Studies toward the total synthesis of gambieric acids, potent antifungal polycyclic ethers: Convergent synthesis of the CDEFG-Ring system

Article abstract of DOI:10.1021/ol050760k

(Chemical Equation Presented) A convergent synthetic route to the CDEFG-ring system of gambieric acids, potent antifungal polycyclic ether marine natural products, has been developed. The present synthesis features convergent union of the CD- and G-rings

Full text of DOI:10.1021/ol050760k

ORGANIC
LETTERS
2005
Vol. 7, No. 12
2441-2444
Studies toward the Total Synthesis of
Gambieric Acids, Potent Antifungal
Polycyclic Ethers: Convergent
Synthesis of the CDEFG-Ring System
Kazushi Sato and Makoto Sasaki*
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences,
Tohoku UniVersity, Tsutsumidori-Amamiya, Aoba-ku, Sendai 981-8555, Japan
masasaki@bios.tohoku.ac.jp
Received April 8, 2005
ABSTRACT
A convergent synthetic route to the CDEFG-ring system of gambieric acids, potent antifungal polycyclic ether marine natural products, has
been developed. The present synthesis features convergent union of the CD- and G-rings through esterification, formation of the E-ring as a
lactone form, stereoselective allylation to set the C26 stereocenter, and ring-closing metathesis reaction to construct the nine-membered
F-ring.
A number of polycyclic ether natural products with potent
and diverse biological activities have been isolated from
marine sources.1 Gambieric acids A-D (1-4, Figure 1) were
isolated by the Yasumoto group from the culture media of
the marine dinoflagellate, Gambierdiscus toxicus, which is
the causative organism responsible for ciguatera seafood
poisoning.2 These polycyclic ethers have attracted consider-
able interest because of their potent antifungal activity against
a variety of filamentous fungi.2c Their antifungal activity
against Aspergillus niger by the paper disk method was 2000
times greater than that of amphotericin B, and they exhibited
only moderate toxicity toward mammalian cells. These
findings make them potential lead compounds for the
discovery of antifungal agents.2 In this letter, we describe a
(1) For reviews on marine polycyclic ethers, see: (a) Yasumoto, T.;
Figure 1. Structures of gambieric acids A-D.
Murata, M. Chem. ReV. 1993, 93, 1897-1909. (b) Murata, M.; Yasumoto,
T. Nat. Prod. Rep. 2000, 293-314. (c) Yasumoto, T. Chem. Rec. 2001, 3,
228-242.
(2) (a) Nagai, H.; Torigoe, K.; Satake, M.; Murata, M.; Yasumoto, T.;
convergent synthesis of the CDEFG-ring system 5 of
gambieric acids.3
During our studies toward the total synthesis of ciguatox-
ins, we have previously reported a convergent route to the
Hirota, H. J. Am. Chem. Soc. 1992, 114, 1102-1103. (b) Nagai, H.; Murata,
M.; Torigoe, K.; Satake, M.; Yasumoto, T. J. Org. Chem. 1992, 57, 5448-
5453. (c) Nagai, H.; Mikami, Y.; Yazawa, K.; Gonoi, T.; Yasumoto, T. J.
Antibiot. 1993, 46, 520-522. (d) Morohashi, A.; Satake, M.; Nagai, H.;
Oshima, Y.; Yasumoto, T. Tetrahedron 2000, 56, 8995-9001.
10.1021/ol050760k CCC: $30.25
© 2005 American Chemical Society
Published on Web 05/17/2005

