Convergent synthesis of the ABCDE ring framework of ciguatoxin

Article abstract of DOI:10.1039/a903063h

An alkylation-metathesis sequence is shown to be a powerful method to synthesize the ABCDE ring framework of ciguatoxin 1.

Full text of DOI:10.1039/a903063h

Convergent synthesis of the ABCDE ring framework of ciguatoxin
Kenji Maeda, Tohru Oishi, Hiroki Oguri and Masahiro Hirama*
Department of Chemistry, Graduate School of Science, Tohoku University, and CREST, Japan Science and
Technology Corporation (JST), Sendai 980-8578, Japan. E-mail: hirama@ykbsc.chem.tohoku.ac.jp
Received (in Cambridge, UK) 19th April 1999, Accepted 4th May 1999
An alkylation–metathesis sequence is shown to be a powerful
method to synthesize the ABCDE ring framework of
ciguatoxin 1.
1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone (DMPU)
gave a separable mixture of the desired diastereomer 12 and the
epimer 13 in a 3: 2 ratio in 58% combined yield (Scheme 3).
When HMPA was used instead of DMPU in this alkylation
Ciguatoxin (CTX1B, 1) is the principal toxin that causes
ciguatera poisoning.1 Its gigantic structure and unique agonist
activity against the sodium channel have attracted considerable
attention among synthetic organic chemists.2 During the course
of our synthetic studies directed toward 1, we developed an
efficient method of constructing trans-fused 6,n,6,6-tetracyclic
H
H
H
H
H
H
O
O
O
O
O
OAc i–iii
OAc
iv–vi
Si
O
Si
O
O
HO
O
H
Si
H
BnO
Si
BnO
OAc
vii
6
7
H
H
H
O
O
ether systems (n
= 7–10) by combining intermolecular
O
O
viii
Si
O
Si
O
alkylation and ring-closing metathesis (RCM) reactions.3 We
describe herein a convergent synthesis of the ABCDE ring
framework 2 of 1 starting from the AB ring 4 and E-ring
fragments 5, using the described alkylation–metathesis strategy
(Scheme 1).
O
O
O
O
H
H
Si
H
BnO
Si
BnO
8
10
H
H
H
O
O
O
I
ix, x
xi, xii
O
OMPM
O
O
H
H
H
H
H
HO
H
O
BnO
OBn
O
I
OMe
OH
H
H
J
11
4
H
O
K
G
H
H
H
H
O
H
H
H
O
H
H
H O
O
B
O H
O
M
O
L
Scheme 2 Reagents and conditions: i, K2CO3 (cat.), MeOH; ii, (TIPDS)Cl2,
pyridine; iii, BnBr, NaH, DMF, THF, 0 °C to room temp., 63% (3 steps); iv,
NBS, THF–H2O (9:1); v, KHMDS, 18-crown-6, toluene, 275 to 0 °C, 4 h;
vi, H2CNCHCH2MgBr, 0 °C to room temp., 53% (3 steps); vii,
