Convergent synthesis of the ABCDE-ring fragment of the Caribbean ciguatoxin C-CTX-1

Article abstract of DOI:10.1016/j.tetlet.2007.01.102

Ciguatoxin C-CTX-1 was isolated as a principal causative toxin of ciguatera seafood poisoning in the Caribbean Sea, and is structurally classified as a ladder-shaped polycyclic ether. In this Letter, we report the convergent synthesis of the pentacyclic l

Full text of DOI:10.1016/j.tetlet.2007.01.102

Tetrahedron Letters 48 (2007) 2171–2175
Convergent synthesis of the ABCDE-ring fragment
of the Caribbean ciguatoxin C-CTX-1
a
a
Masayuki Inoue,a,b, Fumihito Saito, Masafumi Iwatsu,
*
Yuuki Ishiharaa and Masahiro Hiramaa,*
aDepartment of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
bResearch and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Received 2 November 2006; revised 6 January 2007; accepted 18 January 2007
Available online 24 January 2007
Abstract—Ciguatoxin C-CTX-1 was isolated as a principal causative toxin of ciguatera seafood poisoning in the Caribbean Sea, and
is structurally classified as a ladder-shaped polycyclic ether. In this Letter, we report the convergent synthesis of the pentacyclic left
half of C-CTX-1, based on a newly developed acyl radical strategy.
Ó 2007 Elsevier Ltd. All rights reserved.
Me
Ciguatera poisoning is a human intoxication caused by
H
HO
H
J
Me
O
ingestion of tropical fishes contaminated with ciguatox-
ins (CTXs).1 Ciguatera is especially widespread in the is-
lands of the Pacific Ocean, Indian Ocean, and the
Caribbean Sea, but cases are increasingly being reported
in temperate regions with the expansion of tourism and
trade. CTXs arise from precursors that are synthesized
by the benthic dinoflagellate Gambierdiscus toxicus and
are transferred to fishes at different trophic levels within
the marine food chain. It is now apparent that chemically
distinct CTXs are responsible for ciguatera in different
regions. Approximately 20 Pacific CTXs2 (e.g., CTX3C
1,2b Fig. 1), and two Caribbean ciguatoxins (e.g.,
C-CTX-1 23) have been structurally determined to date.
Me
I
H
O
H
H
H
H
OH
H
H
G
O
O
H
H
H
H
H
H
H
H
K
O
O
E
O
H
O
B
H
3
H
O
H
F
O
D
C
O
A
O
O
M
L
H
52
H
Me
7
1
O
Me
H
OH
Me
HO
H
Me
O
I
CTX3C (1)
H
O
H
H
O
J
OH
Me
H
G
O
HO
H
H
H
10
H
O
H
H
K
20
E
O
H
H
3
5
15
H
O
H
F
O
D
C
O
B
A
O
H
L
H
H
1
O
7
H
H
Me
M
O
H
C-CTX-1 (2)
coupling of left and right wing fragments Me
O
N
OH
H
H
NAPO
H
H
H
H
H
57
OH
O
O
B
E
OH
A
C
D
O
H
reductive etherification
O
H
O
H
3
H
H
NAPO
H
H
H
H
O
O
O
B
E
MP
Current difficulties in predicting, detecting, and treating
ciguatera mean that this form of fish poisoning contin-
ues to have large socioeconomic impacts, particularly
in developing countries. Recently, we raised antibodies
against a synthetic fragment of Pacific ciguatoxin
CTX3C 1, and applied them in an enzyme-linked immu-
nosorbent assay (ELISA) format designed to detect 1
specifically.4 Because of their significant structural dif-
ferences from Pacific ciguatoxins, development of an
alternative detection method for Caribbean ciguatoxins
is necessary.
A
7
O
acyl radical cyclization
O
H
O
H
O
4
OTBS
H
H
NAPO
H
H
H
O
O
O
B
E
MP
A
O
O
H
H
O
enol ether introduction
OTBS
CO2Me
5
H
H
NAPO
H
H
O
O
O
B
E
MP
A
O
O
PhS
O,S-acetal formation
H
H
O
H
OTBS
CO2Me
6
H
NAPO
H
HO
H
H
H
H
O
E
MP
O
B
SPh
A
+
Cl
OTBS
O
O
H
H
O
7
8
CO2Me
Keywords: Ciguatoxins; Polyethers; Radicals; Enol ethers; O,S-Acetals.
