Convenient synthesis of cytotoxic (11E)-13-hydroxy-10-oxooctadec-11-enoic acid from undec-10-enoic acid

Article abstract of DOI:10.1039/a706245a

(11E)-13-Hydroxy-10-oxooctadec-11-enoic acid 1 is conveniently synthesized via a Knoevenagel-type reaction of isopropyl 11-phenylsulfinyl-10-oxoundecanoate 2a (itself easily derived from undec-10-enoic acid) with heptanal to form the γ-hydroxyenone functi

Full text of DOI:10.1039/a706245a

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Convenient synthesis of cytotoxic (11E)-13-hydroxy-10-oxooctadec-
11-enoic acid from undec-10-enoic acid
Junzo Nokami,* Masahiro Osafune, Kazuhiro Shiraishi, Shin-ichi Sumida and
Nobuyuki Imai
Department of Applied Chemistry, Faculty of Engineering, Okayama University of Science,
Ridai-cho, Okayama 700, Japan
(11E)-13-Hydroxy-10-oxooctadec-11-enoic acid 1 is con-
OH
O
veniently synthesized via a Knoevenagel-type reaction of
isopropyl 11-phenylsulfinyl-10-oxoundecanoate 2a (itself
easily derived from undec-10-enoic acid) with heptanal to
form the ã-hydroxyenone functionality together with car-
bon chain elongation.
ii
i
(CH2)8CO2Pri
PhS
4
(CH2)8CO2Pri
6
5
iii
O
S
The title compound 1 was discovered in corn extract, and was
also shown to be a stronger cytotoxic fatty acid than linoleic
acid.1 The first synthesis was accomplished by Matsushita et al.
who showed it was also racemic.2†
O
S
OH
O
iv
3a
(CH2)8CO2Pri
(CH2)8CO2Pri
Ph
Ph
7
2a
Scheme 2 Reagents and conditions: i, MCPBA, CH2Cl2, 0 ЊC–room
temp., 5 h, 100%; ii, PhSH, K2CO3, acetone, 0 ЊC–room temp., 2 h, 88%;
iii, MCPBA, CH2Cl2, 0 ЊC, 1 h, 96%; iv, DMSO (20 equiv.), (COCl)2,
Et3N, CH2Cl2, Ϫ60 ЊC, 1 h, 82%
O
CO2H
OH
1
sulfoxide 7 to β-keto sulfoxide 2a was achieved by employing
Swern oxidation4 using an excess amount (20 equiv.) of dime-
thyl sulfoxide (DMSO). The key reaction of 2a with heptanal (2
equiv.) was carried out in the presence of diethylamine (2
equiv.) and acetic acid (0.5 equiv.) in propiononitrile at 70 ЊC
for 2 h to give the isopropyl ester 3a [R1 = (CH2)8CO2Pri,
R2 = (CH2)4CH3 in 3] in 77% yield based on 2a. The analogs 3b–
e were also prepared by a similar reaction of 2a with various
aldehydes, as shown in Table 1.
The notable antitumor activities of naturally occurring 1
shown by these pioneering works prompted us to synthesize it
conveniently from an inexpensive fatty acid, undec-10-enoic
acid, via a Knoevenagel-type reaction of a β-keto sulfoxide 2
with an aldehyde to form the γ-hydroxyenone functionality
(Scheme 1).3
Hydrolysis of the isopropyl ester 3a to the corresponding
carboxylic acid 1 was performed enzymatically using lipase PS
(Amano P)‡ in a phosphate buffer (pH 7.0)–THF (8:1, v/v) at
room temperature for 24 h, quantitatively.2
O
O
S
O
Secondary Amine
R2
R1
Ar
R1
OH
3
2
+
Experimental
R2CH2CHO
aldehyde
Isopropyl 11-phenylsulfinyl-10-oxoundecanoate 2a
To a solution of (COCl)2 (0.3 ml, 3.47 mmol) in CH2Cl2 (16 ml)
at Ϫ60 ЊC was added dimethyl sulfoxide (4.5 ml, 63.2 mmol). A
solution of isopropyl 11-phenylsulfinyl-10-hydroxyundec-
anoate 7 (1.16 g, 3.16 mmol) in CH2Cl2 (5 ml) was added drop-
wise to the above solution over a period of 2 min at Ϫ60 ЊC.
After stirring for 1 h, the mixture was treated with triethylamine
(2.2 ml, 15.8 mmol) then was slowly warmed to room temper-
ature by removal of the cooling bath. The reaction mixture was
poured into water and extracted with chloroform. The com-
bined organic extracts were washed with brine, dried (MgSO4)
and concentrated in vacuo. The residue was recrystallised from
diethyl ether–hexane to afford isopropyl 11-phenylsulfinyl-10-
oxoundecanoate 2a (952 mg, 82%); mp 66–67 ЊC; νmax(neat)/
cmϪ1 2983, 2933, 2857, 1717, 1467, 1445, 1375, 1108, 1045 and
690; δH 1.23 (6 H, d, J 6.3), 1.26–1.30 (12 H, m), 1.47–1.62 (4 H,
m), 2.25 (2 H, t, J 7.6), 2.39–2.54 (2 H, m), 3.76 (1 H, d, J 13.6),
3.88 (1 H, d, J 13.6), 5.00 (1 H, tt, J 6.3, 6.3) and 7.53–7.68 (5 H,
Scheme 1 Reaction of β-keto sulfoxide with aldehyde in the presence
of secondary amine
Isopropyl 11-phenylsulfinyl-10-oxoundecanoate 2a [Ar = Ph,
R1 = (CH2)8CO2Pri in 2] was prepared from undec-10-enoic
acid as follows (Scheme 2). Isopropyl undec-10-enoate 4,
derived from undec-10-enoic acid, was converted to the epoxide
5 by oxidation with m-chloroperbenzoic acid (MCPBA). Iso-
propyl 11-phenylsulfanyl-10-hydroxyundecanoate 6 was ob-
tained by treatment of 5 with thiophenol and potassium
carbonate in acetone, and converted to the corresponding sul-
foxide 7 by MCPBA oxidation. The oxidation of the β-hydroxy
† The optically active 1 and its 14-membered lactone were prepared by
Matsushita et al. via lipoxygenase-catalyzed highly enantio- and regio-
selective oxygenation at C-13 (the allylic carbon) of linoleic acid in 33%
overall yield. They reported that each of the [α]D25 values of naturally
occurring 1 and its 14-membered lactone was almost zero and therefore
they were racemic by comparison with the [α]D25 values of (R) and (S)-1
and the corresponding (R) and (S) lactones (Ϫ12.7, ϩ15.8, ϩ48.8 and
Ϫ49.0 respectively) prepared by them.
‡ Commercially available (10 000 yen kgϪ1). It was used 1 wt. equiv. to
the ester 3a.
J. Chem. Soc., Perkin Trans. 1, 1997
2947

