Total synthesis of Δ12-PGJ2, 15-deoxy-Δ12,14-PGJ2, and related compounds

Article abstract of DOI:10.1016/j.tetlet.2003.11.143

A key cyclopentenone possessing the α-chain was synthesized from TBS ether of 4-cyclopentene-1,3-diol monoacetate, and submitted to aldol reaction at the α′-position with the ω-chain aldehydes followed by dehydration to produce the title compounds. In a similar manner, 5-dehydro compounds (acetylene analogues) were synthesized successfully. In addition, palladium-catalyzed reaction of 4-cyclopentene-1,3-diol monoacetate with methyl malonate, the first step of the synthesis, was improved to afford the product in high yield by using t-BuOK or LDA in place of NaH.

Full text of DOI:10.1016/j.tetlet.2003.11.143

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 1199–1202
Total synthesis of D12-PGJ2, 15-deoxy-D12;14-PGJ2, and
related compounds
Hukum P. Acharya and Yuichi Kobayashi*
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
Received 10 October 2003; revised 26 November 2003; accepted 28 November 2003
Abstract—A key cyclopentenone possessing the a-chain was synthesized from TBS ether of 4-cyclopentene-1,3-diol monoacetate,
and submitted to aldol reaction at the a0-position with the x-chain aldehydes followed by dehydration to produce the title com-
pounds. In a similar manner, 5-dehydro compounds (acetylene analogues) were synthesized successfully. In addition, palladium-
catalyzed reaction of 4-cyclopentene-1,3-diol monoacetate with methyl malonate, the first step of the synthesis, was improved to
afford the product in high yield by using t-BuOK or LDA in place of NaH.
Ó 2003 Elsevier Ltd. All rights reserved.
D12-Prostaglandin J2 (D12-PGJ2) and 15-deoxy-D12;14
-
CO2H
CO2H
PGJ2 are products derived from PGJ2 in vivo,1 and were
reported in the 1980s to possess important biological
activities.2 In the 1990s these compounds were shown to
be ligands for peroxisome proliferator-activated recep-
tors (PPARs), the nuclear receptors, which regulate gene
transcription directly.3;4 In such studies, the compounds
have been supplied by companies.5;6 However, total
synthesis of the compounds was not published until
quite recently,7 though a synthetic effort apparently will
accelerate biological study. Recently, synthesis of D7-
PGA1 methyl ester was achieved in our laboratory.8 The
assured aldol reaction at the a0 position of enones and
the structural similarity between D7-PGA1 methyl ester
and the title compounds encouraged us to develop
synthetic strategy through aldol reaction of cyclopent-
enone 6 with aldehyde 7 (for D12-PGJ2, Scheme 1) or 2-
octenal (15-deoxy-D12;14-PGJ2 ) to assemble the core
structures. Herein, we present a synthesis of D12-PGJ2
(2), 15-deoxy-D12;14-PGJ2 (3), and 5-dehydro analogues
(Fig. 1).
12
O
O
O
O
OH
OH
∆
12-PGJ2 (2)
PGJ2 (1)
CO2H
CO2H
5
15
OH
15-deoxy-∆12,14-PGJ2 (3)
5-dehydro-∆ -PGJ2 (4)
12
Figure 1. PGJ2 and related PGs.
(1) α-chain
OAc
CO2H
(3) aldol
O
RO
(2) [O]
6
C5H11
5 (R = H, TBS)
(1R)-isomer
OHC
OTBS
ω-chain (7)
In order to realize the approach outlined above, we
initially examined synthesis of the key intermediate 10
depicted in Scheme 2 by a sequence through alcohol 8a.
Palladium-catalyzed reaction of monoacetate 5a with
12
∆
-PGJ2 (2)
Scheme 1. Strategy for synthesis of D12-PGJ2.
Keywords: D12-PGJ2; 15-Deoxy-D12;14-PGJ2; 4-Cyclopentene-1,3-diol
monoacetate; Palladium catalyst; Aldol reaction; Cyclopentenone.