FGH-ring system.4 The synthesis features an intramolecular
radical cyclization to form the seven-membered G-ring with
complete stereocontrol and a ring-closing metathesis (RCM)
to construct the nine-membered F-ring. Subsequently, this
approach was further modified and refined by the Hirama
group, culminating in the first total synthesis of ciguatoxin
CTX3C.5 Initially, we planned to synthesize the CDEFG-
ring system 5 of gambieric acids by applying this strategy
(Scheme 1). The nine-membered F-ring of 5 could be
Scheme 2. Synthesis of Alcohols 6a and 6b
Scheme 1. First Synthesis Plan for the CDEFG-Ring System
5
produced primary alcohol 14 (99%), which upon benzylation
followed by desilylation yielded alcohol 6a in 88% yield
for the two steps. Alcohol 14 was converted to a terminal
olefin via o-nitrophenyl selenide by the method of Grieco
and Nishizawa.9 Subsequent desilylation afforded alcohol 6b
in 85% yield for the three steps.
The synthesis of carboxylic acid 7 commenced with
alcohol 15,10 which was converted to methyl ketone 16 by
a four-step sequence in 82% overall yield (Scheme 3).
constructed by RCM from a precursor diene. In turn, the
seven-membered E-ring was envisioned to be formed by an
intramolecular radical cyclization of 8, which would be
derived from alcohol 6 and carboxylic acid 7.
The synthesis of alcohols 6a and 6b started with compound
96 (Scheme 2). Protection as the TBS ether and oxidative
cleavage of the double bond, followed by Wittig reaction
with methyl (triphenylphosphoranilidene)acetate, afforded
enoate 10 in 81% yield for the three steps. Treatment of 10
with methylmagnesium bromide in the presence of TMSCl
and i-propylsalicylaldimine copper(II) complex 117 (THF,
-45 °C) gave the desired adduct 12 as the sole product in
high yield.8 The stereochemistry of the newly generated
stereocenter was confirmed by conversion to lactone 13 and
its NMR analysis as shown. DIBALH reduction of 12
Scheme 3. Synthesis of Carboxylic Acid 7
(3) For synthetic studies of gambieric acids, see: (a) Kadota, I.; Oguro,
N.; Yamamoto, Y. Tetrahedron Lett. 2001, 42, 3645-3647. (b) Kadota, I.;
Takamura, H.; Yamamoto, Y. Tetrahedron Lett. 2001, 42, 3649-3651. (c)
Clark, J. S.; Fessard, T. C.; Wilson, C. Org. Lett. 2004, 6, 1773-1776.
(4) (a) Sasaki, M.; Noguchi, T.; Tachibana, J. Org. Chem. 2002, 67,
3301-3310. (b) Sasaki, M.; Noguchi, T.; Tachibana, K. Tetrahedron Lett.
1999, 40, 1337-1340. (c) Sasaki, M.; Inoue, M.; Noguchi, T.; Takeichi,
A.; Tachibana, K. Tetrahedron Lett. 1998, 39, 2783-2786.
(5) (a) Hirama, M.; Oishi, T.; Uehara, H.; Inoue, M.; Maruyama, M.;
Oguri, H.; Satake, M. Science 2001, 294, 1904-1907. (b) Inoue, M.; Uehara,
H.; Maruyama, M.; Hirama, M. Org. Lett. 2002, 4, 4551-4554. (c) Inoue,
M.; Hirama, M. Synlett 2004, 4, 577-595. (d) Inoue, M.; Miyazaki, K.;
Uehara, H.; Maruyama, M.; Hirama, M. Proc. Natl. Acad. Sci. U.S.A. 2004,
101, 12013-12018. (e) Inoue, M.; Hirama, M. Acc. Chem. Res. 2004, 37,
961-968.
(6) Nicolaou, K. C.; Prasad, C. V. C.; Somers, P. K.; Hwang, C.-K. J.
Am. Chem. Soc. 1989, 111, 5330-5334.
Following desilylation, treatment of the derived alcohol with
ethyl propiolate in the presence of N-methylmorpholine
(NMM) produced â-alkoxyacrylate 17 in 81% yield over the
two steps. Treatment of 17 with samarium(II) iodide in the
(7) Sakata, H.; Aoki, Y.; Kuwajima, I. Tetrahedron Lett. 1990, 31, 1161-
1164.
(8) Matsuo, G.; Kawamura, K.; Hori, N.; Matsukura, H.; Nakata, T. J.
Am. Chem. Soc. 2004, 126, 14374-14376.
2442
Org. Lett., Vol. 7, No. 12, 2005

