Synthesis of 15R-PGD2: A potential DP2 receptor agonist

Article abstract of DOI:10.1016/j.bmcl.2005.02.011

The first total synthesis of 15R-PGD₂ 3 was accomplished. The approach used in this report is also an efficient method to produce 15R-PGE ₂. 15R-PGD₂, a potential DP₂ receptor agonist, could be an important novel tool for defining the role of this receptor in inflammatory diseases.

Full text of DOI:10.1016/j.bmcl.2005.02.011

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1873–1876
Synthesis of 15R-PGD2: a potential DP2 receptor agonist
Seongjin Kim,a Sophie Bellone,a Kirk M. Maxey,b William S. Powell,c
Gue-Jae Leea and Joshua Rokacha,*
aClaude Pepper Institute and Department of Chemistry, Florida Institute of Technology, 150 W. University Blvd.,
Melbourne, FL 32901, USA
bCayman Chemical, 1180 E. Ellsworth Road, Ann Arbor, MI 48108, USA
cMeakins-Christie Laboratories, Department of Medicine, McGill University, Montreal, Quebec, Canada H2X 2P2
Received 10 January 2005; revised 3 February 2005; accepted 4 February 2005
Abstract—The first total synthesis of 15R-PGD2 3 was accomplished. The approach used in this report is also an efficient method to
produce 15R-PGE2. 15R-PGD2, a potential DP2 receptor agonist, could be an important novel tool for defining the role of this
receptor in inflammatory diseases.
Ó 2005 Published by Elsevier Ltd.
Prostaglandin D2 (PGD2) 1,1–6 an arachidonic acid
metabolite, is produced in mast cells,7 dendritic
cells,8 Th2 cells,9 and in the central nervous
system.10
attractant effect of PGD2 on eosinophils and other white
blood cells.21,22 We have shown21 that these cells possess
both inhibitory DP1 receptors and stimulatory DP2
receptors. The balance between these two receptors is
likely to regulate the response of eosinophils and baso-
phils to PGD2. We recently found that 15R-Me-PGD2
2 is a potent and selective agonist for the DP2 receptor,
being about 5 times more potent than PGD2 and 75
times more potent than 15S-Me-PGD2 in stimulating ac-
tin polymerization, chemotaxis, and expression of the
adhesion molecule CD11b23 (Table 1). Of particular
interest is the fact that the stereochemistry of the 15-
hydroxy group in 2 is opposite to that in PGD2 (15S-
OH). In contrast to PGD2, 2 shows no activity on the
DP1 receptor.23 It could therefore be an important novel
tool for defining the physiological role of the DP2 recep-
tor in asthma, mastocytosis, etc.
A large amount of this natural product is released in the
lung during asthma and mastocytosis,11,12 suggesting
that PGD2 may play a role in these two diseases. We
have also proposed that 5-oxo-ETE, a potent chemoat-
tractant for neutrophils13 and eosinophils,14 can be a
causative factor in asthma.15,16 Until recently, PGD2
was known to act by raising intracellular cAMP levels
through its action on a single Gs–protein-coupled recep-
tor termed the DP1 receptor.17 This increase in cAMP
levels results in a strong inhibitory effect on platelet
aggregation18 as well as bronchodilator19 and vasodila-
tor20 effects in humans. However, our group21 and other
researchers22 independently discovered a second Gi–pro-
tein-coupled receptor for PGD2, which we termed the
DP2 receptor, and which is responsible for the chemo-
The high potency of the 15R-Me-PGD2 analog 2 raises
the possibility that inversion of the configuration at
HO
O
HO
O
HO
COOH
COOH
COOH
O
OH
HO Me
OH
1
2
3
15R-PGD2
PGD2
Keywords: Prostaglandin D2; 15R-PGD2; 15R-PGE2; DP2 receptor; Eosinophils.
*
Corresponding author. Tel.: +1 321 674 7329; fax: +1 321 674 7743; e-mail: jrokach@fit.edu
0960-894X/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2005.02.011

