Convergent synthesis of the ABCDE ring fragment of ciguatoxins

Article abstract of DOI:10.1016/j.tetlet.2004.04.083

Synthesis of the ABCDE ring fragment of ciguatoxins has been achieved in a highly stereocontrolled and convergent manner via the B-alkyl Suzuki-Miyaura coupling-based approach.

Full text of DOI:10.1016/j.tetlet.2004.04.083

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4795–4799
Convergent synthesis of the ABCDE ring fragment of ciguatoxins
Haruhiko Fuwa,a,ꢀ Seiji Fujikawa,a Kazuo Tachibana,a Hiroyuki Takakurab
and Makoto Sasakib,*
aDepartment of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
bGraduate School of Life Sciences, Tohoku University, Tsutumidori-amamiya, Aoba-ku, Sendai 981-8555, Japan
Received 17 March 2004; revised 30 March 2004; accepted 5 April 2004
Abstract—Synthesis of the ABCDE ring fragment of ciguatoxins has been achieved in a highly stereocontrolled and convergent
manner via the B-alkyl Suzuki–Miyaura coupling-based approach.
Ó 2004 Elsevier Ltd. All rights reserved.
Ciguatera is a seafood poisoning prevalent in tropical
and subtropical areas with more than 20,000 victims
annually and continues to be a serious public health
problem.1 The principal causative agents, ciguatoxin
(1)2 and its congeners including CTX3C (2)3 and 51-
hydroxyCTX3C (3),4 are extremely potent neurotoxins
that strongly bind to voltage-sensitive sodium channels
and inhibit depolarization to allow inward Naþ influx to
continue (Fig. 1).5 Given the highly complex molecular
architecture, extremely potent biological activity, and
scarcity in natural sources, ciguatoxins are intriguing
target molecules for synthetic chemists. Thus, sub-
stantial efforts toward the total synthesis of ciguatoxins
have been recorded to date,6;7 culminating in the first
total synthesis of CTX3C by Hirama and co-workers.8
As part of our synthetic studies on marine polycyclic
Me
Me
K
H
H
H
H
O
J
OH
H
O
L
I
Me
G
HO
O
O
O
H
O
H
Me
H
M
H
H
H
H
O
O
H
OH
H
H
H
H
H
H
H
Me
O
O
B
E
F
1: ciguatoxin (CTX)
A
C
D
O
H
H
O
O
Me
H
H
OH
HO
G
Me
H
J
O
HO
OH
I
Me
H
O
H
H
H
H
O
H
H
H
O
OH
O
O
B
E
H
H
O
K
H
H
F
A
C
D
H
H
O
O
H
O
H
H
O
M
O
L
O
H
H
H
OH
Me
2: CTX3C (R = H)
3: 51-hydroxyCTX3C (R = OH)
51
Me
R
Figure 1. Structures of ciguatoxin (1) and its congeners [CTX3C (2) and 51-hydroxyCTX3C (3)].
Keywords: Ciguatoxin; Polycyclic ether; Convergent synthesis; B-Alkyl Suzuki–Miyaura coupling.
* Corresponding author. Tel.: +81-22-717-8828; fax: +81-22-717-8897; e-mail: masasaki@bios.tohoku.ac.jp
ꢀ
Present address: Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.083

4796
H. Fuwa et al. / Tetrahedron Letters 45 (2004) 4795–4799
ether toxins,9 we have developed a powerful method for
the convergent synthesis of polycyclic ether arrays based
on the B-alkyl Suzuki–Miyaura coupling10;11 and
already reported the synthesis of the ABCD ring frag-
ment of ciguatoxins.12 In this letter, we describe a syn-
thetic route to the ABCDE ring fragment 4 of
ciguatoxins with more convergency by extensive use of
the B-alkyl Suzuki–Miyaura coupling reaction.
