Regioselective and stereospecific halosilylating cleavage of the oxirane system of glycidol derivatives as an efficient strategy to C2-O-functionalized C3-vicinal halohydrins

Article abstract of DOI:10.1002/ejoc.200800112

Glycidyl esters and ethers undergo a regioselective and stereospecific opening of the oxirane ring upon treatment with trimethylsilyl halides (TMSX, X = Cl, Br, or I) in the presence of pyridine to produce the corresponding C2-O-trimethylsilyl-3(1)-halo-sn-glycerols in high yields. Trifluoroacetylation across the trimethylsilyloxy system of such C3-synthons with trifluoroacetic anhydride (TFAA) in the presence of a halide anion (e.g. Bu₄NX; X = Cl, Br, or I), followed by removal of the trifluoroacetyl transient protection, provides nearly quantitative access to the respective vicinal haloalkanols. Alternatively, C2-O-acylated vicinal halohydrins can be obtained in a highly chemo-/regiospecific manner by direct conversion of the trimethylsilyl protecting group into short- or long-chain ester functionalities by means of a three-component reagent: pyridine-carboxylic acid-TFAA. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800112

FULL PAPER
DOI: 10.1002/ejoc.200800112
Regioselective and Stereospecific Halosilylating Cleavage of the Oxirane
System of Glycidol Derivatives as an Efficient Strategy to C2-O-Functionalized
C3-Vicinal Halohydrins
Stephan D. Stamatov*[a] and Jacek Stawinski*[b,c]
Keywords: Oxygen heterocycles / Ethers / Glycidol derivatives / Carboxylic acids / Halohydrins / Alcohols
Glycidyl esters and ethers undergo a regioselective and
stereospecific opening of the oxirane ring upon treatment
with trimethylsilyl halides (TMSX, X = Cl, Br, or I) in the
presence of pyridine to produce the corresponding C2-O-tri-
methylsilyl-3(1)-halo-sn-glycerols in high yields. Trifluo-
roacetylation across the trimethylsilyloxy system of such C3-
synthons with trifluoroacetic anhydride (TFAA) in the pres-
ence of a halide anion (e.g. Bu4NX; X = Cl, Br, or I), followed
vides nearly quantitative access to the respective vicinal
haloalkanols. Alternatively, C2-O-acylated vicinal halo-
hydrins can be obtained in a highly chemo-/regiospecific
manner by direct conversion of the trimethylsilyl protecting
group into short- or long-chain ester functionalities by means
of a three-component reagent: pyridine–carboxylic acid–
TFAA.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
by removal of the trifluoroacetyl transient protection, pro- Germany, 2008)
means of metal halides,[15,16] ammonium halides,[17] hydro-
Introduction
halides,[18] elemental halogens,[19] etc.) often suffer from
low-to-moderate regioselectivity,[20] substrate incompatibil-
ity,[21] excessive expense,[22] poor availability[23,24] of the rea-
gents employed, or afford mixture of stereoisomers.[15] One
should mention that regioselectivity of the opening of an
epoxide ring can be significantly increased if an additional
functionality permitting coordination of metal cation[24] or
boranes[25] is present.
Vicinal halohydrins (VHs) are among the most versatile
synthetic intermediates that provide access to a vast array
of functional groups[1] and biologically active compounds,[2]
including lipid mediators,[3–7] halogenated marine natural
products,[8] and others.[9] Halohydrins are substrates for a
particular class of enzymes, halohydrin dehalogenases, and
they are also of interest to both asymmetric synthesis[9]
(e.g., chiral resolution of racemic synthons[10]) and bioreme-
diation of the environment (e.g., the removal of pollutants
from soil, groundwater or waste water[11]).
