Total synthesis of the four enantiomerically pure diasteroisomers of the phytoprostanes E1type II and of the 15-E2t-isoprostanes

Article abstract of DOI:10.1021/jo702455g

(Chemical Equation Presented) Syntheses of the four enantiomerically pure diastereoisomers of the phytoprostanes E₁ type II and 15-E _2t-isoprostanes (1-4) are described. The key steps included the preparation of the Freimanis (±)-hyd

Full text of DOI:10.1021/jo702455g

Total Synthesis of the Four Enantiomerically Pure Diasteroisomers
of the Phytoprostanes E1Type II and of the 15-E2t-Isoprostanes
Edith Pinot, Alexandre Guy, Anais Fournial, Laurence Balas, Jean-Claude Rossi, and
Thierry Durand*
Institut des Biomole´cules Max Mousseron, IBMM, UMR CNRS 5247, UniVersite´ Montpellier I, UniVersite´
Montpellier II, Faculte´ de Pharmacie, 15. AV. Ch. Flahault, F-34093 Montpellier cedex 05, France
Thierry.Durand@uniV-montp1.fr
ReceiVed NoVember 15, 2007
Syntheses of the four enantiomerically pure diastereoisomers of the phytoprostanes E1 type II and 15-
E2t-isoprostanes (1-4) are described. The key steps included the preparation of the Fre¨ımanis
(()-hydroxycyclopentenone 5, enzymatic resolution of this racemic hydroxycyclopentenone, Wittig and
Horner-Wadsworth-Emmons (HWE) coupling reactions and finally enantioselective reductions.
Introduction
modulate human dendritic cell (DC) function in a fashion that
favors Th2 cell polarization.9 Two recent studies by Mariani et
al. and Gutermuth et al. confirmed that PPE1 dose-dependently
inhibited LPS-induced IL-12p70 of DCs and were identified to
be one of the key factors leading to the Th2-polarizing potential
of aqueous pollen extracts.10,11
Mammalian isoprostanes (IsoP) and plant based phytopros-
tanes (PP) are formed by a free radical mediated, nonenzymatic
mechanism from arachidonic acid and R-linolenic acid, respec-
tively (Figure 1).1,2
Most of the current knowledge concerning the biological
actions of IsoPs is limited to the F2-series where 15-F2t-IsoP
has been most studied, together, albeit to a lesser extent with
15-E2t-IsoP.3,4 In contrast to PGE2 and PGF2, which exhibit
opposite biological effects, 15-E2t-IsoP is also a vasoconstrictor
and more potent than 15-F2t-IsoP in systemic and pulmonary
vessels. Its activity is mediated through the TP-receptor, and
EP3-receptor activation in the pulmonary vasculature.5,6 Fur-
thermore, 15-E2t-IsoP may also induce relaxation through EP-
receptors.7
In plants, several classes of PPs are constitutively present8
and, notably, their levels increase in a variety of conditions with
enhanced free radical generation. In 2005, Traidl-Hoffmann et
al. proposed that pollen-derived PPEs act as regulators that
To fully assess the physiological activities of each of the
enantiomerically pure PPE1 type II and 15-E2t-IsoPs, we aimed
to obtain sufficient quantities by chemical synthesis.
Over the past 10 years, we have developed a general strategy
toward the synthesis of F-IsoP, neuroprostane (NeuroP) and PP,
using a radical cyclization that serves to construct the required
tetrasubstituted cyclopentane ring whereby the hydroxyl groups
and the carbon side chains are either syn-anti-syn or all cis.12,13
However, using this method, we were unable to access the E
and D type because the protection of the hydroxyl groups was
not orthogonal. We have recently reported a synthesis of the
PPB1 type I and II starting from 2-(8-carboxyoctyl)furan and
2-propylfuran.14 We now wish to report the syntheses of other
classes of IsoP and PP, namely the four diastereoisomers of
* Corresponding author. Tel: 33-4-67-54-86-23. Fax: 33-4-67-54-86-25.
(1) Morrow, J. D.; Hill, K. E.; Burk, R. F.; Nammour, T. M.; Badr, K.
F.; Roberts, L. J., 2nd. Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 9383-9387.
(2) Imbusch, R.; Mueller, M. J. Plant Physiol. 2000, 124, 1293-1304.
(3) Musiek, E. S.; Yin, H.; Milne, G. L.; Morrow, J. D. Lipids 2005, 40,
987-994.
(4) Morrow, J. D. Curr. Pharm. Des. 2006, 12, 895-902.
(5) Janssen, L. J. Trends Pharmacol. Sci. 2002, 23, 59-62.
