Synthesis of a highly selective EP2-receptor agonist

Article abstract of DOI:10.1055/s-2002-19781

A practical method for the synthesis of the prostanoid EP2-receptor agonist 1 was developed. This method includes magnesium-mediated Julia olefination of aldehyde 2 with the optically active sulfone 3, which was prepared from allylic alcohol 4 using the Sharpless asymmetric epoxidation procedure.

Full text of DOI:10.1055/s-2002-19781

LETTER
239
Synthesis of a Highly Selective EP2-Receptor Agonist
Synthesis of
a
Hig
o
hlySelective
u
E
P2-Recept
s
or
A
gonis
u
t
ke Tani,*a Atsushi Naganawa,a Akiharu Ishida,a Hiromu Egashira,a Yoshihiko Odagaki,a Toru Miyazaki,a
Tomoyuki Hasegawa,b Yasufumi Kawanaka,b Hisao Nakai,a Shuichi Ohuchida,a Masaaki Todaa
a
Minase Research Institute, Ono Pharmaceutical Co., Ltd, Shimamoto, Mishima, Osaka 618-8585, Japan
Fax +81(75)9629314; E-mail: k.tani@ono.co.jp
b
Fukui Research Institute, Ono Pharmateutical Co., Ltd., Mikuni, Sakai, Fukui 913-8538, Japan
Received 17 November 2001
Table Biological Profile of 1.
Abstract: A practical method for the synthesis of the prostanoid
EP2-receptor agonist 1 was developed. This method includes mag-
nesium-mediated Julia olefination of aldehyde 2 with the optically
active sulfone 3, which was prepared from allylic alcohol 4 using
the Sharpless asymmetric epoxidation procedure.
Binding Ki (nM)a
EC50 (nM)b
Compounds mEP1
mEP2
3.3
mEP3
> 104
5.0
mEP4
6100
3.1
mEP2
3.8
1
> 104
18
Key words: prostaglandins, asymmetric synthesis, Julia olefina-
tion, magnesium, EP2-receptor agonist
PGE2
38
2.0
Butaprost
AH-13205
> 104
2800
790
320
> 104
49
> 104
2200
26
In preceding publications,1 we reported the development
of the highly selective EP2-receptor agonist 1, which
demonstrates a high affinity for the EP2-receptor of
mouse (m) and human (h). Also in functional studies, 1
showed nearly 10 and 1000 fold higher potency than the
reported selective ligands butaprost2 and AH-13205,3 re-
spectively, in stimulating cAMP production in the cells
expressing mEP2-receptor (Table). The EP2-receptor ag-
onist 1 also showed nearly the same affinity as PGE2 for
the EP2-receptor, and suppressed the spontaneous uterine
motility in anesthetized rats in late-term pregnancy.1a,c
These findings suggest that 1 is a promising candidate of
tocolytic with a new mechanism of action for clinical use.
The information mentioned above prompted us to develop
a practical synthetic method for the newly discovered
EP2-receptor selective agonist 1. According to the report-
ed method1c described in Scheme 1, the undesired 16(R)-
isomer of 1 has to be removed by column chromatography
on silica gel, while this laborious procedure should be suc-
cessfully avoided by this new synthesis (Scheme 2). Ad-
ditionally, removal of the 8,9-olefinic by-product, which
was formed in the chlorination reaction, was found to be
easier with this method. We report here the improved syn-
thesis, which includes enantioselective introduction of 16-
OH by an asymmetric epoxidation and a stereoselective
construction of a 13,14-trans-double bond by magne-
sium-mediated Julia olefination.4
2500
a Using membrane fractions of Chinese hamster ovary (CHO) cells
expressing the mouse prostanoid receptors (mEP1, mEP2, mEP3 and
mEP4), Ki values were determined by the competitive binding assay,
which was performed according to the method of Kiriyama et al.15
with some modifications. When the test compound did not displace
binding of radioligands by 50% even at a concentration of 104 nM, the
Ki value was not determined (expressed > 104).
b With regard to the subtype-receptor agonistic activity, EC50 values
were determined based on the effect of the test compounds on the in-
crease in the intracellular cAMP production in the mouse EP2 recep-
tor.
O
OTBS
CO2Me
I
+
TBSO
I
II
O
CO2Me
OTBS
TBSO
III
Enantioselective Synthesis of 3: As shown in Scheme 2,
the highly selective EP2-receptor agonist 1 can be synthe-
sized by Julia olefination of 2 with 3. Enantioselective
synthesis of 3 is outlined in Scheme 3. Asymmetric epoxi-
dation of the allylic alcohol 4, which was prepared by re-
ducing the corresponding , -unsaturated ethyl ester5
with diisobutylaluminum hydride, afforded 5. Regioselec-
Cl
CO2Me
OH
HO
1
Synlett 2002, No. 1, 01 02 2002. Article Identifier:
1437-2096,E;2002,0,02,0239,0242,ftx,en;Y22301ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
Scheme 1 The reported synthesis of 1

240
K. Tani et al.
LETTER
tive ring opening of epoxide 5 with sodium bis(methoxy- Synthesis of 2: Preparation of the aldehyde 2 from an op-
ethoxy)aluminum hydride gave 6.
