Synthesis and preferred conformations of all regio- and diastereoisomeric methyl 2,3-fluorohydroxyalkanoates

Article abstract of DOI:10.1002/ejoc.201001224

Selective syntheses of enantiopure regio- and diastereomeric methyl 2,3-fluoro-hydroxyalkanoates via four different routes employing two types of fluorination reagents are reported. The anti- and syn-3-fluoro-2- hydroxyalkanoates 1 and 3 were prepared by treating the corresponding epoxides with Olah's reagent (Py·9HF). Cyclic sulfates prepared from the enantiomeric diols were ring-opened with TBAF to give the anti- and syn-2-fluoro-3-hydroxyalkanoates 2 and 4. Thestereochemical analysis was performed mainly by NMR spectroscopy. Applying DFT/B3LYP and SCS-MP2 quantum chemical methods, the coupling constants and relative energies of conformers were calculated. Solvent effects were considered using the COSMO continuum model. Regio- and stereoselective ring opening of enantio-pure epoxides or cyclic sulfates with pyridine·9HF or TBAF delivers anti- or syn-configurated 3-fluoro-2-hydroxy- or 2-fluoro-3-hydroxyalkanoates, respectively. The relative energies of conformers were calculated by quantum chemical methods. Those of 3-fluoro-2-hydroxy isomers are influenced by intramolecular O-H·O=C hydrogen bonds, while the regioisomers show close O-H·F-C contacts. Copyright

Full text of DOI:10.1002/ejoc.201001224

FULL PAPER
DOI: 10.1002/ejoc.201001224
Synthesis and Preferred Conformations of All Regio- and Diastereoisomeric
Methyl 2,3-Fluorohydroxyalkanoates
[
a]
[a]
[a]
[a]
Wibke S. Husstedt, Susanne Wiehle, Christian Stillig, Klaus Bergander,
[a]
[a]
Stefan Grimme,* and Günter Haufe*
Keywords: Organofluorine chemistry / Fluorohydrins / Conformation analysis / Enantioselectivity / Nucleophilic
substitution / Quantum chemical calculations
Selective syntheses of enantiopure regio- and diastereomeric
methyl 2,3-fluoro-hydroxyalkanoates via four different routes
employing two types of fluorination reagents are reported.
The anti- and syn-3-fluoro-2-hydroxyalkanoates 1 and 3
were prepared by treating the corresponding epoxides with
Olah’s reagent (Py·9HF). Cyclic sulfates prepared from the
enantiomeric diols were ring-opened with TBAF to give the
anti- and syn-2-fluoro-3-hydroxyalkanoates 2 and 4. The
stereochemical analysis was performed mainly by NMR
spectroscopy. Applying DFT/B3LYP and SCS-MP2 quantum
chemical methods, the coupling constants and relative ener-
gies of conformers were calculated. Solvent effects were con-
sidered using the COSMO continuum model.
Introduction
fluorohydrins derived from α,β-unsaturated fatty acid esters
and to determine the lowest energy conformations by NMR
methods and high level quantum chemical calculations for
shorter-chain model compounds. Since the phase behavior
depends on the enantiomeric excess, it was necessary to pre-
The substitution of a C–H group by a C–F group causes
dramatic changes of the physico-chemical properties, of the
chemical reactivity, and of the biological behavior of mole-
[
1]
cules. On the one hand a fluorine substituent is almost
isosteric to hydrogen and isopolar to the OH group. This
results in the ability of a C–F group to act as a weak hydro-
gen-bond acceptor with respect to polar X–H-bonds,
though this point is still discussed.[ Due to the similarity
of the bond lengths of aliphatic C–F and C–O bonds (1.39
and 1.43 Å, respectively) and their comparable polarity, the
fluorine substituent can act as a mimic for a hydroxy group.
Although hydrogen bonds of fluorine to OH groups are
weaker than those of the other halogens, they lead to the
preference of a gauche conformation of fluoroethanol in the
[7]
pare highly enantiopure material.
For the synthesis of vicinal fluorohydrins anti-selective
epoxide ring opening with fluorinating reagents is one of
the most frequently used methods, which allows the intro-
duction of a fluorine atom into a broad variety of carbon
skeletons. Various reagents or reagent combinations have
2]
[8]
been used as fluoride donors. Ring opening can occur by
different reaction mechanisms, S 1 or S 2, explaining the
N
N
selectivity of the formal addition of HF. Carbenium ion-
stabilizing substituents favor an S 1 reaction, whereas de-
N
stabilizing substituents favor the S 2 pathway. Additionally,
N
[
3,4]
liquid.
Similar observations both by NMR spectroscopy
the selectivity of these reactions is influenced by steric con-
straints, the acidity of the reagent, the nucleophilicity of
the particular fluoride donor, the solvent and the reaction
and quantum chemical calculations were also made for the
vicinal fluorohydrin fragment in 1,3-difluoropropan-2-ol
and 1-(4-bromophenyl)-2-fluoroethanol as well as for 2-
fluoropropanol and trans-2-fluorocyclohexanol.[ Confor-
mations of fluorohydrins derived from long-chain α,β-un-
saturated fatty acid esters, where the ester function will sig-
nificantly influence the geometry, are not yet known.
[9]
temperature.
5]
Results and Discussion
In order to study the phase behavior at interfaces of such
long-chain fluorinated fatty acid esters,[6] we were interested
Synthesis of Regio- and Stereoisomeric Methyl 2,3-Fluoro-
hydroxyalkanoates
in regio- and stereoselective synthesis of diastereomeric 2,3-
For the selective synthesis of the regioisomeric methyl
,3-fluorohydroxyalkanoates four different routes were
used. The racemic methyl anti-3-fluoro-2-hydroxyalk-
anoates 1 were obtained by ring opening with hydrofluori-
nating agents of the racemic epoxides 6, which were avail-
able from the α,β-unsaturated esters 5 by epoxidation using
[
a] Organisch-Chemisches Institiut, Westfälische Wilhelms-
2
Universität,
Corrensstraße 40, 48149 Münster, Germany
Fax: +49-251-83-39772
E-mail: haufe@uni-muenster.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001224.
Eur. J. Org. Chem. 2011, 355–363
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
355

S. Grimme, G. Haufe et al.
FULL PAPER
m-chloroperoxybenzoic acid. The latter compounds 5 were from both regioisomers in 44–76% yields under S 2 condi-
N
[
14]
prepared from corresponding aldehydes by Wittig reaction tions
using potassium carbonate at room temperature.
[
10]
with (methoxycarbonylmethylene)triphenylphosphorane.
