Total synthesis of isoprostanes via the two-component coupling process

Article abstract of DOI:10.1016/S0040-4039(02)00898-5

A short total synthesis of isoprostanes has been achieved using a two-component coupling process combined with a diastereoselective protonation under reagent control. The F₁-isoprostanes were easily obtained by stereoselective reduction of the C-9 keto group.

Full text of DOI:10.1016/S0040-4039(02)00898-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4575–4579
Total synthesis of isoprostanes via the two-component
coupling process
Ana R. Rodr´ıguez and Bernd W. Spur*
Department of Cell Biology, University of Medicine and Dentistry of New Jersey, SOM, Stratford, NJ 08084, USA
Received 8 April 2002; accepted 10 May 2002
Abstract—A short total synthesis of isoprostanes has been achieved using a two-component coupling process combined with a
diastereoselective protonation under reagent control. The F1-isoprostanes were easily obtained by stereoselective reduction of the
C-9 keto group. © 2002 Elsevier Science Ltd. All rights reserved.
In 1990 Roberts et al. reported that phospholipid-
bound arachidonic acid is converted in vivo by a free
radical oxidation to isoprostanes with a cis-arrange-
ment of the 8- and 12-side chain.1 Subsequent investiga-
tions showed that other polyunsaturated fatty acids
undergo similar transformations.2,3 The levels of iso-
prostanes measured in biological fluids were signifi-
cantly higher than the enzymatically produced
prostaglandins. These metabolites are established mark-
ers of oxidative stress in several diseases including
Alzheimer’s disease.4,5 The release of isoprostanes dur-
ing kidney failure and severe liver diseases has been
reported,6 but there is little known about their biologi-
cal activities. In the interest of evaluating the biological
and pharmacological properties of these compounds it
is necessary to obtain sufficient quantities by chemical
synthesis.
as the key step a Rh II catalyzed cyclization of a-diazo
ketones.14
It was our goal to develop a short general route that
allowed the synthesis of all epimeric forms of iso-
prostanes. The two-component coupling process, typi-
cally used for the synthesis of the natural
prostaglandins,15 would be ideal if the outcome of the
relative configuration of both side chains could be
controlled. Due to their cis 2,3-disubstituted cyclopen-
tanone structure the isoprostanes could be accessible by
diastereoselective protonation of chiral enolates with
chelating proton sources under reagent control.16 Stud-
ies by Krause et al. revealed that five-membered ring
enolates are the most difficult substrates to use.17
In this communication we wish to report the successful
application of the two-component coupling process
towards a short total synthesis of isoprostanes (Fig. 1).
The chiral key intermediates used in the conjugated
addition were easily available on a large scale as previ-
ously described (Scheme 1).18–22
Several approaches towards isoprostanes have been
reported in the literature. Corey et al. described a
biomimetic route to the 8-epi-PGF2a from arachidonic
acid;7 Larock et al. used a Pd promoted intermolecular
coupling of three different alkenes to 12-epi-PGF2a.8 A
chiral pool strategy combined with a free radical
cyclization to the all-cis-Corey lactone was reported by
Rokach et al.9,10 and modified by Durand11 and
Mulzer;12 the side chains were introduced by a Wittig
and an Emmons–Horner reaction. The Corey lactone
has also been transformed to 12-epi-PGF2a.13 Another
general approach was developed by Taber et al. using
The two-component coupling process of the chiral
intermediates 8 and 10 followed by a diastereoselective
protonation gave directly the protected isoprostane 11
(Scheme 1). Under the same conditions 9 was converted
to 12 (Scheme 1).
The evaluation of different chelating proton donors for
the diastereoselective protonation is summarized in
Table 1. Methyl acetoacetate23 (entry 8, Table 1) gave
the desired protected isoprostane 11 with 82% cis-selec-
tivity in 68% isolated yield.24 The salicylates (entries 5
and 6, Table 1), introduced by Krause,16 gave 11 with
46% and 63% selectivity, respectively.
Keywords: isoprostanes; protonation; enolates; stereoselectivity;
cuprate.
* Corresponding author. Tel.: +1-856-566-7016; fax: +1-856-566-6195;
e-mail: spurbw@umdnj.edu
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00898-5

4576
A. R. Rodr´ıguez, B. W. Spur / Tetrahedron Letters 43 (2002) 4575–4579
Fig. 1.
