Convergent synthesis of the IJKLM ring fragment of ciguatoxin CTX3C

Article abstract of DOI:10.1039/a906834a

The IJKLM ring fragment of CTX3C, an important member of the ciguatoxin family, was synthesized via ring-closing metathesis using the Tebbe reagent and an improved method of reductive hydroxy ketone cyclization.

Full text of DOI:10.1039/a906834a

Convergent synthesis of the IJKLM ring fragment of ciguatoxin CTX3C
Tohru Oishi, Yoko Nagumo, Mitsuru Shoji, Jean-Yves Le Brazidec, Hisatoshi Uehara 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) 23rd August 1999, Accepted 7th September 1999
The IJKLM ring fragment of CTX3C, an important member
of the ciguatoxin family, was synthesized via ring-closing
metathesis using the Tebbe reagent and an improved method
of reductive hydroxy ketone cyclization.
Precursors of the esters 8 and 9 were synthesized as shown in
Scheme 2. Carboxylic acid 11 and alcohol 12 were prepared
from the I ring moiety 106,7 by the standard procedures.
Synthesis of the carboxylic acid 19 corresponding to the LM
ring moiety of 2 was initiated with 13.8 Hydroboration of 13
using BBN and treatment of the resulting alcohol with CSA
gave spiroacetal 14 in 92% yield. Conventional protecting
group transformation of 14 yielded alcohol 16. Dess–Martin
periodinane oxidation of 16 followed by asymmetric crotylation
using (R,R,Z)-crotylboronate 179 furnished 18 as a single
stereoisomer. Protection of the hydroxy group of 18 as a benzyl
ether and oxidative cleavage of the double bond gave 19 in 95%
yield. Alcohol 20 corresponding to the LM ring moiety of 1 and
3 was synthesized in an analogous manner starting from 15.8
Synthesis of the IJKLM ring fragment was first attempted via
route A (Scheme 3). Condensation of 11 with 20 using DCC
gave 8 in 54% yield, which was treated with the Tebbe reagent
in THF at 60 °C. However, olefination of the carbonyl group of
8 did not proceed, and only the initial material 8 was recovered
even after 6 h.
Ciguatoxin (CTX1B, 1) and its congeners, CTX3C (2) and 3,
are the causative toxins of ciguatera seafood poisoning
prevalent in the tropics and subtropics.1 Although numerous
synthetic studies have been reported because of the striking
structure and biological activity of these compounds, efficient
synthetic methods are still needed for total synthesis. During the
course of our synthetic studies directed toward 1,2 we recently
succeeded in synthesizing the ABCDE ring framework of 1
based on alkylation and ring-closing metathesis (RCM).3 We
describe herein a convergent synthesis of the IJKLM ring
fragment of 2.
Two synthetic routes were envisaged as outlined in Scheme
1. Tebbe reagent mediated transformation4 of ester 8 (or 9) into
cyclic enol ethers 6 (or 7), followed by hydroboration–oxidation
and reductive hydroxy ketone cyclization protocol5 provides the
IJKLM ring system.
The alternative route B was then examined. Coupling of 12
with 19 gave 9 in 74% yield. In contrast to 8, treatment of 9 with
Scheme 2 Reagents and conditions: i, DIBAL-H, CH2Cl2, 278 °C; ii,
NaClO2, NaH2PO4, 2-methylbut-2-ene, ButOH, H2O, 41% (2 steps); iii,
Ph3P+EtBr2, BuLi, THF, 278 °C to room temp., 48% (Z+E = 4+1, 21%
recovery of aldehyde); iv, DDQ, CH2Cl2, H2O, 0 °C, 89%; v, BBN, THF
then NaOH, H2O2, 88%; vi, CSA, CH2Cl2, 92%; vii, TBAF, THF; viii,
ButCOCl, Et3N, CH2Cl2, 0 °C to room temp.; ix, MOMCl, Pri2EtN, CH2Cl2,
0 to 35 °C; x, LiAlH4, Et2O, 0 °C to room temp., 76% (4 steps); xi, Dess–
Martin periodinane, CH2Cl2: xii, 17, toluene, MS4A, 278 to 260 °C, then
NaBH4, 260 to 0 °C, 45% (2 steps, 70% based on recovery of 16); xiii,
NaH, BnBr, THF, DMF, 89%; xiv, OsO4, NMO, ButOH, H2O, then NaIO4,
pH 7 buffer; xv, NaClO2, NaH2PO4, 2-methylbut-2-ene, ButOH, H2O, 95%
(2 steps).
Scheme 1
Chem. Commun., 1999, 2035–2036
This journal is © The Royal Society of Chemistry 1999
2035

