Chemoselective cross-metathesis reaction. Application to the synthesis of the C1-C14 fragment of amphidinol 3.

Article abstract of DOI:10.1021/ol0157095

[reaction: see text] An efficient synthesis of the C1-C14 fragment of amphidinol 3 is described. The synthesis is based on chemoselective cross-metathesis reactions and enantioselective allyltitanations.

Full text of DOI:10.1021/ol0157095

ORGANIC
LETTERS
2001
Vol. 3, No. 10
1451-1454
Chemoselective Cross-Metathesis
Reaction. Application to the Synthesis
of the C1−C14 Fragment of
Amphidinol 3
Samir BouzBouz* and Janine Cossy*
Laboratoire de Chimie Organique associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 - Paris Cedex 05, France
janine.cossy@espci.fr
Received February 14, 2001
ABSTRACT
An efficient synthesis of the C1−C14 fragment of amphidinol 3 is described. The synthesis is based on chemoselective cross-metathesis
reactions and enantioselective allyltitanations.
Marine dinoflagellates are a rich source of natural products
with diverse structures and highly specific bioactivity, e.g.,
brevetoxins as a voltage-sensitive Na+ channel activator,1
maitotoxin as a Ca2+ influx stimulator,2 and okadaic acid as
a protein phosphatase inhibitor.3 Among other dinoflagellates,
the genus Amphidinium has been recognized as a source of
novel bioactive secondary metabolites with unique chemical
structures.4-8 Among these metabolites, amphidinol 3 (Figure
1), a polyoxygenated diether with antifungal activities,9 has
been isolated from Amphidinium klebsii and its complete
structural elucidation was recently described.9
The difference between amphidinol 3 and most other
dinoflagellates is that amphidinol 3 possesses an extended
chain of unsaturated alcohols, in particular, a sequence of
allylic and homoallylic 1,5-diols also present in tetrafibricin.10
The cross-metathesis reaction is an important reaction
which allows the synthesis of a substituted olefin.11 Here,
(4) (a) Kobayashi, J.; Takahashi, M.; Ishibashi, M. Tetrahedron Lett.
1996, 37, 1449. (b) Ishibashi, M.; Takahashi, M.; Kobayashi, J. J. Org.
Chem. 1995, 60, 6062. (c) Doi, Y.; Ishibashi, M.; Yamaguchi, N.;
Kobayashi, J. J. Nat. Prod. 1995, 58, 1097 and reference cited therein.
(5) (a) Bauer, I.; Maranda, L.; Shimizu, Y.; Peterson, R. W.; Cornell,
L.; Steiner, J. R.; Clardy, J. J. Am. Chem. Soc. 1994, 116, 2657. (b) Bauer,
I.; Maranda, L.; Young, K. A.; Shimizu, Y.; Huang, S. Tetrahedron Lett.
1995, 36, 991. (c) Bauer, I.; Maranda, L.; Young, K. A.; Shimizu, Y.;
Fairchild, C.; Cornell, L.; MacBeth, J.; Huang, S. J. Org. Chem. 1995, 60,
1084.
(6) (a) Satake, M.; Murata, M.; Yasumoto, T.; Fujita, T.; Naoki, H. J.
Am. Chem. Soc. 1991, 113, 9859. (b) Yasumoto, T.; Seino, N.; Murakami,
Y.; Murata, M. Biol. Bull. 1987, 172, 128.
(7) Paul, G. K.; Matsumori, N.; Murata, M.; Tachibana, K. Tetrahedron
Lett. 1995, 36, 6279.
(1) (a) Lin, Y.-Y.; Risk, M.; Ray, S. M.; Van Engen, D.; Clardy, J.;
James, J. C.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773. (b) Shimizu,
Y.; Chou, H.-N.; Bando, H.; Duyne, G. V.; Clardy, J. J. Am. Chem. Soc.
1986, 108, 514. (c) Catterall, W. A.; Risk, M. Mol. Pharmacol. 1981, 19,
345.
(2) (a) Murata, M.; Naoki, H.; Matsunaga, S.; Satake, M.; Yasumoto, T.
J. Am. Chem. Soc. 1994, 116, 7098. (b) Takahashi, M.; Ohizumu, Y.;
Yasumoto, T. J. Biol. Chem. 1982, 257, 7287.
(3) (a) Tachibana, K.; Scheuer, P. J.; Tsukitani, Y.; Kikukchi, H.; Engen,
D. V.; Clardy, J.; Gopichand, Y.; Schmitz, F. J. J. Am. Chem. Soc. 1981,
103, 2469. (b) Murakami, Y.; Oshima, Y.; Yasumoto, T. Bull. Jpn. Soc.
Sci. Fish. 1982, 48, 69. (c) Takai, A.; Bialojan, C.; Troschka, M.; Ruegg,
J. C. FEBS Lett. 1988, 217, 81.
(8) Kobayashi, J.; Ishibashi, M. Chem. ReV. 1993, 93, 1753.
(9) Murata, M.; Matsuoka, S.; Matsumori, N.; Paul, G. K.; Tachibana,
K. J. Am. Chem. Soc. 1999, 121, 870.
(10) Kamiyama, K.; Itezono, Y.; Umino, T.; Satoh, T.; Nakayama, N.;
Matsumori, K. J. Antibiot. 1993, 46, 1047.
10.1021/ol0157095 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/24/2001

