Synthesis of optically active prostaglandin-J2 and 15-deoxy-δ12,14-prostaglandin-J2

Article abstract of DOI:10.1055/s-2003-39885

An efficient route to optically pure prostaglandin-J₂ compounds has been discovered: ent-PGJ₂ is shown to display antiviral activity against Sendai virus with a similar potency to the natural enantiomer.

Full text of DOI:10.1055/s-2003-39885

1170
LETTER
Synthesis of Optically Active Prostaglandin-J2 and 15-Deoxy-D12,14-prosta-
glandin-J2
1
2
P
rostaglan
a
din-J2 and m15-Deoxy-
D
, 14 -proistaglan
e
din-J F. Bickley,a Vasudev Jadhav,a Stanley M. Roberts,a M. Gabriella Santoro,b Alexander Steiner,a
Peter2 W. Sutton*c
a
Robert Robinson Laboratories, Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK
b
Department of Biology, University of Rome-Tor Vergata, Via Della Ricerca Scientifica, 00133 Rome, Italy
c
Stylacats Ltd., Department of Organic Chemistry, University of Barcelona, Marti i Franques 1-11, 08028 Barcelona, Spain
Fax +34(93)3397878; E-mail: pete.sutton@stylacats.com
Received 17 March 2003
Thus, 7-chloronorbornadiene 4 was converted into the 7-
Abstract: An efficient route to optically pure prostaglandin-J2
lithio compound and reacted with trans-oct-2-enal to give
compounds has been discovered: ent-PGJ2 is shown to display anti-
viral activity against Sendai virus with a similar potency to the
natural enantiomer.
the alcohol 7.9 Rearrangement of this alcohol with
methyltrioxorhenium10 (MTO) and silylation under stan-
dard conditions gave the triene 8. After the prescribed
oxidation and Meinwald rearrangement, the hydroxyalde-
hyde 10 was obtained as a mixture of diastereoisomers.
Key words: prostaglandin-J2, 15-deoxy- 12,14-prostaglandin-J2, li-
pase-catalysed resolutions
The efficient preparation of the alcohol 7 is especially
valuable inasmuch as the (E) stereochemistry is estab-
lished for the C14–C15 double bond early in the synthesis
ensuring that the prostaglandin 2 is obtained as a single
geometric isomer. Thus, the alcohol 7 was converted into
the silyl ether and subjected to the oxidative rearrange-
ment and hydrolysis procedure to provide a 2:1 mixture of
hydroxyaldehydes 9.11 Interestingly the pre-existing ste-
reogenic centre seems to influence the sense of the elec-
tron flow on rearrangement of the (protonated)
epoxynorbornene. Wittig reaction, Dess–Martin oxida-
tion and concommitant desilylation/dehydration fur-
nished 15d-PGJ2 2 (Scheme 1).
There is considerable current interest in the biological ac-
tivity of the cyclopentenone prostaglandins.1 In particular,
prostaglandin-J2 (PGJ2) 1 and D12,14-15-deoxyprosta-
glandin-J2 (15-d-PGJ2) 2 (Figure 1) have been shown to
be potent anti-viral agents.2 The latter molecule has also
attracted interest because of its action as an agonist on the
PPAR-gamma receptor,3 its anti-inflammatory activity4
and its cytoprotective potential.5
Both prostaglandins occur naturally, being derived from
prostaglandin-D2 3 by dehydration.6 The same process
can be mimicked in the laboratory, ultimately generating
15d-PGJ2 2 as a mixture of isomers.7
Acetylation of the mixture of diastereomers 10 using
Pseudomonas cepacia lipase efficiently produced a sepa-
rable mixture of two pairs of diastereoisomers (–)-10
(42%) and (+)-11 (41%); hydrolysis of the acetates (+)-
(11) gave the hydroxyaldehydes (+) 10 (Scheme 2).12 The
diastereomeric pairs were converted into PGJ2 1 and 15-
epi-PGJ2 [from (+)-10], ent-PGJ2 and ent-15-epi-PGJ2
[from (–)-10] which were required for biological evalua-
tion.13
8
Some years ago, we developed a synthesis of ( )-PGJ2,
starting from 7-chloronorbornadiene 4, which featured a
Meinwald rearrangement of a norbornadiene mono-ep-
oxide (Scheme 1 steps a–d, g–k). The synthesis suffered
from the protracted conversion of the alkyne 5 into the
triene 8. In the first part of this paper, we report a more
convenient method for the production of the PGJ2 inter-
mediate 8 as well as a new method for the preparation of
15-d-PGJ2. In later paragraphs new methods for the prep-
aration of optically active materials are described.
