Regioselective, haloacylating cleavage of an oxirane system mediated by trifluoroacetic anhydride/trimethylsilyl halides: An efficient entry to 2-acyl-3-haloglycerols

Article abstract of DOI:10.1055/s-2006-948206

Glycidyl esters in the presence of trifluoroacetic anhydride (TFAA) and trimethylsilyl halides (TMSX), undergo a regio-selective opening of the oxirane system with a subsequent migration of the acyl group to afford 1-trifluoroacetyl-2-acyl-3-haloglycerols

Full text of DOI:10.1055/s-2006-948206

LETTER
2251
Regioselective, Haloacylating Cleavage of an Oxirane System Mediated
by Trifluoroacetic Anhydride/Trimethylsilyl Halides: An Efficient Entry to
2-Acyl-3-haloglycerols
Synthesis of
2
t
e
-haloglyce
p
r
ols han D. Stamatov,*a Jacek Stawinski*b,c
a
Department of Chemical Technology, University of Plovdiv, 24 Tsar Assen St., Plovdiv 4000, Bulgaria
b
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, 106 91 Stockholm, Sweden
E-mail: js@organ.su.se
c
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznan, Poland
Received 7 June 2006
techniques and which contain as major, thermodynamic
products, the corresponding 1(3)-isomers.15,16
Abstract: Glycidyl esters in the presence of trifluoroacetic anhy-
dride (TFAA) and trimethylsilyl halides (TMSX), undergo a regio-
selective opening of the oxirane system with a subsequent migration
of the acyl group to afford 1-trifluoroacetyl-2-acyl-3-haloglycerols.
From these, the corresponding 2-acyl-3-haloglycerols can be ob-
tained quantitatively and in high purity (>99%) without chromato-
graphic purification.
In this context, development of isosteres of 2-MAG for
biochemical intervention or as starting materials in a con-
vergent synthesis of various bioconjugates, has become a
timely issue relevant to further progress in this field. Since
the presence of a free, primary hydroxyl group next to an
acyl functionality at the C-2 carbon of glycerol is essential
for maintaining bioactivity of 2-MAG,7 we turned our at-
tention to 2-acyl-3-halo-propanols-1 in view of the close
resemblance to 2-acylglycerols and diverse possibilities
of their synthetic applications, e.g. in the preparation of
1(3)-asymmetrically derivatized isosteres of 2-MAG,
construction of three-functional group models for D/halo-
gen isotope labeling12,13,15 or as regioisomeric ester ana-
logue building blocks for various natural products18,19 or
anticancer agents.20
Key words: glycidyl esters, trimethylsilyl halides, trifluoroacetic
anhydride, 2-O-acylated 1,3-terminal halohydrins, 2-acylglycerol
isosters
2-Monoacylglycerols (2-MAG) have been receiving a
steadily growing interest as potent and diverse modulators
of protective or physiopathological events in living organ-
isms,1 as endogenous carriers of fatty acids through intes-
tinal mucosa,2,3 or metabolic precursors to triglycerides
with biologically important acyl residues at the 2-position
of a glycerol skeleton.3 Due to their dual function as vehi-
cle molecules for biologic information and physiological
effectors per se, isosteric forms of these unique lipid me-
diators surfaced as synthetic tools providing structural
templates for rational design of micromolecular vectors
for drug delivery,4 endocannabinoid ligands mimetics,5–7
antioxidants,8 or triglyceride frameworks of significance
to human nutrition9 and membranology.10 Incorporation
of a halogen atom into either the glycerol backbone or fat-
ty acid residues, along with variations of the substitution
pattern around the C-2 center of ether and ester analogues
of 2-MAG, appeared to be of special interest in develop-
ing new therapeutics,11 or biochemicals,12 and medicinal
diagnostics.13
Although the ring-opening of epoxides to produce vicinal
haloalkanols (e.g., by metal halides,19,21 ammonium ha-
lides,22 hydrohalides,23 elemental halogens24), or to vici-
nal haloesters (e.g. with acyl chlorides alone,25 in the
