Stereocontrolled synthesis of the A/B-ring fragment of gambieric acid B: Reassignment of the absolute configuration of the polycyclic ether region

Article abstract of DOI:10.1021/ol800642t

(Chemical Equation Presented) Stereocontrolled synthesis of the A/B-ring fragment of the originally assigned structure of gambieric acid B and its possible diastereomers has been accomplished. Detailed comparison of their ¹H and ¹³C NMR data with those of the corresponding moiety of the natural product culminated in a stereochemical reassignment of the absolute configuration of the polycyclic ether region of gambieric acid B.

Full text of DOI:10.1021/ol800642t

ORGANIC
LETTERS
2008
Vol. 10, No. 11
2211-2214
Stereocontrolled Synthesis of the
A/B-Ring Fragment of Gambieric Acid B:
Reassignment of the Absolute
Configuration of the Polycyclic Ether
Region
Haruhiko Fuwa,* Tomomi Goto, and Makoto Sasaki*
Laboratory of Biostructural Chemistry, Graduate School of Life Sciences,
Tohoku UniVersity, 1-1 Tsutsumidori-amamiya, Aoba-ku, Sendai 981-8555, Japan
hfuwa@bios.tohoku.ac.jp; masasaki@bios.tohoku.ac.jp
Received March 20, 2008
ABSTRACT
Stereocontrolled synthesis of the A/B-ring fragment of the originally assigned structure of gambieric acid B and its possible diastereomers
1
has been accomplished. Detailed comparison of their H and 13C NMR data with those of the corresponding moiety of the natural product
culminated in a stereochemical reassignment of the absolute configuration of the polycyclic ether region of gambieric acid B.
Gambieric acids A-D (GAA-GAD, Figure 1) are the
prominent members of marine polycyclic ether natural
products,1,2 which were isolated from the cultured media of
the ciguatera causative dinoflagellate Gambierdiscus toxi-
cus.3,4 The structures of gambieric acids were determined
by combining the results of extensive NMR studies, the
modified Mosher method, and chiral fluorometric HPLC
analysis. The relative stereochemistry of the C7-C11 acyclic
portion, however, was correlated mainly on the basis of 3JH,H
analysis and the NOESY and HMBC spectra. Therefore,
unambiguous assignment of the relative configuration of the
C1-C12 moiety have to be made with the aid of organic
synthesis. These natural products exhibit extraordinarily
potent antifungal activity against Aspergillus niger with a
potency that is approximately 2,000 times greater than that
of amphotericin B, whereas they are only weakly toxic
toward mammalian cells.5 It has also been reported that GAA
enhances the cell concentration of G. toxicus in a dose-
dependent manner with inhibition at higher concentrations,
suggesting the possible role of GAA as an endogenous
growth regulator of G. toxicus.6 Moreover, Inoue et al.
reported that GAA inhibits the binding of the tritiated
(1) For reviews of marine polycyclic ether natural products, see: (a)
Yasumoto, T.; Murata, M. Chem. ReV 1993, 93, 1897. Scheuer, P. J.
Tetrahedron 1994, 50, 3. (b) Murata, M.; Yasumoto, T. Nat. Prod. Rep.
2000, 293. (c) Yasumoto, T. Chem. Rec. 2001, 3, 228
.
(2) For recent reviews of the synthesis of polycyclic ethers, see: (a)
Marmsa¨ter, F. P.; West, F. G. Chem. Eur. J. 2002, 8, 4347. (b) Evans,
P. A.; Delouvrie, B. Curr. Opin. Drug DiscoVery DeV. 2002, 5, 986. (c)
Inoue, M. Chem. ReV. 2005, 105, 4379. (d) Nakata, T. Chem. ReV. 2005,
105, 4314. (e) Fuwa, H.; Sasaki, M. Curr. Opin. Drug DiscoVery DeV. 2007,
10, 784
.
(3) (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
.
(5) Nagai, H.; Mikami, Y.; Yazawa, K.; Gonoi, T.; Yasumoto, T. J.
Antibiot. 1993, 46, 520.
(4) Morohashi, A.; Satake, M.; Nagai, H.; Oshima, Y.; Yasumoto, T.
Tetrahedron 2000, 56, 8995
.
(6) Sakamoto, B.; Nagai, H.; Hokama, Y. Phycologia 1996, 35, 350.
10.1021/ol800642t CCC: $40.75
Published on Web 05/13/2008
2008 American Chemical Society

