Synthesis of an A-E gambieric acid subunit with use of a C-glycoside centered strategy

Article abstract of DOI:10.1021/ol0707970

This paper describes our synthesis of the A-E subunit of gambieric acid (GA) in addition to the synthesis of the A-ring and the C-E tricycle The use of an enol ether-olefin RCM strategy to couple the A and C-E subunits and, in the process, generate the B-

Full text of DOI:10.1021/ol0707970

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2227-2230
Synthesis of an A−E Gambieric Acid
Subunit with Use of a C-Glycoside
Centered Strategy
Scott W. Roberts and Jon D. Rainier*
Department of Chemistry, UniVersity of Utah, 315 South 1400 East,
Salt Lake City, Utah 84112
rainier@chem.utah.edu
Received April 3, 2007
ABSTRACT
This paper describes our synthesis of the A
−
E subunit of gambieric acid (GA) in addition to the synthesis of the A-ring and the C
−E tricycle.
The use of an enol ether-olefin RCM strategy to couple the A and C−E subunits and, in the process, generate the B-ring is noteworthy.
The gambieric acids A-D (GA’s) are members of the marine
ladder toxin family of natural products whose isolation from
the marine dinoflagellate Gambierdiscus toxicus was first
reported in 1992 by Yasumoto and co-workers.1 As part of
their initial studies, the Yasumoto group determined the
relative structure of the GA’s; they subsequently elucidated
their absolute structure.2 The polycyclic ether architecture
of the GA’s consists of one 9-membered ring, two 7-mem-
bered rings, six 6-membered rings, and one 5-membered ring
along with 27 stereocenters. The members of this family
differ from one another at the J-ring side chain (free alcohol
vs ester) and the B-ring alcohol (2° vs 3°).
of inhibiting the binding of brevetoxin B (PbTx-3) to site 5
of voltage gated sodium channels.4,5 Interestingly, GA-A is
a potent antifungal agent, has been shown to promote the
growth of Gambierdiscus toxicus, and is the only member
of this family that is excreted into the aqueous medium.6,7
As with the other members of the marine ladder toxin family,
a thorough understanding of the biological activity of the
GA’s awaits their chemical synthesis as they are not gen-
erated in any significant quantity by the producing organism.8
Not surprisingly, the polycyclic ether architecture and
intriguing biological activity of the GA’s has attracted the
attention of chemists interested in their synthesis, including
us.9 Central to our approach to these and other structurally
related targets have been three reactions: the generation of
carbon (C)-glycosides from the single flask coupling of glycal
Equally interesting to their structures is the biological
profile of the GA’s. Most of the preliminary data that have
been published have come from work with GA-A. Although
GA-A lacks toxicity in mice,3 it has been shown to be capable
(4) Inoue, M.; Hirama, M.; Satake, M.; Sugiyama, K.; Yasumoto, T.
Toxicon 2003, 41, 469.
(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.
(2) Morohashi, A.; Satake, M.; Nagai, H.; Oshima, Y.; Yasumoto, T.
Tetrahedron 2000, 56, 8995.
(3) Because of a limited supply, the highest concentration that the GA’s
were tested at was 1 mg/kg. In comparison, the LD50 for ciguatoxin (CTX)
in mice is 0.35 µg/kg. See refs 4 and 6.
(5) Brevenal and gambierol are two other members of this family that
inhibit PbTx-3 binding. See: LePage, K. T.; Rainier, J. D.; Johnson, H.
W. B.; Baden, D. G.; Murray, T. F. Submitted for publication.
(6) Sakamoto, B.; Nagai, H.; Hokama, Y. Phycologia 1996, 35, 350.
(7) Nagai, H.; Makami, Y.; Yazawa, K.; Gonoi, T.; Yasumoto, T. J.
Antibiot. 1993, 46, 520.
(8) A 5000 L fermentation broth yielded 14.9 mg of GA’s A-D.
