C-glycosides to fused polycyclic ethers. An efficient entry into the A-D ring system of gambierol.

Article abstract of DOI:10.1021/ol016434w

[reaction: see text]. This Letter describes our use of C-glycosides to synthesize the A-D ring system of the marine ladder toxin gambierol in 20 steps.

Full text of DOI:10.1021/ol016434w

ORGANIC
LETTERS
2001
Vol. 3, No. 18
2919-2922
C-Glycosides to Fused Polycyclic
Ethers. An Efficient Entry into the A−D
Ring System of Gambierol
Jason M. Cox and Jon D. Rainier*
Department of Chemistry, The UniVersity of Arizona, Tucson, Arizona 85721
rainier@u.arizona.edu
Received July 13, 2001
ABSTRACT
This Letter describes our use of C-glycosides to synthesize the A−D ring system of the marine ladder toxin gambierol in 20 steps.
Gambierol was isolated in 1993 by Yasumoto and co-workers
as part of a screening study to determine the causative agent
of ciguatera poisoning from the marine dinoflagellate Gam-
bierdiscus toxicus.1 As part of this initial study, the Yasumoto
group determined gambierol’s relative configuration; in
subsequent experiments, they elucidated its absolute struc-
ture.2
have also become interested in the synthesis of gambierol.
Retrosynthetically, we envisioned that gambierol’s octacyclic
framework could be constructed from the coupling of a
tetracyclic A-D subunit with a tricyclic F-H subunit. In
turn, we were confident that each of these fragments could
be constructed in a linear fashion using a strategy that would
be similar to the one that we had employed in our formal
synthesis of (()-hemibrevetoxin B.5 Outlined herein is the
partial achievement of these goals through the synthesis of
the gambierol A-D ring system.
From our perspective, the A-D subunit presented several
challenging stereochemical problems, of which the most
noteworthy involved the selective incorporation of the C-7
and C-11 stereocenters where the angular methyl groups were
in a 1,3-diaxial orientation to one another.6 We were hopeful
that our ability to generate C-glycosides having either cis or
trans stereochemistry relative to the adjacent alcohol would
enable us to overcome these challenges.7
Not surprisingly, gambierol’s polycyclic ether architecture
and its intriguing biological activity has attracted the interest
of a number of synthetic chemists. Thus far, this attention
has led to the generation of the A-B, C-G, and E-H ring
systems by Yamamoto3 and the synthesis of the F-H ring
system by Sasaki.4
(3) Kadota, I.; Park, C.-H.; Ohtaka, M.; Oguro, N.; Yamamoto, Y.
Tetrahedron Lett. 1998, 39, 6365. (b) Kadota, I.; Kadowaki, C.; Yoshida,
N.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 6369. (c) Kadota, I.; Ohno,
A.; Matsukawa, Y.; Yamamoto, Y. Tetrahedron Lett. 1998, 39, 6373. (d)
Kadowaki, C.; Chan, P. W. H.; Kadota, I.; Yamamoto, Y. Tetrahedron Lett.
2000, 41, 5769. (e) Kadota, I.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J.
Am. Chem. Soc. 2001, 123, 6702.
(4) Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron Lett. 2000, 41,
8371. (b) Fuwa, H.; Sasaki, M.; Tachibana, K. Tetrahedron 2000, 57, 3019.
(5) Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org. Chem. 2001, 66,
1380.
As part of our program utilizing C-glycosides in the
synthesis of polycyclic ether containing natural products, we
(1) Satake, M.; Murata, M.; Yasumoto, T. J. Am. Chem. Soc. 1993, 115,
361.
(2) Morohashi, A.; Satake, M.; Yasumoto, T. Tetrahedron Lett. 1999,
40, 97.
(6) Sasaki and Yamamoto have employed somewhat circuitous routes
to the similarly substituted gambierol F,G-ring system. See refs 3d and 4.
10.1021/ol016434w CCC: $20.00 © 2001 American Chemical Society
Published on Web 08/08/2001

