Practical route to the left wing of CTX1B and total syntheses of CTX1B and 54-deoxyCTX1B

Article abstract of DOI:10.1002/chem.201405629

Ciguatoxins, the principal causative agents of ciguatera seafood poisoning, are extremely large polycyclic ethers. We report herein a reliable route for constructing the left wing of CTX1B, which possesses the acid/base/oxidantsensitive bisallylic ether m

Full text of DOI:10.1002/chem.201405629

DOI: 10.1002/chem.201405629
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Organic Chemistry
Practical Route to the Left Wing of CTX1B and
Total Syntheses of CTX1B and 54-deoxyCTX1B
Shuji Yamashita ,*[a] Katsutoshi Takeuchi,[a] Takuya Koyama,[a] Yujiro Hayashi,[a] and
Masahiro Hirama*[a, b]
Abstract: Ciguatoxins, the principal causative agents of ci-
guatera seafood poisoning, are extremely large polycyclic
ethers. We report herein a reliable route for constructing the
left wing of CTX1B, which possesses the acid/base/oxidant-
sensitive bisallylic ether moiety, by a 6-exo radical cycliza-
tion/ring-closing metathesis strategy. This new route ena-
bled us to achieve the second-generation total synthesis of
CTX1B and the first synthesis of 54-deoxyCTX1B.
have been challenging targets for organic synthesis.[6] In 2001,
our group reported the first synthesis of a ciguatoxin conge-
ner, CTX3C.[7] Subsequently, we succeeded in the syntheses of
two other Pacific ciguatoxins, 51-hydroxyCTX3C and CTX1B
(1).[8] Our unified strategy realized an efficient assembly of the
polyfunctionalized left and right fragments (e.g., 3+4a!1,
Figure 1).[7,8] Furthermore, we developed a sandwich enzyme-
Introduction
Ciguatera seafood poisoning, an important medical issue in
tropical and subtropical regions, causes gastrointestinal, cardio-
vascular, and neurological disorders that may last for weeks or
even years.[1] It is estimated that more than 50000 people an-
nually are afflicted by this poisoning. Yasumoto and colleagues
revealed that ciguatoxins, the
causative toxins of ciguatera, are
originally produced by an epi-
phytic dinoflagellata, Gambierdis-
cus toxicus.[2] Since the Yasumoto
group elucidated the structures
of ciguatoxins in 1989, more
than twenty natural ciguatoxins
have been described.[3] Ciguatox-
ins have a ladderlike polycyclic
ether structure with five- to
nine-membered ring sizes, and
exhibit potent toxicities (LD50 =
0.25–4 mgkgꢀ1, mice) by binding
to the voltage-sensitive sodium
channels (VSSC) of excitable
membranes.[4,5]
Because of their important
bioactivities and intriguing mo-
Figure 1. Structures of ciguatoxins.
lecular architectures, ciguatoxins
linked immunosorbent assay (ELISA) for their detection.[9] The
synthetic ciguatoxins and their fragments[10] have enabled us
to investigate the SAR and electrophysical properties of cigua-
toxins to understand ciguatoxin–VSSC interactions.[11] However,
a more practical route to the left wing (3) of CTX1B (1)[10c] still
needs to be developed.
[a] Dr. S. Yamashita , Dr. K. Takeuchi, T. Koyama, Prof. Dr. Y. Hayashi,
Prof. Dr. M. Hirama
Department of Chemistry, Graduate School of Science
Tohoku University, Sendai 980-8578 (Japan)
E-mail: syamashita@fas.harvard.edu
hirama@m.tohoku.ac.jp
[b] Prof. Dr. M. Hirama
We have investigated three routes to construct trans-fused
polyether systems utilizing radical reactions: 1) an acyl radical
cyclization/reductive etherification sequence,[10e,12] 2) a 7-exo
radical cyclization using an electron-deficient acrylate/ring-clos-
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University, Sendai 980-8578 (Japan)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405629.
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ing olefin metathesis (RCM) sequence,[7,8,13] and 3) a 6-exo radi-
cal cyclization using a cis-vinyl sulfoxide/RCM sequence.[8g,14] In
this paper we describe a full account of our reliable and scala-
ble route to the left wing (3), and the second-generation syn-
thesis of 1 as well as the first synthesis of 54-deoxyCTX1B (2).
Results and Discussion
A new synthetic plan for the left wing (3) is shown in
Scheme 1. It was envisioned that the O,S-acetal-forming cou-
pling between the AB-ring 5 and the E-ring 6, followed by
elimination of PhSH, would afford the enol ether 7. The seven-
membered D-ring could be constructed from 7 through acyl
radical cyclization and enone formation. Reductive etherifica-
tion of enone 8 would culminate in the target left wing 3.