*
Figure 1. Structures of Caribbean ciguatoxin C-CTX-1 and Pacific
ciguatoxin CTX3C, and retrosynthesis of the left wing fragment of
C-CTX-1.
Corresponding authors. Tel.: +81 22 795 6565; fax: +81 22 795 6566
(M.I.); e-mail addresses: inoue@ykbsc.chem.tohoku.ac.jp; hirama@
ykbsc.chem.tohoku.ac.jp
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.01.102

2172
M. Inoue et al. / Tetrahedron Letters 48 (2007) 2171–2175
In this context, we launched a program directed toward
the total synthesis of C-CTX-1 2 (Fig. 1).5 The synthetic
plan for 2 was based on our previous total syntheses of
Pacific ciguatoxins such as 1: coupling between the
ABCDE- and HIJKLM-ring fragments with subsequent
construction of the central FG-ring system (blue high-
lighting in Fig. 1) generated the entire structure of 1.6
Since 1 and 2 share the common FG-ring structures,
we planned to utilize this unified convergent strategy
for construction of 2. The dissected left half 3 was fur-
ther retrosynthetically disconnected to afford simple
bicyclic 7 and monocyclic 8. In the synthetic direction,
we envisaged assembling these AB- and E-ring systems
into 3 using the recently developed acyl radical method-
ology that we previously applied to the concise synthesis
of the ABCDE-ring fragment of 1.7 Namely, after link-
ing 7 and 8 by forming the C–O bond as its O,S-acetal
6,8 elimination of the sulfide from 6 would produce enol
ether 5, the subsequent acyl radical addition would then
cyclize the seven-membered ether ring corresponding to
the D-ring (5!4).9 The remaining six-membered C-ring
of 3 was in turn to be constructed through reductive
etherification.10
ing to the 6-endo product 13 in a 41% yield (entry 1,
Scheme 1). Since the low yield arose from the acid-in-
duced concomitant removal of the p-methoxyphenyl
(MP) acetal, the substrate was alternatively treated with
PPTS in the presence of MPCH(OMe)2. The yield was
increased to 57% as a result, but further optimization
was necessary. After screening different reagents and
conditions, it was found that [Rh(CO)2Cl]2-promoted
intramolecular ring opening of vinyl epoxides, as
reported by Ha,14 worked well under mild conditions
and gave the cyclized product 13 in an 84% yield.15
The directing group of 13 for the 6-endo cyclization was
then reduced to a saturated alcohol 14 using KBH-
(s-Bu)3 (Scheme 2).16 After conversion of 14 to selenide
15 with o-nitrophenyl selenocyanate and tributylphos-
phine,17 treatment of 15 with hydrogen peroxide gave
the selenoxide, which underwent b-elimination to fur-
nish terminal olefin 16. Introduction of the allyl group
onto the secondary alcohol of 16, and subsequent ring
closing olefin metathesis18 of 17 constructed the seven-
membered ether ring of 18.19 The MP group of 18 was
removed, and the hydroxyl groups of the resultant diol
were protected as TBS ethers, producing 19. Epoxida-
tion of 19 with m-CPBA selectively occurred at the
The six-membered B-ring was cyclized via 6-endo selec-
tive opening of an hydroxy epoxide (Scheme 1). The
known allylic alcohol 9,11 which was prepared from D-
2-deoxyribose in four steps, was subjected to Sharpless
asymmetric epoxidation,12 selectively producing b-epox-
ide 10. Following the method developed by Nicolaou,13
the p-bond was attached to the epoxide unit as a direct-
ing unit to induce the kinetically unfavorable 6-endo
mode cyclization at C5 rather than the 5-exo counter-
part at C6. Specifically, oxidation of primary alcohol
10, followed by Wittig olefination, led to a,b-unsatu-
rated ester 11, the TBS-group of which was removed
using TBAF to generate hydroxy epoxide 12.
