Rapid synthesis of the A-E fragment of ciguatoxin CTX3C

Article abstract of DOI:10.1021/ol0706096

The A-E fragment of the marine natural product CTX3C has been prepared in an efficient manner by using a strategy in which two-directional and iterative ring-closing metathesis (RCM) reactions were employed for ring construction.

Full text of DOI:10.1021/ol0706096

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2091-2094
Rapid Synthesis of the A
Ciguatoxin CTX3C
−E Fragment of
J. Stephen Clark,*,† Joanne Conroy,‡ and Alexander J. Blake‡
WestCHEM, Department of Chemistry, Joseph Black Building, UniVersity of Glasgow,
UniVersity AVenue, Glasgow G12 8QQ, United Kingdom, and School of Chemistry,
UniVersity of Nottingham, UniVersity Park, Nottingham NG7 2RD, United Kingdom
stephenc@chem.gla.ac.uk
Received March 13, 2007
ABSTRACT
The A
−E fragment of the marine natural product CTX3C has been prepared in an efficient manner by using a strategy in which two-directional
and iterative ring-closing metathesis (RCM) reactions were employed for ring construction.
The ciguatoxins are large fused polyether natural products
produced by the marine dinoflagellate Gambierdiscus toxicus
(Scheme 1).1 They are the principal causative agents of
ciguatera, a severe type of food poisoning that afflicts people
in tropical and subtropical regions who have ingested
contaminated fish. Thousands of people suffer from ciguatera
poisoning each year, exhibiting a range of symptoms that
include neurological, gastrointestinal, and cardiovascular
effects.2 In common with other marine polyether toxins, the
ciguatoxins bind at site 5 on voltage-sensitive sodium chan-
nels.3 However, they are more potent toxins than structurally
related compounds such as the brevetoxins; the relatively
low incidence of fatalities associated with cigautera poisoning
belies the toxicity of the ciguatoxins and merely reflects the
extremely low concentrations that are usually encountered
in contaminated fish.
regions possess molecular structures with distinct differences.2c
The ciguatoxins produced by the dinoflagellate are also
subject to oxidative modification as they are transferred
through the food chain and the resulting neurotoxins often
possess enhanced potency.2c
The size and structural complexity of the ciguatoxins
makes them formidable targets. In spite of this, the synthetic
allure of the toxins combined with the shortage of natural
material available for detailed biological evaluation has
encouraged several research groups to embark on total
syntheses of members of the ciguatoxin family. This work
has culminated in very impressive and elegant total syntheses
of CTX3C (1), 51-hydroxyCTX3C (2), and the parent
compound ciguatoxin (3) by Hirama and co-workers.4 These
workers have also developed immunoassays for detecting
the ciguatoxins using protein conjugates of terminal frag-
ments of the natural products as synthetic haptens.5
More than 20 ciguatoxins have been isolated from algal
and fish sources, and those from the Pacific and Caribbean
(4) (a) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.;
Oguri, H.; Satake, M. Science 2001, 294, 1904-1907. (b) Inoue, M.;
Miyazaki, K.; Uehara, H.; Maruyama, M.; Hirama, M. Proc. Natl. Acad.
Sci. U.S.A. 2004, 101, 12013-12018. (c) Inoue, M.; Hirama, M. Acc. Chem.
Res. 2004, 37, 961-968. (d) Inoue, M.; Miyazaki, K.; Ishihara, Y.; Tatami,
A.; Ohnuma, Y.; Kawada, Y.; Komono, K.; Yamashita, S.; Lee, N.; Hirama,
M. J. Am. Chem. Soc. 2006, 128, 9352-9354.
(5) (a) Tsumuraya, T.; Fujii, I.; Inoue, M.; Tatami, A.; Miyazaki, K.;
Hirama, M. Toxicon 2006, 48, 287-294. (b) Nagumo, Y.; Oguri, H.;
Tsumoto, K.; Shindo, Y.; Hirama, M.; Tsumuraya, T.; Fujii, I.; Tomioka,
Y.; Mizugaki, M.; Kumagai, I. J. Immunol. Methods 2004, 289, 137-146.
(c) Oguri, H.; Hirama, M.; Tsumuraya, T.; Fujii, I.; Maruyama, M.; Uehara,
H.; Nagumo, Y. J. Am. Chem. Soc. 2003, 125, 7608-7612.
† University of Glasgow.
‡ University of Nottingham.
(1) (a) Scheuer, P. J.; Takahashi, W.; Tsutsumi, J.; Yoshida, T. Science
1967, 155, 1267-1268. (b) Yasumoto, T.; Bagnis, R.; Thevenin, S.; Garcon,
M. Nippon Suisan Gakkaishi . 1977, 43, 1015-1019. (c) Yasumoto, T.;
Nakajima, I.; Bagnis, R.; Adachi, R. Nippon Suisan Gakkaishi 1977, 43,
1021-1026.
(2) (a) Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897-1909.
(b) Scheuer, P. J. Tetrahedron 1994, 50, 3-18. (c) Lewis, R. J. Toxicon
2001, 39, 97-106. (d) Yasumoto, T. Chem. Rec. 2001, 1, 228-242.
(3) Dechraoui, M.-Y.; Naar, J.; Pauillac, S.; Legrand, A.-M. Toxicon
1999, 30, 125-143.
10.1021/ol0706096 CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/28/2007