Our efforts toward the gambierol A-D subunit began with
the synthesis of the dihydropyran A-ring using a hetero-
Diels-Alder cycloaddition reaction between aldehyde 28 and
diene 3.9 Because of its success in catalyzing the analogous
reaction between Danishefsky’s diene and 2,8 our initial
experiments examined Keck’s titanium BINOL protocol.10
Surprisingly, when diene 3 was subjected to 2, BINOL, and
Ti(Oi-Pr)4, no reaction was observed.11 Although other Lewis
acid/BINOL complexes gave moderate yields of cycloadduct,
the cycloadduct was formed racemically or in low enantio-
meric excess.12
With the failure of the BINOL complexes to catalyze the
asymmetric reaction between 2 and 3, we turned to Jacob-
sen’s tridentate Cr(III) catalyst 5.13 Although 5 had not been
subjected to 3 prior to our work, this catalyst had performed
remarkably well with other substituted dienes. To our delight,
5 catalyzed the reaction between 2 and 3 to give cycloadduct
4 in both high yield and high enantiomeric excess (eq 1).14,15
at C-6 relative to gambierol, we were confident that a
subsequent Mitsunobu inversion would enable us to access
the correct C-6 diastereomer. Moreover, we were hopeful
that the C-6 stereocenter could be used to control the facial
selectivity in the subsequent reaction of 6 with dimethyl
dioxirane.17
Fortunately, we had the opportunity to test this latter notion
immediately. Exposure of 6 to dimethyldioxirane18 followed
by propenylmagnesium chloride19 resulted in the generation
of 7 after acylation of the newly formed 3° hydroxyl group.
As we had hoped-for, the C-3 alkoxy substituent had
controlled the facial selectivity in the oxidation reaction; anti
addition to the glycal anhydride had resulted in the desired
stereochemistry at C-8.
Having established the gambierol A-ring, we investigated
the synthesis of the B-ring using an enol ether-olefin ring
closing metathesis (RCM) protocol.20 As in our previous
work, Takai’s procedure was utilized to generate the acyclic
enol ether from 7.21 Both the Schrock Mo alkylidene 922 and
the 2nd generation Grubbs Ru alkylidene 1023 catalyzed the
conversion of the acyclic enol ether into the cyclic enol ether
8.
With ready access to 8, we were in a position to examine
the use of our C-glycoside forming technology in the
formation of the critical C-11 stereocenter. Unfortunately,
the addition of allyl nucleophiles to the epoxide from 8
resulted in either the exclusive formation of the undesired
C-11 diastereomer or in the formation of mixtures at C-11.24
Our inability to selectively generate the gambierol C-11
stereocenter forced us to consider other methods for its
preparation. It occurred to us that a solution to our problem
might come from the use of a Claisen rearrangement from a
C-10 allyl enol ether. This strategy was appealing not only
because of the likelihood that the C-7 angular methyl would
direct the stereoselectivity in the rearrangement in the desired
sense but also because of the possibility that we could
generate the rearrangement precursor by simply subjecting
a bicyclic ketal precursor to an acid-catalyzed elimination
reaction.25
With an efficient entry into pyrone 4, we set out to convert
it into the gambierol A,B-dihydropyran 8 (Scheme 1). 1,2-
Scheme 1a
To generate the precursor to the Claisen rearrangement,
we subjected glycal 8 to m-CPBA in MeOH. This resulted
in the formation of the corresponding hydroxy ketal as an
inconsequential 2:1 mixture of anomers in a 92% overall
yield. Allyl ether formation then provided rearrangement
(8) McDonald, F. E.; Vadapally, P. Tetrahedron Lett. 1999, 40, 2235.
(9) Miyashita, M.; Yamasaki, T.; Shiratani, T.; Hatakeyama, S.; Miyaza-
wa, M.; Irie, H. Chem. Commun. 1997, 1787. (b) Barrett, A. G. M.; Carr,
R. A. E.; Attwood, S. V.; Richardson, G.; Walshe, N. D. A. J. Org. Chem.
1986, 51, 4840.
(10) Keck, G. E.; Li, X.-Y.; Krishnamurthy, D. J. Org. Chem. 1995, 60,
5998.
(11) The analogous cycloaddition reaction between Danishefsky’s diene
and 2 proceeds in 95% ee and 65% yield. See ref 8.
(12) We examined the use of BINOL with AlMe3 and B(OPh)3.
(13) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew. Chem.,
Int. Ed. 1999, 38, 2398.
a (a) NaBH4, CeCl3‚7H2O, EtOH, -60 °C to rt; (b) PMBCl, NaH,
DMF, 0 °C to rt (95%, 2 steps); (c) DMDO, CH2Cl2, -60 °C to rt;
CH2CHCH2MgCl, THF (65%); (d) Ac2O, i-Pr2NEt, DMAP, CH2Cl2
(78%); (e) TiCl4, Zn, PbCl2, TMEDA, CH2Br2, TMEDA, THF; (f)
10 (20 mol %), rt, 16 h (65%, 2 steps).
(14) Compound 4 is enantiomeric to that expected on the basis of
Jacobsen’s results. See ref 13.
(15) The enantiomeric excess of 4 was determined using a chiracel OD
HPLC column.
(16) Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103, 5454.
(17) Halcomb, R. L.; Danishefsky, S. J. J. Am. Chem. Soc. 1989, 111,
6661.
Reduction of the carbonyl in 4 using Luche’s conditions16
gave 6 after PMB ether formation. Although 6 is epimeric
(7) Rainier, J. D.; Cox, J. M. Org. Lett. 2000, 2, 2707.
2920
Org. Lett., Vol. 3, No. 18, 2001

