Novel synthesis of CP-734432, an EP4 agonist, using Sharpless asymmetric dihydroxylation

Article abstract of DOI:10.1016/j.tetlet.2009.12.092

A novel and efficient asymmetric route to CP-734432, a lactam analog of PGE2, that shows selective agonism against the EP4 receptor subtype, is reported herein. The key steps include a Heck coupling to introduce the aryl ring at C-16 and a highly diastere

Full text of DOI:10.1016/j.tetlet.2009.12.092

Tetrahedron Letters 51 (2010) 1451–1454
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Novel synthesis of CP-734432, an EP4 agonist, using Sharpless asymmetric
dihydroxylation
a
a
b
b
Sajiv K. Nair a, , Jean J. Matthews , Stephan J. Cripps , Chunrong Ma , Elena Z. Dovalsantos ,
Alan W. Grubbs b, Neal W. Sach a, Wolter ten Hoeve c, Han Koster c, Erik J. Flahive b, Steven P. Tanis a,
Matt Renner b, Jim van Wiltenburg c
*
a Medicinal Chemistry, Pfizer Global R&D, 10770 Science Center Drive, La Jolla, CA 92121, USA
b Research-API and Research Analytical, Pfizer Global R&D, La Jolla Laboratories, 10646 Science Center Drive, La Jolla, CA 92121, USA
c Syncom B. V., Kadijk 3, 9747AT Groningen, The Netherlands
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and efficient asymmetric route to CP-734432, a lactam analog of PGE2, that shows selective agon-
ism against the EP4 receptor subtype, is reported herein. The key steps include a Heck coupling to intro-
duce the aryl ring at C-16 and a highly diastereoselective Sharpless asymmetric dihydroxylation to set the
C-15 center.
Received 20 November 2009
Accepted 16 December 2009
Available online 23 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Prostaglandin E2 (PGE2, 1, Fig. 1) is one of the primary products
of cyclooxygenase-initiated arachidonic acid metabolism. Prosta-
noids such as PGE2 are lipid mediators that play key regulatory
roles in various biological events such as vascular hypertension,
inflammation, and tumorigenesis. PGE2 is the endogenous ligand
for four EP receptor subtypes EP1, EP2, EP3, and EP4 which are cell
surface, seven-transmembrane domain receptors that belong to
the G-protein-coupled rhodopsin-type superfamily.1–6 The critical
role of EP4 receptor agonism in PGE2-mediated bone anabolic ef-
fects is well-precedented and provides a potential therapy for oste-
oporosis.7–9
PGE2 exhibits high affinity toward the four EP receptor sub-
types, however, it is not selective toward the individual subtypes
and has some cross-reactivity with at least one other prostanoid
receptor.10 In addition, natural prostaglandins are metabolically
short-lived and exhibit chemical instability.11,12 Thus numerous ef-
forts have focused on discovering analogs of PGE2 with improved
EP4 receptor selectivity, stability, and pharmacological properties.
These efforts have unveiled a new class of lactam analogs of PGE2
over the human EP2 receptor and >500-fold selectivity over human
EP1 and EP3 receptors. The isopropyl ester prodrug of 2, PF-
4475270 (3) is a novel ocular hypotensive compound effectively
lowering intraocular pressure in dogs.20 Herein, we report a novel
and efficient asymmetric route to this potent EP4 agonist 2 and its
prodrug 3.
Most efforts to synthesize these type of lactam analogs have re-
lied on a common strategy of utilizing a Horner–Wadsworth–Em-
mons (HWE) reaction of an aldehyde 6 with the corresponding
phosphonate 7 to afford the (E)-enone 8 and the reduction of this
enone to the allylic alcohol 9 (Scheme 1).13,14,17 Reduction of this
allylic alcohol under catalytic hydrogenation conditions provided
the saturated alcohol 10.
The reduction of the enone 8 is typically carried out using either
hydride-based methods and subsequent resolution of the diaste-
reomers or by asymmetric reduction using CBS-oxazaborolidine
reduction. On applying the CBS-oxazaborolidine reduction21 in
wherein the 11a-hydroxy-containing cyclopentanone ring is re-
O
placed with a lactam.13–18 Other heterocyclic rings such as the pyr-
azolidin-3-one have also been evaluated as a replacement.19
Further modifications to the C-8 and C-12 side chains in these lac-
tams have been shown to render both metabolic stability and EP4
selectivity.
OH
S
OR
O
O
O
8
N
16
Cameron et al. have previously reported one such lactam ana-
log, CP-734432 (2, Fig. 1).17 This compound has a receptor affinity
at the human EP4 receptor (IC50 2 nM) with 125-fold selectivity
15
CF3
12
12
HO
OH
1 (Prostaglandin E2)
OH
2 (CP-734432, R = H)
3 (PF-4475270, R = i-Pr)
* Corresponding author. Tel.: +1 858 526 4894.
E-mail address: sajiv.k.nair@pfizer.com (S.K. Nair).
Figure 1. PGE2 and lactam analogs CP-734432 (2) and PF-4475270 (3).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.092