Scheme 1
As part of a large program directed toward the develop-
DMPU. Desilylation of both hydroxyl groups followed by
selective and high-yielding partial hydrogenation of the
alkyne with Lindlar’s catalyst in the presence of quinoline
afforded the triene 7. The desired two-directional RCM
precursor 8 was then obtained in good yield by alkynylation
of the free hydroxyl group, using the procedure first
developed by Greene and co-workers,8 and used by us during
the construction of related fused polyethers.7c,g,h Simultaneous
diene and enyne RCM to form the A and C rings was
accomplished by treatment of substrate 8 with the ruthenium
complex 9 under an atmosphere of ethene (Scheme 2).9 The
fused tricyclic ether 10 was obtained in a rather modest 58%
ment of a general strategy for the total synthesis of marine
polyethers, we have embarked on a total synthesis of CTX3C
(1).6 Herein, we disclose a relatively short and efficient
approach to the synthesis of the pentacyclic ABCDE frag-
ment of CTX3C in which two-directional and iterative RCM
reactions are used to effect ring construction.7
Our retrosynthetic analysis of ciguatoxin CTX3C (1)
commences with disconnection through rings F and G,
dividing the target into two fragments (i and ii) of similar
size and complexity (Scheme 1). Disconnection of the A-E
fragment i by alkene scission in the E ring leads to the
tetracyclic system iii. Cleavage of the enone side chain at
the ether linkage, removal of the allyl group, and alcohol
oxidation gives the A-D fragment iv. Scission of the alkene
in ring D then produces the tricyclic unit v. Cleavage of the
ether side chain and dehydration delivers the diene vi, which
after simultaneous A and C ring opening by a retrosynthetic
double RCM disconnection gives the B ring fragment vii
(Scheme 1).
Scheme 2
The initial target was the tricyclic ABC fragment, corre-
sponding to vi in the retrosynthetic analysis, which was to
be prepared by simultaneous ring closure of the A and C
rings.7f Preparation of the cyclization precursor 8 commenced
with conversion of the alcohol 4 into the allyl ether 5 and
subsequent cleavage of the di-tert-butylsilylene group (Scheme
2).7f The resulting diol 6 was then subjected to one-pot triflate
and triethylsilyl ether formation followed by triflate displace-
ment with lithium trimethylsilyl acetylide in the presence of
(6) Clark, J. S. Chem. Commun. 2006, 3571-3581.
(7) (a) Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 123-126.
(b) Clark, J. S.; Kettle, J. G. Tetrahedron Lett. 1997, 38, 127-130. (c)
Clark, J. S.; Trevitt, G. P.; Boyall, D.; Stammen, B. Chem. Commun. 1998,
2629-2630. (d) Clark, J. S.; Hamelin, O.; Hufton, R. Tetrahedron Lett.
1998, 39, 8321-8324. (e) Clark, J. S.; Kettle, J. G. Tetrahedron 1999, 55,
8231-8248. (f) Clark, J. S.; Hamelin, O. Angew. Chem., Int. Ed. 2000, 39,
372-374. (g) Clark, J. S.; Elustondo, F.; Trevitt, G. P.; Boyall, D.;
Robertson, J.; Blake, A. J.; Wilson, C.; Stammen, B. Tetrahedron 2002,
58, 1973-1982. (h) Clark, J. S.; Elustondo, F.; Kimber, M. C. Chem.
Commun. 2004, 2470-2471. (i) Clark, J. S.; Kimber, M. C.; Robertson, J.;
McErlean, C. S. P.; Wilson, C. Angew. Chem., Int. Ed. 2005, 44, 6157-
6162.
2092
Org. Lett., Vol. 9, No. 11, 2007

