A New Stereoselective Synthesis of Ciguatoxin Right Wing Fragments

Article abstract of DOI:10.1021/jo049877x

The right wings (13 and 14) of ciguatoxins were synthesized highly stereoselectively. Key transformations in the synthesis are (i) an oxiranyl anion strategy to attach the H ring, (ii) intramolecular carbonyl olefination to cyclize the J ring, (iii) regio- and stereoselective reduction of the epoxyacetal to install the C42-stereocenter, and (iv) stereoselective reductive etherification to construct the K ring. The present procedure greatly improved the stereoselectivity and efficiency in comparison to a previous synthesis. Remarkably, only 23 steps were required from monocyclic I ring 5 to construct the ciguatoxin right wings. The high practicality of the present synthesis ensures a sufficient supply of these complex fragments for total syntheses and biomedical applications.

Full text of DOI:10.1021/jo049877x

A New Ster eoselective Syn th esis of Cigu a toxin Righ t Win g
F r a gm en ts
Masayuki Inoue,* Shuji Yamashita, Atsushi Tatami, Keisuke Miyazaki, and
Masahiro Hirama*
Department of Chemistry, Graduate School of Science, Tohoku University, Aramaki, Aoba-ku,
Sendai 980-8578, J apan, and SORST, J apan Science and Technology Agency (J ST),
Sendai 980-8578, J apan
inoue@ykbsc.chem.tohoku.ac.jp; hirama@ykbsc.chem.tohoku.ac.jp
Received J anuary 21, 2004
The right wings (13 and 14) of ciguatoxins were synthesized highly stereoselectively. Key
transformations in the synthesis are (i) an oxiranyl anion strategy to attach the H ring, (ii)
intramolecular carbonyl olefination to cyclize the J ring, (iii) regio- and stereoselective reduction
of the epoxyacetal to install the C42-stereocenter, and (iv) stereoselective reductive etherification
to construct the K ring. The present procedure greatly improved the stereoselectivity and efficiency
in comparison to a previous synthesis. Remarkably, only 23 steps were required from monocyclic
I ring 5 to construct the ciguatoxin right wings. The high practicality of the present synthesis
ensures a sufficient supply of these complex fragments for total syntheses and biomedical
applications.
In tr od u ction
techniques to minute amounts of samples, Yasumoto et
al. successfully elucidated the structures of ciguatoxin
CTX 4 and CTX4B 3, which were found to be huge
polycyclic ethers with the molecular lengths over 3 nm.2a,b
In subsequent studies, they isolated other congeners
including CTX3C 12d and 51-hydroxyCTX3C 2.2e The
right wings of structures 1 and 2 are the same as 3 and
4, respectively, but the left wings of both 1 and 2 lack
the side chain of 3/4 and have an eight-membered E ring
instead of the seven-membered ring of 3/4.
Motivated by the biological problems of these molecules
and also their fascinating molecular architecture, we
launched a program for the total synthesis of ciguatoxins
and recently achieved the first practical total synthesis
of CTX3C 1.5,6 The final stage of synthesis involved
coupling between the left and right wings with subse-
quent construction of the central FG ring system.5,7 Other
ciguatoxin structural variants (2, 3, and 4) are regarded
as important synthetic targets for their use in antibody
preparation and a detailed structure-activity relation-
ship (SAR) study. Importantly, the presented strategy
for coupling the two halves of the molecule is applicable
to all ciguatoxins because ciguatoxin congeners share the
FG ring structure.2 In this full account, we describe a
significantly improved protocol (Scheme 1) for the concise
and stereoselective synthesis of the protected ciguatoxin
Ciguatera is a human intoxication caused by the
ingestion of a variety of reef fish.1 More than 20 000
victims suffer annually from ciguatera, making it one of
the largest scale food poisoning of nonbacterial origin.
Ciguatoxins are characterized as being principal caus-
ative toxins of this type of poisoning (Figure 1).2 Upon
ingestion, these toxins cause various disorders involving
the neurological, gastrointestinal, and cardiovascular
systems by means of the persistent activation of voltage-
sensitive sodium channels.3 Because the presence of these
toxins in fish is unpredictable, a sensitive immunochemi-
cal method for detecting ciguatoxins has long been
required.4 In 1989, by applying state-of-the-art NMR
* To whom correspondence should be addressed. Fax: +81-22-217-
6566.
(1) For recent reviews, see: (a) Scheuer, P. J . Tetrahedron 1994,
50, 3-18. (b) Lewis, R. J . Toxicon 2001, 39, 97-106. (c) Yasumoto, T.;
Murata, M. Chem. Rev. 1993, 93, 1897-1909. (d) Yasumoto, T. Chem.
Rec. 2001, 1, 228-242.
(2) (a) Murata, M.; Legrand, A. M.; Ishibashi, Y.; Yasumoto, T. J .
