Stereoselective synthesis of an isoprostane synthon via 8,12-free-radical cyclization

Article abstract of DOI:10.1016/S0040-4039(01)00348-3

Aiming at a stereocontrolled biomimetic synthesis of isoprostanes a fully stereocontrolled 8,12-free radical cyclization has been achieved via intermediate 10 by annulating an endocyclic radical to a butenolide acceptor double bond. In this way ent-12-epi-PGF_2α (ent-2) can be prepared.

Full text of DOI:10.1016/S0040-4039(01)00348-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2961–2964
Stereoselective synthesis of an isoprostane synthon via
8,12-free-radical cyclization
Johann Mulzer,a,* Michael Czybowskib and Jan-W. Batsb
aInstitut fu¨r Organische Chemie der Universita¨t Wien, Wa¨hringer Strasse 38, A-1090 Vienna, Austria
bInstitut fu¨r Organische Chemie der Johann Wolfgang Goethe-Universita¨t Frankfurt, Marie Curiestrasse 11,
D-60439 Frankfurt, Germany
Received 4 February 2001; accepted 26 February 2001
Abstract—Aiming at a stereocontrolled biomimetic synthesis of isoprostanes a fully stereocontrolled 8,12-free radical cyclization
has been achieved via intermediate 10 by annulating an endocyclic radical to a butenolide acceptor double bond. In this way
ent-12-epi-PGF2a (ent-2) can be prepared. © 2001 Elsevier Science Ltd. All rights reserved.
Isoprostanes are the products of a non-enzymatic oxida-
tion of arachidonic acid (AA) in the mammalian cell
which, in contrast to the cyclooxygenase mediated pro-
cess, results in the formation of prostanoids with a
cis-arrangement of the 8- and 12-sidechain (Scheme 1).1
However, for biological evaluation both enantiomers of
the compounds would be desirable. As several syntheses
of ‘natural’ 12-epi-PGF2a (2) have been reported,3 we
decided to prepare the unnatural enantiomer (ent-2) via
a stereocontrolled biomimetic free radical 8,12-cycliza-
tion. There is ample literature precedence for iso-
prostane syntheses via such a process, in particular
from the Rockach group;4 however, in all cases
diastereomeric mixtures were obtained. Some time
ago we studied the free radical annulation of a 12-radi-
cal to a butenolide acceptor. Thus, thiocarbonate 3
furnished the Corey-lactone derivatives 4 and 5 in a 2:1
ratio.5
Characteristic examples are 8- and 12-epi-PGF2a (1 and
2), of which 1 has been isolated and shown to be a
potent renal and pulmonary vasoconstrictor.2 2, how-
ever, has not been found in nature, so far, though it
should also be formed via the above-mentioned free
radical cascade. Isoprostanes are generated in racemic
form, which is consistent with a non enzymatic pathway.
HO
HO
HO
(CH2)3CO2H
(CH2)3CO2H
8
(CH2)3CO2H
C5H11
C5H11
C5H11
12
HO
HO
OH
OH
HO
OH
ent-2 (ent-12-epi-PGF2α
)
1 ( 8-epi-PGF2α
O
)
2 (12-epi-PGF2α
O
)
O
O
O
O
TBDPSO
O
TBDPSO
O
nBu3SnH, AIBN
12
BzO
BzO
+
11
8
8
TBDPSO
85 %
O
12
TBDPSO
OPh
OBz
OBz
12-radical
S
4
5
3
Keywords: isoprostanoids; free radical cyclization; biomimetic synthesis.
* Corresponding author. Fax: +43-1-4277-52189; e-mail: johann.mulzer@univie.ac.at
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00348-3