HO
CO2H
CO2H
CO2H
O
O
OH
O
OH
2 ∆12,14-15-deoxyPGJ2
3 PGD2
1 PGJ2
Figure 1
Synlett 2003, No. 8, Print: 24 06 2003.
Art Id.1437-2096,E;2003,0,MM,1170,1174,ftx,en;D06203ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Prostaglandin-J2 and 15-Deoxy-D12,14-prosta-glandin-J2
1171
OTBS
C5H11
OH
C5H11
b
5
6
a
c,d
OTBS
OH
Cl
C5H11
C5H11
e
f,d
4
7
8
d,g
g
CHO
CHO
C5H11
C5H11
OTBS
OTBS
HO
HO
9
10
h-j
h,i,k
l
2
1 + 15-epi-1
Scheme 1 Reagents and conditions: a) 3-silyloxyoct-1-yne, EtMgBr, CuI, THF, reflux, 3 h, 66%; b) TBAF, THF, 14 h, 75%; c) LiAlH4, THF,
reflux, 1 h, 64%; d) TBSCl, imidazole, CH2Cl2, 20 h, 90%; e) i. Li, DTBB, THF, 1 h; ii. trans-oct-2-enal, –78 °C–r.t., 1 h, 90%; f) MTO, CH2Cl2,
2 d, 58%; g) i. Oxone, NaHCO3, acetone, H2O, 0 °C 1.5 h; ii. 2 M HCl, CH2Cl2, 5 d, 48%; h) Br–Ph3P+(CH2)4CO2H, NaHMDS, THF, 1.5 h,
79%; i) Dess–Martin periodinane, CH2Cl2, 1 h, 90%; j) TFA, CH2Cl2, 3 h, 48%; k) HF (aq), MeCN, 1 h, 1 (21%) and 15-epi-1 (25%); l) 1 M
HCl, THF, reflux, 20 min, 14%.
CHO
CHO
CHO
a
+
C5H11
OTBS
C5H11
OTBS
C5H11
RO
OTBS
HO
OH
(-)-10
10
(+)-11 R=Ac
(+)-10 R=H
b
Scheme 2 Reagents and conditions: a) Ps. cepacia lipase, vinyl acetate, PhMe, 20 h, 10 (42%) and 11 (41%); b). K2CO3, H2O, MeOH, 3 h,
79%.
Synlett 2003, No. 8, 1170–1174 ISSN 1234-567-89 © Thieme Stuttgart · New York

1172
J. F. Bickley et al.
LETTER
Interestingly, the mirror image of the natural prostaglan- Secondly, in order to provide access to non-natural (–)-
din ent-1 was almost equi-active to PGJ2 1 as an anti-viral 15-d-PGJ2, (–)-(2), alcohol (7) was acetylated using Can-
agent, exhibiting an IC50 of 4 mM against Sendai virus. dida antarctica A lipase (Scheme 3) as the catalyst, to fur-
The compound was also an effective inhibitor of NF-kB. nish (+)-7 and acetate (–)-12. Simple hydrolysis of the
The epi-prostaglandins exhibited slightly less activity. To latter compound gave (–)-7.15 Oxidative rearrangement of
our knowledge this is the first time that enantiomerically (–)-7 gave hydroxyaldehyde 9 as two diastereomers in a
enriched samples of these non-natural cyclopentenone 2:1 ratio. CaB-catalysed acetylation removed (+)-9 as the
prostaglandins have been made available for biological acetate (+)-13 leaving (–)-9 in an optically pure state.12
testing.
Conversion of (–)-9 into (–)-2 followed the established
routine. The remaining stereochemical assignments of
(+)-9, in relation to the known stereochemistry at C-8,
were found to be 11R, 12S, 13R (PG numbering) by X-ray
analysis of the di-p-bromobenzoate ester 14 (Figure 2).16
Two strategies were evaluated to access optically active
15-d-PGJ2. First, treatment of the aldehydes 9 with No-
vozym 435TM (CaB) and vinyl acetate in toluene led to the
acetylation of only one of the four stereoisomers to afford
acetate (+)-13.12 Hydrolysis furnished hydroxyaldehyde Obviously, this new route to cyclopentenone prostaglan-
(+)-9 which was converted into naturally occurring (+)- dins can be modified to provide a range of prostanoids.
15-d-PGJ2, (+)-(2) as prescribed in Scheme 1 therefore For example, reaction of lithionorbornadiene with octanal
establishing the (S)-stereochemistry at C-8 (PG number- gave the alcohol 15, which was converted smoothly and
ing).14
efficiently into 15-deoxy-PGJ2 16 (Figure 2).