presence of CrO2Cl2,26 CoCl2,27 Bu2SnCl2/Ph3P,28 or by
means of TiCl4/EtOAc/imidazole29), seemed a viable
methodology for our purpose, this chemistry finds no lit-
erature precedents regarding a direct synthesis of 2-acyl-
3-haloglycerols from their appropriate oxirane conge-
ners.30
As part of our research, we recently proposed a general
route to 2-acylglycerols and related prodrug frame-
works,31,32 based on a trifluoroacetic anhydride (TFAA)-
assisted fission of the oxirane ring of glycidyl esters with
a synchronous migration of the acyl group to the internal
C-2 position within the glycerol skeleton. Here, we report
that TFAA in the presence of trimethylsilyl halide
(TMSX; X = Cl, Br or I), can govern a haloacylating
cleavage of the terminal epoxy system with an acyl migra-
tion to produce halotrifluoroacetates 3–6 (step A,
Scheme 1), in practically quantitative yields. Since the
subsequent removal of a trifluoroacetyl transient protec-
tion can be carried out quantitatively and without final pu-
rification (step B, Scheme 1), this two-step reaction
sequence offers a novel strategy to regioisomerically ho-
mogeneous 1(3)-halogenated isosters of 2-MAG 7–10.
2-Monoacylglycerols alone did not contribute much to the
aforementioned applications due to their high susceptibil-
ity to acyl migration during synthesis, isolation, and stor-
age,5,14,15 and also under the experimental conditions of
most biological assays.16 The isomerization process,
which is promoted by acids, bases, heat or polar sol-
vents,17 leads to equilibrium mixtures of acyl glycerols
that are difficult to resolve by means of chromatographic
SYNLETT 2006, No. 14, pp 2251–2255
0
1
.0
9
.2
0
0
6
Advanced online publication: 24.08.2006
DOI: 10.1055/s-2006-948206; Art ID: G17206ST
© Georg Thieme Verlag Stuttgart · New York

2252
S. D. Stamatov, J. Stawinski
LETTER
In contrast to our recent findings that carboxylic acid an- tained from (S)-(+) glycidyl (1) indicated on racemization
hydrides in the presence of trimethylsilyl halides (TMSX) occurring during the course of the reaction.
and halide anions open the oxirane system in 1 without
The produced 1-trifluoroacetyl derivative 3–6 can be
acyl migration to produce the corresponding 1,2-diacyl-3-
treated as storage forms for the corresponding 2-MAG as
haloglycerols,33 preliminary experiments with equimolar
their spectral characteristics (1H NMR and 13C NMR
amounts of TFAA and trimethylsilyl chloride showed that
spectroscopy) remained unchanged upon keeping under
this reagent system effected formation of chloroglyceride
argon at –20 °C for several weeks. On the other hand,
3 from 1 with migration of the acyl group. This could pro-
compounds 3–6 can be conveniently converted into 2-
MAG derivatives 7–10 by treatment in CH2Cl2–pentane
vide a convenient entry to the otherwise difficult-to-ac-
cess 2-acyl-3-haloglycerols of type 7–10.
with pyridine (10 equiv) and methanol (250 equiv) at
room temperature for 20 minutes.37 The removal of the
terminal trifluoroacetyl moiety was quantitative and pro-
duced volatile by-products removable with the solvents
OCOCF3
OCOR
X
OH
OCOR
Step B
Step A
by simple evaporation under reduced pressure. Thus, this
protocol provided positionally homogenous terminal ha-
OCOR
X
O
1
loalkanols 7–10 (purity >99%, H NMR and 13C NMR
1, 2
3–6
Yields: 89–95%
7–10
Yields: 100%
spectroscopy) without any additional purification (step B,
Scheme 1).
Since we previously found that treatment of carboxylic
acid anhydrides with TMSX (e.g. X = Br or I, 1.0 equiv)
at room temperature led to almost instantaneous forma-
tion of equimolar amounts of the corresponding acyl
halides (ACX) and trimethylsilyl carboxylates
(ACOTMS),34 we carried out additional experiments to
elucidate mechanistic contribution of these species in the
haloacylating cleavage of the aforementioned oxirane
systems.
