New synthetic strategies toward pure two-component triglycerides

Article abstract of DOI:10.1055/s-1999-2936

Pure two-component triglycerides were prepared following new synthetic strategies that involve the acylolytic cleavage of glycerol acetals.

Full text of DOI:10.1055/s-1999-2936

LETTER
1835
New Synthetic Strategies Toward Pure Two-Component Triglycerides
Jean-Louis Gras*, Jean-François Bonfanti
Université d’AIX-MARSEILLE III, Laboratoire RéSo, CNRS-UMR 6516, Faculté des Sciences St Jérôme - D12,
F-13397 Marseille Cedex 20, France
E-mail: jean-louis.gras@reso.u-3mrs.fr
Received 2 August 1998
Abstract: Pure two-component triglycerides were prepared follow-
ing new synthetic strategies that involve the acylolytic cleavage of
glycerol acetals.
Key words: acetals, acylation, glycerol, esters
Scheme 1
Triglycerides are the most common compounds among
lipids, especially within food classes such as dairy prod-
cleavage of benzylidene and isopropylidene acetals. The
strategy affords a simple access toward pure glycerides
that circumvents the usual deprotection step.
ucts and vegetable oils. Since triglycerides that make nat-
ural fats include 2 or 3 different fatty acids, the possibility
of isomerism known as glyceridic repartition arises. Ob-
taining pure mixed triglycerides is of great interest partic-
ularly for SAR studies or, simply, to determine the
structure of a given glyceride.1
Benzylidene glycerol 1 can readily be prepared by reflux-
ing glycerol and benzaldehyde under acid catalysis in a
Dean-Stark apparatus.7 The free secondary alcohol was
then esterified under mild conditions with a saturated (va-
leric, capric) or unsaturated (oleic) fatty acid R1COOH us-
ing DCC and DMAP.8 This protocol was more efficient
than use of the Mitsunobu reaction.9 The benzylidene ac-
etal of ester 2 was submitted to acylolytic cleavage with
TFAA combined to a second fatty acid, R2COOH (4
equivalents of each), to afford directly the symmetrical
two-component triglyceride 3 (Scheme 2).10
The classical synthetic approach to glycerides starts with
the esterification of the free alcohol of a diprotected glyc-
erol. Removal of the protecting group frees the two re-
maining alcohols that can then be esterified in turn to
provide a di- or triglyceride. This simple strategy is often
complicated by isomerization, i.e. scrambling of the fatty
chains. Indeed acyltropy, the migration of an acyl chain,
from the internal position to an external position is very
favored,2 and leads to a mixture of isomeric glycerides.
We report here new strategies directed toward the synthe-
sis of mixed triglycerides, that afford pure compounds.
The basic idea was to avoid the classical deprotection step
(source of a free OH), thus preventing isomerization. With
this strategy the hydroxy protecting group was also to
function as a reacting center.
Scheme 2
Acetals of polyols can be cleaved to the corresponding
peracetates, and further to the diols, through acetolysis
with a mixture of acetic anhydride and sulfuric acid.3 The
same cleavage can be obtained using a mixture of trifluo-
roacetic anhydride (TFAA) and AcOH that generates the
mixed anhydride CF3COOAc.4 Reports of use of this re-
action are limited, except a few applications on sugar sys-
tems (for example in the synthesis of L-ribofuranose
derivatives).5 In this reaction of acetals the intermediate
mixed acetal cannot be isolated. Being more reactive than
the precursor, it undergoes a second cleavage faster
(Scheme 1).
Though reaction times may appear somewhat long, this
new bis-esterification is in practice very convenient: com-
mercial grade reagents were used and the reaction was run
at room temperature. Saturated or unsaturated fatty acids
of any length can be employed (Table 1). The strategy did
not generate any free OH and thus the acyltropy phenom-
The anhydride reagent can be replaced by an acid chloride
that, in conjunction with ZnCl2, affords the required acy-
lium ion.6
We have extended the acetolysis of acetals to the use of
fatty acids along with TFAA, to induce an acylolytic
Synlett 1999, No. 11, 1835–1837 ISSN 0936-5214 © Thieme Stuttgart · New York