Because the addition of hypohalous acids and hypohal-
ites to olefins[12] usually shows low regioselectivity and
functionalization of glycerol staring materials,[4–7,13] re-
quires multistep reaction sequences, and painstaking chro-
matographic separations of the target conjugates from the
accompanying byproducts at each synthetic stage, the open-
ing of oxirane systems with various nucleophiles seemed to
be a much more attractive approach to VHs.[14] Neverthe-
less, regioselective and stereospecific incorporation of a
halogen atom, even into a fairly simple three-carbon unit
(e.g., glycerol), could still be an issue. For example, direct
methods for converting oxiranes into halohydrins (e.g., by
An alternative two-step tactic involving insertion of or-
ganosilicon halides into epoxides[26] with a subsequent de-
protection of the thus obtained O-silylated precursors of
vicinal halohydrins[24] is incapable to circumvent the afore-
mentioned shortcomings, as (i) halosilylating fission of oxir-
anes is not always completely regioselective and varies
widely depending upon steric factors in the substrates[24,26]
and (ii) the removal of relatively labile trimethylsilyl (TMS)
and tert-butyldimethylsilyl (TBDMS) ethers requires condi-
tions that either preclude access to derivatives with acid-,[24]
base-,[27] or oxidation/reduction-sensitive functionalities,[28]
or they are known to trigger prohibitive structural re-
arrangements of the molecular skeleton (e.g., acyl mi-
gration, racemization, etc.) after exposure of a free hydroxy
group adjacent to an acyl substituent.[27,29,30]
Despite the growing interest in vicinal haloesters (VHEs)
as building blocks in the synthesis of structurally defined
bioconjugates[3–7,31] of significance to membranology,[32]
enzymology,[33] gene therapy,[13] and drug design,[34] oxirane
chemistry has not been exploited to any significant extent
to produce such a type of O-functionalized VH. This is
probably due to the fact that existing protocols based on
electrophilic cleavage of terminal epoxides with acyl chlo-
[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
[c] Institute of Bioorganic Chemistry, Polish Academy of Sciences,
Noskowskiego 12/14, 61-704 Poznan, Poland
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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S. D. Stamatov, J. Stawinski
FULL PAPER
rides (e.g., alone[35] or in combination with CrO2Cl2,[36] give C2-O-trimethylsilylated haloglycerols (route A,
CoCl2,[37] Bu2SnCl2/Ph3P,[38] or hexaalkylguanidinium chlo- Scheme 2) as common precursors to either vicinal haloalk-
ride[39]) or related haloacylating systems (e.g., TiCl4/EtOAc/ anols or their haloesters, (ii) transformation of the pro-
imidazole[40]), are usually limited by competing side reac- duced trimethylsilyl derivatives into the corresponding C3-
tions or incompatibility with oxidation/Lewis acid sensitive vicinal haloalkanols with the intermediacy of O-trifluo-
substrates, and only low-reactive O-acylated vicinal chloro- roacetates (route B, Scheme 4), and (iii) production of C2-
hydrins are afforded.[5]
O-acylated C3-vicinal halohydrins by direct replacement of
The use of acyl bromides,[41] or a parent species gener- the trimethylsilyl group with a short-/long-chain fatty acid
ated in situ from either LiBr–carboxylic acid anhydrides[42] residue effected by a three-component reagent system, pyr-
or LiBr–oleic anhydride–benzyltributylammonium bro- idine–carboxylic acid (CA)–trifluoroacetic acid (TFAA)
mide[43] for haloacylation of glycidyl esters does not provide (route C, Scheme 6).
remedy for these problems either, as the approaches ap-
Because the depicted transformations apparently occur
peared to be restricted to the production of bromo deriva- without exposure of a free hydroxy functionality within the
tives, or the reaction conditions do not secure complete ste- glycerol skeleton, they may constitute a novel strategy for
reochemical homogeneity of the preparations.[43]
the synthesis of structurally defined C2-O-functionalized
In this context, opening of an epoxide ring to form an C3-vicinal halohydrins and related compounds, which
O-silylated halohydrin intermediate, followed by direct es- should eliminate a perennial problem of glycerolipid chem-
terification across the O-silyl group without exposing a free istry, namely, acyl migration.[29,46]
hydroxy functionality seemed a viable route to VHEs. Un-
fortunately, the sole literature precedent reports a SnX2-
Synthesis of C2-O-Trimethylsilylated C3-Vicinal
Halohydrins (4–10) (Route A, Scheme 2)
promoted fission of 2,3-epoxy ethers with trimethylsilyl ha-
lides (TMSX, X = Cl or Br), which, after acylation, gives
rise to only 2-acetyl-3-halohydrins in rather erratic yields
and with mediocre regioselectivity.[44] Attempted extension
of this methodology to the synthesis of chloroester deriva-
tives from the respective glycidyl esters resulted in extensive
(~80%) acyl migration.[44]
To address the above problems, in this paper we describe
a simple and efficient protocol for the synthesis of configu-
rationally pure C3-chloro-, bromo-, and iodohydrins bear-
ing a vicinal O-trimethylsilyl substituent (route A), a hy-
droxy group (route B), or acyl functionalities (route C) ob-
tainable in high yields and under mild conditions from a
single glycidyl precursor (Scheme 1). A preliminary account
of part of this work has recently been communicated.[45]
For the initial experiments, as a representative substrate,
a racemic glycidyl oleate (racemic 1, Scheme 2) having an
acyl group prone to migration, was chosen. Attempted
opening of the oxirane system by treatment of glycidyl ole-
ate (1) in aprotic solvents (e.g., CH2Cl2 or CHCl3) with ace-
tyl bromide (3.0 equiv.) at room temperature for 12–24 h
produced complex reaction mixtures consisting of the start-
ing material (~30%), 1,3-dibromo-2-oleoylglycerol (~20%),
and 1-oleoyl-2-acetyl-3-bromoglycerol (~35%) and its iso-
meric 1-acetyl-2-oleoyl derivative (~15%) (TLC, 1H and 13
C
NMR spectroscopic analyses). Replacement of acetyl bro-
mide by trimethylsilyl bromide (TMSBr, 3.0 equiv.) under
the same conditions led to practically quantitative forma-
tion of undesired 1,3-dibromo-2-oleoylglycerol (isolated in
91% yield).
Scheme 1.
Scheme 2.