10.1021/ol0707970 CCC: $37.00
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alcohol via the intermediacy of the methyl xanthate gave
olefinic ester cyclization precursor 11.15
Scheme 1
Acyclic enol ether formation with the Takai Utimoto
conditions and enol ether-olefin RCM delivered 13 in 80%
overall yield.16 As we had observed during our gambierol
efforts,10 this reaction required the use of the Grubbs second
generation Ru alkylidene 12 as a consequence of the ability
of 12 to withstand the elevated temperatures required for
tetrasubstituted enol ether formation.17,18
From 13, the conversion to tricycle 15 was accomplished
in two flasks. Oxidation of the D-ring enol ether with DMDO
and reduction of the intermediate anhydride with DIBAL-H
gave alcohol 14 in 95% yield as the only detectable isomer.
Subjecting 14 to PPTS, pyridine, and heat effected cyclization
to the corresponding mixed acetal and elimination to give
the GA E-ring oxepene as 15.19 To incorporate the requisite
atoms needed for a subsequent pairing with a precursor to
the H-J tricycle, we subjected 15 to DMDO and propenyl
magnesium chloride to give 16 as a 2:1 mixture of diastereo-
mers. The mixture of diastereomers resulted from a lack of
anhydrides with nucleophiles, the synthesis of cyclic enol
ethers with ring-closing metathesis (RCM), and the synthesis
of cyclic enol ethers with acid-catalyzed cyclizations.10
With these reactions in mind, the GA’s would arise from
the sequential coupling of appropriately substituted A-ring
(i.e., 6) and C-E (i.e., 7) subunits followed by the pairing
of the resulting pentacycle with an appropriately substituted
tricyclic H-J precursor. As envisioned, key to both building
and combining each of these subunits would be enol ether-
olefin RCM chemistry. Described in this paper are our
preliminary results in this area and the assembly of the A
and C-E rings along with their coupling to generate a GA
A-E pentacycle.
1
selectivity in the oxidation reaction as determined by H
NMR.20 Interestingly, the anhydride from the DMDO oxida-
tion of 15 was unusually robust; its coupling with propenyl
(9) (a) Evans, P. A.; Roseman, J. D.; Garber, L. T. J. Org. Chem. 1996,
61, 4880. (b) Kadota, I.; Oguro, N.; Yamamoto, Y. Tetrahedron Lett. 2001,
42, 3645. (c) Kadota, I.; Takamura, H.; Yamamoto, Y. Tetrahedron Lett.
2001, 42, 3649. (d) Clark, J. S.; Fessard, T. C.; Wilson, C. Org. Lett. 2004,
6, 1773. (e) Sato, K.; Sasaki, M. Org. Lett. 2005, 7, 2441. (f) Clark, J. S.;
Kimber, M. C.; Robertson, J.; McErlean, C. S. P.; Wilson, C. Angew. Chem.,
Int. Ed. 2005, 44, 6157. (g) Sato, K.; Sasaki, M. Angew. Chem., Int. Ed.
2007, 46, 2518.
(10) For an example of the use of this approach in the generation of
ladder toxins see: (a) Majumder, U.; Cox, J. M.; Johnson, H. W. B.; Rainier,
J. D. Chem. Eur. J. 2006, 12, 1736. (b) Johnson, H. W. B.; Majumder, U.;
Rainier, J. D. Chem. Eur. J. 2006, 12, 1747.
After having explored several C-glycoside centered ap-
proaches to the C-E tricycle we settled upon the sequence
of reactions outlined in Schemes 2 and 3 and eqs 1-3.
Scheme 2
(11) We employed a similar sequence in our formal total synthesis of
hemibrevetoxin B. See: (a) Rainier, J. D.; Allwein, S. P.; Cox, J. M. Org.
Lett. 2000, 2, 231. (b) Rainier, J. D.; Allwein, S. P.; Cox, J. M. J. Org.
Chem. 2001, 66, 1380.
(12) Available in 11 steps from L-glucose. See the Supporting Information
and: (a) Boulineau, F. P.; Wei, A. J. Org. Chem. 2004, 69, 3391. (b)
Boulineau, F. P.; Wei, A. Org. Lett. 2004, 6, 119.
(13) Roberts, S. W.; Rainier, J. D. Org. Lett. 2005, 7, 1141.
(14) Majumder, U.; Cox, J. M.; Rainier, J. D. Org. Lett. 2003, 5, 913.
(15) Paquette, L. A.; Oplinger, J. A. J. Org. Chem. 1988, 53, 2953.