Am. Chem. Soc. 1989, 111, 8929-8931. (b) Murata, M.; Legrand, A.-
M.; Ishibashi, Y.; Fukui, M.; Yasumoto, T. J . Am. Chem. Soc. 1990,
112, 4380-4386. (c) Satake, M.; Morohashi, A.; Oguri, H.; Oishi, T.;
Hirama, M.; Harada, N.; Yasumoto, T. J . Am. Chem. Soc. 1997, 119,
11325-11326. (d) Satake, M.; Murata, M.; Yasumoto, T. Tetrahedron
Lett. 1993, 34, 1975-1978. (e) Satake, M.; Fukui, M.; Legrand, A.-M.;
Cruchet, P.; Yasumoto, T. Tetrahedron Lett. 1998, 39, 1197-1198. (f)
Lewis, R. J .; Vernoux, J .-P.; Brereton, I. M. J . Am. Chem. Soc. 1998,
120, 5914-5920. (g) Yasumoto, T.; Igarashi, T.; Legrand, A.-M.;
Cruchet, P.; Chinain, M.; Fujita, T.; Naoki, H. J . Am. Chem. Soc. 2000,
122, 4988-4989.
(3) (a) Lombet, A.; Bidard, J .-N.; Lazdunski, M. FEBS Lett. 1987,
219, 355-359. (b) Dechraoui, M.-Y.; Naar, J .; Pauillac, S.; Legrand,
A.-M. Toxicon 1999, 37, 125-143. (c) Inoue, M.; Hirama, M.; Satake,
M.; Sugiyama, K.; Yasumoto, T. Toxicon 2003, 41, 469-474.
(4) Very recently, we developed the immuno-detection method of
CTX3C using synthetic fragments. Oguri, H.; Hirama, M.; Tsumuraya,
T.; Fujii, I.; Maruyama, M.; Uehara, H.; Nagumo, Y. J . Am. Chem.
Soc. 2003, 125, 7608-7612.
(5) (a) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama,
M.; Oguri, H.; Satake, M. Science 2001, 294, 1904-1907. (b) Inoue,
M.; Uehara, H.; Maruyama, M.; Hirama, M. Org. Lett. 2002, 4, 4551-
4554.
(6) For an account of the total synthesis of CTX3C, see: Inoue, M.;
Hirama, M. Synlett 2004, 577-595.
(7) (a) Imai, H.; Uehara, H.; Inoue, M.; Oguri, H.; Oishi, T.; Hirama,
M. Tetrahedron Lett. 2001, 42, 6219-6222. (b) Inoue, M.; Wang, G.
X.; Wang, J .; Hirama, M. Org. Lett. 2002, 4, 3439-3442. (c) Inoue, M.;
Yamashita, S.; Hirama, M. Tetrahedron Lett. 2004, 45, 2053-2056.
10.1021/jo049877x CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/17/2004
J . Org. Chem. 2004, 69, 2797-2804
2797

Inoue et al.
F IGURE 1. Structures of ciguatoxins.
SCHEME 1. New Syn th etic P la n of th e Righ t Win g
of Cigu a toxin s
segment 7 was constructed from the I (5) and LM (6) ring
segments in a convergent manner by 15 separate trans-
formations. However, the subsequent attachment of the
H ring to 7 required 20 synthetic steps.11 To avoid this
cumbersome construction of the H ring, the four-carbon
unit 8 corresponding to the H ring was to be directly
introduced via the oxiranyl anion strategy developed by
Mori.12 Furthermore, it was planned that the H ring
would be attached to the I ring fragment (5 + 8 f 9)
instead of the IJ KLM ring system 7 to maximize syn-
thetic convergency and minimize protective group ma-
nipulations. After construction of the HI ring system 9,
9 would be coupled with LM ring 10 or protected
51-hydroxyl LM ring 11 to produce the ciguatoxin right
wings (13 or 14 respectively). All alcohol groups except
that of C31 were protected by NAP (2-naphthylmethyl)
groups,13 the utility of which was demonstrated in our
improved total synthesis of CTX3C 1.5b
Syn th esis of LM Rin g F r a gm en ts. Synthesis of the
NAP-protected LM ring 10 of CTX3C (1) began with the
previously reported olefin 15 (Scheme 2).11,14,15 A hy-
(9) For recent synthetic studies of ciguatoxins from other groups,
see: (a) Takakura, H.; Noguchi, K.; Sasaki, M.; Tachibana, K. Angew.