(6) Cracowski, J. L.; Devillier, P.; Durand, T.; Stanke-Labesque, F.;
Bessard, G. J. Vasc. Res. 2001, 38, 93-103.
(7) Catalli, A. E.; Janssen, L. J. Am. J. Physiol. Lung Cell Mol. Physiol.
2004, 287, L1035-L1041.
(8) Mueller, M.-J. Curr. Opin. Plant Biol. 2004, 7, 441-448.
(9) Traidl-Hoffmann, C.; Mariani, V.; Hochrein, H.; Karg, K.; Wagner,
H.; Ring, J.; Mueller, M.-J.; Jakob, T.; Behrendt, H. J. Exp. Med. 2005,
201, 627-636.
(10) Mariani, V.; Gilles, S.; Jakob, T.; Thiel, M.; Mueller, M.-J.; Ring,
J.; Behrendt, H.-T.; Traidl-Hoffmann, C. J. Immunol. 2007, 178, 7623-
7631.
(11) Gutermuth, J.; Bewersdorff, M.; Traidl-Hoffmann, C.; Ring, J.;
Mueller, M.-J.; Behrendt, H.; Jakob, T. J. Allergy Clin. Immunol. 2007,
120, 293-299.
(12) Durand, T.; Guy, A.; Henry, O.; Roland, A.; Bernad, S.; El, Fangour,
S.; Vidal, J. P.; Rossi, J. C. Chem. Phys. Lipids 2004, 128, 15-33.
(13) El, Fangour, S.; Guy, A.; Despres, V.; Vidal, J.-P.; Rossi, J.-C.;
Durand, T. J. Org. Chem. 2004, 69, 2498-2503.
10.1021/jo702455g CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/20/2008
J. Org. Chem. 2008, 73, 3063-3069
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Pinot et al.
FIGURE 1. Phytoprostane E1 and isoprostane E2 pathway.
SCHEME 1. Retrosynthetic Scheme of the PPE1 Type II and 15-E2t-IsoPs
PPE1 type II 1, 2 and 15-E2t-IsoPs 3, 4 starting from 4-hy-
droxycyclopentenone 5 (Scheme 1).
After a Pd-catalyzed alkenyl reduction under a hydrogen
atmosphere, the introduction of the formyl group at C5 was
achieved using a Vilsmeyer reaction thereby affording aldehyde
7. The protection of the aldehyde in the presence of methyl
orthoformate, followed by an electrophilic addition with MeOH/
Br2 under basic conditions afforded the bis-acetal 9. This latter
compound underwent an “aldol-type” cyclization under acidic
hydrolysis and basic treatment leading to the 3-hydroxycyclo-
pentenone 10. Migration of the hydroxyl group with double bond
formation using chloral under basic conditions led to the racemic
4-hydroxycyclopentenone 5 in 28% yield after four steps.
Notably, all these reactions were performed on multigram scale
(50-100 g) and ultimately afforded >20 g of rac-5.20
Results and Discussion
Currently, the synthesis of PPE1 type II has not been reported
in the literature. In contrast, two syntheses of 15-E2t-IsoPs have
been reported by Nakamura and Sakai,15 and more recently the
PPE1 type I, the 15-E1t- and 15-E2t- IsoP were synthesized by
Rodriguez and Spur.16,17
The key steps of our procedure rely on the regioselective
fragmentation of the furan ring present in derivative 7 and its
subsequent cyclization, leading to the 4-hydroxy-2-cyclopen-
tenone 5 (Scheme 2).
Synthesis of 4-Hydroxycyclopentenones (S)-5 and (R)-5
from trans-3-(2-Furyl)acrylic acid. The preparation of the
racemic 4-hydroxycyclopentenone 5, was achieved from com-
mercially available trans-3-(2-furyl)acrylic acid as starting
material, using our previously described procedure.18,19
Using our previously optimized conditions (CAL-B, vinyl
acetate in hexane)18 for this enzymatic kinetic resolution, we
obtained 45% (R)-acetate 11 and 49% alcohol (S)-5 (94% ee,
determined by NMR studies with the help of Mosher’s method).
In addition, enzymatic hydrolysis of the (R)-acetate 11, with
(18) Pinot, E.; Guy, A.; Guyon, A.-L.; Rossi, J.-C.; Durand, T.
Tetrahedron: Asymmetry 2005, 16, 1893-1895.
(14) El Fangour, S.; Guy, A.; Vidal, J.-P.; Rossi, J.-C.; Durand, T. J.
Org. Chem. 2005, 70, 989-997.
(15) Nakamura, N.; Sakai, K. Tetrahedron Lett. 1978, 18, 1549-1552.