Results and Discussion
In the following sections, we will discuss the reaction
Analysis of the chemical structures of the byproducts
pathways and possible mechanisms regarding the regiose- indicated that the initially formed bromohydrin intermedi-
lective and stereospecific (i) halosilylating ring cleavage of ates probably underwent a competing acyl migration
glycidyl esters and ethers with trimethylsilyl halides (triggered, most likely, by intramolecular addition to the
(TMSX, X = Cl, Br, or I) in the presence of pyridine to adjacent carbonyl functionality to form a tetrahedral inter-
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Efficient Strategy to C2-O-Functionalized C3-Vicinal Halohydrins
Scheme 3.
mediate), which led to compounds with the oleoyl group at ane ring opening in 1–3 with TMSX occurred by nucleo-
the C2 position. To remedy this problem, we tried to carry philic attack of the halide anion at the primary carbon cen-
out the reactions in the presence of pyridine to increase ter with simultaneous formation of the silyl ether bond, as
trapping efficiency of the incipient hydroxy functional shown in Scheme 3. The absence of bis(halogenated) by-
group in the form of acetate. Indeed, the course of the reac- products indicated a critical role of pyridine in this reaction,
tion was dramatically changed when the oxirane ring open- which can be due both to releasing a halide nucleophile
ing was carried out in the presence of a small amount of from TMSX and generation of a highly electrophilic spe-
pyridine. In this instance, treatment of glycidyl oleate (1) cies, the N-silylpyridinium cation. Because the latter is ex-
with acetyl bromide (3.0 equiv.) in chloroform containing pected to act as a powerful electrophilic catalyst, the open-
pyridine (6.0 equiv.) at 80 °C (pressure tube) for 0.5–3 h re- ing of the oxirane ring and silylation of the incipient 2-
sulted in highly regioselective formation of the expected 1- hydroxy functionality are likely to be a synchronous pro-
oleoyl-2-acetyl isoster (isolated in Ͼ90% yields; purity cess, which should occur without scrambling of the adjacent
1
Ͼ99% as judged by H and 13C NMR spectroscopy).
Although these preliminary results were most encourag-
ing, the poor availability of acyl halides derived from long-
chain fatty acids (especially the corresponding bromides
and iodides), would make the scope of this reaction rather
narrow. Besides, the approach cannot be applied if C3-vici-
acyl moiety.
Synthesis of C3-Vicinal Haloalkanols (16–20) (Route B,
Scheme 4)
Having developed the reaction conditions for the pro-
nal haloalkanols incorporating a terminal acyl substituent duction of 2-O-trimethylsilylated haloglycerols from the
are desired. Therefore, we turned our attention to trimethyl- corresponding glycidyl derivatives 1–3, we were interested
silyl halides (TMSX, X = Cl, Br, or I) as an alternative to in a direct transformation of 4–10 into the respective tri-
acyl halide agents for fission of oxiranes. These, in combina- fluoroacetyl esters to alleviate drawbacks inherent to direct
tion with pyridine, were expected to provide convenient en- deprotection of the silyl precursors.[47]
try to 2-O-silylated halohydrins as prospective synthons in
The important point of introducing a trifluoroacetyl
the synthesis of vicinal haloalkanols and vicinal haloesters. functionality into a molecule is that it confers stability to
Indeed, the reaction of TMSBr (3 equiv.) with oleate 1 the framework organization (e.g., prevents scrambling of
in chloroform in the presence of pyridine produced cleanly acyl residues within the glycerol skeleton) and on this basis
1-oleoyl-2-O-trimethylsilyl-3-bromoglycerol (racemic 6 in a convenient storage form for labile, biologically active glyc-
Scheme 2). After evaluation of various reaction conditions, erolipids has been proposed.[48] The added value of the tri-
the best results were obtained when a solution of glycidyl fluoroacetyl protection is that this group can be removed
derivatives 1–3 and pyridine (6.0 equiv.) in chloroform was quantitatively under mild conditions to provide pure target
treated with TMSX (1.5 equiv.) as shown in Scheme 2. For compounds without any additional workup or chromato-
trimethylsilyl iodide, the halosilylation went to completion graphic purification.[48,49]
within a few minutes at room temperature, whereas for the
Examples of a direct conversion of various silyloxy sys-
other halide derivatives, the reaction times were longer and tems (e.g., trimethylsilyl-, tert-butyldimethylsilyl-, triiso-
required thermal treatment in a pressure flask at 80 °C propylsilyl-, tert-butyldiphenylsilyl ethers, etc.) into either
1
(30 min for bromides, and ca. 7 h for chlorides). The H acetates (e.g., by using FeCl3–acetic anhydride,[50] pyridine–
and 13C NMR spectra of the isolated products revealed that acetic anhydride–acetic acid, methanol–acetic acid,[51]
in all instances the conversion to target silyl ethers 4–10 was ZnCl2–acetyl chloride,[52] or SnBr2–acetyl bromide[53]) or
nearly quantitative and entirely chemo- and regioselective higher carboxylates[54] are known from the literature. These
(Ͼ99%). The reaction seemed to be rather general, as other methods, however, (i) involve chemical procedures that are
glycidol conjugates (e.g., benzoyl, linoleoyl, isopropyl, or incompatible with trifluoroacetyl derivatives, (ii) are not se-
tert-butyldiphenylsilyl; results not shown) also underwent lective towards any of the commonly employed silyl tran-
nearly quantitative transformation into the corresponding sient protections, and (iii) are inapplicable to the synthesis
2-O-trimethylsilylated vicinal halohydrins.
of C3-vicinal haloalkanols bearing a terminal acyl group.