O
H
H
H
H
H
O
B
O
a,b
OBn
OBn
OBn
OBn
O
A
O
O
H
OBn
OBn
7
10
O
H
H
H
O
c,d
e,f
O
O
O
MP
O
O
H
OH
Our synthetic planning is briefly given in Scheme 1. We
envisaged that the ABCDE ring fragment 4 could be
elaborated by the convergent union of the AB ring
exocyclic enol ether 5 and DE ring ketene acetal phos-
phate 6 based on our B-alkyl Suzuki–Miyaura coupling-
based approach. The AB ring segment 5 should be
prepared from the known bicyclic compound 7.7h On the
other hand, the DE ring segment 6 could be traced back
to the E ring ketene acetal phosphate 8 and olefin 9,
which was planned to be connected by the B-alkyl
Suzuki–Miyaura coupling.
11
O
H
H
H
H
O
O
B
g,h
OH
O
O
A
OMPM
OMPM
O
O
H
OBn
OBn
12
5
Scheme 2. Synthesis of the AB ring exocyclic enol ether 5. Reagents
and conditions: (a) AD-mix b, MeSO2NH2, t-BuOH/t-BuOMe/H2O,
0 °C; (b) Me2C(OMe)2, CSA, CH2Cl2, rt, quant. (two steps); (c) H2,
Pd/C, EtOAc/MeOH, rt; (d) p-MeOC6H4CH(OMe)2, CSA, CH2Cl2,
rt, 99% (two steps); (e) BnBr, KOt-Bu, n-Bu4NI, THF, rt, 92%; (f)
DIBAL-H, CH2Cl2, )78 to 0 °C, quant.; (g) I2, PPh3, imidazole, THF,
rt, 92%; (h) NaH, DMF, 0 °C to rt, 99%.
Synthesis of the AB ring fragment 5 is outlined in
Scheme 2. In order to apply the B-alkyl Suzuki–Miyaura
coupling chemistry, the (Z)-olefin within 7 needed to be
protected from hydroboration. Thus, stereoselective di-
hydroxylation of 7 with AD mix-b gave vic-diol as a
mixture of diastereomers (dr ¼ 87:13), which was pro-
tected as the acetonide to give 10. At this stage, the
minor diastereomer could be readily separated by flash
column chromatography.13 Removal of the benzyl
groups by hydrogenolysis and the ensuing p-meth-
oxybenzylidene acetal formation led to alcohol 11 in
high overall yield. After protection of the remaining
hydroxyl group of 11 as the benzyl ether (92% yield), the
p-methoxybenzylidene acetal was regioselectively
cleaved with DIBAL-H to deliver alcohol 12 in quanti-
tative yield. Iodination of 12 under standard conditions
followed by treatment with NaH in DMF furnished the
AB ring fragment 5 in high yield.
Synthesis of the DE ring fragment 6 began with the E
ring ketene acetal phosphate 812 (Scheme 3). Attachment
OBn
E
O
O
OBn
OBn
OBn
(PhO)2PO
TIPSO
H
a
8
O
H
b
13
TIPSO
9
OBn
OBn
OBn
OBn
EEO
HO
HO
d,e TIPSO
O
O
H
H
c
H
H
H
16
14
f,g
B-alkyl Suzuki-Miyaura coupling
H
H
H
H
H
H
10
OBn
OBn
OH
OBn
OBn
HO
HO2C
AcO
O
O
B
TIPSO
15 E
20
5
A
C
D
O
O
O
OTBS
H
h
H
O
H
H
H
1
H
O
O
H
17
NOE
ONAP
4
15
H
O
H
H
OBn
OBn
O
O
O
B
H
H
(PhO)2PO
E
OBn
OBn
OBn
OBn
O
O
O
(PhO)2PO
i
O
E
+
A
D
O
D
H
H
OMPM
O
6
O
O
H
H
H
OBn
5
18
6
B-alkyl Suzuki-Miyaura coupling
Scheme 3. Synthesis of the DE ring ketene acetal phosphate 6. Re-
agents and conditions: (a) 9-BBN, THF, rt; then aq Cs2CO3, 8,
PdCl2(dppf)ÆCH2Cl2, DMF, 50 °C, 78%; (b) ThexylBH2, THF, 0 °C;
then aq NaOH, 30% H2O2, rt, quant.; (c) Ac2O, Et3N, DMAP,
CH2Cl2, rt, 97%; (d) EVE, PPTS, CH2Cl2, rt; (e) TBAF, THF, rt; (f)
SO3Æpyridine, Et3N, DMSO/CH2Cl2, 0 °C; (g) NaClO2, NaH2PO4, 2-
methyl-2-butene, t-BuOH/H2O, 0 °C to rt; then aq HCl, rt, 83% (four
steps); (h) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt; then
DMAP, toluene, 110 °C, 94%; (i) KHMDS, (PhO)2P(O)Cl, THF/
HMPA, )78 °C.
