Concise synthesis of cyclic ethers via the palladium-catalyzed coupling of ketene acetal triflates and a zinc homoenolate. Synthesis of the DE and GH ring segments of gambierol

Article abstract of DOI:10.1016/S0040-4039(01)00824-3

Concise syntheses of the DE and GH ring segments of gambierol (1) were achieved by the palladium-catalyzed coupling of ketene acetal triflates and a zinc homoenolate, followed by the hydroboration of the resulting cyclic enol ethers and subsequent lactoni

Full text of DOI:10.1016/S0040-4039(01)00824-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4729–4731
Concise synthesis of cyclic ethers via the palladium-catalyzed
coupling of ketene acetal triflates and a zinc homoenolate.
Synthesis of the DE and GH ring segments of gambierol
Isao Kadota,a Hiroyoshi Takamura,b Kumi Satob and Yoshinori Yamamotob,*
aResearch Center for Sustainable Materials Engineering, Institute of Multidisciplinary Research for Advanced Materials,
Tohoku University, Sendai 980-8578, Japan
bDepartment of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 26 March 2001; revised 9 May 2001; accepted 15 May 2001
Abstract—Concise syntheses of the DE and GH ring segments of gambierol (1) were achieved by the palladium-catalyzed coupling
of ketene acetal triflates and a zinc homoenolate, followed by the hydroboration of the resulting cyclic enol ethers and subsequent
lactonization. © 2001 Elsevier Science Ltd. All rights reserved.
In recent years there has been an explosion of interest
in biologically active natural products of marine
origin.1 Due to their structural novelty and toxicity,
polycyclic ethers are particularly attractive targets for
synthetic chemists.2 Gambierol (1), a potent neurotoxin
example, the E ring segment was synthesized from
-ribose in 16 steps. We now report efficient and con-
cise syntheses of the DE and GH ring segments of 1 via
the palladium-catalyzed coupling of ketene acetal tri-
flates and a zinc homoenolate.6
D
isolated from the cultured cells of Gambierdiscus toxi-
cus, has 8 ether rings and 18 stereogenic centers.3 The
compound shows toxicity against mice (LD50 50 mg/kg),
and the symptoms resemble those caused by ciguatox-
ins inferring the possibility that it is also implicated in
ciguatera poisoning.1 We have already reported the
synthesis of the E and H ring segments of 1 via the
intramolecular allylstannane–aldehyde condensation.4,5
However, the syntheses were not particularly efficient
because of the relatively long synthetic schemes. For
The new synthetic strategy is illustrated in Scheme 1.
Since the palladium-catalyzed coupling of alkylzinc
reagents and aryl halides was reported by Negishi in
1977,7 a number of modified reactions have been devel-
oped.8 In 1986, Tamaru reported the palladium-cata-
lyzed coupling of alkenyl triflates, derived from
ketones, and zinc homoenolates.9 It was thought that
the coupling of the ketene acetal triflate 2, derived from
lactones, and the zinc homoenolate 310 would give the
cyclic enol ether 4, and the subsequent hydroboration
H
IZn
O
O
CO2Me
3
O
OTf
O
CO2Me
O
Pd(PPh3)4
H
2
4
5
Scheme 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00824-3