To remedy these problems, the reaction conditions for
The exclusive formation of 2-O-silyl derivatives 4–10 with
defined stereochemistry (e.g., 4–9) suggested that the oxir- direct trifluoroacetylation of 2-O-trimethylsilylated halogly-
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S. D. Stamatov, J. Stawinski
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cerides having representative acyl- (compounds 4, 6–8) or isopropylsilyl- and tert-butyldiphenylsilyl ethers, which
alkyl groups (compound 10) with TFAA in the presence of turned out to be completely stable under the reaction condi-
a halide ion were investigated by changing the type of sol- tions.
vent, ratio of the reactants, etc. [route B (i), Scheme 4].
Mechanistic studies supported by 1H and 13C NMR
spectroscopy (Table 1) showed that TFAA alone (entry 1)
effected trifluoroacetylation across the trimethylsilyloxy
system of compound 8 to produce trifluoroacetate 14, but
the reaction was sluggish and did not go to completion at
room temperature for 1 week.
Other carboxylic acid anhydrides (e.g. acetic anhydride),
when used either alone or in combination with Bu4NX (X
= Cl, Br, or I), remained essentially unreactive even at ele-
vated temperatures (entry 2). As shown in entry 3, TFAA
in the presence of TMSX (X = Cl, Br, or I), was also inef-
ficient in replacing the trimethylsilyl group in the model
substrate by a trifluoroacetyl one, although it is known that
this system generates highly electrophilic species, trifluo-
roacetyl halides.[54] The latter reactions, however, could be
rescued by the addition of the corresponding Bu4NX (entry
4).
Scheme 4.
It was found that when TFAA (2.0 equiv.) was added to
The above observations are consistent with a mechanism
4, 6–8, 10, and Bu4NX (2.0 equiv., X = Cl, Br, or I) in (Scheme 5) that involves initial coordination of a trifluo-
chloroform, and the reaction mixture was left at room tem- roacetyl group to the oxygen atom of the silyloxy system,
perature for 4–5 h, trifluoroacetates 11–15 were formed followed by nucleophilic attack of a halide ion on the sili-
quantitatively and in a highly chemo- and regiospecific con center in intermediate A to produce the ester bond.
fashion (Ͼ99%, 1H and 13C NMR spectroscopy). Com- The combination of nucleophile and electrophile catalysis
pounds 11–15 were isolated in 91–95% yield after simple rationalizes the fact that under the reaction conditions the
solid-phase filtration through a short silica gel pad (see Ex- replacement of the TMS protection by the trifluoroacetyl
perimental Section). To avoid side-product formation due group occurs without scrambling of the proximate acyl
to a possible halogen-exchange process, the halide anion
used was matched to that present in halohydrins 4, 6–8, and
10.
The kinetics of the above transformations was not appre-
ciably affected by electronic features or the type of the func-
tional groups present in 4, 6–8, and 10 (e.g., acyl vs. alkyl
group or chloride vs. bromide or iodide) or the kind of the
halide ion used. Other trimethylsilyl-protected primary, sec-
ondary, or sterically hindered alcohols (e.g., 1,3-propane-
diol, cholesterol, α-tocopherol, etc.) also underwent quanti-
tative trifluoroacetylation, with a notable exception of tri- Scheme 5.
Table 1. Mechanistic studies.
[a] RCO = oleoyl; Bu4N = tetra-n-butylammonium; TFAA = (CF3CO)2O; TMS = trimethylsilyl.
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Efficient Strategy to C2-O-Functionalized C3-Vicinal Halohydrins
moiety (if present), as no free hydroxy group of the glycerol nent system, namely Bu4NBr–TMSBr–carboxylic acid an-
skeleton is exposed. In addition, as no C–O bond scission hydrides, that efficiently effected replacement of silyl tran-
takes place at the stereogenic carbon center, the transforma- sient protections by short- or long-chain acyl residues di-
tion should be stereospecific and occur with retention of rectly.[54] Although utility of this reagent can be extended
configuration. Fair independence of the rate of trifluoroace- to the production of vicinal bromoesters, it appeared to be
tylation on the nature of the external halide used, as well less suitable for the synthesis of C2-O-acylated C3-vicinal
as the formation of only 2-O-trifluoroacetylated halohyd- chloro- and iodohydrins from the corresponding O-trimeth-
rins 11–15 [route B (i), Scheme 4] with defined stereochem- ylsilyl congeners (e.g., type 4 and 8, Scheme 6) as a result
istry (see Experimental Section), and the lack of an intra- of the competitive formation of bromohydrin byproducts
1
molecular acyl rearrangement, are in agreement with this (ca. 10-20%, H and 13C NMR spectroscopy). To alleviate
mechanism.
this problem, we focused on mixed carboxylic anhydrides
An alternative scenario that would invoke nucleophilic that have recently been advocated as reagents for acylolytic
attack by a trifluoroacetate anion on silicon seems less cleavage of some acetals.[56]
plausible, as halide ions are apparently more effective as a
nucleophile for silicon than trifluoroacetate. This is also in
line with the experimental data that trifluoroacetylation was
significantly faster in the presence of external halides.