Scheme 1. Reagents and conditions: (a) lipase (PPL), vinyl acetate; (b) chromatographic separation; (c) 0.5 M guanidine, MeOH,
0°C; (d) TBSCl, imidazole, Et3N, DMF, 84%; (e) 10, n-BuLi, CuCN, MeLi, Et2O, −78°C/methyl acetoacetate, Et2O, −78°C“rt,
CH3COOH, 68%.

A. R. Rodr´ıguez, B. W. Spur / Tetrahedron Letters 43 (2002) 4575–4579
4577
Table 1. Ratio cis/trans obtained in the diastereoselective
protonation using different proton donors (ether, −78°C)
Table 2. Reduction of the keto group at C-9 of com-
pound 11 using different reducing agents
Entry
Proton donors
Ratio cis:transa
Entry
Reducing
agent
Solvent
Temperature Ratio h:ia
(°C)
1
2
3
4
5
CH3–COOH
B1:\99
3:97
3:97
5:95
46:54
CF3–CO–CH2–COOCH2–CH3
CH3–CO–CH2–CO–CH3
CF3–CO–CH2–CO–CH3
1
2
3
4
5
6
L
-Selectride® THF
NaBH4/CeCl3 MeOH
−78
0
B1:\99
79:21
83:17
84:16
88:12
93:7
NaBH4
Me2S·BH3
NaBH4/CeCl3 MeOH
LiBH4 THF
MeOH
THF
0
−20
−65
−40
a The ratios were determined by HPLC [Column: Hypersil-ODS,
mobile phase: gradient CH3CN/H2O, u=210 nm].
6
63:37
the natural prostaglandins reduction of the C-9 keto
group of 11 with
-Selectride® gave 14 with a b-stereo-
L
7
8
CH3–CO–CH2–COOCH2–CH3
CH3–CO–CH2–COOCH3
65:35
82:18
selectivity >99% (entry 1, Table 2),25 whereas lithium
borohydride in THF at −40°C produced 13 with 93%
a-stereoselectivity (entry 6, Table 2).26,27 Removal of
the silyl protective groups from 13 and 14 with HF/Py,
followed by alkaline hydrolysis gave 8-epi-
prostaglandin F1a (1)28 and 8-epi-prostaglandin F1b (2),
respectively (Scheme 2), which were identical in all
aspects with an authentic sample (Cayman Chemical
Company, Ann Arbor, MI).29 Compounds 1 and 2
have been identified in humans.30,31
a The ratios were determined by HPLC [column: Hypersil-ODS,
mobile phase: gradient MeOH/CH3CN/H2O, l=210 nm.]
The synthesis of the 8-epi-PGF1 series from the E-type
intermediates required the stereoselective reduction of
the 9-keto group. The results obtained with different
reducing agents are shown in Table 2. As described for
Scheme 2. Reagents and conditions: (a) LiBH4, THF, −40°C, 62%; (b)
92%; (d) LiOH, THF/H2O, 0°C“rt, 95%.
L
-Selectride®, THF, −78°C, 75%; (c) HF/Py, THF, 0°C“rt,

4578
A. R. Rodr´ıguez, B. W. Spur / Tetrahedron Letters 43 (2002) 4575–4579
Scheme 3. Reagents and conditions: (a) LiBH4, THF, −40°C; (b) L-Selectride®, THF, −78°C; (c) HF/Py, THF, 0°C“rt; (d) LiOH,
THF/H2O, 0°C“rt.
In a similar manner starting from intermediate 12,
11-epi-12-epi-prostaglandin F1b (3) and 11-epi-12-epi-
prostaglandin F1a (4) were obtained (Scheme 3).
7. Corey, E. J.; Shih, C.; Shih, N.-Y.; Shimoji, K. Tetra-
hedron Lett. 1984, 25, 5013–5016.
8. Larock, R. C.; Lee, N. H. J. Am. Chem. Soc. 1991, 113,
7815–7816.
In conclusion we have developed a practical synthesis
of isoprostanes via the tandem two-component cou-
pling process and the diastereoselective protonation
with chelating proton sources under reagent control.
The extension of this methodology towards other natu-
ral products will be reported in due course.
9. Hwang, S.-W.; Adiyaman, M.; Khanapure, S.; Schio, L.;
Rokach, J. J. Am. Chem. Soc. 1994, 116, 10829–10830.
10. Rokach, J.; Khanapure, S. P.; Hwang, S.-W.; Adiyaman,
M.; Schio, L.; FitzGerald, G. A. Synthesis 1998, 569–580.