3, 7 = rac, R = C17H33
4, 8 = rac, R = C17H33
5, 9 = rac, R = C17H33
X = Cl
X = Br
X = I
1 = (S)-(+), R = C17H33
2 = rac, R = (CH3)3C6H2
6, 10 = rac, R = (CH3)3C6H2 X = Br
Step A: TFAA (4.0–5.0 equiv), TMSX (1.2–4.0 equiv), CH2Cl2, r.t., 2–5 h;
Step B: pyridine (10 equiv), MeOH (250 equiv), CH2Cl2–pentane, r.t., 20 min
Scheme 1 Reagents and conditions: step A: (F3CCO)2O (4.0–5.0
equiv), TMSX (1.2–4.0 equiv), CH2Cl2, r.t., 2–5 h; step B: pyridine
(10 equiv), MeOH (250 equiv), CH2Cl2–pentane, r.t., 20 min.
1H NMR and 13C NMR spectroscopy revealed that acetyl
bromide (1.5 equiv) alone effected opening of the oxirane
ring of glycidyl oleate 1 with a predominant migration of
the oleoyl moiety affording a mixture of 1-acetyl-2-
oleoyl- and 1-oleoyl-2-acetyl-3-bromoglycerol in a ratio
of 80:20 (CH2Cl2, r.t., 72 h, isolated yield as a mixture: ca.
75%). Practically the same results were obtained when
TMSBr (1.5 equiv) and acetic anhydride (up to 4 equiv)
were used for the reaction. In contrast, treatment of
glycidyl 1 with TFAA (4.0 equiv) and TMSBr (2.0 equiv)
afforded exclusively 1-trifluoroacetyl-2-oleoyl-3-bro-
moglycerol (4, CH2Cl2, r.t., 3 h; isolated yield: ca. 94%).
However, when equimolar amounts of TFAA and TMSBr
(1.5–4.0 equiv) were used, significant amount of side
products [1-oleoyl-2-trifluoroacetyl-3-bromoglycerol (ca.
5–15%) and 2-oleoyl-1,3-dibromoglycerol (ca. 10–
20%)], along with the desired compound 4 (ca. 70–80%),
were formed.
To assess the scope and generality of this reaction, the
TFAA/TMSX-promoted cleavage of selected oxiranes
bearing either aliphatic (1) or sterically hindered aromatic
acyl residues (2) was investigated under various experi-
mental conditions (different solvents, ratio of reactants,
1
etc., step A, Scheme 1). H NMR and 13C NMR spectral
analysis indicated that both amounts of TFAA and TMSX
as well as their ratios had profound effect on regioselec-
tivity during attempted preparation of haloglycerols 3–6.
The best results were achieved when TFAA and TMSX
were mixed together in dichloromethane [for synthesis of
chloroglyceride 3, TMSCl (4.0 equiv)/TFAA (4.0 equiv);
for bromoglycerides 4 and 6, TMSBr (2.0 equiv)/TFAA
(4.0 equiv); for iodoglyceride 5, TMSI (1.2 equiv)/TFAA
(5.0 equiv)], added to a cooled solution (–20 °C) of 1 or 2
in the same solvent, and the reaction was left at room tem-
perature for 2–5 hours.36 This gave quantitatively and in a
To secure a clean formation of chloroglyceride 3, TFAA
and TMSCl had to be used in equimolar amounts and in
fourfold excess over glycidyl 1. Attempted synthesis of 3
by reacting 1 with TMSCl (2.0 equiv)/TFAA (4.0 equiv),
afforded 1,3-bis(trifluoroacetyl)-2-oleoylglycerol (75%)
and only 25% of the desired product 3. For the synthesis
of iodoglyceride 5, the optimal ratio of TMSI/TFAA that
secured complete regioselectivity of the opening of the
oxirane ring in 1, was found to be 1:4.
