Enantioselective ring-opening of epoxides by HF-reagents: Asymmetric synthesis of fluoro lactones

Article abstract of DOI:10.1016/S0022-1139(01)00486-9

The asymmetric ring opening of meso- and racemic-epoxides with different HF-reagents mediated by enantiopure (salen)chromium chloride provides optically active fluorohydrins with maximum 90% e.e. This reaction as well as lipase-catalyzed deracemization of

Full text of DOI:10.1016/S0022-1139(01)00486-9

Journal of Fluorine Chemistry 112 &2001) 55±61
Enantioselective ring-opening of epoxides by HF-reagents
Asymmetric synthesis of ¯uoro lactones
*
Gunter Haufe , Stefan Bruns, Martina Runge
È
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat, Corrensstraûe 40, D-48149 Munster, Germany
È
È
È
Abstract
The asymmetric ring opening of meso- and racemic-epoxides with different HF-reagents mediated by enantiopure &salen)chromium
chloride provides optically active ¯uorohydrins with maximum 90% e.e. This reaction as well as lipase-catalyzed deracemization of a
¯uorohydrin is applied to synthesize a building block for the preparation of both enantiomers of a ¯uorinated analogue of the prostaglandin
biosynthesis inhibitor lasiodiplodin using a cyclizing ole®n metathesis reaction as a key-step. # 2001 Elsevier Science B.V. All rights
reserved.
Keywords: Fluorinating reagents; Epoxides; Fluorohydrins; Asymmetric synthesis; Lipase-catalyzed racemate cleavage; Fluorinated lactones; Ole®n
metathesis
1. Introduction
Two recent examples, described by two research groups
[9,10] simultaneously, are shown in Scheme 2 proceeding
with 61 or 42% e.e., respectively.
Even a catalytic asymmetric electrophilic ¯uorination
using titanium TADDOLAT complexes of the Seebach
type and F-TEDA &Select¯uor) showing maximum of
90% e.e. has been published by Hintermann and Togni
recently [11].
The second alternative is the nucleophilic ¯uorination.
Until recently, there was only one example of such an
enantioselective introduction of ¯uoride, namely the des-
oxy¯uorination of ethyl 2-&trimethylsilyloxy)propanoate
using an &S)-proline-based enantiopure DAST analogue.
However, a maximum of 16% e.e. was the best result
reported [12] &Scheme 3).
There is a fast growing demand of optically active ¯uori-
nated compounds for many different applications, e.g. in
medicinal chemistry, biochemistry or material sciences.
Consequently, there is a great interest in synthetic methods
for such compounds. Besides syntheses starting from
already optically active building blocks, there are in prin-
ciple two methodologies to obtain optically active ¯uori-
nated compounds: &i) the classical or enzyme-catalyzed
racemate cleavage and &ii) the asymmetric introduction
of ¯uorine into prochiral substrates [1]. Many different
examples of enzyme-catalyzed deracemizations of ¯uori-
nated amino acids, ¯uorinated carboxylic acids, or ¯uori-
nated alcohols have been described. For example, ethyl
10-¯uoro-9-hydroxy-decanoate was deracemized by acety-
lation with acetic anhydride in toluene using Pseudomonas
cepacia lipase as a biocatalyst [2] &Scheme 1).
Asymmetric ¯uorinations of prochiral substrates can be
carried out following two different protocols [3]. The ®rst
option is the enantioselective electrophilic a-¯uorination of
carbonyl enolates, a method which has been discovered by
Differding and Lang [4] and which got much attention in
recent years [5] and most recently by Davis and co-workers
[6,7], Takeuchi and co-workers [8,9] and Cahard et al. [10].
* Corresponding author. Tel.: ‡49-251-83-33281;
fax: ‡49-251-83-39772.
E-mail address: haufe@uni-muenster.de &G. Haufe).
Scheme 1.
0022-1139/01/$ ± see front matter # 2001 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 & 0 1 ) 0 0 4 8 6 - 9

56
G. Haufe et al. / Journal of Fluorine Chemistry 112 52001) 55±61
Scheme 4.
complexes. No results on the application of ¯uoride has been
known before we published our ®rst results [13].
