The total synthesis of gambierol

Article abstract of DOI:10.1021/ja043396d

This communication describes the total synthesis of the marine polyether toxin, gambierol. This work couples our iterative C-glycoside/enol ether-olefin metathesis strategy to the subunits with a unique olefin metathesis/carbonyl olefination reaction to bring the subunits together. Copyright

Full text of DOI:10.1021/ja043396d

Published on Web 12/24/2004
The Total Synthesis of Gambierol
Henry W. B. Johnson, Utpal Majumder, and Jon D. Rainier*
UniVersity of Utah, Department of Chemistry, 315 South 1400 East, Salt Lake City, Utah 84112
Received November 1, 2004; E-mail: rainier@chem.utah.edu
Scheme 2
The unique structural features of the marine polyether toxins,
when combined with their interesting biological properties, have
attracted the attention of the synthetic chemistry community.1
Representative of this family is gambierol, a ladder toxin isolated
from the cultured cells of Gambierdiscus toxicus and published in
1993 by Yasumoto and co-workers.2 Gambierol has shown toxicity
against mice (LD50 50 µg/kg) with symptoms resembling those of
the ciguatoxins, inferring the possibility that gambierol is involved
in ciguatera poisoning.3 To date, two total syntheses of gambierol
have been accomplished.4 Herein we describe our work resulting
in the total synthesis of this interesting target.
Our plan to synthesize gambierol was a convergent one that
centered on the use of an iterative C-glycoside/enol ether-olefin
ring-closing metathesis strategy to form the subunits followed by
an enol ether-olefin ring-closing metathesis reaction to generate
gambierol’s octacyclic core (Scheme 1). We found it attractive that
the subunit coupling chemistry would test the scope and limitations
of enol ether-olefin ring-closing metathesis chemistry; these
reactions had not been employed on substrates as complex as 3.5,6
After the ring closing metathesis, reductive cyclization and
incorporation of the side chain would deliver gambierol.
The successful implementation of this plan is illustrated in
Schemes 2 and 3. Yamaguchi coupling using equimolar quantities
of the A-C and F-H precursors 6 (7) and 8 (9) provided esters
10 (11) in high yield.7 To our dismay, attempts to convert ester 10
into acyclic enol ether RCM precursor 12 using the Takai-Utimoto
titanium methylidene protocol were not successful.8 Instead, we
observed nearly complete decomposition of the terminal olefin and
Scheme 1
a trace amount of cyclic enol ether 14.9-11 In an effort to inhibit
alkene decomposition, we next examined the reaction of internal
olefin 11. Surprisingly, this modification also failed to give acyclic
enol ether (e.g., 13, X ) H). Instead, it produced an increased
amount of cyclic material (e.g., 15), albeit in a capricious 10-
30% yield. Along with cyclic product, significant quantities (10-
20%) of the terminal olefin corresponding to 10 were produced
along with a number of unidentified products that seemed to result
from the decomposition of the terminal olefin. From all of these
experiments it was apparent that the presumed titanium methylidene
from the Takai-Utimoto reagent was preferentially reacting with
the olefin and that this reaction was not regioselective.12 If our
analysis was correct, we believed that the use of a substituted
titanium alkylidene reagent in the place of the normally used
methylidene reagent would extend the lifetime of the internal olefin
and, in theory, lead to a higher yield of cyclic enol ether. That is,
were we to use 1,1-dibromoethane instead of 1,1-dibromomethane
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10.1021/ja043396d CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3 a
(-)-gambierol. The spectroscopic and physical data for synthetic
gambierol were identical to that reported previously.2,4
In conclusion, a highly concise total synthesis of gambierol has
been achieved utilizing our iterative C-glycoside/metathesis meth-
odology. The longest linear sequence to the target was 44 steps
from D-glucal with a 1.2% overall yield. Perhaps most impressive
is the efficiency of the coupling chemistry where only 12 steps
were required to generate gambierol from the A-C and F-H
subunits. This compares very favorably with previous work in this
area and will significantly simplify our efforts to synthesize and
study analogues of this agent. We will report our efforts along these
lines in due course.
Acknowledgment. This manuscript is dedicated to our mentor
and friend, Professor Amos B. Smith, III on the occasion of his
60th birthday. We are grateful to the National Institutes of Health,
General Medical Sciences (GM56677) for support of this work.
We thank Dr. Charles Mayne for help with NMR experiments and
Dr. Elliot M. Rachlin for help in obtaining mass spectra.
Supporting Information Available: Characterization data and
copies of 1H NMR and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
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Prod. Rep. 2000, 17, 293. (b) Yasumoto, T. Chem. Rec. 2001, 1, 228.
