Synthesis of phosphorylcholines possessing 5,6- or 14,15-epoxyisoprostane A2 at sn-2 position

Article abstract of DOI:10.1016/j.tetlet.2005.09.193

Use of the PMBOCH₂ group (PMB: p-MeOC₆H ₄CH₂) as a substitute of CO₂H provided high level of reproducibility and efficiency in construction of the full structure of 5,6-epoxyisoprostane A₂.

Full text of DOI:10.1016/j.tetlet.2005.09.193

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8435–8438
Synthesis of phosphorylcholines possessing 5,6- or
14,15-epoxyisoprostane A2 at sn-2 position
Hukum P. Acharya and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology B52, Nagatsuta-cho 4259, Midori-ku,
Yokohama 226-8501, Japan
Received 8 August 2005; revised 13 September 2005; accepted 16 September 2005
Available online 18 October 2005
Abstract—Use of the PMBOCH2 group (PMB: p-MeOC6H4CH2) as a substitute of CO2H provided high level of reproducibility and
efficiency in construction of the full structure of 5,6-epoxyisoprostane A2. After the construction, the PMBOCH2 group was con-
verted to CO2H by using (1) DDQ, (2) SO3Æpyridine and (3) NaClO2 at pH 7. The acid, thus synthesized, was condensed with lyso-
PC to furnish one of the title compounds. Similarly, 14,15-regioisomer was synthesized.
Ó 2005 Elsevier Ltd. All rights reserved.
A series of planar structures of phosphorylcholines pos-
sessing epoxyisoprostane A2 (Fig. 1) or E2 has been iso-
lated by the Berlinerꢀs group in their study of elucidating
compounds responsible for atherosclerosis.1,2 These
phosphorylcholines induce endothelial cell to synthesize
IL-8 and MCP-1in a dose-dependent fashion between
0.1and 5 lM concentrations. It is also reported that
these compounds are potent activators of PPARa.
Recently, we reported a synthesis of 5,6-epoxyisopros-
tane A2 phosphorylcholine (1), for the first time (Scheme
1), and determined the relative stereostructure as
depicted in Figure 1,3 while a simpler model diaste-
reomer4a and, quite recently,
a mixture of 5,6-
4b
epoxyisoprostanes A2 and E2 have been synthesized
by another group, who used the CH2OPMB group as
the carboxylic acid equivalent in the latter synthesis.
O
O
O
5
O
P
CO2
6
O
O
NMe3
O O
2-(5,6-epoxyisoprostane A2)phosphorylcholine (1)
O
O
CO2
14
O
O
O
P
O O
NMe3
15
O
2-(14,15-epoxyisoprostane A2)phosphorylcholine (2)
Figure 1. Two regioisomeric phosphorylcholines possessing the epoxyisoprostane A2 moiety.
We have also chosen the same group in the present syn-
Keywords: Epoxyisoprostane; Phosphorylcholine; p-Methoxybenzyl;
thesis. 5,6-Epoxyisoprostane A2 intermediate 8 in our
synthesis was constructed through aldol reaction5
between the c-substituted cyclopentenone 5 and the
Aldol reaction; Cyclopentenone.
*
Corresponding author. Tel./fax: +8145 924 5789; e-mail:
ykobayas@bio.titech.ac.jp
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.193

