the cell, followed by rapid disappearance of the parasite from
the host’s bloodstream. This effect is due to the fact that
bloodstream trypomastigotes of the Trypanosome brucei
group depend exclusively on glycolysis for their energy
metabolism.5
(Scheme 1).10 In principle, the Diels-Alder reaction offers
Scheme 1. Synthesis of the Bicyclic [3.3.0] Octene 8
From the synthetic point of view, there has been sustained
interest in the chemistry of these natural products over the
past few decades. Analysis of their molecular structures show
a highly compacted carbon skeleton, with an angularly fused
tricycle pentanoid lactone and different oxidation states in
each of the rings, which combine to present a real synthetic
challenge. Since the first total synthesis of pentalenolactone
was published in 1978, there have been many reports (more
than 20) toward the synthesis of this family of compounds.6
Notwithstanding this, only two research groups have
addressed the issue of optical purity in the synthesis of (-)-
pentalenolactone E methyl ester (2) by an enzymatic resolu-
tion of an advanced synthetic intermediate.7,8 However, to
the best of our knowledge, no general enantiospecific
approach toward the synthesis of this quaternary carbon-
centered polycyclic structure has yet been reported. In light
of these considerations, we were prompted to devise a simple
means for building the pentalenolactone quinane skeleton
in an enantiospecific form.
four possibilities, two different approaches from the R-face
and two from the â-direction, but the outcome of this reaction
is highly diastereoselective and proceeds mainly through the
â-face of the dienophile in an exo manner.11
The bicyclic dienophile 4 is conformationally rigid, and
we expected that the steric hindrance produced by the
anomeric methoxy group on the R-face would preclude any
attack from this face. We relied on this reaction selectivity
to establish the configuration of the quaternary carbon,
pivotal to the angular tricyclic junction.
Our asymmetric strategy relies on the use of D-glucose as
the source of chirality. In a simple and straightforward
synthetic sequence, we have converted the methyl-R-D-
glucopyranoside (3) into the cyclic R,â-unsaturated aldehyde
(4).9
Treatment of aldehyde 4 with cyclopentadiene afforded
the cycloadduct 5 as the only detectable product in 85% yield
(4) For enzyme inhibition studies, see: (a) Duszenko, M.; Mecke, D.
Mol. Biochem. Parasitol. 1986, 19, 223. (b) Cane, D. E.; Sohng, J. K. Arch.
Biochem. Biophys. 1989, 270, 50. (c) Fro¨hlich, K. U.; Wiedmann, M.;
Lottspeich, F.; Mecke, D. J. Antibiot. 1989, 171, 6696. (d) Lambeir, A.
M.; Loiseau, A. M.; Kuntz, D. A.; Vellieux, F. M.; Michels, P. A. M.;
Opperdoes, F. R. Eur. J. Biochem. 1991, 198, 429. (e) Willson, M.; Lauth,
N.; Perie, J.; Callens, M.; Opperdoes, F. R. Biochemistry 1994, 33, 214. (f)
Cane, D. E.; Sohng, J. K. Biochemistry 1994, 33, 6524. (g) For a recent
review on pentalenolactones, see: Spanevello, R. A.; Pellegrinet, S. C. Curr.
Top. Phytochem. 2000, 3, 225.
Even though the initially unexpected exo-isomer has the
olefin bridge with the opposite configuration (it is trans with
respect to the aldehyde group), we found it was equally
suitable to achieve our goal.
Barbier-type nucleophilic addition of ethyllithium, fol-
lowed by a Swern oxidation of the resulting mixture of
epimeric alcohols, yielded ketone 6. Ozonolysis of the double
bond set the stage for assembly of the core bicyclic [3.3.0]
octene framework. Intramolecular aldol condensation, under
basic conditions, of the tricarbonyl intermediate 7 led to the
carbon stereocenter attached to the aldehyde group to become
epimerized and allowed an efficient ring closure. Jones
oxidation of the remaining aldehyde group and esterification
with diazomethane afforded the methyl ester (8) in 49%
overall yield from 5.12 Unfortunately, although compound 8
embodied the carbon skeleton associated with this family of
sesquiterpenes, we failed in all our attempts to form the
required double bond after a conjugate additon of methyl-
lithium to the R,â-unsaturated ketone, to make an SN2′
(5) Opperdoes, F. R. Annu. ReV. Microbiol. 1987, 41, 127.
(6) First total synthesis of (()-pentalenolactone: (a) Danishefsky, S.;
Hirama, M.; Gombatz, K.; Harayama, T.; Berman, E.; Schuda, P. J. Am.
Chem. Soc. 1978, 100, 6536. (b) Danishefsky, S.; Hirama, M.; Gombatz,
K.; Harayama, T.; Berman, E.; Schuda, P. J. Am. Chem. Soc. 1979, 101,
7020. Formal synthesis of (()-pentalenolactone: (c) Parsons, W. H.;
Schlessinger, R. H.; Quesada, M. L. J. Am. Chem. Soc. 1980, 102, 889.
Synthesis of (()-pentalenolactone E and F methyl ester: (d) Paquette, L.
A.; Schostarez, H.; Anis, G. D. J. Am. Chem. Soc. 1981, 103, 6526. (e)
Ohtsuka, T.; Shirajama, H.; Matsumoto, T. Tetrahedron Lett. 1983, 24, 3851.
(f) Cane, D. E.; Thomas, P. J. J. Am. Chem. Soc. 1984, 106, 5295. (g)
Marino, J. P.; Silveira, C.; Comasseto, J.; Petragnani, N. J. Org. Chem.
1987, 52, 4139. (h) Hua, D. H.; Coulter, M. J.; Badejo, I. Tetrahedron
Lett. 1987, 28, 5465. (i) Taber, D. F.; Schuchardt, J. L. Tetrahedron 1987,
43, 5677. (j) Pirrung, M. C.; Thomson, S. A. J. Org. Chem. 1988, 53, 227.
(k) Oppolzer, W.; Xu, J.-Z.; Stone, C. HelV. Chem. Acta 1991, 74, 465.
Synthesis of (()-pentalenolactone G methyl ester: (l) ref 6j. Synthesis of
(()-pentalenolactone P methyl ester: (m) Paquette, L. A.; Kang, H.-J.; Ra,
C. S. J. Am. Chem. Soc. 1992, 114, 7387.
(7) Mori, K.; Tsuji, M. Tetrahedron 1988, 44, 2835.
(8) (a) Rosenstock, B.; Gais, H. J.; Herrmann, E.; Raabe, G.; Binger, P.;
Freund, A.; Wedemann, P.; Kru¨ger, C.; Lindner, H. J. Eur. J. Org. Chem.
1998, 257. (b) Herrmann, E.; Gais, H. J.; Rosenstock, B.; Raabe, G.; Lindner,
H. J. Eur. J. Org. Chem. 1998, 275.
(9) (a) Spanevello, R. A.; Pellegrinet, S. C. Synth. Commun. 1995, 25,
3663. (b) Spanevello, R. A.; Saavedra, D. D. Org. Prep. Proced. Int. 1999,
31, 460.
(10) Pellegrinet, S. C.; Spanevello, R. A. Tetrahedron: Asymmetry 1997,
8, 1983.
(11) (a) Pellegrinet, S. C.; Spanevello, R. A. Org. Lett. 2000, 2, 1073.
(b) Pellegrinet, S. C.; Baumgartner, M. T.; Spanevello, R. A.; Pierini, A.
B. Tetrahedron 2000, 56, 5311.
(12) Pellegrinet, S. C.; Spanevello, R. A. Tetrahedron Lett. 1997, 50,
8623.
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