(16) Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2002, 43, 9249-
9253.
(17) Rodriguez, A. R.; Spur, B. W. Tetrahedron Lett. 2003, 44, 7411-
7415.
(19) Experimental procedures of compounds 7-10 mentioned in the text,
were reported in the Supporting Information. In fact, these procedures were
never published in English, but only in Russian (Loza, E.; Lola, D.;
Freimanis, J.; Turovskis, I.; Gavars, M.; Liepipa, A. LatVijas PSRZA Vestis,
Chem. Ser. 1985, 4, 465-472).
(20) Loza, E.; Lola, D.; Freimanis, J.; Turovskis, I.; Rozite, S.; Bokaldere,
R.; Sakhartova, O. V. Tetrahedron 1988, 44, 1207-1219.
3064 J. Org. Chem., Vol. 73, No. 8, 2008

Phytoprostanes E1Type II and of the 15-E2t-Isoprostanes
SCHEME 2. Synthesis of Precursor rac-5 and Enzymatic Kinetic Resolution of 4-Hydroxycyclopentenone rac-5
SCHEME 3. Synthesis of Tetrasubstituted Cyclopentane Precursor 15
the CAL-B in the presence of a phosphate buffer (0.1 M) at
pH)7, led to the (R)-alcohol 5 with 94% ee in 98% yield.
Synthesis of PPE1 Type II 1a,b and 2a,b from 4-Hydroxy-
cyclopentenones (R)-5 and (S)-5. The syntheses of PPE1 type
II 1a,b and 2a,b were subsequently performed from 4-hydroxy-
cyclopentenones (R)-5 and (S)-5 as shown in Schemes 3-5.
The protection of the hydroxyl group was accomplished with
TBSCl, imidazole/DMF in 92% yield. Our first attempts to
reduce the enone 12, under the reaction conditions (H2/Pd(C),
MeOH) reported by Fre¨ımanis20 failed. We obtained a complex
mixture of inseparable hydrogenation products, and traces of
partial hydrogenolysis of the acetal group to the corresponding
methyl ether. We, therefore, considered protection of the
carbonyl functionality, in an attempt to decrease epimerization,
using both a methyl thioacetal and an isopropylidene acetal.
Unfortunately, all our attempts at hydrogenation, using pal-
ladium or rhodium catalysts, failed and we obtained inseparable
hydrogenation products. Consequently, we decided to reduce
the carbonyl group, using L-Selectride in THF. Under these
conditions 13 was obtained with high stereoselectivity (95:5).
These two diasteroisomers were separable by flash chromatog-
raphy (cyclohexane/EtOAc, 1-10%, with 2% Et3N). The
orthogonal protection of the hydroxyl group with ethoxymethyl
chloride (EOMCl), (diisopropylethyl)amine (DIPEA), in CH2-
Cl2 led to the protected derivative 14 in 90% yield. Another
important challenge in this strategy proved to be the reduction
of 14 to 15. All our first attempts with palladium or rhodium
catalysts failed again. However, we eventually obtained 15 in
an excellent yield with complete diastereoselectivity using
diimide, generated in situ from dipotassium diazodicarboxylate
and acetic acid in MeOH. Interestingly, it has been reported
that diimide21 reacts only slowly with tetrasubstituted alkenyl
derivatives. This led us to optimize the formation of 15 by
controlling the addition speed and by adding butanone in the
reaction mixture to remove the hydrazine formed in situ. Only
under these controlled conditions could 15 be obtained in good
yield with the required syn-anti-syn orientation. Theoretically
the syn-exo reduction is favored,21 but in our case, the syn-
anti-syn orientation of 15 could be explained by electronic
factors leading preferentially to an anti-exo reduction as
reported in the literature.22
(21) Burke, S. D.; Danheiser, R. L. Oxidizing and Reducing Agents; John
Wiley & Sons Ltd: Chichester, U.K., 2000.
(22) Baird, W. C., Jr.; Franzus, B.; Surridge, J. H. J. Am. Chem. Soc.
1967, 89, 410-414.
J. Org. Chem, Vol. 73, No. 8, 2008 3065

Pinot et al.
