Stereocontrolled synthesis of the HIJ ring system of ciguatoxin

Article abstract of DOI:10.1039/a702158e

Divergent synthesis of the HIJ ring framework 21 of ciguatoxin 1 starting with oxocane 10 is achieved using the palladium- and acid-catalysed cyclization reactions of hydroxy epoxides.

Full text of DOI:10.1039/a702158e

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Stereocontrolled synthesis of the HIJ ring system of ciguatoxin
Tohru Oishi, Kenji Maeda and Masahiro Hirama*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-77, Japan
Divergent synthesis of the HIJ ring framework 21 of
ciguatoxin 1 starting with oxocane 10 is achieved using the
palladium- and acid-catalysed cyclization reactions of hy-
droxy epoxides.
catalytic amount of Pd(PPh3)4, gave 16 within 5 min as a single
diastereoisomer in 93% yield in two steps.‡ The stereoche-
mistry of the resulting alcohol with a non-natural orientation
could be readily inverted by reduction of the corresponding
ketone with NaBH4.10
Ciguatoxin 1 is the principal toxin which causes ciguatera
poisoning.1 Its unique structure and agonist activity against Na+
channels have attracted considerable attention from synthetic
organic chemists.2 Although numerous synthetic studies of
fragments of 1 have been reported, the central medium rings,
such as the F and I rings, have eluded synthesis until very
recently.3,4 We describe herein the first divergent synthesis of
the HIJ ring system of 1 via stereocontrolled palladium-5 and
acid-catalysed6 cyclization reactions of hydroxy epoxides
starting with the methyl oxocane I ring.3
Having completed the synthesis of the I and J ring system, we
were now in a position to construct the H ring. The ester 16 was
reduced with DIBAL-H, the resulting alcohols were protected
as benzyl ethers, and transformation of the acetonide into
p-methoxybenzylidene acetal gave 17 in 90% overall yield.
Regiospecific reductive cleavage of the benzylidene acetal with
DIBAL-H furnished the p-methoxybenzyl (MPM) ether, and
the resulting primary alcohol was converted to the methane-
sulfonate, which was then treated with sodium cyanide to yield
the nitrile 18 in 91% overall yield. Extension of the side chain
via DIBAL-H reduction and Wittig olefination with
(carbethoxyethylene)triphenylphosphorane gave the a,b-un-
saturated ester, which was reduced to allylic alcohol 19 in 98%
overall yield. Sharpless asymmetric epoxidation of 19 furnished
the corresponding hydroxy epoxide and further oxidation to the
aldehyde and Wittig olefination gave 20 in 75% overall yield.
Finally, treatment of 20 with 2,3-dichloro-5,6-dicyano-
The palladium-catalysed cyclization procedure5 was exam-
ined first to construct the H and J rings. cis-Epoxide 2 and trans-
epoxide 5, and trisubstituted trans-epoxide 7 were subjected to
a cyclization reaction as models for constructing the J and H
rings, respectively (Scheme 1).† While complete stereocontrol
was realized for 5 to give 6 ( > 99:1), lower selectivities were
observed for 2 and 7 to give mixtures of 3 and 4 (5:1), and 8 and
9 (2.7:1), respectively. The trans-epoxide 15 was therefore
used to construct the J ring, and we chose acid-catalysed
cyclization technology to prepare the H ring.
H
O
CO2Me
OSiMe2But
O
Optically active oxocane 103 was converted to 11 via
protection of the primary alcohol as a benzyloxymethyl (BOM)
ether, removal of the acyl groups and subsequent protection of
the 1,3-diol as the acetonide and of the remaining secondary
alcohol as a triisopropylsilyl ether in 83% overall yield (Scheme
2). The BOM group of 11 was removed by hydrogenolysis and
the resulting primary alcohol was converted to the tri-
fluoromethanesulfonate, which was immediately treated with
the lithium acetylide generated from 22 in THF–
dimethylpropyleneurea (DMPU) (6:1) at 278 °C7 to give the
adduct 12 in 68% overall yield. Selective removal of the
ethoxyethyl (EE) group with pyridinium toluene-p-sulfonate
(PPTS) in propanol8 produced 13 in quantitative yield. The
prop-2-ynyl alcohol 13 was partially reduced with sodium
dihydrobis(2-methoxyethoxy)aluminate (Red-Al)9 to give the
trans-allylic alcohol 14. Sharpless asymmetric epoxidation of
14 using d-(2)-diethyl tartrate (DET) gave the corresponding
a-epoxide exclusively, and successive oxidation of the primary
alcohol with a SO3–pyridine complex and Wittig olefination
gave 15 in 88% overall yield. Stereospecific construction of the
J ring was achieved by the palladium-catalysed cyclization.5
Treatment of 15 with tetrabutylammonium fluoride in THF,
followed by solvent exchange to CH2Cl2 and addition of a
3
O
O
OAc
OAc
i–iii
H
H
O
5 : 1
+
60%
O
CO2Me
2
CO2Me
4
H
H
OSiMe2But
O
O
CO2Me
i–iii
CO2Me
6
>99%
O
O
O
OAc
H
H
> 99 : 1
5
O
O
CO2Me
OSiMe2But
O
8
O
OAc
i–iii
H
H
2.7 : 1
CO2Me
+
63%
CO2Me
7
O
OAc
H
9
Scheme 1 Reagents and conditions: i, Bu4NF, THF; ii, Pd(PPh3)4 (cat.),
PPh3 (cat.), CH2Cl2; iii, Ac2O, pyridine
H
H
HO
H
O
O
I
OH
H
J
H
H
O
K
G
H
H
H
O
H
H
H
O
H
O
H
O
O
O
H
O
L
E
H
M
A
F
H
B
C
D
O
O
O
H
OH
H
H
HO
H
H
H
OH
OH
Ciguatoxin 1
Chem. Commun., 1997
1289