On the other hand, there are many papers on the diastereo-
and regioselective ring opening of epoxides with hydro¯uor-
inating reagents [17,18]. Reactions of terminal epoxides
with Olah's reagent &PyÁ9HF) which form ¯uorohydrins
bearing a secondary ¯uorine proceed via an SN1-like pro-
cess, though there is no evidence for the formation of a free
carbocation as an intermediate [19]. This method has also
been used by Umezawa et al. in synthesis of optically active
¯uorohydrins from enantiopure epoxides, although with
poor yield [20].
Scheme 2.
In contrast, applying more nucleophilic reagents such as
trialkylamine hydrogen-¯uorides or potassium hydrogendi-
¯uoride, products with ¯uorine attached to the primary
position are formed in SN2-like reactions. For these reac-
tions, relatively high temperature is necessary leading some-
times to rearrangements or oligomerization as competitive
processes. An example for the dependence of the regio-
selectivity of ring opening of a terminal epoxide from the
hydro¯uorinating agent is shown in Scheme 5 [21].
During our investigations of ring opening of a-alkyl-
styrene oxides, which are very sensitive to acidic conditions
or high temperatures, we obtained that ring opening with
triethylamine tris&hydrogen¯uoride) &Et3NÁ3HF) can be
catalysed by BF3ÁOEt2 [22]. In this way from cyclohexene
oxide trans-2-¯uorocyclohexanol was obtained in 80% yield
after 24 h at room temperature. Thus, if Lewis acids can
catalyze this type of ring opening, than chiral metal com-
plexes should steer the ring opening asymmetrically. How-
ever, D-Eu&hfc)3 or the polymeric zinc &R,R)-tartrate gave
&S,S)-&‡)-2-¯uorocyclohexanol with maximum of 10% e.e.
[13]. The ®rst ef®cient asymmetric ring opening we
observed in the reaction of cyclohexene oxide with
Et3NÁ3HF in the presence of 100 mol% of Jacobsen's
&salen)-chromium chloride A [23] as the mediator [24]. Ear-
lier, this complex was shown to be a very ef®cient catalyst for
ring opening of epoxides with azide [25,26] &Fig. 1).
However, the conversion to &R,R)-&À)-2-¯uorocyclo-
hexanol of cyclohexene oxide with Et3NÁ3HF was very slow
Scheme 3.
We present here our results of the asymmetric ring open-
ing of meso- and racemic epoxides by hydro¯uorinating
reagents mediated by enantiopure &salen)chromium chloride
[13] and the application of an enantiopure ¯uorohydrin for
synthesis of a ¯uorinated analogue of lasiodiplodin [14].
2. Results and discussion
2.1. Asymmetric ring opening of meso- and racemic
epoxides
Asymmetric ring opening of epoxides by nucleophiles
using enantiopure catalysts or mediators is one of the most
powerful methods in asymmetric syntheses of 1,2-disubsti-
tuted compounds [15,16].
This type of reaction, exempli®ed in Scheme 4, has been
successfully accomplished with many different nucleophiles
such as carbon nucleophiles, thiols, phenols, carboxylic
acids, aromatic amines, azide, cyanide, chloride, bromide
and iodide mediated or catalyzed by different Lewis acidic
Scheme 5.

G. Haufe et al. / Journal of Fluorine Chemistry 112 52001) 55±61
57
¯uorocyclohexanol was formed exclusively with 72% e.e.
Applying 50 mol% of A the e.e. dropped only slightly.
Analogously, cyclopentene oxide and cycloheptene oxide
were asymmetrically opened &Table 1, entries 3±6).
There are at least two mechanistic alternatives for the
enantioselective ring opening, the SN1-like and the SN2-like
mechanism. In the ®rst case, the optically active Lewis acid
complexes the epoxide. Subsequently, a not necessarily free
carbocationic center is formed which is attacked by the
hydro¯uorinating reagent under liberation of the catalyst
and the ¯uorohydrin. In this case, the asymmetric induction
will be quite small, since the chiral auxiliary is remote from
the reaction center &Scheme 7).
