Synthesis of Δ2-OPC-8:0 and OPC-6:0

Article abstract of DOI:10.1055/s-2004-834794

Δ²-OPC-8:0 (6), designed as a β-oxidation-insensitive analogue, was synthesized starting with 4-cyclopentene-1,3-diol monoacetate (5) in a stereocontrolled manner. The C(3)-C(8) moiety was first attached to the cyclopentene ring by using the Cu

Full text of DOI:10.1055/s-2004-834794

2582
LETTER
Synthesis of D2-OPC-8:0 and OPC-6:0
Synthesis of
D
-O
P
2 uC-8:0 and
O
i
PC-6:0chi Kobayashi,* Kaori Yagi, Takayuki Ainai
Department of Biomolecular Engineering, Tokyo Institute of Technology, 4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8501, Japan
Fax +81(45)9245789; E-mail: ykobayas@bio.titech.ac.jp
Received 12 July 2004
The two side chains on the five-membered ring of these
Abstract: D2-OPC-8:0 (6), designed as a b-oxidation-insensitive
metabolites are oriented cis fashion, which restricts com-
patibility of reactions to be used for synthesis due to ther-
analogue, was synthesized starting with 4-cyclopentene-1,3-diol
monoacetate (5) in a stereocontrolled manner. The C(3)–C(8)
modynamic instability. Consequently, the synthetic
methodologies developed for the prostaglandins which
are based on the enolate chemistry would be inadequately
applicable to synthesis of these metabolites.10 Recently,
our group developed copper-catalyzed installation of an
alkyl chain onto 4-cyclopentene-1,3-diol monoacetate
(5)11 and the reaction was successfully applied to synthe-
sis of 12-oxo-PDA and OPC-8:0 in an enolate-free man-
ner.12 Herein, we report synthesis of D2-OPC-8:0 (6) as a
b-oxidation-insensitive analogue by analogy of the D2-
prostaglandins13 (Figure 2). The analogue would be useful
for evaluation of OPC-8:0 (2).14 In addition, we describe
the first synthesis and characterization of OPC-6:0 (3).
moiety was first attached to the cyclopentene ring by using the Cu-
catalyzed SN2-type reaction with TBDPSO(CH2)6MgCl and was
later converted into the full side chain by Wittig reaction. In
addition, OPC-6:0 (3) was synthesized.
Key words: allylations, asymmetric synthesis, copper, cuprates,
stereoselective synthesis
The linolenic acid cascade in plants leading to epi-jas-
monic acid produces 12-oxophytodienoic acid (12-oxo-
PDA) as the first metabolite possessing a five-membered
ring, which is further transformed into 3-oxo-2-cis-(pent-
2Z-enyl)cyclopentyloctanoic acid (OPC-8:0) by the re-
ductase (Figure 1).1,2 Subsequently, b-oxidation follows
three times to produce sequentially OPC-6:0, OPC-4:0,
and finally epi-jasmonic acid. It has become clear that epi-
jasmonic acid is the key compound in the development,
physiology, and defense of plants. These findings have
suggested a biological function of the upper metabolites in
the cascade. Indeed, tendril coiling response,3 induction of
secondary metabolites,4 up-regulation of several genes,5
and expression of the specific genes6 have been reported
for 12-oxo-PDA. However, a biological profile of OPC-
n:0 (n = 8, 6, 4) has not been studied, probably because of
unavailability of these compounds in chemically pure
form and in sufficient quantity.7,8 A biological approach to
these metabolites seems to suffer from low product selec-
tivity and efficiency, because of the fairly fast b-oxidation
of OPC-n:0 to its daughter OPC.9
2
OAc
CO2H
HO
O
5
∆2-OPC-8:0 (6)
Figure 2 Target and starting compounds of the present study.
Our approach to D2-OPC-8:0 (6) is summarized in
Scheme 1. The key intermediate, diol 9, possessing the
two carbon shorter side chain [C(3)–C(8)] was prepared
from 5 through aldehyde 7 and lactone 8, and the full side
chain was constructed by Horner–Emmons–Wittig reac-
tion. The results of this investigation are delineated in
Scheme 2.