H
H
H
H
H
H
O
B
a) KBH(s-Bu)3
MeO2C
O
B
X
O
O
HO
O
MP
HO
H
O
MP
-NO2C6H4SeCN,
H
H
14: X = OH
15: X =
13
b)
o
n-Bu3P
o
-NO2C6H4Se
c) H2O2
PCy3
e)
Cl
Cl
H
H
H
H
Ru
O
B
O
B
OR2
OR2
O
Ph
PCy3
R1O
H
O
MP
O
H
H
16: R1 = H
17: R1 = CH2CH=CH2
f) TFA
18: R2 = CHMP
19: R2 = TBS
d)
Br
g) TBSCl
h) mCPBA
H
H
H
H
H
H
O
B
O
B
O
O
As expected, the acid-catalyst, PPTS, effected selective
OTBS
OTBS
OTBS
2
HO
cleavage of the C–O bond adjacent to the p-bond, lead-
OTBS
21
O
O
O
H
H
H
20β
NOE
H
HO
H
H
H
O
B
O
B
3 A
i) LiAlH4
3
OTBS
OTBS
5
2
D
-2-deoxyribose
O
OH
OTBS
O
OTBS
H
H
H
H
4 steps (ref 11)
a) Ti(Oi-Pr)4, (-)-DET
t-BuOOH
HO
20α
22
j) NAPBr
k) CSA
OH
HO
TBS
TBS
H
H
H
H
O
O
5
O
O
HO
O
O
O
NAPO
6
H
H
H
NAPO
H
H
H
O
B
R3
OTBS
O
O
MP
MP
O
MP
MP
O
SPh
p) (PhS)2,
n-Bu3P
A
A
B
10
9
Y
b) SO3·Py, DMSO
c)
O
OTBS
O
H
Ph3
P
H
CO2Me
l) I2, PPh3
m) NaCN
n) DIBAL-H
o) NaBH4
23: R3 = OH
26: Y = H
q) NCS
24: R3 = CN
H
H
H
H
H
7: Y = Cl
MeO2
C
O
B
MeO2
C
RO
see below
5
6
25: R3 = CH2OH
5
6
O
HO
O
H
13
11: R = TBS
12: R = H
Scheme 2. Reagents and conditions: (a) KBH(s-Bu)3, THF/
EtOH = 100, ꢀ78 °C, 80%; (b) o-NO2C6H4SeCN, n-Bu3P, THF, rt;
(c) H2O2, THF, 0 °C to rt; (d) allyl bromide, DMF/THF = 1/5, 0 °C,
70% (three steps); (e) (PCy3)2Cl2Ru@CHPh, CH2Cl2, rt, 96%; (f) TFA,
THF/H2O = 3.6, rt; (g) TBSCl, imidazole, DMF, rt, 98% (two steps);
(h) m-CPBA, NaHCO3, CH2Cl2, 0 °C to rt, 99% (20a:20b = 4.7:1); (i)
LiAlH4, Et2O, ꢀ20 °C, 91% (22:21 = 4.1:1); (j) NAPBr, TBAI, NaH,
THF/DMF = 3, rt; (k) CSA, MeOH/THF = 1, 0 °C, 51% (two steps);
(l) I2, PPh3, imidazole, THF, rt, 95%; (m) NaCN, DMSO, 45 °C, 90%;
(n) DIBAL-H, CH2Cl2, ꢀ95 °C, then 1 N HCl aq, rt; (o) NaBH4,
MeOH/CH2Cl2 = 1, ꢀ20 °C to rt, 83%; (p) (PhS)2, n-Bu3P, pyridine,
rt, 95%; (q) NCS, CH2Cl2/CCl4 = 1/5, rt.
d) TBAF
entry
reagents
solvent temperature (C°) yield (%)
1
2
3
PPTS
CH2Cl2
toluene
THF
32
80
25
41
57
84
PPTS, MPCH(OMe)2
[Rh(CO)2Cl]2
Scheme 1. Reagents and conditions: (a) Ti(Oi-Pr)4, (ꢀ)-DET,
˚
t-BuOOH, 4 A MS, CH2Cl2, ꢀ30 °C, 89%; (b) SO3ÆPy, DMSO,
Et3N, CH2Cl2, 0 °C; (c) Ph3P@CHCO2Me, THF, rt, 78% (two steps);
(d) TBAF, THF, rt, 95%.

