Total Synthesis of the Eight Diastereomers of the Syn-Anti-Syn Phytoprostanes F1 Types I and II

Article abstract of DOI:10.1021/jo035638i

Syntheses of the eight enantiomerically pure diastereomers of the syn-anti-syn phytoprostanes F₁ types I and II are described starting from D- and L-glucose. Key steps include Wittig coupling, Horner Wadsworth Emmons (HWE) reactions, and enantioselective reduction of α,β -unsaturated ketones.

Full text of DOI:10.1021/jo035638i

Tota l Syn th esis of th e Eigh t Dia ster eom er s of th e Syn -An ti-Syn
P h ytop r osta n es F 1 Typ es I a n d II
Siham El Fangour, Alexandre Guy, Vale´rie Despres, J ean-Pierre Vidal,
J ean-Claude Rossi, and Thierry Durand*
UMR CNRS 5074, Universite´ Montpellier I, Faculte´ de Pharmacie, 3e Etage-15, Avenue Charles Flahault,
F-34093 Montpellier Cedex 05, France
thierry.durand@univ-montp1.fr
Received November 7, 2003
Syntheses of the eight enantiomerically pure diastereomers of the syn-anti-syn phytoprostanes F1
types I and II are described starting from D- and L-glucose. Key steps include Wittig coupling,
Horner Wadsworth Emmons (HWE) reactions, and enantioselective reduction of R,â-unsaturated
ketones.
In tr od u ction
the syntheses of all eight diastereomers of the syn-anti-
syn PPF1 types I and II starting from cyclopentane
precursors 3 and 3′, obtained from D- and L-glucose
(Scheme 1).
Isoprostanes (IsoPs) represent a new family of bio-
markers for oxidative stress generated from peroxidation
of polyunsaturated fatty acids via a free-radical-catalyzed
mechanism.1,2 Higher plants generally do not synthesize
the arachidonate precursor required for isoPs formation,
but rather utilize R-linolenic acid for the formation of
isoprostane F2-like compounds which have been termed
phytoprostanes F1 (PPF1).3 J asmonates are established
plant signaling compounds inducing defense responses.4
Preliminary data indicate that phytoprostanes also in-
duce phytoalexins in a variety of plant species, suggesting
a possible function of phytoprostanes as mediators of
plant defense reactions in response to oxidative stress.5,6
Since we were interested in assessing the physiological
activities of each of the phytoprostanes F1 types I and
II, we found it more attractive to obtain sufficient
quantities by chemical synthesis.
Resu lts a n d Discu ssion
The Phytoprostanes F1 types I and II were identified
from autoxidation of R-linolenic acid by Mueller.3 To
confirm the stereochemistry of the eight enantiomerically
pure diastereomers of phytoprostanes F1 types I and II,
and also to screen the physiological activity of these
phytoprostanes, we have developed a general and flexible
strategy from our common intermediate syn-anti-syn
cyclopentane precursors 3 and 3′ (Scheme 1).
Syn th esis of en t-P h ytop r osta n e F 1 Typ e I 1 a n d
2 fr om D-Glu cose. The syntheses of ent-PPF1 type I 1
and its 16(S) epimer 2 from the cyclopentane percursor
3 is shown in Schemes 2-4 and was published as a note.7
The first 9 steps leading to cyclopentane alkoxyester 3
were achieved in 27% overall yield by using our iodo
pathway.8
In 2003, we published a note describing the syntheses
of ent-PPF1 type I 1 and its 16-epimer 2.7 We now report
The phosphorus synthon 7 was selected for the intro-
duction of the upper chain of the PPF1 type I, and was
prepared by using the procedure outlined in Scheme 2.
The first step is the opening of the ꢀ-caprolactone under
acidic conditions leading to the corresponding hydroxy
methyl ester 5. Subsequent halogenation gave iodo ester
6, which was transformed into the phophonium salt 7 in
98% yield in the presence of PPh3 and a catalytic amount
of K2CO3.
* Address correspondence to this author. Phone: 33-4-67-54-86-23.