According to our protocol to execute the SN2-type
reaction, 3 equivalents of RMgCl was required with
CuCN catalyst to complete the reaction with mono-
acetate 5. To reduce the quantity (3 equivalents) of
TBDPSO(CH2)6MgCl, the hydroxyl group of 5 (>99%
ee), prepared by the literature method,15 was initially
quenched with 1 equivalent of t-BuMgCl at 0 °C. Sub-
sequently, 2 equivalents of TBDPSO(CH2)6MgCl was
added at –18 °C to produce 10 in 81% yield with 92%
regioselectivity after 4 hours. Mitsunobu inversion with
HOAc, DIAD, and PPh3 in toluene at –78 °C followed by
hydrolysis afforded the alcohol (structure not shown) in
83% yield (2 steps). Claisen rearrangement of the alcohol
with CH2=CHOEt at 180–190 °C for 3 days furnished
aldehyde 11, which was converted into acid 12 in 86%
yield. Lactonization with KI3 followed by reaction with
Bu3SnH under the radical conditions afforded lactone 13,
which is equal to the key intermediate 8 proposed in
Scheme 1.
CO2H
CO2H
12
O
O
12-oxo-PDA (1)
OPC-8:0 (2)
CO2H
CO2H
11
O
O
OPC-6:0 (3)
epi-jasmonic acid (4)
Figure 1 Some metabolites of linolenic acid.
SYNLETT 2004, No. 14, pp 2582–2584
Advanced online publication: 20.10.2004
DOI: 10.1055/s-2004-834794; Art ID: U20004ST
© Georg Thieme Verlag Stuttgart · New York
2
2
.1
1
.2
0
0
4

LETTER
Synthesis of D2-OPC-8:0 and OPC-6:0
2583
PCC
(1.5 equiv)
(1) C6 side chain
via SN2 mode
OAc
(CH2)5CH2OR
9
5–10 °C
HO
CHO
(2) Inversion
5
(3) Claisen
(CH2)5CH2OH
(CH2)5CHO
(CH2)5CHO
7
rearrangement
+
+
R
R
R
(CH2)5CH2OR
O
HO
O
23
21
0%
22
70%
30%
O
Scheme 3 Attempted oxidation of diol 9, R = (Z)-CH2CH=CHEt.
Wittig
O
8
H.-E.-Wittig
oxidation of 17 followed by Horner–Emmons–Wittig re-
action under the Masamune conditions afforded the a,b-
unsaturated ester 18. Desilylation of 18 followed by hy-
drolysis of the resulting alcohol 19 gave hydroxyl acid 20
in 79% yield from 18. Finally, Jones oxidation furnished
D2-OPC-8:0 (6) in 90% yield. Analytical data: IR (neat):
3196, 1738, 1699 cm–1. 1H NMR: d = 0.96 (t, J = 7.5 Hz,
3 H), 1.1–2.4 (m, 20 H), 5.36–5.46 (m, 2 H), 5.83 (d,
J = 16 Hz, 1 H), 6.98–7.13 (dt, J = 16, 7 Hz, 1 H).17
(CH2)5CH2OH
∆2-OPC-8:0 (6)
HO
9
Scheme 1 Summary of D2-OPC-8:0 synthesis.
To complete the cis-pentenyl side chain, lactone 13 was
hydrolyzed into hydroxyl acid, which upon esterification
and silylation of the OH group afforded 14 in 80% yield.
Reduction of ester 14 to aldehyde was followed by Wittig
reaction with Ph3P=CHEt to furnish cis-olefin 15, which
upon deprotection afforded the key diol 9 in quantitative
yield.
(CH2)6OH
CrO3, H+
OPC-6:0 (3)
68%
OH
9
Equation 1
In order to obtain aldehyde 21 for synthesis of D2-OPC-
8:0 (6), direct oxidation of diol 9 with PCC was attempted
(Scheme 3). However, the oxidation produced a mixture
of 22 and 23. To avoid this result, we then studied a trans-
formation shown in Scheme 2. Silylation of diol 9 with
TBSCl afforded 16, which upon exposure to PPTS in
EtOH and CH2Cl2 (1:1) at 5–10 °C for 24 hours success-
fully afforded primary alcohol 17 in 89% yield.16 PCC
CO2H
LiOH aq
OPC-6:0 (3)
r.t., 2.5 h
8%
11
11-epi-OPC-6:0 (24)
O
Equation 2
1) AcOH
DIAD, PPh3
1) tert-BuMgCl
OAc
(CH2)6OTBDPS
(CH2)6OTBDPS
1) KI3, NaHCO3
(1 equiv)
HO
HO
COX
2) ClMg(CH2)6OTBDPS
(2 equiv)
2) Bu3SnH
AIBN
2) LiOH aq
3) CH2=CHOEt / Hg2+
5
10, 81%
11, X = H
12, X = OH
71% from 10
83%
CuCN (cat.)
