Tin-mediated synthesis of lyso-phospholipids

Article abstract of DOI:10.1039/b604636c

1-O-Acyl-sn-glycero-3-phosphocholine and 1-O-acyl-sn-glycero-3-phosphoric acid have been prepared selectively and with high yields from the corresponding diols, glycerophosphoryl choline and glycerol-3-phosphate. Starting from the diols, the activated tin ketals were prepared in 2-propanol by reaction with dialkyltin oxide. The intermediates were acylated in the same solvent with long-chain fatty acid chlorides, giving the corresponding 1-acyl-lyso- phospholipids in high yield and with complete regioselectivity. The catalytic nature of the tin-mediated acylation and the relevance of the solvent are discussed. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b604636c

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Tin-mediated synthesis of lyso-phospholipids†
a
a
a
a
b
a
Ezio Fasoli,‡ Alberto Arnone, Antonio Caligiuri, Paola D’Arrigo, Lorenzo de Ferra and Stefano Servi*
Received 30th March 2006, Accepted 12th June 2006
First published as an Advance Article on the web 4th July 2006
DOI: 10.1039/b604636c
1-O-Acyl-sn-glycero-3-phosphocholine and 1-O-acyl-sn-glycero-3-phosphoric acid have been prepared
selectively and with high yields from the corresponding diols, glycerophosphoryl choline and
glycerol-3-phosphate. Starting from the diols, the activated tin ketals were prepared in 2-propanol by
reaction with dialkyltin oxide. The intermediates were acylated in the same solvent with long-chain
fatty acid chlorides, giving the corresponding 1-acyl-lyso-phospholipids in high yield and with complete
regioselectivity. The catalytic nature of the tin-mediated acylation and the relevance of the solvent are
discussed.
Introduction
are obtained. Alternatively, the removal of a fatty acid chain from
structured phospholipids of synthetic origin allows the formation
of compounds with a defined composition of the acyl chain at
position sn-1. However, synthesis of structured phospholipids
is a multi-step process in itself, starting from enantiomerically
Lysophospholipids (LPL) are glycerophospholipids in which
one hydroxyl group in the glycerol backbone is acylated. The
combination of hydrophilic and lypophilic parts in one molecule
in the presence of a free hydroxyl group confers special properties
to LPLs. Their presence modulates the rigidity and stability of cell
pure glycerol derivatives, through tedious protection–deprotection
10,11
steps and then the introduction of the phosphoryl group.
Such
1
wall structure as well as that of model artificial membranes. LPLs
a complex synthetic strategy is not suitable for large-scale prepara-
tion, and hence the use of deacylated glycero-phospholipids, easily
are widely distributed in Nature both in animals and plants, even
though they represent only a small fraction of the cellular lipid
obtainable by alcoholysis of abundant natural phospholipids (PC
2
component. Phosphocholines bearing an acyl chain in the sn-1-
11
or phosphatidyl ethanolamine, PE), as a more viable strategy.
A
position, 1-O-acyl-sn-glycero-3-phosphocholine (1-O-Acyl-PC),
or in the sn-2 position, 2-O-acyl-sn-glycero-3-phosphocholine (2-
O-Acyl-PC), have been studied and synthesised.
LPLs have recently become the focus of special attention, after
it was discovered that in addition to their role in phospholipid
metabolism they also function as secondary messengers, exhibiting
convenient procedure then, is the mono-acylation at position 1 of
12
glycerophosphoryl choline (GPC) 2 (Scheme 1). Compounds of
3
type 2 can be transformed into phospholipids of general structure
9h,12a
5
, through 4 → 3.
However, a direct, selective method of mono-
acylation is not available. As a complement to this strategy, we wish
to report the synthesis of 1-O-acyl-phospholipids starting from
glycerophospholipids, exploiting the high reactivity and selectivity
of stannylene ketals formed in situ (Scheme 1, dashed arrow).
4–7
a broad range of biological activities in their own right.
It is widely accepted that availability of synthetic natural
products is of fundamental importance for solving biomedical
8
problems. Thus synthetic LPC, lysophosphatidic acid (LPA) and
related LPL analogues are needed to elucidate their mechanism
of action, and to study the enzymes involved in their metabolism.
Moreover, they are the key intermediates in the synthesis of all
structured phospholipids. Total synthesis of 1-LPC, LPA and 1-
Results and discussion
Tin-mediated mono-functionalisation of polyols allows us to
achieve two main objectives: high regio- and chemo-selectivity
and rate enhancement.
9
O-acyl-sn-glycero-3-phosphoinositol (1-LPI) have been reported.