Selective tically active intermediate 109 is outlined in Scheme 4.
monotosylation of the primary alcohol 6, followed by the Methanesulfonation of 10, which is easily available from
SN2 reaction under phase transfer conditions, gave the sul- the Corey lactone,9,10 afforded 11. Substitution reaction of
fide 76, oxidation of which with Oxone® afforded sulfone the 9 -methanesulfonate 11 with tetrabutylammonium
8. For purification, 8 was converted to the benzoate 9 prior chloride gave a 9 -chloro derivative 1211 and a 8,9-ole-
to recrystallization. After recrystallization from ethanol, 9 finic by-product. The ratio of the 9 -Cl to the olefinic by-
was again converted to 87 (optical purity 99% ee), protec- product was approximately 5.4:1. After selective depro-
tion of which as a tetrahydropyranyl ether yielded 3.8
tection of the 1-methyl-1-methoxyethyl group,9 com-
pound 13 and the 8,9-olefinic derivative could be easily
separated by column chromatography on silica gel. Oxi-
dation of 13 with a sulfur trioxide-pyridine complex in
dimethyl sulfoxide and triethylamine gave the aldehyde
2.12
Cl
CO2H
OH
HO
Julia olefination of 2 with 3: Synthesis of 1 and its L-
lysine salt 1Ly is outlined in Scheme 5. Julia olefination
of 2 with 3,13 followed by acidic deprotection of THP
groups, gave 15 and the corresponding 13(Z) isomer (E/
Z = 5/1). The Z isomer could be easily removed by col-
umn chromatography on silica gel. Compound 15 was
converted to 1 by alkaline hydrolysis with sodium hydrox-
ide. Addition of L-lysine to a solution of 1 in ethanol, fol-
lowed by dilution with ethyl acetate, afforded the
crystalline salt 1Ly in good yield. As shown in the Figure,
absolute configuration of the 16-OH of 1Ly was finally
determined by X-ray analysis.14
1
Cl
PhO2S
OTHP
CO2Me
+
CHO
THPO
2
3
Scheme 2 Retrosynthesis of 1
OH
O
b
a
c
HO
HO
HO
4
5
6
OH
OR
OTHP
d
h
PhS
PhO2S
PhO2S
3
7
8 : R = H
g
e, f
9 : R = COPh
Scheme 3 Synthesis of the optically active
chain unit 3. Reagents: (a) t-BuOOH, Ti(i-PrO)4, D-(–)-DIPT, CH2Cl2, –20 ºC; (b)
Na(MeOCH2CH2O)2AlH2, toluene (95% from 4); (c) TsCl, n-Bu4NBr, NaOHaq, toluene, then PhSH (99%); (d) Oxone®, MeOH, H2O (quant.);
(e) PhCOCl, DMAP, pyridine then recrystallized from EtOH (71%); (f) NaOHaq, MeOH (quant.); (g) DHP, p-TsOH, CH2Cl2 (96%).
RO
Cl
c
b
CO2Me
CO2Me
O
O
O
OMe
THPO
a
THPO
10 : R = H
12
11 : R = MeSO2
Cl
Cl
d
CO2Me
CO2Me
OH
CHO
THPO
THPO
13
2
Scheme 4 Synthesis of the aldehyde 2. Reagents: (a) MsCl, Et3N, CH2Cl2; (b) n-Bu4NCl, Et3N, toluene, 60 ºC; (c) HClaq, THF (61% from
10); (d) SO3-pyridine, Et3N, DMSO (quant.).
Synlett 2002, No. 1, 239–242 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of a Highly Selective EP2-Receptor Agonist
241
Cl
Cl
d, e
CO2Me
CO2H
L-lysin
a, b
2
+ 3
OR
OH
RO
HO
1Ly
14 : R = THP
15 : R = H
c
Scheme 5 Synthesis of 1 and 1Ly. Reagents: (a) n-BuLi, THF, –78 ºC; (b) Mg (powdered, -50 mesh), TMSCl, MeOH (47% from 3);
(c) p-TsOH, MeOH (78%); (d) NaOHaq, MeOH (81%); (e) L-lysine, EtOH, EtOAc (91%).
T.; Ohuchida, S.; Nakai, H.; Kondo, K.; Toda, M. Bioorg.
