Practical entry into the HIJKLM ring segment of ciguatoxin CTX3C

Article abstract of DOI:10.1039/b009506k

The HIJKLM ring segment (27) of the right half portion of ciguatoxin CTX3C (1) has been synthesized using a ring-closing reaction mediated by a low-valent titanium reagent.

Full text of DOI:10.1039/b009506k

Practical entry into the HIJKLM ring segment of ciguatoxin CTX3C
Tohru Oishi,† Hisatoshi Uehara, Yoko Nagumo, Mitsuru Shoji, Jean-Yves Le Brazidec, Masashi Kosaka 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) 27th November 2000, Accepted 18th January 2001
First published as an Advance Article on the web 8th February 2001
The HIJKLM ring segment (27) of the right half portion of
ciguatoxin CTX3C (1) has been synthesized using a ring-
closing reaction mediated by a low-valent titanium rea-
gent.
internal carbenoid species such as 9 (Scheme 2). Thus, we
reasoned that exclusive formation of 9 would improve the yield
of 4 and that 9 could be prepared from the phenylthioacetal 11
using the low-valent titanium complex Cp2Ti[P(OEt)3]2
recently developed by Takeda.12
During the course of our synthetic studies directed toward
ciguatoxins,1,2 we have recently reported the convergent
synthesis of the ABCDE3 and IJKLM4 ring fragment of 1, based
The dithioacetal 11 was synthesized as shown in Scheme 3.
Although we had synthesized the I-ring moiety of 1 based on a
ring-expansion strategy,13 we developed an alternative route
applicable to large-scale synthesis. Aldol reaction of glycolate
1214 with acrolein gave diene 13 as an epimeric mixture of
alcohols (47%), which was separated from other diastereomers
by flash column chromatography (40% combined yield). RCM
reaction of 13 using Grubbs catalyst, (PCy3)2Cl2RuNCHPh,15
proceeded smoothly to give the eight-membered cyclic ether 14
(60%). Reduction of the ester 14 followed by selective
protection of the resulting primary alcohol as TBDPS ether, and
Swern oxidation of the secondary alcohol gave the enone 15 (3
steps, 68%). Stereoselective introduction of the secondary
methyl group was successfully achieved by conjugate addition
with Me2Cu(CN)Li2 to afford 16 in 74% yield. Removal of the
TBDPS group of 16 using TBAF in the presence of AcOH, and
reduction of the resulting hydroxy ketone with NaBH(OAc)3
gave the diol 17 as a single isomer (92%).16 Bis-benzylation,
acetal hydrolysis followed by a two step cyanation sequence
yielded the nitrile 18 (46% overall yield). Protection, DIBAL-H
reduction and thioacetalization gave the dithioacetal 19 (3 steps,
73%), which was condensed with the carboxylic acid 204 to
afford 11 (58%). Ring-closing reaction of 11 was then
examined. A THF solution of 11 was added to excess Takeda
reagent (Cp2Ti[P(OEt)3]2)12 at rt and then refluxed under an
argon atmosphere for 1 h. Using this protocol, the cyclic enol
ether was formed reproducibly in 52–67% yield even on a one
or two gram scale, while reduction and elimination products of
the phenylthio group, 21 and 22, respectively, were only
produced in minor amount, ca. 10% combined yield.
upon an alkylation-ring closing metathesis (RCM) strategy5,6
and a Tebbe reagent (3)7 mediated ester olefination-ring closing
metathesis sequence,8 respectively. Occasionally, however, the
key transformation of 2 into 4 in the latter sequence turned out
to be non-reproducible. The yield of 4 fluctuated between trace
amount to 63% and concomitant formation of an inseparable
mixture of enol ethers, 5, 6, and 7 tended to occur (Scheme 1).
Unfortunately, irrespective of extensive investigation, secure
conditions to yield 4 uniformly could not be found. At low
conversions 5 sometimes predominated, while 6 and then 7
gradually increased as the reaction time was extended. Since the
intermediacy of the diene 5 in the formation of 4 was
conceivable,8 mixtures which contained 5 as the major product
were treated with 3 or the Schrock catalyst, 2,6-(iPr)2C6H3-
NNMo[OC(CF3)2Me]2NCHCMe2Ph.9–11 However, in remark-
able contrast to literature precedent, 4 was not produced in
appreciable amounts; instead 6 and 7 increased.8 Steric
hindrance around the diene system of 5 is likely to account for
this unexpected failure of converting 5 into 4. Mechanistically,
there should exist an alternative pathway (2 " 8 " 9 " 10 "
4) to provide 4, in which the ester carbonyl group reacts with an
Scheme 1
† Present address: Department of Chemistry, Graduate School of Science,
Osaka University, Osaka 560-0043, Japan.
Scheme 2
DOI: 10.1039/b009506k
Chem. Commun., 2001, 381–382
This journal is © The Royal Society of Chemistry 2001
381