Fax: 33-4-67-54-86-25.
(1) (a) Morrow, J . D.; Hill, K. E.; Burk, R. F.; Nammour, T. M.; Badr,
K. F.; Roberts, L. J ., II Proc. Natl. Acad. Sci. U.S.A. 1990, 87, 9383-
9387. (b) Nourooz-Zadeh, J .; Liu, E. H. C.; Anggard, E. E.; Halliwell,
B. Biochem. Biophys. Res. Commun. 1998, 242, 338-344. (c) Roberts,
L. J ., II; Montine, T. J .; Markesbery, W. R.; Tapper A. R.; Hardy, P.;
Chemtob, S.; Dettbarn, W. D.; Morrow, J . D. J . Biol. Chem. 1998, 273,
13605-13612. (d) Nourooz-Zadeh, J .; Liu, E. H. C.; Yhlen, B.; A¨ nggard,
E. E.; Halliwell, B. J . Neurochem. 1999, 72, 734-740.
(2) (a) Roberts, L. J ., II; Morrow J . D. Free Radical Biol. Med. 2000,
28, 505-513. (b) Cracowski, J . L.; Durand, T.; Bessard, G. Trends
Pharmacol. Sci. 2002, 23, 360-366.
The introduction of the upper chain (Scheme 3) was
achieved by using the above phosphonium salt 7, which
(3) Imbusch, R.; Mueller, M. J . Plant Physiol. 2000, 124, 1293-
12303.
(4) Stintzi, A.; Weber, H.; Reymond, P.; Browse, J .; Farmer, E. E.
Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 12837-12842.
(5) Imbusch, R.; Mueller, M. J . Free Radical Biol. Med. 2000, 28,
720-726.
(6) Thoma, I.; Loeffler, C.; Sinha, A. K.; Gupta, M.; Krischke, M.;
Steffan, B.; Roitsch, T.; Mueller, M. J . Plant J . 2003, 34 (3), 363-375.
(7) El Fangour, S.; Guy, A.; Vidal, J .-P.; Rossi, J .-C.; Durand, T.
Tetrahedron Lett. 2003, 44, 2105-2108.
(8) Durand, T.; Guy, A.; Henry, O.; Vidal, J . P.; Rossi, J . C. Eur. J .
Org. Chem. 2001, 4, 809-819 and references therein.
10.1021/jo035638i CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/05/2004
2498
J . Org. Chem. 2004, 69, 2498-2503

Syntheses of All Syn-Anti-Syn Phytoprostanes F1 Types I and II
SCHEME 1. Retr osyn th etic Sch em e of th e P h ytop r osta n es F 1 Typ es I a n d II a n d En a n tiom er s
SCHEME 2. Syn th esis of P h osp h on iu m Sa lt 7a
a
Reagents and conditions: (a) MeOH, H2SO4, rt, 30 min, 94%. (b) I2, PPh3, imidazole, CH2Cl2 -10 °C, 2 h, 61%. (c) PPh3, CH3CN, 1%
K2CO3, 18 h, 98%.
reacts with the aldehyde 8 to afford the pure (Z)-enic
ester 9 in 70% yield. No trace of trans compound could
ester 15 in 60% overall yield from the alcohol 12. The
relative configurations of the chiral centers were con-
1
1
be detected by 13C and H NMR analyses.
firmed by homonuclear H steady-state-difference NOE
spectroscopy (DNOES) experiments (vide infra).
The diastereoselective reduction of the C16 keto group
in 15 with the chiral reducing agents13 (S)- and (R)-
BINAL-H gave the desired pure 16(S) derivative 16 and
its 16(R) epimer 17 in 85% and 87% yield, respectively
(Scheme 4).
The following reduction of the cis double bond of 9
under hydrogen atmosphere gave the diol 10, which was
protected in the presence of benzoyl chloride in pyridine
in 77% yield.