SCHEME 4. Synthesis of PPE1 Type II 1a and Its 9-Epimer 1b
SCHEME 5. Synthesis of ent-PPE1 Type II 2a and Its 9-Epimer 2b from 4-Hydroxycyclopentenones (S)-5
The methyl ester 15 was converted into the primary alcohol
16 (Scheme 4) in 95% yield by treatment with lithium aluminum
hydride (LAH) in anhydrous ether at room temperature. Tolu-
enesulfonyl chloride treatment led to the formation of tosylate
17 in 84% yield, which was subsequently reduced with LAH
in anhydrous ether to afford the ethyl group constituting the R
chain of the PPE1 type II in 91% yield. The acetal 18 was
converted by acidic hydrolysis with TsOH in acetone into the
aldehyde 19, which was used immediately in the next step. It
was found that the reaction periods needed to be very short, to
avoid the deprotection of the TBS group. The condensation of
19 with dimethyl[9-(ethoxycarbonyl)-2-oxononyl]phosphonate13
in the presence of sodium (hexamethyldisilyl)amide, in anhy-
drous THF, afforded the trans-R,â-enone ester 20 in 70% yield
3066 J. Org. Chem., Vol. 73, No. 8, 2008

Phytoprostanes E1Type II and of the 15-E2t-Isoprostanes
SCHEME 6. Syntheses of 15-E2t-IsoP 3a and Its 15 Epimer 3b
after two steps. Neither detrimental elimination nor epimeriza-
tion was observed during this HWE reaction, as reported
previously in other series.23
and 24b with HF/pyridine in THF at 0 °C at room temperature
gave the desired PPE1 type II 1a and its C9 epimer 1b in 41%
yield. Interestingly, only under these reaction conditions, neither
epimerization nor elimination was observed.
The diastereoselective reduction of the C9 keto group in 20
with the chiral reducing agents24 (S)- or (R)-BINAL-H gave
the desired enantiopure 9(S) derivative 21a and its 9(R) epimer
21b, respectively, in 68% yield (Scheme 4). This type of
diastereoselective reduction constitues a standard approach to
the preparation of both isoprostanes and prostaglandins, and its
stereochemical outcome is well understood. Protection of the
hydroxyl groups 21a and 21b, using tert-butyldiphenylchlo-
rosilane (TBDPSCl), imidazole in DMF afforded the corre-
sponding protected alcohols 22a and 22b in 84% and 81%
yields, respectively. Unfortunately, our preliminary attempts for
the deprotection of the ethoxymethyl (EOM) group, using
chlorocatecholborane25 or bromocatecholborane26,27 led to a
mixture of inseparable hydroxyl derivatives. We then tried
TMSBr/CH2Cl2,28 PPTS/MeOH/CH2Cl2,29 InI3/EtOAc30 and
FeCl3/Ac2O31 without any more success. Finally, the use of BF3‚
Et2O/Me2S32 led to the corresponding deprotected derivatives
23a and 23b with an acceptable 49% yield. Dess-Martin33
oxidation afforded quantitatively the ketones 24a and 24b, which
were used immediately in the next step. Desilylation of 24a
All reactions have been duplicated with the corresponding
4-hydroxycyclopentenone (S)-5, leading to the enantiomerically
pure ent-PPE1 type II 2a and its 9-epimer 2b as shown in
Scheme 5.
Synthesis of 15-E2t-IsoPs 3a,b and 4a,b from 4-Hydroxy-
cyclopentenones (R)-5 and (S)-5, Respectively. 15-E2t-IsoP
3a, its C15 epimer 3b, ent-15-E2t-IsoP 4a and ent-15-epi-15-
E2t-IsoP 4b were prepared by using the same overall procedure
as outlined in Schemes 6 and 7.
The ester 15 was quantitatively converted into the aldehyde
27 by treatment with DIBALH in anhydrous toluene (Scheme
6). The introduction of the R-chain of the isoprostane was
achieved by a Wittig reaction using the commercially available
(4-carboxybutyl)triphenylphosphonium bromide and sodium
(hexamethyldisilyl)amide as a base. The aldehyde 27 reacted
with the ylide in anhydrous THF at room temperature, then a 2
M solution of (trimethylsilyl)diazomethane in ether was added.
This afforded a mixture of inseparable (Z/E, 90:10) methyl esters
(28) Hanessian, S.; Delorme, D.; Dufresne, Y. Tetrahedron Lett. 1984,
25, 2515-2516.
(23) Durand, T.; Henry, O.; Guy, A.; Roland, A.; Vidal, J.-P.; Rossi,
J.-C. Tetrahedron 2003, 59, 2485-2495.
(29) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3nd ed.; Wiley-Interscience: New York, 1999.
(30) Ranu, B. C. Eur. J. Org. Chem. 2000, 13, 2347-2356.
(31) Ganem, B.; Small, V. R. J. J. Org. Chem. 1974, 39, 3728-3730.
(32) Naito, S.; Kawahara, E.; Maruta, K.; Maeda, M.; Sazaki, S. J. Org.