1
highly chemo- and regioselective way (>99%, H NMR
and 13C NMR spectroscopy) products 3–6, which were
isolated in 89–95% yields after solid-phase filtration
through a short silica gel pad. For such optimized runs,
rates of the epoxide opening were not appreciably affected
by electronic and steric features of the acyl group present
in 1 and 2. The reactions examined seemed to be rather
general as other glycidyl esters (e.g. acetate, arachidonate,
4-nitrobenzoate; results not shown) also underwent quan-
titative conversion to the same type of trifluoroacetylated
haloesters. Lack of optical activity for compounds 3–5 ob-
The above data suggest that fission of oxiranes 1 and 2 is
most likely subject to electrophilic catalysis provided by
trifluoroacetyl halides (TFAX) generated in situ from
Synlett 2006, No. 14, 2251–2255 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Acyl-3-haloglycerols
2253
TFAA and TMSX. This involves, most likely, coordina- catalysts differing in the leaving group (e.g. TFAA vs.
tion of the electrophile catalyst to the epoxide oxygen TFACl) would compete in opening of the epoxide ring in
with a synchronous intramolecular attack of the vicinal 1, two products should be formed – 1,3-bistrifluoroacetyl
carbonyl group on the secondary carbon atom as depicted and 1-trifluoroacetyl-3-chloro derivative. This is consis-
in Scheme 2. The combination of electrophile and nucleo- tent with observations that the reactions investigated are
phile catalysis in these reactions should facilitate opening very sensitive to the ratio of TFAA and TMSX used.
of the epoxy system to form cyclic acyliumglycerol cation Thus, for the synthesis of chloroglycerides 3, one has to
A (or B), collapsing then to the epimerized 1-trifluoro- use TFAA and TMSCl in a ratio of 1:1, otherwise TFAA
acetyl-2-acyl-3-haloglycerol by a nucleophilic attack of a present in the reaction mixture can compete as electro-
halide ion on the primary carbon atom of the dioxolane philic catalyst with TFACl and give rise to the formation
ring.
of bistrifluoroacetate derivatives. On the other hand, dur-
ing synthesis of iodoglyceride 5, this ratio of TFAA/TMSI
can be 4:1, due to apparently higher reactivity of the gen-
erated trifluoroacetyl iodide.
Formation of the racemic products in this reaction indi-
cates that acylium cations A and B are in equilibrium with
the corresponding acyclic carbocations, and thus migra-
tion of an acyl group which involves this kind of interme- In conclusion, we have developed an efficient synthetic
diate, is likely to proceed with partial or complete strategy based on a novel, chemo- and regioselective
epimerisation.
opening of the epoxide system of glycidyl esters (e.g. 1, 2)
to produce 1-trifluoroacetyl-2-acyl-3-halo-rac-glycerols
(e.g. 3–6) and hence terminal haloalkanols (e.g. 7–10), as
prospective isosters of 2-MAG.
To explain the observed regiochemistry, one has to as-
sume very low concentration of free halide ions under the
reaction conditions,35 to enable participation of the adja-
cent carbonyl function as nucleophilic catalyst in the The main features of this protocol are: (i) highly regiose-
opening of the oxirane ring of 1. The subsequent coordi- lective and quantitative generation under mild conditions
nation of a halide ion by the acylium cation can be an in- of trifluoroacetyl-protected haloglycerol intermediates 3–
termolecular (intermediate A) or intramolecular reaction 6,which can be either employed as storage forms of or
(intermediate B), depending on stability of the tetrahedral converted into monohalogenated analogues of 2-MAG 7–
intermediate involved. The latter pathway implies also 10; (ii) the produced compounds 7–10 are of high purity
that a nucleophile attacking the acylium cation has to be and their synthesis does not require, potentially detrimen-
part of the electrophile catalyst. Thus, if two electrophile tal to their chemical integrity, chromatographic processes;
F3C
X
TMSO
CF3
F3C
O
CF3
TMSX
+
+
O
O
O
O
O
O
R
F3C
O
O
H
O
X
R
O
CF3
O
O
F3C
O
O
O
R
O
O
X
CF3
O
O
R
X
A
O
X = Cl, Br or I
R = alkyl or aryl
O
X
O
O
F3C
R
O
B
Scheme 2
Synlett 2006, No. 14, 2251–2255 © Thieme Stuttgart · New York

2254
S. D. Stamatov, J. Stawinski
LETTER
(15) Schmid, P. C.; Schwartz, K. D.; Smith, C. N.; Krebsbach, R.
