A concise and stereoselective synthesis of the A-ring fragment of the gambieric acids

Article abstract of DOI:10.1021/ol049483s

Matrix presented. The A-ring fragment of the gambieric acids has been prepared by a short and efficient route. The key 3(2H)-furanone intermediate has been obtained by [2,3] rearrangement of an allylic oxonium ylide generated from intramolecular reaction

Full text of DOI:10.1021/ol049483s

ORGANIC
LETTERS
2004
Vol. 6, No. 11
1773-1776
A Concise and Stereoselective
Synthesis of the A-Ring Fragment of the
Gambieric Acids
J. Stephen Clark,* Thomas C. Fessard, and Claire Wilson
School of Chemistry, UniVersity of Nottingham, UniVersity Park,
Nottingham, NG7 2RD, United Kingdom
j.s.clark@nottingham.ac.uk
Received March 18, 2004
ABSTRACT
The A-ring fragment of the gambieric acids has been prepared by a short and efficient route. The key 3(2H)-furanone intermediate has been
obtained by [2,3] rearrangement of an allylic oxonium ylide generated from intramolecular reaction of a crotyl ether with a copper carbenoid.
A single stereogenic center has been set by using a chiral pool starting material and the other three have been established by using highly
diastereoselective substrate-controlled transformations.
The gambieric acids A-D were isolated from a culture broth
of the marine dinoflagellate Gambierdiscus toxicus, the
organism responsible for ciguatera poisoning in humans, by
Yasumoto and co-workers in 1992.1 The gambieric acids
have aroused considerable interest because of their unusual
polyether structure and their significant antifungal activity
against a variety of filamentous fungi.1c The gambieric acids
display considerably greater antifungal activity than ampho-
tericin B in many assays and only moderate toxicity toward
mammalian cells, making them potential lead compounds
for the discovery of new antifungal agents.1
The gambieric acids possess an array of nine trans-fused
6-, 7-, and 9-membered cyclic ethers and a side chain bearing
an isolated trisubstituted tetrahydrofuran (the A-ring unit).
As part of our research program directed toward the
discovery of efficient routes to the gambieric acids and
related polyether natural products, we have developed a short
and highly diastereoselective synthesis of the tetrahydrofuran
A-ring fragment that is described herein.2
The retrosynthetic analysis of the key A-ring fragment i
is shown in Scheme 1. Functional group interconversion of
the methyl group and hydroxyl protection leads to the
methylene tetrahydrofuran ii as a late synthetic intermediate.
Conversion of the methylene group into a ketone and the
ester group into a hydroxyl group then leads to the 3(2H)-
furanone iii. Retrosynthetic dehydration of the alcohol leads
(1) (a) Nagai, H.; Torigoe, K.; Satake, M.; Murata, M.; Yasumoto, T.;
Hirota, H. J. Am. Chem. Soc. 1992, 114, 1102. (b) Nagai, H.; Murata, M.;
Torigoe, K.; Satake, M.; Yasumoto, T. J. Org. Chem. 1992, 57, 5448. (c)
Nagai, H.; Mikami, Y.; Yazawa, K.; Gonoi, T.; Yasumoto, T. J. Antibiot.
1993, 46, 520. (d) Morohashi, A.; Satake, M.; Nagai, H.; Oshima, Y.;
Yasumoto, T. Tetrahedron 2000, 56, 8995.
(2) For a previous synthesis of the A-ring fragment of the gambieric
acids, see: Kadota, I.; Oguro, N.; Yamamoto, Y. Tetrahedron Lett. 2001,
42, 3645.
10.1021/ol049483s CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/05/2004