H
H
TIPSO
O
B
OBn
OBn
9
A
OBn
OBn
E
O
H
O
OBn
O
(PhO)2PO
H
7
8
Scheme 1. Synthetic planning of the ABCDE ring fragment 4 of
ciguatoxins.

H. Fuwa et al. / Tetrahedron Letters 45 (2004) 4795–4799
4797
of the alkyl chain required for constructing the D ring
was accomplished via the B-alkyl Suzuki–Miyaura
coupling. Thus, coupling of 8 with the alkylborane de-
rived from olefin 9 in the presence of aqueous Cs2CO3
and 10mol % of PdCl 2(dppf) provided endocyclic enol
ether 13 in good yield. Hydroboration of 13 proceeded
stereoselectively to yield alcohol 14 in quantitative yield
as a single stereoisomer. The stereochemical outcome of
the reaction was confirmed by NOE experiment per-
formed on the corresponding acetate 15. Protection of
the resultant alcohol as the ethoxyethyl (EE) ether fol-
lowed by removal of the silyl group led to alcohol 16,
which was then converted to carboxylic acid 17 by a
two-step procedure. Acidic workup of the second oxi-
dation step facilitated deprotection of the EE group.
Lactonization of 17 under Yamaguchi conditions
afforded lactone 18, which was then transformed to the
DE ring fragment 6 following the Nicolaou protocol.14
borane followed by oxidation of the resultant hydroxyl
group with TPAP/NMO15 led to ketone 20. Incorpora-
tion of the double bond to the D ring was cleanly per-
formed by conversion to the corresponding enol silyl
ether followed by exposure to Pd(OAc)16 to effect
dehydrosilylation, leading to enone 21. Deprotection of
the MPM group of 21 followed by treatment with
methyl orthoformate under acidic conditions afforded
mixed methyl ketal 22. Finally, reduction of 22 with
Et3SiH and BF3ÆOEt2 gave rise to hexacyclic compound
23 as a single stereoisomer. The stereostructure of 23
was unambiguously confirmed by 1H NMR analysis
(J8;9 ¼ 9:2 Hz, J9;10eq ¼ 4:2 Hz, J9;10ax ¼ 11:4 Hz, J10eq;11
¼
4:2 Hz, J10ax;11 ¼ 11:4 Hz, J11;12 ¼ 9:1 Hz).
Having constructed the pentacyclic polyether skeleton,
we set out to functionalize the E ring of 23. Based on our
preliminary experiments, we found that deprotection of
the acetonide within 23 required relatively strong acidic
conditions. Therefore, the acetonide was removed prior
to installing sensitive functionalities. The liberated vic-
diol was masked with TBSOTf and Et3N, giving bis-
(silyl) ether 24. The three benzyl groups were then
removed by exposure to lithium di-tert-butylbiphenylide
(LiDBB),17 and the resultant triol was treated with p-
methoxybenzylidene dimethylacetal and PPTS to deliver
alcohol 25. Protection of the remaining hydroxyl group
as the 2-naphthylmethyl (NAP)8b ether (KH, NAPBr)
followed by deprotection of the two silyl groups with
With the requisite AB and DE ring fragments in hand,
we next directed our attention to building up the pen-
tacyclic polyether framework by means of the B-alkyl
Suzuki–Miyaura coupling-based approach (Scheme 4).