* Corresponding author. Tel./fax: +81-45-924-5789; e-mail: ykobayas@
bio.titech.ac.jp
the anion derived from methyl malonate (2–2.5 equiv)
and NaH (2 equiv) in THF at 40–50 °C, according to
Deardorff,9 produced 8a in varying yields of ca. 50–70%
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.143

1200
H. P. Acharya, Y. Kobayashi / Tetrahedron Letters 45 (2004) 1199–1202
CO2Me
CO2Me
CO2Me
OPMB
R
CO2Me
a
c
5a, R = H
5b, R = TBS
89%
base, Pd cat.
TBSO
RO
TBSO
12
84%
see Text and
Table 1
8a, R = H
8b, R = TBS
9, R = CO2Me
10, R = CHO
b
89%
OPMB
OPMB
g,h
d,e
f
88%
H
O
O
OH
13
OTBS
14 anti isomer (β-OH)
syn isomer (α-OH)
OR
e
R
k
∆
12-PGJ2 (2)
92%
94%
O
O
OTBS
OTBS
15, R = PMB, 59% from 13
16, R = H,91%
17, R = CHO
18, R = CO2H
j
i
89%
Scheme 2. Synthesis of D12-PGJ2. Reagents and conditions: (a) KI, DMI/H2O (10:1), 130 °C; (b) DIBAL, CH2Cl2, )78 °C; (c) [Ph3P(CH2)5 OPMB]þ
Brꢀ (11) (2.0 equiv), NaN(TMS)2 (2.0 equiv), )70 °C to rt; (d) TBAF; (e) PCC; (f) LDA (2.0 equiv), )78 °C, THF then 7 (1.2 equiv), )78 °C; (g) MsCl,
Et3N, 0 °C; (h) Al2O3, CH2Cl2; (i) DDQ, CH2Cl2/H2O (19:1); (j) NaClO2 (1.5 equiv), MeCH ¼ C(Me)2 (10 equiv), t-BuOH, phosphate buffer; (k) HF/
MeCN (1:19).
Table 1. Palladium-catalyzed reaction with methyl malonatea
Entry
Substrate
Base
Time (h)
Temperature (°C)
Yield (%)
1
2
3
4
5
6
7
8
5a
5a
5a
5a
5b
5b
5b
5b
NaH
MeONa
LDA
2
rt
69b;c
71b
83b
90
2
rt
1.5
2
rt
t-BuOK
NaH
rt
4
50d
50d
rt
66
87
MeONa
LDA
t-BuOK
3
3
91
93
3
50d
a Reactions were carried out with methyl malonate (2.2 equiv) in the presence of Pd(PPh3)4 (5 mol %) in THF.
b An unidentified by-product was also produced.
c A maximum yield among several repeated reactions is given. See the text for more information.
d No reaction at room temperature for 1 h was monitored by TLC.
after separation of the remaining malonate by using a
somewhat long silica gel column due to close mobilities
on TLC. Reactions attempted in polar solvents, at lower
temperatures, and/or with additional ligand (PPh3) for
the palladium catalyst (Pd(PPh3)4) did not improve the
yield and reproducibility. In addition, after decarbox-
ylation of 8a, tedious chromatography was again
necessitated for purification of the crude product con-
taining the polar solvent used (such as DMF, 1,3-di-
methyl-2-imidazolidinone (DMI), 1,3-dimethyl-3,4,5,6-
tetrahydro-2(1H)-pyrimidinone (DMPU), etc.). For
these reasons, we re-examined the reactions leading to
10.
