for the construction of
large toxins. We herein report a new convergent strategy for
the synthesis of this class of molecules.
Scheme 1. Convergent Strategy for Polycyclic Ethers
a A 3:2 diastereomeric mixture. bA 3:1 diastereomeric mixture.
Acid-catalyzed stereoselective ring closure with p-TsOH
in CHCl3 at 55 °C proceeded only for the cis-(2S,3R)-
diastereomer 4a to afford ketone 6 in 76% yield. However,
conversion of other diastereomers 4b and 5 to ketone 6
could not be achieved under the same conditions. Instead,
the reaction yielded detriethylsilylated products, and pro-
longed reaction times and elevated temperatures gave a
complex mixture of products. Only the diastereomer 4a
could adopta lesshinderedchair conformation suitablefor
6-endo cyclization in the transition state.10 The diastereo-
mers 4b and 5a,b were then subjected to a three-step formal
6-endo cyclization according to previous studies.11 Thus,
acid-catalyzed removal of the triethylsilyl group followed
Our synthetic strategy is outlined in Scheme 1. Alkyla-
tion of an oxiranyl anion generated from epoxy sulfone I
with triflate II followed by cyclization of III provides a six-
membered ketone IV, which serves as a precursor of the
seven-memberedring V by a ring expansion reaction. After
reductive etherification of ketones IV and V, a second six-
membered ether ring is generated. Through the use of this
strategy, two new six-six-membered and six-seven-membered
ring systems VI and VII are constructed from the same
starting materials.
by the epoxide-opening reaction with MgBr2 OEt2
3
afforded bromoketone 7, which was then treated with
DBU to furnish ketone 6 as a single diastereomer in
76ꢀ83% overall yields. This cyclization has the advantage
that neither the stereochemistry of the bromoketone nor
the stereochemistry of epoxy sulfones 4a,b and 5a,b are
(7) (a) Furuta, H.; Hasegawa, Y.; Mori, Y. Org. Lett. 2009, 11, 4382–
4385. (b) Furuta, H.; Hasegawa, Y.; Hase, M.; Mori, Y. Chem.;Eur. J.
2010, 16, 7586–7595.
(8) (a) Mori, Y.; Nogami, K.; Hayashi, H.; Noyori, R. J. Org. Chem.
2003, 68, 9050–9060. (b) Mori, Y.; Takase, T.; Noyori, R. Tetrahedron
Lett. 2003, 44, 2319–2322.
(9) (a) Satake, M; Shoji, M; Oshima, Y; Naoki, H; Fujita, T;
Yasumoto, T. Tetrahedron Lett. 2002, 43, 5829–5832. (b) Satake, M.;
Tanaka, Y.; Ishikura, Y.; Oshima, Y.; Naoki, H.; Yasumoto, T. Tetra-
hedron Lett. 2005, 46, 3537–3540.
(10) Mori, Y.; Yaegashi, K.; Furukawa, H. Tetrahedron Lett. 1999,
40, 7239–7242.
(11) (a) Hashimoto, N.; Aoyama, T.; Shioiri, T. Tetrahedron Lett.
1980, 21, 4619–4622. (b) Mori, Y.; Yaegashi, K.; Furukawa, H. Tetra-
hedron 1997, 53, 12917–12932.
Org. Lett., Vol. 13, No. 21, 2011
5851

relevant, because all stereoisomers converge to the same
requisite diastereomer with an equatorial substituent un-
der base equilibration conditions.
ring system is also an important task.12 The carbonꢀ
carbon bond formation between the methylated mono-
cyclic triflate 13 and trans-epoxy sulfone 14 was performed
under standard conditions (n-BuLi, THF/HMPA, ꢀ100 °C,
in situ trapping method) to afford the product 15 in 71%
yield (Scheme 4). Removal of the TES group followed by
Scheme 3. Synthesis of Tricyclic Ethers 9 and 12
treatment with MgBr2 OEt2 provided bromoketone 16 in
3
91% overall yield. Intramolecular etherification of 16 with
DBU proved to be less efficient than that of 7 owing to the
low reactivity of the tertiary alcohol, giving the desired
methyl-substituted bicyclic ketone 17 in only 22% yield.13
Scheme 4. Synthesis of the Methylated Polyether 19
The next step is a diverging point for our protocol where
ketone 6 serves as a key precursor for polycyclic frame-
works composed of six- and seven-membered ether rings
(Scheme 3). The presence of seven-membered rings usually
complicates the synthesis of marine polycyclic ethers. We
solved this problem by ring enlargement. Thus, ketone
6 was subjected to a ring expansion reaction with tri-
a A 9:1 trans and cis mixture. bBased on the consumed 14.