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I. Kadota et al. / Tetrahedron Letters 42 (2001) 4729–4731
of the double bond of 4 followed by lactonization
would provide the desired cyclic ether 5.
to seven-membered ketene acetal triflates or not. The
reaction of 2d with 3 under the same reaction conditions
afforded the desired cyclic enol ether 4d in 82% yield
(entry 4). Also, 2e gave 4e in 76% yield (entry 5).
The results of the coupling of 2 and 3 are summarized
in Table 1. Treatment of 2a, prepared from the corre-
sponding lactone by the standard procedure,6e with 2
equiv. of the zinc homoenolate 3 in the presence of
Pd(PPh3)4 at room temperature gave the enol ether 4a
in 73% yield (entry 1). Similarly, the reaction of the
six-membered ketene acetal triflates 2b and 2c with 3
under the same reaction conditions gave the corresp-
ponding cyclic enol ethers 4b and 4d, respectively, in
good yields (entries 2 and 3). In order to synthesize the
DE and GH rings, it was necessary to know whether the
palladium-catalyzed coupling methodology is applicable
The synthesis of 4a is representative. To a suspension of
Zn–Cu couple (100 mg, 1.5 mmol) in benzene (3 mL)
and DMA (0.2 mL) was added methyl 3-iodopropi-
onate (120 mL, 1.0 mmol). The mixture was refluxed for
1.5 h and then cooled to room temperature. A solution
of 2a (150 mg, 0.5 mmol) in benzene (2 mL) and
Pd(PPh3)4 (29 mg, 0.025 mmol) were added to the
resulting mixture, successively. After being stirred for
0.5 h, the mixture was quenched with Et3N, filtered
through a silica gel pad, and concentrated. The residue
Table 1. Palladium-catalyzed coupling of ketene acetal triflates 2 and zinc homoenolate 3a
entry
1
enol triflateb
product
yieldc
73%
Me
O
Me
O
O
H
OTf
2a
O
H
CO2Me
CO2Me
4a
4b
H
H
BnO
BnO
78%
74%
82%
76%
2
3
4
5
BnO
BnO
O
OTf
2b
O
H
H
H
H
H
H
H
O
O
H
BnO
BnO
BnO
BnO
O
O
OTf
2c
O
O
CO2Me
CO2Me
H
H
H
4c
4d
H
O
O
Ph
Ph
Ph
OTf
2d
O
O
Me
Me
H
H
O
O
Ph
OTf
2e
O
H
O
H
CO2Me
O
O
4e
aReactions were carried out with 3 (2 equiv) in the presence of Pd(PPh3)4 (5 mol%) in benzene at room temperature.
bKetene acetal triflates were prepared from the corresponding lactones by the standard procedure, and used without
purification. cIsolated yields.
HO
H
H
O
O
O
a
Ph
HO
Ph
O
Me
O
Me
MeO2C
O
6
4d
b
H
H
H
H
O
O
D
O
O
H
O
H
O
O
E
+
Ph
Ph
O
Me
O
Me
O
43:57
7
8
Scheme 2. (a) BH3·SMe2, THF, 0°C to rt, then 30% H2O2, 3N NaOH; (b) TEMPO, NaClO, KBr, CH2Cl2/H2O, 0°C, 79% from
4d.