CrO3
> 99% ee
(CH2)6OTBDPS
(CH2)6OR2
(CH2)6OTBDPS
CO2Me
1) DIBAL
TBSCl
98%
1) LiOH aq
2) Ph3PC3H7Br
NaN(TMS)2
85%
2) CH2N2
3) TESCl
R1O
O
TESO
80%
15, R1 = TES, R2 = TBDPS
9, R1 = R2 = H
14
O
13
TBAF
99%
(CH2)6OR2
CO2R2
CrO3, H+
1) PCC
∆2-OPC-8:0 (6)
2) (EtO)2P(=O)CH2CO2Et
90%
LiCl, DBU
76%
R1O
R1O
18, R1 = TBS, R2 = Et
16, R1 = R2 = TBS
AcOH aq
LiOH aq
PPTS
91%
17, R1 = TBS, R2 = H
19, R1 = H, R2 = Et
20, R1 = R2 = H, 79% (2 steps)
Scheme 2 Synthesis of D2-OPC-8:0.
Synlett 2004, No. 14, 2582–2584 © Thieme Stuttgart · New York

2584
Y. Kobayashi et al.
LETTER
(9) (a) Vick, B. A.; Zimmerman, D. C. Biochem. Biophysic. Res.
Commun. 1983, 111, 470. (b) Vick, B. A.; Zimmerman, D.
C. Plant Physiol. 1984, 75, 458. (c) Matsuura, H.; Ohmori,
F.; Kobayashi, M.; Sakurai, A.; Yoshihara, T. Biosci.
Biotechnol. Biochem. 2000, 64, 2380.
Next, the key diol 9 used above was subjected to Jones ox-
idation to afford OPC-6:0 (3) in 68% yield (Equation 1):
[a]D23 +43 (c 0.274, CHCl3). IR (neat): 3080, 1738, 1709
cm–1. 1H NMR (300 MHz, CDCl3): d = 0.95 (t, J = 7.5 Hz,
3 H), 1.18–1.48 (m, 8 H), 1.56–1.72 (m, 2 H), 1.76–2.42
(m, 10 H), 5.27–5.49 (m, 2 H). 13C NMR (75 MHz,
CDCl3): d = 14.2, 20.7, 22.6, 24.7, 24.8, 27.4, 28.0, 29.3,
33.9, 35.4, 38.7, 53.7, 126.2, 133.1, 179.2, 220.3. In addi-
tion, 3 was exposed to aqueous LiOH for epimerization at
C(11) (Equation 2). The 11-epimer of 3 (i.e., 24) thus syn-
thesized in 81% yield was identical with the racemic 11-
epimer reported in the literature8c by 1H NMR, 13C NMR,
and IR spectroscopy. Purity of OPC-6:0 (3) was >95% by
calculation of the peak heights at d = 38.7 and 53.7 ppm
for 3 and d = 41.2 and 55.1 ppm for 24, respectively, in the
13C NMR spectrum of 3.18
(10) (a) Collins, P. W.; Djuric, S. W. Chem. Rev. 1993, 93, 1533.
(b) Crimmins, M. T. Tetrahedron 1998, 54, 9229.
(c) Noyori, R.; Suzuki, M. Angew. Chem., Int. Ed. Engl.
1984, 23, 847. (d) Noyori, R.; Suzuki, M. Science 1993,
259, 44. (e) Harre, M.; Raddatz, P.; Walenta, R.;
Winterfeldt, E. Angew. Chem., Int. Ed. Engl. 1982, 21, 480.
(11) Ito, M.; Matsuumi, M.; Murugesh, M. G.; Kobayashi, Y. J.
Org. Chem. 2001, 66, 5881.
(12) Ainai, T.; Matsuumi, M.; Kobayashi, Y. J. Org. Chem. 2003,
68, 7825.
(13) (a) Wakatsuka, H.; Kori, S.; Hayashi, M. Prostaglandins
1974, 8, 341. (b) Hirata, K.; Horie, T. Cancer Chemother.
Pharmacol. 2003, 51, 216. (c) Gao, F.; Tomitori, H.;
Igarashi, K.; Horie, T. Life Sciences 2002, 72, 669.
(14) Synthesis of 3-oxa analogue of 13-epi-OPC-8:0 methyl ester
(trans isomer) in racemic form was reported: see ref. 4a.
(15) Sugai, T.; Mori, K. Synthesis 1988, 19.
Acknowledgment
We thank Professor Hiroyuki Ohta of Tokyo Institute of Technolo-
gy, Department of Biological Sciences for helpful information to
start this project. This work was supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science,
Sports, and Culture, Japan.