1836
J.-L. Gras, J.-F. Bonfanti
LETTER
enon was totally avoided. No trace of isomer could be de- We have shown that common diol protecting groups such
1
tected within the range of accuracy of H and 13C NMR as benzylidene or isopropylidene acetals, can be used as
spectroscopy at 200 and 50 MHz.10
reacting centers to introduce two ester functions simulta-
neously onto a 1,2- and 1,3-dihydroxyl substrate. When
applied to glycerol acetals and fatty acids, this acylolytic
cleavage represents a new pathway toward both symmet-
rical or asymmetrical triglycerides. The method is
straightforward and, above all, gives pure compounds.
Industrially produced isopropylidene glycerol (solketal) 4
is a building block complementary to 1 in the sense that
the same strategy, devoted to introduce two fatty chains at
once, would afford asymmetrical triglycerides rather than
symmetrical. Esterification of 4, under the same mild con-
ditions as previously reported, afforded primary ester 5 in
nearly quantitative yield. Acylolytic cleavage of 5 with
TFAA and R2COOH (4 equivalents of each) directly in-
troduced the second fatty acid on the two vicinal positions
of glycerol in a reasonable yield (Scheme 3, Table 2).10
Acknowledgement
The authors are grateful to the Corsican Region Council for a grant
to JFB.
References and Notes
(1) Han, L.; Razdan, R.K. Tetrahedron Lett., 1999, 40, 1631-1634
(2) Selected examples of acyltropy: Kodali, D.R; Tercyak, A.;
Fahey, D.A.; Small, D.M. Chem. Phys. Lipids, 1990, 52, 163-
170; Van Middlesworth, F.; Lopez, M.; Zweerink, M.; Edison,
A.M.; Wilson, K. J.Org.Chem., 1992, 57, 4753-4754
(3) Haskins, W.T.; Hann, R.M.; Hudson, C.S. J.Am.Chem.Soc.,
1942, 132-136; Senkus, M. J. Am.Chem.Soc., 1946, 734
(4) Bourne, E.J.; Burdon, J.; Tatlow, J.C. J.Chem.Soc., 1959,
1864-1870
Scheme 3
(5) Chelain, E.; Floch, O.; Czernecki, S. J.Carbohydr. Chem.,
1995, 14, 1251-1256
(6) Nifant’ev, E.E.; Predvoditelev, D.A.; Russ.Chem.Rev, 1997,
66, 43-52
(7) Crich, D.; Beckwith, A.L.J.; Chen, C.; Yao, Q.; Davison,
I.G.E.; Longmore, R.W.; de Parrodi, C.A.; Quintero-Cortes,
L.; Sandoval-Ramirez, J. J.Am.Chem.Soc., 1995, 117, 8757-
8768
(8) Neises, B.; Steglich, W. Angew.Chem.Int.Ed.Engl., 1978, 17,
522-524
(9) Gras, J.-L.; Dulphy, H.; Marot, C.; Rollin, P. Tetrahedron
Lett., 1993, 34, 4335-4336
The asymmetrical 2-component triglycerides 6 were ob-
tained pure, as indicated by their 200 MHz NMR spectra
which differed from their isomers prepared via the previ-
ous strategy.10 In this case too, saturated or unsaturated
fatty acids could be used, and the reaction was useful for
any chain length.
(10) General procedure for the acylolysis of glycerol acetals 2 and
5: The acetal ester (0.25 mmol) was dissolved in dry CH2Cl2
(1.25 ml). TFAA (1 mmol), then the fatty acid (1 mmol) were
added at 0°C under argon. The ice bath was removed and the
mixture was stirred at rt for 1-3 d according to TLC
monitoring. The solvent was distilled off under vacuum and
the residue was chromatographed to afford triglycerides 3 or
6.
It was found that the reaction could be accelerated by the
assistance of catalytic BF3.Et2O. Solketal ester 7 was
cleaved to glyceride 8 with the acylolyzing mixture palm-
itic acid/TFAA/BF3.Et2O, in 80 % yield (Scheme 4). Less
reagent was needed (3 equiv. of palmitic acid) and the re-
action was much faster (2 h).
NMR differentiation of isomeric triglycerides 3a and 6a:
1,3-dibehenoyl-2-valeroyl-rac-glycerol 3a: 1H NMR (CDCl3,
200 MHz) d in ppm, J in Hz. H1, H3 = 4.27 (dd, J = 11.9, 4.3)
and 4.12 (dd, J = 11.9, 5.9); H2 = 5.25 (m); H5 = 2.30 (t, J =
7.2); H27, H32 = 2.29 (t, J = 7.3); H6, H28, H33 = 1.66-1.51 (m);
H7-H24, H29, H34-H51 = 1.38-1.23 (m); H25, H52 = 0.85 (t, J =
6.7); H30 = 0.89 (t, J = 7.4).13C NMR (CDCl3, 50 MHz) d in
ppm. C1, C3 = 62.2; C2 = 69.0; C4, C26, C31 = 173.4 and 172.9
(2 lines); C5, C32 = 34.1; C27 = 34.0; C6, C33 = 25.0; C28 = 27.0;
C7-C22, C34-C49 = 29.8-29.2 (5 lines); C23, C50 = 32.0; C24, C51
= 22.8; C29 = 22.3; C25, C52 = 14.2; C30 = 13.7.
Scheme 4
Attempts to generalize this new procedure led to mixed
results: the reactions were faster but the yields were
slightly lower, mostly 50-60 %. We did not pursue that
optimization.
Synlett 1999, No. 11, 1835–1837 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
New Synthetic Strategies Toward Pure Two-Component Triglycerides
1837
1-valeroyl-2.3-dibehenoyl-rac-glycerol 6a: 1H NMR (CDCl3,
(2 lines); C5, C27, C32 = 34.1, 34.3, 33.8; C6, C33 = 24.9; C28
27.0; C7-C22, C34-C49 = 29.8-29.2 (5 lines); C23, C50 = 32.0;
C24, C51 = 22.8; C29 = 22.3; C25, C52 = 14.2; C30 = 13.7.
=
200 MHz) d in ppm, J in Hz. H1, H3 = 4.28 (dd, J = 11.9, 4.3)
and 4.12 (dd, J = 11.9, 6.0); H2 = 5.25 (quint, J = 2.4); H5, H27,
H32 = 2.29 (2t, J = 6.8 and 7.7); H6, H28, H33 = 1.65-1.54 (m);
H7-H24, H29, H34-H51 = 1.37-1.23 (m); H25, H52 = 0.86 (t, J =
6.7); H30 = 0.89 (t, J = 7.3). 13C NMR (CDCl3, 50 MHz) d in
ppm. C1, C3 = 62.2; C2 = 68.9; C4, C26, C31 = 173.3 and 172.9
Article Identifier:
1437-2096,E;1999,0,11,1835,1837,ftx,en;G20599ST.pdf
Synlett 1999, No. 11, 1835–1837 ISSN 0936-5214 © Thieme Stuttgart · New York