The obtained trifluoroacetyl derivatives (e.g., 11–15) can
either be stored for several weeks (–20 °C, under an atmo-
sphere of argon) without detectable alterations of their
spectral characteristics (1H and 13C NMR spectroscopy) or
to be employed directly as starting materials for the synthe-
sis of vicinal halohydrins.
To this end, intermediary trifluoroacetates 11–15 were
treated in CH2Cl2/pentane with pyridine (10 equiv.) and
methanol (250 equiv.) at room temperature. The reactions
were quantitative (completion within 20 min) and after re-
moval of volatile products, afforded positionally homogen-
eous vicinal haloalkanols 16–20 (purity Ͼ99%, H and 13C
NMR spectroscopy) without any supplementary purifica-
1
Scheme 6.
tion [route B (ii), Scheme 4].
After evaluating various experimental conditions,[45] in
optimized runs a solution of silyl ethers 4–10 and pyridine
(6.0 equiv.) in chloroform was treated in a pressure ampoule
at 80 °C for 3–7 h with a mixture of the appropriate carbox-
Synthesis of C3-Vicinal Haloesters (21–27) (Route C,
Scheme 6)
As part of our program on new synthetic approaches to ylic acid (6.0 equiv., acetic, palmitic or oleic acid) and tri-
1
glycerolipids,[48,49,55] we developed recently a three-compo- fluoroacetic anhydride (TFAA, 1.5 equiv.) (Scheme 6). H
Scheme 7.
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2639

S. D. Stamatov, J. Stawinski
FULL PAPER
and 13C NMR spectra of the isolated compounds showed
that the conversion of 4–10 into target haloesters 21–27 was
consistently high yielding (80-95%) and occurred in a
strictly chemo- and regioselective manner (Ͼ99%). For
these reactions, no significant differences in rates were ob-
served for the substrates examined.
TFAA seemed to be an indispensable component of the
reagent system, as other carboxylic acid anhydrides (includ-
ing acetic anhydride) were completely unreactive (even in
plates of silica gel 60 F254 (Merck). The spots were visualized by
using the commercially available 3.5% molybdatophosphoric acid
spray reagent (Merck) or 50% sulfuric acid followed by heating at
140 °C. Column chromatography (CC) was carried out on silica gel
60 (70-230 mesh ASTM, Merck) by using appropriate solvent sys-
1
tems (see below). H and 13C NMR spectra were recorded with a
Varian 400 MHz machine and chemical shifts are reported in ppm
relative to TMS. The assignment of proton and carbon resonances
of 1–27 was done on the basis of established or expected chemical
shifts in conjunction with 1H–1H, 1H–13C, and DEPT correlated
neat pyridine), in an attempted replacement of the trimeth- NMR spectroscopy. In several instances, 1H and 13C NMR spectral
characteristics of known compounds were also included to make
up for a deficiency of relevant literature information. Optical rota-
tions were measured with a Perkin–Elmer 241 digital polarimeter.
Melting points were determined with a Kofler melting point appa-
ratus and are uncorrected. (S)-(+)-2-(Oleoyloxymethyl)oxirane (1)
[colorless oil. [α]2D0 = +13.79 (c = 5.18, CHCl3)] and (R)-(–)-2-
(oleoyloxymethyl)oxirane (2) [colorless oil. [α]2D0 = –13.60 (c = 6.11,
CHCl3)] were prepared by acylation of chiral glycidols with oleoyl
chloride (all from Fluka) as described elsewhere.[49] (rac)-(Ϯ)-2-
(Hexadecyloxymethyl)oxirane (3) (white solid, m.p. 34.0-35.1 °C)
ylsilyl group in compounds 4–10. It should be mentioned
that sterically hindered silyl ethers (e.g., tert-butyldimethyl-
silyl-, triisopropylsilyl-, or tert-butyldiphenylsilyl derivatives
of oleyl alcohol, cholesterol, etc.) were also stable under the
reaction conditions when TFAA was used.
Consistent with the above facts, a tentative mechanism
for the displacement of a trimethylsilyl group by an acyl
moiety by using a three-component reagent system (i.e.
CA–TFAA–pyridine) is shown in Scheme 7. It involves gen-
eration of the mixed carboxylic–trifluoroacetic anhydride was obtained from racemic glycidyl tosylate (Fluka) in two steps
by following a standard approach.[58] No attempts were made to
from the corresponding carboxylic acid and TFAA (proba-
optimize these particular procedures that provided glycidyl sub-
bly mediated by pyridine), followed by its activation by pyr-
strates 1–3 with spectral and physicochemical characteristics com-
idine, which results in the formation of reactive N-acylpyri-
dinium cation. The latter species is expected to be a strong
parable to those reported in the literature.[49,58]
General Procedure for the Synthesis of C2-O-Trimethylsilylated C3-
Vicinal Halohydrins 4–10 (Route A): To a solution of glycidyl sub-
strate 1–3 (1.00 mmol) and pyridine (0.484 mL, 6.00 mmol) in
alcohol-free chloroform (5.0 mL) was added a trimethylsilyl halide
(1.50 mmol), and the reaction system was kept under an argon at-
mosphere either at room temperature for ca. 6 min or in a pressure-
proof glass ampoule at 80 °C (bath) for 0.5–7 h. Solvents were re-
moved under reduced pressure. O-Silylated halohydrins 4–10 were
isolated in pure state (purity Ͼ99%, 1H NMR spectroscopy) by
flash column chromatography (silica gel, toluene).
electrophile that may coordinate to the oxygen atom of the
silicon center in A, which thus facilitates cleavage of the
silicon–oxygen bond by the relatively weak nucleophile tri-
fluoroacetate anion.