To this end, the AB ring exocyclic enol ether 5 was
treated with 9-BBN to deliver the corresponding
alkylborane, which was in situ reacted with 6 in the
presence of aqueous Cs2CO3 and PdCl2(dppf) catalyst
(10mol %), giving rise to cross-coupled product 19 in
73% yield from 18. Hydroboration of 19 with thexyl-
H
H
O
O
H
H
H
H
H
H
H
H
OBn
OBn
OBn
OBn
O
O
O
O
5
6
a
O
O
b,c
H
d,e
O
O
H
H
H
H
O
O
O
O
OMPM
OBn MPM
BnO
19
20
H
H
H
TBSO
TBSO
O
O
H
H
H
H
H
H
H
H
H
H
H
H
10
OBn
OBn
OBn
OBn
OBn
O
O
O
O
O
O
11
9
O
O
8
12
f,g
O
i,j
O
O
OBn
H
H
H
H
H
H
H
O
O
O
O
O
O
O
O
H
X
OMPM
22: X = OMe
23: X = H
OBn
OBn
H
BnO
24
21
h
k,l
H
H
H
O
H
H
H
H
TBSO
TBSO
HO
HO
H
H
H
O
H
H
H
H
H
O
O
O
O
O
O
O
MP
MP
m,n
MP
o-q
O
O
O
O
O
O
H
H
H
H
H
O
O
O
O
O
H
H
H
H
H
H
H
H
OH
ONAP
ONAP
25
26
27
r,s
H
H
H
20 OH
21
H
H
H
H
H
H
H
H
H
H
O
O
t,u
v
O
O
O
O
O
O
E
A
B
C
O
D
O
O
OTBS
OTBS
OTBS
H
H
H
H
H
H
O
O
O
O
O
H
H
H
H
H
H
H
H
ONAP
ONAP
ONAP
4
29
28
Scheme 4. Convergent synthesis of the ABCDE ring fragment 4. Reagents and conditions: (a) 9-BBN, THF, rt; then aq Cs2CO3, 6,
ꢀ
PdCl2(dppf)ÆCH2Cl2, DMF, 50 °C, 73% from 18; (b) ThexylBH2, THF, 0 °C; then aq NaOH, 30% H2O2, rt, 78%; (c) TPAP, NMO, 4 A molecular
sieves, CH2Cl2, rt; (d) LiHMDS, THF, )78 °C; then TMSCl, Et3N, )78 °C; (e) Pd(OAc)2, MeCN, rt, 89% (three steps); (f) DDQ, pH 7 buffer/
CH2Cl2, rt, 85%; (g) HC(OMe)3, PPTS, toluene, 50 °C; (h) Et3SiH, BF3ÆOEt2, CH2Cl2/MeCN, )15 °C, 73% (two steps); (i) aq HCl, THF/MeOH,
50 °C; (j) TBSOTf, Et3N, CH2Cl2, rt, 98% (two steps); (k) LiDBB, THF, )78 °C; (l) p-MeOC6H4CH(OMe)2, CSA, CH2Cl2, rt, 77% (two steps); (m)
NAPBr, KH, THF, rt, 96% (based on recovered 25); (n) TBAF, THF, rt; (o) HC(OMe)3, PPTS, CH2Cl2, rt; (p) Ac2O, reflux, 88% (three steps); (q)
ꢀ
CSA, MeOH, 0 °C; (r) TBSCl, imidazole, DMF, 0 °C, 94% (two steps); (s) TPAP, NMO, 4 A molecular sieves, CH2Cl2, rt; (t) LiHMDS, TMSCl,
Et3N, THF, )78 °C; (u) Pd(OAc)2, MeCN, rt, 74% (three steps); (v) NaBH4, CeCl3Æ7H2O, CH2Cl2/MeOH, 0 °C, 91%.