J.; Berdyshev, E. V.; Schmid, H. H. O. Chem. Phys. Lipids
2000, 104, 185.
(16) Rouzer, C. A.; Ghebreselasie, K.; Marnett, L. J. Chem. Phys.
Lipids 2002, 119, 69.
(17) (a) Martin, J. B. J. Am. Chem. Soc. 1953, 75, 5483.
(b) Serdarevich, B. J. Am. Oil Chem. Soc. 1967, 44, 381.
(c) Mattson, F. H.; Volpenhein, R. A. J. Lipid Res. 1962, 3,
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acylated haloglycerols 7–10 as versatile three-carbon
units useful in the preparation of bis(acylated) vicinal ha-
lohydrins or asymmetric triglyceride precursors; (iv) the
method makes use of commercially available reactants
and preparations can easily be scaled up.
Acknowledgment
(18) (a) Martin, J. D.; Palazon, J. M.; Perez, C.; Ravelo, J. L. Pure
Appl. Chem. 1986, 58, 395. (b) Martin, J. D.; Perez, C.;
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Financial support from the Swedish Natural Science Research
Council and the Swedish Foundation for Strategic Research is gra-
tefully acknowledged.
(19) Righi, G.; Bonini, C. Recent Res. Dev. Org. Chem. 1999, 3,
343.
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(35) In separate experiments we found that reaction of 1 with
TFAA and tetrabutylammonium halides or with TFAA and
TMSBr in the presence of pyridine, occurred without acyl
migration and involved a nucleophilic opening of the
oxirane ring with halide ion, facilitated by electrophilic
catalysis exerted by TFAA.
Synlett 2006, No. 14, 2251–2255 © Thieme Stuttgart · New York

LETTER
Synthesis of 2-Acyl-3-haloglycerols
2255
(36) General Procedure for the Synthesis of 1-Trifluoro-
acetyl-2-acyl-3-haloglycerols 3–6 (Step A).
C23H38F3IO4 (562.44): C, 49.11; H, 6.81; I, 22.56. Found: C,
49.18; H, 6.78; I, 22.51.
(S)-(+)-2-(Oleoyloxymethyl)oxirane (1) {[a]D20 +13.89 (c
5.66, CHCl3)} and (rac)-( )-2-(2,4,6-trimethylbenzoyloxy-
methyl)oxirane (2) were obtained by direct acylation of
chiral or racemic glycidols as described elsewhere.32 The Rf
values refer to mobility on a silica gel plates using the
solvent system: pentane–toluene–EtOAc = 40:50:10 (v/v/v).
To a solution of the starting substrate 1, 2 (1.00 mmol) in
CH2Cl2 (3.0 mL), a mixture of TFAA (4.00–5.00 mmol) and
trimethylsilyl halide (1.20–4.00 mmol), prepared in the same
solvent (3.0 mL), was added at –20 °C and the reaction
system was kept under argon at r.t. for 2–5 h. Then, CH2Cl2
and volatile reaction components were evaporated in vacuo,
the residue was taken in toluene (5.0 mL) and passed through
a silica gel pad (ca. 5 g) prepared in the same solvent. The
support was washed with toluene (ca. 100 mL), fractions
containing the target compound were combined, the eluent
was removed under reduced pressure, and the rest was kept
under high vacuum at r.t. for 2–3 h to afford the rearranged
2-O-acylated halohydrin 3–6 (purity >99%, 1H NMR
spectroscopy).
1-Trifluoroacetyl-2-oleoyl-3-chloro-rac-glycerol (3):
obtained from 1 (0.338 g, 1.00 mmol), TFAA (0.556 mL,
4.00 mmol) and TMSCl (0.505 mL, 4.00 mmol) for 5 h.
Yield: 0.428 g (91%, colorless oil); Rf = 0.68. Anal. Calcd
(%) for C23H38ClF3O4 (470.99): C, 58.65; H, 8.13; Cl, 7.53.
