Application of a domino intramolecular enyne metathesis/cross metathesis reaction to the total synthesis of (+)-8-epi-xanthatin

Article abstract of DOI:10.1021/ol051711a

(Chemical Equation Presented) The first total synthesis of the novel sesquiterpene lactone (+)-8-epi-xanthatin (1) has been achieved starting from the commercially available ester 8. The synthesis features an asymmetric aldol reaction and palladium-catalyzed carbonylation/lactonization sequence leading to 4 and a domino ring-closing enyne metathesis/cross metathesis reaction to afford 1.

Full text of DOI:10.1021/ol051711a

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4621-4623
Application of a Domino Intramolecular
Enyne Metathesis/Cross Metathesis
Reaction to the Total Synthesis of
(+)-8-epi-Xanthatin
David A. Kummer, Jehrod B. Brenneman, and Stephen F. Martin*
Department of Chemistry and Biochemistry, The UniVersity of Texas,
Austin, Texas 78712
sfmartin@mail.utexas.edu
Received July 20, 2005
ABSTRACT
The first total synthesis of the novel sesquiterpene lactone (+)-8-epi-xanthatin (1) has been achieved starting from the commercially available
ester 8. The synthesis features an asymmetric aldol reaction and palladium-catalyzed carbonylation/lactonization sequence leading to 4 and
a domino ring-closing enyne metathesis/cross metathesis reaction to afford 1.
The sesquiterpene lactone (+)-8-epi-xanthatin (1), which was
isolated from the extracts of the aerial parts of various species
in the genus Xanthium,1 has also been obtained from the
elimination of acetic acid from the related natural product,
xanthumin 2 (Figure 1).2 8-epi-Xanthatin inhibits the larval
growth of Drosophila melanogaster (fruit fly)1b and also
displays antimalarial activity against the chloroquine-resistant
Plasmodium falciparum strain K1 with an IC50 of 125 µg/
mL.3 More recently, 1 has been shown to inhibit the in vitro
proliferation of several cultured human tumor cell lines,
including A-549 (non-small cell lung), SK-OV-3 (ovary),
SK-MEL-2 (melanoma), XF-498 (central nervous system),
and HCT-15 (colon) with IC50 values ranging between 0.8
and 6.1 µM.4 In conjunction with the tumor inhibition studies,
1 was found to inhibit the farnesylation of human lamin-B
by farnesyltransferase.4b
Despite their biological activities and interesting structures,
synthetic efforts directed toward any of the xanthanolides
has been lacking until recently.5 In the first reported total
synthesis of a xanthanolide, Morken utilized sequential
ruthenium-catalyzed metathesis reactions to prepare (-)-
dihydroxanthatin (3), a related xanthanolide lacking the
reactive exocyclic methylene.6
Our interest in 8-epi-xanthatin arose as a result of our
ongoing efforts to expand the scope of ruthenium-catalyzed
(1) (a) McMillan, C.; Chavez, P. I.; Mabry, T. J. Biochem. Syst. Ecol.
1975, 3, 137. (b) Kawazu, K.; Nakajima, S.; Ariwa, M. Experientia 1979,
35, 1294. (c) Bohlmann, F.; Singh, P.; Joshi, K. C.; Singh, C. L.
Phytochemistry 1982, 21, 1441. (d) Ghazy, N. M.; Omar, A. A.; Elrashidy,
E. M.; Metwally, A. M. Egypt. J. Pharm. Sci. 1988, 29, 39. (e) Ahmed, A.
A.; Jakupovic, J.; Bohlmann, F.; Regaila, H. A.; Ahmed, A. M. Phytochem-
istry 1990, 29, 2211.
(2) Minato, H.; Horibe, I. J. Chem. Soc. 1965, 7009.
(3) Joshi, S. P.; Rojatkar, S. R.; Nagasampagi, B. A. J. Med. Aromat.
Plant Sci. 1997, 19, 366.
Figure 1. Representative xanthanolides: (+)-8-epi-xanthatin (1),
xanthumin (2), and (-)-dihydroxanthatin (3).
10.1021/ol051711a CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/13/2005

