Concise Synthesis of the Chemopreventitive Agent (±)-Deguelin via a Key 6-Endo Hydroarylation

Article abstract of DOI:10.1021/ol035419j

(Equation presented) A concise total synthesis of (±)-deguelin was achieved with a longest linear sequence of six steps in 68% yield. A key step was the platinum-catalyzed 6-endo hydroarylation of an alkynone intermediate.

Full text of DOI:10.1021/ol035419j

ORGANIC
LETTERS
2003
Vol. 5, No. 22
4053-4055
Concise Synthesis of the
Chemopreventitive Agent (±)-Deguelin
via a Key 6-Endo Hydroarylation
Stefan J. Pastine and Dalibor Sames*
Department of Chemistry, Columbia UniVersity, New York, New York 10027
sames@chem.columbia.edu
Received July 28, 2003
ABSTRACT
A concise total synthesis of (±)-deguelin was achieved with a longest linear sequence of six steps in 68% yield. A key step was the platinum-
catalyzed 6-endo hydroarylation of an alkynone intermediate.
In part of a broad program focused on C-H bond function-
alization, we became interested in C-H to C-C bond
transformations at the arene nucleus.1 In this context, we have
centered our attention on intramolecular hydroarylation
methodology, which would provide a direct route to various
carbocyclic and heterocyclic compounds. Specifically, a
structural search identified chromenes and coumarins as
particularly attractive targets due to their frequent occurrence
in biologically relevant natural products. Consequently, we
have developed a new platinum-catalyzed hydroarylation
method that provides direct access to chromene and coumarin
scaffolds from arene-yne substrates.2
skin and mammary tumerogenesis,3 inhibited the growth of
and induced apoptosis in premalignant and malignant human
bronchial epithelial (HBE) cells with minimal effects on
normal HBE cells,4 and suppressed colonic preneoplastic
lesions in Cf-1 mice.5 Its activity has been linked to its potent
inhibition of ornithine decarboxylase activity; in contrast to
other members of the rotenoid family, deguelin does not
inhibit microtubular assembly or tubulin polymerization.6
Previous synthetic efforts toward the rotenoid class,
including two total syntheses of 1,7 have been lengthy and
inefficient,8 and thus a general solution for the synthesis of
this class of compounds has not yet been realized. To obtain
We set out to address the question of whether our
hydroarylation method would be applicable to substrates of
high complexity such as those leading to the rotenoid class
of natural products. Specifically, we were interested in
synthesizing deguelin 1, which has recently received con-
siderable attention for its promising pharmacological proper-
ties. Deguelin has been shown to be an efficacious chemo-
preventitive agent for both in vitro and in vivo models. For
example, it has exhibited chemopreventitive effects in both
(3) Undeani, G. O.; Gerhauser, C. Thomas, C. F.; Moon, R. C.;
Kosmeder, J. W.; Kinghorn, A. D.; Moriarty, R. M.; Pezzuto, J. M. Cancer
Res. 1997, 57, 3424-3428.
(4) Chun, K. H.; Kosmeder, J. W, Sun, S.; Pezzuto, J. M.; Lotan, R.;
Hong, W. K.; Lee, Y. H. J. Natl. Cancer Inst. 2003, 95, 291-302.
(5) (a) Murillo, G.; Salti, G. I.; Kosmeder, J. W.; Pezzuto, J. M.; Mehta,
R. G. Eur. J. Cancer 2002, 38, 2446-2454. (b) Murillo, G.; Kosmeder, J.
W.; Pezzuto, J. M.; Mehta, R. G. Int. J. Cancer 2003, 104, 7-11.
(6) (a) Gerhauser, C.; Lee, S. K.; Kosmeder, J. W.; Moriarty, R. M.;
Hamal, E.; Mehta, R. G.; Moon, R. C.; Pezzuto, J. M. Cancer Res. 1997,
57, 3429-3435. (b) Casida, J. E.; Fang, N. Proc. Natl. Acad. Sci. U.S.A.
1998, 95, 3380-3384.
(1) Sezen, B.; Sames. D. J. Am. Chem. Soc. 2003, 125, 5274-5275.
(2) (a) Pastine, S. J.; Youn, S. W.; Sames, D. Org. Lett. 2003, 5, 1055-
1058. (b) Pastine, S. J.; Youn, S. W.; Sames, D. Tetrahedron 2003, ASAP.
(7) (a) Omokawa, H.; Yamashita, K. Agr. Biol. Chem. 1974, 38, 1731-
1734. (b) Fukami, H.; Oda, J.; Sakata, G.; Nakajima, M. Agr. Biol. Chem.
1961, 25, 252-256.
10.1021/ol035419j CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/26/2003