Ring opening with Olah’s reagent as described above for
Treatment of compounds rac-6 with Olah’s reagent resulted the racemic epoxides provided the target (2S,3R)-3-fluoro-
in the formation of the diastereomerically pure racemic re- 2-hydroxy esters 1 as the sole products in 76–99% yields
gioisomers anti-1. A plausible mechanism is outlined in (Scheme 2).
Scheme 1. Initially the strongly acidic fluorination reagent
protonates the oxirane ring. The preferred position for the
fluoride to open the intermediary cation by back side attack
is the β-position because of better stabilization of the par-
tial positive charge due to inductive and resonance effects
of the substituents. Related regioselectivity was also ob-
served for the ring opening reaction of epoxides derived
from α,β-unsaturated nitriles, esters or amides bearing a
[
11]
phenyl group or two alkyl substituents in β-position.
Scheme 2. Synthetic route to the enantiopure (2S,3R)-3-fluoro-2-
hydroxyalkanoates 1.
In order to prepare methyl (2S,3S)-3-fluoro-2-hydroxy-
octadecanoate (3b) (syn-configuration) the (2S,3R)-2,3-diol
[
15]
7
b obtained from 5b by Sharpless dihydroxylation using
AD-mix-β was esterified selectively at the α-position with
nosyl chloride analogous to a protocol described by Matsu-
[
16]
[17]
ura et al.
According to the work of Sharpless et al.
the introduction of a nosyl- instead of a tosyl group leads
to higher regioselectivities, higher yields and better reactiv-
ities in the following conversion to epoxides, as described
Scheme 1. Synthesis of the racemic methyl anti-3-fluoro-2-hydroxy-
alkanoates 1.
[
16,18]
also in other publications.
group was esterified selectively to give the nosylate (2S,3R)-
However, a free carbenium ion is not likely as an inter- 10b, though the reaction did not go to completion (7b/10b
In our case the α-hydroxy
13
mediate in the presence of Olah’s reagent. More probable, ratio, 1:6, C NMR spectroscopically). Unfortunately,
the fluorohydrins were formed via a bridged intermediate compound (2S,3R)-10b decomposed during silica gel
associated with hydrogen fluoride following a so-called con- chromatography. Therefore epoxide (2R,3R)-11b was di-
veyer-belt mechanism.[ Thus, the methyl anti-3-fluoro-2- rectly prepared from the crude nosylate (2S,3R)-10b via an
hydroxyalkanoates were obtained in 73–80% yields. No S 2-reaction by stirring with K CO at room temperature
12]
N
2
3
other fluorinated compounds were detected in the crude and subsequent chromatographic separation from minor
1
9
product mixture by F NMR spectroscopy.
amounts of unreacted diol (2S,3R)-7b. The epoxide
The corresponding enantiopure (2S,3R)-3-fluoro-2-hy- (2R,3R)-11b was opened using Olah’s reagent at 3-position
droxyalkanoates 1 (anti isomers) and the diasteromeric with inversion of the configuration as described above. In
methyl (2S,3S)-3-fluoro-2-hydroxyoctanoate (3b, syn iso- this way methyl (2S,3S)-3-fluoro-2-hydroxyoctadecanoate
mer) were synthesized via two different routes. Several vari- (3b) was obtained in 52% yield (Scheme 3).
ants of enantioselective epoxidation of α,β-unsaturated es-
No other fluorinated compound was found in the crude
ters were shown to be less enantioselective.[
13]
Thus, product mixture by F NMR spectroscopy. Non-fluori-
19
Sharpless’ dihydroxylation using AD-mix-α was applied to nated impurities were separated chromatographically. In the
provide the (2R,3S)-diols 7 in 72–94% yield and 94–97% remaining product the other enantiomer of 3b could not be
[
19]
ee. Subsequent treatment with HBr in glacial acetic acid detected using the Mosher ester method.
Thus the ee
employing the method described by Mori et al. gave mix- value is above 98%, so all steps are highly diastereoselective.
tures of the regioisomeric bromohydrins (2S,3S)-8 and The synthesis of the anti-regioisomers 2 and the syn-re-
2S,3R)-9. Depending on the chain length different ratios gioisomers 4 was designed by opening of the cyclic sulfates
of the regioisomers were formed (90:10 for n = 12; 79:21 (2R,3S)-12 or (2S,3S)-15, respectively, with tetrabutylam-
[14]
(
[20,21]
for n = 14 and 77:23 for n = 16). However, no separation monium fluoride (TEBAF) through an S 2 process.
N
was necessary since the (2R,3S)-epoxides 6 were formed The sulfates were accessible by two different routes (see
356
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Synthesis and Conformations of Fluorinated Hydroxyalkanoates
able mechanism that leads to the formation of compounds
3 from intermediate (2S,3R)-1 by fluoride-catalyzed HF
1
elimination is shown in Scheme 4.
A number of different fluorinating reagents such as
Bu NF,
Bu NF·3H O,
Me NF·3H O,
Et N·3HF,
3
4
4
2
4
2
pyridine·9HF, and KHF were tested as alternative fluoride
2
sources in several solvents (acetone, DMF, DMSO,
CH Cl ) in order to improve the regioselectivity of the ring
2
2
opening and hence the yields of products (2S,3S)-2. Also
the work-up conditions were changed, but no improvement
[
22]
of the yield was possible. However, compound (2S,3R)-1
was formed as a stable compound under the acidic condi-
tions of epoxide ring opening with pyridine·9HF (see
above).
Scheme 3. Synthetic route to methyl (2S,3S)-3-fluoro-2-hydroxy-
octadecanoate (3b).
The other diastereomer, (2R,3S)-2-fluoro-3-hydroxyocta-
Schemes 4 and 5). The (2R,3S) isomers 12 were prepared decanoate (4b), was designed to be synthesized analogously
from the corresponding diols (2R,3S)-7 in two steps. Open- from the diastereomeric cyclic sulfate (2S,3S)-15b
ing of these sulfates with TEBAF, as previously discussed (Scheme 5).
[
20]
in literature
for compound 12b, resulted in the desired
Consequently, diol (2S,3R)-7b was treated with HBr in
anti-2-fluoro-3-hydroxy isomers 2, however as minor com- glacial acetic acid to give a mixture of the bromohydrins
ponents in our cases. The major products were unexpec- (2R,3R)-8b and (2R,3S)-9b, which on treatment with potas-
tedly methyl 2-oxoalkanoates 13. This type of reaction was sium carbonate gave epoxide (2S,3R)-6b. The subsequent
not previously reported[ and this mode of reaction was acid-catalyzed hydrolytic ring opening did not proceed
not found either for similar ring opening reactions with smoothly and gave only a low yield of the (2S,3S)-2,3-diol
20]
[
15]
[23,24]
other nucleophiles. The reaction might occur due to the 14b in aqueous DMSO at elevated temperature.