94% yield, since separation of product 8b and methyl
malonate is easier work than that of alcohol 8a and the
malonate. Reaction with LDA proceeded at room
temperature, while t-BuOK required a higher tempera-
ture of 50 °C, in both cases producing 8b in high yields
(entries 7 and 8). With regard to the product yields,
reaction temperatures, and preparation/handling of the
bases, we do recommend both bases. Decarboxylation
of 8b with KI in wet DMI proceeded well, and isolation/
purification of TBS ether 9 from DMI was accomplished
quite easily because of the lower polarity of 9. Finally,
reduction of 9 with DIBAL at )78 °C furnished alde-
hyde 10 in 89% yield.
Among the bases listed in Table 1 (MeONa, LDA,
t-BuOK), LDA and t-BuOK were found to be the choice.
The reactions with these bases took place at room
temperature to afford product 8a in good yields after
chromatography (entries 3 and 4). We then applied these
bases to TBS ether 5b, derived from 5a by silylation in
Wittig reaction of aldehyde 10 with the anion derived
from [Ph3P(CH2)5OPMB]þBrꢀ (11) and NaN(TMS)2 at
room temperature, according to the literature proce-
dure,10 proceeded with high stereoselectivity to afford cis
olefin 12 in 84% yield. Setting up the reaction initially at
low temperature (ca. )70 °C) was important since use of

H. P. Acharya, Y. Kobayashi / Tetrahedron Letters 45 (2004) 1199–1202
1201
NMR spectroscopy.14 Without separation, the mixture
was converted to mesylates, which were exposed to
Al2O3 to afford dienone 15 in 59% yield from enone 13.
The stereochemistry of the newly formed olefin was
assigned as depicted (trans) by the literature analogy8;15
(H-C(13): d 6.59 ppm, t, J ¼ 7:5 Hz), while the corre-
sponding cis olefin (structure not shown) was not
O
a
b
HO
HO
C5H11
HO
C5H11
82%
88%
19
20
TBSO
C5H11
c
C5H11
OH
d
94%
76%
OTBS
21
22
1
detected by H NMR spectroscopy.
HO
C5H11
C5H11
OHC
e
The remaining transformation to D12-PGJ2 was func-
tional group manipulation, which was accomplished
successfully. Briefly, the PMB protective group of 15
was removed with DDQ in wet CH2Cl2 to afford alcohol
16, which was converted to acid 18 through aldehyde 17
in 81% yield from 15. Finally, deprotection of the TBS
group with HF in MeCN afforded D12-PGJ2 in 92%
yield. Direct oxidation of 16 with PDC in DMF at room
temperature overnight produced a mixture of products.
The 1H NMR spectrum of synthetic 2 was identical with
that reported (d 5–8 ppm)1a and also provided by Ono
Pharmaceutical Co., Ltd.
OTBS
23
OTBS
94%
7
Scheme 3. Preparation of aldehyde 7. Reagents and conditions: (a)
t-BuOOH (1.4 equiv), l-(+)-DIPT (0.3 equiv), Ti(i-PrO)4 (0.25 equiv),
MS 4A; (b) Red-Al (2.0 equiv), THF; (c) TBSCl; (d) PPTS (1.2 equiv),
EtOH/CH2Cl2 (1:1); (e) PCC.
0 °C at the beginning resulted in production of a minor
compound detected by 13C NMR spectroscopy (ca. 5%),
which is probably responsible for the trans olefin isomer.
Next, the two-step conversion of 12 into enone 13 pro-
ceeded smoothly. Enone 13 is a compound, which is
corresponding to the key intermediate 6 depicted in
Scheme 1.
In a similar manner, aldol reaction of 13 with (E)-2-
octenal followed by the same transformation as
described above produced 15-deoxy-D12;14-PGJ2 (3)
efficiently. The structure of 3 thus synthesized was
confirmed by comparison of the 1H NMR (d 5–8 ppm)1a
and 13C NMR (all peaks)7 spectra with those reported.16
Although the enantiomer is a known compound,11
aldehyde 7 (Scheme 1), the aldol partner of enone 13,
was synthesized from commercially available alcohol 19
Since structural analogues, in general, have been
important tools in pursuing biological investigation with
various purposes, synthesis of 5-dehydro analogue of
D12-PGJ2 was also investigated. As shown in Scheme 4,
acetylene 24 was synthesized from aldehyde 10 by the
Corey–Fuchs method,17 and was submitted to alkylation
with Br(CH2)4 OPMB to afford 25, which upon desilyl-
ation with TBAF produced alcohol 26 in 78% yield.
