Synthetic studies on ciguatoxin: A highly convergent synthesis of the GHIJKLM ring system based on b-alkyl suzuki coupling

Article abstract of DOI:10.1002/1521-3773(20010316)40:6<1090::AID-ANIE10900>3.0.CO;2-W

Access to polycyclic polyethers is facilitated by a synthetic strategy involving two-step B-alkyl Suzuki coupling reactions for the stereo-selective construction of the polyether skeleton. Thus, a convergent synthetic route to the heptacyclic GHIJKLM ring system 1 of ciguatoxin, a marine algal toxin implicated in ciguatera fish poisoning, was developed. Bn = benzyl.

Full text of DOI:10.1002/1521-3773(20010316)40:6<1090::AID-ANIE10900>3.0.CO;2-W

COMMUNICATIONS
synthetic studies by us[4] and others[5, 6] have been reported.
Recently, we developed a powerful strategy for the conver-
gent assembly of a polyether structure based on B-alkyl
Suzuki coupling.[7±9] Here we describe the application of this
strategy to a more highly functionalized system, which led to a
convergent synthesis of the GHIJKLM ring fragment 2 of
ciguatoxin.
[9] L. F. Lindoy, The Chemistry of Macrocyclic Ligand Complexes,
Cambridge University Press, Cambridge, 1989.
[10] P. V. Bernhardt, G. A. Lawrance, Coord. Chem. Rev. 1990, 104, 297.
[11] M. Meyer, V. Dahaoui-Gindrey, C. Lecomte, R. Guilard, Coord.
Chem. Rev. 1998, 180, 1313 ± 1405.
[12] G. Cerveau, R. J. P. Corriu, E. Framery, Chem. Commun. 1999, 2081.
[13] a) G. Cerveau, R. J. P. Corriu, C. Fischmeister-Lepeytre, J. Mater.
Chem. 1999, 9, 1149; b) G. Cerveau, R. J. P. Corriu, C. Fischmeister-
Lepeytre, H. Mutin, J. Mater. Chem. 1998, 8, 2707.
Â
[14] R. J. P. Corriu, J. J. E. Moreau, P. Thepot, M. Wong Chi Man, C.
Á
Chorro, J. P. Lere-Porte, J. L. Sauvajol, Chem. Mater. 1994, 6, 640.
Me
Â
[15] R. J. P. Corriu, J. J. E. Moreau, P. Thepot, M. Wong Chi Man, Chem.
Me
H
H
H
H
H
OH
H
Mater. 1996, 8, 100.
[16] G. Dubois, R. J. P. Corriu, C. Reye, S. Brandes, F. Denat, R. Guilard,
Chem. Commun. 1999, 2283.
[17] C. Gros, F. Rabiet, F. Denat, S. Brandes, H. Chollet, R. Guilard, J.
Chem. Soc. Dalton Trans. 1996, 1209.
[18] a) C. Chuit, R. J. P. Corriu, G. Dubois, C. Reye, Chem. Commun. 1999,
723; b) G. Dubois, C. Reye, R. J. P. Corriu, C. Chuit, J. Mater. Chem.
2000, 10, 1091.
[19] R. M. Izatt, K. Pawlak, J. S. Bradshaw, R. L. Bruening, Chem. Rev.
1995, 95, 2529.
[20] E. Lindner, M. Kemmler, T. Schneller, H. A. Mayer, Inorg. Chem.
1995, 34, 5489.
O
I
HO
F
Me
G
O
J
Â
Á
K
H
O
L
O
O
M
H
O
H
H
H
O
Á
H
H
O
H
Me
H
H
H
H
H
H
OH
H
Me
O
O
B
E
Â
Me
A
C
O
D
O
Â
H
O
H
H
Me
K
BnO
H
H
O
Me
OH
O
I
OBn
H
J
H
HO
O
OH
G
1: ciguatoxin (CTX1B)
H
H
O
O
H
O
BnO
H
O
H
L
M
2
Me
OBn
Me
[21] E. Lindner, T. Schneller, H. A. Mayer, H. Bertagnolli, T. S. Ertel, W.