A general method for the preparation of these compounds is the
In compounds containing three or more hydroxyl groups, the re-
gioselectivity is the prevalent aspect of the reaction and it has been
phospholipase A
2
(PLA ) catalyzed removal of the acyl chain in
2
13
position sn-2 of a naturally occurring or synthetic phospholipid.
When natural phosphatidylcholine (PC) is used as a starting
material, LPLs with mixed fatty acid compositions at position 1
applied in the selective functionalisation of carbohydrates. In
compounds containing primary and secondary hydroxyl groups,
functionalisation at the primary group prevails. Advantages over
conventional chemical acylation are the short reaction time
14
and the higher selectivity. In most reaction protocols, usually
on model substrates, dibutyltin oxide (DBTO) is used in a
stoichiometric amount in a solvent which must be able to dissolve
the diol. For this reason methanol has usually been employed as
a medium, particularly in carbohydrate chemistry. Under these
conditions, large amounts of acylating agent are consumed by
reaction with the solvent. In some cases the catalytic function
of the tin ketal has been demonstrated on model compounds
(phenylethanediol), but the application to very polar compounds
a
Dipartimento di Chimica, Materiali e Ingegneria Chimica, G. Natta
Politecnico di Milano, Via Mancinelli 7, 20131, Milano, Italy. E-mail:
stefano.servi@polimi.it; Fax: +39 2 23993080; Tel: +39 2 23993047
b
Chemi SpA, Patrica (Fr), Italy
†
Electronic supplementary information (ESI) available: General exper-
1
imental procedures, detailed experimental conditions, copies of H and
13
C NMR spectra and ESI MS spectra, and an HPLC trace for a typical
reaction. See DOI: 10.1039/b604636c
Current address: University of Puerto Rico at Humacao, Department of
Chemistry, CUH Station, Humacao 00791, Puerto Rico
‡
2
974 | Org. Biomol. Chem., 2006, 4, 2974–2978
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Scheme 1 Possible ways from natural lecithins to 1-acyl-LPL.
is hampered by the low solubility and low reaction rates when a
Choice of the solvent
non-polar medium is used. We have recently shown that in the
benzoylation of phenylethanediol in the presence of DBTO, the
initially formed tin ketal acts in subsequent steps as the active
Since non-acylated glycerophospholipids are not soluble in non-
protic organic solvents, the choice of the solvent is critical. This
observation finds proof in the different reaction yields obtained
with the use of different solvents.
15
catalyst of the reaction. Several tin ketals obtained from DBTO
and different alcohols (MeOH, 2-PrOH) undergo exchange in the
presence of 1,2-diols, forming primarily the corresponding diol
ketal, which becomes the catalytically active species. If the diol
is not appreciably soluble in the reaction mixture, the formation
of the active ketal is limited and the reaction does not proceed
with the expected mechanism. Applied to the acylation of a
glycerophospholipid, the catalytic cycle can be represented as in
Scheme 2.
In the first experiment, GPC was suspended in a solvent of
low polarity (MTBE, toluene) in the presence of 1 eq. of DBTO,
and the suspension refluxed for 24 h. The mixture was cooled to
◦
0 C and treated with 1.2 eq. of acylating agent (acid chloride)
and 1.2 eq. of triethylamine (TEA). After 15 min at rt, the
mixture was analyzed: only a low conversion was observed (3–
15%), comparable to the one obtained in the absence of the tin
compound. When the experiment was repeated in methanol and
in 2-propanol, the conversions were 40% and >90% respectively.
These results suggest that in non-protic solvents, there is no
catalytic effect from the presence of the tin compound, since either
the ketal is not formed due to the low solubility of the diol or it is
not appreciably soluble. In protic solvents, the tin ketal is readily
The same mechanism has previously been proposed for the
16
tin-catalysed sulfonylation of diols. We present here a reaction
protocol based on the generation of a diol–tin ketal derived from
a glycero-phospholipid in a protic solvent and its reaction with an
acyl chloride to give the 1-LPLs with absolute selectivity and high
yield.
Scheme 2 Catalytic cycle for the tin-mediated monoacylation of glycerophospholipids.
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formed and the reaction proceeds at a higher rate than in the
absence of the tin species. In methanol the conversion is limited
due to the competitive acylation of the solvent.
alkyltin oxide with the diol (or preformed in a separate reaction
and treated with the acylating agents in the presence of a base)
is itself the catalyst of the acylation. Thus GPC was refluxed in
2-propanol in the presence of 5 mol% of DBTO and the mixture
then treated as previously described. After 15 min reaction, the
conversion in this case also exceeded 90%.
