Selective synthesis of unsaturated N-acylethanolamines by lipase-catalyzed N-acylation of ethanolamine with unsaturated fatty acids

Article abstract of DOI:10.2174/157017809789124885

The selective synthesis of unsaturated N-acylethanolamines 1b-6b by lipase-catalyzed direct condensation between unsaturated fatty acids 1a-6a and ethanolamine is reported. Reactions were carried out in hexane at 40 °C, in the presence of Candida antarctica Lipase B as the catalyst, to give the corresponding amides 1b-6b with yields ranging from 80 to 88%.

Full text of DOI:10.2174/157017809789124885

444
Letters in Organic Chemistry, 2009, 6, 444-447
Selective Synthesis of Unsaturated N-Acylethanolamines by Lipase-
Catalyzed N-Acylation of Ethanolamine with Unsaturated Fatty Acids
Pierluigi Plastina*,a, Jocelijn Meijerinka, Jean-Paul Vinckenb, Harry Gruppenb, Renger Witkampa
and Bartolo Gabriele*,c
aDivision of Human Nutrition, Wageningen University, P.O. Box 8129, 6700 EV Wageningen, The Netherlands
bLaboratory of Food Chemistry, Wageningen University, P.O. Box 8129, 6700 EV Wageningen, The Netherlands
cDipartimento di Scienze Farmaceutiche, Università della Calabria, 87036, Arcavacata di Rende, Cosenza, Italy
Received March 31, 2009: Revised April 20, 2009: Accepted April 20, 2009
Abstract: The selective synthesis of unsaturated N-acylethanolamines 1b-6b by lipase-catalyzed direct condensation
between unsaturated fatty acids 1a-6a and ethanolamine is reported. Reactions were carried out in hexane at 40 °C, in the
presence of Candida antarctica Lipase B as the catalyst, to give the corresponding amides 1b-6b with yields ranging from
80 to 88%.
Keywords: Acylation, enzymatic catalysis, lipase, unsaturated N-acylethanolamines, unsaturated fatty acids.
Alkanolamides from fatty acids are an important class of
compounds, with a wide range of applications. They are used
as detergents, shampoos, cosmetics, lubricants, foam control
agents, fungicides, corrosion inhibitors, and water repellents
[1]. Moreover, some fatty acid ethanolamides (N-
acylethanolamines, NAEs) are lipid mediators in animals and
in plants [2]. For example, N-arachidonoylethanolamine
(anandamide) is a well-known endogenous agonist for the
cannabinoid receptors [2g,h]. These compounds are usually
synthesized by the reaction of fatty acid chlorides or
anhydrides with amines [3], or by the direct reaction between
fatty acids and amines in the presence of a condensation
agent, such as 1-ethyl-3-(3-dimethylaminopropyl)carbo-
diimide hydrochloride or 1-cyano-1,2,4-triazole [4].
have been reported to catalyze the reaction of amines with
carboxylic acids [5], Candida antarctica lipase B proved to
be the most effective catalyst for the synthesis of
alkanolamides in organic solvents [6], in ionic liquids [7] or
under solvent-free conditions [8]. It has also been reported
that the chain length of the acyl donor affects the reaction
rate [5c]. In particular, the C-14 alkyl chain resulted the
optimal chain length for lipase QL, the reaction rate in the
case of both shorter and longer chain fatty acids being lower.
So far, lipase-catalyzed N-acylation of different amino
alcohols has been carried out using short or medium chain
fatty acids. Only little or no attention has been paid to the
use of unsaturated fatty acids, especially the poly-
unsaturated ones [5e, 6e].
In this work, we report an alternative approach to the
synthesis of unsaturated N-acylethanolamines (UNAEs) 1b-
6b based on enzyme-catalyzed N-acylation of ethanolamine
with unsaturated fatty acids (UFAs) 1a-6a, according to
equation 1.
Our method consists of the direct condensation reaction
between ethanolamine and UFAs (UFA:ethanolamine molar
ratio = 1:1), carried out at 40 °C in hexane as the solvent, in
the presence of Novozym®435 (consisting of immobilized
Candida antarctica Lipase B) as the catalyst. Typical results
are shown in Table 1. As can be seen, the methodology
could be successfully applied to various UFAs 1a-6a, with
different unsaturation patterns and chain lengths. High yields
of the corresponding UNAEs 1b-6b were consistently
obtained (80-88% entries 1-6). The reaction was completely
selective towards the formation of UNAEs, as no formation
of O-acylated products was observed [9]. Hexane was the
solvent of choice for this reaction. In this solvent, all the
fatty acids tested were easily soluble, and the system
remained homogeneous even after the addition of
ethanolamine. On the contrary, precipitation of the
ammonium salt occurred when ethanolamine was added to a
solution of the fatty acid in a more polar solvent, such as
acetonitrile. Accordingly, less satisfactory results were
obtained in this solvent (entry 7, to be compared with entry
6).