Hörner, Chem. Mater. 1997, 9, 1524.
BnO
[22] T. D. Smith, A. E. Martell, J. Am. Chem. Soc. 1972, 94, 4123.
Á
[23] S. Brandes, C. Gros, F. Denat, P. Pullumbi, R. Guilard, Bull. Soc.
Synthesis of exo-olefin 9, corresponding to the G ring,
Chim. Fr. 1996, 133, 65.
started with methyl a-d-mannopyranoside (3), which was
converted into 4 by a four-step sequence including benzyl-
idene acetal formation, regioselective tin-mediated benzyla-
tion of the equatorial alcohol,[10] and Barton deoxygenation of
the remaining hydroxy group[11] (Scheme 1). Compound 4 was
treated with 1,3-propanedithiol in the presence of concen-
[24] M. Lachkar, R. Guilard, A. Atmani, A. De Cian, J. Fisher, R. Weiss,
Inorg. Chem. 1998, 37, 1575.
[25] S. S. Eaton, K. M. More, B. M. Sawant, G. R. Eaton, J. Am. Chem. Soc.
1983, 105, 6560.
[26] S. S. Eaton, G. R. Eaton, C. K. Chang, J. Am. Chem. Soc. 1985, 107,
3177.
OBn
OH
O
Ph
HO
OH
e,f
a-d
OH
O
MeO
O
MeO
O
Synthetic Studies on Ciguatoxin: A Highly
Convergent Synthesis of the GHIJKLM Ring
System Based on B-Alkyl Suzuki Coupling
H
H
3
4
S
OBn
OBn
O
Ph
OHC
O
Ph
Hiroyuki Takakura, Katsuhiko Noguchi,
Makoto Sasaki,* and Kazuo Tachibana
i,j
g,h
S
O
MeO
O
2C
HO
O
6
5
Ciguatoxin (CTX1B, 1) and its congeners, naturally occur-
ring polycyclic ethers originating from marine unicellular
algae, are the principal toxins associated with ciguatera fish
poisoning.[1, 2] These potent neurotoxins reportedly bind to the
same site of voltage-sensitive sodium channels as brevetoxins,
another class of structurally related marine toxins.[3] Their
structural complexity and exceptionally potent neurotoxicity,
as well as their limited availability from natural sources, have
attracted the interest of synthetic chemists, and a number of
OBn
OBn
H
O
Ph
OTBS
l-p
RO
BnO
G
O
O
O
H
H
H
BnO
RO
9
7: R = H
8: R = Bn
k
Scheme 1. Synthesis of the G ring exo-olefin 9. a) PhCH(OMe)2, CSA,
DMF, RT; b) nBu2SnO, benzene, reflux, then CsF, BnBr, DMF, RT;
c) NaH, CS2, MeI, THF, RT; d) nBu3SnH, AIBN, benzene, reflux, 24% (4
steps); e) HS(CH2)3SH, conc. HCl, CHCl3, RT; f) PhCH(OMe)2, CSA,
CH2Cl2, RT, 46% (2 steps); g) methyl propiolate, NMM, CH2Cl2, RT, 97%:
h) MeI, NaHCO3, MeCN/H2O, RT, 98%; i) SmI2, MeOH, THF/HMPA,
08C; j) LiAlH4, THF, RT, 72% (2 steps): k) NaH, BnBr, DMF, RT, 84%;
l) CSA, MeOH, RT, 89%; m) TBSOTf, 2,6-lutidine, CH2Cl2, RT; n) CSA,
MeOH, 08C, 89% (2 steps); o) I2, PPh3, imidazole, THF, RT, p) tBuOK,
THF, RT, 85% (2 steps). AIBN ˆ 2,2'-azobisisobutyronitrile, Bn ˆ benzyl,
CSA ˆ camphorsulfonic acid, DMF ˆ N,N-dimethylformamide, HMPA ˆ
hexamethylphosphoric triamide, NMM ˆ N-methylmorpholine, OTf ˆ tri-
fluoromethanesulfonate, TBS ˆ tert-butyldimethylsilyl, THF ˆ tetrahydro-
furan.
