Synthesis of natural 1- O -alkylglycerols: A study on the chemoselective opening of the epoxide ring by onium quaternary salts (N and P) and ionic liquids

Article abstract of DOI:10.1039/c9ra09217j

A chemoselective route for the synthesis of 1-O-alkylglycerols chimyl (1), batyl (2), and selachyl (3) is reported. These compounds can be naturally isolated from shark liver oil and the skin of animals such as stingrays and chimeras and exhibit potential anti-fouling activity. The synthetic approach developed in this work included two distinct methods of preparation. The first was based on solvent-free reactions catalyzed by onium quaternary salts (N and P) and ionic liquids; the second methodology was based on a series of one-pot reactions.

Full text of DOI:10.1039/c9ra09217j

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Synthesis of natural 1-O-alkylglycerols: a study on
the chemoselective opening of the epoxide ring by
onium quaternary salts (N and P) and ionic liquids†
Cite this: RSC Adv., 2020, 10, 1050
Thiana Santiago Nascimento, Esther Faria Braga, Giselle Cristina Casaes Gomes,
William Romao Batista, Andre Luıs Mazzei Albert, Rosangela Sabbatini Capella Lopes
˜
´
´
*
and Claudio Cerqueira Lopes
A chemoselective route for the synthesis of 1-O-alkylglycerols chimyl (1), batyl (2), and selachyl (3) is
reported. These compounds can be naturally isolated from shark liver oil and the skin of animals such as
stingrays and chimeras and exhibit potential anti-fouling activity. The synthetic approach developed in
this work included two distinct methods of preparation. The first was based on solvent-free reactions
catalyzed by onium quaternary salts (N and P) and ionic liquids; the second methodology was based on
a series of one-pot reactions.
Received 6th November 2019
Accepted 16th December 2019
DOI: 10.1039/c9ra09217j
rsc.li/rsc-advances
immunological control, production of antibodies, and anti-
inammatory effects.9,10
Introduction
An investigation in the eld of medicine on patients diag-
nosed with cervical cancer showed great recession on the size of
the tumor when submitted to radiation treatment alongside the
administration of mixtures of natural 1-O-alkylglycerols 1, 2,
3.11–13
Natural 1-O-alkylglycerols (alkyl-Gro) are bioactive lipid ethers
present in cells and body uids of marine animals. They are the
precursors of phospholipid ethers which participate in the
structure and membrane functions of certain cells such as red
blood corpuscles and macrophages.1,2
Furthermore, recent studies have been suggesting the use of
these 1-O-alkylglycerols 1, 2, and 3 as anti-fouling agents and
evaluating their efficiency towards fouling processes on metallic
surfaces of ships, platforms, and oil pipelines.13
The methodologies developed with the goal of evaluating the
biological activity of 1-O-alkylglycerols suggest that they may be
incorporated in phospholipids of cell membrane leading to
changes in its physical properties, e.g. uidity, or alter cell
signaling.14–16
There are reports of some preparation methods of 1-O-
alkylglycerols in the literature using derivatives of glycerol as
starting materials.13,17–25
Some studies mention the synthesis of compounds 1, 2, and
3 from solketal, the isopropylidene ketal of glycerol.20–22 These 1-
O-alkylglycerols can also be synthetically obtained from glyci-
dol, an epoxide of chemical structure similar to that of
epichlorohydrin with a hydroxyl group.23
Regarding marine sources, 1-O-alkylglycerols (1, 2, 3) may be
found in shark liver oil and the skin of stingrays and chimeras
(marine animals of the Chimaeridae, Bathoidea and Selachoidea
families).3 These organisms possess high levels of the afore-
mentioned compounds with a mixture of various chain lengths,
abundancy, and position of the unsaturation.4–7 For example,
the composition of alkyl chains in 1-O-alkylglycerols in the
shark liver oil of Centrophorus squamosus, also known as Leaf-
scale gulper shark, has the following values: 12 : 0, 1–2%; 14 : 0,
1–3%; 16 : 0, 9–13%; 16 : 1n-7, 11–13%; 18 : 0, 1–5%; 18 : 1n-9,
54–68%; 18 : 1n-7, 4–6%.4–6
The 1-O-alkylglycerols in the shark liver oil present the ether
moiety with the following prole: C16:0, chimyl alcohol (1);
C18:0, batyl alcohol (2); C18:1, selachyl alcohol (3) (Scheme 1).