Fig. 1.
Alternatively, an SN2-like mechanism can operate. In this
case, the chiral metal complex is closer to the reaction center
and can steer the attack of the ¯uoride equivalent more
effectively. In principle, there is a third alternative, the
intermediary formation of a ¯uorinated chromium&salen)-
complex from which the ¯uoride could be transferred
directly to the epoxide. We cannot differentiate between
the alternatives yet, because silver chloride did not preci-
pitate in the reactions with silver ¯uoride and also in the
reactions with Et3NÁ3HF or KHF2, respectively, only small
amounts of chlorohydrins were formed.
Subsequently, we studied the ring opening of racemic
epoxides. With styrene oxide, 50 mol% of the &salen)complex
and KHF2 &R)-&À)-2-¯uoro-1-phenylethanol was formed in
70% yield &based on 42% conversion) with 90% e.e. Two by-
products, 2-¯uoro-2-phenyl-ethanol &7%, GC) and 2-chloro-
1-phenylethanol &14%, GC), were also found. The part of a
Scheme 6.
and the e.e. was only moderate. After 50 h at 08C 20%
conversion and 43% e.e. was determined &Scheme 6, Table 1,
entry 1). Better results were observed with KHF2 in DMF in
the presence of 18-crown-6 at 608C. However, using this
hydro¯uorinating reagent trans-2-chlorocyclohexanol was
formed as a by-product [13] &Table 1, entry 2). Thus, a
partial liberation of chloride from the catalyst seems to
occur. Since chloride is more nucleophilic than the ¯uoride
it can compete successfully in the ring opening.
Consequently, we changed again the ¯uoride source and
used silver ¯uoride for the ®rst time in ring opening of
epoxides [24]. From cyclohexene oxide in the presence of
equimolar amount of the &salen)complex A &R,R)-&À)-2-
Table 1
Results of ring opening of meso-epoxides in the presence of &salen)chromium chloride A
Entry
n
Fluorinating
reagent
A
&mol%)
Solvent
Temperature
Time
&h)
Conversion
&%)
Yield
&%)a
e.e.
&%)
&8C)
1
2
3
4
5
6
2
2
1
2
2
3
Et3NÁ3HF
KHF2
AgF
100
100
50
CH2Cl2
DMF
0
60
70
50
70
60
50
80
50
50
20
20
20
92
N.D.
64
43
55b
44
72
66
65
CH3CN
CH3CN
CH3CN
CH3CN
85
75
AgF
100
50
100
100
50
90
AgF
AgF
85
82
50
a Based on conversion.
b Additionally 20% &GC) of trans-2-chlorocyclohexanol was formed.
Scheme 7.

58
G. Haufe et al. / Journal of Fluorine Chemistry 112 52001) 55±61
Scheme 8.
chlorohydrin was even 40% &GC) in the reaction of phe-
nylglycidyl ether under the conditions shown in Scheme 8.
The enantiomeric excess of the ¯uorohydrin was determined
to be 62% e.e. &Scheme 8).
distillation under reduced pressure. The identity of the unsa-
turated lactones was proved spectroscopically &cf. Section 4)
and by hydrogenation to the known saturated macrolide [32].
Having shown that ¯uorine substituents do not disturb
ole®n metathesis, we synthesized both enantiomers of ¯uoro
lasiodiplodin following the pathway &Scheme 9) which is
similar to the one used in total synthesis of lasiodiplodin
itself reported by FuÈrstner and Langemann [33]. The ¯uoro-
2.2. Synthesis of both enantiomers of fluoro lasiodiplodin
Now we became interested to apply this asymmetric ring
opening as one key-step in a synthesis of a ¯uorinated
analogue of lasiodiplodin, which is a prostaglandin biosyn-
thesis inhibitor showing anti-cancer activity [27,28] &Fig. 2).
We planned a synthetic pathway, which involves an ole®n
metathesis as one key-step [14] &Scheme 9).