4798
H. Fuwa et al. / Tetrahedron Letters 45 (2004) 4795–4799
Tachibana, K. Tetrahedron 1999, 55, 10949; (h) Sasaki,
M.; Inoue, M.; Takamatsu, K.; Tachibana, K. J. Org.
Chem. 1999, 64, 9399; (i) Inoue, M.; Sasaki, M.; Tachi-
bana, K. J. Org. Chem. 1999, 64, 9416; (j) Sasaki, M.;
Honda, S.; Noguchi, T.; Takakura, H.; Tachibana, K.
Synlett 2000, 838; (k) Sasaki, M.; Noguchi, T.; Tachibana,
K. J. Org. Chem. 2002, 67, 3301.
TBAF led to diol 26. ortho Ester formation of the
resultant diol (HC(OMe)3, PPTS) followed by ther-
molysis (Ac2O, reflux)18 cleanly regenerated the
(Z)-olefin of the A ring to furnish 27. Cleavage of the p-
methoxybenzylidene acetal under mild acidic conditions
and selective protection of the primary alcohol as the
TBS ether, followed by oxidation of the remaining sec-
ondary alcohol, led to ketone 28, which was then
transformed to enone 29 according to the Ito–Saegusa
procedure. Finally, reduction of 29 under Luche con-
ditions19 furnished the targeted ABCDE ring fragment 4
as a single stereoisomer. The stereochemical relationship
between 20-H and 21-H was determined to be anti based
7. For recent synthetic studies on ciguatoxins from other
laboratories, see: (a) Maruyama, M.; Maeda, K.; Oishi, T.;
Hirama, M. Heterocycles 2001, 54, 93; (b) Oishi, T.;
Uehara, H.; Nagumo, Y.; Shoji, M.; Le Brazidec, J.-Y.;
Kosaka, M.; Hirama, M. Chem. Commun. 2001, 381; (c)
Fujiwara, K.; Takaoka, D.; Kusumi, K.; Kawai, K.;
Murai, A. Synlett 2001, 691; (d) Oishi, T.; Tanaka, S.;
Ogasawara, Y.; Maeda, K.; Oguri, H.; Hirama, M. Synlett
2001, 952; (e) Rungnapha, S.; Isobe, M. Heterocycles
2001, 54, 789; (f) Kira, K.; Isobe, M. Tetrahedron Lett.
2001, 42, 2821; (g) Imai, H.; Uehara, H.; Inoue, M.; Oguri,
H.; Oishi, T.; Hirama, M. Tetrahedron Lett. 2001, 42,
6219; (h) Maruyama, M.; Inoue, M.; Oishi, T.; Oguri, H.;
Ogasawara, Y.; Shindo, Y.; Hirama, M. Tetrahedron 2002,
58, 1835; (i) Kira, K.; Hamajima, A.; Isobe, M. Tetrahe-
dron 2002, 58, 1875; (j) Fujiwara, K.; Koyama, Y.; Doi,
E.; Shimawaki, K.; Ohtaniuchi, Y.; Takemura, A.; Souma,
S.-i.; Murai, A. Synlett 2002, 1496; (k) Fujiwara, K.;
Koyama, Y.; Kawai, K.; Tanaka, H.; Murai, A. Synlett
2002, 1835; (l) Inoue, M.; Wang, G.-X.; Wang, J.; Hirama,
M. Org. Lett. 2002, 4, 3439; (m) Uehara, H.; Oishi, T.;
Inoue, M.; Shoji, M.; Nagumo, Y.; Kosaka, M.; Le
Brazidec, J.-Y.; Hirama, M. Tetrahedron 2002, 58, 6493;
(n) Baba, T.; Isobe, M. Synlett 2003, 547; (o) Tatami, A.;
Inoue, M.; Uehara, H.; Hirama, M. Tetrahedron Lett.