[*] Dr. M. Sasaki, Dr. H. Takakura, K. Noguchi, Prof. Dr. K. Tachibana
Department of Chemistry, Graduate School of Science
The University of Tokyo
and
CREST, Japan Science and Technology Corporation (JST)
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax : (‡81)3-5841-8380
E-mail: msasaki@chem.s.u-tokyo.ac.jp
Supporting information for this article is available on the WWW under
http://www.angewandte.com or from the author.
1090
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4006-1090 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 6

COMMUNICATIONS
Me
Me
Me
trated HCl, and the resulting dithiane triol was protected as
the benzylidene acetal 5. Alcohol 5 was converted to the
corresponding b-alkoxyacrylate, which on treatment with
methyl iodide gave aldehyde 6 in 95% yield for the two
steps. SmI2-mediated reductive cyclization[12] of 6 in the
presence of HMPA led to stereoselective formation of a
seven-membered ether ring. Reduction of the unpurified
product thus obtained with LiAlH4 provided diol 7 as a single
isomer in 72% yield for the two steps, which was then
benzylated to give 8. Removal of the benzylidene acetal was
followed by silylation to give a bis-silyl ether. Selective
removal of the primary TBS group followed by iodination of
the resulting alcohol and subsequent treatment with a base
completed the synthesis of the desired exo-olefin 9 (56%
overall yield from 7).
h,i
a-d
e
OR1
OR2
OH
HO
O
OH
12: R1 = Bz, R2 = H
10
14
11
f,g
13: R1 R2 = PhCH
Me
Me
Me
j
k
H
H
H
O
I
HO2C
HO
O
O
O
(PhO)2PO
O
O
O
H
H
Ph
Ph
Ph
O
O
O
15
16
Scheme 2. Synthesis of the I ring enol phosphate 16. a) SO3 ´ pyridine,
Et3N, CH2Cl2, DMSO, 08C; b) Ph3P CHCO2Me, benzene, RT; c) DI-
ˆ
BALH, CH2Cl2, 788C, 86% (3 steps); d) tBuOOH, ( )-DET, Ti(OiPr)4,
4-Š molecular sieves, CH2Cl2, 208C, 92%; e) PhCO2NH4, Ti(OiPr)4,
CH2Cl2, RT, then 5% aqueous H2SO4, 70%; f) KOH, MeOH, RT, 81%;
g) PhCH(OMe)2, CSA, CH2Cl2, RT, 61%; h) OsO4, NMO, acetone/H2O,
RT, then NaIO4, 70%; i) NaClO2, KH2PO4, 2-methyl-2-butene, tBuOH/
H2O, RT, 95%; j) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, then DMAP,
benzene, reflux, 83%; k) KHMDS, (PhO)2P(O)Cl, THF/HMPA, 788C,
95%. DMSO ˆ dimethyl sulfoxide, DIBALH ˆ diisobutylaluminum hy-
dride, DETˆ diethyl tartrate, DMAP ˆ 4-dimethylaminopyridine,
KHMDS ˆ potassium hexamethyldisilazide, NMO ˆ N-methylmorpholine
N-oxide.
Construction of enol phosphate 16, representing the I ring,
began with (S)-( )-citronellol (10; Scheme 2). Oxidation with
SO3 ´ pyridine followed by Wittig reaction gave the homolo-
gated a,b-unsaturated ester, which was subjected to DIBALH
reduction and subsequent asymmetric epoxidation to afford
epoxy alcohol 11 in 79% overall yield. Regioselective opening
[13]
of the epoxide ring with ammonium benzoate and Ti(OiPr)4
gave 1,2-diol 12 in 70% yield as the only isomer detectable by
1H NMR spectroscopy (500 MHz). Methanolysis of the
benzoyl group followed by selective protection of the 1,3-diol
as the benzylidene acetal yielded alcohol 13 in 49% yield for
the two steps. Oxidative cleavage of the double bond and
subsequent oxidation of the resultant aldehyde with sodium
chlorite provided hydroxy acid 14 in 66% overall yield.
