An expeditious synthesis of 4-hydroxy-2(E)-nonenal (4-HNE), its dimethyl acetal and of related compounds

Article abstract of DOI:10.1016/j.chemphyslip.2007.07.003

The facile one step synthesis of 4-hydroxy-2(E)-nonenal and its dimethyl acetal via a cross-metathesis reaction between commercially available octen-3-ol and acrolein or its dimethyl acetal is reported. The method was extended to the synthesis of C₆ and C₁₂ 4-hydroxy-2(E)-enals, their dimethyl acetal and of the 4-hydroxy-2(E)-nonenoic acid (4-HNA).

Full text of DOI:10.1016/j.chemphyslip.2007.07.003

Available online at www.sciencedirect.com
Chemistry and Physics of Lipids 150 (2007) 239–243
Short communication
An expeditious synthesis of 4-hydroxy-2(E)-nonenal (4-HNE),
its dimethyl acetal and of related compounds
Laurent Soulerea,b,c,∗, Yves Queneaua,b,c, Alain Doutheaua,b,c
`
a
ICBMS, Institut de Chimie et Biochimie Mole´culaires et Supramole´culaires, universite´ de Lyon,
universite´ Lyon 1, CNRS, UMR 5246, Lyon F-69622, France
b
CPE Lyon, Villeurbanne F-69616, France
c
Laboratoire de Chimie Organique, INSA-Lyon, 20 avenue Albert Einstein, Villeurbanne F-69621, France
Received 27 March 2007; received in revised form 18 July 2007; accepted 27 July 2007
Available online 26 August 2007
Abstract
The facile one step synthesis of 4-hydroxy-2(E)-nonenal and its dimethyl acetal via a cross-metathesis reaction between com-
mercially available octen-3-ol and acrolein or its dimethyl acetal is reported. The method was extended to the synthesis of C6 and
C12 4-hydroxy-2(E)-enals, their dimethyl acetal and of the 4-hydroxy-2(E)-nonenoic acid (4-HNA).
© 2007 Elsevier Ireland Ltd. All rights reserved.
Keywords: 4-Hydroxy-2(E)-nonenal (4-HNE); 4-Hydroxy-2(E)-alkenals; 4-Hydroxy-2(E)-alkenal dialkyl acetals; 4-Hydroxy-2(E)-nonenoic acid
(4-HNA); Lipid peroxidation; Cross-metathesis
1. Introduction
in the literature. Since the first synthesis of 4-hydroxy-
2(E)-alkenals by Esterbauer et al. more than 35 years
ago using the reaction of the 3,3-diethoxypropynyl
Grignard reagent on aldehydes and subsequent reduc-
tion of the triple bound followed by the hydrolysis
of the acetal function (Esterbauer and Weger, 1967;
Esterbauer, 1971), these syntheses were based on two
sequential oxidation of 3(Z)-nonenol leading to 3,4-
epoxynonenal further converted to 4-HNE in basic
conditions (Gardner et al., 1992) or on Grignard reac-
tions using the fumaraldehyde monodimethyl acetal with
Endogenic 4-hydroxyalkenals, which result from
peroxidation of unsaturated fatty acid derivatives, are
important compounds displaying various biological
activities (Esterbauer et al., 1991; Robino et al., 2001). In
particular 4-hydroxy-2(E)-nonenal (4-HNE) (Comporti,
1998; Petersen and Doorn, 2004) plays a major role in
several biological processes such as oxidative stress (Poli
and Schaur, 2000), apoptosis (Castello et al., 2005) and
regulation of mitochondrial uncoupling (Echtay et al.,
2003).
´
´
the 1-bromo-pentane (Gree and Carrie, 1986; Chandra
andSrivastava, 1997). 4-Hydroxyalkenalsarealsoacces-
sible by DIBAL(H) reduction of 4-hydroxyalkenoic
esters (Bacot et al., 2003) obtained from aldehydes using
the Tanikaga conditions (Tanikaga et al., 1983). Very
recently, Kurangi et al. (2006) reported the synthesis of
4-HNE using Wittig or Horner–Wardsworth–Emmons
reactions between either a phosphorane or a phosphonate
Consequently, several syntheses of 4-HNE and of its
more stable dialkyl acetal precursor, have been reported
∗
Corresponding author at: Laboratoire de Chimie Organique, INSA-
Lyon, 20 avenue Albert Einstein, Villeurbanne F-69621, France.
Tel.: +33 4 72 43 83 42; fax: +33 4 72 43 88 96.
E-mail address: laurent.soulere@insa-lyon.fr (L. Soule`re).
0009-3084/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.chemphyslip.2007.07.003