The latter being in greater amount.8
Some of the benecial effects related to 1-O-alkylglycerols
have already been described in the literature. Among them is
the ability to promote important stimulation for the
Within the perspective of waste recovery from the industries
of rened soy oil and biodiesel produced in Brazil, we used, in
´
´
´
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Laboratorio de Sıntese e Analise de Produtos Estrategicos-Centro de Tecnologia,
´
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Departamento de Quımica Analıtica, Instituto de Quımica, Universidade Federal do
Rio de Janeiro, Bloco A, S. 508, Rio de Janeiro-RJ, CEP 21941-909, Brazil. E-mail:
claudiosabbatini@uol.com.br
† Electronic supplementary information (ESI) available: Experimental section, 1H
and 13C NMR spectra for compounds 1–10, and HRMS spectra for compounds
7–10. See DOI: 10.1039/c9ra09217j
Scheme 1 Representative structures of 1-O-alkylglycerols.
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a recent study, starting materials such as epichlorohydrin13 and
soy lecitins24 for the synthesis of potential biocides. We also
demonstrated that lyso-glycerophosphocholines prepared from
soy lecithins display potential biocide activity on the treatment
of ballast water.24
Herein, we prepared 1-O-alkylglycerols 1, 2, and 3 found in
the skin and liver of sharks, stingrays, and chimeras, marine
animals that do not present biofouling. This characteristic
suggests that these substances (1, 2, and 3) are potential
candidates to be incorporated in anti-fouling paints as biocides,
becoming a green chemistry option to control the process of
biofouling that leads to enormous losses for sea transport.13
It is possible to notice that epichlorohydrin, an organo-
chlorine compound used in various industrial applications, has
been gaining relevance in the synthesis of 1-O-alkylglycer-
ols.13,23,24 Epichlorohydrin is obtained from glycerol, which is
itself a by-product of the biodiesel production (biomass fuel)
and was used in this study as the starting material.
In most commercial marine paint coatings the copper ions
are incorporated as biocide to combat marine biofouling. The
previous biological results demonstrated by our research
group13 indicated that chimyl (1) can be used as a promising
biocide because it is more effective than copper ions against
biolm-forming bacterias involved on marine biofouling
process.
We are making, on macro scale, new marine paints
including the natural 1-O-alkylglycerols chimyl (1), batyl (2), and
selachyl (3) as biocide additive, on different concentrations as
a new technological contribution to prevent the formation of
biolm related with the marine biofouling process. All these
compounds were prepared with the synthetic route described
herein.
The aim of this study was to develop a methodology with
a reduced number of steps, ease of execution, and high yields,
in order to allow for the large-scale synthesis of compounds 1, 2
and 3.
Scheme 2 Mechanistic proposal for the formation of glycidyl ethers 4,
5 and 6.
characteristics (such as TBAHS), and moderate temperatures. A
similar methodology was used by Kang25 and coworkers in
a study that involved the use of phase-transfer catalysts in the
synthesis of similar glycidyl ethers.
The second step of the synthetic route for the preparation of
1-O-alkylglycerols 1, 2, and 3 consisted of an epoxide ring-
opening reaction using benzoic acid and involving the
improvement of the reaction conditions, such as reaction time,
catalyst concentration, and presence or absence of the solvent,
in the search for reproducible yields.
Previously, the epoxide ring opening reaction (second step)
had been performed under different temperature conditions,
ꢀ
where the temperature was increased 20 C at a time ranging
from 30ꢀ to 110 ꢀC. This screening showed that the reaction had
ꢀ
best performance at 110 C using toluene as the solvent.
This step consisted of keeping a mixture of glycidyl ether 4
with benzoic acid in the presence of an onium salt (N or P) in
toluene and under reux (Scheme 3).
Fieen commercial quaternary salts containing a nitrogen or
phosphorus central atom with different R groups and halides
(–Cl, –Br, –I) were used in the ring-opening of compound 4
(Scheme 3).