Lactonization of 14 under Yamaguchi conditions[14] gave
eight-membered lactone 15 (83%), which was readily con-
verted into enol phosphate 16 by the procedure of Nicolaou
et al.[15]
Hydroboration of 9 with 9-BBN and treatment of the
resultant alkylborane with enol phosphate 16 under the
previously reported conditions[7b] afforded cross-coupled
product 17 in high yield (Scheme 3). Hydroboration of 17
with BH3 ´ THF under various conditions provided the desired
alcohol 18 in only low yield, presumably due to the steric
hindrance of the methyl group on the eight-membered ring.
We eventually solved the problem in the following manner:
Epoxidation of 17 with 3,3-dimethyldioxirane[16] proceeded
stereoselectively to yield the corresponding a-epoxide, which
was immediately reduced with Et3SiH in the presence of
BH3 ´ THF to deliver 18 as the only isolable product in 60%
yield for the two steps. Protection of the secondary alcohol as
the p-methoxybenzyl ether, desilylation followed by oxidation
of the resultant alcohol with TPAP/NMO,[17] and oxidative
removal of the PMB group with DDQ provided hemiketal 19
as a single stereoisomer. Exposure of 19 to EtSH and
Zn(OTf)2 effected formation of the mixed thioketal and
removal of the benzylidene group to give a diol. In situ
acetylation of the diol was followed by thiol oxidation to yield
Me
OBn
OH
Me
Me
OBn
BnO
TBS
O
OTBS
HO
H
H
O
H
H
H
d-g
b,c
a
BnO
BnO
BnO
9
O
O
O
O
O
O
H
O
H
O
H
O
H
H
H
H
H
H
H
H
Ph
Ph
Ph
O
O
O
18
19
17
BnO
BnO
BnO
OBn
X
Me
Me
BnO
G
H
Me
H
O
O
H
: NOE
37
h,i
l-o
BnO
I
BnO
36
OR
OR
OTBS
O
J36,37 = 9.3 Hz
O
H
O
H
O
H
H
H
H
BnO
BnO
20: X = SO2Ph, R = Ac
21: X = Me, R = H
22
j,k
Scheme 3. Synthesis of the GHI ring system 22. a) 9-BBN, THF, RT, then 1m aqueous NaHCO3, 16, [Pd(PPh3)4], DMF, 508C, 85% based on 16; b) DMDO,
acetone, 78 ! 208C; c) Et3SiH, BH3 ´ THF, CH2Cl2, 208C, 60% (2 steps); d) tBuOK, PMBCl, nBu4NI, THF, RT, 80%; e) TBAF, THF, RT, 97%;
f) TPAP, NMO, 4-Š molecular sieves, CH2Cl2, RT, quant.; g) DDQ, CH2Cl2/pH 7 phosphate buffer (10/1), RT; h) EtSH, Zn(OTf)2, CH2Cl2, RT, then Ac2O,
DMAP, Et3N, 0 8C, 84% (3 steps); i) mCPBA, CH2Cl2, RT, 96%; j) Me3Al, CH2Cl2, 78 !08C; k) K2CO3, MeOH, RT, 83% (2 steps); l) TBSOTf, 2,6-
lutidine, CH2Cl2, RT; m) CSA, MeOH/CH2Cl2 (1/1), 08C, 84% (2 steps); n) I2, PPh3, imidazole, THF, RT, 94%; o) tBuOK, THF, 08C, 87%. 9-BBN ˆ 9-
borabicyclononane, DDQ ˆ 2,3-dichloro-5,6-dicyanobenzo-1,4-quinone, DMDO ˆ 3,3-dimethyldioxirane, mCPBA ˆ m-chloroperbenzoic acid, PMB ˆ p-
methoxybenzyl, TBAF ˆ tetra-n-butylammonium fluoride, TPAP ˆ tetrapropylammonium perruthenate.