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L. Soule`re et al. / Chemistry and Physics of Lipids 150 (2007) 239–243
Scheme 2. Synthetic route to 4-hydroxy-2(E)-alkenals and to their
related acetal derivatives.
lyst I (0.025 equiv.). Monitoring of the reaction by TLC
showed the appearance of a more polar product com-
pared to the allylic alcohol. Purification of the crude
reaction product by flash column chromatography fur-
nished the corresponding 4-hydroxy-2(E)-alkenals or
acetal derivatives. In the case of acetal derivatives, tri-
ethylamine (0.1%) was added to the eluant to avoid the
hydrolysis of the acetal group on silica gel. The identi-
fication of all compounds was based on the comparison
Scheme 1. Structure of the ruthenium catalyst I.
with glyoxal dimethyl acetal followed by the reduc-
tion of the carbonyl group and hydrolysis of the acetal
function.
In the last years, olefin metathesis proved to be a ver-
satile tool in organic synthesis. The development of new
catalysts for cross-metathesis or ring closure metathe-
sis has indeed promoted the use of this reaction for the
total synthesis of natural products (Prunet, 2003, 2005;
Piscopio and Robinson, 2004; Villar et al., 2007). Par-
ticularly, the Hoveyda–Grubbs catalyst 2nd Generation I
(Scheme 1) has been efficiently employed for the synthe-
sis via cross-metathesis of various functionalized olefins
(Kingsbury et al., 1999; Connon and Blechert, 2003).
To our knowledge, only one 4-hydroxy-alkenal
(4-hydroxy-2(E)-hexenal) has been prepared using
cross-metathesis as an intermediate in the total synthesis
of a natural compound (BouzBouz et al., 2004). None
example are known in the case of 4-hydroxyalkenal
dialkyl acetals.
1
of H NMR spectra with literature data (see Section
3).
As expected (Cossy et al., 2001; Chatterjee et al.,
2003), only the (E) isomer was obtained as shown by
1H NMR spectra (3JH2–H3 = 15.4, 15.6 or 15.8 Hz) of
crude products.
We thus prepared the 4-hydroxy-2(E)-hexenal (4-
HHE, 4) and the corresponding acetal (5) from penten-
3-ol (1) in 85% and 55% yield, respectively, the 4-
hydroxy-2(E)-nonenal (4-HNE, 6) and the related acetal
(7) from octen-3-ol (2) in 75% and 65% yield, respec-
tively, and the 4-hydroxy-2(E)-dodecenal (8) and the
related acetal (9) from undecen-3-ol (3) in 65% and 50%
yield, respectively (Scheme 3).
Here we describe a facile one step synthesis of
4-HNE, 4-hydroxy-2(E)-hexenal (4-HHE), 4-hydroxy-
2(E)-dodecenal (4-HDE) and their corresponding
dimethyl acetal using the cross-metathesis reaction
between readily available allylic alcohols and acrolein
or acrolein dimethyl acetal, respectively, using I as cata-
lyst. The method was also applied to the synthesis of the
4-hydroxy-2(E)-nonenoicacid(4-HNA)viaitstert-butyl
ester.
The synthetic approach proved also to be efficient
for the preparation of the 4-hydroxy-2(E)-nonenoic acid
(4-HNA), a marker of lipid peroxidation resulting from
the metabolism of 4-HNE (Guichardant et al., 2004;
Brichac et al., 2007). Previous works described the mul-
tistep synthesis of this acid as a result of the reaction
of the pentenyl trichloromethyl carbinol (Shamshina
and Snowden, 2006) or the 4-chloro-3(Z)-nonenoic acid
(Kawashima et al., 1988) in aqueous NaOH as last step.
We prepared the 4-hydroxy-2(E)-nonenoic acid in a two
steps sequence: a cross-metathesis reaction between the
octen-3-ol (2) and the tert-butyl acrylate leading to the
4-hydroxy-2(E)-nonenoic acid tert-butyl ester 10 in 65%
yield; this ester was then deprotected in high yield to the
4-HNA (11) (Scheme 4).
2. Results and discussion
The synthetic approach used to prepare 4-hydroxy-
2(E)-alkenals and their related acetals is based on
a cross-metathesis reaction between allylic alcohols
and an excess of acrolein or acrolein dimethyl acetal
(3 equiv.) (Scheme 2).
To summarize we described here the use of cross-
metathesis for the convenient and efficient synthesis of 4-
HNE and related biologically relevant compounds. This
synthetic approach was found to give good yields and
The reaction was performed in dry, oxygen free
dichloromethane in the presence of the ruthenium cata-