(2) (a) Satake, M.; Murata, M.; Yasumoto, T. J. Am. Chem. Soc. 1993, 115,
361. (b) Morohashi, A.; Satake, M.; Yasumoto, T. Tetrahedron Lett. 1998,
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(3) For biological studies on gambierol see ref 1b and: (a) Fuwa, H.; Kainuma,
K.; Tachibana, K.; Tsukano, C.; Satake, M.; Sasaki, M. Chem. Eur. J.
2004, 10, 4894. (b) Ito, E.; Suzuki-Toyota, F.; Tashimori, K.; Fuwa, H.;
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a Reaction conditions: (a) Dimethyldioxirane, CH2Cl2, -78 to 0 °C;
DIBAL, CH2Cl2, 90% (10:1 mixture). (b) TPAP, NMO, 4 Å MS, CH2Cl2,
rt, 97%. (c) imidazole, toluene, 110 °C, 100% (4:1 mix of 14:15). (d) CSA,
MeOH, 0 °C, 90%. (e) Zn(OTf)2, EtSH, CH2Cl2, rt, 91%. (f) Ph3SnH, AIBN,
toluene, 110 °C, 95%. (g) TPAP, NMO, 4 Å MS, CH2Cl2, rt, 98%. (h)
CHI3, PPh3. KOt-Bu, 0 °C, 95%. (i) Zn-Cu couple, MeOH, AcOH, 0 °C,
85%. (j) SiF4, CH3CN, CH2Cl2, 0 °C, 89%. (k) 18, Pd2dba3‚CHCl3, P(furyl)3,
CuI, DMSO, 40 °C, 75%.
(4) (a) Fuwa, H.; Sasaki, M.; Satake, M.; Tachibana, K. Org. Lett. 2002, 4,
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Soc. 2002, 124, 14983. (c) Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.;
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in the preparation of the Takai-Utimoto reagent, regioselectivity
would not be an issue; reaction with the olefin in the undesired
sense would simply regenerate 11 or the olefin isomer of 11;
eventually, the alkylidene would react with the olefin in the desired
sense and lead to the formation of cyclic material. We were
extremely pleased to find that our analysis of this transformation
was accurate: the reaction of 11 with the titanium alkylidene from
1,1-dibromoethane provided cyclic enol ether 15 in 60% yield.
Interestingly, for the first time in our work with the gambierol
skeleton, we also isolated a 30% yield of acyclic enol ether 13
(X ) CH3).13
(5) For a recent review see: Deiters, A.; Martin, S. F. Chem. ReV. 2004,
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Having overcome the E-ring problem, we set out to convert 15
into gambierol’s octacyclic core (Scheme 3). Single-flask dimethyl
dioxirane (DMDO) oxidation of the oxepene and reduction of the
resulting anhydride with DIBAL resulted in the formation of the
C(17) alcohol in 90% yield as a 10:1 mixture of readily separable
diastereomers. Interestingly, the major diastereomer was the result
of epoxidation on the same face of 15 as the C(21) methyl group.14
Oxidation of the alcohols gave diastereomeric ketones 16 and 17.
The minor isomer (i.e., 17) was equilibrated to the major, desired
isomer using imidazole at elevated temperature. Completion of the
gambierol octacycle was accomplished by employing a reductive
cyclization sequence to the D-ring.15 That is, selective removal of
the TES and primary TBS groups using CSA gave the correspond-
ing hydroxy ketone; O,S-ketal formation and free-radical reduction
completed the generation of the gambierol core structure.
With the octacyclic skeleton in hand we turned to Yamamoto
and Sasaki’s protocols to incorporate the skipped triene side chain
and to complete the synthesis.4,16 Oxidation of 18 to the aldehyde
was followed by formation of the corresponding diiodolefin.17
Stereoselective reduction,4c,d global deprotection,18 and Stille
coupling of the resulting triol with dienyl stannane 204c,d provided
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Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem. 1994, 59, 2668.
(9) Attempts to generate the acyclic enol ether using other alkylidene reagents
(Tebbe, Petasis, Takeda) were also unsuccessful.
(10) The Tebbe reagent has been used to carry out related cyclizations. (a)
Stille, J. R.; Grubbs, R. H. J. Am. Chem. Soc. 1986, 108, 855. (b) Stille,
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Nadin, A. J. Am. Chem. Soc. 1996, 118, 10335.
(11) For a related transformation that utilizes the Takeda protocol see: Uehara,
H.; Oishi, T.; Inoue, M.; Shoji, M.; Nagumo, Y.; Kosaka, M.; Le Brazidec,
J.-Y.; Hirama, M. Tetrahedron 2002, 58, 6493.
(12) Mechanistically, we believe that cyclic product results from an olefin
metathesis, carbonyl olefination sequence. Allwein, S. P.; Cox, J. M.;
Howard, B. E.; Johnson, H. W. B.; Rainier, J. D. Tetrahedron 2002, 58,
1997.
(13) We have been able to convert 13 (X ) CH3) into 15 in an unoptimized
60% yield using the Grubbs 2 catalyst.
(14) At present, we do not have a clear explanation for the facial selectivity in
the DMDO oxidation of 15. Sasaki observed similar selectivity in the
hydroboration of a related oxepene in his gambierol work.4a,b
(15) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.; Veale,
C. A. J. Am. Chem. Soc. 1989, 111, 5321.
(16) Kadota, I.; Ohno, A.; Matsukawa, Y.; Yamamoto, Y. Tetrahedron Lett.
1998, 39, 6373.
(17) Michel, P.; Rassat, A. Tetrahedron Lett. 1999, 40, 8579.
(18) Corey, E. J.; Yi, K. Y. Tetrahedron Lett. 1992, 33, 2289.
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