1452
S. K. Nair et al. / Tetrahedron Letters 51 (2010) 1451–1454
O
O
CO R
c
a, b
2
NH
N
N
L
OTBS
OH
5
4
O
O
CO R
OR'
P
O
2
N
d
L
R'O
CO R
2
Ar
14
O
L
O
13
O
Ar
8
7
6
O
O
CO R
CO R
2
e
2
f
N
N
L
L
15
*
*
Ar
Ar
HO
HO
10
9
L = CH CH CH or Ar
2
2
2
Scheme 1. Reagents: (a) NaHMDS, R0Br, DMF; (b) 1 N HCl, MeOH; (c) EDC, DMSO, pyridinium trifluoroacetate, benzene; (d) NaH; (e) NaBH4 or catecholborane, (R)-2-Me-CBS-
oxazaborolidine; (f) H2, Pd/C.
the synthesis of 1, we observed variable diasteroselectivity which
necessitated the chiral separation of the diastereomers of the
allylic alcohol equivalent to 9. Literature reports of diastereoselec-
tive carbonyl reductions of closely related substrates with CBS-
oxazaborolidine or BINAL-H have indicated temperature control,
reagent quality, solvents, and substrate matching as critical vari-
ables that can easily erode diastereoselectivities.22 Furthermore,
substituent effects on the aryl ring at C-16 have shown to play a
key role in potency against the EP4 receptor.17 Thus, from the
standpoint of analogue production, this route was also limited in
its versatility to introduce various aryl groups at C-16 since this re-
quired the iterative and stepwise synthesis of the corresponding b-
keto phosphonates. To overcome the aforementioned issues, we set
out to explore a novel approach to this class of molecules.
To this end, we envisioned a retrosynthetic plan (Scheme 2) that
proceeds through the diol 11, which could be obtained through the
asymmetric dihydroxylation of olefin 12. The subsequent deoxy-
genation of the interim benzylic alcohol at C16 in diol 11 would
provide access to 2. This disconnection offered the advantage of
setting the key C-15 center chiral center in a highly diastereoselec-
tive fashion via the reliable Sharpless asymmetric dihydroxylation
of an (E)-styrene 12. More importantly, this design could also ad-
dress the versatility issue in the introduction of the aryl ring at
C-16 by employing a Heck coupling which would permit variations
on the aryl ring using readily available aryl iodides. Thus in the
case of 2, the aryl group in the styrene 12 could be introduced
via the Heck coupling of terminal olefin 13 with readily available
m-trifluoromethyl phenyl iodide. The olefin could be obtained from
the
The synthesis of 2 begins with the tosylation of the commer-
cially available -pyroglutaminol 14 to provide compound 15 in
D-pyroglutaminol 14.
D
76% yield (Scheme 3). Allylation of this tosylate with allyl magne-
sium chloride (2 equiv) gave the terminal olefin 16.23 The thio-
phene containing side chain was then introduced via alkylation
of the pyrrolidinone amide 16 using NaHMDS and alkyl iodide 17
providing compound 12 in 49% yield over two steps. A Heck cou-
pling of m-trifluoromethyl phenyl iodide with the terminal olefin
13 using Jeffrey’s conditions gave the E-olefin 12 in 63% yield.24,25
The key step of setting the R-alcohol C-15 stereocenter using
Sharpless asymmetric dihydroxylation26 was achieved with dihy-
droquinidine-based ADmix-b to provide the desired (R,R) diol 11
in > 96:4 dr (63% yield over two steps).
The thiophene containing alkyl iodide 17 was synthesized start-
ing from commercially available 5-bromothiophene-2-carboxylic
O
O
S
Oi-Pr
S
S
O
O
OH
CF
O
N
N
N
OH
16
3
CF
3
OH
OH
2
O
11
O
O
S
Oi-Pr
CF
O
Oi-Pr
NH
N
3
OH
12
12
13
14
Scheme 2. Retrosynthesis of CP-734432 (2).