8436
OH
H. P. Acharya, Y. Kobayashi / Tetrahedron Letters 46 (2005) 8435–8438
with slightly acidic conditions for PMB deprotection
O
with DDQ and for oxidation of aldehyde to acid with
NaClO2 in a transformation of the CH2OPMB into
CO2H had not been secured when we started the inves-
tigation. In this letter, we describe results of our study
along this line and application of the PMB manipulation
to synthesis of 14,15-regioisomer (2).
O
OAc
3
4
Synthesis of the epoxy aldehyde 7 delineated in Scheme
2 was executed uneventfully. Thus, reaction of bromide
9 with the dianion derived from propargyl alcohol (NaH
then n-BuLi) followed by reduction afforded allylic alco-
hol 10 in 60% yield. Sharpless10 epoxidation of 10 using
D-(À)-DIPT as a chiral ligand proceeded cleanly, and
the epoxy alcohol 11 was isolated easily after alkaline
hydrolysis of DIPT followed by chromatography. Finally,
oxidation of 11 with SO3Æpyridine produced 711 in good
yield.
O
O
OHC
CO2Me
6
ref. 3
C5H11
5
O
O
present
study
CO2H
O
OHC
CH2OPMB
8
With the new epoxy aldehyde 7 in hand, synthesis of 1
was investigated and results are presented in Scheme 3.
Cyclopentenone 5 was synthesized from 3 (>95% ee) by
using the previous procedure.3 Aldol reaction of the
enolate anion derived from 5 and LDA with aldehyde
7 at À78 °C afforded aldol adduct 12 in 78% yield,
which was a mixture of anti and syn stereoisomers in
ca. 2:1by TLC. Without separation, the aldol mixture
was transformed into the mesylate, which underwent
elimination in the presence of alumina12 to furnish
dienone 1311 in 84% yield in two steps. The C(7)-H
of the undesired stereoisomer 17 possessing the cis
olefin was not detected at the expected13 0.5 ppm up
field region in the 1H NMR spectrum of the crude
dienone 13.
7
Scheme 1. Two routes leading to 5,6-epoxyisoprostane A2 (8).
a-chain aldehyde 6 possessing the necessary epoxy func-
tion. Of the two partners, cyclopentenone 5 was synthe-
sized from 36 by a method developed by us, while epoxy
aldehyde 6 was prepared starting from d-valerolactone
(4) according to the method of Kukhar.7 However, the
synthesis of 6 in our experimentation suffered from
low reproducibility due to the titanium-assisted side
reaction of the CO2Me moiety with the epoxy function
in the asymmetric epoxidation of the corresponding
allylic alcohol and in the accompanying isolation step.8
Attempted modification of work-up by us was fruitless.
Moreover, extremely unstable nature of the epoxy alde-
hyde 6 obtained by oxidation of the epoxy alcohol
imposed high level of discipline for purification before
subjecting to the aldol reaction.
(CH2)4OPMB
O
O
cis
On the other hand, application of the strategy to synthe-
sis of 11,12-epoxy- and 14,15-epoxyisoprostanes A2
phosphorylcholines obviously requires an aldol-compat-
ible equivalent to the CO2R that, after the aldol reaction,
is convertible to the key acid (i.e., epoxyisoprostane A2)
under mild conditions so that the highly reactive olefin-
conjugated epoxide moiety can tolerate.
C5H11
17: cis isomer of 13
The PMB group in dienone 13 was cleaved with DDQ
in wet CH2Cl2 at 0 °C for 45 min to afford alcohol
1411 in 86% yield. Although the conditions were
slightly acidic (pH ca. 4–5), the epoxide moiety was,
to our delight, not at all destroyed. Oxidation of alco-
We selected a PMB ether 79 as an alternative of 6
(Scheme 1), though the compatibility of the epoxide
1) HC≡CCH2OH
NaH, n-BuLi
Br
OPMB
HO
OPMB
THF/HMPA
9
10
2) LiAlH4
60%
SO3·pyridine
Et3N
t-BuOOH
O
7
HO
OPMB
Ti(OPr)4
D-(–)-DIPT
11
93%
95%
Scheme 2. Preparation of epoxyaldehyde 7.