The 2-
strong basicity of fluoride ions in aprotic solvents. A prob- oxo derivative 13b was the major product under these con-
ditions. Variation of the reaction conditions did not im-
prove the yield. Then the cyclic sulfate (2S,3S)-15b was ac-
cessible from (2S,3S)-14b in two steps with thionyl chloride
in dichloromethane according to the method of He et al.[
25]
and subsequent perruthenate oxidation (94% overall yield).
Treatment of sulfate (2S,3S)-15b with TEBAF in DMF
gave the expected methyl (2R,3S)-2-fluoro-3-hydroxyocta-
decanoate (4b) in low yield. Its regioisomer methyl (2R,3R)-
3
-fluoro-2-hydroxyoctadecanoate (3b) was formed as the
major product with an inversion of configuration at C-3
Scheme 5). Compound 4b was isolated by repeated column
(
chromatography.
In contrast to the situation in cyclic sulfate (2R,3S)-12b,
the 2-position of diastereomer (2S,3S)-15b seems less ac-
cessible towards an S 2-like fluoride attack. Consequently,
N
(2R,3S)-4 is formed as the minor product with (2R,3R)-3b.
In contrast to its diastereomer (2S,3R)-1, no HF elimi-
nation from (2R,3R)-3-fluoro-2-hydroxyoctadecanoate (3b)
Scheme 4. Formation of methyl (2S,3S)-2-fluoro-3-hydroxyalk-
anoates (2) and 2-oxo compounds 13.
Scheme 5. Synthesis of methyl (2R,3R)-3-fluoro-2-hydroxyoctadecanoate (3b) and methyl (2R,3S)-2-fluoro-3-hydroxyoctadecanoate (4b).
357
Eur. J. Org. Chem. 2011, 355–363
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Grimme, G. Haufe et al.
was observed in the reaction of (2S,3S)-15b with TEBAF, Table 2. Calculated[a] energy differences ΔE (kJ/mol), populations
FULL PAPER
3
3
(
percentage at 293 K in parentheses), JHF and JHH (in Hz) for
maybe due to the disfavored anti-conformation of fluorine
and hydrogen needed for an E2 process. Thus, both enantio-
mers of 3b were prepared from the same diol (2S,3R)-7b
with high regioselectivity.
different conformers of methyl anti- and syn-3-fluoro-2-hydroxy-
butanoates.
Conf.
mer
ΔE B3LYP ΔE B3LYP ΔE SCS-MP2
(ε = 1) (ε = 2.4) (ε = 2.4)
3JHF 3JHH
anti
Conformations of Regio- and Stereoisomeric Methyl 2,3-
Fluorohydroxyalkanoates
A
B
C
0.52 (33.4) 0.00 (41.9) 0.00 (44.1)
1.20 (25.4) 1.08 (26.9) 0.78 (31.2)
0.00 (41.2) 0.72 (31.2) 1.35 (24.7)
14.9 2.2
26.6 0.8
–0.4 7.7
In order to prove the anti-configuration of the methyl
-fluoro-2-hydroxyalkanoates (1) prepared from the trans-
syn
3
A
B
0.00 (92.7) 0.00 (90.2) 0.00 (89.9)
27.7 2.0
25.1 1.2
epoxides 6, the NMR spectra in toluene of the C -
1
8
6.56 (7.3)
5.36 (9.8)
5.39 (10.1)
3
fluorohydrin 1b was studied and the J
coupling con-
HF
[
a] Single-point energies in the gas phase (ε = 1) and in solution
stants were compared to those calculated (SCS-MP2, rela-
using the COSMO continuum solvation model at a dielectric con-
stant of ε = 2.4 (toluene). The TZV(2df,2pd) AO basis set and
tive energies and B3LYP-computed J values, vide infra) for
the mixture of the most stable conformers of methyl anti- B3LYP (ε = 1) optimized structures are employed. The coupling
constants were calculated at the B3LYP/TZV(d,p) level.
and syn-3-fluoro-2-hydroxybutanoates as model com-
pounds for the long-chain compounds 1 and 3 (Table 1).
Table 1. Temperature dependency of 3JHF coupling constants of the
methyl anti- and syn-3-fluoro-2-hydroxyalkanoates in toluene.
3
-Fluoro-2-hydroxy
Coupling constants 3JHF
compounds
253 K
293 K
353 K
[
a]
(
3S,3R)-1b, measured
19.2 Hz
14.9 Hz
–
–
18.4 Hz
14.8 Hz
31.4 Hz
27.4 Hz
17.4 Hz
14.6 Hz
–
–
[
b]
calculated (anti)
Figure 1. Calculated [B3LYP/TZV(2df,2pd)] most stable conform-
ers of methyl anti-3-fluoro-2-hydroxybutanoate. Short intramolecu-
lar O–H···O=C contacts are given in pm.
[
c]
[d]
(
2S,3S)-3b, measured
[
e]
calculated (syn)
1
[
1
a] Determined from the H NMR spectra (600 MHz) of (3S,3R)-
b. [b] Average value for the three most stable conformers (see
Table 2) at the given temperatures. [c] No temperature effect is ex-
pected because similar coupling constants are expected for both
conformations. [d] Measured for (2S,3S)-3b. [e] Average value for
the two most stable conformers with a ratio of 89.9%: 10.1% at
293 K, see Table 2.
Comparison of the values calculated for the model com-
pounds (Table 1) with the experimental ones suggested the
correct assignment as the anti isomer 1b as well as for the ers of methyl syn-3-fluoro-2-hydroxybutanoate. Short intramolecu-
syn isomer (2S,3S)-3b. Expecting very small effects, we also
Figure 2. Calculated [B3LYP/TZV(2df,2pd)] most stable conform-
lar O–H···O=C/F–C contacts are given in pm.
determined the temperature dependency of the coupling
constants for 1b. Indeed, slightly increasing values were
The relative energies and corresponding Boltzmann pop-
found with decreasing temperature for the JHF coupling ulations of the various conformers are given in Table 2. In
Table 1), which is in agreement with the anti-configuration. addition to the standard DFT-B3LYP method, results from
3
(
3
Also the J
of 3.2 Hz calculated for the equilibrium of the recently developed improved Møller–Plesset pertur-
HH
[
33]
the three most stable conformers (Table 2) of methyl anti-3- bation theory (SCS-MP2 ) were taken into account. All
fluoro-2-hydroxybutanoate as a model compound is in data have been obtained by approximate inclusion of sol-
good agreement with the 3.5 Hz measured for compound vent effects via the COSMO continuum solvation model.[
34]
1b.