Angew. Chem. Int. Ed. 2001, 40, No. 6
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1433-7851/01/4006-1091 $ 17.50+.50/0
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COMMUNICATIONS
[20]
sulfone 20 in 62% overall yield from 18. Reaction of 20 with
Me3Al[7d, 18] provided the desired methylated compound along
with the product of its monodeacetylation at the primary
position. Methanolysis of this mixture gave diol 21 in 83%
yield for the two steps. Straightforward protecting and
functional group manipulations transformed 21 into the
requisite exo-olefin 22. The configuration of 22 was unambig-
uously determined by the coupling constant J36,37 ˆ 9.3 Hz and
NOE experiments, as shown in Scheme 3.
Synthesis of the KLM ring enol phosphate 34a is summar-
ized in Scheme 4. Bicyclic lactone 23[4d] was transformed into
nitrile 25 via bis-tosylate 24 in a six-step sequence. Reduction
of 25 with DIBALH followed by removal of the TES group
with acid gave the corresponding hemiacetal, which was then
oxidized with TPAP/NMO to give lactone 26 in 78% yield for
the three steps. Methylation of the lithium enolate derived
from 26 led exclusively to methylated lactone 27 in 82% yield.
Construction of the spiroketal M ring was accomplished by
asymmetric dihydroxylation with Coreyꢁs ligand[19] by follow-
ing the previously reported method.[4d] Treatment of tricyclic
29 with Me2S and BF3 ´ OEt2 effected selective cleavage of
the methyl acetal portion to give a hemiacetal, which was
subjected to Wittig methylenation and protection of the
resulting alcohol as the TES ether to give olefin 30 in 73%
overall yield. Hydroboration with 9-BBN followed by oxida-
tive workup provided alcohol 31 (98%), which was oxidized
in a two-step procedure to give, after desilylation, hydroxy
acid 32 in 55% overall yield. Lactonization of 32 according to
the Yamaguchi protocol yielded seven-membered lactone 33
(93%), which could be easily converted to enol phosphate
34a in 87% yield.
With the required coupling partners 22 and 34a in hand, we
next investigated the crucial coupling reaction. However,
phosphate 34a proved to be a poor substrate for B-alkyl
Suzuki coupling. Attempted coupling of the alkylborane
derived from 22 with 34a (aqueous 1m NaHCO3, [Pd(PPh3)4],
DMF, rt !508C) gave a trace of the desired coupled product
35, and unconsumed phosphate 34a could be recovered. After
extensive investigation, it was discovered that the crucial
B-alkyl Suzuki coupling could be accomplished by using the
more reactive enol triflate 34b, which was prepared from 33
(Scheme 4). The alkylborane derived from 22 was coupled in
situ with 34b[7a] to furnish the desired 35 in 71% yield based
on 34b (Scheme 5). Hydroboration of 35 with BH3 ´ THF
followed by oxidation led to alcohol 36 as a single stereo-