S. K. Nair et al. / Tetrahedron Letters 51 (2010) 1451–1454
1453
O
O
O
O
S
b
a
NH
NH
NH
Oi-Pr
I
76%
OH
14
OTs
15
16
17
O
O
S
S
O
O
Oi-Pr
CF
Oi-Pr
Oi-Pr
d
c
N
N
49%, 2 steps
3
13
11
12
O
S
O
e
N
OH
63%, 2 steps
CF
3
OH
Scheme 3. Reagents and conditions: (a) TsCl, Et3N, DMAP, CH2Cl2; (b) allylmagnesium chloride, THF/Et2O (5:3) 0 °C to rt; (c) i. NaHMDS, DMF 0 °C to rt; (d) m-trifluoromethyl
phenyl iodide, Pd(OAc)2, NaHCO3, n-Bu4NCl, DMF, 40 °C; (e) ADmix-b, CH3SO2NH2, t-BuOH, H2O, 0 °C.
S
b
O
O
S
a
S
S
Cl
a, b
c
87%
Br
OH
S
O-i-Pr
71%
78%
HO
75%
21
2 steps
18
19
O
O
c
O
S
d
65%
17
S
Cl
O-i-Pr
98%
O-i-Pr
I
O-i-Pr
HO
22
20
17
Scheme 5. Reagents and conditions: (a) n-BuLi, ꢀ50 °C, 1-bromo-3-chloropropane,
ꢀ78 °C to rt; (b) n-BuLi, ꢀ50 °C, isopropylchoroformate; ꢀ60 °C; (c) NaI, methyl
ethylketone, 60 °C, 48 h.
Scheme 4. Reagents and conditions: (a) isopropanol, HCl; (b) propargyl alcohol,
Pd(PPh3)4, CuI, Et2NH; (c) H2, Pd/C; (d) PPh3, I2, imidazole.
thiophene (Scheme 5). The modified route commences with the
ortho-lithiation of thiophene and subsequent quenching of the an-
ion with 1-bromo-3-chloropropane to provide the chloride 21. A
second lithiation at C-5 on the thiophene ring followed by acyla-
tion with isopropyl chloroformate gave the ester 22. The conver-
sion of the chloride to the iodide 17 was then achieved using
Finkelstein conditions.
acid (Scheme 4). Esterification under acidic conditions with isopro-
panol and subsequent Sonogashira coupling27 with propargyl alco-
hol provided the alkyne 19. Hydrogenation with Pd/C and treating
the resultant saturated alcohol 20 with iodine, PPh3, and imidaz-
ole28 afforded 17. An alternative three-step approach to 17, that
was more amenable to scaleup, was also developed starting from
O
O
S
Oi-Pr
S
Oi-Pr
O
O
b
a
N
N
OH
82%, 2 steps
CF
3
CF
3
OH
11
O
O
23
O
O
O
S
S
Oi-Pr
OH
O
O
c
N
N
96%
CF
3
CF
3
OH
OH
2
3
Scheme 6. Reagents and conditions: (a) CDI, THF, 50 °C; (b) H2, 10% Pd/C, Et3N, EtOH; (c) LiOH, MeOH, THF, H2O.

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S. K. Nair et al. / Tetrahedron Letters 51 (2010) 1451–1454
12. Diczfalusy, U. Prog. Lipid Res. 1994, 33, 403.
In the end game of the synthesis, we evaluated concise ways to
13. Billot, X.; Chateauneuf, A.; Chauret, N.; Denis, D.; Greig, G.; Mathieu, M.-C.;
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reduce the provisional benzylic alcohol functionality in diol 11 to
the C-15 mono-alcohol 3 (Scheme 6). Attempts to effect a direct
reduction of diol under catalytic hydrogenation29,30 conditions
with various catalysts, solvents, and additives as well as ionic
hydrogenation conditions such as Et3SiH/TFA31 failed to give the
reduced mono-alcohol.
The activation of the diol 11 by converting it to a carbonate was
anticipated to facilitate a more facile hydrogenolysis.32 Accord-
ingly, the carbonate 23 was obtained by the reaction of diol with
1,10-carbonyldiimidazole (CDI). The hydrogenolysis of this carbon-
ate could be carried out under standard hydrogenation conditions
(10% Pd/C) using triethylamine as an additive in ethanol to provide
the mono-alcohol 3 (PF-4475270, 82%, two steps).33 The diastereo-
selective purity and assignment of stereochemistry of the C-15
alcohol in 3 were determined by 1H NMR analysis of the corre-
sponding Mosher’s ester.34 The ester functionality in the penulti-
mate 3 was hydrolyzed to the acid 2 (CP-734432) using lithium
hydroxide.
16. Maruyama, T.; Kambe, T.; Maruyama, T.; Yoshida, H.; Nishiura, A. WO 2003/
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In summary, we have demonstrated a novel, highly diastereose-
lective, and protection-free route to CP-733432 (2), a lactam analog
of PGE2 and its prodrug 3 (PF-4475270). The key features of this
synthesis are (a) the introduction of the C-16 aryl group via a Heck
reaction that allows the use of readily available aryl halides as a
source of diversity at this position (b) a highly enantioselective
Sharpless dihydroxylation to set the crucial C-15 stereocenter,
and (c) an efficient approach that precludes protection–deprotec-
tion steps that are characteristic of earlier approaches.
25. Jeffrey, T. Synthesis 1987, 70–71.
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Acknowledgment
We thank Dr. Jennifer Lafontaine for careful review of this
Letter.
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33. <10% of the separable overreduction product 24 was observed.
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