Scheme 1. Synthetic Plan for the A/B-Ring Fragment 1a
Scheme 2. Synthesis of Vinyl Iodide 4
Figure 1. Proposed and revised structures of gambieric acids A-D.
brevetoxin-B derivative ([3H]PbTx-3) to site 5 of the voltage-
sensitive sodium channels of excitable membranes.7 These
intriguing biological aspects coupled with the synthetically
formidable molecular architecture of these natural products
have spurred the interest of the synthetic community.8–12 In
this Letter, we report a stereocontrolled synthesis and
structure analysis of the A/B-ring fragment of GAB, which
ultimately led to the reassignment of the absolute configu-
ration of the polycyclic ether region of the originally
proposed structure.
We envisaged that the A/B-ring fragment 1a of GAB
would be synthesized from alcohol 2 via a diastereoselective
bromoetherification,12 which in turn could be derived from
alkylborate 3 and vinyl iodide 4 through B-alkyl Suzuki-
Miyaura coupling13 (Scheme 1). The synthesis of vinyl iodide
4 was planned from allylic alcohol 5 with Sharpless
asymmetric epoxidation used as a key step to introduce the
C914 stereocenter.
methyl ketone 8, which was desilylated and subsequently
reacted with methyl propiolate in the presence of NMM to
afford ꢀ-alkoxyacrylate 9. Upon treatment with SmI2 in the
presence of methanol,16 reductive cyclization of 9 proceeded
smoothly to yield tricyclic lactone 10 as a single stereoiso-
mer. The newly generated stereocenters were established by
NOE experiments as shown. DIBALH reduction of 10
followed by a Wittig reaction, and TMS protection of the
remaining alcohol provided enoate 11. After DIBALH
reduction, the resultant allylic alcohol 5 was subjected to
Sharpless asymmetric epoxidation using (+)-DET, yielding
hydroxy epoxide 12 as a single stereoisomer. Hydroxy
epoxide 12 was efficiently transformed into propargylic
alcohol 14 via chloro-epoxide 13 by the Takano protocol.17
Iodination of 14, followed by diimide reduction18 of the
resultant iodoalkyne 15, afforded vinyl iodide 4.
The synthesis of vinyl iodide 4 started with alcohol 6,15
which was converted to nitrile 7 via the corresponding
mesylate (Scheme 2). Exposure of 7 to MeLi provided
(7) Inoue, M.; Hirama, M.; Satake, M.; Sugiyama, K.; Yasumoto, T.
Toxicon 2003, 41, 469.
(8) (a) Kadota, I.; Oguro, N.; Yamamoto, Y. Tetrahedron Lett. 2001,
42, 3645. (b) Kadota, I.; Takamura, H.; Yamamoto, Y. Tetrahedron Lett.
2001, 42, 3649
.
(9) (a) Clark, J. S.; Fessard, T. C.; Wilson, C. Org. Lett. 2004, 6, 1773.
(b) Clark, J. S.; Kimber, M. C.; Robertson, J.; McErlean, C. S. P.; Wilson,
C. Angew. Chem., Int. Ed. 2005, 44, 6157
.
(10) Roberts, S. W.; Rainier, J. D. Org. Lett. 2007, 9, 2227
.
(11) (a) Sato, K.; Sasaki, M. Org. Lett. 2005, 7, 2441. (b) Sato, K.;
Sasaki, M. Angew. Chem., Int. Ed. 2007, 46, 2518. (c) Sato, K.; Sasaki, M.
Tetrahedron 2007, 63, 5977
.
(12) Fuwa, H.; Suzuki, A.; Sato, K.; Sasaki, M. Heterocycles 2007, 72,
139
.
(13) For reviews of Suzuki-Miyaura coupling, see: (a) Suzuki, A.;
Miyaura, N. Chem. ReV. 1995, 95, 2457. (b) Chemler, S. R.; Trauner, D.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40, 4544.
(14) The numbering of carbon atoms of all compounds in this paper
corresponds to that of the natural product.
(16) Hori, N.; Matsukura, H.; Matsuo, G.; Nakata, T. Tetrahedron 2002,
58, 1853.
(15) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J. Am. Chem.
Soc. 2002, 124, 14983.
(17) Takano, S.; Samizu, K.; Sugihara, T.; Ogasawara, K. J. Chem. Soc.,
Chem. Commun. 1989, 1344.
2212
Org. Lett., Vol. 10, No. 11, 2008

