Convergent synthesis of the BCDE-ring part of ciguatoxin

Article abstract of DOI:10.1055/s-2002-34904

The BCDE-ring part of ciguatoxin has been convergently synthesized by a sequence of reactions involving coupling of the E-ring part having a Z-enal group with the B-ring part as an acyl anion equivalent, selective removal of a p-bromobenzyl protective gro

Full text of DOI:10.1055/s-2002-34904

LETTER
1835
Convergent Synthesis of the BCDE-Ring Part of Ciguatoxin
Convergent
S
ynthe
e
sis of the
B
n
CDE-Ring P
s
art of Cig
h
uatoxin u Fujiwara,* Yasuhito Koyama, Kentaro Kawai, Hideki Tanaka, Akio Murai*1
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo 060-0810, Japan
Fax +81(11)7064924; E-mail: fjwkn@sci.hokudai.ac.jp
Received 14 August 2002
Me
Abstract: The BCDE-ring part of ciguatoxin has been convergent-
ly synthesized by a sequence of reactions involving coupling of the
E-ring part having a Z-enal group with the B-ring part as an acyl an-
ion equivalent, selective removal of a p-bromobenzyl protective
group using Miyaura’s conditions, and reductive cyclization.
Me
H
H
H
OH
O
Me
HO
H
I
O
J
H
O
L
K
O
H
H
O
O
M
H
H
G
H
H
H
O
O
H
H
H
H
H
H
H
H
O
O
B
Me
E
F
OH
Me
A
C
O
D
O
Key words: heterocycles, stereoselective synthesis, natural prod-
ucts, polyethers, polycycles
H
H
Ciguatoxin (1)
O
HO
H
OH
OH
OBn
OBn
1
H
H
OBn
OBn
OBn
Ciguatoxin (1) has been isolated as a causative toxin of
ciguatera seafood poisoning. Its unique trans-fused poly-
ether structure and strong bioactivity have attracted the at-
tention of synthetic chemists.2–5 From the synthetic point
of view, the convergent construction of such a large fused
polyether structure has been a significant challenge. Much
effort by synthetic chemists aiming at the concise con-
struction of the polyether framework6 as well as comple-
tion of the total synthesis of 1 and its congeners4 is
ongoing. During the course of our studies toward the total
synthesis of 1,7 we have developed a convergent synthetic
method for the fused 6/6 and 6/7 cyclic systems using the
coupling reaction of an acyl anion equivalent followed by
sequential reductive cyclization reactions.7g,i We now de-
scribe the synthesis of the BCDE-ring part 2 of 1 having
continuous trans-fused 7-membered unsaturated cyclic
ethers using our convergent method.
H
H
H
H
O
O
3
O
O
E
E
14
D
9
10
19
B
C
O
B
D
6
O
O
6
H
H
BnO
BnO
O
OBn
H
H
OH
BnO
BnO
2
3
PBB: p-bromobenzyl
OBn
3 O
O
MeS
OTBDPS
OBn
1
HO
OBn
OBn
OBn
H
SMe
O
O
14
E
E
9
9
B
6
10
B
10
O
O
6
19
OBn
OHC
OPBB
H
BnO
HO
OPBB
OBn
OBn
5
BnO
6
4
Scheme 1
RO
O
RO
O
R1
OR2
b
g
O
O
5
BnO
BnO
PMP
OBn
9: R1=OH, R2=H
OBn
7: R=H
8: R=Bn
Our synthetic plan for 2 is shown in Scheme 1. The central
CD-ring of 2 would be constructed by a stepwise reduc-
tive cyclization via δ-hydroxy ketone 3 from α,ε-dihy-
droxy-β,γ-unsaturated ketone 4. The α-hydroxy keto part
of 4 would be synthesized by the coupling reaction of an
aldehyde group with an acyl anion equivalent. Therefore,
we started the synthesis of 2 from the E-ring part 6 having
a Z-enal group and the B-ring part 5 having a dithioacetal
mono-S-oxide group.8 While the protective group for the
oxygen atom at C6 was required to be stable under the
Lewis acidic conditions during the reductive cyclization
steps, selective removal of the protective group was nec-
essary at the later stage of this plan. Thus, we intended to
use a p-bromobenzyl (PBB) group for the protection,
which would be distinguishable from a benzyl (Bn) group
under its removal conditions.