Conclusions
We developed a novel, simple, and efficient strategy for
the synthesis of C2-O-functionalized C3-vicinal halo-
hydrins. The protocol is based on a regioselective and
stereospecific opening of the oxirane system of glycidyl es-
ters and ethers with trimethylsilyl halides in the presence
of pyridine to produce the corresponding 2-O-trimethylsilyl
intermediate, followed by the replacement of the silyl group
either by a trifluoroacetyl transient protection (using
TFAA/Bu4NX, X = Cl, Br, or I) or short-/long-chain acyl
moiety (using CA–TFAA–pyridine), without exposing a
free hydroxy functionality. The reactions are clean and al-
low chloro-, bromo-, or iodohydrin derivatives incorporat-
ing a vicinal silyl-, hydroxyl-, or ester functionality to be
obtained from a single glycidol precursor under mild condi-
tions and in high yields. The approach seems to be general,
makes use of commercially available reactants, and can eas-
ily be scaled up.
1-Oleoyl-2-O-trimethylsilyl-3-chloro-sn-glycerol (4): Obtained from
1 (0.338 g, 1.00 mmol) and TMSCl (0.189 mL, 1.50 mmol) at 80 °C
after 7 h. Yield: 0.411 g (92%, colorless oil). Rf (pentane/toluene/
EtOAc, 40:50:10) = 0.77. [α]2D0 = +1.69 (c = 10.70, CHCl3).
C24H47ClO3Si (447.17): calcd. C 64.46, H 10.59, Cl 7.93; found C
64.53, H 10.53, Cl 7.90.
1-Chloro-2-O-trimethylsilyl-3-oleoyl-sn-glycerol (5): Obtained from
2 (0.338 g, 1.00 mmol) and TMSCl (0.189 mL, 1.50 mmol) at 80 °C
after 7 h. Yield: 0.398 g (89%, colorless oil). [α]2D0 = –1.70 (c =
12.94, CHCl3). All other physicochemical and spectral characteris-
tics were identical to those of 4.
1-Oleoyl-2-O-trimethylsilyl-3-bromo-sn-glycerol (6): Obtained from
1 (0.338 g, 1.00 mmol) and TMSBr (0.195 mL, 1.50 mmol) at 80 °C
after 30 min. Yield: 0.471 g (96%, colorless oil). Rf (pentane/tolu-
ene/EtOAc, 40:50:10) = 0.73. [α]2D0 = +1.91 (c = 13.10, CHCl3).
C24H47BrO3Si (491.62): calcd. C 58.63, H 9.64, Br 16.25; found C
58.72, H 9.59, Br 16.20.
1-Bromo-2-O-trimethylsilyl-3-oleoyl-sn-glycerol (7): Obtained from
2 (0.338 g, 1.00 mmol) and TMSBr (0.195 mL, 1.50 mmol) at 80 °C
after 30 min. Yield: 0.474 g (96%, colorless oil). [α]2D0 = –1.88 (c =
10.11, CHCl3). All other physicochemical and spectral characteris-
tics were identical to those of 6.
Experimental Section
General: All reagents were commercial grade (Fluka, Lancaster,
Merck, Sigma) with purity Ͼ98% and were used as provided. Sol-
vents were dried and distilled prior to use according to standard
protocols.[57] Reaction conditions were kept strictly anhydrous un-
less otherwise stated. Progress of the reactions was monitored by
analytical thin-layer chromatography (TLC) on precoated glass
1-Oleoyl-2-O-trimethylsilyl-3-iodo-sn-glycerol (8): Obtained from 1
(0.338 g, 1.00 mmol) and TMSI (0.204 mL, 1.50 mmol) at room
temperature after ca. 6 min. Yield: 0.521 g (97%, colorless oil). Rf
2640
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 2635–2643

Efficient Strategy to C2-O-Functionalized C3-Vicinal Halohydrins
(pentane/toluene/EtOAc, 40:50:10) = 0.76. [α]2D0 = +2.41 (c = 13.60,
CHCl3). C24H47IO3Si (538.62): calcd. C 53.52, H 8.79, I 23.56;
found C 53.47, H 8.83, I 23.63.
uum at room temperature for 2–3 h to give deprotected haloalkan-
ols 16–20 (purity Ͼ99%, H NMR spectroscopy).
1
1-Oleoyl-3-chloro-sn-glycerol (16): Obtained from 11 (0.471 g,
1.00 mmol). Yield: 0.375 g (100%, colorless oil). Rf (pentane/tolu-
ene/EtOAc, 40:50:10) = 0.31. [α]2D0 = +3.00 (c = 5.66, CHCl3).