Synthesis of the acyl radical precursor 7 began with the AB-
ring 5,[15] which possesses the dihydroxybutenyl side chain at
the C5 position (Scheme 2). After careful chlorination of sulfide
5 with freshly recrystallized N-chlorosuccinimide,[16] the resul-
tant a-chlorosulfide 9 was coupled with the E-ring alcohol 6[15]
through the silver-mediated O,S-acetal formation to give 10
(60% from 5).[17] Treatment of 10 with AgOTf and Hꢁnig’s base
in benzene, followed by hydrolysis and then seleno esterifica-
tion with (PhSe)2 and nBu3P, afforded the enol ether 7 as a 1:1
mixture of cis- and trans-isomers.[10e,12,18]
In contrast to the successful construction of the CTX3C and
C-CTX D-rings,[10e,f] acyl radical cyclization of 7 did not afford
the desired seven-membered ketone 11, despite much effort
(Scheme 2). Instead, treatment of 7 with nBu3GeH[19] and Et3B
at room temperature provided hexacyclic compounds 14a and
14b, which were generated through 6-exo/5-exo tandem radi-
cal cyclization (7!12!13!14). The high SOMO of the nucle-
Scheme 1. Initial synthetic plan of left wing (3).
Scheme 2. Attempted 7-exo acyl radical cyclization: a) NCS, CCl4, CH2Cl2, RT; b) AgOTf, DTBMP, CH2Cl2, 4 ꢂ MS, ꢀ78 to ꢀ158C, 60% (2 steps); c) AgOTf,
iPr2NEt, benzene, 4 ꢂ MS, RT, 87%; d) LiOH·H2O, 1,4-dioxane, H2O, RT; e) (PhSe)2, nBu3P, DMF, RT, 70% (2 steps); f) nBu3GeH, Et3B, benzene, RT, 14a: 42%; 14b:
28%. DTBMP=2,6-di-tert-butyl-4-methylpyridine; NCS=N-chlorosuccinimide.
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ophilic acyl radical 12 reacted with the low LUMO of the C21ꢀ
C22 double bond in preference to the high LUMO of the elec-
tron-rich enol ether (C14ꢀC15).[20]
Table 1. Reductive etherification of enone 23.
Thus, to achieve CꢀC bond formation between the acyl radi-
cal and the C15 position, we turned to the kinetically more fa-
vored 6-exo cyclization (Scheme 3). The requisite seleno ester
16 was synthesized from 9 and the alcohol 15,[10 h] which has
a one-carbon contracted side chain. Acyl radical cyclization of
16 afforded the desired six-membered ketone 17 with good
diastereoselectivity. The yield, however, was low (28%) and the
tandem cyclization byproduct 18 was obtained as the major
product (34%).
Practical and reliable construction of the D-ring by acyl radi-
cal cyclization was then achieved using the C21ꢀC22 saturated
E-ring[15] (Scheme 4). Treatment of 20 under the radical condi-
tions afforded the six-membered ether 21 in 64% yield as
a single isomer. Ring expansion of ketone 21 according to the
Shioiri method (TMSCHN2 and Me3Al)[21,22] and successive Ito–
Saegusa oxidation[23] gave rise to the seven-membered ring 22.
Treatment of 22 with HF·pyridine provided the D-ring enone
23 in 53% overall yield.
The attempted reductive etherification[24] of 23 is summar-
ized in Table 1. Upon treatment of 23 with TMSOTf and
Entry Conditions
Results
1
2
3
TMSOTf, CH2Cl2, ꢀ78 to ꢀ358C
BF3·OEt2, CH2Cl2, ꢀ78 to ꢀ358C
26 75%
26 75%
BF3·OEt2, MeCN/CH2Cl2 =2, ꢀ60 to ꢀ108C 24 30–62%, 26 50–30%
BF3·OEt2 in the presence of an excess amount of Et3SiH in
CH2Cl2, unexpected nine-membered ether 26 was produced
(Table 1, entries 1 and 2). We speculated that formation of 26
entailed the Lewis acid promoted CꢀO bond cleavage at C5,
followed by nine-membered ring formation from bisallylic
cation 25. After many unsuccessful experiments, we found the
desired 24 was obtained as a major product by treatment with
BF3·OEt2 and Et3SiH in MeCN/CH2Cl2 mixed solvents (entry 3).
However, a significant amount of 26 was still generated (30–
50%). On the basis of these results and the low reproducibility
on large-scale synthesis, we were forced to abandon the acyl
radical/reductive etherification strategy.
The alternative strategy toward 3 is outlined in Scheme 5.
The O,Se-acetal 29 was chosen as the key intermediate, which
Scheme 3. Attempted acyl radical cyclization of 16 to form six-membered
ketone (17).
Scheme 4. Synthesis of the D-ring enone 23: a) nBu3GeH, Et3B, benzene, RT, 64%; b) TMSCHN2, Me3Al, CH2Cl2, 4 ꢂ MS, ꢀ908C; c) toluene, 1408C; d) Pd(OAc)2,
MeCN, RT, 59% (3 steps); e) HF·pyridine, THF, RT, 90%.