M. Inoue et al. / Tetrahedron Letters 48 (2007) 2171–2175
2173
H
H
H
H
H
NAPO
mCPBA
H
H
H
O
O
H
5
H
H
5
H
O
B
E
a) AgOTf, DTBMP
MP
MP
11
7 + 8
A
OTBS
OTBS
OTBS
OTBS
O
O
SPh
O
O
H
H
O
O
H
O
O
mCPBA
OTBS
MeO
6
H
H
H
H
O
H
b) AgOTf,
i-Pr2NEt
19
20α
NAPO
H
H
H
H
O
O
O
B
E
11O
trans
Figure 2. Energy-minimized three-dimensional structures of 19 and
20a (MM2*, MacroModel Ver. 8.5).
R
11
A
cis
O
O
R
O
H
O
e)
n
-Bu3GeH
H
H
OTBS
X
Et3B
29
O
5: X = OMe
c) LiOH·H2
O
a-face of the molecule, and 20a was isolated in a 75%
yield (20a:20b = 4.7:1). Reductive opening of epoxide
20a was promoted by LiAlH4 to generate the desired
product 22 as the major isomer (22:21 = 4.1:1).20 Thus,
all the stereocenters necessary for the AB-ring fragment
had been successfully introduced by this stage.
d) (PhSe)2
, n-Bu3P
27: X = SePh
28: X = H
NOE
H
H
NAPO
H
H
H
H
H
H
H
H
O
O
O
B
O
O
B
E
MP
11
A
7
O
O
H
H
O
O
H
OTBS
H
OTBS
4
30
f) LiN(TMS)2, TMSCl
H
H
NAPO
NAPO
NAPO
H
H
H
H
O
O
O
As shown in Figure 2, the desirable selectivities observed
in the epoxidation and the subsequent reduction were
considered to originate from the intrinsic conformations
of 19 and 20a. In both cases, the reagent access route
leading to the undesired isomers was sterically blocked
by the projecting C5-hydrogen.
O
B
E
MP
A
31: R1 = TMS
O
O
R1
OTBS
O
H
H
H
H
H
H
O
g) Pd(OAc)2
H
H
H
H
H
OR3
O
B
E
A
D
OR3
O
32: R2 = TBS, R3 = CHMP
33: R2 = H, R3 = H
O
O
H
OR2
h) HF
An additional eight-step reaction sequence transformed
22 into the coupling substrate 7 (Scheme 2). The second-
ary alcohol of 22 was converted to its 2-naphthylmethyl
(NAP) ether,21 and the TBS-group at the less-hindered
position was selectively removed under acidic condi-
tions, leading to alcohol 23. A reagent combination of
I2, PPh3, and imidazole22 chemoselectively transformed
the alcohol of 23 into the iodide, and subsequent cya-
nide introduction gave the one-carbon homologated
product 24. Then, stepwise reduction of nitrile 24 using
DIBAL-H and NaBH4 resulted in alcohol 25. Finally,
treatment of 25 with (PhS)2 and n-Bu3P23 generated
phenylsulfide 26, and the chloride was subsequently
introduced into the a-position of the sulfide by the
action of NCS to afford a-chlorosulfide 7.24
i) Et3SiH, TMSOTf
H
34: R4 = OH
35: R4 = OTs
36: R4 = CN
H
H
H
H
O
j) TsCl
OH
R4
O
E
k) NaCN
A
B
C
O
D
12
O
l) DIBAL-H
O
H
H
H
3: R4 = CH=CH2
m) PPh3=CH2
Scheme 3. Reagents and conditions: (a)
8 (1.5 equiv), AgOTf,
˚
DTBMP, 4 A MS, CH2Cl2/CCl4 = 5, ꢀ90 °C to ꢀ15 °C, 70% from 7
˚
(dr = 1:1); (b) AgOTf, i-Pr2NEt, 4 A MS, benzene, rt, 93% (cis:
trans = 1:2.1); (c) LiOHÆH2O, 1,4-dioxane/H2O = 1.7, rt; (d) (PhSe)2,
n-Bu3P, DMF, rt, 80% (two steps); (e) n-Bu3GeH, Et3B, benzene, 63%
(4), 7% (28), 21% (30); (f) LiN(TMS)2, TMSCl, THF, ꢀ95 °C, 52%; (g)
Pd(OAc)2, CH3CN, rt, 83%; (h) HF aq, CH3CN, rt; (i) Et3SiH,
˚
TMSOTf, 4 A MS, CH2Cl2, ꢀ90 to ꢀ15 °C, 86% (two steps); (j) TsCl,
pyridine, rt, 75%; (k) NaCN, DMSO, 45 °C, 100%; (l) DIBAL-H,
CH2Cl2, ꢀ90 to ꢀ72 °C, then 1 N HCl aq, rt; (m) CH3PPh3Br,
t-BuOK, THF, 0 °C, 37% (two steps).