L. Soule`re et al. / Chemistry and Physics of Lipids 150 (2007) 239–243
241
Scheme 3. Structure of the allylic alcohols used as starting materials and of the synthetic 4-hydroxy-2(E)-alkenals and their corresponding dimethyl
acetals.
to be rapid and easy to carry out with commercially or
readily available starting materials.
H2SO4. Silica gel (Kieselgel 60, 70–230 mesh ASTM,
Merck) was used for flash chromatography. The 1H
(300 MHz) and 13C (75 MHz) spectra were recorded
with a Bruker ALS300 or DRX300 spectrometer. The
signal of the residual protonated solvent was taken as
reference. Chemical shift (δ) and coupling constants (J)
are reported in ppm and Hz, respectively. IR spectra were
recorded on a Nicolet Magna 550 FT-IR Spectrometer.
3. Experimental procedures
3.1. Materials
All chemicals (allylic alcohols 1 and 2, acrolein,
acrolein dimethyl acetal and the catalyst I) were
purchased from Sigma–Aldrich. Undecen-3-ol was pre-
pared from nonanal and vinyl magnesium bromide
(Ramiandrasoa and Descoins, 1990). The reactions were
performed under nitrogen and were monitored by thin-
layer chromatography on Silica Gel 60 F254 (Merck);
detection was carried out by charring with a 5% phos-
phomolybdic acid solution in ethanol containing 10% of
3.2. General procedure
To a solution of allylic alcohol (1 mmol, 1 equiv.)
and acrolein (3 equiv.) or acrolein dimethyl acetal
(3 equiv.) in dry, oxygen free CH2Cl2 was added the
Hoveyda–Grubbs catalyst I (0.025 equiv.) in two equal
portion at t = 0 and t = 5 h. After stirring for further 20 h
Scheme 4. Synthesis of the 4-hydroxy-2(E)-nonenoic acid (4-HNA, 11).