Chem. 1995, 60, 4419-4427.
(24) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J. Am. Chem.
Soc. 1984, 106, 6709-6716.
(25) Golinski, M.; Heine, M.; Watt, D. S. Tetrahedron Lett. 1991, 32,
1553-1556.
(26) Boeckman, R. K. J.; Potenza, J. C. Tetrahedron Lett. 1985, 26,
1411-1414.
(33) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277-
7287.
(27) King, P. F.; Stroud, S. G. Tetrahedron Lett. 1985, 26, 1415-1418.
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Pinot et al.
SCHEME 7. Syntheses of ent-15-E2t-IsoP 4a and ent-15-epi-15-E2t-IsoP 4b
28 in 65 yield after 3 steps. Due to difficulties in removing the
unrequired alkenyl isomer the mixture of 28 was used for the
next two steps. However, luckily, we were able to remove the
(E)-stereoisomer after the diastereoselective reduction of the C15
keto group in 30.
starting from trans-3-(2-furyl)acrylic acid 6, using the key
intermediate 4-hydroxycyclopentenone rac-5. Using the same
strategy we were able to reach the pure diasteroisomers of the
15-E2t-IsoP. Further syntheses of other phytoprostanes and
isoprostanes, as well as the assessment of their individual
biological activities, are in progress and will be reported in due
course.
The acetal 28 was converted by acidic hydrolysis with TsOH
in acetone into the aldehyde 29, which was used immediately
in the next step. As reported above (Scheme 4), the reaction
time must be very short, to avoid loss of the TBS group. The
condensation of 29 with the commercially available dimethyl-
(2-oxoheptyl)phosphonate in the presence of sodium hydride,
in anhydrous THF, afforded the trans-R,â-enone ester 30 in 72%
yield after two steps. Neither elimination nor epimerization was
observed during this HWE reaction, as for enone 20.
The diastereoselective reduction of the C15 keto group in 30
with the chiral reducing agents13 (S)- or (R)-BINAL-H gave
the desired enantiopure 15(S) derivative 31a and its 15(R) epimer
31b, respectively, in 70% yield (Scheme 6). In our hands and
for enone 30, during the reduction process with (R)-BINAL-H
and ethanol, we could not avoid the transesterification of the
methyl ester to the ethyl ester.34 Protection of the hydroxyl
groups present in 31a and 31b, using TBDPSCl, imidazole in
DMF afforded the corresponding protected alcohols 32a and
32b in 89% yield. As before, the EOM group was deprotected
with BF3‚Et2O/Me2S,32 leading to the corresponding alcohols
33a and 33b with 30% yield and degradation. Dess-Martin33
oxidation led quantitatively to the ketones 34a and 34b, which
were used without purification in the next step. Desilylation of
34a and 34b with HF/pyridine under the same conditions as
for 24a and 24b gave the desired 15-E2t-IsoPs 3a and its 15
epimer 3b in 34% yield. All our data are in good agreement
with those of Rodriguez and Spur.16,17
Experimental Section
(4R)-4-O-Acetoxy-3-(dimethoxymethyl)-2-(methylcarboxy-
methyl)cyclopent-2-enone, (R)-11, and (4S)-3-(Dimethoxymeth-
yl)-4-hydroxy-2-(methylcarboxymethyl)cyclo-pent-2-enone, (S)-
5. To a solution of compound rac-5 (15 g, 60 mmol, 1 equiv) in
hexane (540 mL) was added dry vinyl acetate (60 mL), followed
by the Candida antarctica lipase B (3 g, 0.2 w/w). The reaction
mixture was stirred at room temperature for 20 h. The reaction
was monitored by HPLC using a chiral stationary phase (Chiralcel
OD 250 × 4.6 mm, 5% 2-propanol in hexane). Once finished, the
reaction mixture was filtered and the filtrate was concentrated under
reduced pressure. The crude material was purified by column
chromatography on silica gel (10-50% ethyl acetate in cyclohex-
ane) to give acetate (R)-11 (7.79 g, 45%) and alcohol (S)-5 (7.10
g, 49%).
Compound (S)-5. Rf: 0.46 (cyclohexane/ethyl acetate: 70/30).