ketone cyclization. Further studies directed toward total synthe-
sis of ciguatoxins are currently in progress in our laboratory.
Fellowships to Y. N. and J.-Y. L. B. from the Japanese
Society for the Promotion of Science are gratefully acknowl-
edged.
Notes and references
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Scheme 3 Reagents and conditions: i, DCC, DMAP, CSA, CH2Cl2, 35 °C,
54% (38% recovery of 20); ii, Tebbe reagent, THF, 60 °C, 95% recovery of
8; iii, DCC, DMAP, CSA, CH2Cl2, 35 °C, 74%; iv, Tebbe reagent, THF,
60 °C, 63%; v, BH3, THF, 0 °C then NaOH, H2O2, 0 °C, 73%; vi, Dess–
Martin periodinane, CH2Cl2, 100%; vii DBU, CH2Cl2, room temp., 1 h; viii,
TMSBr, CH2Cl2, 278 to 250 °C, 24: 30%, 25: 30%; ix, CH(OMe)3, CSA,
benzene, 70 to 80 °C, 50%; x, Et3SiH, BF3·OEt2, CH2Cl2, 273 to 0 °C,
71%.
7 The concise route to 10 via RCM has been recently developed: T. Oishi,
M. Kosaka and M. Hirama, unpublished results.
8 T. Oishi, M. Shoji, N. Kumahara and M. Hirama, Chem. Lett., 1997,
845.
the Tebbe reagent at 60 °C resulted in the formation of cyclic
enol ether 7 in 63% yield via methylenation and subsequent
RCM.4 Hydroboration of 7 followed by Dess–Martin period-
inane oxidation gave a separable 3+1 mixture of 22 and 23 in
73% yield. The undesired isomer 22 was effectively converted
to a 1+1 mixture of 22 and 23 by treatment with DBU in CH2Cl2
at room temperature. Removal of the MOM group of 23 with
TMSBr gave keto alcohol 24 (30%) and hemiacetal 25 (30%).
Direct treatment of the mixture of 24 and 25 with Et3SiH–
TMSOTf5 gave no products due to reductive hydroxy ketone
cyclization. However, reduction of the corresponding methyl
acetal3 26, which was prepared from the mixture of 24 and 25,
proceeded stereoselectively using BF3·OEt2 (1.0 equiv.) and
Et3SiH in excess to afford the IJKLM ring fragment 5 in 71%
yield without affecting the spiroacetal LM ring moiety.10 The
stereochemistry of 5 was unambiguously determined by 1H
NMR analysis (NOESY and NOE experiments).11
9 W. R. Roush, K. Ando, D. B. Powers, A. D. Palkowitz and R. L.
Halterman, J. Am. Chem. Soc., 1990, 112, 6339.
10 Excess amount of BF3·OEt2 caused reductive opening of the spiro-
acetal.
11 Selected data for 5: dH (600 MHz, CDCl3) 0.89 (3H, d, J 6.3, Me57),
1.02 (3H, d, J 6.0, Me56), 1.08 (3H, d, J 7.1, Me54), 1.11 (3H, d, J 7.7,
Me55), 1.41 (1H, br q, J 11.7, H40ax), 1.50–1.57 (2H, m, H48, H47),
1.63 (1H, br dt, J 14.2, 10.2, H37), 1.68 (1H, br ddd, J 15.2, 9.5, 6.4,
H35), 1.73–1.81 (2H, m, H51, H50), 1.83–1.88 (1H, m, H37), 1.90–1.98
(4H, m, H50, H36, H35, H51), 2.15 (1H, qdd, J 7.7, 4.6, 3.5, H43), 2.40
(1H, br dt, J 12.0, 4.8, H40eq), 2.87 (1H, dd, J 9.3, 4.6, H42), 3.06 (1H,
br td, J 9.6, 3.0, H38), 3.23 (1H, ddd, J 11.3, 9.0, 4.4, H39), 3.35 (1H,
t, J 9.5, H46), 3.41 (1H, br td, J 9.2, 2.8, H34), 3.43 (1H, br dd, J 3.5,
1.0, H44), 3.44 (1H, dd, J 10.0, 6.5, H32), 3.60 (1H, br ddd, J 9.3, 6.5,
2.1, H33), 3.64 (1H, dd, J 9.5, 1.0, H45), 3.68 (1H, dd, J 10.0, 2.1, H32),
3.75 (1H, br q, J 7.5, H52), 3.82 (1H, ddd, J 11.2, 9.3, 5.0, H41), 3.87
(1H, br td, J 7.8, 4.5, H52), 4.32 (1H, d, J 11.1, CH2Ph), 4.55 (2H, s,
CH2Ph), 4.58 (1H, d, J 11.1, CH2Ph), 4.63 (1H, d, J 12.2, CH2Ph), 4.68
(1H, d, J 12.2, CH2Ph), 7.20–7.40 (15H, m, Ph); MALDI-TOF MS calc.
for C46H60O8Na (M+Na+) 763.4186, found 763.4151.
In conclusion, we have established a highly convergent route
to the IJKLM ring fragment of CTX3C via the Tebbe reagent
mediated ring-closing metathesis and an improved hydroxy
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Chem. Commun., 1999, 2035–2036