yield and efforts to increase the yield by optimization of the
double RCM reaction were not successful.
Scheme 4
Sequential construction of the A and C rings was also
explored (Scheme 3). Formation of the A ring was achieved
Scheme 3
by RCM of the allyl ether 5, using the ruthenium complex
11.9a Removal of the di-tert-butylsilylene group then afforded
the diol 12 in excellent yield. From this stage onward, the
route was analogous to that used to prepare the double RCM
precursor 10 (Scheme 2). One-pot triflate and triethylsilyl
ether formation followed by triflate displacement with lithium
trimethylsilyl acetylide in the presence of DMPU and
subsequent desilylation delivered the alkyne 13. Partial
hydrogenation of the alkyne with Lindlar’s catalyst in the
presence of quinoline afforded the alcohol 14, which was
then converted into the corresponding alkynyl ether 15.8
Enyne RCM with use of the complex 9 in the presence of
ethene delivered the fused tricyclic ether 10 in 70% yield.
Although the yield of the tricyclic ether 10 obtained from
RCM reaction of the alkynyl ether 15 is higher than that
obtained from double RCM of the precursor 8, the routes
shown in Schemes 2 and 3 are found to be of similar
efficiency when both the yield and the number of steps are
considered. Operationally, however, it was easier to scale
up the route shown in Scheme 3 to produce gram quantities
of the required tricyclic ether 10.
The efficient synthesis of the tricyclic ABC fragment 10
meant that construction of the D and E rings could be
explored. Formation of the D ring began with selective
epoxidation of the electron-rich enol ether in compound 10,
using dimethyldioxirane at 0 °C. The reaction delivered an
unstable mixture (5:2 ratio) of diastereomeric epoxides that
was used in the subsequent step without purification (Scheme
4). Regioselective reduction of this mixture of vinylic
epoxides proved to be challenging and several reducing
agents and sets of reaction conditions were screened before
the transformation could be performed in a reliable manner.
The best results were obtained when the mixture of epoxides
was treated with triethylsilane in the presence of boron
trifluoride etherate in acetonitrile at -40 °C. Under these
reaction conditions, the diastereomeric alcohols 16a and 16b
were obtained in 71% yield from the diene 10. To confirm
the stereochemical outcome of the reaction, the crystalline
acetate 17 was prepared from the major alcohol diastereo-
isomer 16a. X-ray analysis of the acetate 17 revealed that
the alcohol 16a possessed the required configuration at both
the vinyl- and hydroxyl-bearing stereogenic centers. Oxida-
tion of the minor alcohol 16b by using the Dess-Martin
protocol and reduction of the resulting ketone with sodium
borohydride afforded the alcohol 16a, which had been
obtained during reductive opening of the mixture of anomeric
epoxides. This result shows that reduction of the 5:2 mixture
of epoxides delivers the correct configuration at the vinyl-
bearing stereogenic center irrespective of the stereochemistry
of the anomeric epoxide, i.e., reduction of each of the two
oxocarbenium ions obtained from the epoxide mixture occurs
from the same face giving products with the required
configuration at the allylic ether stereogenic center.
Construction of the D and E rings with RCM of enone
precursors was now explored. Following procedures de-
scribed by Cossy et al.10 and employed by us in a recent
synthesis of the tetracyclic core of hemibrevetoxin B,11 the
hydroxyl group of the tricyclic alcohol 16a was alkylated
with triphenylchloroacetonylphosphorane (Scheme 4).12 Treat-
ment of the resulting ylide with formaldehyde in diethyl ether
(8) Moyano, A.; Charbonnier, F.; Greene, A. E. J. Org. Chem. 1987,
52, 2919-2922.
(9) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039-2041. (b) Scholl, M.; Ding, S.; Lee,
C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956.
(10) Cossy, J.; Taillier, C.; Bellosta, V. Tetrahedron Lett. 2002, 43,
7263-7266.
(11) Clark, J. S.; Grainger, D. M.; Ehkirch, A. A.-C.; Blake, A. J.; Wilson,
C. Org. Lett. 2007, 9, 1033-1036.
Org. Lett., Vol. 9, No. 11, 2007
2093