(16) Takai, K.; Kakiuchi, T.; Kataoka, Y.; Utimoto, K. J. Org. Chem.
1994, 59, 2668.
(17) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(18) Sanford, M. S.; Love, J. A.; Grubbs, R. H. J. Am. Chem. Soc. 2001,
123, 6543.
(19) (a) Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson, H. W. B.;
Rainier, J. D. Tetrahedron 2002, 58, 1997. (b) Rainier, J. D.; Allwein, S.
P. Tetrahedron Lett. 1998, 39, 9601.
(20) For a theoretical discussion of the effect of substitution on anhydride
formation see: Orendt, A. M.; Roberts, S. W.; Rainier, J. D. J. Org. Chem.
2006, 71, 5565.
Central to our synthesis of this subunit was a 3-step sequence
to the D- and E-rings from the fully functionalized C-ring
11.11 Starting from L-glucal derived C-ketoside8,12,13 8,
esterification with 5,5-dimethoxypentanoic acid (9) and TMS
ether hydrolysis gave 10.14 Deoxygenation of the C(17)
2228
Org. Lett., Vol. 9, No. 11, 2007

Scheme 3
Scheme 4
(Scheme 4). Our efforts to this subunit began with 21 (avail-
able in six steps from the alkylation of Myer’s pseudoephe-
drine auxiliary).9b,22 Oxidation of 21 and treatment of the
resulting aldehyde with HCl and MeOH resulted in hydroly-
sis of the TBS ether and cyclization to give tetrahydrofuran
22 in 75% yield. The addition of allylsilane to 22 in the
presence of BF3‚Et2O resulted in the formation of 23 in
quantitative yield as a single diastereomer as evidenced by
1H NMR of the crude reaction mixture.23,24 Conversion of
23 into the corresponding C(9) aldehyde 24 and the coupling
of 24 with the TBS ketene acetal of methyl acetate gave the
chelated 1,3-induction product 25 as the major diastereo-
mer.25 The completion of the A-ring coupling precursor 26
was accomplished by protection of the 2° alcohol as the
corresponding TIPS ether and hydrolysis of the ester.
With precursors 19, 20, and 26 in hand, we were prepared
to examine their combination and, in the process, the
generation of the GA B-ring. As mentioned above, central
to our approach to solving problems like this has been the
use of an enol ether-olefin RCM coupling sequence.26 The
union of 19 and 26 by using the Yamaguchi protol gave ester
27 in an unoptimized 69% yield (Scheme 5).27 Although ester
27 underwent quantitative conversion to acyclic enol ether
28 the subsequent RCM reaction gave a multitude of products
regardless of the conditions and catalyst used. Our best results
involved the use of the Schrock Mo catalyst 2928 and gave
<50% yield of a mixture that contained a significant quantity
of cyclic enol ether 30 but that also contained other unknown
substances that we have tentatively assigned as oligomers
of 28.
magnesium chloride required 3 h at room temperature.21
Although the lack of selectivity in the formation of 16 was
obviously an undesired outcome, it turned out to be of little
consequence as the mixture could be converted to the desired
stereoisomer (i.e., 17) through the illustrated three-step
equilibration sequence.
In addition to examining the incorporation of the appropri-
ate E-ring functionality, we also utilized 15 to model the
coupling of a C-E tricycle (i.e., 19 and 20) with the A-ring
precursor (i.e., 26). The conversion of 15 into 18 and 19 is
illustrated in eq 2 and involved the reduction of the oxepene,
removal of the silylene, generation of the 1° triflate and 2°
TBS ether, and displacement of the triflate with allyl cuprate.
Hydrolysis of the TBS ether gave terminal olefin coupling
precursor 19.
Internal olefin coupling precursor 20 was generated from
18 with use of standard conditions (eq 3).
(22) (a) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky,
D. J.; Gleason, J. L. J. Am. Chem. Soc. 1997, 119, 6496. (b) White, J. D.;
Xu, Q.; Lee, C.-S.; Valeriote, F. A. Org. Biomol. Chem. 2004, 2, 2092.
(23) We also examined the coupling of 24 with enol silanes without any
success.