Scheme 1
Scheme 2
stereocenter at C(10) would be obtained from enantiomeri-
cally pure 8, which is commercially available. We now report
the reduction of this strategy to practice.
The synthesis commenced with the conversion of com-
mercially avaliable ester 8 into the corresponding tosylate 9
(Scheme 2). Reduction of 9 provided an unstable aldehyde
that was immediately subjected to the Corey-Fuchs olefi-
nation protocol in the presence of 2,6-lutidine to provide the
vinyl dibromide 10 in 62% yield over the two steps.11 When
10 was treated with excess n-BuLi and the resultant acetylide
anion trapped with TIPSOTf, the protected alkyne 11 was
obtained in 70% yield. One-carbon homologation of 11 via
reaction with KCN afforded the corresponding nitrile in 64%
yield, reduction of which with DIBAL-H furnished aldehyde
6 in 83% yield.
domino olefin metathesis reactions in the context of natural
product total synthesis.7 Thus, we envisioned that the ring-
closing enyne metathesis (RCM) of 4 would generate an
intermediate ruthenium carbene that would participate in a
subsequent cross metathesis (CM) reaction with methyl vinyl
ketone to generate the seven-membered carbocycle and (E)-
conjugated dienone subunits present in 1 in a single synthetic
transformation (Scheme 1). The exocyclic R-methylene
lactone functionality present in 4 would be introduced via
the palladium-catalyzed carbonylation of enol triflate 5.
Because Paquette has shown that R-methylene-γ-butyrolac-
tones are unaffected by ruthenium-catalyzed RCM condi-
tions, we reasoned that this reactive moiety in 4 would not
interfere with the desired metathesis cascade.8 An asymmetric
aldol reaction9 between the functionalized aldehyde 6 and
the known oxazolidinone 710 would establish the two
stereocenters at C(7) and C(8) in 1, whereas the remaining
With aldehyde 6 in hand, our attention was focused upon
establishing the two remaining stereocenters in 1 via an
asymmetric aldol reaction.9 Toward this end, the boron
enolate derived from oxazolidinone 7 was allowed to react
with aldehyde 6 to provide alcohol 12 in 88% yield (dr >95:5
1
based upon the H NMR spectrum) (Scheme 3). Exchange
(4) (a) Ahn, J.-W.; No, Z.; Ryu, S.-Y.; Zee, O.-P.; Kim, S.-K. Nat. Prod.
Sci. 1995, 1, 1. (b) Kim, Y. S.; Kim, J. S.; Park, S.-H.; Choi, S.-U.; Lee,
C. O.; Kim, S.-K.; Kim, Y.-K.; Kim, S. H.; Ryu, S. Y. Planta Med. 2003,
69, 375.
Scheme 3
(5) For synthetic studies directed toward the preparation of compounds
related to 1, see: (a) Nosse, B.; Chhor, R. B.; Jeong, W. B.; Bo¨hm, C.;
Reiser, O. Org. Lett. 2003, 5, 941. (b) Rudler, H.; Alvarez, C.; Parlier, A.;
Perez, E.; Denise, B.; Xu, Y.; Vaissermann, J. Tetrahedron Lett. 2004, 45,
2409.
(6) Evans, M. A.; Morken, J. P. Org. Lett. 2005, 7, 3371.
(7) For the application of ruthenium-catalyzed metathesis reactions in
our laboratory, see: (a) Martin, S. F.; Chen, H.-J.; Courtney, A. K.; Liao,
Y.; Pa¨tzel, M.; Ramser, M. N.; Wagman, A. S. Tetrahedron 1996, 52, 7251.
(b) Fellows, I. M.; Kaelin, D. E., Jr.; Martin, S. F. J. Am. Chem. Soc. 2000,
122, 10781. (c) Deiters, A.; Martin, S. F. Org. Lett. 2002, 4, 3243. (d)
Humphrey, J. M.; Liao, Y.; Ali, A.; Rein, T.; Wong, Y.-L.; Chen, H.-J.;
Courtney, A. K.; Martin, S. F. J. Am. Chem. Soc. 2002, 124, 8584. (e)
Washburn, D. G.; Heidebrecht, R. W., Jr.; Martin, S. F. Org. Lett. 2003, 5,
3523. (f) Neipp, C. E.; Martin, S. F. J. Org. Chem. 2003, 68, 8867. (g)
Brenneman, J. B.; Machauer, R.; Martin, S. F. Tetrahedron 2004, 60, 7301.
(8) (a) Paquette, L. A.; Me´ndez-Andino, J. Tetrahedron Lett. 1999, 40,
4301. (b) Me´ndez-Andino, J.; Paquette, L. A. AdV. Synth. Catal. 2002, 344,
303.
(9) Evans, D. A.; Bartroli, J.; Shih, T. L. J. Am. Chem. Soc. 1981, 103,
2127.
(10) Crimmins, M. T.; King, B. W.; Zuercher, W. J.; Choy, A. L. J.
Org. Chem. 2000, 65, 8499.
4622
Org. Lett., Vol. 7, No. 21, 2005