O
O
lipase
- H2O
OH
OH
(1)
R1
OH
+
R1
N
H
H2N
1a-6a
1b-6b
Enzymes have recently acquired a growing importance as
catalysts for organic synthesis. In fact, the use of enzymes
allows working under mild reaction conditions, leading to
more selective and atom-economical processes. In particular,
lipases (triacyl glycerol hydrolases, EC 3.1.1.3) are the most
commonly used enzymes in organic synthesis due to their
high stability in organic media and their ability to work with
a great variety of substrates. Among the various lipases that
*Address correspondence to these authors at the Dipartimento di Scienze
Farmaceutiche, Università della Calabria, 87036, Arcavacata di Rende,
Cosenza, Italy; Fax: +39 984 49 20 44;
In conclusion, we have reported a simple and convenient
approach for the selective synthesis of unsaturated N-
E-mail: p.plastina@unical.it; b.gabriele@unical.it
1570-1786/09 $55.00+.00
© 2009 Bentham Science Publishers Ltd.

Lipase-Catalyzed Synthesis of N-Acylethanolamines
Letters in Organic Chemistry, 2009, Vol. 6, No. 6
445
Table 1. Synthesis of Unsaturated N-Acylethanolamines (UNAEs) 1b-6b by Lipase-Catalyzed N-Acylation of Ethanolamine with
Unsaturated Fatty Acids (UFAs) 1a-6aa
Entry
UFAb
t (h)
Conv (%)c
UNAEd
Yield (%)e
1
2
3
4
5
6
7i
Oleic acid (1a)
Linoleic acid (2a)
CLA (3a)f
6
6
90
89
89
90
91
91
32
1b
2b
3b
4b
5b
6b
6b
88
85
80
84
80
83
20c
6
Linolenic acid (4a)
EPA (5a)g
6
15
15
15
DHA (6a)h
DHA (6a)h
aUnless otherwise noted, all reactions were carried out in hexane (0.2 mmol UFA in 1 mL hexane) at 40 °C, in the presence of 50 mg of immobilized Candida Antarctica Lipase B.
bUFA = Unsaturated Fatty Acid. cDetermined by HPLC. dUNAE = Unsaturated N-acylethanolamine. eUnless otherwise noted, all yields are isolated. fAccording to the manufacturer,
the conjugated linoleic acid (CLA) used was a complex mixture of octadecadienoic acids, namely: ~ 50% (9E,11Z) + (9Z,11E), ~ 40% (10E,12Z), ~ 10% (10Z,12Z). gEPA = cis-
5,8,11,14,17-eicosapentaenoic acid. hDHA = cis-4,7,10,13,16,19-docosahexaenoic acid. iThe reaction was carried out in acetonitrile.
acylethanolamines (UNAEs) 1b-6b, by lipase-catalyzed N-
acylation of ethanolamine with unsaturated fatty acids
(UFAs) 1a-6a. Formation of UNAEs occurs under mild
conditions (40 °C) and with high yields (80-88%).
set at 205 nm. UNAEs were purified by preparative HPLC,
using a Water Binary Gradient Module, equipped with a
fraction collector, and using an XTerra Prep RP18OBD
column (5 μm, 19 x 150 mm, Waters) with the gradient
elution program described before.
EXPERIMENTAL SECTION
General
Acylation Procedure
The appropriate unsaturated fatty acid (0.2 mmol) and
ethanolamine (12.2 mg, 0.2 mmol) were diluted with hexane
(1.0 mL) in a stoppered glass bottle. The resulting mixture
was placed in a thermoconstant orbital shaker and held at 40
°C for 5 minutes. Novozym®435 (50 mg) was then added,
and the mixture shaken at 200 r.p.m. for the required time
(see Table 1). After cooling, the solvent was evaporated
under reduced pressure, and the products purified by
preparative HPLC as described above. The product yields,
obtained in each experiment, are reported in Table 1.