HPLC (min): 37.2. IR ν (cm-1): 3448 (OH), 1738 and 1711 (Cd
1
O), 1662 (CdC). H NMR (300 MHz, CDCl3), δ: 2.37 (dd, J )
6.3, 18.7 Hz, 1H), 2.78 (dd, J ) 6.3, 18.7 Hz, 1H), 3.17 (brs, 1H),
3.32 (s, 3H), 3.33 (AB, J ) 12.4 Hz, 1H), 3.34 (AB, J ) 12.4 Hz,
1H), 3.39 (s, 3H), 3.65 (s, 3H), 5.00 (d, J ) 5.7 Hz, 1H), 5.45 (s,
1H). 13C NMR (75.5 MHz, CDCl3), δ: 28.2, 42.6, 52.1, 52.6, 54.0,
69.0, 100.8, 137.2, 166.1, 170.0, 204.0. [R]D20: -19.1 (10-2
,
MeOH). Anal. Calcd for C11H16O6: C, 54.09; H, 6.60. Found: C,
53.98; H, 6.71.
Furthermore, all reactions have been duplicated with 4-hy-
droxycyclopentenones (S)-5 leading to the enantiomerically pure
ent-15-E2t-IsoP 4a and ent-15-epi-15-E2t-IsoP 4b, as shown in
Scheme 7.
Compound (R)-11. Rf: 0.71 (cyclohexane/ethyl acetate: 30/
70). HPLC (min): 26.4. IR ν (cm-1): 1732 and 1718 (CdO), 1663
1
(CdC). H NMR (300 MHz, CDCl3), δ: 2.05 (s, 3H) 2.29 (dd, J
) 1.6, 19.0 Hz, 1H), 2.78 (dd, J ) 6.4, 19.0 Hz, 1H), 3.25 (s, 3H),
3.34 (s, 3H), 3.44 (AB, J ) 20.1 Hz, 1H), 3.51 (AB, J ) 20.1 Hz,
1H), 3.64 (s, 3H), 5.26 (s, 1H),5.85 (br d, J ) 6.4 Hz, 1H). 13C
NMR (75.5 MHz, CDCl3), δ: 20.7, 28.6, 41.3, 51.9, 52.1, 54.2,
70.0, 99.8, 140.5, 162.6, 170.1, 203.2. [R]D20: -50.0 (10-2, MeOH).
Conclusion
In conclusion, the first synthesis of the optically pure
diastereoisomers of the PPE1 type II has been accomplished
(4R)-3-(Dimethoxymethyl)-4-hydroxy-2-(methylcarboxymeth-
yl)cyclopent-2-enone, (R)-5. To a solution of acetate (R)-11 (4.0
g, 14 mmol, 1 equiv) in acetonitrile (6.1 mL) were added a solution
of a phosphate buffer (0.1 M, pH ) 7.240 mL) and the enzyme
CAL-B (3.2 g, 0.8 w/w), and the reaction mixture was stirred at
room temperature for 48 h. The reaction was monitored by TLC.
Once finished, the reaction mixture was saturated with crystalline
(34) We have done Noyori’s reduction many times in the past without
problems and, as reported in this manuscript, the reduction proceeded well
for compounds 20, 25, 35 and only with (S)-BINAL-H for 30 leading to
31a. Astonishingly, we observed a transesterification during the reaction
with (R)-BINAL-H with 30 leading to 31b ethyl ester instead of methyl
ester. But the difference between a methyl ester and an ethyl ester is not
important and 31b was nicely used anyway.
3068 J. Org. Chem., Vol. 73, No. 8, 2008

Phytoprostanes E1Type II and of the 15-E2t-Isoprostanes
NaCl then filtered. The filtrate was washed with an aqueous solution
of sodium hydrogenocarbonate (75 mL). The aqueous layer was
extracted three times with ethyl acetate (75 mL). The combined
organic layers were washed with water (75 mL) and brine (75 mL),
dried over MgSO4, and concentrated under reduced pressure. The
crude product was purified by column chromatography on silica
gel (cyclohexane/ethyl acetate 80/20) to give alcohol (R)-5 (3.39
g, 98%). In chiral HPLC (min): 35.8. [R]D20: +21.2 (10-2, MeOH).
Anal. Calcd for C11H16O6: C, 54.09; H, 6.60. Found: C, 54.18; H,
6.80.
12H), 1.42-1.75 (m, 5H), 1.85 (brs, 1H), 2.24-2.32 (m, 3H),
2.48-2.60 (m, 2H), 2.97 (t, J ) 7.9 Hz, 1H), 4.03-4.14 (m, 3H),
4.32 (brs,1H), 5.29 (dd, J ) 9.7, 15.3 Hz, 1H), 5.68 (dd, J ) 6.2,
15.3 Hz, 1H). 13C NMR (75 MHz, CDCl3), δ: 12.0, 14.2, 18.4,
24.8, 25.1, 28.9, 29.0, 29.1, 34.3, 37.2, 44.9, 51.3, 51.8, 60.1, 72.1,
72.3, 126.3, 137.2, 173.8, 217.0. [R]D20: +66.5 (2.5 × 10-3
,
MeOH). Anal. Calcd for C20H34O5: C, 67.76; H, 9.67. Found: C,
67.58; H, 9.59.