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but instead enol ether 34a (Table 2, entry 1). Formation of enol
ether 34a might entail the abstraction of the C20 allylic terti-
ary hydrogen by the C17 radical, which was generated by CꢀC
bond formation between C15 and C16. Upon treatment with
Ph3SnH instead of nBu3SnH, a trace amount of 33a was
formed (entry 2). Although a variety of experimental factors
were examined (entries 3–6), 33 was only produced in low
yield.
Therefore, we were forced to saturate the C21ꢀC22 double
bond of the E-ring to avoid these undesired side reactions. A
reliable route to the left wing 3 is described in Scheme 6. Ya-
maguchi esterification[26] between the AB-ring carboxylic acid
27[15] and the C21ꢀC22 saturated E-ring alcohol 36,[15] and sub-
sequent DIBAL reduction and acetylation, gave the O,O-
acetal,[27] which was then converted to the corresponding O,Se-
acetal 38 by the action of iBu2AlSePh[28] in 56% overall yield.
Cleavage of the TBDPS- and TES-ethers of 38 with TBAF fol-
lowed by selective reprotection of the primary alcohol afforded
the secondary alcohol, upon which the cis-vinyl sulfoxide was
installed by the action of NaH and (S)-alkynyl sulfoxide[29] to
give the radical reaction precursor 39 in 80% overall yield. The
6-exo radical cyclization of 39 was conducted with Et3B and
nBu3SnH in toluene at ꢀ788C to furnish the C-ring ether 40 in
80% yield as a single isomer. Pummerer rearrangement[30] of
the sulfoxide 40 and Wittig reaction of the resultant aldehyde
afforded 41 (79%). TBDPS ether 41 was converted to the olefin
42 through TBAF deprotection, Dess–Martin oxidation,[31] and
Wittig olefination in 80% overall yield. Construction of the
seven-membered D-ring was achieved using Grubbs’ 1st-gen-
eration catalyst 43.[32] Subsequent acid treatment produced
Scheme 5. Alternative strategy toward 3.
could be prepared from carboxylic acid 27 and alcohol 28.
The synthesis would begin with C-ring formation through 6-
exo radical cyclization to the cis-vinyl sulfoxide 29 as the radi-
cal acceptor with
a lower LUMO. Next,
RCM would afford the
seven-membered D-
ring. These reaction
Table 2. Attempted 6-exo radical cyclization of 32.
conditions
without
the use of strong
Lewis acids were ex-
pected to establish
a practical route to 3
without affecting the
bisallylic A-ring sys-
tem.
First, the key 6-exo
radical cyclization was
Entry
1
R3
Conditions
Results
tested
in
model
nBu3SnH toluene, ꢀ788C
33a: 0%, 34a: ~50%, 35a: ~10%
system 32[15] (Table 2).
The O,Se-acetal 32
was treated with the
conditions optimized
for the synthesis of
the C-rings of CTX3C
and C-CTX (nBu3SnH
and Et3B in toluene at
ꢀ788C).[8g,14,25] How-
ever, the product was
not the desired 33a
2
3
4
5
6
Ph3SnH, benzene, RT
Ph3SnH, benzene, RT
Ph3SnH, benzene, RT
Ph3SnH, benzene, RT
Ph3SnH, benzene, RT
33a: trace, 34a: ~30%, 35a: ~20%
33b: ~10%, 34b: ~40%, 35b: ~30%
complex mixture
33d: trace, 34d: ~20%, 35d: ~40%
33e: trace, 34e: ~30%, 35e: ~20%
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Scheme 6. Practical synthesis of the left wing 3: a) 2,4,6-trichlorobenzoyl chloride, Et3N, DMAP, toluene, RT, 89%; b) DIBAL, CH2Cl2, ꢀ788C; Ac2O, DMAP, pyri-
dine, ꢀ78 to 08C, 78%; c) iBu2AlSePh, CH2Cl2, hexane, 08C, 81%; d) TBAF, THF, RT, 94%; e) TBDPSCl, imidazole, DMF, RT, 94%; f) (S)-1-ethynyl para-tolyl sulfox-
ide, NaH, THF, RT, 90%; g) nBu3SnH, Et3B, toluene, ꢀ788C, 80%; h) TFAA, pyridine, MeCN, CH2Cl2, 08C; K2CO3, H2O, RT to 508C; i) Ph3PCH3Br, NaHMDS, THF, 08C
to RT, 79% (2 steps); j) TBAF, THF, RT, 99%; k) Dess–Martin periodinane, CH2Cl2, RT, 86%; l) Ph3PCH3Br, NaHMDS, THF, 08C to RT, 94%; m) 43, CH2Cl2, 408C,
89%; n) TsOH·H2O, CH2Cl2, MeOH, RT, 98%; o) TsCl, pyridine, 508C; p) NaCN, DMSO, 558C, 78% (2 steps); q) DIBAL, CH2Cl2, ꢀ788C; r) Ph3PCH3Br, NaHMDS, THF,
08C to RT, 73% (2 steps); s) Dess–Martin periodinane, CH2Cl2, RT, 92%; t) LiHMDS, TMSCl, Et3N, THF, ꢀ788C; u) Pd(OAc)2, MeCN, RT, 70% (2 steps); v) NaBH4,
CeCl3·7H2O, MeOH, CH2Cl2, ꢀ658C, 91%. DIBAL=diisobutylaluminium hydride; DMAP=4-dimethylaminopyridine; LiHMDS=lithium hexamethyl disilazide;
TBAF=tetrabutylammonium fluoride; TFAA=Trifluoroacetic anhydride.