then provided the enone 18 in 56% yield over two steps.
Construction of ring D was then accomplished by treatment
of the enone 18 with the ruthenium complex 9, giving the
required ABCD system 19 in 70% yield (Scheme 4).
therefore converted into the corresponding N,N-dimethyl-
hydrazone. Sequential deprotonation of the hydrazone, eno-
late alkylation, and hydrazone cleavage then produced a 4:1
mixture of the alkylated ketones 20a and 20b in reasonable
1
yield. H NMR NOE experiments revealed that the major
Attachment of the eight-membered E ring to the A-D
fragment 19 was accomplished by using the sequence of
enone formation and RCM that had been employed to
construct the D ring (Scheme 5). Construction of the E-ring
product was the diastereoisomer 20a possessing incorrect
configuration at the newly created sterogenic center. The
ketone 20a was epimerized by treatment with 2-tert-butyl-
1,1,3,3-tetramethylguanidine (Barton’s base)13 to give mainly
the required isomeric compound 20b (1:4 ratio, 20a:20b).
Reduction of the mixture of enones 20a and 20b (1:4) using
standard Luche conditions then gave the crystalline allylic
alcohol 21 in good yield. X-ray analysis of this compound
confirmed its structure and also established that the con-
figurations of all eight stereogenic centers matched those in
the A-D fragment of the natural product. The remaining
enone-containing side chain was then installed in the same
way as before (cf. 16a f 18, Scheme 4) to afford diene 22
in 55% yield over two steps. Completion of the A-E
fragment of CTX3C was accomplished by RCM of the enone
22 mediated by the complex 9, which delivered the eight-
membered cyclic ether and produced the pentacyclic system
23 in 50% yield.
Scheme 5
In summary, the pentacyclic A-E fragment of CTX3C
has been synthesized in 21 steps from the alcohol 4, which
is prepared from commercially available tri-O-acetal-D-
glucal.7f Efficient assembly of the A-C fragment was
achieved by using a two-directional double RCM reaction.
The D and E rings were then constructed by elaboration of
the A-C fragment by using an iterative side chain introduc-
tion and enone RCM protocol.
Acknowledgment. We thank the University of Notting-
ham for funding this work and EPSRC for funding of X-ray
diffractometers. Financial support by Novartis through the
Novartis European Young Investigator Award in Chemistry
to J.S.C. and by Merck Research Laboratories is also
gratefully acknowledged.
Supporting Information Available: Spectroscopic and
other data for the key compounds 10, 16a, 16b, 17, 18, 19,
21, 22, and 23, plus X-ray data (CIF files) for compounds
17 and 21. This material is available free of charge via the
Internet at http://pubs.acs.org.
commenced with introduction of an allyl group. Previous
studies performed in our group had demonstrated that it was
not possible to effect direct deprotonation and enolate
alkylation of 4-oxapen-3-one systems related to the enone
19, and that it was necessary to convert the ketone into a
hydrazone prior to enolate generation.11 The ketone 19 was
OL0706096
(13) (a) Barton, D. H. R.; Elliott, J. D.; Ge´ro, S. J. Chem. Soc., Perkin
Trans. 1 1982, 2085-2090. (b) Ishikawa, T.; Kumamoto, T. Synthesis 2006,
737-752.
(12) Hudson, R. F.; Chopard, P. A. J. Org. Chem. 1963, 28, 2446-
2447.
2094
Org. Lett., Vol. 9, No. 11, 2007