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H
H
i–iv
OSiPri3
OBOM
v–vii
OBz
OH
BzO
AcO
OSiPri3
O
O
O
O
O
O
O
OEE
H
H
10
11
12
viii
H
H
H
OSiPri3
OSiPri3
OSiPri3
O
O
O
x–xii
ix
O
O
O
O
O
O
O
OH
H
H
H
O
15
13
14
OH
xiii, xiv
OMe
H
H
H
H
H
xv–xviii
xiv–xxi
O
MPMO
NC
O
O
O
O
I
O
p-MeOC6H4
J
O
O
O
O
O
O
H
H
H
H
H
17
OMe
OBn
OBn
OBn
OH
OBn
16
18
xxii–xxiv
57
H
H
O
H
H
39
56
O
O
xxviii
xxv–xxvii MPMO
37
41
MPMO
O
I
J
H
45
33
O
O
O
H
H
H
H
43
35
OBn
OBn
OBn
OBn
OBn
OBn
HO
19
20
21
BOM = BnOCH2
EE = EtOC2H4
HO
MPM = p-MeOC6H4CH2
2158E/S2
Scheme 2 Reagents and conditions: i, BnOCH2Cl, Pri2EtN, Bu4NI (cat.), (CH2Cl)2, 40 °C, 99%; ii, K2CO3, MeOH, 99%; iii, 2,2-dimethoxypropane, PPTS
(cat.), MeCN, 85%; iv, Pri3SiOSO2CF2, 2,6-lutidine, (CH2Cl)2, 230 °C, quant.; v, H2, Pd(OH)2–C (cat.), AcOEt, 87%; vi, (CF3SO2)2O, Et3N, (CH2Cl)2,
215 °C; vii, HC·CCH2C2H4OEt 22, BuLi, THF–DMPU (6:1), 278 °C, 78% (2 steps); viii, PPTS (cat.), PrOH; ix, Red-Al, Et2O, 0 °C to room temp., 97%
(2 steps); x, (2)-DET, Ti(OPri)4, ButOOH, molecular sieves 4A, CH2Cl2, 220 °C, 97%; xi, SO3·pyridine, Et3N, DMSO, (CH2Cl)2, 0 °C to room temp.; xii,
Ph3PNCHCO2Me, toluene, 94% (2 steps); xiii, Bu4NF, THF; xiv, Pd(PPh3)4 (cat.), PPh3 (cat.), CH2Cl2, 93% (2 steps); xv, DIBAL-H, CH2Cl2, 278 °C, 98%;
xvi, BnBr, NaH, DMF–THF (1:1), 0 °C, 92%; xvii, p-MeC6H4SO3H·H2O (cat.), MeOH; xviii, p-MeOC6H4CH(OMe)2, PPTS (cat.), (CH2Cl)2, quant. (2
steps); xix, DIBAL-H, CH2Cl2, 240 °C, 97%; xx, MeSO2Cl, Et3N, CH2Cl2, 0 °C, quant.; xxi, NaCN, 18-crown-6 (cat.), DMF, 50 °C, 94%; xxii, DIBAL-H,
CH2Cl2, 260 °C; xxiii, Ph3PNCMeCO2Et, toluene, 98% (2 steps); xxiv, DIBAL-H, CH2Cl2, 278 °C, quant.; xxv, (2)-DET, Ti(OPri)4, ButOOH, molecular
sieves 4A, CH2Cl2, 220 °C, 90%; xxvi, SO3·pyridine, Et3N, DMSO, (CH2Cl)2, 0 °C to room temp.; xxvii, Ph3P+CH3Br2, NaN(SiMe3)2, THF, 0 °C, 83%
(2 steps); xxviii, DDQ, CH2Cl2–H2O (20:1), 88%.
10.5, 5.0 Hz, H36), 3.40 (1 H, ddd, J 10.5, 9.5, 3.6 Hz, H37), 3.46 (1 H, ddd,
J 12.2, 4.6, 3.6 Hz, H34), 3.52 (1 H, ddd, J 11.2, 9.2, 4.7 Hz, H42),
3.56–3.58 (1 H, m, H44), 3.86–3.88 (1 H, m, H45). The relative
stereochemistry was unambiguously determined by NOE experiments.
1,4-benzoquinone (DDQ) in CH2Cl2 and water (20:1) resulted
in cleavage of the MPM ether, and spontaneous cyclization of
the resulting hydroxy epoxide prevailed under the weakly acidic
conditions to afford 21 in 88% yield.§ The overall yield of 21
from 10 was 25% in 28 steps. Thus each step effectively
References
proceeded in good yield (!95% yield).