OH
OR
OH
a
C5H11
C5H11
C5H11
+
(+)-7
(-)-12 R=Ac
(-)-7 R=H
7
b
CHO
CHO
CHO
S
c
H
R
H
H
+
C5H11
C5H11
C5H11
OTBS
RO
OTBS
OH
OTBS
HO
(-)-9
(+)-13 R=Ac
(+)-9 R=H
9
b
d
d
(-)-2
(+)-2
Scheme 3 Reagents and conditions: a) Candida antarctica A lipase, vinyl acetate, toluene, 2 d, 7 (41%) and 12 (41%); b) K2CO3, H2O,
MeOH, 3 h, 83%; c) Candida antarctica B lipase, vinyl acetate, PhMe, 24 h, 9 (24%) and 13 (57%); d) 3 steps (See Scheme 1).
OH
CO2H
OCOPh-p-Br
S
C7H15
C7H15
H
R
C5H11
O
OH
p-Br-PhOCO
14
15
16
Figure 2
Synlett 2003, No. 8, 1170–1174 ISSN 1234-567-89 © Thieme Stuttgart · New York

LETTER
Prostaglandin-J2 and 15-Deoxy-D12,14-prosta-glandin-J2
solution of 7-[1¢-(dimethyl-t-butylsilyloxy)oct-2¢-
1173
Acknowledgement
enyl]bicyclo[2.2.1]hepta-2,5-diene (0.25 g) in acetone (30
mL) was added and the solution stirred for a further 1.5 h.
The resultant solution was diluted with ethyl acetate (100
mL) and washed with water (2 × 100 mL) and brine (100
mL), dried (MgSO4) and the solvent removed by distillation
under reduced pressure. The residue was diluted with
CH2Cl2 (10 mL) and a 2 M aqueous solution of HCl (10 mL)
and stirred slowly for 5 d and the organic portion separated,
dried (MgSO4) and the solvent removed by distillation under
reduced pressure. The residue was purified by
chromatography over silica using ethyl acetate in hexane
(1:3) as eluent to afford the title compound 9 (0.13 g, 48%)
as a straw yellow oil; Rf = 0.25 (ethyl acetate/hexane); NMR
(CDCl3, 400 MHz, 1:2 mixture of diastereoisomers) d 9.75
(2 H, t, J = 1.3 Hz, CHO), 9.72 (1 H, t, J = 1.3 Hz, CHO),
5.73 (6 H, s, H-2 and H-3), 5.60 (3 H, m, H-3¢), 5.38 (3 H,
m, H-2¢), 4.70 (1 H, dd, J = 4.8 Hz, 1.0 Hz, H-4), 4.61 (2 H,
d, J = 4.6 Hz, H-4), 4.15 (3 H, m, H-1¢), 2.89 (2 H, m, H-1),
2.79 (1 H, m, H-1), 2.75 (2 H, ddd, J = 17.7 Hz, 5.3 Hz,1.3
Hz, CHCHO), 2.66 (1 H, ddd, J = 18.0 Hz, 5.8 Hz, 1.3 Hz,
CHCHO), 2.53 (2 H, ddd, J = 17.7 Hz, 8.1 Hz, 1.3 Hz,
CHCHO), 2.47 (1 H, ddd, J = 18.0 Hz, 8.0 Hz, 1.3 Hz,
CHCHO), 2.00 (6 H, m, H-4¢), 1.82 (3 H, m, H-5), 1.36–1.23
(18 H, m, H-5¢, H-6¢ and H7¢), 0.85 [36 H, m, CH3 and
(CH3)3], 0.02 [18 H, m, Si(CH3)2]; 13C NMR (CDCl3; 75.4
MHz, 1:2 mixture of diastereoisomers) d 201.88 and 201.73,
135.71 and 135.35, 133.01and 132.97, 132.96 and 132.90,
131.58 and 131.18, 79.82 and 79.19, 76.23 and 75.66, 60.71
and 60.53, 50.02 and 49.57, 40.94 and 40.66, 32.12 and
32.08, 31.39 and 31.38, 28.82 and 28.73, 25.83 and 25.82,
22.43, 18.01, 14.01 and 14.00, –3.75 and –3.92, –4.81 and
–4.86; HRMS (CI, NH3): calcd for [M + H]+ C21H39O3Si:
367.2669; found: 367.2675.