Figure 1.
we report a diastereoselective synthesis of 1,5-diols and,
consequently, the synthesis of the C1-C14 fragment of
amphidinol 3 by using an iterative sequence of enantio-
selective allytitanations and chemoselective cross-metathesis
reactions12 by using Hoveyda’s recyclable catalyst I13
(Scheme 1).
were conducted on dienols 1 and 2 (Scheme 2). When dienol
1 was treated with catalyst I (5 mol %), in CH2Cl2 at room
Scheme 2
Scheme 1
temperature for 4 h in the presence of acrolein (3 equiv),
the unsaturated dialdehyde 3 was isolated in 70% yield. This
As we wished to employ nonprotected alcohols of type A
(R ) H) (Scheme 1) in this synthesis, preliminary studies
Scheme 3
(11) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b)
Chatterjee, A. K.; Morgan, J. R.; Scholl, M.; Grubbs, R. H. J. Am. Chem.
Soc. 2000, 122, 3783. (c) Morgan, J. R.; Grubbs, R. H. Org. Lett. 2000, 2,
3153.
(12) Cossy, J.; BouzBouz, S.; Hoveyda, A. H. J. Organomet. Chem. In
press.
(13) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791. (b) Garber, S. B.; Kingsbury, J.
S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168.
1452
Org. Lett., Vol. 3, No. 10, 2001

selective as the unsaturated dialdehyde 3 and the unsaturated
aldehydes 4 and 5 were obtained with E:Z ratios up to 30/1.
Scheme 4. Proposed Mechanism for the Selective
Cross-Metathesis Reaction
As the cross-metathesis reaction was not selective on
alcohols of type A (R ) H), they were transformed to their
corresponding acetates. When acetates 6 and 7 were treated
with acrolein (3 equiv) in the presence of catalyst I (5 mol
%) in CH2Cl2 at room temperature, the unsaturated aldehydes
8 (73%) and 9 (71%) were isolated, indicating that the acetate
group deactivates the allylic double bond. Furthermore, the
stereoselectivity was again high as the E:Z ratio of isomers
of unsaturated aldehydes 8 and 9 was 30/1. The results are
summarized in Scheme 3.
The chemoselectivity of the cross-metathesis reaction of
unsaturated acetates of type B (Scheme 4) can result from
the deactivation of the allylic acetate double bond due to
the electron-withdrawing effect of the acetate group (com-
plexes C f C′) or, it could be due to a nonreactive complex
such as D′, which comes from D, where one metalla complex
is deactivated through complexation of the ruthenium atom
with the acetate group. Because of this complexation, only
one metallacyclobutane can react with acrolein to produce
the observed cross-metathesis product (Scheme 4).
On the basis of these results, the synthesis of the C1-
C14 fragment of amphidinol 3 was initiated from the
enantiomerically pure homoallylic alcohol 10.14 When com-
pound 10 was treated with acrolein in the presence of catalyst
I (5 mol %) at room temperature for 12 h, unsaturated
aldehyde 11 was formed (79% yield) stereoselectively (E:Z
> 50/1). The addition of the allyltitanium complex (S,S)-II
to 11 led to dienediol 1215 diastereoselectively in 86% yield
(Scheme 5). A second chemoselective cross-metathesis
reaction was envisaged to elaborate the C8-C10 fragment
result demonstrates that the allylic and homoallylic olefins
have a similar reactivity under the cross-metathesis conditions
used. When the allylic olefin was disubstitued, as in dienol
2, the cross-metathesis reaction was not selective as com-
pounds 3 and 4 were isolated in 41% and 37% yields
(Scheme 2). In the case of dienol 12 (for its synthesis, see
Scheme 5), the unsaturated dialdehyde 5 (43%) and aldehyde
11 (31%) were isolated from the cross-metathesis reaction.
It is worth noting that under these conditions the cross-
metathesis reaction is not chemoselective but highly stereo-
Scheme 5
Org. Lett., Vol. 3, No. 10, 2001
1453

of amphidinol 3 from diacetate 13. The acetylation of 12 by
using acetic anhydride in pyridine at 25 °C afforded the
diacetate 13 (dr ) 95/5)16 in 95% yield. This latter compound
was then subjected to the cross-metathesis with acrolein,
under the conditions used previously [acrolein (3 equiv); I
(5 mol %); rt; 12 h] which led to aldehyde 14 (yield ) 63%,
E:Z > 50/1).
10 with an overall yield of 17.5%. It offers certain advantages
over a more traditional Wittig-Horner route by virtue of
minimizing protection and deprotection steps and allowing
the use of highly base-sensitive intermediates. Because of
high chemoselectivity observed in the cross-metathesis
reaction, mechanistic and synthetic studies are under inves-
tigation.
When aldehyde 14 was treated with the allyltitanium
complex (S,S)-II, the corresponding alcohol 15 was isolated
in 80% yield with excellent diastereoselectivity (dr > 95/
5).15 A third cross-metathesis reaction was then conducted
on triacetate 1616 with ethyl acrylate [ethyl acrylate (3 equiv);
25 °C; 12 h; I (5 mol %)] to furnish the unsaturated ester
C1-C14 fragment 17 of amphidinol 3 in 61% yield.
The present route to the C1-C14 fragment of amphidinol
3 was achieved in seven steps from the homoallylic alcohol
Acknowledgment. The authors are indebted to Dr. R.
O. Duthaler for a generous gift of chiral cyclopentadienyl-
dialkoxytitanium chloride complexes, Dr. A. H. Hoveyda for
a generous gift of ruthenium catalyst, and Eli Lilly (In-
dianapolis, IN) for financial support.
Supporting Information Available: Experimental pro-
cedure and analytical and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(14) BouzBouz, S.; Cossy, J. Org. Lett. 2000, 2, 3975.
(15) The diastereoselectivity has been determined from the corresponding
acetate.
(16) The diastereoselectivity has been determined by GC/MS (electron
impact ionization using a 5971 Hewlett-Packard instrument at 70 eV).
OL0157095
1454
Org. Lett., Vol. 3, No. 10, 2001