Fig. 1 ORTEP drawing of bis-p-bromobenzoate 25.
Notes and references
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34, 1975; M. Satake, A. Morohashi, H. Oguri, T. Oishi, M. Hirama, N.
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Satake, M. Fukui, A. M. Legrand, P. Cruchet and T. Yasumoto,
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2 T. Suzuki, O. Sato, M. Hirama, Y. Yamamoto, M. Murata, T. Yasumoto
and N. Harada, Tetrahedron Lett., 1991, 32, 4505; H. Oguri, S.
Hishiyama, T. Oishi and M.Hirama, Synlett, 1995, 1252; H. Oguri, S.
Hishiyama, O. Sato, T. Oishi, M. Hirama, M. Murata, T. Yasumoto and
N. Harada, Tetrahedron, 1997, 53, 3057; T. Oishi, M. Shoji, N.
Kumahara and M. Hirama, Chem. Lett., 1997, 845; T. Oishi, Y. Nagumo
and M. Hirama, Synlett, 1997, 980; H. Oguri, S. Sasaki, T. Oishi and M.
Hirama, Tetrahedron Lett., 1999, 40, 5405; H. Oguri, S. Tanaka, S.
Hishiyama, T. Oishi, M. Hirama, T. Tumuraya, Y. Tomioka and M.
Mizugaki, Synthesis, 1999, 1431; H. Oguri, S. Tanaka, T. Oishi and M.
Hirama, Tetrahedron Lett., 2000, 41, 975; K. Maeda, T. Oishi, H. Oguri
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studies of other groups, see: M. Sasaki, H. Fuwa, M. Ishikawa and K.
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Scheme 3 Reagents and conditions: i, LDA, acrolein, THF, 278 °C, 10
min, separation, 47%; ii, (PCy3)2Cl2RuNCHPh (10 mol%), CH2Cl2 (0.01
M), reflux, 24 h, 60%; iii, LAlH, THF, 0 °C to rt, 5 h, 98%; iv, TBDPSCl,
Et3N, DMAP, CH2Cl2, rt, 16 h, 88%; v, (COCl)2, DMSO, Et3N, CH2Cl2,
260 °C, 30 min, 79%; vi, Me2Cu(CN)Li2, Et2O, 278 °C, 30 min, 74%; vii,
TBAF, AcOH, THF, rt, 5 h, 95%; viii, NaBH(OAc)3, AcOH, CH3CN,
220 °C, 2 h, 97%; ix, BnBr, NaH, THF, DMF, 0 °C to rt, 20 h; x,
TsOH·H2O, MeOH, H2O, rt, 1 d, 68%; xi, I2, PPh3, imidazole, THF, 0 °C
to rt, 1 d, 87%; xii, NaCN, DMSO, 40 °C, 2 d, 78%; xiii, TESOTf,
2,6-lutidine, CH2Cl2, 230 to 220 °C, 15 min, quant.; xiv, DIBAL-H,
CH2Cl2, 270 to 260 °C, 1 h; xv, PhSSPh, Bu3P, benzene, rt, 12 h, 73% (2
steps); xvi, TBAF, THF, rt, 3 h, 95%; xvii, EDC·HCl, DMAP, CH2Cl2, rt,
12 h, 58%; xviii, Cp2Ti[P(OEt)3]2 (3 or 4 eq.), THF, reflux, 1 h, 4: 52–67%,
21, 22: ~ 10%.
3 M. Maruyama, K. Maeda, T. Oishi, H. Oguri and M. Hirama,
Heterocycles, 2001, 54, 93.
4 T. Oishi, Y. Nagumo, M. Shoji, J.-Y. Le Brazidec, H. Uehara and M.
Hirama, Chem. Commun., 1999, 2035.
5 T. Oishi, Y. Nagumo and M. Hirama, Chem. Commun., 1998, 1041.
6 Recent reviews on ring-closing metathesis reactions, see: S. K.
Armstrong, J. Chem. Soc., Perkin Trans. 1, 1998, 371; R. H. Grubbs and
S. Chang, Tetrahedron, 1998, 54, 4413.
7 S. H. Pine, R. Zahler, D. A. Evans and R. H. Grubbs, J. Am. Chem. Soc.,
1980, 102, 3270.
8 K. C. Nicolaou, M. H. D. Postema and C. F. Claiborne, J. Am. Chem.
