ORGANIC
LETTERS
2006
Vol. 8, No. 14
3101-3104
Cross Metathesis as a General Strategy
for the Synthesis of Prostacyclin and
Prostaglandin Analogues
Neil A. Sheddan and Johann Mulzer*
Institut fu¨r Organische Chemie, Wa¨hringerstrasse 38, A-1090 Wien, Austria
johann.mulzer@uniVie.ac.at
Received May 10, 2006
ABSTRACT
A cross metathesis (CM) approach has been successfully applied to introduce fully functionalized
and prostaglandin analogues, resulting in high (E)-selectivities for the C13
15R-TIC, carbacyclin, and PGF2 and the formal syntheses of 15-deoxy-TIC and PGJ2.
ω
-side chain appendages of various prostacyclin
−
C14 double bond and leading to the total syntheses of isocarbacyclin,
r
Since the discovery of prostacyclin (PGI2) by Vane et al.,1a
the search for a more chemically and metabolically stable
analogue has been ongoing,2 resulting in such compounds
as isocarbacyclin (1),3 15R-TIC (15R-16-(m-tolyl)-17,18,-
19,20-tetranorisocarbacyclin) (2),4 15-deoxy-TIC (3),5 and
carbacyclin (6)6 (Figure 1). In recent years, a great increase
in activity in the field of prostaglandin (PG) and isocarba-
cyclin analogue synthesis has been observed, primarily
arising from the expectation that neuroscience will represent
a leading principle in the area of PG life science in the
coming decades.7 A convenient and practical access to these
compounds within a few synthetic steps would therefore be
advantageous.
In addition to their important biological properties,1b,c,7,8
these compounds still present demanding synthetic chal-
lenges, regioselectivity of the endo cyclic double bond (C6-
C9R) and R-side chain introduction for isocarbacyclin
analogues, to which we have recently suggested a plausible
solution;5b more generally, there is the problem of how to
introduce stereoselectively the C15 hydroxyl functionality
of the ω-side chain. To date, the standard method to introduce
(1) (a) Moncada, S.; Gryglewski, R.; Bunting, S.; Vane, J. R. Nature
1976, 263, 663. (b) Gryglewski, R. J.; Stock, G. Prostacyclin and its Stable
Analogue Iloprost; Springer: Heidelberg, 1987. (c) Wise, H.; Jones, R. L.;
Prostacyclin and its Receptors; Kluwer Academic Publishers: New York,
2000.
(2) For a review, see: Collins, P. W.; Djuric, S. W. Chem. ReV. 1993,
93, 1533.
(3) Shibasaki, M.; Torisawa, Y.; Ikegami, S. Tetrahedron Lett. 1983,
24, 3493.
(4) Suzuki, M.; Kato, K.; Noyori, R.; Watanabe, Y.; Takechi, H.;
Matsumura, K.; Långstro¨m, B.; Watanabe, Y. Angew. Chem., Int. Ed. Engl.
1996, 35, 334.
(5) (a) Suzuki, M.; Kato, K.; Watanabe, Y.; Satoh, T.; Matsumura, K.;
Watanabe, Y.; Noyori, R. Chem. Commun. 1999, 307. (b) Sheddan, N. A.;
Mulzer, J. Org. Lett. 2005, 7, 5115 and references therein.
(6) Kojima, K.; Sakai, K. Tetrahedron Lett. 1978, 19, 3743.
(7) For lead references on prostacyclin and prostaglandin analogues, see
(a) Suzuki, M.; Noyori, R.; Långstro¨m, B.; Watanabe, Y. Bull. Chem. Soc.
Jpn. 2000, 73, 1053. (b) Durand, T.; Guy, A.; Vidal, J.-P.; Rossi, J.-C. J.
Org. Chem. 2002, 67, 3615. (c) Lai, S.; Lee, D.; J. S. U.; Cha, J. K. J. Org.
Chem. 1999, 64, 7213. (d) Fox, M. E.; Jackson, M.; Lennon, I. C.; McCague,
R. J. Org. Chem. 2005, 70, 1227. (e) Komoto, J.; Yamada, T.; Watanabe,
K.; Woodward, D. F.; Takusagawa, F. Biochemistry 2006, 45, 1987. (f)
Kramp, G. J.; Kim, M.; Gais, H.-J.; Vermeeren, C. J. Am. Chem. Soc. 2005,
127, 17910. (g) Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh,
V. K. J. Am. Chem. Soc. 1987, 109, 7926. (h) Maruyama et al. Bioorg.
Med. Chem. 2002, 10, 2103. (i) Kim, S.; Bellone, S.; Maxey, K. M.; Powell,
W. S.; Lee, G.-J.; Rokach, J. Bioorg. Med. Chem. Lett. 2005, 15, 1873.
(8) (a) Noyori, R.; Suzuki, M. Science 1993, 259, 44. (b) Suzuki, M.;
Koyano, H.; Noyori, R. J. Org. Chem. 1987, 52, 5583.
10.1021/ol061141u CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/16/2006