This is of particular importance especially for the anti iso-
The most stable conformations[26–32] of the syn- and anti mer where the energy differences are only around 1 kJ/mol.
isomers of methyl 3-fluoro-2-hydroxybutanoates, the model Furthermore, in this case the energetic ordering changes
compounds for 1 and 3, are shown in Figure 1 and Fig- when going from the gas phase (C is most stable) to toluene
ure 2, respectively. In the case of the anti isomers all ener- solution (A is most stable).
The calculated (B3LYP/TZV(d,p) ) J and 3JHH cou-
[
35] 3
getically low-lying structures have an O–H···O=C hydrogen
HF
bond with H···O distances in the range 207–212 pm. This pling constants are given in Table 2. These calculations are
also holds for conformer A of the syn-form. The second fully analytic and include beside the most important Fermi-
lowest energy structure B (about 5.4 kJ/mol) has a relatively contact term also the diamagnetic spin-orbit, paramagnetic
short (263 pm) O–H···F–C contact indicating a quite weak spin-orbit, and spin-dipole contributions; for details and
[
36]
hydrogen bond.
further references see ref. For the conformer C we obtain
358
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Synthesis and Conformations of Fluorinated Hydroxyalkanoates
a tiny 3JHF value of –0.4 Hz, while large positive values for data in Table 3, compared to the 3-fluoro-2-hydroxybut-
A (14.9 Hz) and B (26.6 Hz) were calculated (at 293 K, see anoates, there are even more conformers quite close in en-
Table 2). The average value of 14.77 Hz for these three con- ergy (i.e. four and five vs. three and two). One of the reasons
formers compares favorably with the experimental number for the different behavior are the more favorable O–H···F–
of 18.4 Hz obtained for methyl (3S,3R)-3-fluoro-2-hydroxy- C interactions in the 2-fluoro-3-hydroxybutanoates (i.e. for
icosanoate (1b), while 27.4 Hz was calculated for the equi- the syn-form, four out of five conformers show short O–
librium of conformers A and B of the methyl syn-3-fluoro- H···F–C contacts) compared to the preferred C=O···H–O
2-hydroxybutanoate. This value is in good agreement with bridges found in the 3-fluoro-2-hydroxybutanoates. The
the value of 31.4 Hz measured for (2R,3R)-3b. predicted populations are very similar for B3LYP and SCS-
The temperature dependence of the coupling constant MP2 methods although it is noted that they differ by the
can be estimated by considering the temperature depen- lowest energy conformer (anti: A with B3LYP and B with
dence of the populations of the different conformers ac- SCS-MP2, syn: A with B3LYP and D with SCS-MP2).
cording to a Boltzman distribution. For the anti-3-fluoro-
2
-hydroxy isomer (model for compounds 1) the averaged
3
JHF values at the B3LYP level are 13.24 (253 K), 13.28
(293 K) and 13.34 (353 K) Hz. With the SCS-MP2 relative
energies and derived populations we obtain 14.90 (253 K),
4.77 (293 K) and 14.61 Hz (353 K) (Table 1). The larger
1
coupling constants and the direction of temperature depen-
dence as computed by SCS-MP2 are in better agreement
with experiment indicating the higher quality of the SCS-
MP2 compared to the B3LYP energetic description which
differs in the ordering of conformers B and C. For the syn
isomer (model for compounds 3) the temperature depen-
dence is insignificant because both contributing species al-
most have the same coupling constant.
A similar conformational analysis of low energy con-
Figure 3. Calculated [B3LYP/TZV(2df,2pd)] most stable conform-
formers has been performed for the diastereomeric methyl ers of methyl anti-2-fluoro-3-hydroxybutanoate. Short intramolecu-
lar O–H···O=C/F–C contacts are given in pm.
2-fluoro-3-hydroxybutanoates, the models for compounds 2
or 4, respectively. In these cases no temperature-dependent
NMR spectra were recorded because of several energeti-
cally very similar conformations. The energy differences/
populations and plots of the most stable structures are
given in Table 3 and Figures 3 and 4, respectively. As noted
before, inclusion of a solvation model is crucial to obtain
conclusive answers as in the gas phase, for the anti isomer
only one conformer is dominating. As can be seen from the
Table 3. Calculated[a] energy differences ΔE (kJ/mol) and popula-
3
3
tions (percentage at 293 K in parentheses), JHF and JHH (in Hz)
for different conformers of methyl anti- and syn-2-fluoro-3-hy-
droxybutanoates.
Conf. ΔE B3LYP (ε = 2.4)
ΔE SCS-MP2 (ε = 2.4) 3JHF 3JHH
anti
Figure 4. Calculated [B3LYP/TZV(2df,2pd)] most stable conform-
ers of methyl syn-2-fluoro-3-hydroxybutanoate. Short intramolecu-
lar O–H···O=C/F–C contacts are given in pm.
A
B
C
D
0.00 (47.8)
2.00 (20.7)
2.00 (21.0)
3.64 (10.5)
0.50 (24.8)
0.00 (30.6)
0.46 (25.2)
1.10 (19.4)
–1.1 7.5
17.3 2.4
21.7 2.8
17.8 2.0
syn
Conclusions
A
B
C
D
E
0.00 (32.5)
2.20 (13.3)
1.83 (15.5)
0.62 (25.6)
2.23 (13.1)
0.43 (26.5)
2.52 (11.2)
1.82 (14.9)
0.00 (31.9)
1.73 (15.5)
20.4 1.2
11.5 7.0
5.9 4.9
21.1 1.6
13.8 6.7
All regioisomeric and diastereoisomeric methyl anti- and
syn-2,3-fluorohydroxyalkanoates with C , C , and C
20
chains were synthesized in diastereomerically and enantio-
merically pure form. While S 1-like ring opening of cis- or
trans-2,3-epoxides with pyridine·9HF lead selectively to the
16
18
N
[
a] Single-point energies using the COSMO continuum solvation
model at dielectric constant of 2.4 (toluene). The
a
ε =
3-fluoro-2-hydroxyalkanoates, the S 2-like ring opening of
TZV(2df,2pd) AO basis set and B3LYP (ε = 1) optimized structures
N
are employed.
cyclic sulfates derived from the corresponding 2,3-diols with
Eur. J. Org. Chem. 2011, 355–363
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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359

S. Grimme, G. Haufe et al.
FULL PAPER
the more nucleophilic tetrabutylammonium fluoride lead to available AD-mix-α for (2R,3S)-7 or AD-mix-β for (2S,3R)-7. The
physical constants and spectroscopic data obtained for the prod-
the 2-fluoro-3-hydroxyalkanoates in low yields, probably
due to steric constraints of the 2-position. The lowest en-
ergy conformations of these compounds have been esti-
mated by quantum chemical calculations [B3LYP/
TZV(2df,2pd)] on shorter-chain homologues. All three al-
most equally stable conformations of methyl anti-3-fluoro-
ucts agree with those given in literature for methyl (2R,3S)-2,3-
[
10c]
dihydroxyhexadecanoate,
methyl (2R,3S)-2,3-dihydroxyoctade-
canoate,[
10c]
methyl (2S,3R)-2,3-dihydroxyoctadecanoate
methyl (2R,3S)-2,3-dihydroxyicosanoate.
