A new strategy to synthesize pure mixed diglycerides

Article abstract of DOI:10.1055/s-2000-6484

The acylolytic cleavage of glycerol methylene acetals with fatty acids provides a new synthetic strategy that leads to pure mixed 1,2-diglycerides.

Full text of DOI:10.1055/s-2000-6484

2
48
LETTER
A New Strategy to Synthesize Pure Mixed Diglycerides
*
Jean-Louis Gras , Jean-François Bonfanti
Université d’AIX-MARSEILLE III, Laboratoire RéSo, CNRS-UMR 6516, Faculté des Sciences St Jérôme - D12, 13397 Marseille
Cedex 20, France
E-mail: jean-louis.gras@reso.u-3mrs.fr
Received 29 October 1999
Abstract: The acylolytic cleavage of glycerol methylene acetals
with fatty acids provides a new synthetic strategy that leads to pure
mixed 1,2-diglycerides.
Key words: methylene acetals, acylation, glycerol
Scheme 1
Diglycerides are important bioagents, precursors of tri-
1
2
glycerides, of phospholipids and of glycolipids. The
symmetrical or asymmetrical monoacid diglycerides are
relatively easy to prepare and the 1,3-isomer usually crys-
tallizes. The mixed asymmetrical diglycerides are more
difficult to obtain, particularly as a single isomer. Various
approaches have been developed that mostly used protect-
drolyzed or methanolyzed to the alcohol, and the overall
process leads to a hydroxyl ester.
15
We have applied this new strategy to the synthesis of fatty
esters of 5-hydroxy-1,3-dioxane (1). Methyleneglycerol 1
can be selectively prepared by transacetalization of glyc-
1
6
3
erol and dimethoxymethane or by chemoselective reac-
ed forms of glycerol such as the carbonate, or protected
forms of solketal: trityl-, benzyl-, MEM-ether. Several
protected forms of glycidol have also been used as sources
tions of glyphoral.17 Esterification of the secondary
4
5
6
1
alcohol in 1 with a fatty acid R COOH and dicyclohexyl-
7
8
9
carbodiimide (DCC) in the presence of 4-dimethylami-
nopyridine (DMAP) afforded dioxane esters 2 (table).
of diglycerides: ester, levulinate, trityl-, and silyl
1
0
ether.
The methylene acetal function of ester 2 underwent an
These classical strategies employed the chemoselective
1
1
acylolytic cleavage upon reaction with TFAA and a sec-
esterification of a primary vs a secondary alcohol or pro-
tection/deprotection sequences on hydroxyl groups. Dur-
ing these synthetic operations the migration of a fatty
chain from the internal (2) position to an external (1 or 3)
position, or equilibrium leading to mixtures of isomers,
plagued most syntheses of pure diglycerides. Chemists
have thus focused their interest on the use of specific
2
ond fatty acid R COOH, 2.2 equivalents of each at room
temperature. The slow reaction, between 1 and 5 days,
was finally quenched by selective methanolysis of the sta-
ble trifluoroacetate intermediate, to give hydroxyl ester 3
in fairly good yields (table method A).18
methods that would limitate the phenomenon of acyltro-
py.12, 13
We describe herein a new strategy aimed at the synthesis
of mixed asymmetric diglycerides (1,2-diglycerides) that
affords pure compounds. The strategy is based on the spe-
cific properties of methylene acetals, a protecting group
never used in glycerolipid chemistry.
Scheme 2
We have shown that the cleavage of glycerol acetals by an
acyl ion (acylolysis) was a convenient method for the syn-
The mild experimental conditions for the initial methyl-
ene acetal cleavage and for the final methanolysis allowed
the formation of pure mixed diglycerides 3, as indicated
by their NMR spectra. NMR is suitable to identify and to
determine the purity of the diglycerides.19 The chemical
shifts of protons and carbons are nearly unaffected of the
nature of the attached acyl chains. Therefore 1,2- and 1,3-
diglycerides display a characteristic NMR spectrum for
1
4
thesis of pure mixed triglycerides. It made possible the
double connection of a fatty chain directly onto the pro-
tected diol synthon of glycerol monoesters. For the syn-
thesis of diglycerides we took advantage of the specific
reactivity of methylene acetals that allowed desymmetri-
zation of the two oxygen atoms forming the acetal bridge
(
Scheme 1).
2
0
the protons and carbons of the glyceryl backbone. Only
in the case of short chains (C , C ) have we observed trac-
The mixture of a carboxylic acid and trifluoroacetic anhy-
dride (TFAA) generates a mixed anhydride that cleaves a
methylene acetal moiety to an ester and a trifluoroacetoxy
methyl ether. This latter function can be selectively hy-
2
5
es of the 1,3-isomer (<5%).
The reaction was possible in the presence of an unsatura-
1
tion. When R was unsaturated, the reaction simply re-
Synlett 2000, No. 2, 248–250 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
A New Strategy to Synthesize Pure Mixed Diglycerides
249
Table Synthesis of asymmetric mixed 1,2-diglycerides 3 from 2 in
the presence of Triflic anhydride (Method A: without BF ∑OEt acti-
In conclusion we have described the acylolytic cleavage
of methylene acetals by a fatty acid combined to TFAA.