OBn
H
OBn
OBn
H
Me
Me
OR
Me
O
O
R
O
g-i
a-c
O
MeO
O
MeO
O
X
MeO
O
H
H
H
Me
Me
Me
24: R = Ts, X = OTs
25: R = TES, X = CN
23
26: R = H
27: R = Me
d-f
j
Me
TBS
OBn
OBn
H
H
Me
Me
H
O
O
BnO
Me
O
O
Me
O
L
M
OR
o-q
O
O
OBn
OBn
H
k-m
a
22
O
H
H
MeO
O
Me
Me
O
O
O
O
H
BnO
H
Me
Me
35
H
TES
28: R = H
29: R = Bn
OBn
30
n
Me
OBn
Me
Me
BnO
OBn
H
Me
Me
OTBS
HO
O
H
O
H
Me
O
OBn
O
OBn
s-u
BnO
Me
O
r
O
OBn
H
b
O
HO2C
Me
Me
HO
O
H
H
O
HO
O
O
BnO
H
Me
Me
H
TES
36
H
31
32
Me
OBn
H
OBn
H
OBn
Me
Me
Me
X
BnO
O
O
Me
M
O
OBn
O
L
OBn
w
v
H
EEO
O
K
Me
BnO
Me
O
O
Me
Me
O
O
OBn
H
H
H
c-e
O
Me
Me
O
H
H
O
33
34a: X = OP(O)2(OPh)2
34b: X = OTf
O
O
BnO
H
H
37
H
Me
Scheme 4. Synthesis of the KLM ring system 34. a) DIBALH, CH2Cl2,
788C; b) NaBH4, MeOH, 08C; c) TsCl, Et3N, DMAP, CH2Cl2, RT, 68%
(3 steps); d) KCN, DMSO, 708C; e) Mg, MeOH, RT; f) TESCl, imidazole,
DMF, RT, 83% (3 steps); g) DIBALH, CH2Cl2, 788C; h) HOAc/THF/
H2O, RT; i) TPAP, NMO, 4-Š molecular sieves, CH2Cl2, RT, 78% (3 steps);
j) LiHMDS, MeI, THF, 788C, 82%; k) allylmagnesium bromide, THF,
788C, 68%; l) OsO4, N,N'-bis(2,4,6-trimethylbenzyl)-(S,S)-1,2-diphenyl-
1,2-diaminoethane, CH2Cl2, 908C, then aqueous NaHSO3, THF, 708C;
m) CSA, benzene, RT, 79% (2 steps); n) NaH, BnBr, DMF, RT, 98%;
OBn
Me
BnO
Me
X
H
Me
BnO
H
O
O
H
Me
I
O
: NOE
OBn
H
f
J
H
O
K
G
H
H
O
O
M
BnO
O
H
L
H
Me
‡
OBn
38: X = SEt
2: X = H
Me
o) BF3 ´ OEt2, Me2S, CH2Cl2, 08C; p) Ph3PP CH3Br , NaHMDS, THF,
g
BnO
408C; q) TESOTf, 2,6-lutidine, CH2Cl2, RT, 73% (3 steps); r) 9-BBN, THF,
RT !408C, then 3m NaOH, 30% H2O2, RT, 98%; s) SO3 ´ pyridine, Et3N,
CH2Cl2/DMSO, 08C; t) NaClO2, KH2PO4, 2-methyl-2-butene, tBuOH/
H2O, RT; u) 0.5m HCl, THF, RT, 55% (3 steps); v) 2,4,6-trichlorobenzoyl
chloride, Et3N, THF, then DMAP, benzene, reflux, 93%; w) KHMDS,
(PhO)2P(O)Cl or PhNTf2, THF/HMPA, 788C, 87% for 34a, 88% for
34b. TES ˆ triethylsilyl, Ts ˆ p-toluenesulfonyl.
Scheme 5. Synthesis of the GHIJKLM ring system 2. a) 9-BBN, THF, RT,
then 3m aqueous Cs2CO3, 34b, [Pd(PPh3)4], DMF, 08C, 71% based on 34b;
b) BH3 ´ THF, THF, RT, then 3m NaOH, 30% H2O2, RT, 81%; c) EVE,
CSA, CH2Cl2, RT; d) TBAF, THF, RT; e) TPAP, NMO, 4-Š molecular
sieves, CH2Cl2, RT; f) EtSH, Zn(OTf)2, CH2Cl2, RT; g) Ph3SnH, AIBN,
toluene, reflux, 56% (5 steps). EVE ˆ ethyl vinyl ether.
1092
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
1433-7851/01/4006-1092 $ 17.50+.50/0
Angew. Chem. Int. Ed. 2001, 40, No. 6

COMMUNICATIONS
[9] For recent applications of B-alkyl Suzuki coupling in syntheses of
natural products, see a) D. Meng, S. J. Danishefsky, Angew. Chem.
1999, 111, 1582 ± 1585; Angew. Chem. Int. Ed. 1999, 38, 1485 ± 1488;
b) D. Trauner, J. B. Schwarz, S. J. Danishefsky, Angew. Chem. 1999,
111, 3756 ± 3758; Angew. Chem. Int. Ed. 1999, 38, 3542 ± 3545; c) C. R.