The next steps were first a selective deprotection of
the tert-butyldiphenylsilyl ether 11 with hydrogen chlo-
ride,11 a Dess-Martin oxidation12 of 12, followed by a
HWE coupling reaction in the presence of dimethyl-2-
oxobutylphosphonate 14,10 yielding the trans-R,â-enone
Finally, saponification of ester functions, followed by
treatment with an excess of CH2N2, afforded the desired
ent-PPF1 type I 1 and its 16 epimer 2 in 20% and 19%
yields, respectively, from 3, after 9 steps.
(9) Roland, A.; Durand, T.; Egron, D.; Vidal, J . P.; Rossi, J . C. J .
Chem. Soc., Perkin Trans 2 2000, 245-251 and references therein.
(10) Copolla, G. A. Synthesis 1988, 81-84.
Syn th esis of en t-P h ytop r osta n es F 1 Typ e II 31
a n d 32 fr om D-Glu cose. Since the PPF1 type II diaster-
(11) Nashed, E. M.; Glaudemans, C. P. J . J . Org. Chem. 1987, 52,
5255-5260.
(12) Dess, D. B.; Martin, J . C. J . Org. Chem. 1983, 48, 4155-4156.
Ireland, R. E.; Liu, L. J . Org. Chem. 1993, 58, 2899.
(13) Noyori, R.; Tomino, I.; Tanimoto, Y.; Nishizawa, M. J . Am.
Chem. Soc. 1984, 106, 6709-6716.
J . Org. Chem, Vol. 69, No. 7, 2004 2499

El Fangour et al.
SCHEME 3. Syn th esis of P r ecu r sor 15a
a
Reagents and conditions: (a) 1.1 equiv of DIBAL-H (1
M
in toluene), toluene, -80 °C, 30 min, 97%. (b) 2.25 equiv of
methoxycarbonylpentyltriphenylphosphonium iodide, 2.2 equiv of KN(SiMe3)2, THF, -80 to 20 °C, 2 h, 70%. (c) H2, Pd/C 10%, EtOH, 4
h, 98%. (d) 3 equiv of BzCl, pyridine, 20 °C, 1 h, 77%. (e) HCl 3% in MeOH, 20 °C, overnight, 80%. (f) Periodinane, CH2Cl2, rt, 2 h. (g) 3.3
equiv of dimethyl 2-oxobutylphosphonate 14, 3 equiv of NaN(SiMe3)2, THF, 20 °C, 30 min, 60%.
SCHEME 4. Syn th esis of en t-P h ytop r osta n es F 1 Typ e I 1 a n d 2a
a
Reagents and conditions: (a) (S)-BINAL-H, -100 °C, 2 h, 85%. (b) (R)-BINAL-H, -100 °C, 2 h, 87%. (c) 1 N NaOH, THF-MeOH, rt,
1 h, then CH2N2 91% for 1 and 93% for 2.
2500 J . Org. Chem., Vol. 69, No. 7, 2004

Syntheses of All Syn-Anti-Syn Phytoprostanes F1 Types I and II
SCHEME 5. Syn th esis of â-Ketop h osp h on a te 19a
SCHEME 6. Syn th esis of P r ecu r sor 27a
a
Reagents and conditions: (a) (i) n-BuLi, THF, -78 °C; (ii)
diethylazelate, -78 °C, 3.5 h, 57%.
TABLE 1. [r]20 (1 × 10-2, MeOH) for All Dia ster eom er s
D
of P P F 1 Typ es I a n d II
diastereomer
[R]20 [R]20
diastereomer
D
D
ent-PPF1 type I (1)
ent-16-epi-PPF1 type I (2) -13 +14 16-epi-PPF1 type I (2′)
ent-PPF1 Type II (31)
-30 +25 PPF1 type I (1′)
-26 +23 PPF1 type II (31′)
-7 +7 9-epi-PPF1 type II (32′)
ent-9-epi-PPF1 type II (32)
eomers had never previously been prepared, we have
performed the synthesis of these type II PPF1 as shown
in Schemes 6 and 7.