H. P. Acharya, Y. Kobayashi / Tetrahedron Letters 46 (2005) 8435–8438
8437
HO
O
O
1) LDA
1) MsCl, Et3N
OPMB
5
2) 7
2) Al2O3
84%
THF, –78 ˚C
12
78%,
anti : syn = 2 : 1
O
O
SO3·pyridine
O
OR
CHO
Et3N
15
93%
13, R = PMB
14, R = H
DDQ
86%
O2CC15H31
H
HO
(16)
NaClO2
O-PC
O
CO2H
1
Me2C=CHMe
conditions, see text
97%
2,4,6-Cl3C6H2COCl
8
DMAP
53%
Scheme 3. Synthesis of 1.
hol 14 to aldehyde 1511 was investigated with SO3Æpyr-
idine due to mildness and simplicity of the operation.
This reagent with Et3N in CH2Cl2/DMSO at 0 °C
for 2 h proceeded cleanly by TLC. Aldehyde 15 iso-
lated in 93% yield was then subjected to further oxida-
tion with NaClO2. However, the oxidation carried out
under the standard conditions14 (pH 3.6) at 0 °C for
1h afforded a mixture of products containing the
desired acid 8 as a minor product. The oxidation with
NaClO2 requires acidic conditions in theory. Neverthe-
less, the reaction was studied under the neutral condi-
tions at pH 7. Fortunately, the reaction took place
quite cleanly without delay in reaction to furnish acid
811 in 97% yield after chromatography. Finally, the
acid was condensed with optically active lyso-PC (16)
by using the highly efficient reagent system3 (2,4,6-
Cl3C6H2COCl and DMAP) in CH2Cl2 at room tem-
perature for 36 h to afford a mixture of 1 and DMAP
after normal phase chromatography. The mixture was
subsequently subjected to reverse phase chromatogra-
phy to furnish the title compound 1 in 53% yield.
HO
O
O
1) LDA
OPMB
5
2)
O
OHC
(CH2)4OPMB
ent-7
18
1) DDQ
O
2) SO3·pyridine
O
1) MsCl, Et3N
2) Al2O3
Et3N
OPMB
3) NaClO2
Me2C=CHMe
pH 7
19, 55% from 5
O
O
CO2H
16
5,6-diastereomer
of 1
2,4,6-Cl3C6H2COCl
DMAP
56%
20, 70% from 19
ref. 3
Scheme 4. Synthesis of 5,6-diastereomer of 1.
1
The H NMR spectrum of 1 was identical with that
synthesized previously.3
ing allylic alcohol followed by oxidation with SO3Æpyri-
dine, afforded aldol 23 in 66% yield, which was
transformed into the cross-conjugated dienone 2411 ste-
reoselectively in 91% yield. Transformation of 24 to
14,15-epoxyisoprostane A2 (27)11 by the method men-
tioned above proceeded successfully in good overall
yield. Finally, the acid was subjected to condensation
with lyso-PC (16) using 2,4,6-Cl3C6H2COCl/DMAP to
produce 2 in 50% yield after chromatography.
Similarly, enantiomer of 7 (i.e., ent-7) was subjected to
aldol reaction with 5 (Scheme 4). Aldol 18, thus ob-
tained, was converted into dienone 19 in 55% yield from
5. Conversion of the C(1) carbon to CO2H by using the
procedure developed above was executed quite effi-
ciently to furnish 20 in 70% yield. This isoprostane
was transformed into 5,6-diastereomer of 1 in 56%
yield.3,11
In summary, we have utilized the PMBOCH2 group as
the successful substituent of CO2H in the synthesis of
1 and the diastereomer of 1. Moreover, the PMB meth-
od was applied to the first synthesis of 14,15-regioisomer
2. In addition, we found oxidation of the aldehyde to
acid with NaClO2 proceeds unexpectedly under the neu-
tral conditions, which would be useful in organic synthe-
sis of acid labile compounds.
The PMB strategy is highlighted by the synthesis of
14,15-epoxyisoprostane A2 phosphorylcholine (2),2
which is summarized in Scheme 5. The key cyclopente-
none 21 was synthesized again from 3 (>95% ee)
by the method previously reported for synthesis of
D12-PGJ2.9 Aldol reaction with epoxy aldehyde 22,
obtained by asymmetric epoxidation of the correspond-