We wish to thank Professor Francisco López-Calahorra and the
Fundació Bosch i Gimpera (FBG301658) for their help in this
project.
References
(1) (a) Roberts, S. M.; Santoro, M. G.; Sickle, E. S. J. Chem.
Soc., Perkin Trans 1. 2002, 1735. (b) Straus, D. S.; Glass,
C. K. Med. Res. Rev. 2001, 21, 185. (c) Santoro, M. G.;
Roberts, S. M. Drug News Perspect. 1999, 12, 395.
(2) Santoro, M. G. Trends in Microbiology 1997, 5, 276.
(3) (a) Söderström, M.; Wigren, J.; Surapureddi, S.; Glass, C.
K.; Hammarström, S. Biochim. Biophys. Acta 2003, 1631,
35. (b) Forman, B. M.; Tontonoz, P.; Chen, J.; Brun, R. P.;
Spielgelman, B. M.; Evans, R. M. Cell 1995, 83, 803.
(c) Kliewer, S. A.; Lenhard, J. M.; Wilson, T. M.; Patel, I.;
Morris, D. C.; Lehmann, J. M. Cell 1995, 83, 813.
(4) (a) Ricote, M.; Li, A. C.; Wilson, T. M.; Kelly, C. J.; Glass,
C. K. Nature (London) 1998, 391, 79. (b) Jiang, C.; Ting,
A. T.; Seed, B. Nature (London) 1998, 391, 82.
(5) (a) Suguira, S.; Toru, T.; Tanaka, T.; Hazato, A.; Okamura,
N.; Bannai, K.; Manabe, K.; Kurozumi, S.; Noyori, R. Chem.
Pharm. Bull. 1984, 32, 4658. (b) Kato, T.; Fukushima, M.;
Kurozumi, S.; Noyori, R. Cancer Res. 1986, 46, 3538.
(6) Fitzpatrick, F. A.; Wynalda, M. A. J. Biol. Chem. 1983, 258,
713.
(7) Wakatsuki, H.; Yamoto, T.; Hashimoto, S. Eur. Pat. Appl.,
EP97023, 1997.
(8) Baxter, A. D.; Binns, F.; Javad, T.; Roberts, S. M.; Sadler,
P.; Scheinmann, F.; Wakefield, B. J.; Lynch, M.; Newton, R.
F. J. Chem. Soc., Perkin Trans. 1 1986, 889.
(9) Preparation of 7-(1¢-Hydroxyoct-2¢-
(12) Enantiomeric excesses were determined to be >99% by
synthesis and analysis of the Mosher ester derivatives.
(13) Compounds gave satisfactory NMR (1H and 13C) and mass
spectral data in accord with the literature. Specific rotations
were (+)-PGJ2 1, [a]D +175.9 (c 1.1, CHCl3); (+)-15-epi-
PGJ2, [a]D +168.0 (c 1.2, CHCl3); (–)-PGJ2, [a]D –171.7 (c
1.4, CHCl3); (–)-15-epi-PGJ2, [a]D –171.7 (c 1.1, CHCl3).
(14) Compound (+)-2 gave satisfactory NMR (1H) and mass
spectral data in accord with the literature; [a]D +194.3 (c 0.7,
CHCl3); 13C NMR (CDCl3; 75.4 MHz) d 197.45, 178.86,
160.75, 146.98, 135.15, 134.85, 131.83, 131.23, 125.89,
125.50, 43.43, 33.44, 33.34, 31.37, 30.63, 28.42, 26.55,
24.42, 22.45, 13.99.
