CHART 1. Som e Rep r esen ta tive Exa m p les of
Cyclop en ten on e P r osta gla n d in s
A f J P r osta gla n d in Sw a p : A New Ta ctic
for Cyclop en ten on e P r osta gla n d in
Syn th esis
Giuseppe Zanoni,* Francesca Castronovo,
Eleonora Perani,† and Giovanni Vidari*
Dipartimento di Chimica Organica, Universita` di Pavia,
Via Taramelli 10, 27100 Pavia, Italy gzanoni@unipv.it
gzanoni@unipv.it
Received April 18, 2003
Abstr a ct: A practical methodology for the synthesis of
J -type prostaglandins has been developed starting from the
well-consolidated approaches established for the synthesis
of A-type prostaglandins. An efficient 1,3-allylic transposi-
tion of the C-9 hydroxyl group of intermediate 4 furnished
the advanced precursor 5 for J 2 synthesis. Our optimized
A-J swap protocol employed selenium chemistry, involving
the [2,3] sigmatropic rearrangement of secondary allylic
selenoxide 11a .
alternate means to achieve this important class of
biologically active compounds.
In this note we report for the first time a versatile
approach to transform an advanced A2 synthetic inter-
mediate into a suitable synthon for the J 2 synthesis. This
A-J prostaglandin swap should allow one to capitalize
on almost all the already developed approaches to
prepare PGA2’s for the synthesis of J 2 analogues. A
common intermediate described in the PGA2 synthesis
was the allylic alcohol 4;6b therefore, an efficient allylic
1,3-transposition across the allylic alcohol was envisioned
to furnish the advanced precursor 5 for J 2 prostaglandin
synthesis (Scheme 1).
To achieve the best procedure to perform the A-J
swap, we explored a few allylic rearrangement tactics on
the model compound 6 (Scheme 2).7 The task proved to
be not trivial.
In fact, a number of appealing 1,3-allylic transposition
reactions, in principle amenable to accomplish the ex-
pected A-J swap, proved to be unfeasible for the allylic
alcohol 6. In the event, rearrangement of epoxy alcohol
9 according to the Li’s procedure (path a-b) afforded the
desired allyl alcohol 8 in an unsatisfactory 12% overall
In the past decade there was a renewed interest in
prostaglandins of the structurally related A and J classes,
in particular in the latter group of cyclopentenone
derivatives (Chart 1).1
Thanks to the progress of molecular biology, a remark-
able activity of prostaglandins of the A2 and J 2 series
against a wide variety of DNA and RNA viruses, includ-
ing HIV-1 and influenza virus, has been proved. These
compounds also possess a potent antiinflammatory activ-
ity and induce the arrest of cell mitosis at the G1 phase
or the apoptosis of tumor cells, depending on the cell
type.2 Among the prostaglandins of the A2 and J 2 series,
the latter exert the more powerful activities.3 Indeed, a
considerable interest was generated in 1995 by the
discovery that 15-deoxy-∆12,14-PGJ 2 3 was the natural
activating ligand for γ isoform of the peroxisome prolif-
erator-activated receptor (PPARγ). PPARγ is the key
regulator of adipocite differentiation and the molecular
target of antidiabetic drugs such as troglitizone and
rosiglitazone.4 Therefore, prostaglandin 3 is a potent
inducer of adipogenesis, promoting differentiation of pre-
adipocytes into mature triglyceride-containing fat cells.
Surprisingly, despite the impressive number of reports
regarding the biological activities of J 2 prostaglandins,
less attention was paid to their synthesis.5
(5) To date only a limited number of total syntheses have been
reported in the literature: (a) Ali, S. M.; Chapleo, B. C.; Finch, M. A.
W.; Roberts, S. M.; Wooley, G. T.; Cave, R. C.; Newton, R. F. J . Chem.
Soc., Perkin Trans. 1 1980, 2093-2097. (b) Bundy, G. L.; Morton, D.
R.; Peterson, D. C.; Nishizawa, E. E.; Miller, W. L. J . Med. Chem. 1983,
6, 790-799. (c) Ali, M. S.; Finch, M. A. W.; Roberts, S. M.; Newton, R.
F. J . Chem. Soc., Chem. Commun. 1979, 679-682.
(6) (a) Krafft, M. E.; Wright, C. Tetrahedron Lett. 1992, 33, 151-
152 and references therein. (b) ApSimon, J . The Synthesis of Prosta-
glandins; Vol. 4, The Total Synthesis of Natural Product; Bindra, J .
S., Ed.; Wiley-Interscience Publication: New York, 1981; pp 353-449.
(7) (a) Compound 6 was readly prepared in three synthetic steps
from the known lactone 7:7b
On the other hand, a great number of known ap-
proaches exist for the synthesis of the structurally related
PGA2’s;6 therefore, a general method to swap from the
A2 to the J 2 family is highly desirable as a practical
† Present address: Centro Grandi Strumenti, Universita` di Pavia,
Via Bassi 21, 27100 Pavia.
(1) Neghishi, M.; Katoh, H. Prostaglandins Lipid Mediators 2002,
68-69, 611-617 and references therein.
(2) Straus, D. S.; Glass, C. K. Med. Res. Rev. 2001, 21, 185-210
and references therein.
(3) Rossi. A.; Elia. G.; Santoro, M. G. Proc. Natl. Acad. Sci. U.S.A.
1997, 94, 746-750.
(4) (a) Forman, B. M.; Tontonoz, P.; Brun, R. P.; Spiegelman, B. M.;
Evans, R. M. Cell 1995, 83, 803-812. (b) Kliewer, S. A.; Lenhard, J .
M.; Willson, T. M.; Patel, I.; Lehmann, J . M. Cell 1995, 83, 813-819.
(b) Larock, R. C.; Hightower, T. R. J . Org. Chem. 1993, 58, 5298-
5300.
10.1021/jo034501p CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/19/2003
J . Org. Chem. 2003, 68, 6803-6805
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