Oxidation produced the key enone 27 in good yield. The
remaining transformation of enone 27 to 5-dehydro-D12-
PGJ2 (4) was carried out through the same transfor-
mation as that shown in Scheme 2 for D12-PGJ2 (2).
24
D
through epoxy alcohol 2012 (½aꢁ )43° (c 0.45, CHCl3);
27
25
lit.12 ½aꢁ )42.7° (c 4.7, CHCl3)) in five steps in 48%
D
overall yield (Scheme 3): ½aꢁ +6.7° (c 0.21, CHCl3) for
D
24
D
7 synthesized; lit.11 ½aꢁ )5.0° (c 1.0, CHCl3) for the
enantiomer. Synthetic advantages of this method are as
follows. Epoxide ring opening proceeded with 22:1
regioselection by H NMR spectroscopy to afford 21 in
1
good yield. Regioselective desilylation of the bis-silyl
ether 22 to mono alcohol 23 was accomplished in 76%
yield with PPTS (1.2 equiv), which allowed us to bypass
the rather conventional protection/deprotection steps.13
Aldol reaction of enone 13 with aldehyde 7 afforded a
1
mixture of anti and syn isomers in a 3:1 ratio by H
In a similar way, 5-dehydro analogue of 3 (structure not
shown) was also accomplished.
OPMB
OPMB
c
e
a,b
10
94%
69%
RO
O
TBSO
25, R = TBS
26, R = H
27
24
d
78% from 24
OPMB
g,h
43% from 27
R
l
f
5-dehydro-∆12-PGJ2 (4)
95%
H
O
O
OH
OTBS
OTBS
29, R = CH2OPMB
30, R = CO2H
i,j,k
75%
28
Scheme 4. Synthesis of acetylene analogue of D12-PGJ2. Reagents and conditions: (a) PPh3 (4.0 equiv), CBr4 (2.0 equiv), 0 °C, 30 min; (b) n-BuLi
(2.5 equiv), )78 °C, 1 h; (c) n-BuLi (1.2 equiv), PMBO(CH2)4Br (1.2 equiv), THF/DMPU (4:1), )78 °C to rt; (d) TBAF; (e) PCC; (f) LDA (2.0 equiv)
then 7 (1.2 equiv), )78 °C; (g) MsCl, Et3N, 0 °C, 1 h; (h) Al2O3; (i) DDQ; (j) PCC; (k) NaClO2 (1.5 equiv), MeCH ¼ C(Me)2, t-BuOH, phosphate
buffer (pH 3.6); (l) HF/MeCN (1:19).

1202
H. P. Acharya, Y. Kobayashi / Tetrahedron Letters 45 (2004) 1199–1202
In summary, we have succeeded in synthesis of D12-PGJ2
(2), 15-deoxy-D12;14-PGJ2 (3), and acetylene analogues
based on an aldol strategy starting with the TBS ether of
monoacetate 5a. Since preparation of 5a has been
established, high efficiency and flexibility of the present
method will allow synthesis of analogues other than that
mentioned in the text, thus spurring biological investi-
gation. In addition, we established conditions for Pd-
catalyzed reaction of 5 (R ¼ H, TBS) with malonate
anion, which would encourage use of products 8 (R ¼ H,
TBS) as key compounds in various fields.
Dussault, I.; Forman, B. M. Prostaglandins Other Lipid
Mediat. 2000, 62, 1–13.
5. Cayman supplies D12-PGJ2 and 5-deoxy-D12;14-PGJ2, the
latter probably being synthesized by degradation of
PGD2,6 while Ono Pharmaceutical has gifted D12-PGJ2
to research groups.