Ethanolamine and UFAs 1a-6a were purchased from
Sigma-Aldrich. Novozym®435 was supplied by Novozymes
A/S. HPLC grade acetonitrile (Sigma-Aldrich) was used for
HPLC analysis and preparative-HPLC experiments. Water
for HPLC was purified with a Milli-Q system (Millipore).
Acetic acid and hexane were purchased from Merck.
Melting points were determined with
a Reichert
Thermovar melting point apparatus and are uncorrected.
Elemental analyses were carried out with a Carlo Erba
Elemental Analyzer Mod. 1106. H NMR and 13C NMR
1
spectra were recorded at 25 °C on a Bruker AC 300
spectrometer in CDCl3 solutions at 300 MHz and 75 MHz,
respectively, with Me4Si as internal standard. Chemical
shifts (ꢀ) and coupling constants (J) are given in ppm and in
Hz, respectively. IR spectra were taken with a BIORAD
FTS6000 spectrometer. Mass spectra were taken on a linear
quadrupole ion trap mass spectrometer (LCQ Deca XP
MAX, Thermo Fisher Scientific) equipped with an
electrospray ionization source interface (positive ion mode).
The operating parameters were as follows: the heated
capillary temperature was set at 250 °C, the vaporizer
temperature at 250 °C, the auxiliary gas at 2 arbitrary units,
and the sheath gas at 40 psi. For MS/MS analysis, helium
(He) was used in the collision cell; the collision energy was
set at 25 eV.
Characterization of Products
(Z)-Octadec-9-enoic acid (2-hydroxyethyl)amide (1b)
Colorless solid, mp 60-61 °C (lit. [4b]: 60-61 °C). IR
(KBr) 3297 (s), 2919 (m), 2850 (w), 1643 (s), 1564 (m) cm-1;
1H NMR ꢀ 5.95 (s, br, 1 H, NH), 5.37-5.32 (m, 2 H,
HC=CH), 3.73 (t, J = 5.0, 2 H, CH2OH), 3.46-3.39 (m, 2 H,
CH2NH), 2.36 (s, br, 1 H, OH), 2.21 (t, J = 7.7, 2 H,
CH2C=O), 2.06-1.96 (m, 4 H, CH2CH=CHCH2), 1.68-1.58
(m, 2 H, CH2CH2C=O), 1.38-1.20 [m, 20 H, CH3(CH2)6 +
=CHCH2(CH2)4], 0.88 (t, J = 6.9, 3 H, CH3); 13C NMR ꢀ
174.4, 130.1, 129.8, 62.7, 42.6, 36.8, 32.0, 29.84, 29.77,
29.6, 29.38, 29.33, 29.29, 29.19, 27.32, 27.25, 25.8, 22.7,
14.1; MS m/z 326.34 [(M+H)+, 65], 308.30 (25), 265.10 (16),
223.06 (11), 198.07 (100), 155.16 (14). Anal. Calcd for
C20H39NO2: C, 73.79; H, 12.08; N, 4.30. Found C, 73.95; H,
12.05; N, 4.29.
All reaction mixtures were analyzed by HPLC using a
Thermo Separation Spectra System P4000, with an XTerra
RP18 column (3.5 μm, 4.6 x 150 mm, Waters) using: (A)
MQ water + 0.1% acetic acid and (B) acetonitrile + 0.1%
acetic acid as mobile phases. The optimized gradient elution
program was as follows: 0-5 min: 65% B isocratic; 5-20 min:
65-80% B; 20-35 min: 80-88% B; 35-37 min: 88% B
isocratic; 37-38 min: 65% B; The column was run at room
temperature at a flow rate of 1.0 mL/min. UV detection was
(Z,Z)-Octadeca-9,12-dienoic acid (2-hydroxyethyl)amide
(2b)
Colorless solid, mp 38-40 °C (lit. [3d]: 38-39.5 °C). IR
(KBr) 3297 (s), 2917 (m), 2848 (w), 1643 (s), 1559 (m) cm-1;
1H NMR ꢀ 6.27 (s, br, 1 H, NH), 5.44-5.27 (m, 4 H, 2
HC=CH), 3.70 (t, J = 5.0, 2 H, CH2OH), 3.44-3.36 (m, 2 H,

446 Letters in Organic Chemistry, 2009, Vol. 6, No. 6
Plastina et al.