C21H39ClO3 (374.98): calcd. C 67.26, H 10.48, Cl 9.45; found C
67.30, H 10.52, Cl 9.40.
1-Iodo-2-O-trimethylsilyl-3-oleoyl-sn-glycerol (9). Obtained from 2
(0.338 g, 1.00 mmol) and TMSI (0.204 mL, 1.50 mmol) at room
temperature after ca. 6 min. Yield: 0.517 g (96%, colorless oil).
[α]2D0 = –2.45 (c = 11.20, CHCl3). All other physicochemical and
spectral characteristics were identical to those of 8.
1-Oleoyl-3-bromo-sn-glycerol (17): Obtained from 12 (0.515 g,
1.00 mmol). Yield: 0.418 g (100%, colorless oil). Rf (pentane/tolu-
ene/EtOAc, 40:50:10) = 0.33. [α]2D0 = +2.45 (c = 8.53, CHCl3).
C21H39BrO3 (419.44): calcd. C 60.13, H 9.37, Br, 19.05; found C
60.20, H 9.33, Br 19.00.
1-O-Hexadecyl-2-O-trimethylsilyl-3-chloro-rac-glycerol (10). Ob-
tained from
3 (0.298 g, 1.00 mmol) and TMSCl (0.189 mL,
1.50 mmol) at 80 °C after 7 h. Yield: 0.362 g (89%, colorless oil). Rf
(pentane/toluene/EtOAc, 40:50:10) = 0.81. C22H47ClO2Si (407.15):
calcd. C 64.90, H 11.63, Cl 8.71; found C 64.95, H 11.59, Cl 8.68.
1-Bromo-3-oleoyl-sn-glycerol (18): Obtained from 13 (0.515 g,
1.00 mmol). Yield: 0.416 g (100%, colorless oil). [α]2D0 = –2.48 (c =
7.27, CHCl3). All other physicochemical and spectral characteris-
tics were identical with those of 17.
General Procedure for the Direct Transformation of C2-O-Trimeth-
ylsilyl Ethers 4, 6–8, and 10 Into O-Trifluoroacetates 11–15 [Route
B (i)]: To a solution of silyl ether 4, 6–8, or 10 (1.00 mmol) and
tetra-n-butylammonium halide (2.00 mmol) in alcohol-free chloro-
form (5.0 mL) was added trifluoroacetic anhydride (0.278 mL,
2.00 mmol), and the reaction was left under an argon atmosphere
at room temperature for 5 h. Solvents were evaporated in vacuo,
and the residue was taken into toluene (5.0 mL) and passed
through a silica gel pad (~5 g) prepared in the same solvent. The
support was washed with toluene (~100 mL), fractions containing
the target compounds were combined, the eluent was removed un-
der reduced pressure, and the residue was kept under high vacuum
at room temperature for 2–3 h to give trifluoroacetate 11–15 (purity
1-Oleoyl-3-iodo-sn-glycerol (19): Obtained from 14 (0.562 g,
1.00 mmol). Yield: 0.466 g (100%, white solid, m.p. 33.0–33.6 °C).
Rf (pentane/toluene/EtOAc, 40:50:10) = 0.36. [α]2D0 = +2.39 (c =
8.37, CHCl3); ref.[7] [α]2D0 = +1.9 (c = 10, CHCl3) M.p. 33.4 °C.
C21H39IO3 (466.44): calcd. C 54.07, H 8.43, I 27.21; found C 54.14,
H 8.40, I 27.26.
1-O-Hexadecyl-3-chloro-rac-glycerol (20): Obtained from 15
(0.431 g, 1.00 mmol). Yield: 0.334 g (100%, amorphous white so-
lid). Rf (pentane/toluene/EtOAc, 40:50:10) = 0.40. C19H39ClO2
(334.96): calcd. C 68.13, H 11.74, Cl 10.58; found C 68.17, H 11.71,
Cl 10.62.
1
Ͼ99%, H NMR spectroscopy).
1-Oleoyl-2-trifluoroacetyl-3-chloro-sn-glycerol (11): Obtained from
4 (0.447 g, 1.00 mmol) and Bu4NCl (0.556 g, 2.00 mmol). Yield:
0.429 g (91%, colorless oil). Rf (pentane/toluene/EtOAc, 40:50:10)
= 0.66. [α]2D0 = +0.28 (c = 9.65, CHCl3). C23H38ClF3O4 (470.99):
calcd. C 58.65, H 8.13, Cl 7.53; found C 58.70, H 8.09, Cl 7.55.