As shown in Scheme 3, coupling between the AB-ring
electrophile 7 and the E-ring nucleophile 825 was pro-
moted by AgOTf in the presence of 2,6-di-tert-butyl-4-
methylpyridine (DTBMP) to generate adduct 6 as a
diastereomeric mixture (dr = 1:1) in a 70% yield.6,8,26
Efficient C–O bond formation from the hindered
secondary alcohol 8 as well as compatibility of the acid
sensitive MP acetal proved the high generality of this
O,S-acetal formation. The sulfide of adduct 6 was then
activated with the same silver salt in the presence of
with complete stereochemical control. This excellent ste-
reocontrol is ascribed to the strongly favored transition
state conformation of 29, in which the A1,3-strain is min-
imized. Although premature reduction and decarbonyl-
ation of the acyl radical generated aldehyde 28 (7%) and
tetrahydropyran 30 (21%), respectively, as minor
byproducts, chemo- and stereoselective intramolecular
addition to the electron-rich alkene to form the seven-
membered ring as the major product highlights the ver-
satility of the present acyl radical strategy.
Hunig’s base, resulting in effective formation of the
¨
chemically labile enol ether 5 as a mixture of geometric
isomers (93% yield, cis:trans = 1:2.1).7,27 Next, the
methyl ester of 5 was transformed into phenylselenyl
ester 27 via saponification and subsequent treatment
with (PhSe)2 and n-Bu3P.28
Introduction of olefin to oxepane 4 was realized in two
steps: regioselective TMS-enol ether formation using a
reagent combination of LiN(TMS)2 and TMSCl,
followed by Saegusa oxidation31 of 31 with Pd2+ to yield
a,b-unsaturated ketone 32. The TBS and acetal protec-
tive groups of 32 were removed with aqueous hydrogen
fluoride, resulting in triol 33. Then, reductive etherifica-
tion32 of hydroxy ketone 33, using TMSOTf and Et3SiH,
established the C12 stereocenter via axial-attack of the
hydride on the oxonium cation intermediate, yielding
the requisite pentacyclic ABCDE-ring structure 34.
Lastly, the R4 side chain was modified through standard
Phenylselenide 27 was then subjected to the radical cycli-
zation conditions (n-Bu3GeH and Et3B),29 recently opti-
mized for the synthesis of the ABCDE ring fragment of
CTX3C 1.7b,30 During this step, acyl radical intermedi-
ate 29, generated through homolytic cleavage of the
C–Se bond of 27, reacted with the enol ether to produce
the seven-membered ring in oxepane 4 in a 63% yield

2174
M. Inoue et al. / Tetrahedron Letters 48 (2007) 2171–2175
Ohnuma, Y.; Kawada, Y.; Komano, K.; Yamashita, S.;
Lee, N.; Hirama, M. J. Am. Chem. Soc. 2006, 128,
9352.
functional group manipulations. The primary alcohol of
34 was tosylated to give 35, which was treated with
sodium cyanide to afford 36. DIBAL-H reduction of
nitrile 36 to the aldehyde and subsequent Wittig methyl-
enation delivered the targeted left wing fragment 3.33
7. (a) Inoue, M.; Ishihara, Y.; Yamashita, S.; Hirama, M.