Chem., Int. Ed. 2001, 40, 1090-1093. (b) Sasaki, M.; Ishikawa, M.;
Fuwa, H.; Tachibana, K. Tetrahedron 2002, 58, 1889-1911. (c)
Takakura, H.; Sasaki, M.; Honda, S.; Tachibana, K. Org. Lett. 2002,
4, 2771-2774. (d) Fujiwara, K.; Koyama, Y.; Doi, E.; Shimawaki, K.;
Ohtaniuchi, Y.; Takemura, A.; Souma, S. Murai, A. Synlett 2002,
1496-1499. (e) Fujiwara, K.; Koyama, Y.; Kawai, K.; Tanaka, H.;
Murai, A. Synlett 2002, 1835-1838. (f) Tanaka, H.; Kawai, K.;
Fujiwara, K.; Murai, A. Tetrahedron 2002, 58, 10017-10031. (g) Kira,
K.; Hamajima, A.; Isobe, M. Tetrahedron 2002, 58, 1875-1888. (h)
Takai, S.; Sawada, N.; Isobe, M. J . Org. Chem. 2003, 68, 3225-3231.
(i) Baba, T.; Huang, G.; Isobe, M. Tetrahedron 2003, 59, 6851-6872.
(j) Bond, S.; Perlmutter, P. Tetrahedron 2002, 58, 1779-1787. (k)
Clark, J . S.; Hamelin, O. Angew. Chem., Int. Ed. 2000, 39, 372-374
and references therein.
(10) A part of this study was published as a preliminary account.
Tatami, A.; Inoue, M.; Uehara, H.; Hirama, M. Tetrahedron Lett. 2003,
44, 5229-5233.
right wings 13 and 14. An available synthesis of these
compounds enables the total syntheses of various cigua-
8-10
toxins and the future preparation of antibodies.
(11) (a) Oishi, T.; Uehara, H.; Nagumo, Y.; Shoji, M.; Le Brazidec,
J .-Y.; Kosaka, M.; Hirama, M. Chem. Commun. 2001, 381-382. (b)
Uehara, H.; Oishi, T.; Inoue, M.; Shoji, M.; Nagumo, Y.; Kosaka, M.;
Le Brazidec, J .-Y.; Hirama, M. Tetrahedron 2002, 58, 6493-6512.
(12) (a) Mori, Y.; Yaegashi, K.; Furukawa, H. J . Am. Chem. Soc.
1996, 118, 8158-8159. (b) Mori, Y.; Furuta, H.; Takase, T.; Mitsuoka,
S.; Furukawa, H. Tetrahedron Lett. 1999, 40, 8019-8022. For their
recent applications to polyether syntheses, see: (c) Mori, Y.; Yaegashi,
K.; Furukawa, H. J . Am. Chem. Soc. 1997, 119, 4557-4558. (d) Mori,
Y.; Yaegashi, K.; Furukawa, H. J . Org. Chem. 1998, 63, 6200-6209.
(e) Mori, Y.; Takase, T.; Noyori, R. Tetrahedron Lett. 2003, 44, 2319-
2322.
Resu lts a n d Discu ssion
Syn th etic P la n . In the previous synthesis of the right
half of CTX3C (12, Scheme 1), the entire IJ KLM ring
(8) For reviews of polyether synthesis, see: (a) Alvarez, E.; Cande-
nas, M.-L.; Pe´rez, R.; Ravelo, J . L.; Mart´ın, J . D. Chem. Rev. 1995, 95,
1953-1980. (b) Mori, Y. Chem. Eur. J . 1997, 3, 849-852. (c) Yet, L.
Chem. Rev. 2000, 100, 2963-3007. (d) Marmsa¨ter, F. P.; West, F. G.
Chem. Eur. J . 2002, 8, 4347-4353.
2798 J . Org. Chem., Vol. 69, No. 8, 2004

Stereoselective Synthesis of Ciguatoxin Right Wing Fragments
SCHEME 2. Syn th esis of th e LM Rin g of CTX3Ca
using the undesired isomer 25R were investigated (Table
1). Whereas CSA typically caused decomposition of the
compound at high temperature, products 25R and 25â
survived under PPTS treatment even at 80 °C. The ratio
of the desired 25â depended considerably on the solvent,
and acetonitrile was found to be the best solvent of those
studied (25â/25R ) 8.5:1). Application of these modified
conditions for the acetal formation step led directly to
the selective formation of 25â (85% yield, Scheme 3) in
the same ratio (8.5:1). The isolated 25R was again
isomerized to obtain additional 25â in 75% yield. The
other Sharpless asymmetric dihydroxylation product,
C51 epimer 22, was subjected to transacetalization to
selectively afford 24â (24â/24R ) 5:1). The C51 stereo-
center of 24â was then inverted under Mitsunobu condi-
tions18 to obtain 25â in 91% yield after saponification of
the benzoyl ester.9i
The secondary alcohol of spiroacetal 25â was tempo-
rarily masked with TIPS in 96% yield, and the benzyl
group was then removed by hydrogenolysis to provide
primary alcohol 26. After oxidation of 26, addition of 1916
to aldehyde 27 created the two stereocenters (C43, C44),
giving rise to 28 with complete stereochemical control
(79% for three steps). Removal of the TIPS group from
28 and introduction of the NAP group produced bis-NAP
ether 29 in 99% overall yield. Finally, oxidative cleavage
of the terminal olefin of 29, followed by oxidation to the
carboxylic acid, led to the 51-hydroxyl LM ring fragment
11 in 82% yield for two steps.