Med. Chem., in press. (c) Tani, K.; Naganawa, A.; Ishida,
A.; Egashira, H.; Sagawa, K.; Harada, H.; Ogawa, M.;
Maruyama, T.; Ohuchida, S.; Nakai, H.; Kondo, K.; Toda,
M. Bioorg. Med. Chem., in press.
(2) Gardiner, P. J. Br. J. Pharmac. 1986, 87, 45.
(3) Nials, A. T.; Vardey, C. J.; Denyer, L. H.; Thomas, M.;
Sparrow, S. J.; Shepherd, G. D.; Coleman, R. A.
Cardiovascular Drug Review 1993, 11, 165.
(4) Lee, G. H.; Lee, H. K.; Choi, E. B.; Kim, B. T.; Pak, C. S.
Tetrahedron Lett. 1995, 36, 5607.
(5) The , -unsaturated ester was prepared by Horner–Emmons
reaction of triethyl phosphono acetate with 2,2-
(trimethylene)butanal, the preparation of which was
described in ref.1b of this report.
(6) Spectrum data of compound 7: IR(neat): 3441, 2962, 1584,
1481, 1439, 1310, 1272, 1071, 1026, 737, 690 cm–1; 1H
NMR (200 MHz, CDCl3): = 7.40–7.10 (m, 5 H), 3.80–3.65
(m, 1 H), 3.28–2.94 (m, 2 H), 2.00–1.20 (m, 11 H), 0.88 (t,
J = 7.5 Hz, 3 H); TLC: Rf = 0.52 (n-hexane/AcOEt = 4:1).
(7) Spectrum data of compound 8: IR(neat): 3525, 2963, 2936,
2878, 1447, 1304, 1148, 1087, 1072, 748, 689, 599, 533 cm–
1; 1H NMR (200 MHz, CDCl3): = 8.00–7.90 (m, 2 H),
7.70–7.50 (m, 3 H), 3.66–3.55 (m, 1 H), 3.50–3.10 (m, 2 H),
2.00–1.30 (m, 11 H), 0.88 (t, J = 7.5 Hz, 3 H); TLC:
Rf = 0.32 (n-hexane/AcOEt = 2:1). The optical purity of
compound 8 was determined based on the result of HPLC
analysis of its benzoyl derivative 9.
(8) Spectrum data of compound 3: IR(neat): 2939, 2864, 1446,
1305, 1150, 1075, 1031, 987 cm–1; 1H NMR (200 MHz,
CDCl3): = 8.00–7.90 (m, 2 H), 7.70–7.50 (m, 3 H), 4.40
(m, 1 H), 3.94–3.70 (m, 1 H), 3.62–3.28 (m, 3 H), 3.17–3.04
(m, 1 H), 2.24–1.20 (m, 16 H), 0.85 (t, J = 7.4 Hz, 3 H);
TLC: Rf = 0.42 and 0.37 (n-hexane/AcOEt = 4:1).
(9) Hayashi, M.; Arai, Y.; Wakatsuka, H.; Kawamura, M.;
Konishi, Y.; Tsuda, T.; Matsumoto, K. J. Med. Chem. 1980,
23, 525.
(10) Corey, E. J.; Schaaf, T. K.; Huber, W.; Koelliker, U.;
Weinshenker, N. M. J. Am. Chem. Soc. 1970, 92, 397.
(11) Buchmann, B.; Skuballa, W.; Vorbruggen, H. Tetrahedron
Lett. 1990, 31, 3425.
(12) Spectrum data of compound 2: IR(neat): 2947, 2868, 2736,
1439, 1352, 1323, 1247, 1201, 1154, 1133, 1077, 1034,
1021, 970 cm–1; 1H NMR (200 MHz, CDCl3): = 9.76 and
9.73 (2 d, J = 2.0 Hz, 1 H), 5.60–5.30 (m, 2 H), 4.65–4.50
(m, 2 H), 4.15–3.95 (m, 1 H), 3.90–3.70 (m, 1 H), 3.67 (s, 3
H), 3.60–3.40 (m, 1 H), 2.80–1.40 (m, 18 H); TLC: Rf = 0.60
(n-hexane/AcOEt = 2/1).
(13) Typical Experimental Procedure for the Synthesis of 14
from 2 and 3: To a stirred solution of 3 (19.8 g, 54.0 mmol)
in dry THF (125 mL) was added n-butyllithium (1.6 M in
Figure X-ray crystallographic structure of 1Ly14
In summary, we have succeeded in developing a practical
synthesis of the highly selective EP2-receptor agonist 1,
which was converted to the crystalline L-lysine salt 1Ly
demonstrating excellent physicochemical properties such
as good crystalline property, good water-solubility and so
on. In the process, a Julia olefination of aldehyde 2, pre-
pared from 10, with the optically active sulfone 3, pre-
pared from the optically active epoxide 5, was included as
a key reaction (Scheme 2).