(24) Larsen, C. H.; Ridgway, B. H.; Shaw, J. T.; Smith, D. M.; Woerpel,
K. A. J. Am. Chem. Soc. 2005, 127, 10879.
(25) (a) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am.
Chem. Soc. 2001, 123, 10840. (b) Evans, D. A.; Allison, B. D.; Yang, M.
G. Tetrahedron Lett. 1999, 40, 4457.
(26) See ref 10 and: Johnson, H. W. B.; Majumder, U.; Rainier, J. D. J.
Am. Chem. Soc. 2005, 127, 848.
(27) Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull.
Chem. Soc. Jpn. 1979, 52, 1989.
Having successfully uncovered an approach to the GA
C-E ring precursors, we next pursued the GA A-ring
(21) We observed a similar result in our hemibrevetoxin B work. See
ref 11.
(28) Schrock, R. R.; Murdzek, J. S.; Bazan, G. C.; Robbins, J.; DiMare,
M.; O’Regan, M. B. J. Am. Chem. Soc. 1990, 112, 3875.
Org. Lett., Vol. 9, No. 11, 2007
2229

cross-metathesis. Much to our surprise and delight, when
dibromoethane rather than dibromomethane was used to
generate the Takai-Utimoto reagent we did not observe any
acyclic enol ether but instead only cyclized product 30.29,30
Presumably, 30 comes from an olefin metathesis, carbonyl
olefination mechanism implying that the more sterically
hindered titanium ethylidene reagent preferentially undergoes
reaction with the olefin in 31.31 That the product distribution
from olefinic ester cyclizations can be effected by simple
changes in the alkylidene reagent is a potentially powerful
discovery. We are currently examining this phenomenon with
other substrates.
Scheme 5
In summary, we have synthesized the A-E subunit of the
marine ladder toxin gambieric acid A utilizing a C-glycoside
and enol ether olefin RCM centered strategy. In addition to
the generation of the C-E subunit from L-glucal, of note in
these studies is the efficient generation of the A-ring, the
convergent coupling of the A- and C-E subunits, and the
generation of the B-ring using an in situ prepared titanium
ethylidene reagent. Future efforts include the generation of
the H-J ring system, the completion of the synthesis of GA,
and the examination of GA’s fascinating biological profile.
Acknowledgment. We are grateful to the National
Institutes of Health, General Medical Sciences (GM56677)
for support of this work. We would like to thank the support
staff at the University of Utah and especially Dr. Charles
Mayne (NMR), and Mr. Elliot M. Rachlin and Dr. Jim Muller
(mass spectrometry) for help in obtaining data.
In our total synthesis of gambierol we had overcome
problems associated with oligomer formation by utilizing an
internal rather than a terminal olefin as a cyclization precursor
and decided to adopt this tactic in our GA B-ring efforts.
To this goal, we coupled 20 with 26 to give 31 in quantitative
yield (Scheme 6). In the acyclic enol ether forming reaction
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.
Scheme 6
OL0707970
(29) As 30 decomposed upon standing at -40 °C for 12 h in neutralized
chloroform, we believe that the moderate yield for this transformation is a
result of the relative instability of 30. We plan to address this problem
when we turn to the real GA precursor.
(30) Related reactions have been reported. See refs 10, 26, 31 and: (a)
Stille, J. R.; Grubbs, R. H. J. Am. Chem. Soc. 1986, 108, 855. (b) Stille, J.
R.; Santarsiero, B. D.; Grubbs, R. H. J. Org. Chem. 1990, 55, 843. (c)
Nicolaou, K. C.; Postema, M. H. D.; Claiborne, C. F. J. Am. Chem. Soc.
1996, 118, 1565. (d) Nicolaou, K. C.; Postema, M. H. D.; Yue, E. W.;
Nadin, A. J. Am. Chem. Soc. 1996, 118, 10335.
(31) (a) Allwein, S. P.; Cox, J. M.; Howard, B. E.; Johnson, H. W. B.;
Rainier, J. D. Tetrahedron 2002, 58, 1997. (b) Majumder, U.; Rainier, J.
D. Tetrahedron Lett. 2005, 46, 7209.
we decided to employ a titanium ethylidene rather than a
methylidene to avoid complications resulting from olefin
2230
Org. Lett., Vol. 9, No. 11, 2007