a
Reagents and conditions: (a) (Sia)2BH, THF, 0 °C, then
NaHCO3, H2O2; (b) CSA, (CH2Cl)2, rt, 75% (three steps); (c) H2,
Pd(OH)2/C, EtOAc, rt, 100%; (d) (COCl)2, DMSO, Et3N, CH2Cl2,
-80 to -60 °C; (e) 19, toluene, -80 to -70 °C; (f) NAPBr, NaH,
DMF, THF, rt, 52% (three steps); (g) OsO4, NMO, t-BuOH/H2O
(1:1), rt, then NaIO4, rt; (h) NaClO2, NaH2PO4‚2H2O, 2-methyl-
2-butene, t-BuOH/H2O (4:1), rt, 99% (two steps).
droboration-oxidation sequence was carried out on the
terminal olefin of 15 followed by acid treatment to afford
the thermodynamically stable spiroacetal 16 as a single
isomer in 75% overall yield. The liberation of the primary
alcohol of 16 by hydrogenolysis and subsequent oxidation
under Swern conditions led to aldehyde 18.11 Subsequent
treatment of 18 with (R,R)-diisopropyl tartrate (Z)-
crotylboronate 1916 resulted in stereoselective introduc-
tion of both the C43-methyl and C44-hydroxyl groups.
After NAP protection of the newly formed secondary
alcohol, 20 was isolated as a single isomer in 52% yield
from 17. Finally, oxidative cleavage of the olefin of 20
and subsequent oxidation provided carboxylic acid 10
quantitatively.
As illustrated in Scheme 3, the same starting material
15 was used for the synthesis of the 51-hydroxyl LM ring
fragment 11. After conversion of hemiacetal 15 to methyl
acetal 21 (94%), the 51-OH group was installed by
Sharpless asymmetric dihydroxylation using (DHQ)2PYR
as a ligand,17 yielding desired diol 23 as the major
diastereomer (23/22 ) 4:1, 97% yield). Subsequent M ring
formation of the isolated 23 under the conditions used
to prepare 16 [CSA, (CH2Cl)2] exhibited little preference
for the presumably thermodynamically more stable 25â
(25â/25R ) 2:1). Thus, conditions for transacetalization
Syn th esis of HI Rin g F r a gm en t. The common
coupling partner of 10 and 11, HI ring fragment 9, was
efficiently prepared from the known I ring 5 using Mori’s
oxiranyl anion strategy (Scheme 4).12 Diol 511b was con-
verted to unstable triflate 30 by stepwise addition of Tf2O
and TESOTf in the presence of 2,6-lutidine and molecular
sieves 4A. A mixture of the resultant 30 and epoxysulfone
812d in THF-HMPA was treated with n-BuLi at -110
°C for 30 min, leading to the formation of the desired
coupling adduct 31. At this stage, 6-endo cyclization to
construct the H ring was realized by subjecting 31 to
p-TsOH in CHCl3 with p-methoxybenzaldehyde dimethyl
acetal to afford fused ether 32 through concomitant
removal of TES (51% from 5). The presence of the
dimethyl acetal in the reaction mixture was necessary
for in situ reattachment of the MP acetal to partially
deprotected 31 and/or 32. The obtained 32 was stereo-
selectively reduced using NaBH4, and the newly formed
alcohol was protected as its TIPS ether to give 33 as the
sole isomer in quantitative yield (two steps), thus com-
pleting five-step construction of the H ring from 5. After
acid-promoted removal of the MP acetal from 33, one-
carbon extension of 34 at the primary alcohol via iodi-
nation (87%) and displacement with cyanide (99%) led
to 35. TES protection of secondary alcohol 35 yielded 36
quantitatively. Nitrile 36 was reduced to the correspond-
ing aldehyde, which was then converted to dithioacetal
37 using phenyl disulfide and PBu3 (83% yield, two
steps).19 For the next coupling reaction, the TES group
of the tris-silylated 37 was selectively removed using
(13) (a) Gaunt, M. J .; Yu, J .; Spencer, J . B. J . Org. Chem. 1998, 63,
4172-4173. (b) Wright, J . A.; Yu, J .; Spencer, J . B. Tetrahedron Lett.
2001, 42, 4033-4036. (c) Xia, J .; Abbas, S. A.; Locke, R. D.; Piskorz,
C. F.; Alderfer, J . L.; Matta, K. L. Tetrahedron Lett. 2000, 41, 169-
173.
(14) Oishi, T.; Shoji, M.; Kumahara, N.; Hirama, M. Chem. Lett.
1997, 845-846.
(15) The numbering of carbon atoms in all compounds in this paper
corresponds to that of CTX3C.
(16) Roush, W. R.; Ando, K.; Powers, D. B.; Palkowitz, A. D.;
Halterman, R. L. J . Am. Chem. Soc. 1990, 112, 6339-6348.