H2CNCHCH2Br, NaH, 0 °C to room temp., 93%; viii, 9 (cat.), CH2Cl2,
94%; ix, TBAF, THF; x, PPTS (cat.), p-MeOC6H4CH(OMe)2, (CH2Cl)2; xi,
DIBAL-H, CH2Cl2, 278 to 220 °C, 75% (3 steps); xii, I2, PPh3, imidazole,
toluene, 82%.
E
H
A
F
H
C
O
D
O
O
OH
H
H
Ciguatoxin (1)
HO
H
H
OH
OH
H
H
H
H
O
OTBDPS
OTBDPS
O
20 E
9B
13
A
O
15D
C
O
5
O
H
H
H
H
BnO
2
RCM
+
4
5
H
H
H
H
O
OTBDPS
OTBDPS
O
i
H
H
H
H
H
H
H
H
O
O
O
O
O
O
H
H
O
H
H
O
O
+
3
BnO
CO2But
CO2But
O
O
O
O
OMPM
OMPM
O
O
H
H
H
H
H
OBn
OBn
12
13
O
RCM
O
3 : 2
O
O
I
E
O
A
O
B
+
ButO
ii, iii
O
ii–v
O
OMPM
H
H
H
H
O
H
H
H
H
H
O
O
O
4
OBn
5
OTBDPS
OTBDPS
OTBDPS
OTBDPS
CO2But
OMPM
O
O
O
O
O
H
H
OBn
MPM =
OBn
16
vi
14
OMe
iv, v
Scheme 1
H
H
H
H
O
O
O
15
+
16
OTBDPS
OTBDPS
The synthesis of the iodide 4 is shown in Scheme 2. Tri-O-
acetyl-d-glucal was converted to 6 via methanolysis of the
acetate and successive protection of the resulting triol as the
tetraisopropyldisiloxanediyl (TIPDS) and benzyl ether. Epox-
idation of 6 using Spilling’s method4 followed by addition of
CH2NCHCH2MgBr resulted in the formation of 7 in 53%
overall yield. Allylation of the secondary alcohol of 7 gave 8,
which was subjected to RCM reaction using Grubbs’ catalyst,
(PCy3)2Cl2RuNCHPh 95 to afford the 7,6-bicyclic system 10 in
94% yield.6 The TIPDS group of 10 was removed using TBAF
and the 1,3-diol was converted to the p-methoxybenzylidene
acetal 11. Reductive cleavage of the benzylidene acetal with
DIBAL-H followed by conversion of the resulting primary
alcohol to an iodide gave 4 regioselectively.7
1 : 1
O
O
O
H
H
15
OBn
vii, viii
H
O
H
H
H
O
H
OTBDPS
OTBDPS
ix
x
3
2
O
O
O
H
OBn
MeO
17
Scheme 3 Reagents and conditions: i, LDA, DMPU, THF, 278 to 0 °C,
58% (based on recovery of 4; 23%); ii, PPTS (cat.), MeOH; iii, TBDPSCl,
imidazole, DMF, 71% (2 steps); iv, DDQ, (CH2Cl)2–H2O (20:1), 91%; v,
CSA (cat.), toluene, 80 °C, 80%; vi, imidazole, toluene, reflux, 80%
(15:16 = 1:1); vii, H2CNCHMgBr, Et2O, 278 to 260 °C, 91%; viii, CSA
(cat.), HC(OMe)3, CH2Cl2, 75%; ix, BF3·OEt2, Et3SiH, CH2Cl2, 245 °C,
96%; x, 9, CH2Cl2, 40 °C, 93%.
Alkylation of the tert-butyl ester 5, which was readily
prepared from d-glucose8 with 4 using LDA in the presence of
Chem. Commun., 1999, 1063–1064
1063