Found: C, 58.72; H, 8.10; Cl, 7.51.
1-Trifluoroacetyl-2-oleoyl-3-bromo-rac-glycerol (4):
obtained from 1 (0.338 g, 1.00 mmol), TFAA (0.556 mL,
4.00 mmol) and TMSBr (0.259 mL, 2.00 mmol) for 3 h.
Yield: 0.479 g (93%, colorless oil); Rf = 0.67. Anal. Calcd
(%) for C23H38BrF3O4 (515.44): C, 53.59; H, 7.43; Br, 15.50.
Found: C, 53.56; H, 7.41; Br, 15.51.
1-Trifluoroacetyl-2-(2,4,6-trimethylbenzoyl)-3-bromo-rac-
glycerol (6): obtained from 2 (0.220 g, 1.00 mmol), TFAA
(0.556 mL, 4.00 mmol) and TMSBr (0.259 mL, 2.00 mmol)
for 3 h. Yield: 0.353 g (89%, colorless oil); Rf = 0.71. Anal.
Calcd (%) for C15H16BrF3O4 (397.18): C, 45.36; H, 4.06; Br,
20.12. Found: C, 45.41; H, 4.01; Br, 20.18.
(37) General Procedure for the Synthesis of 2-Acyl-3-
haloglycerols 7–10 (Step B).
To a solution of trifluoroacetyl halohydrin 3–6 (1.00 mmol)
in pentane–CH2Cl2 (3:1, v/v, 5.0 mL), a mixture of pyridine
(0.8 mL, 10 mmol) and MeOH (10.1 mL, 250 mmol) in the
same solvents (5.0 mL) was added at 0 °C and the reaction
system was left at r.t. for 20 min. Solvents were evaporated
under reduced pressure (bath temp. 50 °C) and the residue
was kept under high vacuum at r.t. for 2–3 h to give the
deprotected haloalkanol 7–10 (purity >99%, 1H NMR
spectroscopy).
2-Oleoyl-3-chloro-rac-glycerol (7): obtained from 3 (0.471
g, 1.00 mmol). Yield: 0.374 g (100%, colorless oil);
Rf = 0.25. Anal. Calcd (%) for C21H39ClO3 (374.98): C,
67.26; H, 10.48; Cl, 9.45. Found: C, 67.22; H, 10.51; Cl,
9.50.
2-Oleoyl-3-bromo-rac-glycerol (8): obtained from 4 (0.515
g, 1.00 mmol). Yield: 0.419 g (100%, colorless oil);
Rf = 0.23. Anal. Calcd (%) for C21H39BrO3 (419.44): C,
60.13; H, 9.37; Br, 19.05. Found: C, 60.08; H, 9.40; Br,
19.00.
2-Oleoyl-3-iodo-rac-glycerol (9): obtained from 5 (0.562 g,
1.00 mmol). Yield: 0.466 g (100%, yellowish oil); Rf = 0.34.
Anal. Calcd (%) for C21H39IO3 (466.44): C, 54.07; H, 8.43;
I, 27.21. Found: C, 54.13; H, 8.40; I, 27.24.
2-(2,4,6-Trimethylbenzoyl)-3-bromo-rac-glycerol (10):
obtained from 6 (0.397 g, 1.00 mmol). Yield: 0.300 g (100%,
colorless oil); Rf = 0.24. Anal. Calcd (%) for C13H17BrO3
(301.18): C, 51.84; H, 5.69; Br, 26.53. Found: C, 51.79; H,
5.72; Br, 26.57.
1-Trifluoroacetyl-2-oleoyl-3-iodo-rac-glycerol (5):
obtained from 1 (0.338 g, 1.00 mmol), TFAA (0.695 mL,
5.00 mmol) and TMSI (0.163 mL, 1.20 mmol) for 2 h. Yield:
0.534 g (95%, colorless oil); Rf = 0.66. Anal. Calcd (%) for
Synlett 2006, No. 14, 2251–2255 © Thieme Stuttgart · New York