(17) (a) Crispino, G. A.; J eong, K. S.; Kolb, H. C.; Wang, Z. M.; Xu,
D.; Sharpless, K. B. J . Org. Chem. 1993, 58, 3785-3786. For a review,
see: (b) Kolb, H. C.; VanNieuwenhze, M. S.; Sharpless, K. B. Chem.
Rev. 1994, 94, 2483-2547.
(18) For reviews on Mitusnobu reaction, see: (a) Mitsunobu, O.
Synthesis 1981, 1-28. (b) Hughes, D. L. Org. React. 1992, 42, 335-
656.
(19) Tazaki, M.; Takagi, M. Chem. Lett. 1979, 767-770.
J . Org. Chem, Vol. 69, No. 8, 2004 2799

Inoue et al.
SCHEME 3. Syn th esis of th e LM Rin g of 51-Hyd r oxyCTX3Ca
a
Reagents and conditions: (a) (MeO)3CH, CSA, (CH2Cl)2, rt, 99%; (b) OsO4, (DHQ)2PYR, K3Fe(CN)6, K2CO3, t-BuOH/H2O (1:1), 0 °C,
23: 78%, 22: 19%; (c) PPTS, MeCN, 80 °C, 24â: 75%, 24R: 15%; (d) PPTS, MeCN, 80 °C, 25â: 85%, 25R: 10%; (e) CSA, (CH2Cl)2, rt,
25â: 60%, 25R: 30%; (f) DEAD, Ph3P, BzOH, toluene, rt; (g) NaOH, MeOH, rt, 91% (two steps); (h) PPTS, MeCN, 80 °C, 25â: 75%, 25R:
9%; (i) TIPSOTf, 2,6-lutidine, CH2Cl2, -78 °C, 96%; (j) H2, Pd(OH)2/C, EtOAc, rt; (k) (COCl)2, DMSO, CH2Cl2, -78 °C, then Et3N; (l) 19,
4 Å MS, toluene, -78 °C, 79% (three steps); (m) TBAF, THF, rt; (n) NAPBr, TBAI, NaH, THF/DMF (3:1), 0 °C to rt, 99% (two steps); (o)
OsO4, NMO, t-BuOH/H2O (1:1), rt, then NaIO4; (p) NaClO2, NaH2PO4‚H2O, 2-methyl-2-butene, t-BuOH/H2O (4:1), 82% (two steps).
TABLE 1. Aceta l Isom er iza tion of 25r
protocol for cyclization of a similar, less functionalized
substrate.11 Indeed, this reaction was also successful for
tetracyclic 38; treatment of 38 with Cp2Ti[P(OEt)3]2
under refluxing THF closed the six-membered J ring to
afford 39 in 80% yield.
The next stage of the synthesis involved the stereo-
selective introduction of hydrogen at C42 and subsequent
ketone formation at C41 to prepare for formation of the
K ring by reductive etherification (42â, Scheme 5). For
this purpose, hydroboration and subsequent alcohol-
oxidation of 39 appeared to be the most logical choice.
Disappointingly, hydroboration of enol ether 39, followed
by oxidative workup, led predominantly to the wrong
stereoisomer 40 (40/41 ) 3:1, 76% combined yield).
Because the stereoselectivity of this hydroboration was
opposite to that expected based on other literature
examples,22 the preferred formation of the undesired
product 40 was considered to originate from the intrinsic
conformation of 39. As illustrated in Figure 2, the 1,3-
allylic strain in 39 would align H41 and H43 in a syn
relationship, and indeed this is supported by the observed
ROE. Thus, the sterically demanding LM ring portion
projects toward the â-face in this conformation, the
reagent attacks from the less congested R-face, and 40
is obtained in preference over desired stereoisomer 41.
solvent
ratio (25â/25R)a
(CH2Cl)2
DME
CH3NO2
CH3CN
2:1
2:1
6:1
8.5:1
PPTS in MeOH-CH2Cl2 at 0 °C to produce the HI ring
alcohol 9 in 94% yield.
Syn th esis of th e Righ t Win g of CTX3C. The re-
quired fragments now secured, coupling and subsequent
construction of the J K ring of CTX3C 1 were pursued
(Scheme 5). Condensation of alcohol 9 and carboxylic acid
10 using the Yamaguchi protocol20 produced the corre-
sponding ester 38 in 90% yield. Construction of the J ring
from 38 through C-C bond formation was challenging
because of the steric hindrance at C42 and the complexity
of the molecule. We previously demonstrated that in-
tramolecular carbonyl olefination using the low-valent
titanium reagent developed by Takeda21 was powerful
(20) Inanaga, J .; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. J pn. 1979, 52, 1989-1993.
(22) For representative examples, see: (a) Hanessian, S.; Martin,
M.; Desai, R. C. J . Chem. Soc., Chem. Commun. 1986, 926-927. (b)
Schmidt, R. R.; Preuss, R.; Betz, R. Tetrahedron Lett. 1987, 28, 6591-
6594. (c) Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J . Am.