the free diol 44 (87%). Selective tosylation of the primary alco-
hol of 44 followed by substitution with NaCN furnished the
corresponding nitrile, which was transformed to the terminal
olefin 45 by DIBAL reduction and Wittig reaction. Finally, the
C21–C22 double bond was installed through Dess–Martin oxi-
dation of the C23ꢀOH, Saegusa oxidation, and Luche reduc-
tion,[33] giving rise to the left wing (3) in 59% overall yield.
With a sufficient amount of the left wing 3 in hand, we
launched the most critical coupling reaction, of the left and
right wings, 3 and 46,[34] toward constructing the two major
Pacific ciguatoxins, CTX1B (1) and 54-deoxyCTX1B (2), as de-
scribed in Scheme 7. Chlorination of the right wing sulfide
46a[8f,34] was carried out using freshly recrystallized NCS, and
the resultant a-chlorosulfide 4a was coupled without purifica-
tion to the left wing alcohol 3 (3 equiv) by the action of AgOTf
to provide O,S-acetal 47a. Despite our efforts, the yield of 47a
was not improved (~26%). An appreciable amount of sulfoxide
was always formed, albeit it could be reduced back to 46a
with SO3-py/NaI. Other chlorinating agents, such as N-chlor-
ophthalimide and sulfuryl chloride afforded complex mixtures.
Furthermore, alternative methods (e.g., 1) coupling between a-
fluorosulfide and alcohol[10k] or 2) esterification of carboxylic
acid and alcohol, followed by O,Se-acetal forming reaction[8g,14]
)
were unsuccessful. After removal of the TIPS group, the elec-
tron-withdrawing pentafluorophenyl acrylate[35] was attached
to 48a to afford 49a in 75% yield. Formation of the seven-
membered G-ring was achieved by radical reaction with
nBu3SnH and AIBN, which gave rise to 50a in 42% yield along
with the 6-exo product 51a (20%).[8f,g] The resulting carboxylic
acid 50a was converted to the corresponding terminal olefin
52a via methyl ester formation, DIBAL reduction, and Wittig
olefination (73%). RCM reaction promoted by Grubbs’ catalyst
43 constructed the nine-membered F-ring in 63% yield. Lastly,
oxidative removal of the six 2-naphthylmethyl (NAP) groups[36]
of 53a with DDQ (30 equiv, 1.1 mm in CH2Cl2/H2O), followed by
acid treatment of the resultant 2-naphthylidene acetal 54a,
furnished 1 in 20% overall yield.
The synthesis of 54-deoxyCTX1B (2) was similarly accom-
plished from 3 and 46b[8b,34b] except for the final removal of
the NAP groups (Scheme 7). Upon treatment of the NAP-pro-
tected 54-deoxyCTX1B 53b with DDQ under slightly diluted
conditions (25 equiv, 0.85 mm in CH2Cl2/H2O), a significant
amount of mono-NAP ether 55b was incidentally produced
along with naphthoate 56b and the naphthylidene acetal 54b.
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Scheme 7. Total syntheses of CTX1B (1) and 54-deoxyCTX1B (2): a) NCS, CCl4, CH2Cl2, RT; b) AgOTf, DTBMP, CH2Cl2, CCl4, 4 ꢂ MS, ꢀ78 to 08C, 47a: 26% from
46a; 47b: 23% from 46b; c) TBAF, THF, 358C, 48a: 86%; 48b: 88%; d) Me3P, pentafluorophenyl propiolate, CH2Cl2, RT, 49a: 88%; 49b: 79%; e) nBu3SnH,
AIBN, toluene, 858C, 50a: 42%; 51a: 20%; 50b: 46%; 51b: 13%; f) TMSCHN2, MeOH, benzene, RT; g) DIBAL, CH2Cl2, ꢀ908C; h) Ph3PCH3Br, tBuOK, THF, 08C,
52a: 73% (3 steps); 52b: 40% (3 steps); i) 43, CH2Cl2, 408C, 53a: 63%; 53b: 58%; j) DDQ, CH2Cl2, H2O, RT; k) 1m HCl, MeOH, RT, 1: 20% from 53a; l) DDQ,
CH2Cl2, H2O, RT; m) 0.5m HCl, MeOH, RT; n) DDQ, CH2Cl2, RT; o) 5% aq. NaOH, MeOH, RT, 2: 30% from 53b. AIBN=azobisisobutyronitrile; DDQ=2,3-dichloro-
5,6-dicyano-1,4-benzoquinone; TIPS=triisopropylsilyl.