the oxonium ylide generated from the Z-crotyl ether to
rearrange via the exo transition state (vi f viii) or the ylide
generated from the E-crotyl ether to rearrange via the endo
transition state (v f ix).
Scheme 1
It was not possible to predict whether rearrangement of
the oxonium ylide would proceed via an exo or endo
transition state based on literature data.5b,6 Consequently, we
prepared both the E- and Z-crotyl ether precursors and treated
each of them with copper(II) acetylacetonate to determine
the stereochemical outcome of the oxonium ylide formation
and [2,3] rearrangement process.
The Z-crotyl ether precursor was prepared from dimethyl
malate (1), using the route shown in Scheme 3. Regioselec-
Scheme 3
to the alkene iv, the key intermediate in our route. The
intermediate iv is then disconnected to give the diazo ketones
v/vi (Vide infra) and further functional group interconversion
and cleavage of the crotyl ether gives the methyl ester vii,
which can be obtained from (S)-malic acid.3
The key reaction in our route was to be the generation of
a copper carbenoid from the diazo ketone v/vi followed by
oxonium ylide formation and rearrangement, resulting in
C-O and C-C bond formation with concomitant ring
closure and the creation of two stereogenic centers (Scheme
2).4,5 If the rearrangement of the ylide proceeded through
Scheme 2
tive directed ester reduction, using conditions first described
by Moriwake and co-workers,3 followed by selective tert-
butyldiphenylsilyl protection of the resulting primary hy-
droxyl group afforded the alcohol 2. The alcohol was then
converted into the propargylic ether 3 by triethylsilyl
trifluoromethanesulfonate or trifluoromethanesulfonic acid
mediated reaction with butynyl 2,2,2-trichloroacetimidate,7
and subsequent Lindlar reduction produced the Z-crotyl ether
4a in a highly stereoselective manner. The Z-crotyl ether 4a
was transformed into the cyclization precursor 5a by mild
the exo transition state, the 3(2H)furanone viii would be
obtained, whereas rearrangement through the endo transition
state would deliver the isomeric product ix. Thus, to obtain
the required diastereoisomer iv, it would be necessary for
(5) (a) Pirrung, M. C.; Werner, J. A. J. Am. Chem. Soc. 1986, 108, 6060.
(b) Roskamp, E. J.; Johnson, C. R. J. Am. Chem. Soc. 1986, 108, 6062. (c)
Eberlein, T. H.; West, F. G.; Tester, R. W. J. Org. Chem. 1992, 57, 3479.
(d) West, F. G.; Eberlein, T. H.; Tester, R. W. J. Chem. Soc., Perkin Trans.
1 1993, 2857. (e) West, F. G.; Naidu, B. N.; Tester, R. W. J. Org. Chem.
1994, 59, 6892. (f) Tester, R. W.; West, F. G. Tetrahedron Lett. 1998, 39,
4631. (g) Marmsater, F. P.; West, F. G. J. Am. Chem. Soc. 2001, 123, 5144.
(h) Marmsater, F. P.; Vanecko, J. A.; West, F. G. Tetrahedron 2002, 58,
2027.
(6) Doyle, M. P.; McKervey, M.; Ye, T. Modern Catalytic Methods with
Diazo Compounds; Wiley: New York, 1998; Chapter 7, pp 355-432.
(7) (a) Overman, L. E.; Clizbe, L. A. J. Am. Chem. Soc. 1976, 98, 2352.
(b) Wei, S.-Y.; Tomooka, K.; Nakai, T. J. Org. Chem. 1991, 56, 5973. (c)
Wei, S.-Y.; Tomooka, K.; Nakai, T. Tetrahedron 1993, 49, 1025.
(3) Saito, S.; Hasegawa, M.; Inaba, M.; Nishida, R.; Fujii, T.; Nomizu,
S.; Moriwake, T. Chem. Lett. 1984, 1389.
(4) (a) Clark, J. S. Tetrahedron Lett. 1992, 33, 6193. (b) Clark, J. S.;
Krowiak, S. A.; Street, L. J. Tetrahedron Lett. 1993, 34, 4385. (c) Clark,
J. S.; Whitlock, G. A. Tetrahedron Lett. 1994, 35, 6381. (d) Clark, J. S.;
Dossetter, A. G.; Whittingham, W. G. Tetrahedron Lett. 1996, 37, 5605.
(e) Clark, J. S.; Dossetter, A. G.; Blake, A. J.; Li, W.-S.; Whittingham, W.
G. Chem. Commun. 1999, 749. (f) Clark, J. S.; Bate, A. L.; Grinter, T.
Chem. Commun. 2001, 459. (g) Clark, J. S.; Whitlock, G. A.; Jiang, S.;
Onyia, N. Chem. Commun. 2003, 2578.
1774
Org. Lett., Vol. 6, No. 11, 2004