[10c]
and
[10c]
Synthesis of the Bromohydrins 8 and 9
2
-hydroxybutanoate are mostly determined by strong hy- Analogously to the published procedure[14] a solution of the corre-
drogen bonds of the OH group to the carbonyl oxygen sponding diol (1.0 equiv.) was dissolved in HBr (33% in glacial
characterized by quite short distances of 2.08 Å (A), 2.07 Å acetic acid, 3.6 equiv.) and stirred for 1 h at 45 °C. Then methanol
was added and the mixture was heated at the indicated temperature
(
B), and 2.12 Å (C). The OH group and fluorine are in a
for another 12 h. After cooling to room temp. the solution was
poured into ice-water and neutralized with NaHCO . The aqueous
phase was extracted with diethyl ether (3ϫ50 mL) and dried with
MgSO . Removal of the solvent gave the corresponding bromo-
gauche position in conformers A and B, but lacking any
close O–H···F–C contact. In conformer C these two groups
are in anti position. Similarly, also conformation A of the
syn isomer is determined by strong interaction of the OH
and the C=O groups. Only in the less stable conformer syn-
B a weak hydrogen bond stabilizes this arrangement. In
contrast, all conformers of methyl anti-2-fluoro-3-hydroxy-
butanoate and four out of five of its syn isomer are stabi-
lized by weak O–H···F–C hydrogen bonds exhibiting short
H···F distances, well below the sum of the van-der-Waals
radii of 267 pm. Also, the most stable conformations of 2-
3
4
hydrins as white solids.
Synthesis of Cyclic Sulfates 12: Similar to a published procedure,[20]
to an argon-covered solution of the corresponding diol 7 (1 equiv.)
in CCl
mixture was refluxed. Then the solvent was evaporated completely.
The residue was dissolved in CCl and CH CN (5 mL each). NaIO
1.5 equiv.), RuCl ·3H O (1 mol-%) and water (7.5 mL) were added
and the solution was stirred at room temperature until the starting
4
thionyl chloride (1.2 equiv.) was added and the reaction
4
3
4
(
3
2
fluoroethanol, 2-fluoropropanol and 3-fluorobutan-2-ol in material was consumed (DC). After adding of diethyl ether (50 mL)
[
37,38]
liquid phase are those with fluorine gauche to oxygen
the two layers were separated and the aqueous layer was extracted
giving rise to the formation of hydrogen bonds, which was with diethyl ether. The combined organic layer was washed with
[
39–42]
water, saturated NaHCO and brine and then dried with MgSO .
Removal of the solvent gave the cyclic sulfates as white solids.
proved by experimental results
tions.
and theoretical calcula-
3
4
[
2a,3,43,44]
The question of whether the fluorine gauche
effect, which is responsible for the higher stability of the Synthesis of Methyl anti-3-Fluoro-2-hydroxyalkanoates 1: In a dry
gauche- over the anti-1,2-difluoroethane,[ significantly in- polypropylene flask Olah’s reagent (10 equiv.) was cooled to 0 °C.
fluences the relative energy of vicinal fluorohydroxy com- Then the corresponding epoxide 6 or 11 (1 equiv.) dissolved in
45]
2 2
CH Cl was carefully added. After reaching room temperature the
pounds will possibly be answered by our further investi-
gations.
solution was stirred for another 6 h. The reaction mixture was then
poured into ice-cooled 2 m ammonia and neutralized with concen-
trated ammonia. The organic layer was separated and the aqueous
layer was extracted three times with small portions of CH
combined organic layer was dried with MgSO . Removal of the
CH Cl gave the fluorohydrins as white solids.
2 2
Cl . The
Experimental Section
4
Synthesis of Methyl trans-Alk-2-enoates 5: Methyl hexadec-2-eno-
ate, methyl octadec-2-enoate and methyl icos-2-enoate were synthe-
sized by Wittig reaction of the corresponding aldehydes and (meth-
oxycarbonylmethylene)triphenylphosphorane. The phosphorane
was synthesized from methyl bromoacetate. Tetradecanal, hexa-
decanal, and octadecanal were obtained by Swern oxidation of the
corresponding alcohols. All conversions followed standard pro-
cedures. The measured physical constants and spectroscopic data
agree with those given in literature for (methoxycarbonylmethyl-
2
2
Methyl anti-3-Fluoro-2-hydroxyhexadecanoate (rac-1a): Olah’s rea-
gent (0.5 mL, 15.0 mmol), the epoxide rac-6a (0.43 g, 1.5 mmol),
CH
2
Cl
2
(2 mL); yield 0.32 g (73%) after column chromatography
1
(
cyclohexane/ethyl acetate, 10:1); m.p. 50 °C. H NMR (CDCl ,
3
3
1
00 MHz): δ = 0.86 (t, J = 6.7 Hz, 3 H), 1.20–1.36 (m, 22 H), 1.41–
.89 (m, 2 H), 3.14 (d, J = 6.5 Hz, 1 H), 3.81 (s, 3 H), 4.32 (ddd,
J = 18.3, J = 6.2, J = 3.5 Hz, 1 H), 4.64 (dddd, J = 47.6, J = 9.2,
13
J = 3.4, J = 3.4 Hz, 1 H) ppm. C NMR (CDCl
4.0 (q), 22.6 (t), 25.0 (dt, J = 2.6 Hz), 29.2 to 29.6 (8t), 30.0 (dt,
J = 21.4 Hz), 31.9 (t), 52.7 (q), 72.6 (dd, J = 23.1 Hz), 94.4 (dd, J
3
, 75.5 MHz): δ =
1
[46] 13
[47]
[48]
ene)triphenylphosphorane ( H NMR,
C NMR, GC/MS ),
1
1
[10c,49] 13
[10c]
GC/MS[10c]), hexa-
GC/MS ), octa-
methyl octadec-2-
tetradecanal ( H NMR,
C NMR,
1
[10c,50]
13C NMR,
[10c,50,51]
[10c]
decanal ( H NMR,
19
=
3
177.3 Hz), 172.0 (d, J = 8.7 Hz) ppm. F NMR (CDCl ,
[
10,52]
[10c]
decanal,
methyl hexadec-2-enoate,
2
1
82 MHz): δ = –191.2 (dddd, J = 66.1, J = 17.6, J = 17.6, J =
7.6 Hz) ppm. GC-MS m/z (%) = 304 (0.1) [M ], 284 (3), 269 (0.5),
[
10b,10c]
[10c]
enoate,
and methyl eicos-2-enoate.