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J. Mulzer et al. / Tetrahedron Letters 42 (2001) 2961–2964
8
H
H
(CH2)3CO2H
C5H11
(CH2)3CO2H
O
O2
O
8
(CH2)3CO2H
C5H11
O
8
H
H
AA
+
O
O
O
12
12
12
H
C5H11
H
1
O2
O2
2
Scheme 1.
Ph
Ph
1. O3, PPh3
2.
1. Swern-oxid.
O
O
2. Alpine-borane
Li
CO2Et
X
Y
O
O
7a or 7b
CO2Et
yield and
de ca. 90 %
83 %
OTBS
6
CO2Et
OTBS
7a X = OH, Y = H
7b X = H, Y = OH
Ph
Ph
O
1. Lindlar, H2
2. silicagel
1. HF/pyridine
2. PhOC(S)Cl
O
O
S
O
O
O
O
O
12
O
7a
8
9
90 %
95 %
OPh
OTBS
8
O
1. CSA, MeOH
2. BzCl, pyridine
3. TBSCl
O
Ph
O
O
O
nBu3SnH, AIBN
O
O
O
8
12
12
86 %
73 %
OBz
TBSO
8
O
O
10
12
Ph
11
O
HO
Ph
(CH2)3CO2H
O
O
O
O
S
O
nBu3SnH, AIBN
89 %
C5H11
7b
11
HO
OH
OPh
O
O
O
15 (11-epi-PGF2α
)
Ph
14
13
Scheme 2.