ester cleavage using potassium trimethylsilanolate,8 conver-
sion of the resulting carboxylic acid into the corresponding
acid chloride, and then reaction with diazomethane. Treat-
ment of the diazo ketone 5a with copper(II) acetylacetonate
in THF at reflux afforded the required 3(2H)-furanone 6a
in 75% yield and with an excellent level of diastereocontrol
(>95:5). Only two of the four possible diastereoisomers were
obtained, and neither of the cis-3(2H)-furanone diastereo-
isomers was produced.
displacement product) with the former predominating. The
ester 4b was converted into the cyclization precursor 5b by
using the same ester cleavage and diazo ketone formation
procedure that was employed to obtain the isomeric com-
pound 5a. Treatment of the diazo ketone 5b with copper(II)
acetylacetonate in THF at reflux afforded the required 3(2H)-
furanone 6a in 88% yield and with excellent diastereo-
selectivity (>92:8).12 Once again, two of the four possible
diastereomeric products were isolated and neither of the
possible cis-3(2H)-furanone diastereoisomers was obtained
from the reaction. The 3(2H)-furanone 6b was a solid and
X-ray analysis9 (Figure 1) revealed the relative stereochem-
istry of the major isomer to be that shown in Scheme 4 (i.e.,
the required configuration at the methyl-bearing carbon had
been obtained), confirming that [2,3] rearrangement had
occurred via the endo transition state.
The 3(2H)-furanone 6a was a solid compound and crystals
suitable for X-ray analysis were obtained (Figure 1).9,10 The
X-ray data revealed that the relative stereochemistry of the
major isomer is that shown in Scheme 3 (i.e., the product
with incorrect configuration at the methyl-bearing carbon had
been obtained) and established that [2,3] rearrangement had
occurred via the endo transition state.
Scheme 4
The synthesis of the A-ring fragment was then completed
by the sequence shown in Scheme 5. Regioselective hydro-
boration of the alkene was accomplished by using excess
dicyclohexylborane, a reaction that proceeded with con-
comitant ketone reduction. Subsequent oxidation with excess
PDC then delivered the keto acid 7 in reasonable yield.
Esterification to give either the methyl or tert-butyl ester
followed by ketone methylenation with the Nysted reagent13
and titanium(IV) chloride then afforded the methylene
tetrahydrofurans 8 and 9. Attempted hydrogenation of the
alkene with use of palladium on carbon resulted in a complex
mixture of isomeric products. Further investigation of the
reaction suggested that competitive isomerization of the
allylic ether was occurring to give the corresponding dihydro-
furan and this compound then underwent hydrogenation to
give a mixture of products.14
Figure 1. X-ray structures (displacement elipsoid plot drawn at
the 50% probability level) of 3(2H)-furanones (()-6a and (()-6b
(H atoms on the tert-butyldiphenylsilyl group removed for clarity).
The synthesis of the corresponding E-crotyl ether cycliza-
tion precursor was also undertaken. The alcohol 2 was treated
with E-crotyl 2,2,2-trichloroacetimidate11 in the presence of
trifluoromethanesulfonic acid to give a separable mixture of
the required ether 4b and the isomeric ether 4c (the SN2′
(8) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 51, 5831.
(9) The crystals used for X-ray analysis were obtained by recrystallization
of racemic material.
(10) The crystallographic data (excluding structure factors) for the
compounds (()-6a and (()-6b have been deposited (6a CCDC 226336;
6b CCDC 226337) with the Cambridge Crystallographic Data Centre.
Copies of the data can be obtained, free of charge, on application to CCDC,
12 Union Road, Cambridge, CB2 1EZ, UK [fax +44(0) 1223 336033; e-mail
deposit@ccdc.cam.ac.uk].
(12) The E-crotyl alcohol used to prepare the E-crotyl 2,2,2-trichloro-
acetimidate contained a small amount (5-8%) of Z-crotyl alcohol, and so
the level of stereocontrol during rearrangement of the oxonium ylide is
actually greater than that reflected by the isomer ratio in this case.
(13) Matsubara, S.; Sugihara, M.; Utimoto, K. Synlett 1998, 313.
(14) Bueno, J. M.; Cotero´n, J. M.; Chiara, J. L.; Ferna´ndez-Mayoralas,
A.; Fiandor, J. M.; Valle, N. Tetrahedron Lett. 2000, 41, 4379.
(11) (a) Overman, L. E. J. Am. Chem. Soc. 1976, 98, 2901. (b) Patil, V.
J. Tetrahedron Lett. 1996, 37, 1481. (c) Maleczka, R. E., Jr.; Geng, F. Org.
Lett. 1999, 1, 1111.
Org. Lett., Vol. 6, No. 11, 2004
1775

In summary, we have constructed the A-ring fragment of
the gambieric acids by a novel and efficient 12-step route
from (S)-dimethylmalate. In this sequence, one stereogenic
center has been obtained from the chiral pool and the other
three centers have been introduced by using highly dia-
stereoselective substrate-controlled reactions. Stereoselective
ring formation has been accomplished by tandem catalytic
carbenoid generation, ylide formation, and [2,3] rearrange-
ment.
Scheme 5
Coupling of the A-ring fragment and further synthetic
endeavors toward the gambieric acids are in progress and
will be reported in due course.
Acknowledgment. We thank the EPSRC and University
of Nottingham for financial support.
Supporting Information Available: Experimental pro-
cedures along with spectroscopic and other data for com-
pounds 6a, 6b, and 7-11. This material is available free of
charge via the Internet at http://pubs.acs.org.
To circumvent the isomerization problem, we removed the
silicon protecting group from the esters 8 and 9 and then
performed hydroxyl-directed hydrogenation using Wilkin-
son’s catalyst. In both cases, the reaction delivered the
gambieric acid A-ring fragment 10/11 as a single isomer in
good yield.15
OL049483S
(15) The stereochemical outcome of the hydrogenation reaction was
confirmed by comparison of 1H NMR chemical shift and coupling constant
data for the alcohols 10 and 11 with that of the natural product (ref 1).
1776
Org. Lett., Vol. 6, No. 11, 2004