c
f
a
10: R1=OTBS, R2=H
d
e
11: R1=OTBS, R2=PBB
12: R1=OH, R2=PBB
13: R1=I, R2=PBB
PMP: p-methoxyphenyl
Scheme 2 Reagents and conditions a) NaH, BnBr, TBAI, t-BuOK
(cat.), THF, 24 °C, 20 h, 99%; b) 1 M HCl–THF (1:1), 25 °C, 17 h,
98%; c) TBSCl, DMAP (cat.), Et3N, CH2Cl2, 24 °C, 3.5 h, 99%;
d) NaH, TBAI (cat.), PBBBr, THF, 24 °C, 3 h; e) TBAF, THF, 24 °C,
6 h, 96% for 2 steps; f) I2, PPh3, imidazole, PhH, 23 °C, 30 min, 90%;
g) MeS(O)CH2SMe, BuLi, THF, –20 °C, 45 min, then 22 °C, 45 min,
82%.
Preparation of the B-ring part 5 was begun from C-glyco-
side 77d,f (Scheme 2). Protection of a primary hydroxy
group with BnBr followed by removal of the acetal part
gave diol 9, which was converted to iodide 13 through a
4-step process [(i) protection of the primary hydroxy
group of 9 with TBSCl, (ii) protection of the secondary al-
cohol part with PBBBr, (iii) removal of the TBS group,
and (iv) conversion of the resultant alcohol to 13]. The io-
dide 13 was then reacted with the anion of methyl methyl-
sulfinylmethyl sulfide to produce 5 as a mixture of four
diastereomers.8
Synlett 2002, No. 11, Print: 29 10 2002.
Art Id.1437-2096,E;2002,0,11,1835,1838,ftx,en;U06602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1836
K. Fujiwara et al.
LETTER
OBn
OBn
O
oxidation followed by Wittig reaction to provide 2,2-di-
bromovinyl compound 20, which was transformed into
acetylene 2110 in 66% overall yield for 5 steps. Hydrolysis
of 21 and the subsequent treatment with BnBr produced
23 (62% for 2 steps), which was converted to propargyl
alcohol 25 by a stepwise process via ester 24 (74% for 2
steps). The acetylene part of 25 was partially hydrogenat-
ed to give Z-allyl alcohol 26, which was oxidized to Z-
enal 6 (98% for 2 steps).
O
a
b
c
OTBS
OTBS
OPHB
11
10
BnO
O
BnO
BnO
14
OBn
15
B
PHB: p-hydroxybenzyl
O
O
Scheme 3 Reagents and conditions a) Bis(pinacolato)diboron,
PdCl2(dppf), KOAc, DMSO, 80 °C, 12 h; b) 5 M NaOH aq–30%
H2O2 aq–THF (2:1:10), 0 °C, 30 min, 15: 68% for 2 steps; c) DDQ,
CH2Cl2–H2O (10:1), 0 °C → 22 °C, 30 min, 97%.
The convergent synthesis of the BCDE-ring part is shown
in Scheme 5. Deprotonation of 5 with LDA followed by
the addition to 6 produced 27 as a mixture of diastereo-
O
MeS
RO
SMe
OBn
OBn
At this stage, we examined the selective detachment of a
PBB group in co-existence with Bn protective groups
(Scheme 3). Since the selective and direct cleavage of a
PBB ether was difficult, the conversion of the PBB group
to another removable group was planned. Model com-
pound 11 was converted to pinacolatoboron derivative 14
under Miyaura’s conditions using bis(pinacolato)diboron
and PdCl2(dppf),9 which was treated with basic hydrogen
peroxide to give p-hydroxybenzyl (PHB) ether 15 in 68%
overall yield. The PHB group was readily and selectively
removed by treatment with DDQ in wet CH2Cl2 to afford
alcohol 10 in 97% yield. Thus, the conditions for the se-
lective removal of the PBB group were established.
