phytoprostanes are 18-carbon compounds and chiefly differ
from prostaglandins in the lengths of their side chains. There
are several classes of phytoprostanes, and their levels increase
under conditions of enhanced free-radical generation.7 More-
over, due to their structural similarity to isoprostanes, phyto-
prostanes can interfere with these at the receptor level.8 To
date, different series of phytoprostanes are known (E, B, A,
and J): PPB1 type I and PPB1 type II, both of which show
interesting biological properties9 (Figure 1).
Figure 2. General retrosynthetic analysis of prostanes B1.
Our approach is outlined in Figure 2. We envisaged synthe-
sizing prostanes B1 (Figure 2, compounds I) by olefination of
the aldehydes II with suitable chiral hydroxy-alkyl fragments.
We expected that II could be readily obtained from the protected
hydroxymethylcyclopentenones III, which would be obtained
by Pauson-Khand reaction of ethylene and the appropriate
internal acetylene.
The underlying challenge was regiochemical control of the
reaction since the two sides of the acetylene are fairly similar.
In Pauson-Khand reactions of acetylenes in which the steric
hindrance for each substituent is similar, Greene and Gimbert13
showed that regioselectivity is mostly influenced by the differ-
ence in electronegativity between both substituents. In these
cases, the most electron-withdrawing group usually goes to the
ꢀ position. We reasoned that, although low, the electronegativity
of a silyloxymethyl group could be sufficient to enable control
over regioselectivity. Thus, we planned to synthesize III by
Pauson-Khand reaction of acetylenes containing an aliphatic
chain and a hydroxymethyl group protected as tert-butyldim-
ethylsilyl ether.
To optimize the conditions, we chose the alkyne 3 as a
precursor to phytoprostane PPB1 type II. Commercially
available pent-3-yn-1-ol was protected as the tert-bu-
tyldimethylsilyl ether under standard conditions (91%
yield) and subsequently treated with octacarbonyl dicobalt
in hexanes. After concentration in vacuo, the cobalt
complex was submitted to several Pauson-Khand condi-
tions (see Table 1). The standard thermal conditions under
Figure 1. Structures of the methyl esters of prostanes B1: PGB1,
PPB1 type I, and PPB1 type II.
The biological importance of prostanes and the challenges
inherent to their synthesis have stimulated research on efficient,
stereoselective chemistry for their preparation.10,11 The disub-
stituted cyclopentenone common to prostaglandin B1 and
phytoprostanes B1 suggests that these compounds could be
obtained via intermolecular Pauson-Khand reaction between
an internal alkyne and ethylene. Although Pauson-Khand
chemistry is now widely used for five-membered hydrocar-
bon cycles,12 the intermolecular version using internal
alkynes has scarcely been used, probably because of the
lower reactivity of these alkynes (compared to the terminal
ones) as well as the difficulty of regioselective control.
Herein we describe a straightforward, regio- and stereo-
selective route to prostaglandin B1 and phytoprostanes B1
(Figure 1) which is based on intermolecular Pauson-Khand
reaction of internal alkynes.
(7) Loeffler, C.; Berger, S.; Guy, A.; Durand, T.; Bringmann, G.; Dreyer,
M.; Von Rad, U.; Durner, J.; Mueller, M. J. Plant Physiol. 2005, 137, 328.
(8) Thoma, I.; Krischke, M.; Loeffler, C.; Mueller, M. J. Chem. Phys.
Lipids 2004, 128, 135.
Table 1. Pauson-Khand Synthesis of the Cyclopentenone 4
Using Ethylene or Equivalent Compounds
(9) (a) Imbusch, R.; Mueller, M. J. Free Radical Biol. Med. 2000, 28,
720. (b) Imbush, R.; Mueller, M. J. Plant Physiol. 2000, 124, 1293.
(10) Reviews on the synthesis of prostaglandins and analogues: (a) Das,
S.; Chandrasekhar, S.; Yadav, J. S.; Gree, R. Chem. ReV. 2007, 107, 3286.
(b) Sheddan, N. A.; Czybowski, M.; Mulzer, J. Chem. Commun. 2007, 2107
.
(11) Selected syntheses of prostanes B1: (a) Schmidt, A.; Boland, W. J.
Org. Chem. 2007, 72, 1699. (b) El Fangour, S.; Guy, A.; Vidal, J.; Rossi,
J.; Durand, T. J. Org. Chem. 2005, 70, 989. (c) Mikolajczyk, M.; Midura,
W. H.; Ewas, A. M. M.; Perlikowska, W.; Mikina, M.; Jankowiak, A.
Phosphorus, Sulfur 2008, 183, 313. (d) Mikolajczyk, M. Phosphorus, Sulfur
2002, 177, 1839. (e) Mikolajczyk, M.; Mikina, M.; Jankowiak, A. J. Org.
Chem. 2000, 65, 5127. (f) Hyuga, S.; Hara, S.; Suzuki, A. Bull. Chem.
Soc. Jpn. 1992, 65, 2303. (g) Naora, H.; Onuki, T.; Nakamura, A. Bull.
reagent
conditions
toluene, 90 °C
CH2Cl2, NMO, rt
CH2Cl2, NMO, rt
Tol/MeOH, NMO, rt
CH2Cl2, NMO, rt
CH2Cl2, 4 Å MS, NMO, rt
Yield
CH2dCH2, 7.5 bar
CH2dCH-OBz
CH2dCH-OAc
CH2dCH2, 6 bar
CH2dCH2, 6 bar
CH2dCH2, 6 bar
25%
19%
22%
46%
54%
67%
Chem. Soc. Jpn. 1988, 61, 2859
.
(12) Other Pauson-Khand routes to prostanes: (a) Mulzer, J.; Graske,
K. D.; Kirste, B. Liebigs Ann. Chem. 1988, 891. (b) Iqbal, M.; Evans, P.;
Lledo´, A.; Verdaguer, X.; Perica`s, M. A.; Riera, A.; Loeffler, C.; Sinha,
A. K.; Mueller, M. J. ChemBioChem 2005, 6, 276. (c) Iqbal, M.; Duffy,
P.; Evans, P.; Cloughley, G.; Allan, B.; Lledo´, A.; Verdaguer, X.; Riera,
A. Org. Biomol. Chem. 2008, 6, 4649.
6-8 bar pressure of ethylene gave only 25% yield of the
desired product, but we were delighted to see that the
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