After several unsuccessful attempts, we found that stepwise
procedures afforded 2 from 55b and 56b. Thus, DDQ oxida-
tion of 55b under anhydrous conditions afforded naphthoate
56b, which was hydrolyzed with aqueous NaOH in MeOH to
generate 2. Acid treatment of the naphthylidene acetal 54b
smoothly gave 2 in 30% combined yield from 53b.
lished. Highlights of the total syntheses include: 1) efficient
coupling of the AB- and E-rings through Yamaguchi esterifica-
tion followed by O,Se-acetal formation (27+36!38); 2) cis-se-
lective installation of vinyl sulfoxide as a radical acceptor (38!
39); 3) stereoselective construction of the C-ring by 6-exo radi-
cal cyclization (39!40); 4) seven-membered D-ring formation
by RCM reaction (42!44); 5) O,S-acetal formation to connect
the polyfunctionalized left and right wings (3+46!47); 6) 7-
exo radical cyclization to form the G-ring in a stereoselective
manner (49!50); 7) RCM reaction to form the F-ring (52!
53); and 8) global deprotection of NAP-ethers to afford CTX1B
Conclusion
A practical, reliable, and stereoselective route to the Pacific ci-
guatoxins, CTX1B (1) and 54-deoxyCTX1B (2), has been estab-
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[8] a) M. Inoue, H. Uehara, M. Maruyama, M. Hirama, Org. Lett. 2002, 4,
4551–4554; b) M. Inoue, K. Miyazaki, H. Uehara, M. Maruyama, M.
Hirama, Proc. Natl. Acad. Sci. USA 2004, 101, 12013–12018; c) M. Inoue,
M. Hirama, Synlett 2004, 577–595; d) M. Inoue, M. Hirama, Acc. Chem.
Res. 2004, 37, 961–968; e) M. Hirama, Chem. Rec. 2005, 5, 240–250;
f) M. Inoue, K. Miyazaki, Y. Ishihara, A. Tatami, Y. Ohnuma, Y. Kawada, K.
Komano, S. Yamashita, N. Lee, M. Hirama, J. Am. Chem. Soc. 2006, 128,
9352–9354; g) S. Yamashita, Y. Ishihara, H. Morita, J. Uchiyama, K. Takeu-
chi, M. Inoue, M. Hirama, J. Nat. Prod. 2011, 74, 357–364.
[9] a) H. Oguri, M. Hirama, T. Tsumuraya, I. Fujii, M. Maruyama, H. Uehara, Y.
Nagumo, J. Am. Chem. Soc. 2003, 125, 7608–7612; b) T. Tsumuraya, I.
Fujii, M. Inoue, A. Tatami, K. Miyazaki, M. Hirama, Toxicon 2006, 48, 287–
294; c) M. Inoue, N. Lee, T. Tsumuraya, I. Fujii, M. Hirama, Toxicon 2009,
53, 802–805; d) T. Tsumuraya, I. Fujii, M. Hirama, Toxicon 2010, 56, 797–
803; e) T. Tsumuraya, K. Takeuchi, S. Yamashita, I. Fujii, M. Hirama, Toxi-
con 2012, 60, 348–357; f) T. Tsumuraya, I. Fujii, M. Hirama, J. AOAC Int.
2014, 97, 373–379.
and 54-deoxyCTX1B (53!1 and 2). It is noteworthy that no
significant decomposition of the A-ring bisallylic ether system
was observed in any of the steps of the latest successful route.
Synthetic fragment 3 and ciguatoxins 1 and 2 will play key
roles in the preparation of antibodies for controlling ciguatera
seafood poisoning and the analysis of the causative toxins in
ciguatera fish poisoning globally,[3d] and furthermore, in under-
standing the mechanism of action of the symptomatology of
ciguatera food poisoning and its long-term neurological symp-
toms.[4]
Acknowledgements
[10] a) M. Inoue, G. X. Wang, J. Wang, M. Hirama, Org. Lett. 2002, 4, 3439–
3442; b) M. Inoue, J. Wang, G. X. Wang, Y. Ogasawara, M. Hirama, Tetra-
hedron 2003, 59, 5645–5659; c) S. Kobayashi, B. H. Alizadeh, S. Sasaki,
H. Oguri, M. Hirama, Org. Lett. 2004, 6, 751–754; d) S. Kobayashi, Y. Ta-
kahashi, K. Komano, B. H. Alizadeh, Y. Kawada, T. Oishi, S. Tanaka, Y. Oga-
sawara, S. Sasaki, M. Hirama, Tetrahedron 2004, 60, 8375–8396; e) M.
Inoue, S. Yamashita, Y. Ishihara, M. Hirama, Org. Lett. 2006, 8, 5805–
5808; f) M. Inoue, F. Saito, M. Iwatsu, Y. Ishihara, M. Hirama, Tetrahedron
Lett. 2007, 48, 2171–2175; g) K. Yoshikawa, M. Inoue, M. Hirama, Tetra-
hedron Lett. 2007, 48, 2177–2180; h) M. Inoue, M. Iwatsu, S. Yamashita,
M. Hirama, Heterocycles 2007, 72, 327–338; i) N. Lee, M. Inoue, M.
Hirama, Heterocycles 2009, 79, 325–330; j) S. Yamashita, N. Iijima, T.