The compilation of the results presented in Table 1 showed
that a variety of quaternary ammonium and phosphonium salts
Results and discussion
A reaction medium containing an alcohol of long aliphatic
chain, such as cetyl, stearyl, and oleyl alcohols, and epichloro-
hydrin in the presence of a quaternary ammonium salt phase-
transfer catalyst, in alkaline and solvent-free medium was
kept under stirring at 70 ꢀC for 7 hours. This reaction led to the
formation of glycidyl ethers 4, 5, and 6 with yields from 92–98%
(Scheme 2). In the formation of the glycidyl ethers, two different
ammonium quaternary salts were used, tetrabutylammonium
bromide (TBAB) and tetrabutylammonium hydrogen sulfate
(TBAHS), with the latter providing better yields for compounds
4, 5, and 6.
Our experimental data show that the HSO4ꢁ ion is a slightly
better leaving group than the bromide ion. Therefore, we ob-
tained better yields when TBAHS was used as catalyst instead of
TBAB. A mechanistic proposal for the formation of glycidyl
ethers 4, 5 and 6 is described on Scheme 2. It was possible to
notice from this reaction that high yields are obtained with
Scheme 3 Epoxide ring-opening mediated by an onium quaternary
a solvent-free system, a phase-transfer catalyst with acid salt (N, P).
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Table
1
Epoxide ring opening of glycidyl ether 4 catalyzed by Table 2 Solvent-free opening of the epoxide ring of compound 7
catalyzed by onium quaternary salta,b
quaternary ammonium or phosphonium salta,b
Reaction Entry
time
Surfactant
(7)b %
(8c)b %
Entry
Surfactant
(7)b %
(8a, 8b or 8c)b %
1
2
3
4
5
6
MePPh3I (25 mol%)
MePPh3I (12.5 mol%)
MePPh3I (10 mol%)
MePPh3I (5 mol%)
MePPh3I (2.5 mol%)
MePPh3I (1 mol%)
ꢂ95
ꢂ95
100
100
100
100
ꢂ5
<5
Trace
—
—
—
1
2
3
4
5
6
7
8
C
C
16H33N Me3Br
16H33N Me3Cl
80
80
90
80
80
90
80
80
80
80
95
80
70
70
70
20
20
10
20
20
10
20
20
20
20
ꢂ5
20
30
30
30
20 h
20 h
14 h
13 h
9 h
n-Bu4NI
n-Bu4NBr
n-Bu4PBr
MePPh3Br
PropPPh3Br
BuPPh3Br
PentPPh3Br
HexPPh3Br
MePPh3I
PropPPh3I
BuPPh3I
PentPPh3I
HexPPh3I
9 h
a
Reaction conditions: 4 (1 mmol), PhCO2H (2 mmol), surfactant
13 h
15 h
14 h
15 h
7 h
9 h
9 h
12 h
10 h
(MePPh3I) (25 mmol%–1 mmol %), solvent-free reaction. T ¼ 100 ꢀC.
b
Isolated yield aer ash chromatography.
9
10
11
12
13
14
15
needed for the completion of the reaction (4.0 hours) and the
amount of collateral product 8c (X ¼ I) are both reduced
(Table 2).
a
Reaction conditions: 4 (1 mmol), PhCO2H (2 mmol), surfactant
The ideal concentration of the phosphonium quaternary salt
was also analyzed. According to the data presented in Table 2, it
is possible to infer that there is a correlation between surfactant
concentration and the yield of the hydroxy ester 7, since the
lower the concentration of the surfactant, the higher the yield of
the hydroxy ester. Thereby, a solvent-free system and catalytic
amounts of the quaternary salt favor the evolution of the
reaction.
Additionally, the inuence of several ionic liquids (ILs) –
alternative catalysts for the onium quaternary salts – in the
process of opening the epoxide ring in the substrates already
used was investigated. The experimental protocol for this study
consisted in a water/solvent-free reaction using glycidyl ether 4,
b
[(R0)4QX] (25 mmol%), reux (T ¼ 100 ꢀC). Isolated yield aer ash
chromatography.
adequately assist the epoxide ring-opening process, favoring the
hydroxy ester intermediate 7.
Furthermore, the most efficient surfactant among the
analyzed salts was methyltriphenylphosphonium iodide (entry
11), producing intermediate 7 with a shorter reaction time (7 h)
and 95% yield.