H
BnO
O
c
a
5
O
6
H
BnO
OPBB OH
BnO
27: R=TBDPS
28: R=H
b
HO
O
OBn
OBn
H
O
d
BnO
O
H
BnO
OPBB OH
4
BnO
OBn
O
OBn
H
H
H
O
O
OBn
O
The E-ring part 6 was prepared from oxepene 167j
(Scheme 4). After conversion of 16 to 18 by a 2-step pro-
cess [(i) protection with TBDPSCl and (ii) removal of a
pivaloyl group], the hydroxy group of 18 was subjected to
H
1
BnO
BnO
OBn
H
H
OH
30
OPBB
H
O
BnO
14
9
10
O
OBn
O
H
BnO
BnO
OBn
H
OH
29
H
OPBB
O
BnO
Me N
O
OPBB
O
H
BnO
H
BnO
R1O
R2O
TBDPSO
X
BnO
H
O
O
c
e
31
Ph
Ph
O
O
O
O
OBn
H
16: R1=H, R2=Piv
19: X=O
20: X=CBr2
BnO
O
O
e, f
h
a
b
d
17: R1=TBDPS, R2=Piv
18: R1=TBDPS, R2=H
OBn
29
O
H
BnO
OH
OR
BnO
O
OR1
OR1
TBDPSO
TBDPSO
32: R=PHB
33: R=PMB
Ph
f
j
g
O
O
O
H
R2
OBn
OBn
H
H
H
22: R1=H, R2=H
23: R1=Bn, R2=H
j
O
21
BnO
O
g
2
h
i
O
24: R1=Bn, R2=CO2Me
25: R1=Bn, R2=CH2OH
O
H
BnO
OR
BnO
OBn
OBn
TBDPSO
HO
34: R=PMB
3: R=H
i
k
6
O
Scheme 5 Reagents and conditions a) LDA (5 equiv), 5 (5 equiv),
–78 °C, 15 min, then 6, –78 °C, 1 h, 27: 86% from 6, 5: 75% recovery;
b) TBAF, THF, 25 °C, 2.5 h, 91%; c) THF–H2O–TFA (10:5:1),
25 °C, 2.5 h; d) Et3SiH, TMSOTf, CH3CN, 0 °C, 12 min, 29: 43%, 30:
15%, 31: 6%; e) bis(pinacolato)diboron (270 equiv), PdCl2(dppf) (3
equiv), KOAc (82 equiv), 4-bromoanisole (26 equiv), DMSO, 80 °C,
24 h; f) 5 M NaOH aq–30% H2O2 aq–THF (2:1:10), 25 °C, 1 h, 32:
64% for 2 steps, 29: 33% recovery; g) K2CO3, MeI, DMF, 55 °C,
14 h, ~100%; h) (COCl)2, DMSO, CH2Cl2, –78 °C, 20 min, then Et3N,
–78 °C → –20 °C, 30 min, ~100%; i) DDQ, NaHCO3, CH2Cl2–H2O
(5:1), 0 °C, 1.5 h, ~100%; j) Et3SiH, TMSOTf, CH2Cl2, 0 °C, 13 min,
~100%.
26
Scheme 4 Reagents and conditions a) TBDPSCl, imidazole, DMF,
70 °C, 22.5 h; b) DIBALH, CH2Cl2, –78 °C, 1 h, 89% for 2 steps;
c) (COCl)2, DMSO, CH2Cl2, –78 °C, 20 min, then Et3N, –78 °C →
–47 °C, 30 min; d) PPh3, CBr4, CH2Cl2, –78 °C, 6 h; e) MeLi, THF,
–78 °C, 1 h, then 25 °C, 45 min, 74% for 3 steps; f) THF–H2O–TFA
(10:10:3), 25 °C, 3.5 d, 69%; g) NaH, BnBr, TBAI (cat.), THF, 25 °C,
9 h, 91%; h) BuLi, ClCO2Me, –78 °C, 3 h, 76%; i) DIBALH, CH2Cl2,
–78 °C, 4 h, 98%; j) H2, Lindlar cat., EtOH–quinoline (250:1), 25 °C,
3 d, 98%; k) (COCl)2, DMSO, CH2Cl2, –78 °C, 20 min, then Et3N,
–78 °C → –45 °C, 30 min, ~100% (crude).
Synlett 2002, No. 11, 1835–1838 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Convergent Synthesis of the BCDE-Ring Part of Ciguatoxin
Yasumoto, T. J. Am. Chem. Soc. 1990, 112, 4380.