Org. Lett. 2006, 8, 5801; (b) Inoue, M.; Yamashita, S.;
Ishihara, Y.; Hirama, M. Org. Lett. 2006, 8, 5805.
8. Inoue, M.; Wang, G. X.; Wang, J.; Hirama, M. Org. Lett.
2002, 4, 3439.
In summary, we have synthesized the ABCDE ring frag-
ment 3 of the Caribbean ciguatoxin C-CTX-1 in a highly
convergent manner (13 steps from the fragments 7 and
8). Key reactions of the synthesis include: (i)
[Rh(CO)2Cl]2-catalyzed, 6-endo selective, hydroxy epox-
ide cyclization to construct the B-ring; (ii) stereo- and
regioselective introduction of the hydroxy group of the
A-ring; (iii) direct construction of the O,S-acetal to
couple the AB- and E-ring fragments, and following
efficient formation of an electron-rich enol ether; (iv)
stereoselective acyl radical cyclization to the seven-mem-
bered D-ring; and (v) stereoselective reductive etherifica-
tion to build the six-membered C-ring. The left wing
fragment prepared here will serve both as a hapten for
preparing anti-ciguatoxin antibodies to control Carib-
bean ciguatera and as a fragment for a total synthesis
of C-CTX-1.
9. For reviews on acyl radicals, see: (a) Boger, D. L. Israel J.
Chem. 1997, 37, 119; (b) Chatgilialoglu, C.; Crich, D.;
Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991.
10. For syntheses of the BCDE, ABCD or ABCDE ring units
of the Pacific ciguatoxins from other groups, see: (a) Kira,
K.; Isobe, M. Tetrahedron Lett. 2001, 42, 2821; (b)
Fujiwara, K.; Koyama, Y.; Kawai, K.; Tanaka, H.;
Murai, A. Synlett 2002, 1835; (c) Sasaki, M.; Ishikawa,
M.; Fuwa, H.; Tachibana, K. Tetrahedron 2002, 58, 1889;
(d) Fuwa, H.; Fujikawa, S.; Tachibana, K.; Takakura, H.;
Sasaki, M. Tetrahedron Lett. 2004, 45, 4795; (e) Fujiwara,
K.; Goto, A.; Sato, D.; Ohtaniuchi, Y.; Tanaka, H.;
Murai, A.; Kawai, H.; Suzuki, T. Tetrahedron Lett. 2004,
45, 7011.
11. Inoue, M.; Wang, J.; Wang, G.-X.; Ogasawara, Y.;
Hirama, M. Tetrahedron 2003, 59, 5645.
12. (a) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 5765; (b) Katsuki, T.; Martin, V. S. Org. React. 1996,
48, 1.
Acknowledgments
13. Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang,
C.-K. J. Am. Chem. Soc. 1989, 111, 5330.
14. Ha, J. D.; Shin, E. Y.; Kang, S. K.; Ahn, J. H.; Choi, J.-K.
Tetrahedron Lett. 2004, 45, 4193.
This work was supported financially by SORST, Japan
Science and Technology Agency (JST), and a Grant-
in-Aid for Scientific Research (S) from the Japan Society
for the Promotion of Science (JSPS).
15. The mechanism of the [Rh(CO)2Cl]2-promoted reaction
could be different from that of the proton-catalyzed
reaction. Ha proposed that the rhodium catalyst induced
the formation of an enyl or a p-allyl intermediate prior to
the cyclization. For similar reactions, see: Fagnou, K.;
Lautens, M. Org. Lett. 2000, 2, 2319.
References and notes
16. Fortunato, J. M.; Ganem, B. J. Org. Chem. 1976, 41,
2194.
17. Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem.
1976, 41, 1485.
18. For reviews, see: (a) Trnka, T. M.; Grubbs, R. H. Acc.
Chem. Res. 2001, 34, 18; (b) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012; (c) Deiters, A.; Martin, S. F. Chem.
Rev. 2004, 104, 2199; (d) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490.
19. Eriksson, L.; Guy, S.; Perlmutter, P. J. Org. Chem. 1999,
64, 8396.
1. (a) Scheuer, P. J. Tetrahedron 1994, 50, 3; (b) Lewis, R. J.
Toxicon 2001, 39, 97; (c) Yasumoto, T.; Murata, M.