References
(1) (a) Tani, K.; Naganawa, A.; Ishida, A.; Egashira, H.;
Sagawa, K.; Harada, H.; Ogawa, M.; Maruyama, T.;
Ohuchida, S.; Nakai, H.; Kondo, K.; Toda, M. Bioorg. Med.
Chem. Lett. 2001, 11, 2025. (b) Tani, K.; Naganawa, A.;
Ishida, A.; Sagawa, K.; Harada, H.; Ogawa, M.; Maruyama,
Synlett 2002, No. 1, 239–242 ISSN 0936-5214 © Thieme Stuttgart · New York

242
K. Tani et al.
LETTER
sulfate, and concentrated in vacuo to afford a crude oil,
hexane, 33.8 mL, 54.0 mmol) at –78 ºC under an argon
atmosphere. The reaction mixture was stirred for 1 h at –78
ºC and then added to a stirred solution of 2 (16.0 g, 41.5
mmol) in 125 mL of dry THF (125 mL) at –78 ºC. After
stirring for 1 h at –78 ºC, the resulting mixture was treated
with acetic anhydride (7.85 mL, 83.0 mmol) and allowed to
warm up to ambient temperature over 1 h. The reaction
mixture was treated with sat. aq ammonium chloride and
extracted with EtOAc repeatedly. The combined organic
layers were washed with water, then brine, dried over anhyd
magnesium sulfate, and concentrated in vacuo to afford a
crude acetoxy sulfone (40.1 g) as a dark-brown viscous oil.
TLC: Rf = 0.41 (n-hexane/EtOAc = 3:1); IR(neat): 2943,
2863, 1740, 1447, 1371, 1307, 1228, 1150, 1131, 1075, 1031
cm–1; 1H NMR (200 MHz, CDCl3): = 8.00–7.45 (m, 5 H),
5.70–5.20 (m, 2 H), 5.00–3.20 (m, 14 H), 2.60–1.20 (m, 37
H), 1.10–0.80 (m, 3 H).
To a stirred solution of the crude acetoxy sulfone (10.6 g,
11.0 mmol) in 100 mL of methanol was added powdered
magnesium (-50 mesh, 2.40 g, 100 mmol) under an argon
atmosphere. The mixture was again stirred (15 min), and a
catalytic amount of chloro trimethylsilane (0.1 mL) was
added. After stirring for 1 h at ambient temperature, the
reaction mixture was poured into ice-cold aq ammonium
chloride and extracted with EtOAc. The organic layer was
washed with water, then brine, dried over anhyd magnesium
which was purified by column chromatography on silica gel
to give a mixture of 13E- (compound 14) and 13Z-olefinic
compounds (3.0 g, 47% yield from aldehyde 2) as a pale
yellow oil (E/Z = 5:1). The undesired Z isomer was easily
removed by silica gel column chromatography after
deprotection. TLC: Rf = 0.66 (n-hexane/EtOAc = 3:1);
IR(neat): 2942, 2875, 1741, 1440, 1352, 1200, 1115, 1077,
1032, 977 cm–1; 1H NMR (200 MHz, CDCl3): = 5.80–5.25
(m, 4 H), 4.60 (m, 2 H), 4.15–3.75 (m, 4 H), 3.57 (s, 3 H),
3.55–3.35 (m, 3 H), 2.50–1.40 (m, 34 H), 1.00–0.85 (m, 3
H).
(14) X-Ray analysis (Figure)of the salt 1Ly consisting of a 1/1
molar ratio of 1 and L-lysine was conducted. The absolute
configuration of the 16-OH was determined to be an S-form
based on its configuration relative to the absolute
configuration of L-lysine in the crystal lattice. Lattice
Parameters: a = 32.91(2) Å, b = 5.91(2) Å, c = 17.64(2) Å,
= 112.52(6)°V = 3169(10) Å3. Space Group: C2. Cu-K
radiation ( = 1.54178 cm–1) graphite monochromated was
used for data collection. 1307 Reflections with I > 3 (I) was
used for final structure factor calculations. R = ||Fobs|–
|Fcalc||/ |Fobs| = 0.104. Rw = (( w(|Fobs|–|Fcalc|)2/
wFobs2)1/2 = 0.119, where w = 1/ 2(Fobs).
(15) Kiriyama, M.; Ushikubi, F.; Kobayashi, T.; Hirata, M.;
Sugimoto, Y.; Narumiya, S. Br. J. Pharmac. 1997, 122, 217.
Synlett 2002, No. 1, 239–242 ISSN 0936-5214 © Thieme Stuttgart · New York