J. Mulzer et al. / Tetrahedron Letters 42 (2001) 2961–2964
2963
Figure 1. Transition states for the radical annulations as derived from the crystal structures of the cyclization products 11 and 14.
The annulation to the butenolide exclusively generates
the cis-fused system, however, the 12-radical, as in all
the cases reported so far,4 lacks facial selectivity, due to
rapid rotation around the 11,12-axis. To inhibit such a
rotation the incorporation of the 11,12-bond into a
cyclic template appeared appropriate, following an ear-
lier precedence by RajanBabu.6 Thus, in our synthesis
of ent-2 the known benzylidene acetal (6)7 was trans-
formed into an epimeric mixture of the acetylides 7a/b.
To rectify the configuration of the C-4-carbinol the
mixture was oxidized to the ketone and then reduced
with Alpine-borane8 to give either 7a or 7b with high
diastereocontrol (Scheme 2). Pure alcohol 7a was
hydrogenated and cyclized to the butenolide 8, which
was converted into thiocarbonate 9 and then into free
radical 10.9 Twofold cis-annulation occurred to give the
ent-12-epi-Corey lactone derivative 1110,11 as a single
stereoisomer in high yield. By routine functional group
manipulation 11 was transformed into 12, i.e. the enan-
tiomer of Rockach’s intermediate in his synthesis of 2.3b
Analogously thiocarbonate 13, obtained from 7b, was
converted into 14,10,11 again as a single stereoisomer
(Scheme 2), which may serve as an intermediate in a
synthesis of 11-epi-PGF2a (15).
II, L. J.; Hoover, R. L.; Badr, K. F. J. Clin. Invest. 1992,
90, 136.
3. (a) Lai, S.; Lee, D.; U, J. S.; Cha, J. K. J. Org. Chem.
1999, 64, 7213; (b) Hwang, S. W.; Adiyaman, M.;
Khanapure, S. P.; Rokach, J. Tetrahedron Lett. 1996, 37,
779; (c) Larock, R. C.; Lee, N. H. J. Am. Chem. Soc.
1991, 113, 7815; (d) Brown, E. D. Ger. Offen. DE 2, 360,
893, 12 June 1973; Chem. Abstr. 1974, 81, 120096e; (e)
Brewster, D.; Meyers, M.; Ormerod, J.; Otter, P.; Smith,
A. C. B.; Spinner, M. E.; Turner, S. J. Chem. Soc., Perkin
Trans. 1 1973, 2796.
4. (a) Hwang, S. W.; Adiyaman, M.; Khanapure, S.; Schio,
L.; Rockach, J. J. Am. Chem. Soc. 1994, 116, 10829; (b)
Rockach, J.; Khanapure, S. P.; Hwang, S.-W.; Adiya-
man, M.; Schio, L.; FitzGerald, G. A. Synthesis 1998,
569; (c) Rockach, J.; Khanapure, S. P.; Hwang, S.-W.;
Adiyaman, M.; Lawson, J. A.; FitzGerald, G. A.
Prostaglandins 1997, 54, 823; (d) For an earlier example,
see: Corey, E. J.; Shih, Ch.; Shih, N. Y.; Shimoji, K.
Tetrahedron Lett. 1984, 25, 5012; (e) Corey, E. J.; Shih,
C.; Shimoji, K. J. Am. Chem. Soc. 1984, 106, 6425.
5. Mulzer, J.; Kermanchahi, A. K.; Buschmann, J.; Luger,
P. Liebigs Ann. Chem. 1994, 531.
6. RajanBabu, T. V. J. Org. Chem. 1988, 53, 4522.
7. Nicolaou, K. C.; Nugiel, D. A.; Couladouros, E.; Hwang,
C.-K. Tetrahedron 1990, 46, 4517.
8. Midland, M. M.; Zderic, S. A. J. Am. Chem. Soc. 1982,
104, 525.
The transition states of the respective free radical
cyclizations may be rationalized in terms of the crystal
structures of 11 and 14, respectively (Fig. 1). This figure
clearly indicates the stereochemical course of the addi-
tion of an endocyclic cyclohexyl type radical to the
butenolide acceptor double bond. Both the cis-annula-
tion to the six-membered acetal and the cis-annulation
to the butenolide guarantee the stereochemical outcome
of the cyclization. In conclusion we have described a
fully stereocontrolled 8,12-free radical cyclization in the
isoprostane series and demonstrated its utility for the
synthesis of ent-2.
9. Barton, D. H. R.; McCombie, S. W. J. Chem. Soc.,
Perkin Trans. 1 1975, 1574.
1
10. 11: mp 154°C. H NMR (250 MHz, CDCl3) l 7.34–7.27
(m, 5H), 5.33 (s, 1H), 5.11 (t, J=6.9 Hz, 1H), 4.36–4.33
(m, 1H), 4.26–4.23 (m, 2H), 3.46 (dd, J=18 Hz, J=3.3
Hz, 1 H), 3.21–3.08 (m, 1H), 2.64 (dd, J=18.5 Hz,
J=11.9 Hz, 1H), 2.38 (d, J=15.8. Hz, 1H), 1.98–1.87 (m,
2H). 13C NMR (67.9 MHz, CDCl3) l 177.30, 137.48,
128.99, 128.26, 126.25, 101.25, 85.37, 80.02, 65.92, 39.75,
39.73, 39.69, 31.29 ppm. MS (ESI): m/z 261.1 (M+).
[h]2D0=−98.7 (c 2.42, CHCl3). Anal. calcd for C15H16O4:
C, 69.22; H, 6.20. Found: C, 68.95; H, 6.31. 14: mp
149°C. 1H NMR (250 MHz, CDCl3) l 7.39–7.26 (m, 5H),
5.38 (s, 1H), 5.04 (m, 1H), 4.40–4.37 (m, 1H), 4.19–4.13
(m, 1H), 4.03 (d, J=12 Hz, 1H), 3.33–3.23 (m, 1H), 2.75
(dd, J=18 Hz, J=9 Hz, 1H), 2.80–2.28 (m, 2H), 2.12–
2.02 (m, 1H), 1.67–1.61 (m, 1H): 13C NMR (67.9 MHz,
CDCl3) l 176.31, 137.90, 128.90, 128.17, 125.76, 100.50,
85.17, 79.72, 65.44, 44.28, 40.37, 38.78, 33.60 ppm. MS
(ESI) m/z 261.1 (M+). [h]D20=−88.6 (c 2.11, CHCl3). Anal.
References
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Campell, M. D.; Zackert, W. E.; Daniel, V. C.; Badr, K.
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4317 and earlier work.
2. (a) Morrow, J. D.; Hill, K. E.; Burk, R. F.; Mammour,
T. M.; Badr, K. F.; Roberts, II, L. J. Proc. Natl. Acad.
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T. M.; Fukunaga, M.; Ebert, J.; Morrow, J. D.; Roberts,

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J. Mulzer et al. / Tetrahedron Letters 42 (2001) 2961–2964
calcd for C15H16O4: C, 69.22; H, 6.20. Found: C, 68.99;
H, 6.35.
11. Crystallographic data (excluding structure factors) for the
structures of 11 and 14 have been deposited with the
Cambridge Crystallographic Data Centre as supplemen-
tary publication numbers CCDC 157310 and 157311.
Copies of the data can be obtained free of charge on
application to CCDC, 12 Union Road, Cambridge, CB2
1EZ, UK [(fax: +44(0)-1233-336033 or e-mail: deposit@
ccdc.cam.ac.uk].
.
.