precursor 11. When 11 was exposed to PPTS and pyridine
in PhCH3 we isolated an 8:1 mixture of C-glycosides 13 and
14 in 97% yield. As predicted, the major isomer from the
rearrangement (i.e., 13) had the desired C-11 stereochem-
istry.26 Although it was not isolated, we presume that the
reaction proceeded through allyl enol ether intermediate 12
and a subsequent Claisen rearrangement.27
the Schrock Mo catalyst 9 and the Grubbs Ru catalyst 10
could be used to generate 18, the Schrock catalyst provided
a significantly higher yield.
Scheme 2
Our next challenge was to establish the C-13 and C-14
stereochemistry. Assuming that the epoxidation of 18 with
dimethyl dioxirane would occur from the face opposite the
C-11 angular methyl group, our plan was to establish the
C-13 stereocenter through the use of a subsequent reduction
reaction. In this context, we were hopeful that the epoxide
oxygen could be used to deliver hydride to an oxocarbenium
ion at C-14.31 In the event, exposure of tricyclic glycal 18
to dimethyl dioxirane followed by DIBAl resulted in the
formation of the desired alcohol 20 in 69% yield. As
illustrated (eq 3), we presume that the 18 f 20 transforma-
tion occurs through the intermediacy of oxocarbenium ion
19 and the intramolecular delivery of hydride.
With an efficient approach to 13, we were prepared to
examine the inversion of the C-6 stereocenter. Oxidative
hydrolysis of the PMB ether and inversion of the resulting
2° alcohol using Martin’s Mitsunobu protocol28 gave 15
having the desired gambierol stereochemistry at C-6 after
TMS ether formation.29 Reduction of the C-10 ketone to the
desired equatorial alcohol30 was followed by esterification
with 17 to give RCM precursor 16.
Scheme 3a
To complete our synthesis of the A-D subunit of
gambierol, it remained to convert 20 into 21. Exposure of
20 to PPTS, pyridine, and heat resulted in the formation of
21 in 95% yield.25
Of note is the fact that the conversion of the functionalized
A,B ring system (i.e., 16) into the A-D tetracycle 21
required only four transformations. From our perspective,
this demonstrates the efficiency with which C-glycosides can
be used in the synthesis of fused polycyclic ethers.
a (a) DDQ, CH2Cl2, H2O (93%); (b) DEAD, PPh3, p-NO2C6H4-
CO2H PhCH3, 110 °C; (c) NaOH, H2O, THF, MeOH (70%, 2
steps); (d) TMSOTf, i-Pr2NEt, CH2Cl2 (87%); (e) NaBH4, EtOH;
(f) DCC, DMAP, (MeO)2CH(CH2)2CO2H (17), CH2Cl2 (91%, 2
steps).
As in the conversion of 7 into 8, acyclic enol ether
formation using the Takai protocol was followed by enol
ether-olefin RCM to give tricyclic enol ether 18. While both
To conclude, this Letter has described the use of C-
(18) Adam, W.; Bialas, J.; Hadjiarapoglou, L. Chem. Ber. 1991, 124,
2377.
glycosides in the formation of the A-D tetracyclic subunit
Org. Lett., Vol. 3, No. 18, 2001
2921