1874
S. Kim et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1873–1876
Table 1. Effects of 15-methyl analogs of PGD2 on DP2 mediated
responses (EC50, nM) in eosinophils and DP1, mediated cAMP
formation (EC10, nM) in platelets
methyldisilyl amide (LiHMDS) or sodium hexamethyl-
disilyl amide (NaHMDS) as a base, produced 6 in
80% and 96% yield, respectively. Depending on the base
used, different byproducts are formed as shown in
Scheme 2.
Compound
DP2
Actin
DP1
CD11b
Chemotaxis
cAMP
PGD2
15R-Me-PGD2
15S-Me-PGD2
7
13
10
11
>10,000
2100
In the case of NaHMDS, the eliminated compound 21 is
obtained in variable amounts (1–10%), whereas with
LiHMDS, the Z-isomer 22 is obtained in 20% yield. Gi-
ven the difficulty to separate the Z-isomer 22 from the E-
isomer 6, the use of the NaHMDS base was preferred.
The yield of these byproducts can be reduced from
20% to 5% in the case of 22 and to 1% in the case of
21 by maintaining the reaction at À78 °C for 3 h.
Reduction of enone 6 with (S)-BINAL-H gave the ex-
pected S-isomer in >95% ee. Unfortunately the reduc-
tion of 6 with (R)-BINAL-H was not stereoselective
and afforded a mixture of 15-S and 15-R. This was sur-
prising considering that we have performed (R)-BINAL-
H reduction in the isoprostane series with excellent stereo-
control.27 A check of the literature reveals that simi-
lar compounds to 6 on reaction with (R)-BINAL-H
also did not show much selectivity for the R-isomer.28
Other reducing agents and other C11–OH protecting
groups have also been reported.29 We elected to carry
the reduction of enone 6 with sodium borohydride,
which gave a mixture of the S- and R-isomers, 7 and
8. Flash column chromatography afforded the S- and
R-isomer in 45% and 40%, respectively. The structural
assignment of 7 and 8 was accomplished as shown in
Scheme 3.
1.4
99
3.8
333
1.7
128
carbon 15 of PGD2 itself may result in enhanced DP2
receptor activity. To this end we decided to undertake
the total synthesis of 15R-PGD2 (3). The synthesis of
3 was performed in 11 steps as described in Scheme 1.
This approach to 15R-PGD2 is also an efficient method
to synthesize 15R-PGE2 20.
One general comment on the synthetic design is war-
ranted. From the outset we decided that the generation
of the 11-oxo group of 15R-PGD2 would be performed
at the last step of the synthesis. The facile elimination of
the b-hydroxy group in PGE2 and PGD2 and related
derivatives and analogs is well known.24,25 In addition,
we also elected not to use a protected carbonyl group,
as the deprotection step could be too harsh. We did
not want to find this out at the end of the synthesis.
The commercially available lactone benzoate aldehyde
426 was our starting point. The Horner–Emmons reac-
tion of 4 with the phosphonate 5, using lithium hexa-
O
O
O
O
O
O
O
O
MeO
P
O
O
O
O
c
b
OMe
5
+
BzO
BzO
a
CHO
BzO
BzO
BzO
OTBDMS
OH
7
9
O
6
OH
8
4
OH
O
O
O
HO
O
O
OH
e
f
d
+
TESO
TESO
12
TESO
HO
OTBDMS
13
OTBDMS
g
OTBDMS
OTBDMS
HO
10
11
COOH
HO
HO
HO
HO
Ph3P
Br
14
COOMe
i
j
COOMe
COOH
h
15
TESO
16
OTBDMS
OTBDMS
OTBDMS
17
k
O
HO
O
HO
O
COOH
COOH
l
m
COOH
COOH
+
+
O
HO
HO
OH
15R-PGD2
3
OH
19
OTBDMS
OTBDMS
20
18
15R-PGE2
Scheme 1. Reagents and conditions: (a) NaHMDS, THF, À78 °C to rt, 96%; (b) NaBH4, CeCl3Æ7H2O, EtOH, 0 °C to rt, 45% 7, 40% 8;
(c)TBDMSCl, imidazole, THF, 60 °C, 83%; (d) K2CO3, MeOH, rt, 96%; (e) TESCl, pyridine, 60 °C, 98%; (f) DIBAL-H, CH2Cl2, À78 °C, 99%; (g)
Dess Martin, CH2CI2, rt; (h) (i) t-BuOK, HMPA, THF, 0 °C to rt, (ii) CH2N2, 62%; (i) DDQ, H2O, and THF, 0 °C to rt, 82%; (j) 5% KOH, THF, rt,
75%; (k) K2CO3, MeOH, rt, 48 h, 79%; (l) Dess Martin, CH2Cl2, rt, 94%; (m) formic acid/THF/H2O (6:3:1), 29% 15R-PGD2, 58% 15R-PGE2.