Chem. Soc. 1996, 118, 1565-1566. (d) Liu, L.; Postema, M. H. D. J .
Am. Chem. Soc. 2001, 123, 8602-8603. (d) Postema, M. H. D.; Piper,
J . L. Org. Lett. 2003, 5, 1721-1723. (e) Clark, J . S.; Kettle, J . G.
Tetrahedron 1999, 55, 8231-8248.
(21) (a) Horikawa, Y.; Watanabe, M.; Fujiwara, T.; Takeda, T. J .
Am. Chem. Soc. 1997, 119, 1127-1128. (b) Rahim, M. A.; Fujiwara,
T.; Takeda, T. Tetrahedron 2000, 56, 763-770. (c) Rahim, M. A.;
Sasaki, H.; Saito, J .; Fujiwara, T.; Takeda, T. Chem. Commun. 2001,
625-626. (d) Takeda, T.; Fujiwara, T. J . Synth. Org. Chem. J pn. 1998,
56, 1048-1057.
2800 J . Org. Chem., Vol. 69, No. 8, 2004

Stereoselective Synthesis of Ciguatoxin Right Wing Fragments
SCHEME 4. Syn th esis of th e HI Rin ga
a
Reagents and conditions: (a) Tf2O, 2,6-lutidine, 4 Å MS, CH2Cl2, then TESOTf, -78 °C; (b) 8, n-BuLi, HMPA, THF, -110 °C; (c)
p-TsOH‚H2O, CHCl3, (MeO)2CH(p-MeOPh), rt to 40 °C, 51% (three steps); (d) NaBH4, CH2Cl2/MeOH (1:1), -78 °C, 100%; (e) TIPSOTf,
2,6-lutidine, (CH2Cl)2, 50 °C, 100%; (f) TFA/THF/H2O (1:10:5), rt, 87%; (g) Ph3P, I2, imidazole, 4 Å MS, THF, -30 °C to 0 °C, 87%; (h)
NaCN, DMSO, 40 °C, 99%; (i) TESOTf, 2,6-lutidine, CH2Cl2, -78 °C, 100%; (j) DIBAL, CH2Cl2, -78 °C; (k) PhSSPh, n-Bu3P, 40 °C, 83%
(two steps); (l) PPTS, MeOH/CH2Cl2 (5:1), 0 °C, 94%.
Oxidation of the mixture of 40 and 41 with Dess-
Martin periodinane gave a separable mixture of ketones
42R (71%) and 42â (24%). The major isomer 42R could
be converted to 42â by DBU-mediated isomerization, but
the ratio obtained of 42R and 42â was 1:1. Thus, three
cycles of the isomerization-separation sequence were
applied to obtain 42â in 60% yield along with the
recovered 42R in 19% yield.
the epoxide (entry 3), lithium borohydride generated the
undesired isomer 40 as the sole product (entry 4). The
screening was satisfactorily concluded with the extremely
potent reductant LiBHEt3,27 known to generally react in
an SN2 manner (entry 5). Treatment of 43 with LiBHEt3
exclusively led to the desired product 44 in 85% yield
(44/40 ) 15:1). Alcohol 44 was then oxidized with Dess-
Martin periodinane to afford 42â in 95% yield. Thus, the
C42-stereogenic center was successfully installed by
means of epoxidation and reduction. Significantly, the
stereoselectivity of this method is complementary to that
of hydroboration, and thus the protocol developed here
Although a synthetic route to 42â was secured, this
procedure involved repeated isomerization reactions, and
was not sufficiently practical. A more stereoselective
route to 42â was subsequently developed (Scheme 6).
Interestingly, epoxidation of 39 using dimethyldioxirane
(DMDO)23 was found to occur selectively to give R-epoxide
43, again indicating the strong conformational bias of 39
to accept the reagent from the R-face. Having realized
the stereoselective oxidation of enol ether 39, this alter-
native synthesis aimed to establish the C42 stereocenter
through the regio- and stereoselective reduction of 43.24
It was presumed that the correct isomer 44 would be
formed by SN2-type hydride delivery to the C42-acetal
epoxide of 43. However, this type of reaction was not
predicted to occur easily, because of the presumed low
reactivity of the sterically congested C42 as well as the
low accessibility of the hydride to the shielded â-face of
43. Furthermore, it was possible that the activated
epoxide would readily form oxonium cation 45,25 which
could lead to the incorrect isomer 40 via R-hydride attack.
With these considerations in mind, the reagents and
conditions were carefully screened (Scheme 6). First,
sodium cyanoborohydride was used with a weak activator
such as trifluoroethanol or water26 but the product was
only a mixture of isomers 44 and 40 (entry 1 and 2).