In a second set of experiments, GPC was treated with 1 eq. of
DBTO in methanol (2.5 g in 100 ml) and the suspension refluxed
for 3 h. This treatment afforded a clear solution, presumably
17
containing the corresponding tin-ketal. The solvent was removed
from the clear solution and the residue resuspended in the series of
non-protic solvents as above, and treated with the acylating agent
under the same conditions as described before. The conversions
observed with this procedure are between 3% (MTBE) and 22%
Significance of the tin-mediated acylation of glycerophospholipids
When compared to other methods of mono-functionalisation of
GPCs, the present approach gives mono-acyl derivatives free from
the regioisomer usually produced by reaction protocols involving
the use of acidic conditions during the reaction or in the isolation
procedure. The possibility of forming the stannylene ketal and the
successive acylation reaction in a protic solvent that does not inter-
fere with the acylation reaction is the key point of the procedure.
The method is general, giving comparable yields with saturated
and unsaturated fatty acid derivatives of different lengths. Thus,
in completely identical procedures, 1-stearoyl-, 1-lauroyl- and 1-
oleyl-LPCs were obtained. The method is applicable also to the
acylation of 3-glycerophosphate (GPA). Glycerophosphoric acid
disodium salt, insoluble in 2-propanol, was transformed into the
mono-DMAP salt to improve its solubility. This was suspended in
(
DMF), suggesting that the solubility of the ketal controls the
entire reaction cycle. Suspending the crude material obtained from
the above treatment in 2-propanol and treating it further with acid
chloride and base led to an excellent yield of the mono-acylated
compound, with an excellent selectivity as well. Thus, the synthesis
of tin-ketal was then performed directly in 2-propanol, and these
conditions proved to be the most efficient for the mono-acylation
of GPC; in fact, esterification of the solvent does not occur at a
comparable rate. GPC was refluxed for 1 h in 2-propanol in the
presence of 1 eq. of DBTO at a concentration of 2.5 g in 100 ml. The
◦
reaction was cooled to 25 C and treated with 1.2 eq. of acylating
agent and 1.2 eq. of TEA. The mixture was stirred at rt for 15 min.
HPLC analysis of the reaction showed a 95% yield of 1-LPC. The
product was purified by extraction and crystallisation, as described
in the Experimental section. The positional purity was evaluated
2
-propanol and refluxed in the presence of Bu SnO, leading to a
2
soluble tin ketal derivative. Palmitoylation with 1.2 eq. of the acid
chloride in the presence of 1.2 eq. of TEA was rapid, complete
and selective, giving 1-palmitoyl-LPA with more than 90% yield
1
13
from HPLC, H and C NMR, and showed no detectable trace
(Scheme 3) and again free from the regioisomer. The selectivity
10b,g,h
of the isomeric mono-acyl derivative.
The thermodynamic
and reaction rate observed in this case are particularly surprising
due to the highly functionalised nature of the molecule. Removal
of the tin-containing material from the products was achieved
with a selective extraction/precipitation procedure followed by
crystallisation (see Experimental). The use of catalytic amounts of
tin reagents or an immobilised catalyst should allow an easier and
mixture of 1-LPC and 2-LPC obtained by acyl migration of one
fatty acid chain from the sn-1 to the sn-2 position and vice versa
was formed in slightly acidic conditions or in methanol solution in
a time-dependent manner. On the other hand, acylation of GPC
without the formation of tin ketal gave the usual ratio of isomers
with a much lower reaction rate. The amount of acylating agent
determines the conversion when methanol is used as a solvent. In
the case of 2-propanol, an optimum of conversion was obtained
with 1.2 eq. of palmitoyl chloride at rt (97%). As an alternative to
the acid chloride, palmitoyl anhydride, palmitic acid and methyl
palmitate were used. In the case of anhydride, 15% conversion
was observed, while there was no reaction with the ester or the
carboxylic acid. Using 4-(dimethylamino)pyridine (DMAP) as the
base had no advantages over TEA, which was required in a 1 : 1
ratio with the acyl chloride.
19
complete removal of tin from the reaction mixture.
Scheme 3 Reagents and conditions: i) 2-PrOH, DBTO, reflux; ii) TEA,
ꢀꢀꢀ
R COCl, rt.
Acylation of the preformed tin intermediate obtained as de-
scribed was strongly dependent on the solvent used. Using 1.2 eq.
of palmitoyl chloride in 40 volumes of solvent at rt for 15 min,
the conversions ranged from 3% for MTBE to 22% for DMF,
the remaining solvents giving conversions in the following order:
Conclusions
Glycerophosphorylcholine, easily obtained from natural lecithins
by purification-hydrolysis, is the natural synthon from which most
structured phospholipids can be obtained, through the sequential
introduction of acyl chains and eventual modification of the polar
head via transphosphatidylation reaction catalysed by phospho-
lipase D. However, mono-functionalisation of glycerophosphate
derivatives is not efficient due to their low solubility in organic
solvents and the low selectivity of the acylation step. We have
shown in this paper that mono-acylation of the tin ketal (easily
prepared from either a stoichiometric or a catalytic amount
of dialkyltin oxides or their equivalent), can be performed in
2-propanol, in which the solubility and reactivity of GPC is
CHCl
3
< t-BuOH < CH
3
CN < CH
2
2
Cl < Tol < THF < DMF.