Shida, M. Hirama, Heterocycles 2010, 82, 761–774; k) M. Inoue, S. Yama-
shita, M. Hirama, Tetrahedron Lett. 2004, 45, 2053–2056.
This work was supported financially by a Grant-in-Aid for Spe-
cially Promoted Research from the Ministry of Education, Cul-
ture, Sports, Science and Technology in Japan (MEXT).
Keywords: ciguatoxin · polycyclic ether · radical reaction ·
ring-closing metathesis · total synthesis
[1] a) R. J. Lewis, Toxicon 2001, 39, 97–106; b) T. Yasumoto, M. Murata,
Chem. Rev. 1993, 93, 1897–1909; c) P. J. Scheuer, Tetrahedron 1994, 50,
3–18; d) T. Yasumoto, Chem. Rec. 2001, 1, 228–242.
[2] T. Yasumoto, I. Nakajima, R. Bagnis, R. Adachi, Bull. Jpn. Soc. Sci. Fish.
1977, 43, 1021–1026.
[11] a) M. Inoue, N. Lee, K. Miyazaki, T. Usuki, S. Matuoka, M. Hirama, Angew.
Chem. Int. Ed. 2008, 47, 8611–8614; Angew. Chem. 2008, 120, 8739–
8742; b) Y. Ishihara, K. Miyazaki, S. Yamashita, M. Hirama, Chem. Lett.
2009, 38, 886–887; c) Y. Ishihara, N. Lee, N. Oshiro, S. Matsuoka, S. Ya-
mashita, M. Inoue, M. Hirama, Chem. Commun. 2010, 46, 2968–2970;
d) K. Yamaoka, M. Inoue, H. Miyahara, K. Miyazaki, M. Hirama, Br. J. Phar-
macol. 2004, 142, 879–889; e) K. Yamaoka, M. Inoue, K. Miyazaki, M.
Hirama, C. Kondo, E. Kinoshita, H. Miyoshi, I. Seyama, J. Biol. Chem.
2009, 284, 7597–7605; f) K. Yamaoka, M. Inoue, M. Hirama, Forensic Tox-
icol. 2011, 29, 125–131.
[12] M. Inoue, Y. Ishihara, S. Yamashita, M. Hirama, Org. Lett. 2006, 8, 5801–
5804.
[13] For studies of artificial polyether compounds, see: ref. [10a] and [10b].
[14] S. Yamashita, R. Uematsu, M. Hirama, Tetrahedron 2011, 67, 6616–6626.
[15] Preparation: See the Supporting Information.
[3] a) M. Murata, A.-M. Legrand, Y. Ishibashi, T. Yasumoto, J. Am. Chem. Soc.
1989, 111, 8929–8931; b) M. Murata, A.-M. Legrand, Y. Ishibashi, M.
Fukui, T. Yasumoto, J. Am. Chem. Soc. 1990, 112, 4380–4386; c) R. J.
Lewis, J.-P. Vernoux, I. M. Brereton, J. Am. Chem. Soc. 1998, 120, 5914–
5920; d) P. Otero, S. Pꢃrez, A. Alfonso, C. Vale, P. Rodrꢄguez, N. N. Gou-
veia, N. Gouveia, J. Delgado, P. Vale, M. Hirama, Y. Ishihara, J. Molgꢅ,
L. M. Botana, Anal. Chem. 2010, 82, 6032–6039; e) K. Yogi, N. Oshiro, Y.
Inafuku, M. Hirama, T. Yasumoto, Anal. Chem. 2011, 83, 8886–8891.
[4] a) T. Yasumoto, M. Fukui, K. Sasaki, K. Sugiyama, J. AOAC Int. 1995, 78,
574–582; b) K. Yogi, S. Sakugawa, N. Oshiro, T. Ikehara, K. Sugiyama, T.
Yasumoto, J. AOAC Int. 2014, 97, 398–402; c) S. Perez, C. Vale, E. Alonso,
C. Alfonso, P. Rodriguez, P. Otero, A. Alfonso, P. Vale, M. Hirama, M. R.
Vieytes, L. M. Botana, Chem. Res. Toxicol. 2011, 24, 587–596; d) V.
Martin, C. Vale, A. Antelo, M. Hirama, S. Yamashita, M. Vieytes, L. Botana,
Chem. Res. Toxicol. 2014, 27, 1387–1400.
[16] T. Mukaiyama, T. Sugaya, S. Marui, T. Nakatsuka, Chem. Lett. 1982, 11,
1555–1558.
[17] J. C. McAuliffe, O. Hindsgaul, Synlett 1998, 307–309.
[5] For recent research on ciguatera and marine toxins, see: Special issue
on “Ciguatera and Related Biotoxins,” Toxicon 2010, 56, 653–847, and
references therein.