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Ed., 1998, 37, 965; M. Sasaki, T. Noguchi and K. Tachibana,
Tetrahedron Lett., 1999, 40, 1337.
3 T. Oishi, Y. Nagumo and M. Hirama, Chem. Commun., 1998, 1041.
4 C. H. Marzabadi and C. D. Spilling, J. Org. Chem., 1993, 58, 3761.
5 P. Schwab. R. H. Grubbs and J. W. Ziller, J. Am. Chem. Soc., 1996, 118,
100.
6 M. Delgago and J. D. Martín, Tetrahedron Lett., 1997, 38, 6299.
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201.
8 I. Kadota, A. Ohno, Y. Matsukawa and Y. Yamamoto, Tetrahedron
Lett., 1998, 39, 6373.
9 We found that reduction of the ketal rather than the corresponding
hemiacetal using Et3SiH and BF3·OEt2 gave a remarkably higher yield
of the reduction product; 0–70% yield in the case of hemiacetal under
the same reduction conditions. Also see ref. 3.
10 D. L. Lewis, J. K. Cha and Y. Kishi, J. Am. Chem. Soc., 1982, 104,
4976.
11 The stereochemistry of 2 was unambiguously determined by 1H NMR
analysis. Selected data for 2: dH (500 MHz, CDCl3) 0.98 (9H, s,
TBDPS), 0.99 (9H, s, TBDPS), 1.55 (1H, q, J 11.4, H14ax), 1.53–1.60
(1H, m, H22), 1.62–1.69 (1H, m, H22A), 1.71–1.78 (1H, m, H21),
2.05–2.14 (1H, m, H21A), 2.29 (1H, dt, J 11.4, 4.1, H14eq), 2.31-2.38
(1H, m, H8), 2.64 (1H, ddd, J 16.0, 7.7, 3.5, H8A), 3.08–3.15 (2H, m,
H12, H13), 3.28(0) (1H, ddd, J 8.4, 7.7, 3.8, H9), 3.28(5) (1H, ddd, J
11.4, 8.9, 4.1, H15), 3.31–3.40 (2H, m, H20, H24), 3.35 (1H, dd, J 9.0,
8.4, H10), 3.48 (1H, t, J 9.0, H11), 3.62–3.70 (3H, m, H23, H25, H25A),
3.88 (1H, dq, J 8.9, 2.3, H16), 4.01 (1H, dq, J 16.0, 2.8, H5), 4.12 (1H,
dq, J 9.0, 2.3, H19), 4.29 (1H, dd, J 16.0, 5.7, H5A), 4.83 (1H, d, J 11.5,
CH2Ph), 4.89 (1H, d, J 11.5, CH2Ph), 5.64 (1H, dt, J 13.0, 2.3, H18),
5.77 (1H, dddd, J 11.8, 5.1, 3.5, 2.8, H7), 5.83 (1H, dt, J 13.0, 2.3, H17),
5.87 (1H, ddt, J 11.8, 5.7, 2.8, H6), 7.23–7.43 (17H, m, Ph), 7.52–7.56
(4H, m, Ph), 7.59–7.66 (4H, m, Ph).
reaction, the ratio became 1: 1. Although further attempts to
improve the diastereoselectivity and to epimerize 13 were
unsuccessful at this stage, we found that the epimerization could
be obtained at a later stage (vide infra). Acidic methanolysis of
the acetonide 12 followed by protection of the resulting 1,3-diol
as TBDPS ethers gave 14. Removal of the p-methoxybenzyl
group using DDQ followed by treatment with CSA in toluene at
80 °C gave the d-lactone 15. The epimeric lactone 16 was also
synthesized from 13 in an analogous manner. This lactone was
found to undergo epimerization by treatment with imidazole in
toluene under reflux to give a separable 1: 1 mixture of 15 and
16 in 80% yield, while stronger bases such as ButOK and DBU
caused only decomposition. Thus, the undesired epimer 13 was
successfully converted into 15. Treatment of the lactone 15 with
CH2NCHMgBr followed by conversion of the resultant hemi-
acetal to the corresponding methyl acetal afforded 17 as a 1: 1
mixture of anomers. Reduction of the anomeric mixture 179
10
with Et3SiH in the presence of BF3·OEt2 gave 3 as a single
isomer in 96% yield. Finally RCM reaction of 3 with Grubbs’
catalyst 9 at 40 °C in CH2Cl2 gave the ABCDE ring 2 in 93%
yield.11
In conclusion, we have demonstrated that the alkylation–
metathesis strategy is versatile for the convergent synthesis of
the pentacyclic segment 2 of 1. Further studies directed toward
the total synthesis of 1 are currently in progress in our
laboratory.
Notes and references
1 M. Murata, A. M. Legrand, Y. Ishibashi, M. Fukui and T. Yasumoto,
J. Am. Chem. Soc., 1990, 112, 4380; M. Satake, A. Morohashi, H.
Oguri, T. Oishi, M. Hirama, N. Harada and T. Yasumoto, J. Am. Chem.
Soc., 1997, 119, 11325.
2 For recent synthetic studies, see: T. Oishi, M. Shoji, K. Maeda, N.
Kumahara and M. Hirama, Synlett, 1996, 1165; T. Oishi, K. Maeda and
M. Hirama, Chem. Commun., 1997, 1289; T. Oishi, M. Shoji, N.
Kumahara and M. Hirama, Chem. Lett., 1997, 845; T. Oishi, Y. Nagumo
and M. Hirama, Synlett, 1997, 307; S. Hosokawa and M. Isobe, Synlett,
1996, 351; T. Oka, K. Fujiwara and A. Murai, Tetrahedron, 1996, 37,
Communication 9/03063H
1064
Chem. Commun., 1999, 1063–1064