According to the data presented, it is possible to infer that
the process is highly regioselective given that the formation of
the monohydroxy ester 7 is preferred in most reactions. The
yields of the formation of halohydrin 8a, 8b, and 8c (X ¼ Cl, Br, I
respectively) ranged from 5 to 30%. Halohydrins 8a, 8b, and 8c
are generated when the halide ion provided by the quaternary
salt attacks the least substituted carbon in the epoxide ring
leading to its opening.
Considering the results obtained and reaction factors such
as solvent effect and surfactant molar concentration, a solvent-
free ring-opening reaction was developed using the methyl-
triphenylphosphonium salt (Scheme 4).
ꢀ
in the presence of benzoic acid and the ionic liquid at 110 C.
This particular type of reaction becomes interesting given the
fact that ionic liquids allow a homogeneous system without the
need of further organic solvents (Scheme 5).
In order to analyze the catalytic efficiency of the ionic liquids
in the epoxide ring-opening reaction, compound 4 was used
along with eight commercial ionic liquids derived from imid-
azole. To facilitate the identication of the substances in the
course of the discussion, the ionic liquids will be referred to by
the rst letter of their carbonyl chain and halides, for instance,
1,3-dimethylimidazole iodide will be dubbed [MMIm]I, where
the methyl groups will be represented by the letter M, the
imidazole group by Im, and the iodide by I. The code for the
In this synthetic approach to the opening of the epoxide ring
the concentration of the reagents, which was initially optimized
in the wet-method, was maintained. This strategy allowed the
conclusion that the solvent-free reaction leads to similar results
when compared to the reaction in toluene. However, the time
Scheme
4
Epoxide ring-opening of
4
catalyzed by methyl- Scheme 5 Opening of the epoxide ring in compound 4 using the ionic
triphenylphosphonium without solvent.
liquids.
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Table 3 Epoxide ring-opening using ionic liquidsa,b,c
Reaction
time
Entry
Ionic liquid
% (7)c
% (8b) or (8c)c
1
2
3
4
5
6
7
8
[MMIm]I
[PMIm]I
[BMIm]I
ꢂ100
ꢂ95
ꢂ95
ꢂ95
95
95
95
95
—
5 h
5 h
7 h
7 h
6 h
6 h
7 h
7 h
Trace
Trace
Trace
ꢂ5
Scheme 7 Synthetic strategy for 1-O-alkyl glycerols 1, 2 and 3 by one-
pot reaction.
[HMIm]I
[PMIm]Br
[BMIm]Br
[PentMIm]Br
[HMIm]Br
ꢂ5
ꢂ5
processes, purication of intermediates, saves time, resources
and in some cases leads to better yields.
ꢂ5
a
M ¼ methyl; P ¼ propyl; B ¼ butyl; Pent ¼ pentyl; H ¼ hexyl; Im ¼
In this approach, the sequence of reactions is initiated by the
formation of glycidyl ethers 4, 5 and 6. Next, there is the
conversion to the corresponding hydroxyl esters 7, 9, and 10 by
the action of benzoic acid catalyzed by a surfactant (MePPh3I or
1,3-dimethylimidazole). Hydroxy esters 7, 9 and 10 are turned
into the aimed 1-O-alkyl glycerols 1, 2, and 3 by basic hydrolysis.
In the conditions used, 1-O-alkylglycerols 1, 2, and 3 were ob-
tained by the one-pot method in yields of 85%, 80% and 87%,
respectively. The total synthesis of 1, 2 and 3 is described on
Scheme 7.
It was observed that the yields obtained by the one-pot
method were lower for compounds 1 (85%) and 2 (80%) when
compared to the conventional method (Scheme 7). In the latter,
compounds 1, 2, and 3 were obtained in overall yields of 90%,
93%, 87%, respectively. This may be associated with the time
required for the maximum conversion of epichlorohydrin to
glycidyl ether, and operational errors during purication of the
targeted product which is relatively polar.
b
imidazole; I ¼ iodide; Br ¼ bromide. Reaction conditions: 4 (1
mmol), PhCO2H (2 mmol), ionic liquid (1 mmol%). T ¼ 100 ꢀC.
c
Isolated yield aer ash chromatography.
other ionic liquids will follow the same pattern and logic, as
seen in Table 3.
