Convergent synthesis of an HIJK ring model of ciguatoxin via Suzuki cross-coupling reaction

Article abstract of DOI:10.1016/S0040-4039(99)02307-2

Convergent synthesis of HIJK ring model compound 1 of ciguatoxin is described. The present synthesis relied on a palladium-catalyzed Suzuki cross-coupling reaction between eight-membered ketene acetal phosphate 2 and seven-membered alkylborane 6. (C) 2000

Full text of DOI:10.1016/S0040-4039(99)02307-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1425–1428
Convergent synthesis of an HIJK ring model of ciguatoxin via
Suzuki cross-coupling reaction
Makoto Sasaki,∗ Katsuhiko Noguchi, Haruhiko Fuwa and Kazuo Tachibana
Department of Chemistry, School of Science, The University of Tokyo CREST, Japan Science and Technology Corporation
(JST), Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 4 November 1999; revised 29 November 1999; accepted 3 December 1999
Abstract
Convergent synthesis of HIJK ring model compound 1 of ciguatoxin is described. The present synthesis relied
on a palladium-catalyzed Suzuki cross-coupling reaction between eight-membered ketene acetal phosphate 2 and
seven-membered alkylborane 6. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: coupling reactions; polyethers; Suzuki reactions; toxins.
Marine polycyclic ethers, such as brevetoxins, ciguatoxins, and maitotoxin, present formidable and
challenging synthetic targets due to their structural complexity and exceptionally potent biological
activities.1 One most critical issue in the synthesis of these large natural products is the development
of synthetic methodology for convergent coupling of polyether fragments.2,3 In connection with our
synthetic studies on ciguatoxin and its congeners,4 we have recently developed a new strategy for
convergent synthesis of the polyether framework based on Suzuki cross-coupling of alkylboranes with
cyclic ketene acetal triflates4f and phosphates.4i In these previous reports we utilized only six-membered
rings as the alkylborane coupling partners. The use of medium-sized alkylboranes will pave the way for
a general entry to the convergent assembly of polyether natural products. In this communication, we
describe a convergent and stereoselective synthesis of the HIJK ring model 1 of ciguatoxins via cross-
coupling of a seven-membered alkylborane with an eight-membered ketene acetal phosphate.
∗
Corresponding author. Tel: +81-3-5841-4357; fax: +81-3-5841-8380; e-mail: msasaki@chem.s.u-tokyo.ac.jp (M. Sasaki)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02307-2
tetl 16235

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Tetracyclic ether 1 was chosen as an appropriate target to model the synthesis of the HIJK ring system
of ciguatoxins. We envisioned that compound 1 could be prepared from ketene acetal phosphate 2 and
alkylborane derived from exo-olefin 3 (Scheme 1).
Scheme 1.
Ketene acetal phosphate 2 was prepared from the corresponding lactone5 following the procedure of
Nicolaou et al.6 Synthesis of seven-membered exo-olefin 3 began with the known alcohol 47 (Scheme 2).
Protection of 4 as its TBS ether and oxidative cleavage of the double bond followed by NaBH4 reduction
of the resultant aldehyde provided alcohol 5. Iodination of 5 followed by treatment with KOt-Bu afforded
3.
Scheme 2. Reagents and conditions: (a) TBSCl, imidazole, DMF, rt, 73%; (b) OsO4, NMO, acetone:H2O (4:1), rt, then NaIO4,
rt; (c) NaBH4, MeOH, 0°C, 95% (two steps); (d) I2, Ph3P, imidazole, benzene, rt; (e) KOt-Bu, THF, 0°C, 96% (two steps)
Hydroboration of seven-membered exo-olefin 3 with 9-BBN (2.6 equiv., THF) proceeded stereo-
selectively to give the corresponding 9-alkyl-9-BBN 6,8 which was sequentially treated with 1 M
aqueous NaHCO3 (3 equiv.), ketene acetal phosphate 2 (2 equiv.), and Pd(PPh3)4 (0.1 equiv.) in DMF
at 50°C for 20 h to provide cross-coupled product 7 in 86% yield. Stereoselective hydroboration of 7
using thexylborane followed by oxidative workup and further oxidation of the resulting alcohol with
TPAP/NMO9 gave ketone 8. The stereochemistry of 8 was determined by NOE experiments.
The C39 methyl group10 was then installed by 1,4-addition of Me2CuLi to enone 9 (Scheme 3). Thus,
ketone 8 was converted to enone 9 using the Ito–Saegusa protocol.11 Reaction of 9 with Me2CuLi
proceeded in a stereoselective manner to give the desired methylated product 10. The stereochemistry
of the methyl group was confirmed by a prominent NOE between 37-H and 39-H. Treatment of 10
with camphorsulfonic acid (CSA) in MeOH effected removal of the silyl and benzylidene acetal groups
and concomitant methyl acetal formation giving a dihydroxy methyl acetal, which was protected as its
diacetate 11. Finally, treatment of 11 with Et3SiH–BF3·OEt2 led to the desired HIJK ring model 1 as a
single stereoisomer in 90% yield.12

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Scheme 3. Reagents and conditions: (a) 9-BBN, THF, rt, then 1 M NaHCO3, 2, Pd(PPh3)4, DMF, 50°C, 86%; (b) thexylborane,
THF, 0°C, H2O2, NaOH, rt, 75%; (c) TPAP, NMO, 4 Å MS, CH2Cl2, rt, quant.; (d) LiHMDS, TMSCl, Et3N, THF, −78°C; (e)
Pd(OAc)2, CH3CN, 60°C, 77% (two steps); (f) Me2CuLi, Et2O, −20°C, 71%; (g) p-TsOH, MeOH, rt, 98%; (h) Ac2O, DMAP,
CH2Cl2, 0°C, 97%; (i) Et3SiH–BF·OEt2, CH2Cl2–CH3CN (1:1), 0°C, 90%
In conclusion, the described synthesis demonstrated the potential of the Suzuki cross-coupling protocol
for a general entry to the convergent synthesis of polyether compounds. Further studies toward the total
synthesis of ciguatoxins and related natural products based on the present strategy are currently underway
and will be reported in due course.
References
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12. The newly generated stereocenter at C41 was unambiguously determined by spin–spin coupling constant, J41-H,42-H=9.2
Hz. Selected data for compound 1: 1H NMR (500 MHz, C6D6) δ 5.09 (1H, m, 48-H), 4.20 (1H, d, J=11.6, 6.4 Hz, 50-H),
4.12 (1H, dd, J=11.6, 4.6 Hz, 50-H), 3.77 (1H, ddd, J=6.4, 4.7, 4.6 Hz, 49-H), 3.69 (1H, m, 33-H), 3.09 (1H, ddd, J=11.0,
9.2, 4.6 Hz, 42-H), 3.08–2.84 (6H, m), 2.27 (1H, ddd, J=12.2, 4.6, 4.6 Hz, 43-H), 2.02–1.95 (2H, m), 1.90–1.74 (5H, m),
1.72–1.50 (3H, m), 1.70 (3H, s, Ac), 1.63 (3H, Ac), 1.49–1.22 (4H, m), 0.96 (1H, d, J=7.3 Hz, 39-Me); HRMS (FAB) calcd
for C23H36O8Na [(M+Na)+]: 463.2308; found: 463.2309.