Chem. Rev. 1993, 93, 1897; (d) Yasumoto, T. Chem. Rec.
2001, 1, 228.
2. (a) Murata, M.; Legrand, A.-M.; Ishibashi, Y.; Fukui, M.;
Yasumoto, T. J. Am. Chem. Soc. 1990, 112, 4380; (b)
Satake, M.; Murata, M.; Yasumoto, T. Tetrahedron Lett.
1993, 34, 1975; (c) Yasumoto, T.; Igarashi, T.; Legrand,
A.-M.; Cruchet, P.; Chinain, M.; Fujita, T.; Naoki, H. J.
Am. Chem. Soc. 2000, 122, 4988.
3. Lewis, R. J.; Vernoux, J.-P.; Brereton, I. M. J. Am. Chem.
Soc. 1998, 120, 5914.
20. (a) Rickborn, B.; Quartucci, J. J. Org. Chem. 1964, 29,
3185; (b) Rickborn, B.; Lamke, W. E., Jr. J. Org. Chem.
1967, 32, 537; (c) Murai, S.; Murai, T.; Kato, S. Reduction
of Epoxide. In Comprehensive Organic Synthesis; Trost, B.
M., Fleming, I., Eds.; Pergamon, 1991; Vol. 8, pp 871–
893.
21. (a) Wright, J. A.; Yu, J.; Spencer, J. B. Tetrahedron Lett.
2001, 42, 4033; (b) Xia, J.; Abbas, S. A.; Locke, R. D.;
Piskorz, C. F.; Alderfer, J. L.; Matta, K. L. Tetrahedron
Lett. 2000, 41, 169; (c) Inoue, M.; Uehara, H.; Maruyama,
M.; Hirama, M. Org. Lett. 2002, 4, 4551.
4. (a) Oguri, H.; Hirama, M.; Tsumuraya, T.; Fujii, I.;
Maruyama, M.; Uehara, H.; Nagumo, Y. J. Am. Chem.
Soc. 2003, 125, 7608–7612; (b) Tsumuraya, T.; Fujii, I.;
Inoue, M.; Tatami, A.; Miyazaki, K.; Hirama, M. Toxicon
2006, 48, 287.
5. For reviews of polyether synthesis, 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) Yet, L. Chem. Rev. 2000, 100, 2963; (d)
Marmsa¨ter, F. P.; West, F. G. Chem. Eur. J. 2002, 8, 4347;
(e) Nakata, T. Chem. Rev. 2005, 105, 4314; (f) Inoue, M.
Chem. Rev. 2005, 105, 4379; (g) Clark, J. S. Chem.
Commun. 2006, 3571.
22. Garegg, P. J.; Sammuelsson, B. J. Chem. Soc., Chem.
Commun. 1979, 978.
23. Nakagawa, I.; Hata, T. Tetrahedron Lett. 1975, 16, 1409.
24. Paquette, L. A. Org. React. 1977, 25, 1.
6. (a) Inoue, M.; Miyazaki, K.; Uehara, H.; Maruyama, M.;
Hirama, M. Proc. Natl. Acad. Sci. U.S.A. 2004, 101,
12013; (b) Inoue, M.; Hirama, M. Acc. Chem. Res. 2004,
37, 961; (c) Hirama, M. Chem. Rec. 2005, 5, 240; (d)
Inoue, M.; Miyazaki, K.; Ishihara, Y.; Tatami, A.;
25. Compounds 8 were synthesized by standard functional
group transformation from the previously reported E-ring
fragment of CTX3C. Maruyama, M.; Inoue, M.; Oishi, T.;
Oguri, H.; Ogasawara, Y.; Shindo, Y.; Hirama, M.
Tetrahedron 2002, 58, 1835.

M. Inoue et al. / Tetrahedron Letters 48 (2007) 2171–2175
2175
25
26. McAuliffe, J. C.; Hindsgaul, O. Synlett 1998, 307.
27. The geometric isomer ratio of 5 did not reflect the
diastereomer ratio at the O,S-acetal carbon center of 6,
indicating an E1-like mechanism of the reaction.