1 M. Murata, A. M. Legrand, Y. Ishibashi and T. Yasumoto, J. Am. Chem.
Soc., 1989, 111, 8929; M. Murata, A. M. Legrand, Y. Ishibashi,
M. Fukui, and T. Yasumoto, J. Am. Chem. Soc., 1990, 112, 4380.
2 E. Alvarez, M.-L. Candenas, R. Pe´rez, J. L. Ravelo and J. D. Mart´ın,
Chem. Rev., 1995, 95, 1953 and references cited therin; H. Oguri,
S. Hishiyama, T. Oishi and M. Hirama, Synlett, 1995, 1252; H. Oguri,
In conclusion, we have demonstrated that the appropriate
combination of stereoselective pyran formation methodologies
allows us to synthesize the central HIJ ring system of 1 starting
with oxocane 10. Further synthetic studies directed towards 1
are in progress in our laboratory. We thank the Uehara
Memorial Foundation, The Naito Foundation, and the Ministry
of Education, Science and Culture, Japan for financial support.
S. Hishiyama, O. Sato, T. Oishi, M. Hirama, M. Murata, T. Yasumoto
and N. Harada, Tetrahedron, 1997, 53, 3057.
3 Oishi, M. Shoji, K. Maeda, N. Kumahara and M. Hirama, Synlett, 1996,
1165.
4 M. Inoue, M. Sasaki and K. Tachibana, Tetrahedron Lett., 1997, 38,
1611.
5 T. Suzuki, O. Sato and M. Hirama, Tetrahedron Lett., 1990, 31,
4747.
6 K. C. Nicolaou, C. V. C. Prasad, P. K. Somers and C.-K. Hwang, J. Am.
Chem. Soc., 1989, 111, 5330.
7 H. Kotsuki, I. Kadota and M. Ochi, Tetrahedron Lett., 1990, 31,
4609.
8 H. A. Tius and A. H. Faug, J. Am. Chem. Soc., 1986, 108, 1035.
9 S. E. Denmark and T. K. Jones, J. Org. Chem., 1982, 47, 4595.
10 Y. Mori, K. Yaegashi and H. Furukawa, J. Am. Chem. Soc., 1996, 118,
8158.
Footnotes
* E-mail: hirama@ykbsc.chem.tohoku.ac.jp
† Epoxides 2, 5 and 7 were prepared from (2S,3R)-2-ethenyl-3-hydroxy-
tetrahydropyran (ref. 6).
‡ On the other hand, acid-catalysed cyclization (ref. 6) of the 15 gave the
5-exo cyclization product (tetrahydrofuran) exclusively.
§ Representative data for 21: [a]2D522.14 (c 0.35, CHCl3); H NMR (600
1
MHz, CDCl3): d 1.04 (3 H, d, J 7.2 Hz, H57), 1.26 (3 H, s, H56), 1.51 (1
H, ddd, J 13.5, 11.2, 2.7 Hz, H43ax), 1.52 (1 H, ddd, J 14.3, 9.5, 6.2 Hz,
H38ax), 1.59 (1 H, d, J 3.6 Hz, OH), 1.63 (1 H, td, J 12.2, 11.0 Hz, H35ax),
1.74 (1 H, ddd, J 14.4, 10.6, 8.0 Hz, H40ax), 1.84 (1 H, br dd, J 14.3, 3.6
Hz, H38eq), 1.84–1.89 (1 H, m, H39), 1.88 (1 H, br d, J 14.4 Hz, H40eq),
2.12 (1 H, ddd, J 12.2, 5.0, 4.6 Hz, H35eq), 2.28 (1 H, ddd, J 13.5, 4.7, 3.1
Hz, H43eq), 3.20 (1 H, ddd, J 10.6, 9.2, 3.1 Hz, H41), 3.23 (1 H, ddd, J 11.0,
Received in Cambridge, UK, 1st April 1997; Com. 7/02158E
1290
Chem. Commun., 1997