2003, 44, 5229; (p) Baba, T.; Huang, G.; Isobe, M.
Tetrahedron 2003, 59, 6851; (q) Kobayashi, S.; Alizadeh,
B. H.; Sasaki, S.; Oguri, H.; Hirama, M. Org. Lett. 2004,
6, 751; (r) Inoue, M.; Yamashita, S.; Hirama, M.
Tetrahedron Lett. 2004, 45, 2053, and references cited
therein.
1
on H NMR analysis (J20;21 ¼ 9:5 Hz).
In summary, we have succeeded in the synthesis of the
ABCDE ring fragment of ciguatoxins via the Suzuki–
Miyaura coupling-based approach. The highly stereo-
controlled, convergent nature of the present synthesis
allowed an efficient and straightforward production of
the ABCDE ring fragment. Further efforts toward the
total synthesis of ciguatoxins are currently underway
and will be reported in due course.
Acknowledgements
This work was financially supported by CREST, Japan
Science and Technology Agency (JST) and Suntory
Institute for Bioorganic Research (SUNBOR).
References and notes
8. (a) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.;
Maruyama, M.; Oguri, H.; Satake, M. Science 2001,
294, 1904; (b) Inoue, M.; Uehara, H.; Maruyama, M.;
Hirama, M. Org. Lett. 2002, 4, 4551; (c) Inoue, M.;
Hirama, M. Synlett 2004, 577.
1. For reviews, see: (a) Yasumoto, T.; Murata, M. Chem.
Rev. 1993, 93, 1897; (b) Scheuer, P. J. Tetrahedron 1994,
50, 3; (c) Murata, M.; Yasumoto, T. Nat. Prod. Rep. 2000,
17, 293; (d) Yasumoto, T. Chem. Rec. 2001, 1, 228.
2. (a) Murata, M.; Legrand, A.-M.; Ishibashi, Y.; Yasumoto,
T. J. Am. Chem. Soc. 1989, 111, 8929; (b) Murata, M.;
Legrand, A.-M.; Ishibashi, Y.; Fukui, M.; Yasumoto, T.
J. Am. Chem. Soc. 1990, 112, 4380; (c) Satake, M.;
Morohashi, A.; Oguri, H.; Oishi, T.; Hirama, M.; Harada,
N.; Yasumoto, T. J. Am. Chem. Soc. 1997, 119, 11325; (d)
Yasumoto, T.; Igarashi, T.; Legrand, A.-M.; Cruchet, P.;
Chinain, M.; Fujita, T.; Naoki, H. J. Am. Chem. Soc.
2000, 122, 4988.
3. Satake, M.; Murata, M.; Yasumoto, T. Tetrahedron Lett.
1993, 34, 1975.
4. Satake, M.; Fukui, M.; Legrand, A.-M.; Cruchet, P.;
Yasumoto, T. Tetrahedron Lett. 1998, 39, 1197.
5. (a) Lombet, A.; Bidard, J.-N.; Lazdunski, M. FEBS Lett.
1987, 219, 355; (b) Dechraoui, M.-Y.; Naar, J.; Pauillac,
S.; Legrand, A.-M. Toxicon 1999, 37, 125.
6. (a) Sasaki, M.; Hasegawa, A.; Tachibana, K. Tetrahedron
Lett. 1993, 34, 8489; (b) Sasaki, M.; Inoue, M.; Tachibana,
K. J. Org. Chem. 1994, 59, 715; (c) Inoue, M.; Sasaki, M.;
Tachibana, K. Tetrahedron Lett. 1997, 38, 1611; (d) Inoue,
M.; Sasaki, M.; Tachibana, K. Angew. Chem., Int. Ed.