Whereas sodium borohydride did not react at all with
(24) We also attempted the 1,2-hydride shift of epoxide i using
various Lewis acids directly to obtain ii. However, only 6,6-spiroacetal
iii was observed as a major product, which arose from the nucleophilic
attack of C46-oxygen and concomitant loss of the MOM group. For a
successful application of the related 1,2-hydride shift, see: Bazin, H.
G.; Wolff, M. W.; Linhardt, R. J . J . Org. Chem. 1999, 64, 144-152.
(25) For reduction of the related epoxy acetals presumably through
oxocarbenium cation, see: (a) Nicolaou, K. C.; Prasad, C. V. C.; Ogilvie,
W. W. J . Am. Chem. Soc. 1990, 112, 4988-4989. (b) Fujiwara, K.;
Awakura, D.; Tsunashima, M.; Nakamura, A.; Honma, T.; Murai, A.
J . Org. Chem. 1999, 64, 2616-2617. (c) Cox, J . M.; Rainier, J . D. Org.
Lett. 2001, 3, 2919-2922. (d) Majumder, U.; Cox, J . M.; Rainier, J . D.
Org. Lett. 2003, 5, 913-916. see also 9a, c.
(26) Zimmermann, P. J .; Blanarikova, I.; J a¨ger, V. Angew. Chem.,
Int. Ed. 2000, 39, 910-912.
(27) Krishnamurthy, S.; Schubert, R. M.; Brown, H. C. J . Am. Chem.
Soc. 1973, 95, 8486-8487.
(23) (a) Murray, R. W. Chem. Rev. 1989, 89, 1187-1201. (b) Adam,
W.; Curci, R.; Edwards, J . O. Acc. Chem. Res. 1989, 22, 205-211. (c)
Danishefsky, S. J .; Bilodeau, M. T. Angew. Chem., Int. Ed. Engl. 1996,
35, 1380-1419.
J . Org. Chem, Vol. 69, No. 8, 2004 2801

Inoue et al.
SCHEME 6. Ster eoselective Syn th esis of th e J
SCHEME 5. Syn th esis of th e J Rin ga
Rin g
a
Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride,
ring system 47 in 81% yield. The 1H-1H coupling constant
(J 41,42 ) 9.5 Hz) of 47 verified the axial-attack of the
hydride. In this way, the J K ring was assembled from
fragment 9 in only 7 synthetic operations.
Et3N, toluene, then DMAP, 35 °C, 90%; (b) Cp2Ti[P(OEt)3]2, THF,
reflux, 80%; (c) BH3‚SMe2, THF, 0 °C to rt, then NaOH, H2O2,
76% (40/41 ) 3:1); (d) Dess-Martin periodinane (DMP), CH2Cl2,
42R: 71%, 42â: 24%; (e) DBU, CH2Cl2, rt, (42R/42â ) 1:1, after
three cycles, 42R: 19% 42â: 60%).
To complete the synthesis of the right wing of CTX3C,
the carbon chain corresponding to the G ring was
introduced (Scheme 7). HF‚pyridine effected the selective
removal of the primary TBPS of 47 in the presence of
the secondary TIPS to afford 48 (91% yield), which was
in turn oxidized with SO3‚pyridine to 49. Aldehyde 49
was subjected to MgBr2-promoted allylation29 using al-
lyltributyltin and then the partially formed C49-acetal
epimer was re-isomerized using CSA to generate alcohol
50 (73%) and the C29-epimer (12%). Finally, NAP protec-
tion of 50 gave rise to the targeted right wing 13 in 98%
yield.
Syn th esis of th e Righ t Win g of 51-h yd r oxyCTX3C.
As shown in Scheme 8, right wing 14 of 51-hydroxyCTX3C
was synthesized from the fragments 9 and 11 similarly
to the route described for 13. The HI ring segment 9 was
coupled with the 51-hydroxy LM ring 11 using Yamagu-
F IGURE 2. Observed ROE and probable local conformation
of enol ether 39.
should be generally applicable to enol ether substrates
from which hydroboration leads to undesired selectivity.
Once the correct C42-isomer 42â was successfully
obtained, the remaining tasks for the synthesis of the
right wing were formation of the K ring and extension
of the carbon chain to the left side (Scheme 7). When 42â
was exposed to triflic acid and (MeO)3CH in hexane,
seven-membered methyl acetal 46 was directly formed
with concomitant loss of the MOM group (62% yield).
Reductive etherification28 of acetal 46 using Et3SiH and
BF3‚OEt2 in the presence of molecular sieves 4A led to
construction of the final ether ring to afford the HIJ KLM
(28) (a) Oishi, T.; Nagumo, Y.; Shoji, M.; Le Brazidec, J .-Y.; Uehara,
H.; Hirama, M. Chem. Commun. 1999, 2035-2036. (b) Lewis, M. D.;
Cha, J . K.; Kishi, Y. J . Am. Chem. Soc. 1982, 104, 4976-4978. (c)
Nicolaou, K. C.; Hwang, C.-K.; Nugiel, D. A. J . Am. Chem. Soc. 1989,
111, 4136-4137.