The investigation on the use of ILs showed that the promo-
tion of a more homogeneous reaction environment even in
solvent-free conditions allows the reagents to interact in a more
effective way, enhancing the efficacy of the collision between the
molecules and leading to the decrease of reaction time to form
compound 7. The results presented in Table 3 indicate that 1,3-
dimethylimidazole iodide (entry 1) can be considered the most
convenient for the epoxide ring-opening reaction.
Aer conrming the optimal conditions for the preparation
of compound 7 – ideal concentration and type of catalyst – they
were extended to substances 9 and 10 (the hydroxyl esters
containing stearyl (18:0) and oleyl (18:n9) groups, respectively,
in the 1-O-alkyl chain).
The nal step consisted in the treatment of hydroxy esters 7,
9 and 10 with a basic solution (NaOH 30%) to convert them into
the natural 1-O-alkylglycerols 1, 2 and 3 in quantitative yields
(Scheme 6).
Aer achieving the optimal conditions for all three steps
leading to the formation of compounds 1, 2 and 3, an one-pot
reaction was used in order to replicate this synthetic strategy
in a macromolar scale in the future. The one-pot methodology
appears to be ideal since it avoids tedious separation/extraction
It is worth of mention that the yields in this work were
calculated through the mass/mass ratio of isolated pure prod-
ucts and some were puried through conventional ash
chromatography.
Conclusion
The rst step of this study consisted of the synthesis of the three
glycidyl ethers 4, 5, and 6 through a solvent-free reaction using
epichlorohydrin as starting material in the presence of long
chain alcohols – cetyl, stearyl and oleyl, and having tetrabuty-
lammonium hydrogen sulfate as phase-transfer catalyst in basic
medium. This methodology proved to be efficient, robust and of
easy experimental execution, allowing the preparation of
desired compounds 4, 5, and 6 in high yields (95, 98, 92%
respectively).
In the second step, the preparation of hydroxyl esters 7, 9,
and 10 was developed starting with a chemoselective epoxide
ring-opening reaction of glycidyl ethers 4, 5, and 6, employing
ammonium/phosphonium salts and ionic liquids. In all cases,
the preferential formation of mono-esters 7, 9, and 10 was
observed. Moreover, among the ammonium/phosphonium
salts studied, methyltriphenylphosphonium iodide was shown
to be the most selective. The ILs turned out to be alternative
catalysts to the onium quaternary salts, given that they favor the
formation of intermediates 7, 9, and 10, decreasing the reaction
time in solvent-free conditions.
Scheme 6 Total synthesis of 1-O-alkyl glycerols 1, 2 and 3.
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The third step involved the preparation of 1-O-alkylglycerols
1, 2, and 3, which were obtained by a basic hydrolysis of
hydroxyl esters 7, 9, and 10 in alcoholic medium with full
conversion.
8 B. Z. Ngwenya and D. M. Foster, Proc. Soc. Exp. Biol. Med.,
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9 M. Yokota, S. Yahagi, Y. Tokudome and H. Masaki, J. Oleo
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In conclusion, the pathways followed for the preparation of 10 A. Brohult, J. Brohult and S. Brohult, Acta Chem. Scand.,
chimyl (1), batyl (2) and selachyl (3) alcohols enabled the 1970, 24, 730.
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ates, diminishes the number of steps, saves time and reagents
in addition to generating less residues for the environment.
A. L. M. Albert, L. G. F. Chantre, S. de P. Machado,
R. S. C. Lopes and C. C. Lopes, International Journal of
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Conflicts of interest
14 B. Hallgren, Ether Lipids, Biochemical and Biomedical Aspects,
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The authors declare no competing nancial interest.
Acknowledgements
The authors acknowledge and thank the nancial support from
´
17 M. Sutter, W. Dayoub, E. Metay, Y. Raoul and M. Lemaire,
˜
`
Fundaçao Carlos Chagas Filho de Amparo a Pesquisa do Estado
Green Chem., 2013, 15, 786.
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do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvi-
´
´
˜
mento Cientıco e tecnologico (CNPq) and Coordenaçao de
´
Aperfeiçoamento de Pessoal de Nıvel Superior (CAPES).
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