General Procedure for the Direct Conversion of C2-O-Trimethyl-
silylated C3-Vicinal Halohydrins 4–10 Into Their C2-O-Acylated
Isosteric Forms 21–27 (Route C): To a solution of the silylated
halohydrins 4–10 (1.00 mmol) and pyridine (0.484 mL, 6.00 mmol)
in alcohol-free chloroform (3.0 mL) was added a mixture of the
requisite carboxylic acid (6.00 mmol) and trifluoroacetic anhydride
(0.209 mL, 1.50 mmol), prepared in the same solvent (3.0 mL), and
the reaction system was kept under an atmosphere of argon in a
pressure-proof glass ampoule at 80 °C (bath) for 3–7 h. The solu-
tion was passed through a chloroform-filled aluminum oxide pad
(~5 g), the support was washed with chloroform (~150 mL), and
the volatile products were removed under reduced pressure. Purifi-
cation of the crude compound by flash column chromatography
(silica gel; mobile phase for 21, 25, and 27: pentane/toluene/EtOAc,
40:50:10; mobile phase for 22–24 and 26: toluene) gave target ha-
1-Oleoyl-2-trifluoroacetyl-3-bromo-sn-glycerol (12): Obtained from
6 (0.492 g, 1.00 mmol) and Bu4NBr (0.645 g, 2.00 mmol). Yield:
0.490 g (95%, colorless oil). Rf (pentane/toluene/EtOAc, 40:50:10)
= 0.69. [α]2D0 = +3.47 (c = 8.05, CHCl3). C23H38BrF3O4 (515.44):
calcd. C 53.59, H 7.43, Br 15.50; found C 53.63, H 7.40, Br 15.55.
1-Bromo-2-trifluoroacetyl-3-oleoyl-sn-glycerol (13): Obtained from
7 (0.492 g, 1.00 mmol) and Bu4NBr (0.645 g, 2.00 mmol). Yield:
0.492 g (95%, colorless oil). [α]2D0 = –3.40 (c = 10.08, CHCl3). All
other physicochemical and spectral characteristics were identical to
those of 12.
1
1-Oleoyl-2-trifluoroacetyl-3-iodo-sn-glycerol (14): Obtained from 8
(0.539 g, 1.00 mmol) and Bu4NI (0.739 g, 2.00 mmol). Yield:
0.529 g (94%, colorless oil). Rf (pentane/toluene/EtOAc, 40:50:10)
= 0.74. [α]2D0 = +6.40 (c = 10.01, CHCl3). C23H38F3IO4 (562.44):
calcd. C 49.11, H 6.81, I 22.56; found C 49.15, H 6.78, I 22.60.
loesters 21–27 (purity Ͼ99%, H NMR spectroscopy).
1-Oleoyl-2-acetyl-3-chloro-sn-glycerol (21): Obtained from
4
(0.447 g, 1.00 mmol) and acetic acid (0.343 mL, 6.00 mmol) after
7 h. Yield: 0.334 g (80%, colorless oil). Rf (pentane/toluene/EtOAc,
40:50:10) = 0.60. [α]2D0 = +1.28 (c = 9.50, CHCl3). C23H41ClO4
(417.02): calcd. C 66.24, H 9.91, Cl 8.50; found C 66.30, H 9.85,
Cl 8.53.
1-O-Hexadecyl-2-trifluoroacetyl-3-chloro-rac-glycerol (15). Ob-
tained from 10 (0.407 g, 1.00 mmol) and Bu4NCl (0.556 g,
2.00 mmol). Yield: 0.396 g (92%, colorless oil). Rf = 0.82 (pentane/
toluene/EtOAc, 40:50:10). C21H38ClF3O3 (430.97): calcd. C 58.52,
H 8.89, Cl 8.23; found C 58.55, H 8.83, Cl 8.26.
1-Chloro-2-palmitoyl-3-oleoyl-sn-glycerol (22): Obtained from 5
(0.447 g, 1.00 mmol) and palmitic acid (1.54 g, 6.00 mmol) after
6 h. Yield: 0.582 g (95%, colorless oil). Rf (pentane/toluene/EtOAc,
40:50:10) = 0.68. [α]2D0 = –2.06 (c = 8.49, CHCl3). C37H69ClO4
(613.39): calcd. C 72.45, H 11.34, Cl 5.78; found C 72.50, H 11.30,
Cl 5.80.
General Procedure for the Cleavage of O-Trifluoroacetates 11–15 To
Produce Vicinal Haloalkanols 16–20 [Route B (ii)]: To a solution of
trifluoroacetylated halohydrin 11–15 (1.00 mmol) in pentane/
CH2Cl2 (3:1, 5.0 mL), was added a mixture of pyridine (0.8 mL,
10 mmol) and methanol (10.1 mL, 250 mmol) in the same solvents
(5.0 mL) at 0 °C, and the reaction mixture was left at room tem-
perature for 20 min. Solvents were evaporated under reduced pres-
sure (bath temp. 50 °C), and the residue was kept under high vac-
1,2-Dioleoyl-3-bromo-sn-glycerol (23): Obtained from 6 (0.492 g,
1.00 mmol) and oleic acid (1.90 mL, 6.00 mmol) after 5 h. Yield:
0.636 g (93%, colorless oil). Rf (pentane/toluene/EtOAc, 40:50:10)
= 0.70. [α]2D0 = +2.97 (c = 7.71, CHCl3); ref.[6] [α]2D0 = +2.9 (c = 10,
Eur. J. Org. Chem. 2008, 2635–2643
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2641

S. D. Stamatov, J. Stawinski
FULL PAPER
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Received: January 30, 2008
Published Online: April 2, 2008
Eur. J. Org. Chem. 2008, 2635–2643
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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