[18] U. Singh, S. K. Ghosh, M. S. Chadha, V. R. Mamdapur, Tetrahedron Lett.
1991, 32, 255–258.
[6] a) T. Yasumoto, T. Igarashi, A.-M. Legrand, P. Cruchet, M. Chinain, T.
Fujita, H. Naoki, J. Am. Chem. Soc. 2000, 122, 4988–4989; b) M. Satake,
M. Murata, T. Yasumoto, Tetrahedron Lett. 1993, 34, 1975–1978; c) M.
Satake, M. Fukui, A.-M. Legrand, P. Cruchet, T. Yasumoto, Tetrahedron
Lett. 1998, 39, 1197–1198; for recent total synthesis and synthetic stud-
ies from other groups, see: d) M. Isobe, A. Hamajima, Nat. Prod. Rep.
2010, 27, 1204–1226; e) A. Hamajima, M. Isobe, Angew. Chem. Int. Ed.
2009, 48, 2941–2945; Angew. Chem. 2009, 121, 2985–2989; f) J. S.
Clark, J. Conroy, A. J. Blake, Org. Lett. 2007, 9, 2091–2094; g) A. Goto, K.
Fujiwara, A. Kawai, H. Kawai, T. Suzuki, Org. Lett. 2007, 9, 5373–5376;
h) I. Kadota, T. Abe, M. Uni, H. Takamura, Y. Yamamoto, Tetrahedron Lett.
2008, 49, 3643–3647; i) I. Kadota, T. Abe, M. Uni, H. Takamura, Y. Yama-
moto, Tetrahedron 2009, 65, 7784–7789; j) H. Takamura, N. Nishiuma, T.
Abe, I. Kadota, Org. Lett. 2011, 13, 4704–4707; k) K. Shiroma, H. Taka-
mura, I. Kadota, Heterocycles 2012, 86, 997–1001; l) H. Takamura, T. Abe,
N. Nishiuma, R. Fujiwara, T. Tsukeshiba, I. Kadota, Tetrahedron 2012, 68,
2245–2260; m) K. Nogoshi, D. Domon, K. Fujiwara, N. Kawamura, R. Ka-
toono, H. Kawai, T. Suzuki, Tetrahedron Lett. 2013, 54, 676–680; n) K.
Shiroma, H. Asakura, T. Tanaka, H. Takamura, I. Kadota, Heterocycles
2014, 88, 969–973.
[19] a) L. J. Johnston, J. Lusztyk, D. D. M. Wayner, A. N. Abeywickreyma,
A. L. J. Beckwith, J. C. Scaiano, K. U. Ingold, J. Am. Chem. Soc. 1985, 107,
4594–4596; b) P. Pike, S. Hershberger, J. Hershberger, Tetrahedron 1988,
44, 6295–6304; c) W. Russell Bowman, S. L. Krintel, M. B. Schilling, Org.
Biomol. Chem. 2004, 2, 585–592.
[20] B. Giese, Angew. Chem. Int. Ed. Engl. 1983, 22, 753–764; Angew. Chem.
1983, 95, 771–782.
[21] a) N. Hashimoto, T. Aoyama, T. Shioiri, Chem. Pharm. Bull. 1982, 30, 119–
124; b) K. Maruoka, A. B. Concepcion, H. Yamamoto, Synthesis 1994,
1283–1290; c) Y. Mori, Y. Yaegashi, J. Furukawa, J. Am. Chem. Soc. 1997,
119, 4557–4558.
[22] a) A. G. Brook, D. M. MacRae, W. W. Limburg, J. Am. Chem. Soc. 1967, 89,
5493–5495; b) G. L. Larson, R. Berrios, J. A. Prieto, Tetrahedron Lett.
1989, 30, 283–286.
[23] Y. Ito, T. Hirao, T. Saegusa, J. Org. Chem. 1978, 43, 1011–1013.
[24] a) M. D. Lewis, J. K. Cha, Y. Kishi, J. Am. Chem. Soc. 1982, 104, 4976–
4978; b) K. C. Nicolaou, C.-K. Hwang, D. A. Nugiel, Angew. Chem. Int. Ed.
Engl. 1988, 27, 1362–1364; Angew. Chem. 1988, 100, 1413–1415;
c) K. C. Nicolaou, C.-K. Hwang, D. A. Nugiel, J. Am. Chem. Soc. 1989, 111,
4136–4137. For applications to construct the C-ring of ciguatoxins, see:
[7] M. Hirama, T. Oishi, H. Uehara, M. Inoue, M. Maruyama, H. Oguri, M.
Satake, Science 2001, 294, 1904–1907.
Chem. Eur. J. 2014, 20, 1 – 9
www.chemeurj.org
7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

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d) M. Sasaki, H. Fuwa, M. Ishikawa, K. Tachibana, Org. Lett. 1999, 1,
1075–1077; e) K. Fujiwara, D. Takaoka, K. Kusumi, K. Kawai, A. Murai,
Synlett 2001, 691–693; f) K. Fujiwara, Y. Koyama, K. Kawai, H. Tanaka, A.