CH2NH), 2.77 (t, J = 5.7, 2 H, HC=CHCH2CH=CH), 2.20 (t,
J = 7.7, 2 H, CH2C=O), 2.09-2.00 (m, 4 H, CH2CH=
CHCH2CH=CHCH2), 1.69-1.57 (m, 2 H, CH2CH2C=O),
1.42-1.22 [m, 14 H, CH3(CH2)3 + =CHCH2(CH2)4], 0.89 (t, J
= 6.8, 3 H, CH3). (Note: the OH signal was too broad to be
detected); 13C NMR ꢀ 174.5, 130.3, 130.1, 128.2, 128.0,
62.4, 42.5, 36.7, 31.6, 29.7, 29.4, 29.3, 29.2, 27.3, 25.8, 25.7,
22.6, 14.0; MS m/z 324.34 [(M+H)+, 71], 306.30 (22),
263.20 (16), 240.06 (11), 202.07 (100), 145.16 (14). Anal.
Calcd for C20H37NO2: C, 74.25; H, 11.53; N, 4.33. Found C,
74.42; H, 11.51; N, 4.30.
(Z,Z,Z,Z,Z,Z)-Docosa-4,7,10,13,16,19-hexaenoic acid (2-
hydroxyethyl)amide (6b)
Colorless oil. IR (film) 3289 (s), 2919 (m), 2847 (w),
1
1647 (s), 1551 (m) cm-1; H NMR ꢀ 6.27 (s, br, 1 H, NH),
5.48-5.28 (m, 12 H, 6 HC=CH), 3.70 (t, J = 5.0, 2 H,
CH2OH), 3.44-3.36 (m, 2 H, CH2NH), 2.91-2.77 (m, 10 H, 5
CH=CHCH2CH=CH), 2.40 (t, J = 6.6, 2 H, CH2C=O), 2.30-
2.23 (m,
2 H, CH2CH2C=O), 2.14-2.01 (m, 2 H,
CH=CHCH2CH3), 0.97 (t, J = 7.6, 3 H, CH3). (Note: the OH
signal was too broad to be detected); 13C NMR ꢀ 173.7,
132.1, 129.6, 128.7, 128.5, 128.4, 128.2, 128.1, 128.0, 127.2,
62.3, 42.5, 36.4, 29.8, 25.8, 25.72, 25.66, 23.5, 20.6, 14.3;
MS m/z 372.20 [(M+H)+, 100], 354.00 (49), 344.14 (47),
331.78 (11), 261.27 (18), 168.02 (14). Anal. Calcd for
C24H37O2: C, 77.58; H, 10.04; N, 3.77. Found C, 77.65; H,
10.01; N, 3.75.
Conjugated N-(2-Hydroxyethyl)linoleamide (3b) (mixture
of isomers)
Colorless solid, mp 49-52 °C. IR (KBr) 3298 (s), 2917
(m), 2848 (w), 1647 (s), 1551 (m) cm-1; 1H NMR ꢀ 6.37-6.24
(m, 1 H, =CH), 6.04-5.89 (m, 2 H, =CH + NH), 5.72-5.58
(m, 1 H, =CH), 5.36-5.24 (m, 1 H, =CH), 3.74 (t, J = 5.0, 2
H, CH2OH), 3.47-3.39 (m, 2 H, CH2NH), 2.77 (s, br, 1 H,
OH), 2.26-2.05 (m, 6 H, CH2C=O + CH2CH=CHCH=
CHCH2), 1.72-1.58 (m, 2 H, CH2CH2C=O), 1.50-1.30 (m, 16
H), 0.94-0.86 (m, 3 H, CH3); MS m/z 324.36 [(M+H)+, 88],
307.22 (44), 263.28 (9), 245.12 (52), 202.11 (100), 144.99
(27). Anal. Calcd for C20H37NO2: C, 74.25; H, 11.53; N,
4.33. Found C, 74.31; H, 11.51; N, 4.32.
ACKNOWLEDGEMENTS
The authors gratefully acknowledge Dr. Henk Schols for
his generous gift of Novozym®435, Ing. Mark Sanders for
his professional technical support, and Fondazione Carical
for a post-doctoral grant for P.P.
(Z,Z,Z)-Octadeca-9,12,15-trienoic acid (2-hydroxyethyl)
amide (4b)
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1
1643 (s), 1556 (m) cm-1; H NMR ꢀ 6.04 (s, br, 1 H, NH),
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