+
Methyl trans-2,3-Epoxyalkanoates 2: The racemic epoxides were
prepared from the corresponding α,β-unsaturated esters 5 using m-
266 (1), 252 (2), 225 (34), 214 (2), 130 (9), 103 (10), 90 (76), 43
(100). C17
H 10.95.
3
H33FO (304.4): calcd. C 67.07, H 10.93; found C 67.19,
2 2
chloroperoxybenzoic acid in refluxing CH Cl . The physical con-
stants and spectroscopic data obtained agree with those given in
Methyl anti-3-Fluoro-2-hydroxyoctadecanoate (rac-1b): Olah’s rea-
gent (0.4 mL, 12.0 mmol), the epoxide rac-6b (0.37 g, 1.2 mmol),
[10c]
the literature for methyl trans-2,3-epoxyhexadecanoate,
methyl
[10c]
trans-2,3-epoxyoctadecanoate,
and methyl trans-2,3-epoxyicos-
CH
cyclohexane/ethyl acetate, 10:1); m.p. 57 °C. H NMR (CDCl
Synthesis of Methyl (2R,3S)- and (2S,3R)-2,3-Dihydroxyalkanoates 300 MHz): δ = 0.88 (t, J = 6.7 Hz, 3 H), 1.21–1.36 (m, 26 H), 1.41–
2 2
Cl (1.5 mL); yield 0.30 g (75%) after column chromatography
[
10c]
anoate.
1
(
3
,
7
: The diols were synthesized from the corresponding α,β-unsatu-
1.89 (m, 2 H), 3.01 (d, J = 6.8 Hz, 1 H), 3.83 (s, 3 H), 4.34 (ddd,
J = 18.4, J = 6.6, J = 3.4 Hz, 1 H), 4.65 (dddd, J = 47.4, J = 9.3,
rated esters 5 by Sharpless dihydroxlylation using the commercially
360
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 355–363

Synthesis and Conformations of Fluorinated Hydroxyalkanoates
J = 3.4, J = 3.4 Hz, 1 H) ppm. 13C NMR (CDCl
4.1 (q), 22.7 (t), 25.0 (dt, J = 4.0 Hz), 29.2 to 29.6 (10t), 30.0 (dt,
, 75.5 MHz): δ =
the α-ketocarboxylic esters 13 as white solids. The desired products
2 and 4 were isolated in Ͼ97% purity by repeated careful column
3
1
J = 19.5 Hz), 31.9 (t), 52.7 (q), 72.7 (dd, J = 22.8 Hz), 94.4 (dd, J chromatography. In order to demonstrate the identity of the α-keto-
=
176.6 Hz), 172.0 (d, J = 9.1 Hz) ppm. 19F NMR (CDCl
3
,
carboxylic esters, compound 13b was isolated chromatographically.
2
1
2
82 MHz): δ = –191.9 (dddd, J = 64.9, J = 16.6, J = 16.6, J =
6.6 Hz) ppm. GC-MS m/z (%) = 332 (0.5) [M ], 312 (3), 294 (4),
80 (12), 253 (100), 242 (13), 130 (38), 103 (37), 90 (100).
Methyl (2S,3S)-2-Fluoro-3-hydroxyhexadecanoate (2a): From the
sulfate (2R,3S)-12a (0.182 g, 0.5 mmol); yield 0.033 g (22%) after
column chromatography (cyclohexane/ethyl acetate, 8:1); m.p.
+
19 3
C H37FO (332.5): calcd. C 68.63, H 11.22; found C 68.43, H
2
0
1
D 3 3
61 °C. [α] = –6.2 (c = 1.0, CHCl ). H NMR (CDCl , 300 MHz):
1
1.23.
Methyl anti-3-Fluoro-2-hydroxyicosanoate (rac-1c): Olah’s reagent
0.5 mL, 15.0 mmol), the epoxide rac-6c (0.51 g, 1.5 mmol),
CH Cl (2.0 mL); yield 0.42 g (80%) after column chromatography
pentane/Et
δ = 0.88 (t, J = 6.7 Hz, 3 H), 1.21–1.36 (m, 22 H), 1.47–1.63 (m, 2
H), 2.27 (br. s, 1 H), 3.82 (s, 3 H), 3.95–4.10 (dm, J = 17.7 Hz, 1
1
3
(
H), 4.87 (dd, J = 48.4, J = 4.1 Hz, 1 H) ppm. C NMR (CDCl3,
75.5 MHz): δ = 14.0 (q), 22.7 (t), 25.3 (t), 28.9 (t), 29.3 to 29.6 (8t),
2
2
1
(
2
O, 30:1); m.p. 64 °C. H NMR (CDCl
3
, 600 MHz): δ 31.5 (dt, J = 5.9 Hz), 31.9 (t), 52.4 (q), 71.7 (dd, J = 21.5 Hz), 91.3
1
9
=
0.88 (t, J = 6.7 Hz, 3 H), 1.21–1.36 (m, 30 H), 1.41–1.89 (m, 2
(dd, J = 186.8 Hz), 168.5 (d, J = 23.9 Hz) ppm. F NMR (CDCl3,
282 MHz): δ = –199.8 (dd, J = 47.8, J = 17.7 Hz) ppm. GC-MS
H), 3.01 (d, J = 6.0 Hz, 1 H), 3.83 (s, 3 H), 4.34 (dm, J = 17.8 Hz,
+
1
H), 4.65 (dddd, J = 47.4, J = 9.3, J = 3.5, J = 3.5 Hz, 1 H) ppm.
m/z (%) = 304 (2) [M ], 303 (8), 289 (0.5), 286 (2), 284 (0.1), 266
13
C NMR (CDCl
3
, 151 MHz): δ = 14.1 (q), 22.7 (t), 25.0 (dt, J =
(1), 227 (1), 214 (23), 213 (9), 121 (23), 105 (8), 92 (100). HRMS:
C H O F calcd. 286.2308; found 286.2277.