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Table 1 Reaction of 2a with various aldehydes in the presence of
60 or Fuji Silysia, silica gel BW-300) with 25% ethyl acetate in
hexane as the eluent to provide 3a (75 mg, 77%); νmax(neat)/
cmϪ1 3449, 2978, 2931, 2857, 1731, 1676, 1632, 1467, 1374,
1110, 754 and 725; δH 0.89 (3 H, t, J 6.6), 1.22 (6 H, d, J 6.3),
1.26–1.63 (20 H, m), 2.25 (2 H, t, J 7.5), 2.55 (2 H, t, J 7.4), 4.32
(1 H, m), 5.00 (1 H, tt, J 6.3, 6.3), 6.30 (1 H, dd, J 1.4, 15.9) and
6.80 (1 H, dd, J 5.1, 15.9); δC 21.8, 22.5, 24.1, 24.9, 29.0, 29.1,
31.6, 34.6, 36.7, 40.7, 67.3, 71.3, 127.9, 147.8, 173.4 and 200.8.
(Found: Mϩ, 354.5321. C21H38O4 requires M, 354.5303).
diethylamine and acetic acida,b
Product 3c
Aldehyde
equiv.
Reaction
time/h
Recovered
Yield/% 2a/%
R2
heptanal
2.0
propanal
2.0
3-phenyl-
propanal
2.0
2 (2)
2 (2)
2 (4)
a (CH3(CH2)4
b CH3
77 (68)
64 (51)
67 (62)
10 ( 4)
21 (23)
8 (26)
c PhCH2
Acknowledgements
nonanal
2.0
citronellal
4.0
2 (4)
d CH3(CH2)6
71 (63)
58 (47)
6 (23)
We are grateful to Professor T. Matsui and Professor Y. Matsu-
shita of Miyazaki University for information concerning the
title compound and their preliminary reports.2 This work was
supported by a Grant for Cooperative Research administered
by the Japan Private School Promotion Foundation.
e
4 (48)
22 ( 0)
a Carried out in propiononitrile at 70 ЊC. b The values in the parentheses
show the result in the absence of acetic acid. c R1 = (CH2)8CO2Pri.
References
m);§ δC 21.8, 22.9, 24.9, 28.8, 28.9, 29.0, 34.6, 44.9, 67.3, 68.0,
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K. Uenakai, The 37th Symposium on the Chemistry of Natural
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Isopropyl (11E)-13-hydroxy-10-oxooctadec-11-enoate 3a
To a solution of 2a (100 mg, 0.27 mmol) with diethylamine (57
µl,0.55mmol)andaceticacid(8µl,0.13mmol)inpropiononitrile
(5 ml) was added heptanal (76 µl, 0.54 mmol) at 70 ЊC. After
stirring was continued for 2 h at 70 ЊC, chloroform (5 ml) and
saturated aqueous ammonium chloride (1 ml) were added to
the reaction mixture at 0 ЊC. The aqueous layer was extracted
with chloroform, and the combined organic layers were washed
with brine, dried (MgSO4) and concentrated in vacuo. The resi-
due was purified by column chromatography (Merck, silica gel
4 A. J. Mancuso, S.-L. Hung and D. Swern, J. Org. Chem., 1978, 43,
2480; A. J. Mancuso and D. Swern, Synthesis, 1981, 165; T. T.
Tidwell, Synthesis, 1990, 857.
Paper 7/06245A
Received 27th August 1997
Accepted 1st September 1997
§ J Values are given in Hz.
2948
J. Chem. Soc., Perkin Trans. 1, 1997