This reaction, activated or not by BF ∑OEt , provides a
3
2
vation; method B: with BF ∑OEt )
3
2
3
2
new strategy for the synthesis of mixed 1,2-diglycerides
when applied to the dioxane isomer of glycerol formals.
The method is simple, applicable to saturated and unsatur-
ated fatty chains, and affords topologically pure glycer-
ides.
Acknowledgement
The authors are grateful to the Corsican Region Council for a grant
to JFB.
References and Notes
(
(
(
(
1) Martin, S.F.; Josey, J.A.; Wong, Y.-L.; Dean, D.W.
J.Org.Chem. 1994, 59, 4805-4820
2) Auzely-Velty, R.; Benvengu, T.; Mackenzie, G.; Goodby,
J.W.; Plusquellec, D. Carbohydr. Res. 1998, 314, 65-77
3) Pfeiffer, F.R.; Cohen, S.R.; Williams, K.R.; Weisbach, J.A.
Tetrahedron Lett. 1968, 32, 3549-3552
4) Cordi, A.; Lacoste, J.M.; Duhault, J.; Espinal, J.; Boulanger,
M.; Broux, O.; Husson, B.; Volland, J.P.; Mahieu, J.P.
Arzneim.-Forsch./Drug/Res. 1995, 45 (II), 997-1001;
Ogorodniichuk, A.S.; Skryma, R.N.; Budyga, F.V.;
Prevarskaya, N.B.; Luik, A.I.; Shilin, U.V. Ukr.Khim.ZH.
2
quired 3 equiv of the next fatty acid R COOH. When this
second acid was unsaturated, the acylolysis was also pos-
sible but was too slow to be of practical interest. We relat-
ed these behaviors to complexation between the double
bond and the acyl ion that initiates the cleavage. The reac-
tion is not applicable in the presence of other functional
groups such as an alcohol (12-hydroxy stearic acid) or a
pyridine (nicotinic acid) that directly reacted with the acy-
lolyzing agent.
1
991, 57, 327-329; Chem. Abstr. 1991, 115, 197 998d
(5) Kodali, D.R.; Duclos, R.I. Chem. Phys. Lipids 1992, 61, 169-
173; Golding, B.T. Chem. Ind. 1988, 617-621
(
(
(
(
6) Duralski, A.A.; Spooner, P.J.R.; Watts, A. Tetrahedron Lett.
989, 30, 3585-3588
7) Mank, A.P.J.; Ward, J.P.; Van Dorp, D.A. Chem. Phys. Lipids
976, 16, 107-114
1
1
8) Fröling, A.; Pabon, H.J.J.; Ward, J.P. Chem. Phys. Lipids
1984, 36, 29-38
9) Lok, C.M. Chem. Phys. Lipids 1978, 22, 323-337
Methylene acetals are much more stable than the corre-
sponding ketals and their cleavage was comparatively
slower. This fact and the stability of the trifluoroacetoxy
methyl ether intermediate, allowed to stop the acylolysis
at this stage thus differentiating the oxygens. Although the
reaction could be accelerated by gentle warming to 40 °C,
acyltropy increased up to 25% in the case of esters with a
(
10) Burgos, C.E.; Ayer, D.E.; Johnson, R.A. J.Org.Chem. 1987,
2, 4973-4977
5
(
(
(
11) Jurzak, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447-448
12) Buchnea, D. Lipids 1971, 6, 734-739
13) Eibl, H.; Wooley, P. Chem. Phys. Lipids 1986, 41, 53-63; Eibl,
H.; Wooley, P. Chem. Phys. Lipids 1988, 47, 47-53
short chain like a valerate. Simple acetolysis of sugars has (14) Gras, J.-L.; Bonfanti, J.-F. Synlett 1999, 1835-1837
2
1
(15) Dulphy, H.; Gras, J.-L.; Lejon, T. Tetrahedron 1996, 52, 8517
been effected with Ac O in the presence of BF ∑OEt .
2
3
2
(
(
16) Gras, J.-L.; Nouguier, R.; Mchich, M. Tetrahedron Lett. 1987,
8, 6601-6604
We envisaged that the use of this Lewis acid might accel-
erate the current generalized acylolysis either by activat-
ing the reagent or by neutralizing the electron rich
carbonyl group of the secondary fatty ester in 2.
2
17) Gras, J.-L.; Dulphy, H.; Marot, C.; Rollin, P. Tetrahedron
Lett. 1993, 34, 4335-4336
(18) General procedure for the acylolysis of dioxane ester 2 to
diglyceride 3 (method A): The dioxane ester 2 (0.5 mmol) was
dissolved in dry CH Cl (1.5 mL). TFAA (1.1 mmol or 1.65
Thus, BF ∑OEt (0.1 equiv) was mixed with dioxane ester
3
2
2
2
2
before addition of the acylolyzing mixture. The results
mmol for unsaturated esters) then the fatty acid (1.1 or 1.65
mmol) were added at 0 °C under argon. The ice bath was
removed after 10 min and the solution was stirred at rt until no
starting material was left. The reaction flask was cooled to
reported in the Table are striking: all the reactions involv-
ing saturated acids were completed within 2 h using meth-
od B. Moreover, only 1.1 equiv of the acid was needed,
and the yields were comparable with (or even improved)
the non-activated procedure (Table; method B). The di-
glycerides were obtained with the same purity, i.e. only
trace amounts of the 1,3-isomer in a few cases. However,
0
°C and NaHCO (5 mmol) and MeOH (1.5 mL) were added.
3
After stirring efficiently for 3-5 h the mixture was filtered
through a short pad of silica gel. The solution was
concentrated under reduced pressure and the diglyceride 3
was purified by chromatography on silica.
In the activated reactions (method B), BF ∑OEt (0.05 mmol)
was simply added prior to TFAA.
the BF ∑OEt activation was not applicable to unsaturated
3
2
3
2
compounds due to substantial degradation of the olefin,
both in the acid and in the target glyceride.
(19) Serdarevich, B. J. Amer. Oil Chem. Soc. 1967, 44, 381-393
Synlett 2000, No. 2, 248–250 ISSN 0936-5214 © Thieme Stuttgart · New York