4
7
8
6
.3 Hz), 29.2 to 29.7 (12t), 30.0 (dt, J = 19.3 Hz), 31.9 (t), 52.7 (q),
1
7
31
2
2.7 (dd, J = 22.8 Hz), 94.5 (dd, J = 176.4 Hz), 172.0 (d, J =
.8 Hz) ppm. 1 F NMR (CDCl
9
Methyl (2S,3S)-2-Fluoro-3-hydroxyoctadecanoate (2b): From the
sulfate (2R,3S)-12b (0.196 g, 0.5 mmol); yield 0.030 g (18%) after
column chromatography (cyclohexane/ethyl acetate, 8:1); m.p.
3
, 282 MHz): δ = –191.9 (dddd, J =
5.7, J = 17.0, J = 17.0, J = 17.0 Hz) ppm. GC-MS m/z (%) = 360
+
(
0.1) [M ], 340 (23), 322 (3), 308 (5), 281 (92), 270 (6), 130 (21),
03 (20), 90 (100). C21 (360.6): calcd. C 69.96, H 11.46;
found C 69.88, H 11.50.
2
0
1
6
D 3 3
5 °C. [α] = –5.5 (c = 1.01, CHCl ). H NMR (CDCl , 300 MHz):
1
H41FO
3
δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.21–1.34 (m, 26 H), 1.48–1.63 (m, 2
H), 3.83 (s, 3 H), 3.95–4.08 (dm, J = 17.6 Hz, 1 H), 4.86 (dd, J =
Methyl (2S,3R)-3-Fluoro-2-hydroxyhexadecanoate (1a): Epoxide
13
4
1
3
1
–
3
8.4, J = 3.9 Hz, 1 H) ppm. C NMR (CDCl , 75.5 MHz): δ =
(2R,3S)-6a (1.53 g, 5.4 mmol), purified on silica gel (cyclohexane/
4.1 (q), 22.7 (t), 25.4 (t), 29.2 to 29.7 (10t), 31.5 (dt, J = 4.7 Hz),
2
0
ethyl acetate, 10:1); yield 1.45 g (88%); m.p. 50 °C. [α]
=
D
= –5.6 (c
1.9 (t), 52.4 (q), 71.8 (dd, J = 21.4 Hz), 91.3 (dd, J = 186.9 Hz),
1.02, CHCl
3
).
19
3
68.5 (d, J = 23.4 Hz) ppm. F NMR (CDCl , 282 MHz): δ =
199.8 (dd, J = 48.2, J = 17.8 Hz) ppm. GC-MS m/z (%) = 333
Methyl-(2S,3R)-3-Fluoro-2-hydroxyoctadecanoate (1b): Epoxide
+
+
+
(
0.1) [MH ], 332 (0.1) [M ], 331 (0.1) [M – H], 314 (4), 312 (0.1),
294 (1), 279 (0.5), 255 (0.5), 242 (26), 241 (10), 121 (38), 105 (8),
2 (100). HRMS C19 F calcd. 314.2621; found 314.2629.
(2R,3S)-6b (0.37 g, 1.2 mmol) purified on silica gel (cyclohexane/
2
0
ethyl acetate, 10:1); yield 0.30 g (76%); m.p. 57 °C. [α]
=
D
= –8.4 (c
9
35 2
H O
1.01, CHCl
3
).
Methyl 2-Oxo-octadecanoate (13b): Isolated as the main product of
Methyl (2S,3R)-3-Fluoro-2-hydroxyicosate (1c): Epoxide (2R,3S)-6c
the former reaction by chromatography; yield 0.078 g (50%); m.p.
0
1
.10 g (0.3 mmol) purified on silica gel (cyclohexane/ethyl acetate,
1
0:1); yield 0.11 g (99%); m.p. 64 °C. [α]2
0
= –3.4 (c = 1.01, CHCl
).
57 °C (cyclohexane/ethyl acetate). H NMR (CDCl , 300 MHz): δ
3
D
3
=
0.88 (t, J = 6.7 Hz, 3 H), 1.21–1.41 (m, 26 H), 1.63 (m, 2 H),
Methyl (2S,3S)-3-Fluoro-2-hydroxyoctadecanoate (3b): Olah’s rea-
gent (0.6 mL, 18 mmol), the epoxide (2S,3S)-11b (0.624 g,
13
3.84 (s, 3 H) ppm. C NMR (CDCl
3
, 75.5 MHz): δ = 14.0 (q),
2
2.7 (t), 23.0 (t), 28.9 (t), 29.2 to 29.6 (10t), 31.9 (t), 39.3 (t), 52.7
2.0 mmol), CH
2
Cl
2
(9 mL); yield 0.348 g (52%) after column
+
(
q), 161.7 (s), 194.2 (s) ppm. GC-MS m/z (%) = 313 (0.5) [MH ],
chromatography (cyclohexan/ethyl acetate, 10:1 and 6:1); m.p.
+
+
312 (1) [M ], 331 (0.1) [M – 1], 280 (0.1), 254 (24), 253 (100), 235
0
6
9 °C. [α]2
Mosher’s ester). H NMR (CDCl
.6 Hz, 3 H), 1.22–1.36 (m, 26 H), 1.42–1.52 (m, 2 H), 2.17 (s, 1
H), 3.85 (s, 3 H), 4.16 (dd, J = 1.6, J = 30.6 Hz, 1 H), 4.76 (ddt, J
1.6, J = 46.9, J = 10.8 Hz, 1 H) ppm. 13C NMR (CDCl
D 3
= –12.0 (c = 1.01, CHCl
), Ͼ98% ee (determined by
, 300 MHz): δ = 0.88 (t, J =
(
(
(
4), 137 (6), 123 (12), 111 (8), 109 (17), 97 (23), 95 (26), 85 (37), 83
28), 71 (55), 69 (22), 57 (82), 55 (32), 43 (45), 41 (22). C19
312.5): calcd. C 73.03, H 11.61; found C 72.94, H 11.47. The
1
3
H
36
13
O
C
3
6
[53]
NMR spectroscopic data agree with published ones.
=
3
,
75.5 MHz): δ = 14.1 (CH
3
), 22.7 (CH
2
), 25.0 (CH
2
), 29.3 to 29.7
Methyl (2S,3S)-2-Fluoro-3-hydroxyicosanoate (2c): From the sulfate
(
10 CH ), 30.5 (d, J = 20.8 Hz, CH
2
2
), 32.0 (CH
2
), 52.9 (CH
3
), 72.0 (2R,3S)-12c (0.210 g, 0.5 mmol); yield 0.027 g (15%) after column
2
0
(d, J = 21.2 Hz, CH), 93.0 (d, J = 175.8 Hz, CH), 172.4 (d, J =
chromatography (cyclohexane/ethyl acetate, 8:1); m.p. 66 °C. [α]
D
19
1
3
.4 Hz, 1 C) ppm. F NMR (CDCl
3
3 3
, 282 MHz): δ = –195.6 (dddd, = –3.8 (c = 0.84, CHCl ). H NMR (CDCl , 300 MHz): δ = 0.89
J = 46.9, J = 30.4, J = 17.1, J = 13.3 Hz) ppm. HRMS (ESI) m/z:
calcd. for C19 Na 335.2619; found 335.2619.