of the marine ladder toxin gambierol in 20 synthetic
transformations from diene 3. In addition to the successful
application of our previously reported strategies to fused
polycyclic ethers, we have also found a unique Claisen
rearrangement approach to C-glycosides. We are continuing
our efforts in each of these areas.
Acknowledgment. We gratefully acknowledge the Na-
tional Institutes of Health (GM56677), Research Corporation,
and Gencorp for support of this work. We would like to thank
Professor Michael P. Doyle for the use of his HPLC and
Professor Doyle and Professor Dominic McGrath for the use
of their polarimeters. The authors would also like to thank
Dr. Arpad Somagyi and Dr. Neil Jacobsen for help with mass
spectra and NMR experiments, respectively.
(19) For the addition of propenylmagnesium chloride to glycal epoxides,
see: (a) Best, W. M.; Ferro, V.; Harle, J.; Stick, R. V.; Tilbrook, D. M. G.
Aust. J. Chem. 1997, 50, 463. (b) Evans, D. A.; Trotter, B. W.; Coˆte´, B.
Tetrahedron Lett. 1998, 39, 1709. (c) Rainier, J. D.; Allwein, S. P. J. Org.
Chem. 1998, 63, 5310.
(20) For recent reviews on RCM, see: (a) Fu¨rstner, A. Angew. Chem.,
Int. Ed. 2000, 39, 3012. (b) Grubbs, R. H.; Chang, S. Tetrahedron 1998,
54, 4413.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(21) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem.
1994, 59, 2668.
(22) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare,
M.; O’Regan, M. B. J. Am. Chem. Soc. 1990, 112, 3875. (b) Fujimura, O.;
Fu, G. C.; Grubbs, R. H. J. Org. Chem. 1994, 59, 4029.
(23) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953. (b) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 3783. (c) Rainier, J. D.; Cox, J. M.; Allwein, S. P.
Tetrahedron Lett. 2001, 42, 179.
(24) The use of propenylmagnesium chloride resulted in the selective
formation of the undesired â-C-allyl glycoside, whereas the use of triallyl
aluminum and triallyl borane resulted in the formation of 1.5:1 and 1:1.5
mixtures of R- and â-C-allyl glycosides, respectively.
(25) Rainier, J. D.; Allwein, S. P. Tetrahedron Lett. 1998, 39, 9601.
(26) Determined from NOE experiments. See Supporting Information
(27) To the best of our knowledge, this is the first example of this
reaction. For related Claisen rearrangements to C-glycosides, see: (a) Vidal,
T.; Haudrechy, A.; Langlois, Y. Tetrahedron Lett. 1999, 40, 5677. (b)
Wallace, G. A.; Scott, R. W.; Heathcock, C. H. J. Org. Chem. 2000, 65,
4145 and references therein.
OL016434W
(28) Martin, S. F.; Dodge, J. A. Tetrahedron Lett. 1991, 32, 3017.
(29) The relative stereochemistry was established through the use of
extensive NOE experiments. The absolute stereochemistry was established
through the conversion of 13 into the corresponding C-6 Mosher’s esters
and using the Kakisawa method for determining the absolute stereochem-
istry. See ref 2 and Ohtani, I.; Kusumi, T.; Kashman, Y.; Kakisawa, H. J.
Am. Chem. Soc. 1991, 113, 4092.
(30) The selectivity in the NaBH4 reduction of the C-10 ketone is
expected on the basis of axial attack on the ketone and from the side opposite
the C-7 angular methyl group. For a discussion of related reductions in
cyclohexanones, see: Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereo-
chemistry of Organic Compounds; Wiley: New York, 1994; pp 734-735.
(31) Murai has carried out a related reaction. See: Fujiwara, K.; Awakura,
D.; Tsunashima, M.; Nakamura, A.; Honma, T.; Murai, A. J. Org. Chem.
1999, 64, 2616.
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Org. Lett., Vol. 3, No. 18, 2001