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L. Soule`re et al. / Chemistry and Physics of Lipids 150 (2007) 239–243
at room temperature, the solvent was evaporated and the
residue was purified by flash column chromatography
(Et2O/pentane: 50/50 for 4, AcOEt/pentane: 30/70 for 6
and Et2O/pentane: 40/60 for 8) to give the 4-hydroxy-
2(E)-alkenals or (Et2O/pentane with 0.1% Et3N: 50/50
for 5 and 7 and 40/60 for 9) to give the 4-hydroxy-
2(E)-alkenal dimethyl acetals. 4-Hydroxy-2(E)-hexenal
(4, 4-HHE, 85% yield): IR (neat) νmax 970, 1116,
J = 4.9, 1H), 5.58 (ddd, J = 1.1, 4.9 and 15.8, 1H), 5.84
(ddd, J = 1.1, 5.7 and 15.8, 1H); 13C NMR (acetone, d6):
δ 14.4, 23.3, 26.3, 30.0, 30.3, 30.4, 32.6, 38.3, 54.47,
52.51, 71.7, 103.5, 126.7, 139.2. HR-MS (ESI) calcd for
C14H28NaO3 (MNa+): 267.1936, found: 267.1935.
4-Hydroxy-2(E)-nonenoic acid tert-butyl ester (10):
this compound (colourless oil) was prepared according
the general procedure via a cross-metathesis reaction
between the octen-3-ol (1 equiv.) and the acrylic acid
tert-butyl ester (3 equiv.) in 65% yield. IR (neat) νmax
1
1692, 2839, 2959, 3436 cm−1; H NMR (acetone, d6)
(BouzBouz et al., 2004): δ 0.97 (t, J = 7.5, 3H), 1.53–1.72
(m, 2H), 4.30 (d, J = 4.9, 1H), 4.32–4.40 (m, 1H), 6.26
(ddd, J = 1.9, 7.9 and 15.8, 1H), 7.02 (dd, J = 4.1, 15.8,
1H), 9.6 (d, J = 7.9, 1H); 13C NMR (acetone, d6): δ 9.6,
29.8, 71.9, 130.8, 161.0, 193.9.
4-Hydroxy-2(E)-nonenal (6, 4-HNE, 75% yield): IR
(neat) νmax 983, 1633, 1686, 2866, 2932, 3437 cm−1; 1H
NMR (acetone, d6) (De Montarby et al., 1989): δ 0.88 (t,
J = 6.7, 3H), 1.29–1.36 (m, 4H), 1.40–1.70 (m, 4H), 4.28
(d, J = 5.3, 1H), 4.38–4.46 (m, 1H,), 6.25 (ddd, J = 1.7,
7.9 and 15.6, 1H), 7.01 (dd, J = 4.3, 15.6, 1H), 9.6 (d,
J = 7.9, 1H); 13C NMR (acetone, d6): δ 14.2, 23.1, 25.5,
32.3, 37.1, 70.8, 130.8, 161.6, 194.0.
996, 1260, 1314, 1659, 1715, 2853, 2936, 3429 cm−1
;
1H NMR (CDCl3): δ 0.89 (t, J = 6.8, 3H), 1.28–1.44 (m,
6H), 1.49 (s, 9H), 1.54–1.59 (m, 2H), 4.27–4.28 (m, 1H),
5.96 (dd, J = 1.5 and 15.4, 1H), 6.84 (dd, J = 4.9 and 15.4,
1H); 13C NMR (CDCl3): δ 13.9, 22.5, 24.8, 28.0, 31.6,
36.6, 71.1, 80.4, 121.9, 148.9, 165.8. HR-MS (CI) calcd
for C13H25O3 (MH+): 229.1804, found: 229.1805.
4-Hydroxy-2(E)-nonenoic acid (11, 4-HNA): to a
solution of 10 (0.06 g, 0.26 mmol) in CH2Cl2 (4 mL)
was added TFA (2 mL). After 3 h of stirring at room
temperature, 10 mL of toluene was added and the sol-
vent was evaporated. The residue was purified by flash
column chromatography (Et2O/pentane: 70/30) to give a
colourless oil (0.04 g, 90%). IR (neat) νmax 1268, 1407,
1653, 1699, 2919, 3390 cm−1; 1H NMR (CDCl3) (Alevi
et al., 1993): δ 0.89 (t, J = 6.4, 3H), 1.31–1.45 (m, 6H),
1.56–1.64 (m, 2H), 4.31–4.37 (q, J = 5.0, 1H), 6.06 (d,
J = 15.8, 1H), 7.05 (dd, J = 5.0 and 15.8); 13C NMR
(CDCl3): δ 13.9, 22.4, 24.8, 31.5, 36.3, 71.1, 119.4,
152.6, 171.4.
4-Hydroxy-2(E)-dodecenal (8, 65% yield): IR (neat)
νmax 983, 1135, 1692, 2855, 2925, 3447 cm−1; 1H NMR
(acetone, d6) (Iriye et al., 1990): δ 0.88 (t, J = 7.0, 3H),
1.28–1.33 (m, 10H), 1.39–1.68 (m, 4H), 4.27 (d, J = 5.3,
1H), 4.38–4.46 (m, 1H,), 6.25 (ddd, J = 1.9, 7.9 and 15.4,
1H), 7.02 (dd, J = 4.1, 15.4, 1H), 9.6 (d, J = 7.9, 1H); 13
C
NMR (acetone, d6): δ 14.3, 23.3, 25.9, 32.6, 38.2, 52.5,
71.7, 103.6, 126.7, 139.2.
4-Hydroxy-2(E)-hexenal, dimethyl acetal (5, 55%
yield): IR (neat) νmax 963, 1062, 1348, 1460, 2826, 2979,
3450 cm−1; 1H NMR (acetone, d6) (Rees et al., 1995):
δ 0.90 (t, J = 7.5, 3H), 1.45–1.55 (m, 2H), 3.24 (s, 6H).
3.80 (d, J = 4.9, 1H), 3.98–4.06 (m, 1H), 4.75 (d, J = 4.9,
1H), 5.58 (ddd, J = 1.5, 4.9 and 15.8, 1H), 5.83 (ddd,
J = 1.1, 5.7 and 15.8, 1H); 13C NMR (acetone, d6): δ 9.9,
30.8, 52.4, 72.8, 103.4, 126.8, 138.6.
Acknowledgments
Financial support from MENESR and CNRS are
gratefully acknowledged.
Appendix A. Supplementary data
4-Hydroxy-2(E)-nonenal, dimethyl acetal (7, 65%
yield): IR (neat) νmax 977, 1070, 1370, 1467, 2853, 2939,
Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/
j.chemphyslip.2007.07.003.
1
3436 cm−1; H NMR (acetone, d6) (De Montarby et
al., 1989): δ 0.88 (t, J = 6.8, 3H), 1.28–1.37 (m, 4H),
1.43–1.50 (m, 4H). 3.24 (s, 6H), 3.77 (d, J = 4.5, 1H),
4.06–4.11 (m, 1H), 4.75 (d, J = 4.9, 1H), 5.57 (ddd,
J = 1.1, 4.9 and 15.4, 1H), 5.84 (ddd, J = 1.1, 5.0 and
15.4, 1H); 13C NMR (acetone, d6): δ 14.4, 23.3, 26.0,
30.0, 30.3, 32.6, 37.3, 71.0, 130.9, 161.7, 194.1.
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