Murai, Synlett 2002, 1835–1838; g) M. Maruyama, M. Inoue, T. Oishi, H.
Oguri, Y. Ogasawara, Y. Shindo, M. Hirama, Tetrahedron 2002, 58, 1835–
1851; h) M. Sasaki, M. Ishikawa, H. Fuwa, K. Tachibana, Tetrahedron
2002, 58, 1889–1911; i) K. Fujiwara, A. Goto, D. Sato, Y. Ohtaniuchi, H.
Tanaka, A. Murai, H. Kawai, T. Suzuki, Tetrahedron Lett. 2004, 45, 7011–
7014; j) ref. [10e] and [10f] and references therein.
[28] K. Maruoka, T. Miyazaki, M. Ando, Y. Matsumura, S. Sakane, K. Hattori, H.
Yamamoto, J. Am. Chem. Soc. 1983, 105, 2831–2843.
[29] a) H. Kosugi, M. Kitaoka, K. Tagami, A. Takahashi, H. Uda, J. Org. Chem.
1987, 52, 1078–1082; b) G. Solladiꢃ, J. Hutt, A. Girardin, Synthesis 1987,
173.
[30] For a recent review, see: S. K. Bur, A. Padwa, Chem. Rev. 2004, 104,
2401–2432.
[31] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155–4156.
[32] P. Schwab, R. H. Grubbs, J. W. Ziller, J. Am. Chem. Soc. 1996, 118, 100–
110.
[33] J. L. Luche, J. Am. Chem. Soc. 1978, 100, 2226–2227.
[34] a) A. Tatami, M. Inoue, H. Uehara, M. Hirama, Tetrahedron Lett. 2003, 44,
5229–5233; b) M. Inoue, S. Yamashita, A. Tatami, K. Miyazaki, M. Hirama,
J. Org. Chem. 2004, 69, 2797–2804.
[35] a) T. Kan, Y. Ohfune, Tetrahedron Lett. 1995, 36, 943–946; b) Y. Ohfune,
T. Kan, T. Nakajima, Tetrahedron 1998, 54, 5207–5224.
[36] a) M. J. Gaunt, J. Yu, J. B. Spencer, J. Org. Chem. 1998, 63, 4172–417;
b) J. Xia, S. A. Abbas, R. D. Locke, C. F. Piskorz, J. L. Alderfer, K. L. Matta,
Tetrahedron Lett. 2000, 41, 169–173; c) J. A. Wright, J. Yu, J. B. Spencer,
Tetrahedron Lett. 2001, 42, 4033–4036.
[25] For selected examples of radical reaction using cis-vinyl sulfoxides, see:
a) M. Zahouly, M. Journet, M. Malacria, Synlett 1994, 388–368; b) G.
Keum, S. B. Kang, Y. Kim, E. Lee, Org. Lett. 2004, 6, 1895–1897; c) J. H.
Jung, Y. W. Kim, M. A. Kim, S. Y. Choi, Y. K. Chung, T.-R. Kim, S. Shin, E.
Lee, Org. Lett. 2007, 9, 3225–3228; d) T. Kimura, M. Hagiwara, T. Nakata,
Tetrahedron Lett. 2007, 48, 9171–9175; e) J. H. Jung, E. Lee, Angew.
Chem. Int. Ed. 2009, 48, 5698–5700; Angew. Chem. 2009, 121, 5808–
5810; f) T. Kimura, M. Hagiwara, T. Nakata, Tetrahedron 2009, 65, 10893–
10900.
[26] a) J. Inanaga, K. Hirata, H. Saeki, T. Katsuki, M. Yamaguchi, Bull. Chem.
Soc. Jpn. 1979, 52, 1989–1993; b) M. Sasaki, M. Inoue, T. Noguchi, A.
Takeichi, K. Tachibana, Tetrahedron Lett. 1998, 39, 2783–2786.
[27] a) V. H. Dahanukar, S. D. Rychnovsky, J. Org. Chem. 1996, 61, 8317–
8320; b) I. Kadota, A. Ohno, K. Matsuda, Y. Yamamoto, J. Am. Chem. Soc.
2001, 123, 6702–6703.
Received: October 13, 2014
Published online on && &&, 0000
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FULL PAPER
&
Organic Chemistry
S. Yamashita ,* K. Takeuchi, T. Koyama,
Y. Hayashi, M. Hirama*
&& – &&
Practical Route to the Left Wing of
CTX1B and Total Syntheses of CTX1B
and 54-deoxyCTX1B
Try, try again! Ciguatoxins, the principal
causative agents of ciguatera seafood
poisoning, are extremely large polycyc-
lic ethers. A route to the left wing utiliz-
ing radical cyclization realized a practical
total syntheses of CTX1B and 54-hydrox-
yCTX1B (see figure).
Chem. Eur. J. 2014, 20, 1 – 9
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9
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