J . Org. Chem. 2001, 66, 7443-7448
7443
Tota l Syn th esis of (()-Aster isca n olid e
M. E. Krafft,* Y. Y. Cheung, and K. A. Abboud†
Departments of Chemistry, Florida State University, Tallahassee, Florida 32306-4390 and
University of Florida, Gainesville, Florida 32611-7200
Received J une 18, 2001
The total synthesis of asteriscanolide (1) has been achieved by taking advantage on an
intermolecular Pauson-Khand cycloaddition and a ring-closing metathesis as key bond-forming
transformations. The approach incorporates the cyclooctane stereogenic center prior to ring
formation. Interestingly, the ring-closing metathesis generates a new eight-membered ring with
an “in-out” intrabridgehead relationship.
In tr od u ction
Sch em e 1
The cyclooctane sesquiterpene lactone, asteriscanolide
, has recently been the focus of a number of research
1
groups. Since its initial isolation from the hexane extract
1
of Asteriscus aquaticus by Feliciano, it has succumbed
2
to total synthesis by the Wender group, who incorpo-
rated a Ni(0)-catalyzed [4 + 4] cycloaddition as the pivotal
3
step, very recently by the Snapper group incorporating
a ring-opening metathesis/Cope rearrangement strategy,
and by the Paquette group.4 However, the structural
challenges associated with the construction of the [6.3.0]
carbocyclic skeleton bearing a bridging butyrolactone and
five cis stereocenters has prompted other creative ap-
proaches, which include both inter- and intramolecular
[
2 + 2] cycloadditions followed by a de Mayo type5-7
fragmentation. Furthermore, the studies by Booker-
Milburn have shown that the C-7 methyl cannot be
introduced via alkylation of the corresponding des-methyl
ing eight-membered rings via RCM. This was a major
contributing factor to our judicious choice of C-C bond
disconnection for the eight-membered ring of 1. As a
consequence of pursuing this challenging approach, we
have developed a synthetic route, which proceeds via the
cyclooctane, and thus the stereocenter must be estab-
lished prior to eight-membered ring formation.7
We have developed a novel synthetic strategy, which
meets the criteria mentioned above and also features the
1
1
stereoselective formation of an “inside-outside” eight-
membered ring. In this paper, we wish to present a
detailed account of these synthetic studies, which cul-
8
Pauson-Khand cycloaddition and ring-closing metath-
esis (RCM) as key steps (Scheme 1). Recently, there has
been much effort devoted to the application of RCM for
1
2
minated in the total synthesis of asteriscanolide, 1′.
9
the formation of medium-sized rings, but eight-mem-
bered rings are still generally regarded a most difficult
ring size to achieve by this means.10 Moreover, there is
still relatively little known about the formation of bridg-
Resu lts a n d Discu ssion
In our retrosynthetic analysis we envisaged that the
formation of the bridging eight-membered ring could be
achieved through ring-closing metathesis of diene 2
(Scheme 1). This would enable stereoselective incorpora-
†
University of Florida.
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(
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1999, 32, 75. (f) Pariya, C.; J ayaprakash, K. N.; Sarkar, A. Coord.
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1
988, 110, 5904.
(
(
3) Limanto, J .; Snapper, M. L. J . Am. Chem. Soc. 2000, 122, 8071.
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Am. Chem. Soc. 2000, 122, 2742.
(
(
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Fang, J . M. Tetrahedron Lett. 1998, 39, 8365.
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997, 37, 12319.
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(
1
(
Schore, N. E. In Comprehensive Organic Synthesis; Trost, B. M., Ed.;
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1
991, 40, 1. Schore, N. E. In Comprehensive Organometallic Chemistry
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1
0.1021/jo010623a CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/29/2001