(16) The conditions used here for the selective desilylation are
also successful in other cases.
(17) Spectral data (1H NMR at 300 MHz and 13C NMR at 75 MHz
in CDCl3) and specific rotations of the intermediates.
Lactone 13: [a]D24 –5.7 (c 0.53, CHCl3). IR (neat): 1771,
1111 cm–1. 1H NMR: d = 0.97 (s, 9 H), 1.10–1.36 (m, 10 H),
1.42–2.20 (m, 5 H), 2.35 (dd, J = 19, 6 Hz, 1 H), 2.42 (dd,
J = 19, 10 Hz, 1 H), 2.78–2.92 (m, 1 H), 3.58 (t, J = 6 Hz, 2
H), 4.95 (t, J = 6 Hz, 1 H), 7.33– 7.43 (m, 6 H), 7.63–7.69
(m, 4 H). 13C NMR: d = 19.3, 25.7, 26.9, 28.5, 28.7, 28.9,
29.5, 30.6, 32.5, 33.1, 40.5, 42.8, 63.9, 86.2, 127.6, 129.6,
134.2, 135.6, 178.1. Ester 14: [a]D23 +0.10 (c 1.98, CHCl3).
IR (neat): 1741, 1112 cm–1. 1H NMR: d = 0.55 (q, J = 8 Hz,
6 H), 0.93 (t, J = 8 Hz, 9 H), 1.04 (s, 9 H), 1.08–1.93 (m, 15
H), 2.20 (dd, J = 15, 5.5 Hz, 1 H), 2.32–2.44 (m, 1 H), 2.46
(dd, J = 15, 7.5 Hz, 1 H), 3.64 (t, J = 6.5 Hz, 2 H), 3.65 (s,
3 H), 4.17–4.24 (m, 1 H), 7.33–7.43 (m, 6 H), 7.64–7.70 (m,
4 H). 13C NMR: d = 4.9, 6.9, 19.3, 25.9, 26.9, 28.1, 28.4,
29.5, 29.7, 31.7, 32.7, 32.8, 39.6, 43.8, 51.4, 64.1, 75.0,
127.6, 129.6, 134.3, 135.7, 174.9. Olefin 15: [a]D25 +2.2 (c
0.368, CHCl3). IR (neat): 1428, 1112, 701 cm–1. 1H NMR: d
= 0.56 (q, J = 8 Hz, 6 H), 0.95 (t, J = 8 Hz, 9 H), 0.96 (t,
J = 7.5 Hz, 3 H), 1.04 (s, 9 H), 1.15–1.88 (m, 16 H), 1.98–
2.24 (m, 4 H), 3.65 (t, J = 6.5 Hz, 2 H), 4.06–4.19 (m, 1 H),
5.24–5.48 (m, 2 H), 7.34–7.43 (m, 6 H), 7.64–7.70 (m, 4 H).
13C NMR: d = 5.0, 7.0, 14.4, 19.3, 20.8, 22.4, 25.9, 26.9,
28.5, 28.8, 29.8, 31.8, 32.7, 33.4, 39.9, 48.7, 64.1, 75.5,
127.6, 129.5, 129.9, 131.1, 134.3, 135.7. Diol 9: [a]D24 +12
(c 0.388, CHCl3). IR (neat): 3350, 1056 cm–1. 1H NMR: d =
0.98 (t, J = 7.5 Hz, 3 H), 1.19–1.95 (m, 17 H), 2.20–2.50 (m,
5 H), 3.64 (t, J = 6.5 Hz, 2 H), 4.14–4.26 (m, 1 H), 5.34–5.49
(m, 2 H). 13C NMR: d = 14.5, 20.9, 22.8, 25.9, 28.9, 29.1,
29.8, 31.8, 32.9, 33.2, 40.1, 47.9, 63.1, 75.5, 128.7, 132.1.
Hydroxyl acid 20: IR (neat): 3410, 1699, 1652 cm–1. 1H
NMR: d = 0.96 (t, J = 7.5 Hz, 3 H), 1.13–2.44 (m, 21 H),
4.15–4.25 (m, 1 H), 5.22–5.51 (m, 2 H), 5.82 (d, J = 16 Hz,
1 H), 6.98–7.13 (dt, J = 16, 7 Hz, 1 H). 13C NMR: d = 14.4,
20.8, 22.7, 28.0, 28.6, 29.0, 29.5, 31.7, 32.4, 33.1, 40.0, 47.8,
75.5, 120.8, 128.7, 132.3, 152.3, 171.8.
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Synlett 2004, No. 14, 2582–2584 © Thieme Stuttgart · New York