6. Base-catalyzed decomposition of PGD2 produces five
compounds, from which 15-deoxy-D12;14-PGJ2 is isolated
as an olefinic mixture at C(14)–(15): Maxey, K. M.;
Hessler, E.; MacDonald, J.; Hitchingham, L. Prostaglan-
dins Other Lipid Mediat. 2000, 62, 15–21.
7. The synthesis, however, suffers from low efficiency in
several steps: Bickley, J. F.; Jadhav, V.; Roberts, S. M.;
Santoro, M. G.; Steiner, A.; Sutton, P. W. Synlett 2003,
1170–1174.
8. Kobayashi, Y.; Murugesh, M. G.; Nakano, M.; Takahisa,
E.; Usmani, S. B.; Ainai, T. J. Org. Chem. 2002, 67, 7110–
7123.
9. Deardorff, D. R.; Linde, R. G., II, Martin, A. M.;
Shulman, M. J. J. Org. Chem. 1986, 54, 2759–2762.
10. Bestmann, H. J.; Stransky, W.; Vostrowsky, O. Chem.
Ber. 1976, 109, 1694–1700; Viala, J.; Santelli, M. Synthesis
1988, 395–397.
Acknowledgements
This work was supported by a Grant-in-Aid for Scien-
tific Research from the Ministry of Education, Science,
Sports, and Culture, Japan. We thank Ono Pharma-
ceutical Co., Ltd. for providing us 1H NMR spectrum of
D12-PGJ2.
11. Kiyooka, S.; Hena, M. A. J. Org. Chem. 1999, 64, 5511–
5523.
12. Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.;
Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987,
109, 6765–6780.
References and notes
13. In contrast to the previous synthesis of the enantiomer,11
the present method seems convenient with regard to the
total number of steps including preparation of the aldol
partner and the catalyst.
1. (a) Fitzpatrick, F. A.; Wynalda, M. A. J. Biol. Chem.
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1988, 263, 16619–16625.
14. The stereochemistries of the isomers were tentatively
determined by comparison of Rf values and 1H NMR
chemical shifts with those of related aldol products.8
15. (a) Zhu, J.; Yang, J.-Y.; Klunder, A. J. H.; Liu, Z.-Y.;
Zwanenburg, B. Tetrahedron 1995, 51, 5847–5870; (b)
Takeda, K.; Nakajima, A.; Yoshii, E. Synlett 1997, 255–
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16. The 1H NMR spectrum of 3 at 500 MHz is presented
below since the spectrum measured at 300 MHz was
insufficient for determination of the olefin geometry at
C(14)–(15): 1H NMR (500 MHz, CDCl3) d 0.89 (t,
J ¼ 7 Hz, 3H), 1.22–1.36 (m, 4H), 1.39–1.49 (m, 2H),
1.62–1.72 (m, 2H), 2.04 (q, J ¼ 7 Hz, 2H), 2.18–2.37 (m,
5H), 2.56–2.62 (m, 1H), 3.56–3.61 (m, 1H), 5.33–5.40 (m,
1H), 5.42–5.49 (m, 1H), 6.23 (dt, J ¼ 15, 7 Hz, 1H), 6.31
(ddt, J ¼ 15, 11, 1 Hz, 1H), 6.36 (dd, J ¼ 6, 2 Hz, 1H),
6.95 (d, J ¼ 11 Hz, 1H), 7.47 (ddd, J ¼ 6, 2.5, 1 Hz, 1H).
1
Note that the reference for the H NMR spectrum of 3 is
not indicated in Ref. 7, in which the authors state
accordance of the 1H NMR spectrum of 3 with that
reported.
4. Reviews: (a) Bishop-Bailey, D.; Wray, J. Prostaglandins
Other Lipid Mediat. 2003, 71, 1–22; (b) Straus, D. S.;
Glass, C. K. Med. Res. Rev. 2001, 21, 185–210; (c)
17. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 13,
3769–3772.