28. Singh, U.; Ghosh, S. K.; Chadha, M. S.; Mamdapur, V.
R. Tetrahedron Lett. 1991, 32, 255.
29. Johnston, L. J.; Lusztyk, J.; Wayner, D. D. M.; Abey-
wickreyma, A. N.; Beckwith, A. L. J.; Scaiano, J. C.;
Ingold, K. U. J. Am. Chem. Soc. 1985, 107, 4594.
30. Evans successfully constructed the seven-membered ether
rings through acyl radical addition to electron deficient
olefins such as vinyl esters and sulfonates: (a) Evans, P. A.;
Roseman, J. D. J. Org. Chem. 1996, 61, 2252; (b) Evans, P.
A.; Roseman, J. D.; Garber, L. T. J. Org. Chem. 1996, 61,
4880; (c) Evans, P. A.; Manangan, T. Tetrahedron Lett.
1997, 38, 8165; (d) Evans, P. A.; Manangan, T. J. Org.
Chem. 2000, 65, 4523; (e) Evans, P. A.; Raina, S.; Ahsan,
K. Chem. Commun. 2001, 2504.
33. Physical data for 3: Colorless solid; ½aꢁD ꢀ81.5 (c 0.67,
CH2Cl2); IR (film) m 2928, 2872, 1455, 1353, 1271, 1091,
856, 817, 771 cmꢀ1 1H NMR (500 MHz, C6D6); d 7.69
;
(1H, m, NAP), 7.67–7.63 (3H, m, NAP), 7.41 (1H, dd,
J = 9, 1.5 Hz, NAP), 7.26 (2H, dddd, J = 14.5, 7, 7,
1.5 Hz, NAP), 5.99 (1H, ddt, J = 17, 10, 7 Hz, H23), 5.95
(1H, dt, J = 12.5, 2.5 Hz, H13), 5.81 (1H, dt, J = 12.5,
2.5 Hz, H14), 5.77 (1H, dddd, J = 11.5, 11.5, 6.5, 5 Hz,
H18), 5.55 (1H, dd, J = 11.5, 5 Hz, H19), 5.12 (1H, dd,
J = 17, 2 Hz, H240), 5.08 (1H, dt, J = 10, 2 Hz, H240), 4.47
(1H, d, J = 12 Hz, NAP), 4.41 (1H, d, J = 12 Hz, NAP),
4.14 (1H, dd, J = 8.5, 2.5 Hz, H15), 3.99 (1H, m, H20),
3.83–3.78 (2H, m, H1, H12), 3.70 (1H, ddd, J = 9.5, 9.5,
3 Hz, H5), 3.55–3.48 (2H, m, H3, H16), 3.18–3.04 (4H, m,
H1, H6, H11, H21), 2.92 (1H, ddd, J = 9, 7, 4 Hz, H8),
2.87 (1H, ddd, J = 11, 8.5, 4 Hz, H9), 2.69–2.59 (2H, m,
H17, H22), 2.52–2.47 (2H, m, H4, H7), 2.34 (1H, dt,
J = 8.5, 4 Hz, H10), 2.22–2.14 (2H, m, H17, H22), 1.91–
1.84 (1H, m, H2), 1.82–1.71 (4H, m, H2, H4, H7, 10H);
13C NMR (125 MHz, C6D6) d 137.5, 136.9, 136.0, 135.8,
133.9, 133.5, 131.3, 126.6, 126.4, 126.0, 117.1, 86.1, 84.9,
81.29, 81.25, 79.5, 78.8, 77.8, 76.7, 76.3, 73.0, 72.1, 70.50,
70.45, 66.3, 39.0, 37.8, 37.7, 37.5, 36.8, 32.9, 30.2; HRMS
(ESI), calcd for C35H42O7Na 597.2823 (M+Na+), found
597.2821.
31. Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43,
1011.
32. (a) Lewis, M. D.; Cha, J. K.; Kishi, Y. J. Am. Chem. Soc.
1982, 104, 4976; (b) Nicolaou, K. C.; Hwang, C.-K.;
Nugiel, D. A. Angew. Chem., Int. Ed. Engl. 1988, 27, 1362;
(c) Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J. Am.
Chem. Soc. 1989, 111, 4136.