The â-ketophosphonate 19 was selected and prepared
by using the following procedure published by Miftakhov
et al.14 and outlined in Scheme 5. The lithio derivative
of dimethyl methylphosphonate 18 reacts with the di-
ethylazelate to afford the corresponding â-ketophospho-
nate 19 in 57% yield.
The alkoxyester 3 was converted into the primary
alcohol 20 by treatment with lithium aluminum hydride
(LAH) in anhydrous ether in 94% yield (Scheme 6). The
following protection, using toluenesulfonyl chloride, led
to the corresponding tosylate 21 in 97% yield, which was
reduced, once again, by LAH in refluxing ether to afford
the methyl group of the R chain in 91% yield.
The introduction of the ω chain of the PPF1 type II
started by the regioselective deprotection of the bistri-
ethylsilyloxy ether in the presence of tert-butyldiphenyl-
silyl ether, using ammonium fluoride in MeOH/THF to
afford the diol 23 in 82% yield. The protection of the
hydroxyl functions of 23 with benzoyl chloride in dry
pyridine gave the diester 24 in 94% yield.
The tert-butyldiphenylsilyl ether 24 was converted into
the alcohol 25 by treatment with a solution of 3%
hydrogen chloride11 in methanol/diethyl ether (1:1). Oxi-
dation of the alcohol 25 with the Dess-Martin periodi-
nane12 provided the unstable aldehyde 26, which was
immediately used in the next step without purification.
The condensation of 26 with dimethyl 9-(ethoxycarbo-
nyl)-2-oxononylphosphonate 19,14 in the presence of
sodium hexamethyldisilyl amide, in anhydrous THF at
room temperature, afforded the trans-R,â-enone ester 27
in 79% overall yield from alcohol 25 (Scheme 7). During
the HWE reaction, it was not possible to avoid the
formation of compound 28 derived from the elimination
of the benzoyl group at C13, as already observed in other
a
Reagents and conditions: (a) 1.5 equiv of LAH (1 M in THF),
diethyl ether, -78 °C, 1 h, 94%. (b) DMP, TEA, 1.5 equiv of TsCl,
CH2Cl2, rt, 2 h, 97%. (c) 1.1 equiv of LAH (1 M in THF), diethyl
ether, reflux, 91%. (d) 4 equiv of NH4F, MeOH/THF (7:3), reflux,
2 h, 82%. (e) 3 equiv of BzCl, pyridine, rt, 1 h, 94%. (f) HCl 3% in
MeOH/Et2O (1:1), rt, overnight, 97%. (g) Periodinane, CH2Cl2, rt,
30 min. (h) 3 equiv of dimethyl 9-(ethoxycarbonyl)-2-oxononylphos-
phonate 19, 2.8 equiv of NaN(SiMe3)2, THF, rt, 1 h, 79%.
series. The relative configurations of the chiral centers
were confirmed by homonuclear 1H steady-state-differ-
ence NOE spectroscopy (DNOES) experiments (vide
infra).
The diastereoselective reduction of the C9 keto group
in 27 with the chiral reducing agents13 (R)- and (S)-
BINAL-H gave the desired pure 9(R) derivative 29 and
its 9(S) epimer 30 in 82% and 89% yield, respectively
(Scheme 7).
Finally, deprotection of the benzoyl groups in 29 and
30, in the presence of 1 N NaOH at room temperature,
followed by excess of CH2N2, afforded the desired ent-
PPF1 type II 31 and its 9 epimer 32 in 38% and 42%
yields, respectively, from the cyclopentane alkoxyester
3, in 10 steps.
Syn th eses of P h ytop r osta n es F 1 Typ es I a n d II 1′,
2′, 31′, a n d 32′ fr om L-Glu cose. All reactions of D-
glucose have been duplicated with L-glucose leading to
(14) Miftakhov, M. S.; Akhmetvaleev, R. R.; Imaeva, L. R.; Vostrikov,
N. S.; Saitova, M. Yu.; Zarudij, F. S.; Tolstikov G. A. Khim.-Pharm.
Zurnal. 1996, 30 (8), 22-27.