1837
mers (86% from 6) along with recovered 5 (75% recov-
ery).8 The TBDPS group of 27 was detached with TBAF
to afford 28 (91%), which was hydrolyzed under acidic
conditions (THF–H2O–TFA = 10:10:3) to provide α,ε-di-
hydroxy-β,γ-unsaturated ketone 4 as a mixture of diaste-
reomers. The ketone 4 was stable enough to be purified by
flash chromatography using silica gel neutralized with 5%
Et3N, and the purification was essential to success of the
next reductive cyclization reaction. Reductive cyclization
of 4 with Et3SiH in the presence of TMSOTf in
acetonitrile11,12 produced the desired tricycle 2913 as a ma-
jor component in 43% yield from 28 and the stereoisomer
3013 (15% for 2 steps) along with 3114 (6% for 2 steps).
The PBB ether 29 was converted to PHB ether 32 by
Miyaura’s method9 followed by oxidative rearrangement
in 64% overall yield along with unreacted 29 (33% recov-
ery). Under the cross-coupling conditions, we used 4-bro-
moanisole as a dummy substrate together with 29 in order
to keep the ratio of PdCl2(dppf) to the aryl bromides con-
stant and to obtain reproducible results. Since the PHB
group was not appropriate for the next oxidation step, 32
was converted to PMB ether 33 (~100%). Swern oxida-
tion of 33 followed by treatment with DDQ in the pres-
ence of NaHCO3 gave δ-hydroxy ketone 3 in quantitative
yield, which was smoothly cyclized with Et3SiH in the
presence of TMSOTf to produce 215 (~100%) stereoselec-
tively. The trans-junction between the B- and C-rings was
confirmed by the presence of ROE (H6/H10 in pyridine-
d5) and NOE (H9/H14 in CD3CN) as well as the large val-
ue of 3JH9-H10 (9.2 Hz in CD3CN).
(f) Satake, M.; Morohashi, A.; Oguri, H.; Oishi, T.; Hirama,
M.; Harada, N.; Yasumoto, T. J. Am. Chem. Soc. 1997, 119,
11325. (g) For reviews of ciguatoxin and related marine
toxins, see: Yasumoto, T.; Murata, M. Chem. Rev. 1993, 93,
1897. (h) See also: Scheuer, P. J. Tetrahedron 1994, 50, 3.
(i) For a review of ciguatera, see: Lewis, R. L. Toxicon 2001,
39, 97.
(3) For the bioactivities of ciguatoxin and related compounds,
see: (a) Bidard, J.-N.; Vijverberg, H. P. M.; Frelin, C.;
Chungue, E.; Legrand, A.-M.; Bagnis, R.; Lazdanski, M. J.
Biol. Chem. 1984, 259, 8353. (b) Lombet, A.; Bidard, J. N.;
Lazdanski, M. FEBS Lett. 1987, 219, 355. (c) For a review,
see: Dechraoui, M.-Y.; Naar, J.; Pauillac, S.; Legrand, A.-M.
Toxicon 1999, 37, 125; see also the references cited in ref.
11.
(4) For the total synthesis of CTX3C, a congener of ciguatoxin,
see: Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.;
Maruyama, M.; Oguri, H.; Satake, M. Science 2001, 294,
1904.
(5) For the recent synthetic studies of ciguatoxins, see:
(a) Takakura, H.; Sasaki, M.; Honda, S.; Tachibana, K. Org.
Lett. 2002, 4, 2771. (b) Uehara, H.; Oishi, T.; Inoue, M.;
Shoji, M.; Nagumo, Y.; Kosaka, M.; Brazidec, J.-Y. L.;
Hirama, M. Tetrahedron 2002, 58, 6493. (c) Sasaki, M.;
Noguchi, T.; Tachibana, K. J. Org. Chem. 2002, 67, 3301.
(d) Takai, S.; Isobe, M. Org. Lett. 2002, 4, 1183. (e) Bond,
S.; Perlmutter, P. Tetrahedron 2002, 58, 1779.
(f) Maruyama, M.; Inoue, M.; Oishi, T.; Oguri, H.;
Ogasawara, Y.; Shindo, Y.; Hirama, M. Tetrahedron 2002,
58, 1835. (g) Kira, K.; Hamajima, A.; Isobe, M.