enyl)bicyclo[2.2.1]hepta-2,5-diene 7. 4,4¢-Di-tert-butyl-
biphenyl (DTBB) (8.40 g, 31.6 mmol) was added to a stirred
suspension of lithium granules (11.25 g, 1.61 mol) in dry
THF (300 mL) under an atmosphere of dry argon gas. After
30 min the resultant dark green solution was cooled to –78
°C and 7-chloronorbornadiene 4 (26.70 g, 0.21 mol) added
followed by trans-2-octenal (31.40 mL, 0.21 mol) after a
further 30 min. After 1 h, the excess lithium was removed by
filtration and the solvent removed by distillation under
reduced pressure. The residue was purified by
chromatography over silica using ethyl acetate in hexane
(1:10) as eluent to afford the title compound 7 (44.91 g,
90%) as a straw yellow oil; Rf = 0.15 (ethyl acetate/hexane,
1:6); IR (film/cm–1) 3332, 2926, 2856, 1466, 1309; 1H NMR
(CDCl3, 400 MHz) d 6.85 (2 H, m, H-2 and H-3), 6.62 (2 H,
m, H-5 and H-6), 5.56 (1 H, dt, J = 15.4 Hz, 6.8 Hz, H-3¢),
5.36 (1 H, ddt, J = 15.4 Hz, 7.4 Hz, 1.3 Hz, H-2¢), 3.93 (1 H,
dd, J = 9.3 Hz, 7.4 Hz, H-1¢), 3.64 (1 H, m, H-1), 3.25 (1 H,
m, H-4), 2.41 (1 H, d, J = 9.3 Hz, H-7), 2.00 (2 H, m, 2 × H-
4¢), 1.32 (6 H, m, 2 × H-5¢, 2 × H-6¢ and 2 × H-7¢), 0.89 (3 H,
t, J = 6.8 Hz, 3 × H-8¢); 13C NMR (CDCl3; 75.4 MHz) d
145.07, 144.64, 140.58, 140.55, 133.08, 132.16, 91.49,
73.39, 52.16, 52.05, 32.59, 31.75, 29.26, 22.85, 14.38;
HRMS (CI, NH3): calcd for [M + H]+ C15H22O: 219.1749;
found: 219.1751.
(15) Lipase Resolution of 7-(1¢-Hydroxyoct-2¢-
enyl)bicyclo[2.2.1]hepta-2,5-diene 7. Lipase A from
Candida antarctica (0.77 g) was added to a slowly stirred
solution of the alcohol 7 (1.99 g, 9.14 mmol) in vinyl acetate
(1.6 mL, 173.76 mmol) and toluene (25 mL). After 20 h the
mixture was filtered through a glass sinter and the solvent
removed by distillation under reduced pressure. The residue
was purified by chromatography over silica using ethyl
acetate in hexane (1:50) as eluent to afford the acetate 12
(0.97 g, 41%) as a clear colourless oil. Further elution using
ethyl acetate in hexane (1:10) as eluent afforded the alcohol
(+)-7 (0.817 g, 41%) as a clear colourless oil; [a]D+22.5 (c
1.5, CHCl3). Potassium carbonate (5.04 g, 36.49 mmol) was
added to a stirred solution of the acetate 12 (0.968 g, 3.72
mmol) in methanol (20 mL) and water (10 mL). After 20 h
the mixture was diluted with CH2Cl2 (50 mL) and washed
with a 10% aqueous solution of citric acid (2 × 25 mL) and
brine (25 mL), dried (MgSO4) and the solvent removed by
distillation under reduced pressure. The residue was purified
by chromatography over silica using ethyl acetate in hexane
(10) (a) Jacob, J.; Espenson, J. H.; Jensen, J. H.; Gordon, M. S.
Organometallics 1998, 17, 1835. (b) Espenson, J. H. Chem.
Commun. 1999, 479.
(11) Preparation of {5-[1¢-(Dimethyl-t-butylsilyloxy)oct-2¢-
enyl]-4-hydroxycyclopent-2-enyl}acetaldehyde 9. Oxone
(2.32 g, 3.77 mmol) was added in one portion to a
suspension of NaHCO3 (0.63 g, 7.50 mmol) in acetone (30
mL) and water (30 mL) stirred at 0 °C. After 10 min, a
Synlett 2003, No. 8, 1170–1174 ISSN 1234-567-89 © Thieme Stuttgart · New York

1174
J. F. Bickley et al.
LETTER
(1:10) as eluent to afford the alcohol (–)-7 (0.67 g, 83%) as
a clear colourless oil; [a]D –21.2 (c 1.5, CHCl3).
Enantiomeric excesses were determined to be >99% by
synthesis and analysis of the Mosher ester derivatives of
aldehydes 9.
16.695(3) Å, b = 98.689(4)°, U = 1385.4(5) Å3, m(Mo-Ka) =
1.487 mm–1, 5565 reflections measured, 3004 unique (Rint
=
0.0413). R1 = 0.1634, wR2 = 0.4116 (all data); Crystals
consisted of fine hairy needles of low scattering power and
high mosaicity, which contributed to the high R-value.
However, the model refined well and allowed the
determination of the molecular connectivity. The absolute
configuration could not be determined.
(16) Crystal data (Figure 3). C29H32Br2O5, M = 620.37, T =
100(2)K, crystal dimensions = 0.25 × 0.05 × 0.02 mm,
Spacegroup P21, a = 5.0940(11), b = 16.480(3), c =
Figure 3
Synlett 2003, No. 8, 1170–1174 ISSN 1234-567-89 © Thieme Stuttgart · New York