I. Kadota et al. / Tetrahedron Letters 42 (2001) 4729–4731
4731
MeO2C
HO
H
H
H
H
H
H
H
O
O
O
a
b
G
O
H
O
O
O
O
HO
H
H
O
O
Ph
O
Ph
Ph
H
10
4e
9
Scheme 3. (a) i. thexylborane, THF, 0°C–rt, then 30% H2O2, 3N NaOH, ii. LiAlH4, ether, 0°C; (b) TEMPO, NaClO, KBr,
CH2Cl2/H2O, 0°C, 68% from 4e.
was purified by silica gel chromatography using hexane/
EtOAc as an eluent to give 4a (88 mg, 73%).
Pe´rez, R.; Ravelo, J. L.; Mart´ın, J. D. Chem. Rev. 1995,
95, 1953–1980; (b) Nicolaou, K. C. Angew. Chem., Int.
Ed. Engl. 1996, 35, 589–607; (c) Mori, Y. Chem. Eur. J.
1997, 3, 849–852.
We next examined the synthesis of the DE and GH ring
segments of 1. Treatment of 4d with BH3·SMe2 fol-
lowed by oxidative work-up gave the diol 6 as a mix-
ture of diastereomers (Scheme 2). Although the
mechanism is not yet clear, the unexpected reduction of
the ester group of 4d seems to proceed via an
intramolecular hydrogen transfer. TEMPO oxidation of
6 gave a 43:57 mixture of the DE ring segment 7 and its
stereoisomer 8 in 79% yield from 4d.11 Although several
attempts such as the use of bulky borane reagents were
made to improve the stereoselectivity, the diastereomer
ratio remained about 1:1.
3. (a) Satake, M.; Murata, M.; Yasumoto, T. J. Am. Chem.
Soc. 1993, 115, 361–362; (b) Morohashi, A.; Satake, M.;
Yasumoto, T. Tetrahedron Lett. 1999, 39, 97–100.
4. (a) Kadota, I.; Kadowaki, C.; Yoshida, N.; Yamamoto,
Y. Tetrahedron Lett. 1998, 39, 6369–6372; (b) Kadota, I.;
Ohno, A.; Matsukawa, Y.; Yamamoto, Y. Tetrahedron
Lett. 1998, 39, 6373–6376.
5. For other synthetic studies, see: (a) Kadota, I.; Park,
C.-H.; Ohtaka, M.; Oguro, N. Yamamoto, Y. Tetra-
hedron Lett. 1998, 39, 6365–6368; (b) Kadowaki, C.;
Philip, W. H. C.; Kadota, I.; Yamamoto, Y. Tetrahedron
Lett. 2000, 41, 5769–5772; (c) Fuwa, H.; Sasaki, M.;
Tachibana, K. Tetrahedron Lett. 2000, 41, 8371–8375.
6. For the synthesis of cyclic ethers via the coupling of
ketene acetal triflates derived from lactones, see: (a)
Tsushima, K.; Araki, K.; Murai, A. Chem. Lett. 1989,
1313–1316; (b) Tsushima, K.; Murai, A. Chem. Lett.
1990, 761–764; (c) Feng, F.; Murai, A. Chem. Lett. 1992,
1587–1590; (d) Feng, F.; Murai, A. Synlett 1995, 863–
865; (e) Fujiwara, K.; Tsunashima, M.; Awakura, D.;
Murai, A. Tetrahedron Lett. 1995, 36, 8263–8266; (f)
Nicolaou, K. C.; Theodorakis, E. A.; Rutjes, F. P. J. T.;
Tiebes, J.; Sato, M.; Untersteller, E.; Xiao, X.-Y. J. Am.
Chem. Soc. 1995, 117, 1171–1171; (g) Nicolaou, K. C.;
Theodorakis, E. A.; Rutjes, F. P. J. T.; Sato, M.; Tiebes,
J.; Xiao, X.-Y.; Hwang, C.-K.; Duggan, M. E.; Yang, Z.;
Couladouros, E. A.; Sato, F.; Shin, J.; He, H.-M.; Bleck-
man, T. J. Am. Chem. Soc. 1995, 117, 10239–10251; (h)
Nicolaou, K. C.; Sato, M.; Miller, N. D.; Gunzner, J. L.;
Renaud, J.; Untersteller, E. Angew. Chem., Int. Ed. Engl.
1996, 35, 889–891; (i) Sasaki, M.; Fuwa, H.; Inoue, M.;
Tachibana, K. Tetrahedron Lett. 1998, 39, 9027–9030.
7. Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem.
1977, 42, 1821–1823.
Scheme 3 describes the synthesis of the GH ring seg-
ment. Hydroboration of 4e with thexylborane gave a
mixture of the diol 9 and unidentified compounds hav-
ing ester and aldehyde groups. Treatment of this mix-
ture with LiAlH4 gave pure 9 as a single stereoisomer.
Oxidation of 9 gave the GH ring segment 10 in 68%
yield in three steps from 4e.
In conclusion, we have developed a novel method for
the concise synthesis of trans-fused cyclic ethers via the
palladium-catalyzed coupling of ketene acetal triflates
and a zinc homoenolate. We are now in a position to
synthesize the DE and GH ring segments of gambierol
efficiently with a shorter number of steps (11 and 10
steps from 2-deoxy-
D-ribose, respectively) in compari-
son with previous methods.
Acknowledgements
This work was financially supported by the Grant-in-
Aid for Scientific Research from the Ministry of Educa-
tion, Science and Culture of Japan.
8. For recent reviews, see: (a) Erdik, E. Tetrahedron 1992,
48, 9577–9648; (b) Knochel, P.; Singer, R. D. Chem. Rev.
1993, 93, 2117–2188; (c) Knochel, P.; Perea, J. J. A.;
Jones, P. Tetrahedron 1998, 54, 8275–8391.
References
9. Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z.
Tetrahedron Lett. 1986, 27, 955–958.
1. For recent reviews, see: (a) Shimizu, Y. Chem. Rev. 1993,
93, 1685–1698; (b) Yasumoto, T.; Murata, M. Chem.
Rev. 1993, 93, 1897–1909.
10. Tamaru, Y.; Ochiai, H.; Nakamura, T.; Tsubaki, K.;
Yoshida, Z. Tetrahedron Lett. 1985, 26, 5559–5562.
11. Anelli, P. L.; Banfi, S.; Montanari, F.; Quici, S. J. Org.
Chem. 1989, 54, 2970–2972.
2. For recent reviews, see: (a) Alvarez, E.; Candenas, M.-L.;
.