Tetrahedron 2002, 58, 1875. (h) Sasaki, M.; Ishikawa, M.;
Fuwa, H.; Tachibana, K. Tetrahedron 2002, 58, 1889.
(i) Candenas, M. L.; Pinto, F. M.; Cintado, C. G.; Morales,
E. Q.; Brouard, I.; Díaz, M. T.; Rico, M.; Rodríguez, E.;
Rodríguez, R. M.; Pérez, R.; Pérez, R. L.; Martín, J. D.
Tetrahedron 2002, 58, 1921. (j) Takakura, H.; Noguchi, K.;
Sasaki, M.; Tachibana, K. Angew. Chem. Int. Ed. 2001, 40,
1090. (k) Oishi, T.; Tanaka, S.-i.; Ogasawara, Y.; Maeda,
K.; Oguri, H.; Hirama, M. Synlett 2001, 952. (l) Imai, H.;
Uehara, H.; Inoue, M.; Oguri, H.; Oishi, T.; Hirama, M.
Tetrahedron Lett. 2001, 42, 6219. (m) Kira, K.; Isobe, M.
Tetrahedron Lett. 2001, 42, 2821. (n) Saeeng, R.; Isobe, M.
Heterocycles 2001, 54, 789. (o) Oguri, H.; Tanaka, S.;
Oishi, T.; Hirama, M. Tetrahedron Lett. 2000, 41, 975.
(p) Sasaki, M.; Noguchi, K.; Fuwa, H.; Tachibana, K.
Tetrahedron Lett. 2000, 41, 1425. (q) Kira, K.; Isobe, M.
Tetrahedron Lett. 2000, 41, 5951. (r) Liu, T.-Z.; Isobe, M.
Tetrahedron 2000, 56, 5391. (s) Liu, T.-Z.; Isobe, M.
Tetrahedron 2000, 56, 10209.
Thus, the BCDE-ring part 2 of ciguatoxin 1 was conver-
gently synthesized from the B ring part 5 and the E-ring
part 6 in 20% overall yield from 6 in 10 steps. During the
course of these studies, efficient selective removal of a p-
bromobenzyl protective group using Miyaura’s condi-
tions was also developed. Further studies toward the total
synthesis of 1 are currently under way in this laboratory.
Acknowledgement
The authors are grateful to Mr. Kenji Watanabe and Dr. Eri Fukushi
(GC-MS and NMR Laboratory, Graduate School of Agriculture,
Hokkaido University) for the measurements of mass spectra. The
authors also thank Mr. Yasuhiro Kumaki (High Resolution NMR
Laboratory, Graduate School of Science, Hokkaido University) for
the measurements of NMR spectra.
(6) For the convergent approaches, see: (a) Nicolaou, K. C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 589; and the
references cited therein. (b) Alvarez, E.; Díaz, M. T.;
Hanxing, L.; Martín, J. D. J. Am. Chem. Soc. 1995, 117,
1437. (c) Alvarez, E.; Pérez, R.; Rico, M.; Rodríguez, R. M.;
Martín, J. D. J. Org. Chem. 1996, 61, 3003. (d) Ravelo, J.
L.; Regueiro, A.; Rodríguez, E.; de Vera, J.; Martín, J. D.
Tetrahedron Lett. 1996, 37, 2869. (e) Oishi, T.; Nagumo,
Y.; Hirama, M. Synlett 1997, 980. (f) Oishi, T.; Nagumo,
Y.; Hirama, M. Chem. Commun. 1998, 1041. (g) Sasaki,
M.; Fuwa, H.; Inoue, M.; Tachibana, K. Tetrahedron Lett.
1998, 39, 9027. (h) Sasaki, M.; Fuwa, H.; Ishikawa, M.;
Tachibana, K. Org. Lett. 1999, 1, 1075. (i) Inoue, M.;
Sasaki, M.; Tachibana, K. Tetrahedron 1999, 55, 10949.
(j) Fujiwara, K.; Morishita, H.; Saka, K.; Murai, A.
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Synlett 2002, No. 11, 1835–1838 ISSN 0936-5214 © Thieme Stuttgart · New York

1838
K. Fujiwara et al.
LETTER
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stereochemistry has not been successful. The isomerization
at C9 and improvement of the selectivity during the
reductive cyclization of 4 are under investigation.