enyne 4 and methyl vinyl ketone in the presence of catalyst
15 (20 mol %) provided 1 in 83% yield (Scheme 4). The
phosphine-free ruthenium catalyst 1518 was employed in this
step because it had been reported to be superior as a catalyst
in previously reported tandem RCM/CM reactions17b and in
CM reactions involving electron-deficient olefins.19 The 1H
and 13C NMR spectral data of the synthetic 1 thus obtained
were consistent with those previously reported.1b,4a,b,20 More-
Scheme 4
over, it exhibited an optical rotation {[R]24 ) +23.4 (c
D
0.333, CHCl3)} in close accord with the previously reported
value {[R]20 ) +25 (c 0.5, CHCl3)}.4b
D
In summary, the first total synthesis of (+)-8-epi-xanthatin
(1) has been achieved in 14 steps from the ester 8 in 5.5%
overall yield. The approach featured a palladium-catalyzed
carbonylation/lactonization sequence for the construction of
the R-methylene-γ-butyrolactone functionality and a domino
enyne RCM/CM reaction to elaborate the seven-membered
carbocycle and complete the synthesis. Other applications
of olefin metathesis to solving challenging problems in total
synthesis are under active investigation, and the results of
these studies will be disclosed in due course.
Acknowledgment. We thank the National Institutes of
Health (GM 31077), Pfizer, Inc., Merck Research Labora-
tories, and the Robert A. Welch Foundation for their generous
support of this research. We are also grateful to Dr. Richard
Fisher (Materia, Inc.) for catalyst support and helpful
discussions. We additionally thank Dr. Shi Yong Ryu of the
Korea Research Institute of Chemical Technology for
of the chiral auxiliary with the corresponding N,O-dimethyl
amide was accomplished in 60% yield by treating alcohol
12 with the preformed aluminum amide derived from HCl‚
HN(OMe)Me.12 Subsequent protection of the secondary
alcohol as a silyl ether afforded 13 in nearly quantitative
yield. Treatment of amide 13 with MeMgBr provided the
corresponding ketone, which was readily transformed into
the enol triflate 5 in 85% overall yield by kinetic deproto-
nation with KHMDS followed by trapping of the resultant
enolate with N-(5-chloro-2-pyridyl)triflimide (Comins re-
agent).13
The enol triflate 5 was then converted into the acrylate
14 in 85% yield under standard conditions for palladium-
catalyzed carbonylation (Scheme 4).14 Removal of the silyl
protecting groups from 14 using TBAF was accompanied
by spontaneous lactonization of the intermediate hydroxy
ester to provide 4 in 78% yield.15
1
providing H and 13C NMR spectra of natural 1. D.A.K.
thanks Pfizer, Inc. for an undergraduate research fellowship.
1
Supporting Information Available: H NMR spectra for
all new compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL051711A
(16) For reviews of enyne metathesis, see: (a) Mori, M. In Handbook
of Metathesis; Grubbs, R. H., Ed.; Wiley-VCH: Weinheim, 2003; Vol. 2,
p 176. (b) Mori, M. In Topics in Organometallic Chemistry; Springer-
Verlag: New York, 1998; Vol. 1, p 133. (c) Poulsen, C. S.; Madsen, R.
Synthesis 2003, 1. (d) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004, 104,
1317. (e) For a general review of RCM, see: Deiters, A.; Martin, S. F.
Chem. ReV. 2004, 104, 2199.
(17) (a) Randl, S.; Lucas, N.; Connon, S. J.; Blechert, S. AdV. Synth.
Catal. 2002, 344, 631. (b) Royer, F.; Vilain, C.; Elkaim, L.; Grimaud, L.
Org. Lett. 2003, 5, 2007. (c) Lee, H.-Y.; Kim, H. Y.; Tae, H.; Kim, B. G.;
Lee, J. Org. Lett. 2003, 5, 3439. (d) Clark, J. S.; Elustondo, F.; Kimber, M.
C. Chem. Commun. 2004, 2470. (e) Kitamura, T.; Sato, Y.; Mori, M.
Tetrahedron 2004, 60, 9649. (f) Salim, S. S.; Bellingham, R. K.; Brown,
R. C. D. Eur. J. Org. Chem. 2004, 800.
With enyne 4 in hand, the stage was set for the pivotal
domino enyne RCM/CM sequence. The enyne RCM reaction
has emerged as a powerful synthetic transformation,16 but
only recently has this process been coupled in a domino
process with a subsequent CM.17 In the event, reaction of
(11) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
(12) Basha, A.; Lipton, M.; Weinreb, S. M. Tetrahedron Lett. 1977, 48,
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(14) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1985, 26, 1109.
(15) Crisp, G. T.; Meyer, A. G. Tetrahedron 1995, 51, 5831.
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Chem. Soc. 2000, 122, 8168.
(19) Dewi, P.; Randl, S.; Blechert, S. Tetrahedron Lett. 2005, 46, 577
and references therein.
(20) Yokotani-Tomita, K.; Kato, J.; Kosemura, S.; Yamamura, S.;
Kushima, M.; Kakuta, H.; Hasegawa, K. Phytochemistry 1997, 46, 503.
Org. Lett., Vol. 7, No. 21, 2005
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