(t, J = 6.9 Hz, 3 H), 1.23–1.36 (m, 30 H), 1.47–1.63 (m, 2 H), 1.80
H37FO
3
(br. s, 1 H), 3.85 (s, 3 H), 4.02 (dddd, J = 17.5, J = 8.5, J = 4.3, J
1
3
=
4.3 Hz, 1 H), 4.88 (dd, J = 48.3, J = 4.0 Hz, 1 H) ppm.
C
Synthesis of the Methyl 2-Fluoro-3-hydroxyalkanoates (2S,3S)-2 and
2R,3S)-4: To a solution of the corresponding cyclic sulfate (2S,3S)-
2 or (2R,3S)-15 in DMF, Bu NF (Ͼ 2 equiv.) was given and
3
NMR (CDCl , 75.5 MHz): δ = 14.1 (q), 22.7 (t), 25.4 (t), 29.3, 29.4,
(
29.5, 29.6, 29.7 (12t), 31.5 (dt, J = 4.2 Hz), 31.9 (t), 52.4 (q), 71.8
1
4
(
dd, J = 21.4 Hz), 91.3 (dd, J = 188.3 Hz), 168.5 (d, J = 23.8 Hz)
stirred at room temperature till no starting material was detected
anymore (DC). The solvent was evaporated and the sticky crude
1
9
3
ppm. F NMR (CDCl , 282 MHz): δ = –199.8 (dd, J = 47.9, J =
1
3
(
+
8.1 Hz) ppm. GC-MS m/z (%) = 360 (0.1) [M ], 342 (8), 340 (0.1),
22 (3), 307 (0.1), 281 (1), 270 (30), 269 (12), 121 (43), 105 (8), 92
F calcd. 342.2934; found 342.2970.
product was dissolved in a 1:1 mixture of Et
and stirred until the spot at R = 0 has disappeared. The two layers
were separated and the aqueous layer was extracted with a small
amount of CH Cl . The combined organic layer was washed with
water and 10% NaHCO solution and dried with MgSO . Removal
of the solvent gave crude mixtures of the fluorohydrins 2 and 4 and
2 2 4
O and H SO (20%)
f
100). HRMS: C21
H
39
O
2
2
2
Methyl (2R,3R)-3-Fluoro-2-hydroxyoctadecanoate (3b): Isolated as
major product from the reaction of cyclic sulfate (2S,3S)-15b
3
4
2
0
(0.392 g, 1.0 mmol); yield 0.153g (46%) [α]
D
= +8.4 (c = 0.37,
Eur. J. Org. Chem. 2011, 355–363
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org 361

S. Grimme, G. Haufe et al.
FULL PAPER
CHCl
3
); m.p. 64 °C. The spectroscopic data agree with those of the
[6] a) X. Chen, S. Wiehle, L. Chi, C. Mück-Lichtenfeld, R. Rudert,
D. Vollhardt, H. Fuchs, G. Haufe, Langmuir 2005, 21, 3376–
(2S,3S)-enantiomer.
3
383; b) X. Chen, S. Wiehle, M. Weygand, G. Brezesinski, U.
Methyl (2R,3S)-2-Fluoro-3-hydroxyoctadecanoate (4b): Isolated as
minor product from the reaction of cyclic sulfate (2S,3S)-15b
Klenz, H.-J. Galla, H. Fuchs, G. Haufe, L. Chi, J. Phys. Chem.
B 2005, 109, 19866–19875.
(0.392 g, 1.0 mmol); yield 0.009g (3%) after repeated column
[7] a) S. Steffens, J. Oldendorf, G. Haufe, H.-J. Galla, Langmuir
2006, 22, 1428–1435; b) S. Steffens, U. Höweler, T. Jödicke, J.
Oldendorf, R. Rudert, G. Haufe, H.-J. Galla, Langmuir 2007,
chromatography (cyclohexane/ethyl acetate, 10:1); m.p. 71 °C.
2
0
1
[α]
D
= +3.6 (c = 0.64, CHCl
3 3
). H NMR (CDCl , 600 MHz): δ =
2
3, 1880–1887.
0.88 (t, J = 6.4 Hz, 3 H), 1.26 (s, 16 H), 1.66–1.57 (m, 2 H), 3.84
[
8] For reviews, see: a) N. Yoneda, Tetrahedron 1991, 47, 5329–
5365; b) G. Haufe, J. Prakt. Chem. 1996, 338, 99–113; c) G.
Haufe, J. Fluorine Chem. 2004, 125, 875–894.
(
4
2
s, 3 H), 4.09–3.94 (dm, J = 24.6 Hz, 1 H), 4.86 (dd, J = 2.5, J =
8.0 Hz, 1 H) ppm. 1 C NMR (CDCl
3
3
, 151 MHz): δ = 14.1 (CH
), 29.3 to 29.8 (8 CH ), 32.7 (CH ), 52.5
3
), 71.8 (d, J = 20.4 Hz, CH), 90.6 (d, J = 188.5 Hz, CH), 168.8
3
),
2.7 (CH
2
), 25.5 (CH
2
2
2
[
9] a) For reviews, see: R. Miethchen, D. Peters, Introduction of
Fluorine with Anhydrous Hydrogen Fluoride, Aqueous Solutions
of Hydrogen Fluoride, and HF-Base Complexes, in: Methods of
Organic Chemistry (Houben-Weyl), vol. E10a (Eds.: B. Baasner,
H. Hagemann, J. T. Tatlow), Thieme, Stuttgart, Germany,
(
(
–
CH
d, J = 24.5 Hz, 1 C) ppm. F NMR (CDCl
209.2 (dd, J = 48.0, J = 24.5 Hz) ppm. HRMS (ESI): m/z calcd.
for C19 Na 355.2619 found: 355.2625.
19
3
, 282 MHz): δ =
H37FO
3
1
999, pp. 95–158; b) S. Böhm, Synthesis of Fluorinated Com-
Supporting Information (see also the footnote on the first page of
this article): Experimental remarks, synthetic procedures and spec-
troscopic data for compounds 6a–c, 8a–c/9a–c, 10b, 11b, 12a–c,
pounds by Introduction of Fluorine with Preservation of the Car-
bon Skeleton of Oxygen Substituents Having a C-O Bond, in:
Methods of Organic Chemistry (Houben-Weyl), vol. E10b
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Received: August 30, 2010
Published Online: November 17, 2010
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