appreciable quantities for pharmacological studies, deguelin
was prepared in four steps from the related natural product,
rotenone, in a modest overall yield (22%).9 In light of the
preceding points, we felt that developing an efficient total
synthesis of deguelin was of interest.
Scheme 2
Scheme 1
Encouraged by these results, the synthesis commenced
with conversion of phenol 10 to the propargyl ether 4 in
quantitative yield (Scheme 3). Treatment of 4 with n-BuLi
Our approach to 1 was based on two key cyclization steps,
including the conversion bis-chromene 2 to 1 and the
platinum-catalyzed 6-endo hydroarylation of alkynone 3
(Scheme 1).10 Precursor 3 could then be assembled by the
convergence of intermediates 4 and 5. Although our hy-
droarylation protocol worked well with alkynoate esters, we
were uncertain as to whether alkynones were viable sub-
strates. Since the inherent electron-withdrawing ability of
the ketone is greater than that of the ester moiety, we were
uncertain about the regiochemical outcome of the hydro-
arylation step with respect to the 6-endo versus the 5-exo
cyclization mode. To test this regiochemical issue, substrate
6 was prepared and subjected to our Pt(IV) protocol. Much
to our delight, ketone 6 afforded the 6-endo cyclization
product 7 exclusively in an encouraging 50% yield (Scheme
2). Noteworthy is the fact that 6-endo cyclization requires
the umpolung of the alkynone group, effected in situ by the
platinum catalyst. Treatment of 6 with PtCl2 in toluene11 also
provided product 7, however, in significantly lower yield
(32%), and recovered starting material 6 (30%). Similar
results were obtained with methyl ester 8; the Pt(II) condi-
tions gave lower yield (26%), while the Pt(IV) method
afforded 51% yield of product 9. These results were
consistent with our previous studies, which had demonstrated
that PtCl4 was superior to PtCl2 in the cyclization of electron-
deficient alkynes.2
Scheme 3
(8) For some representative examples, see: (a) Gabbutt, C. D.; Hepworth,
J. D.; Heron, M. J. Chem. Soc., Perkin Trans. 1 1994, 653-657. (b)
Crombie, L.; Josephs, J. L. J. Chem. Soc., Perkin Trans. 1 1993, 2591-
2597. (c) Ahmad-Junan, S. A.; Amos, P. C.; Whiting, D. A. J. Chem. Soc.,
Perkin Trans. 1 1992, 539-545. (d) Lai, S. M. F.; Orchison, J. J. A.;
Whiting, D. A. Tetrahedron 1989, 45, 5895-5906.
(9) Anzenveno, P. B. J. Org. Chem. 1979, 44, 2578-2580.
(10) Thermal Claisen rearrangements of acetylenic intermediates similar
to 3 have resulted in poor yields; see refs 7a and 8b.
in THF, followed by reaction with aldehyde 5,12 produced
the crude alcohol, which was oxidized without purification
(11) Chatani, N.; Inoue, H.; Ikeda, T.; Murai, S. J. Org. Chem. 2000,
65, 4913-4918.
(12) Aldehyde 5 was prepared in two steps according to a literature
procedure: Geneive, H. E.; Jacobs, H. Tetrahedron 2001, 57, 5235-5338.
4054
Org. Lett., Vol. 5, No. 22, 2003

with manganese dioxide to yield the alkynone 3 in 87% yield
for two steps. With this key intermediate in hand, we set
out to apply the Pt(IV) hydroarylation protocol, mindful of
the increased complexity of 3 relative to the substrates
previously studied in our laboratory. Unfortunately, even after
extensive optimization, we were only able to obtain the
desired product 2 in a modest isolated yield (40%; 5 mol %
PtCl4, 0.1 M dioxane, 65 °C). Displeased with this result,
we subsequently focused our attention on the use of PtCl2
as a catalyst, although with some trepidation as the previous
studies demonstrated that PtCl2 was inefficient in converting
alkynoate esters and alkynones to the chromene products.
However, we were delighted to find that under the action of
5 mol % PtCl2 (0.1 M toluene, 55 °C), alkyne 3 was
converted to the desired cyclization product 2 in an excellent
91% yield. Remarkably, none of the undesired ortho cy-
clization product was detected in the crude reaction mixture.
The advanced intermediate 2 was finally converted to the
target molecule in 86% yield by selective demethylation with
boron trichloride, followed by base-catalyzed intramolecular
oxo-Michael addition (Scheme 3). Thus, (()-deguelin 1 was
synthesized in six linear steps in 68% yield.
comparison to Pt(II) salts does not always translate into better
yields, particularly in the context of electron-rich arene
substrates. This may be due to the greater degree of
decomposition of both the product and the starting material
in the presence of a “hot” catalyst (see Scheme 2, no starting
material was recovered in the experiments with PtCl4). Thus,
in the case of a complex substrate such as 3, milder and
more selective PtCl2 proved to be far superior to PtCl4,
affording the desired product in excellent yield. This study
further demonstrated the complementarity of Pt(II) and Pt-
(IV) catalysts for alkyne hydroarylation reactions and the
applicability of this method to the synthesis of complex
natural products.
In summary, (()-deguelin has been prepared in 68% yield
in six steps from known compounds. The crucial step in this
synthesis involved the platinum-catalyzed 6-endo hydro-
arylation of a complex alkynone intermediate. This method
should be applicable to the synthesis of other rotenoids.
Acknowledgment. Generous support for this work was
provided by GlaxoSmithKline, Johnson & Johnson Pharma-
ceutical R&D, and Merck. D.S. is a recipient of the Alfred
P. Sloan Fellowship and the Camille Dreyfus Teacher-
Scholar Award. We thank Dr. J. B. Schwarz for editorial
assistance.
The key step of this sequence, namely, the 6-endo
hydroarylation of alkynone intermediate 3, was achieved in
excellent yield and regioselectivity (91% isolated yield) in
the presence of PtCl2 as the catalyst. This was a surprising
finding, since model studies (Scheme 2) and previous
investigations in our laboratories2 indicated that Pt(II) was
poorly suited for hydroarylation of electron-deficient alkynes.
At the same time, the higher reactivity of Pt(IV) in
Supporting Information Available: Experimental details
and compound spectral characterization. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL035419J
Org. Lett., Vol. 5, No. 22, 2003
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