(29) Charette, A. B.; Mellon, C.; Rouillard, L.; Malenfant, EÄ . Synlett
1993, 81-82.
2802 J . Org. Chem., Vol. 69, No. 8, 2004

Stereoselective Synthesis of Ciguatoxin Right Wing Fragments
SCHEME 7. Syn th esis of th e Righ t Win g of
CTX3Ca
chi esterification to give 51 in 77% yield. Treatment of
51 with the low-valent titanium complex Cp2Ti[P(OEt)3]2
in refluxing THF generated enol ether 52 in 68% yield.
DMDO-epoxidation of 52 afforded R-epoxide 53 with
complete stereocontrol, which was in turn reduced using
LiBHEt3 to produce 54 as the predominant isomer in 78%
yield for two steps (stereoselectivity at C42 >20:1). The
newly formed secondary alcohol of 54 was oxidized to
ketone 55 (80%), which was subjected to direct acetal-
ization to give seven-membered methyl acetal 56 in 62%
yield. Lewis-acid promoted reductive etherification of 56
set the C41-stereocenter, leading to hexacyclic ether 57
(78% yield). Selective removal of the TBPS group (76%
yield), followed by Swern oxidation, converted 58 to
aldehyde 59, to which allylstannane addition in the
presence of MgBr2 installed the C29 stereogenic center
to form 60 in 69% yield (two steps). Finally, the C29-
secondary alcohol was protected as its NAP ether to
afford right wing 14 of 51-hydroxyCTX3C in 91% yield.
The coupling and J K ring construction outlined were
shown to be applicable to the right wings of ciguatoxins
(1,2,3,4).
Con clu sion s
In conclusion, the ciguatoxin right wings (13 and 14),
which can be readily coupled with the left wings after
modification of the terminal olefin, were synthesized in
a stereoselective fashion using a significantly improved
protocol. The key transformations in the synthesis are
an oxiranyl anion strategy to attach the I ring, intra-
molecular carbonyl olefination to cyclize the J ring and
regio- and stereoselective reduction of the epoxyacetal to
install the C42-stereocenter. The present procedure
greatly improved the efficiency in comparison to previous
syntheses. In particular, the utilization of the epoxyacetal
approach contributed to a high overall stereoselectivity
a
Reagents and conditions: (a) TfOH, (MeO)3CH, hexane, rt,
62%; (b) BF3‚OEt2, Et3SiH, 4 Å MS, CH2Cl2, -50 to -20 °C, 81%;
(c) HF‚Py, Py/THF (1:2), rt, 91%; (d) SO3‚Py, Et3N, DMSO/CH2Cl2
(1:1), 0 °C to rt; (e) allylSnBu3, MgBr2‚OEt2, 4 Å MS, CH2Cl2, -78
°C to rt, then CSA, (CH2Cl)2, rt, 73% (two steps), C29-epimer 12%
(two steps); (f) NAPBr, TBAI, NaH, THF/DMF (3:1), rt, 98%.
SCHEME 8. Syn th esis of th e Righ t Win g of 51-Hyd r oxyCTX3Ca
a
Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, toluene, then DMAP, 35 °C, 77%; (b) Cp2Ti[P(OEt)3]2, THF, reflux,
68%; (c) DMDO, CH2Cl2, -40 to 0 °C; (d) LiBHEt3, THF, 0 °C to rt, 78% (two steps); (e) Dess-Martin periodinane, CH2Cl2, 80%; (f) TfOH,
(MeO)3CH, hexane, rt, 62%; (g) BF3‚OEt2, Et3SiH, 4 Å MS, CH2Cl2, -50 to -20 °C, 78%; (h) HF‚Py, Py/THF (1:2), rt, 76%; (i) (COCl)2,
DMSO, CH2Cl2, Et3N, -78 °C; (j) allylSnBu3, MgBr2‚OEt2, 4 Å MS, CH2Cl2, -78 °C to rt, 69% (two steps), C29-epimer 14% (two steps);
(k) NAPBr, TBAI, NaH, THF/DMF (3:1), rt, 91%.
J . Org. Chem, Vol. 69, No. 8, 2004 2803

Inoue et al.
of the synthesis. Remarkably, only 23 steps were required
from monocyclic I ring 5 to the right wings of ciguatoxins,
whereas the previous procedure for 11 involved 35
steps.11 The high practicality of the synthesis established
here ensures a supply of these complex fragments for
total syntheses and biomedical applications. These stud-
ies are now under active investigation in our laboratory.
Society for the Promotion of Science (J SPS). We are
grateful to Dr. Takashi Iwashita and Dr. Tsuyoshi
Fujita of Suntory Institute for Bioorganic Research for
their high-resolution mass spectroscopy measurements.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, characterization data, and copies of 1H NMR spectra
data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research (S) from the J apan
J O049877X
2804 J . Org. Chem., Vol. 69, No. 8, 2004