Catalytic nature of the tin-mediated acylation
3
1
During the reaction of GPC with DBTO, the P NMR spectra
of the mixture showed a peak attributed to the tin ketal, which
18
never exceeded 40%. Since in these conditions the conversion
with respect to the acylating agent was close to 100%, the data
confirms a catalytic mechanism.
We have recently shown in the simple benzoylation of
phenylethanediol that the tin ketal formed in situ by reaction of an
2
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appreciable, and the acylation of the solvent by the long-chain
fatty acid chlorides of little significance. Under these conditions,
the formation of 1-acyl-LPC is rapid and complete. The reaction
has also been applied to the preparation of 1-acyl-LPA from (R)-
glycerophosphate with high yields and selectivity.
ice bath, and TEA (1.2 ml, 7.9 mmol) and stearoyl chloride (2.3 g,
7.9 mmol) were added. The reaction was stirred for 35 min at room
temperature. A sample from the reaction mixture was analysed
(HPLC) and shown to contain 1-stearoyl-LPC and GPC in the
ratio 95 : 5. Isolation of the product was performed as previously
described for the palmitoyl analogue.
Experimental
1-O-Oleoyl-sn-glycero-3-phosphocholine (1-O-Oleo-PC)
1-O-Hexadecanoyl-sn-glycero-3-phosphocholine (1-O-Palm-PC)
A suspension of GPC (1.85 g, 7.2 mmol) and DBTO (1.90 g,
7
6
.6 mmol) in 2-propanol (30 ml) was heated under reflux for
h. The resulting suspension was then cooled to 25 C in an
GPC (10 g, 39 mmol) and DBTO (10.65 g, 43 mmol) were
suspended in 2-propanol (400 ml) and refluxed for 1 h. The
mixture was cooled to 25 C, and treated with TEA (6.5 ml,
◦
◦
ice bath, and TEA (1.2 ml, 7.9 mmol) and oleoyl chloride (2.1 g,
.9 mmol) were added. The reaction was stirred for 35 min at room
temperature. A sample from the reaction mixture was analysed
HPLC) and shown to contain 1-oleoyl-LPC and GPC in the
7
4
7 mmol) and palmitoyl chloride (12.8 g, 47 mmol). The formation
of the lysoPC and the disappearance of GPC was followed by
HPLC. After 15 min at rt, a sample from the reaction mixture
was analysed (HPLC) and shown to contain 1-palmitoyl-sn-
(
ratio 95 : 5. Isolation of the product was performd as previously
described for the palmitoyl analogue.
2-lyso-phosphatidylcholine (97%) and GPC (3%) as the only
phospholipids. The solution was treated with water (400 ml) and
extracted with heptane (400 ml). The water–alcohol solution was
extracted again with heptane (3 × 250 ml). The heptane phase
contained the tin compounds and the product of reaction between
excess palmitoyl chloride and the solvent (isopropyl palmitate).
The water–alcohol solution was evaporated, the residue dissolved
1
-O-Dodecanoyl-sn-glycero-3-phosphocholine (1-O-Laur-PC)
A suspension of GPC (1.85 g, 7.2 mmol) and DBTO (1.90 g,
7
2
.6 mmol) in 2-propanol (30 ml) was heated under reflux for
◦
h. The resulting suspension was then cooled to 25 C in an
ice bath, and TEA (1.2 ml, 7.9 mmol) and lauroyl chloride (1.6 g,
.9 mmol) were added. The reaction was stirred for 35 min at
room temperature. A sample from reaction mixture was analysed
HPLC) and shown to contain 1-lauroyl-LPC and GPC in the
in ethanol (100 ml) and precipitated with acetone (400 ml) at
7
◦
−
10 C, leading to 15 g of a white powder (80%). The product was
crystallised from ethanol (7.5 g, 40%). Elemental analysis showed
a tin content of 90 ppm. H NMR and C NMR spectra were
identical to those reported in the literature
(
1
13
ratio 95 : 5. Isolation of the product was performed as previously
described for the palmitoyl analogue.
9e,20
1
-O-Hexadecanoyl-sn-glycero-3-phosphoric acid DMAP salt
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