For 2b (ent-9-epi-PPE1 type II methyl ester), the characteristics
are the same with [R]D20 ) - 66.5 (2.5 × 10-2, MeOH). Anal. Calcd
for C20H34O5: C, 67.76; H, 9.67. Found: C, 67.63; H, 9.80.
15-E2t-IsoP Methyl Ester 3a. 1H NMR (300 MHz, CDCl3), δ:
0.86 (t, J ) 6.6 Hz, 3H), 1.20-1.36 (m, 6H), 1.43-1.53 (m, 2H),
1.56-1.69 (m, 5H), 1.87-2.09 (m, 4H), 2.26 (t, J ) 7.4 Hz, 3H),
2.28-2.35 (m, 1H), 2.36-2.46 (m, 1H), 2.51 (dd, J ) 5.8 and
19.2 Hz, 1H), 2.68-2.75 (m, 1H), 2.93-3.00 (m, 1H), 3.64 (s,
3H),4.05 (q, J ) 6.1 Hz, 1-H), 4.32-4.36 (m, 1H), 5.25-5.39 (m,
3H), 5.66 (dd, J ) 6.4 and 15.3 Hz, 1H). 13C NMR (75 MHz,
CDCl3), δ: 13.9, 22.5, 23.2, 24.6, 25.0, 26.7, 31.6, 33.3, 37.3, 44.7,
50.6, 51.4, 51.5, 72.1, 72.2, 126.2, 127.5, 130.0, 137.6, 174.1, 216.5.
[R]D20: +70.5 (2 × 10-3, MeOH). Anal. Calcd for C21H34O5: C,
68.82; H, 9.35. Found: C, 66.69; H, 9.17.
(1S,2S,3R,4R)-4-O-(tert-butyldimethylsilyl)-3-(dimethoxyme-
thyl)-1-O-(ethoxymethyl)-2-(methylcarboxymethyl)cyclopentane-
1,4-diol, 15. To a solution of alkene 14 (7.3 g, 17.5 mmol, 1 equiv)
in dry methanol (71.6 mL) were added butanone (50 mL), pyridine
(21.2 mL, 262 mmol, 15 equiv) and dipotassium diazodicarboxylate
(17.0 g, 87.3 mmol, 5 equiv) at room temperature under nitrogen.
The reaction mixture was refluxed of methanol. Then a solution of
acetic acid (10.0 mL, 174.6 mmol, 10 equiv) in MeOH (64.9 mL)
was added dropwise over 2 h. Once the addition was finished, this
procedure was repeated twice, then water (400 mL) was added,
and the aqueous layer was extracted three times with diethyl ether
(400 mL). The combined organic layers were washed twice with
water (250 mL) and brine (250 mL), then dried over MgSO4, and
concentrated under reduced pressure. The same reaction was
repeated four times until the consumption of the starting product
was completed. The crude material was purified by column
chromatography on silica gel (0-10% ethyl acetate in cyclohexane)
to give compound 15 (5.3 g, 72%). Rf: 0.68 (cyclohexane/ethyl
acetate: 70/30). IR ν (cm-1): 1738 (CdO), 1463 (C-Si). 1H NMR
(300 MHz, CDCl3), δ: 0.01 (s, 3H), 0.02 (s, 3H), 0.85 (s, 9H),
1.16 (t, J ) 7.1 Hz, 3H), 1.45-1.55 (m, 1H), 2.32-2.52 (m, 4H),
2.55-2.72 (m, 1H), 3.27 (s, 3H), 3.29 (s, 3H), 3.49-3.60 (m, 2H),
3.64 (s, 3H), 3.69 (q, J ) 7.4 Hz, 1H), 4.09-4.19 (m, 2H), 4.61
(AB, J ) 10.8 Hz, 1H), 4.63 (AB, J ) 10.8 Hz, 1H. 13C NMR (75
MHz, CDCl3), δ: -4.8, -4.9, 14.9, 18.2, 25.6 (3C), 33.1, 41.6
(2C), 49.5, 51.4, 54.0, 55.1, 63.0, 71.5, 80.7, 94.3, 105.4, 177.0.
[R]D20: +17 (10-2, MeOH). Anal. Calcd for C20H40O7Si: C, 57.11;
H, 9.59. Found: C, 57.30; H, 9.47.