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to the intermediate cyclic oxonium ion generated from 4
with TMSOTf during the course of the reaction.
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(15) Representative data for 2: Colorless needles; mp 118–
119 °C; [ ]D24 –13.6 (c 0.02, CHCl3); 1H NMR (600 MHz,
CD3CN, CHD2CN as 1.93 ppm): = 7.39–7.25 (30 H, m,
Ph), 5.81 (1 H, dt, J = 13.2, 2.5 Hz, H15), 5.67 (1 H, brd,
J = 13.2 Hz, H12), 5.64 (1 H, br d, J = 13.2 Hz, H11), 5.60
(1 H, dt, J = 13.2, 2.5 Hz, H16), 4.91 (1 H, d, J = 11.0 Hz,
Bn), 4.85 (1 H, d, J = 11.0 Hz, Bn), 4.75 (1 H, d, J = 11.0 Hz,
Bn), 4.61 (1 H, d, J = 11.4 Hz, Bn), 4.59 (1 H, d, J = 11.0 Hz,
Bn), 4.53 (1 H, d, J = 12.1 Hz, Bn), 4.49 (1 H, d, J = 12.1 Hz,
Bn), 4.47 (1 H, d, J = 12.1 Hz, Bn), 4.43 (1 H, d, J = 11.4 Hz,
Bn), 4.40 (1 H, d, J = 12.1 Hz, Bn), 4.18 (1 H, br d, J = 9.2
Hz, H13), 4.06 (1 H, dq, J = 8.2, 2.1 Hz, H17), 4.03 (1 H, dq,
J = 9.2, 2.1 Hz, H14), 3.81 (1 H, br d, J = 9.2 Hz, H10), 3.70
(1 H, ddd, J = 8.2, 5.9, 2.8 Hz, H18), 3.64 (1 H, dd, J = 11.0,
2.8 Hz, H19a), 3.56–3.51 (4 H, m, H1, H5, H19b), 3.39 (1 H,
td, J = 9.2, 6.6 Hz, H3), 3.35 (1 H, ddd, J = 11.4, 9.2, 4.8 Hz,
H9), 3.21 (1 H, t, J = 9.2 Hz, H4), 3.05–3.15 (2 H, m, H6,
H7), 2.20 (1 H, m, H8a), 2.02 (1 H, m, H2a), 1.56 (1 H, m,
H2b), 1.41 (1 H, q, J = 11.4 Hz, H8b); 13C NMR (100 MHz,
CD3CN, CD313CN as 118.2 ppm): = 140.1 (C in Ph), 139.8
(C in Ph), 139.60 (C in Ph), 139.56 (C in Ph), 139.2 (C in
Ph), 134.3 (C12), 133.4 (C16), 131.6 (C11), 130.8 (C15),
128.2–129.2 (CH in Ph 25), 84.49 (C5), 84.46 (C18), 83.8
(C14), 83.7 (C13), 82.7 (C6), 82.5 (C4), 80.8 (C10), 79.8
(C9), 77.4 (C17), 76.8 (C3), 75.6 (Bn), 75.1 (Bn), 73.9 (C7),
73.6 (Bn), 73.0 (Bn), 71.9 (Bn), 71.7 (C19), 66.7 (C1), 37.4
(C8), 32.9 (C2); IR(film): max = 3091, 3062, 3030, 2954,
2925, 2854, 1453, 1092, 738, 695 cm–1; HR-FDMS: calcd
for C54H59O9 [M + H]+: 851.4159. Found: 851.4182.
(12) When CH2Cl2 was used as the solvent for the cyclization, the
yield of 29 was reduced (35%) and many unidentified
byproducts were formed.
(13) Stereochemistries at C9 and C10 of 29 were confirmed by
the presence of NOE (H9/H14) and the absence of NOE (H9/
H10) as well as the large value of 3JH9-H10 (7.5 Hz). The
stereochemistries at C9 and C10 of 30 were determined by
the absence of NOEs (H9/H14 and H9/H10) and the large
Synlett 2002, No. 11, 1835–1838 ISSN 0936-5214 © Thieme Stuttgart · New York