11. Guy, A.; Durand, T.; Vidal, J.-P.; Rossi, J.-C. Tetra-
hedron Lett. 1997, 38, 1543–1546.
12. Mulzer, J.; Czybowski, M.; Bats, J.-W. Tetrahedron Lett.
2001, 42, 2961–2964.
13. Lai, S.; Lee, D.; U, J. S.; Cha, J. K. J. Org. Chem. 1999,
64, 7213–7217.
Acknowledgements
14. Taber, D. F.; Herr, R. J.; Gleave, D. M. J. Org. Chem.
1997, 62, 194–198.
15. Sih, C. J.; Heather, J. B.; Sood, R.; Price, P.; Peruzzotti,
G.; Hsu Lee, L. F.; Lee, S. S. J. Am. Chem. Soc. 1975, 97,
865–874.
Financial support of this research in part by USDA
(95-37200-1648) and the Department of Cell Biology
UMDNJ–SOM is gratefully acknowledged.
16. Krause, N.; Ebert, S.; Haubrich, A. Liebigs Ann./Recueil
1997, 2409–2418.
17. Krause, N.; Ebert, S. Eur. J. Org. Chem. 2001, 3837–
3841.
18. Babiak, K. A.; Ng, J. S.; Dygos, J. H.; Weyker, C. L.;
Wang, Y.-F.; Wong, C.-H. J. Org. Chem. 1990, 55,
3377–3381.
19. Rodr´ıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.
Eur. J. Org. Chem. 1999, 2655–2662.
20. Corey, E. J.; Bakshi, R. K. Tetrahedron Lett. 1990, 31,
611–614.
21. Rodr´ıguez, A.; Nomen, M.; Spur, B. W.; Godfroid, J. J.
Tetrahedron Lett. 1999, 40, 5161–5164.
22. Rodr´ıguez, A.; Spur, B. W. Tetrahedron Lett. 2001, 42,
6057–6060.
References
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USA 1990, 87, 9383–9387.
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32650–32655.
3. Roberts, L. J., II; Montine, T. J.; Markesbery, W. R.;
Tapper, A. R.; Hardy, P.; Chentob, S.; Dettbarn, W. D.;
Morrow, J. D. J. Biol. Chem. 1998, 273, 13605–13612.
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Q.; Rokach, J.; FitzGerald, G. A. Ann. Neurol. 2000, 48,
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565–568.
23. Eames, J. Tetrahedron Lett. 1999, 40, 5787–5790.
24. To a −78°C solution of 10 (1.0 g, 2.70 mmol) in diethyl
ether (4 ml), in a flame dried flask under argon, was
added a 1.6 M solution of n-butyllithium in hexane (1.8
ml, 2.90 mmol) and stirred at −78°C for 2 h. Copper(I)
6. Morrow, J. D.; Moore, K. P.; Awad, J. A.; Ravenscraft,
M. D.; Marini, G.; Badr, K. F.; Williams, R.; Roberts, L.
J., II J. Lipid Mediators 1993, 6, 417–420.

A. R. Rodr´ıguez, B. W. Spur / Tetrahedron Letters 43 (2002) 4575–4579
4579
cyanide (0.24 g, 2.70 mmol) was placed in a second flame
dried flask and suspended in diethyl ether (8 ml). The
mixture was cooled at −78°C and a 1.4 M solution of
methyllithium in diethyl ether (2.0 ml, 2.74 mmol) was
slowly added. After 20 min at 0°C the clear solution was
cooled to −78°C and the previously prepared vinyllithium
reagent was added via cannula. The reaction was slowly
warmed to −30°C and kept at this temperature for 20
min. After cooling to −78°C compound 8 (0.48 g, 1.35
mmol) in diethyl ether (3 ml) was added. The reaction
mixture was stirred at −78°C (20 min) and at −40°C (10
min) and cooled again to −78°C. The reaction was trans-
ferred into a solution of methyl acetoacetate (2 ml, 19.0
mmol) in diethyl ether (40 ml) which was kept at −78°C.
The mixture was slowly warmed to room temperature
and acetic acid (0.8 ml, 13.6 mmol) was added. The
solution was filtered through a pad of celite and washed
with a saturated solution of sodium bicarbonate and
brine. Drying (Na2SO4) and evaporating under vacuo
gave crude 11. The excess of methyl acetoacetate was
removed in high vacuo (0.1 mm) at room temperature.