In order to explore whether such a cyclizing metathesis
can be employed to ¯uorinated dienes, we ®rst investigated
a model reaction of this type. For this reason, 1-¯uorooct-
7-en-2-ol [29] was synthesized in 83% yield from 7,8-
epoxyoctene by ring opening with KHF2 in the presence
of 18-crown-6 in DMF and subsequent chromatographic
separation from its regioisomer &Scheme 10).
Subsequently &1-¯uorooct-7-en)-2-yl pent-4-enoate was
synthesized in 82% yield from 1-¯uorooct-7-en-2-ol and
pent-4-enoic acid using the method by Hasser and Alexanian
with dicyclohexyl carbodiimide &DCC) and a catalytic
amount of dimethylaminopyridine &DMAP) [30]. The cycliz-
ing ole®n metathesis of this ester occurred at room tempera-
ture in high dilution in methylene chloride using Grubbs
catalyst [31] to yield a 64:36 mixture of the &E,Z)-isomeric
unsaturated macrolides &Scheme 11) contaminated with 15%
&GC) of diolides which were separated by bulb to bulb
Scheme 9.
Fig. 2.
Scheme 10.

G. Haufe et al. / Journal of Fluorine Chemistry 112 52001) 55±61
59
enantiomeric acetate, prepared by acetylation with Ac2O
from the &R)-&‡)-¯uorohydrin, the CD is negative over the
whole range of wave lengths proving the &R)-con®guration
for this enantiomer.
Having both enantiomers of the ¯uorohydrin in hands, we
synthesizedbothantipodesofthedesired¯uorinatedanalogue
ofthenaturallasiodiplodinonthepathwayshowninScheme9
as a retrosynthesis [14]. Esteri®cation of the salicylic acid
using Yamaguchi and co-worker's method [37] gave the
enantiomers of the ester in 62 or 67% yields, respectively.
After activation of the phenolic OH-group, the Stille coupling
gave the dienes in 62 or 73% yields, respectively. The Grubbs
metathesis proceeded with 60 or 66% yields, respectively, to
give 86:14 mixtures of the &E,Z)-isomeric 12-membered rings
in both cases. Finally, the catalytic hydrogenation gave the
desired products in 80 or 85% yields [14].
Scheme 11.
hydrin was available in optically active form by asymmetric
ring opening from 7,8-epoxyoctene. However, the reaction
proceeded with low enantioselectivity, 50% e.e. was found
under the yet most selective conditions [24]. Consequently,
racemic 1-¯uorooct-7-en-2-ol &Scheme 10) was derace-
mized by enzyme-catalyzed acetylation with vinyl acetate
in an organic solvent using Candida antarctica lipase as a
biocatalyst [14] &Scheme 12).
3. Conclusion
Asymmetric epoxide ring opening has been presented as
the ®rst ef®cient method for the enantioselective introduc-
tion of ¯uoride into organic molecules. For the total syn-
thesis of a ¯uorinated analogue of the natural biosynthesis
inhibitor lasiodiplodin, however, the ring opening of 7,8-
epoxyoct-1-ene with KHF2 to racemic 1-¯uorooct-7-en-2-ol
and subsequent lipase-catalyzed cleavage was shown to
proceed with higher enantioselectivity than the asymmetric
ring opening. Consequently, this way was used for the
synthesis of the enantiomers of 1-¯uorooct-7-en-2-ol. Sub-
sequently, it has been shown that ring closing metathesis of a
¯uorinated a,o-unsaturated ester was successful in case of
synthesis of the model lactone, 11-¯uoroundec-4-en-10-
olide, from &1-¯uorooct-7-en)-2-yl pentenoate. This method
was than used as a key-step in the synthesis of both
enantiomers of ¯uoro lasiodiplodin.