methylsilyldiazomethane11 in the presence of BF3 OEt2
3
followed by treatment of the resulting R-trimethylsilyl
ketone with p-TsOH to afford the seven-membered ketone
10 in 66% yield. Heating the six-membered ketone 6 with p-
TsOH in CHCl3/MeOH at 55 °C caused sequential clea-
vage of the TBS group and acetalization, and a mixture of
hemiacetal 8a and acetal 8b was obtained in 95% combined
yield. Moreover, 8a and 8b were prepared directly from
epoxy sulfone 4a by treatment with the same acidic condi-
tions. The acetal mixture was then reduced with triethylsi-
After several attempts to forge the ether ring, treatment
of 16 with NaH in THF at ꢀ20 °C proved the most
expedient to afford the cyclic ketone 17 in 82% yield.
Acetalization followed by reductive etherification of 17
provided polyether 19 with an angular methyl group in
44% yield for the two steps.
Finally, application of our convergent approach to the
synthesis of larger molecules was demonstrated as shown
in Scheme 5. A coupling reaction of the bicyclic epoxy
sulfone 21, prepared from diol 2014 as a mixture of four
diastereomers at the epoxide site, with the monocyclic
triflate 22 in the presence of n-BuLi at ꢀ100 °C afforded
a diastereomeric mixture of epoxy sulfone 23 in 76% yield.
Conversion of the products to the desired ketone was
lane in the presence of BF3 OEt2 to provide tricyclic ether 9
3
in 87% yield. In the case of the seven-membered ketone 10,
acetal 11 was obtained in 77% yield as the sole product
under the same acidic conditions. Subsequent reductive
etherification afforded tricyclic ether 12 with an oxepane
ring in 95% yield.
We next investigated the synthesis of cyclic ether with
an angular methyl group that is often encountered as a
structural unit of marine toxins. The construction of such a
(13) A cyclopropane hydrate i was obtained in 23% yield under
standard reaction conditions (1.1 equiv of DBU, CH2Cl2, rt). Treatment
of 16 with 3.3 equiv of DBU afforded 17 in 32% yield and a carboxylic
acid ii, a Favorskii rearrangement product, in 32% yield. See Supporing
Information.
(12) (a) Kadota, I.; Kishi, T.; Fujisawa, Y.; Yamagami, Y.; Takamura,
H. Tetrahedron Lett. 2010, 51, 3960–3961. (b) Kimishima, A.; Nakata, T.
Tetrahedron Lett. 2008, 49, 6563–6565. (c) Robert, S. W.; Rainier, J. D. Org.
Lett. 2007, 9, 2227–2230. (d) Furuta, H.; Takase, T.; Hayashi, H.; Noyori,
R.; Mori, Y. Tetrahedron 2003, 59, 9767–9777. (e) Matsuo, G.; Hori, N.;
Nakata, T. Tetrahedron Lett. 1999, 40, 8859–8862. (f) Nicolaou, K. C.;
Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.; Veale, C. A. J. Am. Chem.
Soc. 1989, 111, 5321–5330.
(14) Mori, Y.; Hayashi, H. J. Org. Chem. 2001, 66, 8666–8668.
Org. Lett., Vol. 13, No. 21, 2011
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Scheme 5. Synthesis of Pentacyclic Ring Systems 25 and 27
a See Supporting Information. bA 1:1 cis and trans mixture.
accomplished through the standard three-step sequence in-
volving removal of the TES group followed by bromoketone
formation with MgBr2 OEt2 and cyclization with DBU, to
arrays consisting of six- and seven-membered ether rings
from the same starting materials and allows for the con-
struction of a methyl-substituted polyether ring system.
Further development of the present technology and its
application to the total synthesis of marine polycyclic
ethers are in progress.
3
afford the cyclic ketone 24 in 85% yield as a single isomer. A
ring expansion reaction of 24 with trimethylsilyldiazo-
methane proceeded uneventfully to afford the seven-mem-
bered ketone 26 in 66% yield. The acid-catalyzed acetali-
zation of ketones 24 and 26 followed by reductive etherifica-
tion afforded pentacyclic polyethers 25 and 27, respectively.
The latter represents the FGHIJ ring system of gymnocin-A.
In conclusion, we have developed a new [Xþ2þY]-type15
convergent methodology for the synthesis of polycyclic
ethers based on an oxiranyl anion strategy. The present
method features a flexible approach toward polycyclic
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research (C) (21590029) and
a Grant-in-Aid for Young Scientists (B) (23790027) from
the Japan Society for the Promotion of Science (JSPS).
Supporting Information Available. Experimental proce-
dures, spectroscopic data, and copies of 1H and 13C NMR
spectra of all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(15) The reader is referred to ref 3a for the terminology of the
[Xþ2þY] convergent synthesis.
Org. Lett., Vol. 13, No. 21, 2011
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