Purification by flash chromatography (silica gel, hex-
ane:EtOAc 95:5) afforded 0.55 g (68%) of 11.
29.05, 27.42, 25.82 (3C), 25.73 (3C), 25.01, 24.94, 24.74,
22.56, 18.16, 17.98, 13.88, −4.46, −4.81 (2C), −4.90. [h]D25
−49 (c 0.21, CHCl3). Compound 13: 1H NMR (CDCl3,
300 MHz): l 5.5–5.4 (dd, J=15.3, 6.6 Hz, 1H), 5.2–5.1
(dd, J=15.3, 10.2 Hz, 1H), 4.1–3.9 (m, 2H), 3.8 (m, 1H),
3.6 (s, 3H), 2.7–2.6 (m, 1H), 2.3–2.2 (t, J=7.5 Hz, 2H),
2.2–2.1 (m, 1H), 2.1 (m, 1H), 1.6 (m, 3H), 1.5–1.2 (m,
16H), 1.0–0.8 (m, 21H), 0.1–0.0 (4s, 12H); 13C NMR
(CDCl3, 75.5 MHz): l 174.34, 136.48, 127.51, 78.42,
78.15, 73.49, 54.37, 51.31, 50.81, 43.14, 38.48, 34.04,
31.78, 29.61, 29.46, 29.07, 28.12, 25.81 (3C), 25.72 (3C),
24.90, 24.82, 22.55, 18.15, 17.90, 13.89, −4.38, −4.77,
−4.83, −4.94. Compound 14: 1H NMR (CDCl3, 300
MHz): l 5.5 (dd, J=15.3, 9.9 Hz, 1H), 5.4 (dd, J=15.3,
6.6 Hz, 1H), 4.3 (m, 1H), 4.2–4.1 (m, 1H), 4.0 (m, 1H),
3.6 (s, 3H), 2.4 (m, 1H), 2.3 (t, J=7.5 Hz, 2H), 2.2–2.1
(m, 1H), 2.1–1.9 (m, 2H), 1.7–1.2 (m, 18H), 1.0–0.8 (m,
21H), 0.1–0.0 (br. s, 12H); 13C NMR (CDCl3, 75.5 MHz):
l 174.25, 135.54, 130.33, 78.57, 74.56, 73.74, 54.89, 51.31,
46.03, 45.37, 38.72, 34.07, 31.87, 29.58, 29.12, 27.91,
25.91 (3C), 25.87 (3C), 25.79, 24.95, 24.91, 22.62, 18.19,
18.00, 13.93, −4.24, −4.61, −4.72, −4.76. Compound 16:
1H NMR (CDCl3, 300 MHz): l 5.6 (dd, J=15.3, 10.2
Hz, 1H), 5.5–5.4 (dd, J=15.3, 7.2 Hz, 1H), 4.4–4.2 (m,
2H), 4.1–4.0 (m, 1H), 3.6 (s, 3H), 2.5 (m, 1H), 2.3 (t,
J=7.5 Hz, 2H), 2.2 (m, 1H), 2.2–2.1 (m, 1H), 2.0–1.8 (m,
1H), 1.8–1.2 (m, 18H), 0.9 (t, J=6.6 Hz, 3H); 13C NMR
(CDCl3, 75.5 MHz): l 174.33, 135.08, 132.09, 78.13,
74.24, 73.08, 54.49, 51.33, 46.30, 44.23, 37.45, 34.00,
31.74, 29.44, 29.00, 27.85, 25.61, 25.08, 24.79, 22.55,
13.88. Compound 1: 1H NMR (CD3OD, 300 MHz): l
5.5–5.4 (dd, J=15.3, 6.6 Hz, 1H), 5.4 (dd, J=15.3, 9.3
Hz, 1H), 4.0–3.9 (m, 1H), 3.9 (m, 1H), 3.8 (m, 1H),
2.7–2.6 (m, 1H), 2.5–2.4 (m, 1H), 2.3–2.2 (t, J=7.5 Hz,
2H), 2.0 (m, 1H), 1.7–1.2 (m, 19H), 0.9 (t, J=6.6 Hz,
3H); 13C NMR (CD3OD, 75.5 MHz): l 177.74, 136.89,
130.84, 77.02, 76.71, 73.91, 54.25, 50.55, 43.75, 38.50,
34.94, 32.95, 30.63, 30.18, 29.85, 28.98, 26.23, 26.06,
23.65, 14.28. [h]2D5 +23 (c 0.075, MeOH). Compound 4: 1H
NMR (CD3OD, 300 MHz): l 5.6 (dd, J=15.3, 10.2 Hz,
1H), 5.5–5.4 (dd, J=15.3, 6.6 Hz, 1H), 4.3–4.2 (m, 1H),
4.1–4.0 (m, 1H), 4.0–3.9 (m, 1H), 2.5–2.4 (m, 1H), 2.3–2.2
(t, J=7.5 Hz, 2H), 2.2–2.1 (m, 1H), 2.1–2.0 (ddd, J=
14.4, 6.9, 2.1 Hz, 1H), 1.9–1.8 (dt, J=14.4, 5.4 Hz, 1H),
1.7–1.2 (m, 18H), 0.9 (t, J=6.9 Hz, 3H); 13C NMR
(CD3OD, 75.5 MHz): l 177.91, 135.79, 132.71, 79.11,
74.77, 73.42, 55.28, 47.63, 44.89, 38.56, 35.02, 32.96,
30.67, 30.21, 29.22, 26.82, 26.22, 26.09, 23.61, 14.26. [h]D25
+9 (c 0.078, MeOH).