The unreacted &R)-¯uorohydrin was isolated in 34% yield
with 92% e.e., while the &S)-&‡)-acetate was isolated in 49%
yield with 98% e.e. After conventional hydrolysis of the
acetate, the &S)-alcohol was obtained in excellent yield
having 98% e.e. The absolute con®guration of &‡)-7-acet-
oxy-8-¯uorooct-1-ene &98% e.e.) has been determined by
CD spectroscopy [34]. An UV and subsequently a CD
spectrum was measured from a 1:48 Â 10À3 M solution in
cyclohexane &d ˆ 1 cm). lmax has been determined as
205 nm and the CD is positive over the complete range
of wave lengths between 200 and 245 nm. From the carb-
oxylate-sector rules [35] relevant for the acetate-chromo-
phore, an &S)-con®guration for the stereogenic center is
predicted based on the following assumptions: The
&CH2)n-backbone in long-chain alkanes prefers a trans-
anti-orientation &zig±zag), the OAc group is smaller than
the alkenyl rest, one H atom at C8 and the C=O double bond
both point in the same direction, and the in¯uence of the
alkenyl function &C1) can be neglected due to its far distance
from the stereogenic center. This assignment agrees with
the known stereopreference of the enzyme [36]. For the
4. Experimental
4.1. General remarks
General remarks on the used reagents, separation techni-
ques, the spectrometers &cf. [13,14]). The asymmetric ring
opening of meso- and racemic epoxides using KHF2 and the
Jacobsen complex A have been described [13] and also the
enantioselective synthesis of both enantiomers of the ¯uori-
nated analogue of lasiodiplodin has been published recently
[14].
4.2. Ring opening of epoxides with AgF in the presence
of 5salen)chromium chloride A
4.2.1. General procedure
Under an argon atmosphere a mixture of the epoxide
&1 mmol) and the chromium complex A &632 mg, 1 mmol,
Scheme 12.

60
G. Haufe et al. / Journal of Fluorine Chemistry 112 52001) 55±61
‡
or 316 mg, 0.5 mmol, respectively) in dry DMF &5 ml) was
stirred for 15 min at room temperature, treated with AgF
&252 mg, 1.5 mmol) and heated with stirring at the tem-
perature and for the time given in Table 1. In order to
monitor the progress of the reaction samples of the reac-
tion mixture were taken and worked up. After cooling to
room temperature, the mixture was poured into water
&25 ml) and extracted with CH2Cl2 &5 Â 10 ml). The com-
bined organic layer was washed with water &2 Â 10 ml)
and dried with MgSO4. The solvent was evaporated and
the crude product was ®ltered &column with 3 cm of silica
gel, cyclohexane/ethyl acetate 5:1) in order to remove
traces of the metal complex, silver salts, and oligomeric
material. After removing the solvent, the residue was
analyzed by GC &HP1, 40±2808C, heating rate 108C/
min) and chiral GC &Beta-Dex1 120, isothermic, tempera-
ture between 80 and 1108C depending on the products).
Pure ¯uorohydrins were obtained by column chromato-
graphy &silica gel 70±260 mesh, cyclohexane/ethyl acetate
5:1). Yields and enantiomeric excesses are given in
Table 1. Spectroscopic data of the optically active ¯uor-
ohydrins agree with those published for the racemic
compounds [13,38,39].
[C4H7] . Anal. Calcd. for C13H21O2F &228.3): C, 68.39;
H, 9.27. Found C, 68.70; H, 9.37.