Scheme 4. Attempted Synthesis of O-Linked Oxacycle 26
presence of methanol effected reductive cyclization11 to
mixture of the desired O-linked oxepane 24,13 its diastere-
omer 25, and reduction product 26 in a ratio of ca. 1:4:3,
along with recovered 23. The outcome of this radical
cyclization can be explained as follows (Figure 2). Severe
deliver bicyclic ester 18 as the sole product in high yield.
After protection as the tert-butyldimethylsilyl (TBS) ether,
DIBALH reduction of the ester moiety to the aldehyde
followed by Wittig reaction gave olefin 19 in 81% yield for
the three steps. Hydroboration using 9-BBN followed by
oxidative workup gave an alcohol (91%), which was then
oxidized by a two-step procedure (SO3‚pyr/DMSO then
NaClO2) to provide acid 7 in 96% yield for the two steps.
With the desired fragments 6 and 7 in hand, we next turned
our attention to their coupling. Yamaguchi esterification of
6a with 7 proceeded smoothly to afford ester 20 in high yield
(Scheme 4). Conversion to the R-acetoxy ether 21 was
carried out according to the procedure of Rychnovsky
(DIBALH, CH2Cl2, -78 °C; then Ac2O, DMAP, pyridine,
-78 °C f room temperature).12 Subsequent treatment with
TMSSPh in the presence of TMSOTf and 2,6-di-tert-butyl-
4-methylpyridine (DTBMP) generated, after desilylation,
mixed thioacetal 22 in 85% overall yield from 20. The
â-alkoxyacrylate unit was attached to the tertiary alcohol by
treatment with methyl propiolate and trimethylphosphine to
provide 23 in modest yield (47%; 84% yield based on
recovered 21). However, radical cyclization of 23 (Bu3SnH,
AIBN toluene, 80 °C) was sluggish and yielded a complex
Figure 2. Possible rationale for radical cyclization.
steric repulsion between the C2114 tertiary methyl group and
the â-hydrogen on the acrylate unit in the transition state
structure A resulted in a preference for the structure B, which
leads to 25. A similar result has been reported by Nakata
and co-workers in the SmI2-mediated reductive cyclization.15
Accordingly, we next investigated an alternative route as
summarized in Scheme 5. Alcohol 6b and carboxylic acid 7
(13) Stereostructure of compound 24 was assigned by NOE between 21-
Me and 26-H and the coupling constant, J25,26 ) 3.5 Hz. In a related
O-linked oxepane ring system, a small coupling constant, J ) 0 Hz, between
Ha and Hb was observed. See: Sasaki, M.; Noguchi, T.; Tachibana, K. J.
Org. Chem. 2002, 67, 3301-3310.
(9) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41,
1485-1486.
(10) Nicolaou, K. C.; Hwang, C. K.; Marron, B. E.; DeFrees, S. A.;
Couladouros, E. A.; Abe, Y.; Carroll, P. J.; Snyder, J. P. J. Am. Chem.
Soc. 1990, 112, 3040-3054.
(11) (a) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron
Lett. 1999, 40, 2811-2814. (b) Hori, N.; Matsukura, H.; Nakata, T. Org.
Lett. 1999, 1, 1099-1101. (c) Matsuo, G.; Hori, N.; Nakata, T. Tetrahedron
Lett. 1999, 40, 8859-8862. (d) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata,
T. Tetrahedron 2002, 58, 1853-1864.
(12) (a) Dahanukar, V. H.; Rychnovsky, S. D. J. Org. Chem. 1996, 61,
8317-8320. (b) Kopecky, D. J.; Rychnovsky, S. D. J. Org. Chem. 2000,
65, 191-198. (c) Kopecky, D. J.; Rychnovsky, S. D. Org. Synth. 2003, 80,
177-183.
(14) Numbering of carbon atoms of all compounds in this paper
corresponds to that of gambieric acid A.
(15) Suzuki, K.; Matsukura, H.; Matsuo, G.; Koshino, H.; Nakata, T.
Tetrahedron Lett. 2002, 43, 8653-8655.
Org. Lett., Vol. 7, No. 12, 2005
2443

Scheme 5. Synthesis of the CDEFG-Ring System 5
were coupled through esterification to afford 27 (92%), which
the action of the second-generation Grubbs’ catalyst 3418,19
to furnish the targeted CDEFG-ring system 5 in 98% yield.
The stereochemistry of 5 was unambiguously established by
NOE experiments and the coupling constant.
In summary, we have developed a synthetic route to the
CDEFG-ring system 5 of gambieric acids through convergent
union of the CD- and G-rings. Further studies toward the
total synthesis of gambieric acids along these lines are in
progress and will be reported in due course.
was subjected to reductive acetylation to give an R-acetoxy
ether as a 3:1 mixture of diastereomers. Subsequent treatment
with TMSCN in the presence of TMSOTf and DTBMP
generated nitrile 28,16 which was desilylated to produce
alcohol 29 in 68% yield over the three steps. The nitrile group
was hydrolyzed under alkaline conditions to give carboxylic
acid 30 as a 1:1 mixture of isomers. Yamaguchi lactonization
produced a mixture of seven-membered lactones, which was
separated by flash column chromatography to give 31a and
31b in 38 and 40% yield, respectively.17 Reduction of lactone
31a with DIBALH followed by in situ acetylation produced
acetate 32 in 93% yield as the sole product. Upon treatment
of 32 with allyltrimethylsilane in the presence of BF3‚OEt2
(MeCN, -40 f 0 °C), stereoselective allylation occurred
from the less hindered R-face of the molecule to generate
diene 33 in 67% yield. Stereochemistry at the C26 position
was determined by NOE between 21-Me and 26-H. Finally,
construction of the nine-membered F-ring was achieved by
Acknowledgment. This work was financially supported
by the Sumitomo Foundation and a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science,
Sports, Culture and Technology, Japan.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 10, 12-
14, 6b, 16-19, 7, 27-33, and 5. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL050760K
(16) Synthesis of R-cyano ether in a related system; see: Oishi, T.;
Watanabe, K.; Murata, M. Tetrahedron Lett. 2003, 44, 7315-7319.
(17) Attempted isomerization of the undesired 31b to 31a under various
basic conditions was unsuccessful.
(18) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953-956.
(19) For a recent review, see: Deiters, A.; Martin, S. F. Chem. ReV.
2004, 104, 2199-2238.
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Org. Lett., Vol. 7, No. 12, 2005