The key fragment assembly and the completion of the
synthesis are illustrated in Scheme 3. A mixture of iodide
Scheme 3. Synthesis of A/B-Ring Fragment 1a
Figure 2. A plausible rationale for the stereochemical outcome of
the bromoetherification of 2.
group, followed by reprotection of the 1,3-diol moiety as its
benzylidene acetal, gave an alcohol, which was oxidized to
the corresponding acid and subsequently esterified to afford
methyl ester 20. Finally, removal of the TBS group by the
action of TASF22 and saponification provided the A/B-ring
fragment 1a.
1
The H and 13C NMR chemical shifts for the C1-C13
portion of 1a (1:1 CD3OD/C5D5N) were compared with those
of the corresponding moiety of GAB (Table 1). It was
1
Table 1. H and 13C NMR Chemical Shift Deviations between
GAB and Model Compounds 1a-d (1:1 CD3OD/C5D5N)a
17, obtained by iodination of alcohol 16,12 and B-MeO-
9-BBN was treated with t-BuLi in diethyl ether.19 The
generated alkylborate 3 was coupled in situ with iodide 4 in
the presence of a [PdCl2(dppf)]/Ph3As catalyst system and
cesium carbonate in aqueous THF/DMF at 50 °C. This
process provided the desired cis-olefin 18 in 75% yield. After
silylation of the C9 hydroxy group, the MPM group was
removed to give alcohol 2. Exposure of 2 to NBS in CH3CN
resulted in a diastereoselective bromoetherification to provide
a bromide,20 which was immediately reduced under radical
conditions to furnish the desired tricyclic compound 19 in
an excellent overall yield. The stereochemistries at the C4,
C5, and C7 positions were unambiguously confirmed by an
NOESY experiment as shown. The desired isomer 19 would
be derived from the transition state A (TS-A) after radical
reduction, whereas TS-B would give the corresponding C7-
epimer 19 (Figure 2). TS-A would be energetically more
stable than TS-B, which suffers from the steric interaction
between the C51 methyl group and the C7-C9 moiety.21
Hydrogenolysis of 19 with a concomitant loss of the TMS
1H NMR [∆(δN - δS)]
13C NMR [∆(δN - δS)]
position
2
1a
1b
1c
1d
1a
1b
0.6
1c
1d
0.7
0.06
0.00
0.00
0.02
0.04
0.06
0.01
0.01
0.01
0.05
0.10
0.02
0.01
0.08
0.08
0.09
0.02
0.02
0.00
0.06
0.6
0.6
3
4
5
6
0.0
0.3
0.1
0.1
0.2
0.0
0.3
0.4
0.1
0.3
0.1
0.3
0.2
0.0
0.2
0.5
-0.02 -0.01
-0.02 -0.09
0.02 -0.03
0.02 -0.11
7
8
0.06
0.16
0.02
0.11 -0.5 -2.3 -0.2 -2.4
0.0 0.6
-0.15 -0.09 -0.04 -0.29 -1.7 -1.0
0.12 -0.02 -0.04
0.00
0.19
9
10
0.08
0.09
0.10
0.18
0.04
1.4
0.5
0.4
0.8
0.1 -1.3
0.3
0.12 -0.11 -0.09
0.01 -0.11 -0.11
0.4
11
12
13
-0.39 -0.38 -0.06 -0.08
1.4
0.3
0.3
1.7
0.3
0.3
0.1
0.2
0.6
0.3
0.2
1.2
-0.05 -0.05 -0.06 -0.01
-0.10 -0.11 -0.05 -0.06
50
51
0.10
0.03
0.12
0.02
0.05
0.05
0.12
0.03
0.3
0.1
0.5
0.3
0.0
0.5
0.1
0.1
0.7
0.4
0.1
0.8
12Me -0.02 -0.03 -0.01 -0.01
(18) Myers, A. G.; Zheng, B.; Movassaghi, M. J. Org. Chem. 1997, 62,
7307.
a
1H and 13C NMR spectra of natural GAB and 1a-d were recorded
at 400 MHz (100 MHz) and 600 MHz (150 MHz), respectively. Chemical
shifts are reported in ppm relative to the internal residual solvent (1H
NMR, CD2HOD 3.31 ppm; 13C NMR, CD3OD 49.8 ppm). δN and δS
are chemical shifts of the natural product and synthetic model com-
pounds, respectively.
(19) Marshall, J. A.; Johns, B. A. J. Org. Chem. 1998, 63, 7885.
(20) For selected related examples, see: (a) Fukuyama, T.; Wang, T. L. J.;
Kishi, Y. J. Am. Chem. Soc. 1979, 101, 260. (b) Braddock, D. C.; Bhuva,
R.; Millan, D. S.; Pe´rez-Fuertes, Y.; Roberts, C. A.; Sheppard, S. N.; Solanki,
S.; Stokes, E. S. E.; White, A. J. P. Org. Lett. 2007, 9, 445.
(21) Our previous explanation12 for the stereochemical outcome of the
bromoetherification has turned out to be misleading, since this method could
also be effective for the construction of the A-ring of compounds 1b-d.
For plausible rationales for the diastereoselectivity of the bromoetherifica-
tions in the synthesis of 1b-d, see Supporting Information.
observed that the H and 13C NMR chemical shifts of the
C7-C11 moiety of 1a significantly deviated from those of
1
Org. Lett., Vol. 10, No. 11, 2008
2213