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9 R. R. Schrock, J. S. Murdzek, G. C. Bazan, J. Robbins, M. DiMare and
M. O’Regan, J. Am. Chem. Soc., 1990, 112, 3875.
10 J. S. Clark and J. G. Kettle, Tetrahedron Lett., 1997, 38, 123; J. S. Clark
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Kettle, Tetrahedron, 1999, 55, 8231.
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Tetrahedron, 2000, 56, 763.
Scheme 4 Reagents and conditions: i, H2, Pd(OH)2/C, EtOAc, MeOH, rt,
1 d; ii, p-MeOC6H4CH(OMe)2, CSA, CH2Cl2, rt, 30 min, 89% (2 steps); iii,
BOMCl, iPr2NEt, (CH2Cl)2, 40 °C, 12 h, 88%; iv, DIBAL-H, CH2Cl2, 280
to 230 °C, 2 h, 85%; v, MsCl, Et3N, (CH2Cl)2, 0 °C, 40 min; vi, NaCN,
18-crown-6, DMF, 50 °C, 3 d, 98% (2 steps); vii, DIBAL-H, CH2Cl2, 280
to 270 °C, 30 min; viii, Ph3PNC(Me)CO2Et, toluene, rt, 3 h, 84% (2 steps);
ix, DIBAL-H, CH2Cl2, 270 °C, 20 min, 94%; x,
-(2)-DET, Ti(OiPr)4,
D
ButOOH, MS4A, CH2Cl2, 250 to 230 °C, 2 h, 80%; xi, SO3·Py, Et3N,
CH2Cl2, 0 °C to rt, 2 h; xii, Ph3P+CH3Br2, NaHMDS, THF, 0 °C, 20 min,
96% (2 steps); xiii, DDQ, H2O, CH2Cl2, rt, 2 h, 82%.
13 T. Oishi, M. Shoji, K. Maeda, N. Kumahara and M. Hirama, Synlett,
1996, 1165; T. Oishi, M. Maruyama, M. Shoji, K. Maeda, N. Kumahara,
S. Tanaka and M. Hirama, Tetrahedron, 1999, 55, 7471.
14 The glycolate 12 was prepared from D-2-deoxyribose in 3 steps by
The enol ether 4 was converted to the IJKLM-ring fragment
23 according to our previously reported procedure (Scheme 4).4
The stereochemistry of 23 was unambiguously determined by
X-ray crystallography of the corresponding bis-p-bromo-
benzoate 25 (Fig. 1).17 Furthermore, the H-ring moiety was
successfully constructed in 23 in a similar manner to our
previously established route18 in 32% overall yield utilizing
acid catalyzed vinylepoxide–alcohol cyclization methodol-
ogy.19
In short, a practical synthetic route to the HIJKLM ring
fragment 27 has been establised. Further studies directed
towards the total synthesis of ciguatoxin CTX3C (1) are
currently in progress in our laboratory.
standard procedures.
15 G. C. Fu, S. T. Nguyen and R. H. Grubbs, J. Am. Chem. Soc., 1993, 115,
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1996, 118, 100.
16 D. A. Evans, K. T. Chapman and E. M. Carreira, J. Am. Chem. Soc.,
1988, 110, 3560.
17 Crystal data: C39H48O10Br2, M = 836.61, orthorhombic, space group
P212121, Dc = 1.440 g cm23, Z = 4, a = 5.5284(3), b = 25.006(2), c
= 27.913(2) Å, V = 3858.7(4) Å3, F(000) = 1728, m(Mo-Ka) = 21,63
cm21, R = 0.053, Rw = 0.152. CCDC 154471. See http://www.rsc.org/
suppdata/cc/b0/b009506k/ for crystallographic files in .cif format.
18 T. Oishi, K. Maeda and M. Hirama, Chem. Commun., 1997, 1289.
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Chem. Soc., 1989, 111, 5330.
382
Chem. Commun., 2001, 381–382