Harris, S. D. Kuduk, A. Balog, K. Savin, P. W. Glunz, S. J. Danishefsky,
J. Am. Chem. Soc. 1999, 121, 7050 ± 7062; d) B. Zhu, J. S. Panek, Org.
Lett. 2000, 2, 2575 ± 2578; e) N. C. Kallan, R. L. Halcomb, Org. Lett.
2000, 2, 2687 ± 2690; f) S. R. Chelmer, S. J. Danishefsky, Org. Lett.
2000, 2, 2695 ± 2698; g) C. B. Lee, T.-C. Chou, X.-G. Zhang, Z.-G.
Wang, S. D. Kuduk, M. D. Chappell, S. J. Stachel, S. J. Danishefsky, J.
Org. Chem. 2000, 65, 6525 ± 6533, and references therein.
[10] Review: T. B. Grindley, Adv. Carbohydr. Chem. Biochem. 1998, 53,
17 ± 142.
isomer in 81% yield. Protection as the ethoxyethyl (EE) ether
followed by desilylation and oxidation of the resulting alcohol
with TPAP/NMO provided ketone 37. Exposure of 37 to EtSH
in the presence of Zn(OTf)2 gave mixed thioketal 38. Finally,
radical reduction[18] of 38 furnished the target GHIJKLM ring
system 2 in 56% overall yield from 36. The configuration of 2
was unambiguously determined by NOE experiments.
In conclusion, we have developed a highly convergent
synthetic route to the GHIJKLM ring system 2 of ciguatoxin.
The present synthesis demonstrates the general applicability
of a strategy based on B-alkyl Suzuki coupling to the
convergent synthesis of a polyether system. Progress toward
the completion of the total synthesis of ciguatoxins is under-
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Received: September 18, 2000 [Z15822]
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Turning On Cell Migration with Electroactive
Substrates**
Muhammad N. Yousaf, Benjamin T. Houseman, and
Milan Mrksich*
Herein we describe an electroactive substrate that was
designed to turn on the migration of mammalian cells. The
migration of cells is important in many developmental and
disease processes that are temporally regulated.[1] Mechanistic
studies of cell migrationÐwhich depend on specific interac-
tions of cell-surface receptors with ligands of the extracellular
matrix[2]Ðare complicated by the large number of ligands
present in the matrix and the changes in ligand activity over
Â
[6] For reviews, see a) E. Alvarez, M.-L. Candenas, R. Perez, J. L. Ravelo,
[*] Prof. M. Mrksich, M. N. Yousaf, B. T. Houseman
Department of Chemistry
J. D. Martín, Chem. Rev. 1995, 95, 1953 ± 1980; b) Y. Mori, Chem. Eur.
J. 1997, 3, 849 ± 852.
The University of Chicago
Chicago, IL 60637 (USA)
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1998, 39, 9027 ± 9030; b) M. Sasaki, H. Fuwa, M. Ishikawa, K.
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H. Fuwa, K. Tachibana, Tetrahedron Lett. 2000, 41, 1425 ± 1428; d) H.
Fuwa, M. Sasaki, K. Tachibana, Tetrahedron Lett. 2000, 41, 8371 ±
8375.
[8] For reviews on Suzuki reaction, see a) N. Miyaura, A. Suzuki, Chem.
Rev. 1995, 95, 2457 ± 2483; b) A. Suzuki, J. Organomet. Chem. 1999,
576, 147 ± 168.
Fax : (‡1)773-702-0805
E-mail: mmrksich@midway.uchicago.edu
[**] We are grateful for support of this work by DARPA and the National
Institute of Health (GM 54621). This work used facilities of the
MRSEC supported by the National Science Foundation (DMR-
9808595). M. M. is a Searle Scholar and an A. P. Sloan Fellow. B. T.
Houseman is supported by MD/PhD Training Grant HD-09007.
Angew. Chem. Int. Ed. 2001, 40, No. 6
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
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