For ent-15-E2t-IsoP methyl ester 4a, the characteristics are the
20
same with [R]D ) -70.3 (2 × 10-3, MeOH). Anal. Calcd for
C21H34O5: C, 68.82; H, 9.35. Found: C, 66.98; H, 9.50.
15-epi-15-E2t-IsoP Ethyl Ester 3b. 1H NMR (400 MHz, CDCl3),
δ: 0.87 (t, J ) 6.7 Hz, 3H), 1.23 (t, J ) 7.1 Hz, 3H),1.24-1.32
(m, 6H), 1.40-1.57 (m, 4H), 1.59-1.70 (m, 2H), 1.91-2.07 (m,
3H), 2.27 (t, J ) 7.3 Hz, 2H), 2.33-2.34 (m, 1H), 2.38-2.46 (m,
1H), 2.51 (dd, J ) 5.8 Hz, 19.2 Hz, 1H), 2.68-2.77 (m, 1H), 2.93-
3.00 (m, 1H), 4.01-4.14 (m, 3H), 4.31-4.34 (m, 1H), 5.28 (ddd,
J ) 1.0, 9.7, and 15.3 Hz, 1H), 5.35-5.38 (m, 2H), 5.66 (dd, J )
6.4 and 15.3 Hz, 1H). 13C NMR (75.5 MHz, CDCl3), δ: 14.0, 14.2,
22.6, 23.1, 24.7, 25.1, 26.8, 31.7, 33.7, 37.3, 44.8, 50.7, 51.4, 60.4,
72.3, 72.4, 126.3, 127.7, 130.2, 138.0, 173.9, 216.4. [R]D20: +46
(10-2, MeOH). Anal. Calcd for C22H36O5: C, 69.44; H, 9.54.
Found: C, 69.68; H, 9.38.
For ent-15-epi-15-E2t-IsoP methyl ester 4b, the characteristics
are the same with [R]D ) -46 (10-2, MeOH). Anal. Calcd for
20
For ent-15, the characteristics are the same with [R]D20 ) -17
(10-2, MeOH).
C21H34O5: C, 68.82; H, 9.35. Found: C, 66.93; H, 9.51.
1
Phytoprostane E1 Type II Methyl Ester 1a. H NMR (300
Acknowledgment. We gratefully acknowledge the Ministe`re
de l’Education Nationale et de la Recherche for financial support
for one of us (EP). We are deeply grateful to Pr. Jean-Yves
Lallemand and the ICSN for their generous financial support.
We thank Pr. Paul Evans from UCD, Dublin, Ireland, for helpful
discussions and for carefully reading the manuscript.
MHz, CDCl3), δ: 0.90 (t, J ) 7.1 Hz, 3H), 1.19-1.29 (m, 12H),
1.43-1.73 (m, 5H), 2.23-2.32 (m, 3H), 2.47-2.56 (m, 2H), 2.95
(t, J ) 8 Hz, 1H), 4.00-4.13 (m, 3H), 4.30-4.32 (m, 1H), 5.25
(dd, J ) 10.0, 15.2 Hz, 1H), 5.64 (dd, J ) 6.8, 15.2 Hz, 1H). 13C
NMR (75 MHz, CDCl3), δ: 11.9, 14.2, 18.5, 24.8, 25.1, 28.9, 29.0,
29.1, 34.3, 37.2, 44.9, 51.4, 51.8, 60.1, 72.0, 72.6, 127.0, 137.1,
173.8, 217.2. [R]D20: +60.8 (2.5 × 10-3, MeOH). Anal. Calcd for
C20H34O5: C, 67.76; H, 9.67. Found: C, 67.89; H, 9.54.
Supporting Information Available: Experimental procedures
1
for selected compounds, a table of optical rotations, and H NMR
and 13C NMR spectra for compounds 6, 7, 8, rac-5, (R)-11, 12-
18, 20, 21a, 21b, 22a, 22b, 23a, 23b, 28, 30, 31a, 31b, 32a, 32b,
33a, 33b, and the target compounds 1a, 1b, 3a, 3b. This material
is available free of charge via the Internet at http://pub.acs.org.
For 2a (ent-PPE1 type II methyl ester), the characteristics are
20
the same with [R]D ) -61.2 (2.5 × 10-2, MeOH). Anal. Calcd
for C20H34O5: C, 67.76; H, 9.67. Found: C, 67.59; H, 9.46.
1
9-epi-Phytoprostane E1 Type II Methyl Ester 1b. H NMR
(300 MHz, CDCl3), δ: 0.92 (t, J ) 7.4 Hz, 3H), 1.20-1.39 (m,
JO702455G
J. Org. Chem, Vol. 73, No. 8, 2008 3069