GAB.23 These spectroscopic discrepancies suggested that
the original stereochemical assignment of GAB should be
reexamined. According to Satake and co-workers, the relative
stereochemical correlations between C7/C9 and C9/C11 were
determined unambiguously by the modified Mosher method,
1c represents an enantiomer of the A/B-ring fragment of
GAB. Thus, the present result indicates that the configuration
of the polycyclic ether region of GAB should be revised such
that it is the opposite of the original assignment. Overall,
we revised the structure of GAB as shown in Figure 1.
3
performed mainly on the basis of JH,H analysis and NOE
data, and the absolute configuration of the C9 hydroxy group
was established by the modified Mosher method.4 Since
unambiguous assignment of the relative configuration of the
C7-C11 moiety deemed necessary, we decided to synthesize
three possible diastereomers 1b-d as potential candidates
of the A/B-ring substructure of GAB (Figure 3).
In conclusion, we have described a stereocontrolled
synthesis of the A/B-ring fragment of GAB, wherein the
fragment assembly was efficiently accomplished by Suzuki-
1
Miyaura coupling. However, the H and 13C NMR data of
the A/B-ring fragment 1a differed significantly from those
of the C1-C13 moiety of GAB, respectively, indicating that
the original stereochemical assignment should be reexamined.
Fortunately, the high convergency of our synthetic route
allowed us to elaborate three possible diastereomers 1b-d
1
efficiently. We finally found that the H and 13C NMR
chemical shifts of 1c matched well those of GAB, concluding
that the absolute configuration of the polycyclic ether region
of GAB should be revised such that it is the opposite of the
original assignment. In view of biosynthesis, the structures
of other gambieric acids should also be revised in a similar
manner.
Figure 3. Possible diastereomeric compounds for the A/B-ring
fragment of GAB.
Acknowledgment. This research was financially supported
in part by Grants-in-Aid for Scientific Research from the
Japan Society for Promotion of Science (JSPS) and the
Ministry of Education, Culture, Sports, Science and Technol-
ogy (MEXT), Japan. We wish to thank Professor Masayuki
Satake (The University of Tokyo), Professor Yasukatsu
Oshima (Tohoku University), and Dr. Takeshi Yasumoto
(Japan Food Research Laboratories) for providing copies of
1H NMR and HSQC spectra of gambieric acid B and for
valuable discussions.
Model compounds 1b-d were synthesized in a manner
similar to that described for 1a.24 Their H and 13C NMR
1
chemical shifts measured in 1:1 CD3OD/C5D5N are sum-
marized in Table 1. Clearly, the 1H and 13C NMR chemical
shifts of 1c matched well those of GAB, while the other
diastereomers displayed different spectroscopic properties.
3
Furthermore, conformational analysis of 1c based on JH,H
values and the NOESY and HMBC spectra revealed that 1c
reproduces not only the relative stereochemistry but also the
conformation of the C7-C11 moiety of the parent com-
pound.24 Because the C9 absolute configuration of 1c is
opposite to that of the natural product that had been
Supporting Information Available: Synthetic schemes
1
for compounds 1b-d, detailed H and 13C NMR chemical
shifts of compounds 1a-d, conformational analysis of
compound 1c, and full experimental details and copies of
1H and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(22) (a) Barrett, A. G. M.; Pen˜a, M.; Willardsen, J. A. J. Org. Chem.
1996, 61, 1082. (b) Scheidt, K. A.; Chen, H.; Follows, B. C.; Chemler,
S. R.; Coffey, D. S.; Roush, W. R. J. Org. Chem. 1998, 63, 6436.
(23) Similarly, the 1H and 13C NMR chemical shifts of the C7-C11
moiety of 1a in C5D5N differed from those of GAB in C5D5N. See
Supporting Information for details.
(24) See Supporting Information for details.
OL800642T
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Org. Lett., Vol. 10, No. 11, 2008