8438
H. P. Acharya, Y. Kobayashi / Tetrahedron Letters 46 (2005) 8435–8438
OPMB
OPMB
OAc
1) LDA, –78 ˚C
1) MsCl, Et3N
O
2) Al2O3
91%
O
2)
H
C5H11
ref. 9
O
O
OH
OH
21
OHC
23
3
22
66%
OR
SO3·pyridine
16
R
O
O
2
2,4,6-Cl3C6H2COCl
88%
O
DMAP
50%
O
24, R = PMB
25, R = H
26, R = CHO
27, R = CO2H
DDQ
89%
NaClO2
Me2C=CHMe
pH 7
95%
Scheme 5. Synthesis of 2.
J = 7 Hz, 3H), 1.14–1.40 (m, 6H), 1.46–1.78 (m, 6H),
1.97 (q, J = 6 Hz, 2H), 2.20–2.37 (m, 1H), 2.48–2.60 (m,
1H), 2.94–3.02 (m, 1H), 3.37 (dd, J = 8, 2 Hz, 1H), 3.45 (t,
J = 6 Hz, 2H), 3.60–3.69 (m, 1H), 3.79 (s, 3H), 4.42 (s, 2H),
5.28–5.40 (m, 1H), 5.44–5.62 (m, 1H), 6.19 (d, J = 8 Hz,
1H), 6.35 (d, J = 6 Hz, 1H), 6.87 (d, J = 9 Hz, 2H), 7.25 (d,
J = 9 Hz, 2H), 7.54 (dd, J = 6, 2 Hz, 1H); compound 14
(300 MHz) d 0.88 (t, J = 7 Hz, 3H), 1.14–1.44 (m, 6H),
1.48–1.84 (m, 7H), 1.97 (q, J = 6 Hz, 2H), 2.31(dt, J = 1 5,
7 Hz, 1H), 2.55 (dt, J = 15, 7 Hz, 1H), 2.96–3.02 (m, 1H),
3.39 (dd, J = 8, 2 Hz, 1H), 3.60–3.72 (m, 3H), 5.28–5.40
(m, 1H), 5.45–5.58 (m, 1H), 6.19 (d, J = 8 Hz, 1H), 6.35
(dd, J = 6, 2 Hz, 1H), 7.54 (dd, J = 6, 2 Hz, 1H);
compound 15 (300 MHz) d 0.88 (t, J = 7 Hz, 3H), 1.15–
1.40 (m, 6H), 1.54–2.02 (m, 6H), 2.32 (dt, J = 15, 8 Hz,
1H), 2.48–2.62 (m, 3H), 2.95–3.02 (m, 1H), 3.39 (dd, J = 8,
2 Hz, 1H), 3.62–3.70 (m, 1H), 5.27–5.38 (m, 1H), 5.45–5.58
(m, 1H), 6.18 (d, J = 8 Hz, 1H), 6.35 (dd, J = 6, 2 Hz, 1H),
7.54 (dd, J = 6, 2 Hz, 1H), 9.79 (t, J = 1Hz, 1H);
compound 24 (300 MHz) d 0.89 (t, J = 7 Hz, 3H), 1.20–
1.75 (m, 12H), 1.97 (q, J = 6 Hz, 2H), 2.22–2.40 (m, 1H),
2.48–2.64 (m, 1H), 2.99 (dt, J = 1.5, 5 Hz, 1H), 3.37 (dd,
J = 8, 1.5 Hz, 1H), 3.42 (t, J = 6 Hz, 2H), 3.62–3.70 (m,
1H), 3.80 (s, 3H), 4.42 (s, 2H), 5.28–5.40 (m, 1H), 5.44–5.56
(m, 1H), 6.19 (d, J = 8 Hz, 1H), 6.34 (dd, J = 6, 2 Hz, 1H),
6.87 (d, J = 9 Hz, 2H), 7.25 (d, J = 9 Hz, 2H), 7.52 (dm,
J = 6 Hz, 1H); compound 27 (300 MHz) d 0.89 (t,
J = 7 Hz, 3H), 1.2–1.8 (m, 10H), 1.98–2.14 (m, 2H),
2.24–2.38 (m, 3H), 2.48–2.64 (m, 1H), 2.97 (dt, J = 1.5,
5 Hz, 1H), 3.36 (dd, J = 8, 1.5 Hz, 1H), 3.63–3.73 (m, 1H),
5.32–5.58 (m, 2H), 6.22 (d, J = 8 Hz, 1H), 6.36 (dd, J = 6,
2 Hz, 1H), 7.53 (dm, J = 6 Hz, 1H); 5,6-diastereomer of 1
(500 MHz, CHCl3 in CDCl3 at 7.24 ppm) d 0.86 (t,
J = 7 Hz, 6H), 1.1–2.7 (m, 44 H), 2.93–3.05 (m, 1H), 3.19–
3.43 (m, 10H), 3.58–4.43 (m, 9H), 5.14–5.24 (m, 1H), 5.26–
5.38 (m, 1H), 5.45–5.54 (m, 1H), 6.07 (d, J = 9 Hz, 1H),
6.33 (dd, J = 6, 2 Hz, 1H), 7.54 (dd, J = 6, 2 Hz, 1H).
12. Yamada, K.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1998, 63, 3666–3672.
Acknowledgements
We thank Professor Tomoko Matsuda for helpful dis-
cussion. This work was supported by a Grant-in-Aid
for Scientific Research from the Ministry of Education,
Science, Sports, and Culture, Japan, and the Sasakawa
Scientific Research Grant from The Japan Science
Society.
References and notes
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11. 1H NMR (CDCl3) spectra: compound 7 (300 MHz) d 1.50–
1.78 (m, 6H), 3.13 (dd, J = 6, 2 Hz, 1H), 3.22 (dt, J = 2,
6 Hz, 1H), 3.45 (t, J = 6 Hz, 2H), 3.80 (s, 3H), 4.43 (s, 2H),
6.88 (d, J = 9 Hz, 2H), 7.25 (d, J = 9 Hz, 2H), 9.00 (d,
J = 6 Hz, 1H); compound 13 (300 MHz) d 0.88 (t,