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El Fangour et al.
SCHEME 7. Syn th eses of en t-P h ytop r osta n es F 1 Typ e II 31 a n d 32a
a
Reagents and conditions: (a) (S)-BINAL-H, -100 °C, 2 h, 89%. (b) (R)-BINAL-H, -100 °C, 2 h, 82%. (c) 1 N NaOH, THF/MeOH, rt,
1 h, then CH2N2 96% for 31 and 94% for 32.
SCHEME 8. Syn th eses of P h ytop r osta n es F 1 Typ e I a n d Typ e II 1′, 2′, 31′, a n d 32′
the enantiomerically pure PPF1 types I and II diastere-
omers 1′, 2′, 31′, and 32′ as shown in Scheme 8.
Str u ctu r a l Deter m in a tion of R,â-En on es 15, 15′,
27, a n d 27′. The relative configurations of chiral centers
were confirmed by homonuclear 1H steady-state-differ-
ence NOE spectroscopy (DNOES) experiments as shown
in Figure 1.
The physicochemical properties of the enantiomerically
pure PPF1 types I and II diastereomers 1′, 2′, 31′, and
32′ were identical with those of 1, 2, 31, and 32 except
for the sign of specific optical rotation, as mentioned in
Table 1.
For compound 15, the relative cis configuration of the
protons 11-H, 1-H, 4-H, and 6-H was determined by
2502 J . Org. Chem., Vol. 69, No. 7, 2004

Syntheses of All Syn-Anti-Syn Phytoprostanes F1 Types I and II
F IGURE 1. Observed NOEs resulting from irradiation of main protons are indicated with solid lines.
irradiation of 11-H, which induced NOEs of 1.3% on 1-H,
3.9% on 6-H, 5.2% on 4-H, and 0.7% on 7-H. Irradiation
of 6-H induced NOEs of 1.0% on 1-H and 0.75% on 4-H.
Similar results were observed for compound 15′, the
enantiomer of compound 15.
Con clu sion
In conclusion, the first synthesis of the eight enantio-
merically pure diastereomers of the syn-anti-syn phyto-
prostanes F1 types I and II has been accomplished
starting form enantiopure alkoxyesters 3 and 3′. Further
studies of other phytoprostanes or analogues, as well as
the assessment of individual biological activities in
human and/or plant, are in progress and will be reported
in due course.
Irradiation of 11-H induces a NOE of 6.3% on 6-H, 2.4%
on 1-H, and 8.1% on 4-H, while irradiation of 6-H induces
a NOE of 2.1% on 1-H and 1.3% on 4-H. These observa-
tions verify the relative cis configuration of the protons
1-H, 4-H, 6-H, and 11-H.
Concerning 27, the irradiation of 6-H showed a NOE
of 2.8% on 8-H, 2.1% on 4-H, and 0.88% on 1-H. Likewise,
the irradiation of 8-H induces a NOE of 1.9% on 1-H and
1.3% on 4-H. These observations allow one to check the
relative cis configuration of protons 1-H, 4-H, 6-H, and
8-H.
Ack n ow led gm en t. We gratefully acknowledge the
Ministe`re de l’Education Nationale et de la Recherche
for financial support for one of us (S.E). The authors
are grateful to Dr. A. Vidal for carefully reading the
manuscript.
For compound 27′, the enantiomer of compound 27, the
relative cis configuration of the protons 1-H, 4-H, 6-H,
and 8-H was determined by irradiation of 6-H, which
induced NOEs of 3.1% on 4-H, 1.8% on 1-H, and 2.4% on
8-H. Irradiation of 8-H induced NOEs of 3.0% on 1-H and
1.9% on 4-H.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for syntheses and 1H NMR and 13C NMR data for
compounds 5-7, 8-17, 19, 20-30, and the target compounds
1, 2, 31, 32, 1′, 2′, 31′, and 32′. This material is available free
of charge via the Internet at http://pubs.acs.org.
J O035638I
J . Org. Chem, Vol. 69, No. 7, 2004 2503