S. Kim et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1873–1876
1875
O
O
O
O
NaHMDS
+
O
P
O
O
MeO
O
BzO
OMe
O
O
O
5
6
21
O
O
CHO
O
O
BzO
4
+
O
LiHMDS
BzO
BzO
6
22
Scheme 2. Side products of the Horner–Emmons reaction depending on the base used.
Table 2. Effect of 15R-PGD2 on actin polymerization and cAMP
The identity of isomer 7 was derived from the well estab-
lished relationship between (S)-BINAL-H and S-stereo-
chemistry of the OH product. To confirm the identity of
the isomer 8, we oxidized each pure isomer separately
with the Dess Martin reagent giving the identical enone
6. Only the R-isomer 8 was used for the following steps
of the synthesis.
Treatment
Actin polymerization
(eosinophils)
(% above control)
cAMP (platelets)
(pmol)
Vehicle
15R-PGD2 (1 lM)
PGD2 (1 lM)
—
83.8 7.5
86.2 4.2
0.05 0.02
0.83 0.21
15.48 1.97
Protection of 8 with the TBDMS group gave the com-
pound 9 in 83% yield. The benzoate protection, too la-
bile in basic conditions, was replaced in two steps by
the more stable TES group to give the product 11. Then
reduction of the lactone 11 using DIBAL-H provided
the lactol 13 in 99% yield. Some diol 12 was obtained
(1–10%), which can be reoxidized into the lactol 13 with
the Dess Martin reagent as shown in Scheme 1.
2031 in 58% yield. The identity of 20 was confirmed by
comparison with an authentic sample.
15R-PGD2 is currently being analyzed for its potential
activity on PGD2 receptors. Preliminary results suggest
that its activity at the DP2 receptor is similar to that
of PGD2, but it has very little activity at the DP1 recep-
tor. As shown in Table 2, 15R-PGD2 and PGD2, using
methodology we described recently,23 induce virtually
identical increases in actin polymerization in human
eosinophils, which is a DP2 receptor-mediated response.
In contrast, 15R-PGD2 induces only a very modest in-
crease in cAMP levels in platelets, which is mediated
by the DP1 receptor. The cAMP response elicited by
PGD2 is about 20 times greater than 15R-PGD2. Thus
it would appear that 15R-PGD2 is highly selective for
the DP2 receptor. Further studies are underway on the
biological effects of this compound.
Wittig reaction of 13 with the phosphonium salt 14,
using potassium tert-butoxide as a base, produced selec-
tively the Z-isomer 15 in 62% yield. Compound 15 was
treated with dichlorodicyanobenzoquinone (DDQ), to
deprotect the TES group to afford 16, followed by 5%
aqueous potassium hydroxide to hydrolyze the methyl
ester and give 17. Alternatively, compound 15 can be
treated with potassium bicarbonate in methanol for
48 h to simultaneously deprotect the 11-hydroxy and
the methyl ester to give 17 in 79% yield. This shortcut
is the preferred modification we now use.
Oxidation of 17 with the Dess Martin periodinane
reagent produced the compounds 18 and 19 in a 65:35
ratio. Although 18 and 19 separate on TLC (methanol/
ethylacetate/hexane, 3:65:32), we found the separation
by flash column chromatography to be quite tedious
and the isolation of the desired 15R-PGD2 was realized
at the final step of the synthesis after deprotecting the
mixture 18 and 19 with formic acid. We obtained not
only 15R-PGD2 330 in 29% yield, but also 15R-PGE2
Acknowledgments
We wish to acknowledge the NIH for support under
Grants DK-44730 and HL-69835 (J.R.), the NSF for
an AMX-360 NMR Instrument Grant CHE-90-13145
(J.R.), and the CIHR of Canada for Grant MOP-6254
(W.S.P.), and Korea Science & Engineering Foundation
(KOSEF).
O
O
O
O
O
O
(S)-BINAL
(R)-BINAL
+
7
Dess Martin
Dess Martin
BzO
BzO
OH
BzO
OH
O
7
6
8
95% ee
25-30% ee
Scheme 3. Identification of the S- and R-isomers.

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S. Kim et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1873–1876
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1979, 210, 134.
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1
CDCl3), d 5.6 (m, 2H), 5.45 (m, 2H), 4.55 (m, 1H), 4.18
(q, J = 13 and 6.3 Hz, 1H), 2.8 (dd, J = 12.1 and 8.5 Hz,
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25.5, 25, 23, 14.
1
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CDCl3), d 5.72 (dd, J = 15.4 and 6.4 Hz, 1H), 5.6 (dd,
J = 15.4 and 8.3 Hz, 1H), 5.45 (m, 2H), 4.15 (q, J = 15.3
and 9 Hz, 2H), 2.75 (dd, J = 18.5 and 7.5 Hz, 1H), 2.35 (m,
4H), 2.25 (m, 2H), 2.1 (m, 3H), 1.6 (m, 4H), 1.3 (m, 6H),
0.9 (t, J = 6 Hz, 3H).