25. Suzuki, M.; Yanagisawa, A.; Noyori, R. J. Am. Chem.
Soc. 1988, 110, 4718–4726.
26. Corey, E. J.; Nicolaou, K. C.; Machida, Y.; Malmsten,
C. L.; Samuelsson, B. Proc. Natl. Acad. Sci. USA 1975,
72, 3355–3358.
27. Gemal, A. L.; Luche, J.-L. J. Am. Chem. Soc. 1981, 103,
5454–5459.
28. Hulle, F. V.; Sipido, V.; Vandewalle, M. Tetrahedron
Lett. 1973, 14, 2213–2216 The synthesis of (dl) 8-epi-
PGF1a has been reported.
29. Satisfactory spectroscopic data were obtained for all
compounds. Selected physical data: Compound 11: 1H
NMR (CDCl3, 300 MHz): l 5.6 (dd, J=15.3, 6.6 Hz,
1H), 5.1–5.0 (dd, J=15.3, 10.2 Hz, 1H), 4.2 (m, 1H), 4.0
(m, 1H), 3.6 (s, 3H), 3.0–2.8 (m, 1H), 2.7–2.5 (m, 1H), 2.4
(dd, J=18.9, 5.1 Hz, 1H), 2.3 (t, J=7.5 Hz, 2H), 2.2 (br.
d, J=18.9 Hz, 1H), 1.8–1.0 (m, 18H), 0.9 (m, 21H),
0.1–0.0 (4s, 12H); 13C NMR (CDCl3, 75.5 MHz): l
218.35, 174.24, 138.04, 125.92, 73.34, 72.96, 52.10, 51.25,
49.69, 45.41, 38.31, 33.98, 31.71, 29.13, 28.94, 27.15,
25.76 (3C), 25.67 (3C), 24.91, 24.83, 24.71, 22.49, 18.08,
17.90, 13.81, −4.45, −4.80, −4.95, −5.04. [h]2D5 +48 (c 1.4,
1
CHCl3). Compound 12: H NMR (CDCl3, 300 MHz): l
5.6 (dd, J=15.3, 6.3 Hz, 1H), 5.1 (ddd, J=15.3, 10.2, 0.9
Hz, 1H), 4.2–4.1 (m, 1H), 4.0 (m, 1H), 3.6 (s, 3H), 2.9 (m,
1H), 2.6 (m, 1H), 2.4 (dd, J=18.9, 5.1 Hz, 1H), 2.3 (t,
J=7.5 Hz, 2H), 2.2 (br. d, J=18.9 Hz, 1H), 1.8–1.1 (m,
18H), 0.9 (m, 21H), 0.1–0.0 (4s, 12H); 13C NMR (CDCl3,
75.5 MHz): l 218.21, 174.18, 137.78, 125.80, 73.31, 72.95,
52.02, 51.31, 49.94, 45.52, 38.37, 34.07, 31.77, 29.21,
30. Taylor, P. L. Prostaglandins 1979, 17, 259–267.
31. Svanborg, K.; Bygdeman, M.; Eneroth, P. Biomed. Mass
Spectrom. 1983, 10, 495–498.