4.3.2. Ring closing metathesis of 51-fluorooct-7-en)-
2-yl pentenoate
Under an argon atmosphere solutions of &1-¯uorooct-7-
en)-2-yl pentenoate &114 mg, 0.5 mmol) in dry CH2Cl2
&30 ml) and of benzylidenebis&tricyclohexylphosphine)di-
chloro-ruthenium &14 mg, 0.017 mmol, 3.4 mol%) [33] in
dry CH2Cl2 &30 ml) were dropped simultaneously to re¯ux-
ing dry CH2Cl2 over a period of 12 h. After stirring for
another 24 h at that temperature, the solvent was removed in
vacuo, and the residue was puri®ed by ¯ash chromatography
&silica gel, cyclohexane/ethyl acetate 3:1) to give 70 mg of
crude diastereomeric mixture of the lactone containing 15%
of diolides. Bulb to bulb distillation &1428C at 18 mbar) gave
60 mg &60%) of a 64:36 mixture of the &E/Z)-isomeric 11-
¯uoroundec-4-en-10-olides. 1H NMR &300 MHz, CDCl3): d
0.95±1.90 &m, 8H, H2-7 to H2-9, H2-2); 2.20±2.44 &m, 4H,
2
H2-3 and H2-6); 4.24±4.55 &dm, JH;F ˆ 47:5 Hz, 2H, H2-
11); 4.96±5.15 &m, 1H, H-10); 5.23±5.49 &m, 2H, H-4 and H-
5). 13C NMR &75 MHz, CDCl3): d 19.1 and 24.9 &2t, C-8 and
C-7); 29.3 &dt, 3JC;F ˆ 5:1 Hz, C-9); 30.4, 32.7 and 35.5 &3t,
1
C-2, C-3 and C-6); 71.6 &dd, JC;F ˆ 17:8 Hz, C-10); 83.6
4.3. Synthesis of 11-fluoroundec-4-en-10-olide
&dt, 1JC;F ˆ 172:9 Hz, C-11); 129.3 and 131.6 &2d, C-4 and
C-5); 173.6 &s, C-1). 19F NMR &282 MHz, CDCl3): d À230.2
2
3
4.3.1. Esterification of 1-fluorooct-7-en-2-ol with
pentenoic acid
&dt, JF;H ˆ 47:7 Hz, JF;H ˆ 21:0 Hz, F-11). MS: GC/MS,
‡ ‡
70 eV), m/z &%): 201 &2) [MH] , 200 &24) [M] , 182 &18)
[M±H2O] , 167 &5) [M±CH2F] , 162 &8) [182-HF] , 140
‡
‡
‡
Under argon a solution of pentenoic acid &525 mg,
5 mmol), DCC &1.14 g, 5.5 mmol), 1-¯uorooct-7-en-2-ol
&813 mg, 5.5 mmol) [14] and DMAP &61 mg, 0.55 mmol)
in dry CH2Cl2 &30 ml) was stirred at room temperature for
15 h. The precipitated N,N-dicyclohexylurea was ®ltered-off
and the solution was washed successively with water
&3 Â 50 ml), 5% diluted aqueous HOAc &3 Â 50 ml), and
with water again &3 Â 50 ml). The organic layer was dried
over MgSO4, the solvent was removed and the residue was
chromatographed through a 5 cm column with silica gel
using CH2Cl2 as the eluent to give 93 mg &82%) pure &1-
¯uorooct-7-en)-2-yl pentenoate. 1H NMR &300 MHz,
CDCl3): d 1.29±1.47 &m, 4H, H2-40 and H2-50); 1.58±1.69
&m, 2H, H2-30); 2.01±2.09 &m, 2H, H2-60); 2.34±2.47 &m, 4H,
‡
&14) [182-C3H6] , 120 &20), 108 &23), 95 &52), 80 &80), 67
‡
&100) [C6H7] . Anal. Calcd. for C11H17O2F &200.3): C,
65.98; H, 8.56. Found C, 66.04; H, 8.98.
Acknowledgements
This research project was generously supported by the
Deutsche Forschungsgemeinschaft and the Fonds der Che-
mischen Industrie. The kind donation of chemicals and
enzymes by the Bayer AG, Leverkusen, the HuÈls AG, Marl
and Novo Nordisk, Denmark, are gratefully acknowledged.
2
2
H2-3 and H2-2); 4.36 &ddd, JH;F ˆ 47:2 Hz, JH;H
ˆ
References
10:1 Hz, JH;H ˆ 4:8 Hz, 1H, H-10); 4.47 &ddd, JH;F
ˆ
3
2
47:5 Hz, JH;H ˆ 10:3 Hz, JH;H ˆ 3:3 Hz, 1H, H-10);
4.92±5.13 &m, 5H, H2-5, H2-80 and H-20); 5.71±5.89 &m,
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30); 33.4 and 33.6 &2t, C-3 and C-60); 72.2 &dd,
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