1998, 37, 965; (e) Sasaki, M.; Inoue, M.; Noguchi, T.;
Takeichi, A.; Tachibana, K. Tetrahedron Lett. 1998, 39,
2783; (f) Sasaki, M.; Noguchi, T.; Tachibana, K. Tetra-
hedron Lett. 1999, 40, 1337; (g) Inoue, M.; Sasaki, M.;
9. For reviews on the synthesis of marine polycyclic ether
ꢁ
toxins, see: (a) Alvarez, E.; Candenas, M.-L.; Perez, R.;
Ravelo, J. L.; Martın, J. D. Chem. Rev. 1995, 95, 1953; (b)
ꢁ
€
Mori, Y. Chem. Eur. J. 1997, 3, 849; (c) Marmsater, F. P.;
West, F. G. Chem. Eur. J. 2002, 8, 4347; (d) Evans, P. A.;
Benedicte, D. Curr. Opin. Drug. Dis. Dev. 2002, 5, 986.
10. For reviews on Suzuki-Miyaura coupling, see: (a)
Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b)
Suzuki, A. J. Organomet. Chem. 1999, 576, 147; (c)
Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew.
Chem., Int. Ed. 2001, 40, 4544.
11. (a) Sasaki, M.; Fuwa, H.; Inoue, M.; Tachibana, K.
Tetrahedron Lett. 1998, 39, 9027; (b) Sasaki, M.; Fuwa,
H.; Ishikawa, M.; Tachibana, K. Org. Lett. 1999, 1, 1075;
(c) Sasaki, M.; Noguchi, K.; Fuwa, H.; Tachibana, K.
Tetrahedron Lett. 2000, 41, 1425; (d) Fuwa, H.; Sasaki,
M.; Tachibana, K. Tetrahedron Lett. 2000, 41, 8371; (e)
Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron 2001,
57, 3019; (f) Takakura, H.; Noguchi, K.; Sasaki, M.;
Tachibana, K. Angew. Chem., Int. Ed. 2001, 40, 1090; (g)
Fuwa, H.; Sasaki, M.; Tachibana, K. Org. Lett. 2001, 3,
3549; (h) Sasaki, M.; Tsukano, C.; Tachibana, K. Org.
Lett. 2002, 4, 1747; (i) Takakura, H.; Sasaki, M.; Honda,
S.; Tachibana, K. Org. Lett. 2002, 4, 2771; (j) Fuwa, H.;
Sasaki, M.; Satake, M.; Tachibana, K. Org. Lett. 2002, 4,
2981; (k) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki,

H. Fuwa et al. / Tetrahedron Letters 45 (2004) 4795–4799
4799
M. J. Am. Chem. Soc. 2002, 124, 14983; (l) Sasaki, M.;
Tsukano, C.; Tachibana, K. Tetrahedron Lett. 2003, 44,
4351; (m) Tsukano, C.; Sasaki, M. J. Am. Chem. Soc.
2003, 125, 14294.
15. Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
16. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43,
1011.
12. Sasaki, M.; Ishikawa, M.; Fuwa, H.; Tachibana, K.
Tetrahedron 2002, 58, 1889.
13. Stereostructure of the minor diastereomer was established
by NOE between 3-H and 5-H.
€
14. Nicolaou, K. C.; Shi, G. Q.; Gunzner, J. L.; Gartner, P.;
Yang, Z. J. Am. Chem. Soc. 1997, 119, 5467.
17. (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980,
45, 1924; (b) Ireland, R. E.; Smith, M. G. J. Am. Chem.
Soc. 1988, 110, 854.
18. Ando, M.; Ohhara, H.; Takase, K. Chem. Lett. 1986,
879.
19. Luche, J.-L. J. Am. Chem. Soc. 1978, 100, 2226.