2
50
J.-L. Gras, J.-F. Bonfanti
LETTER
(
20) Haraldsson, G.G.; Gudmundsson, B.O.; Almarsson, O.
Tetrahedron 1995, 51, 941-952; Rabiller, C.; Maze, F. Magn.
Reson. Chem. 1989, 27, 582-584.
(21) Lichtenthaler, F.W.; Breunig, J.; Fisher, W. Tetrahedron Lett.
1971, 30, 2825-2828
Protons of 1,2-diglycerides resonate in 3 groups near 4.2
(
CH -OC), 5.0 (CH-O), 3.7 (CH -OH), and protons of 1,3-
Article Identifier:
2
2
diglycerides resonate in 2 groups near 4.0 (CH -O), 5.3 (CH-
1437-2096,E;2000,0,02,0248,0250,ftx,en;G26299ST.pdf
2
O) (d ppm in CDCl at 200 MHz). The carbon signals are
3
clearly separated: 62.2 (CH -OC), 72.2 (CH-OC), 61.5 (CH -
2
2
OH) in 1,2-diglycerides, and 65.1 (CH -OC), 68.1 (CH-OH)
2
in 1,3-diglycerides.
Synlett 2000, No. 2, 248–250 ISSN 0936-5214 © Thieme Stuttgart · New York