Asymmetric photodeconjugation: Highly stereoselective synthesis of α-fluorocarboxylic derivatives

Article abstract of DOI:10.1055/s-2002-20028

Irradiations of α-fiuoro-α,β-unsaturated esters lead to the corresponding α-fluoro-β,γ-unsaturated isomers in good yields. The reaction required the use of an achiral base (typically an amine) to promote the protonation of the photodienolic intermediate. By replacing the ethyl group with a diacetone-D-glucose moiety, the reaction can be carried out in a diastereoselective manner to furnish the deconjugated esters with similar yields and selectivities up to 95%. The adducts were submitted to osmylation conditions to deliver α-fluoro-β-hydroxy-butyrolactones in one single step.

Full text of DOI:10.1055/s-2002-20028

FEATURE ARTICLE
427
Asymmetric Photodeconjugation: Highly Stereoselective Synthesis of
-Fluorocarboxylic Derivatives
H
ighly Stereos
r
elective
é
Synthesis
o
d
f
-Fluoroca
é
rboxylic
D
r
erivative
i
s
c Bargiggia, Sylvia Dos Santos, Olivier Piva*
Laboratoire de Chimie Organique - Photochimie et Synthèse - UMR 5622 CNRS, Université Claude Bernard-Lyon I,
43, Bd du 11 novembre 1918, 69622 Villeurbanne, France
Fax +33(4)72448136; E-mail: piva@univ-lyon1.fr
Received 23 November 2001
(Scheme 2). The formation of the new chiral centre result-
ed from a stereoselective protonation6 of one of the two
faces of a prochiral dienol.7 The highest values were ob-
tained by using diacetone D-glucose8 as chiral alkoxy
Abstract: Irradiations of -fluoro- , -unsaturated esters lead to the
corresponding -fluoro- , -unsaturated isomers in good yields. The
reaction required the use of an achiral base (typically an amine) to
promote the protonation of the photodienolic intermediate. By re-
placing the ethyl group with a diacetone-D-glucose moiety, the re- group.9 This strategy was successfully applied to the syn-
action can be carried out in a diastereoselective manner to furnish
thesis of natural products, especially pheromones or terpe-
nes by us10 and more recently by Bach and co-workers. 11
the deconjugated esters with similar yields and selectivities up to
95%. The adducts were submitted to osmylation conditions to deliv-
er -fluoro- -hydroxy-butyrolactones in one single step.
OR*
Key words: photochemistry, protonations, asymmetric synthesis,
lactones -fluoro esters
hν
R1
R2
R1
CH2Cl2
OH
R2
OR*
R3
N
OH
O
R3
Due to its strong electronegativity, the presence of one
fluorine atom has considerable influence on the biological
activities1 and physical properties of organic molecules.
The control of the stereoselectivity of the center bearing
the fluorine atom is therefore of considerable interest es-
pecially for pharmaceutical compounds.2 Important
achievements have been made for the formation of new
C–F bonds starting from carboxylic derivatives3 and also
more recently from enolisable ketones4 (Scheme 1). This
strategy requires the use of stoichiometric N-fluorosul-
fonamides salts and chiral entities, which are usually both
expensive.5
O
O
R2
R1
HO
OR*
*
R3
O
(R)
O
R*OH =
O
O
Scheme 2
In order to generalize this process to other chiral com-
pounds substituted in position by one halogen atom
(R1 = X), we first tested the photochemical reactivity of
unsaturated -bromo and -fluoro esters 1 and 2, easily
prepared in few steps according to published procedures
(Scheme 3, Table 1).12–14
O
O
O
F
"F+"
*
Base
Xc*
Xc*
Xc*
R1
R1
R1
O
O
O
*
Table 1 Preparation of Ethyl Esters 2
"F+"
F
Base
*
R2
R2
R2
R1
Me
Et
R2
Me
Et
2
a
b
c
d
e
f
Yield (%) (E/Z)
R1
R1
R1
88
84
87
64
83
68
80
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
Scheme 1
As part of our interest for the creation of new stereogenic
centers during photochemical processes, we reported a
few years ago the possibility to perform highly diastereo-
selective photodeconjugation of -alkyl- , -unsaturated
esters to give the corresponding , -unsaturated isomers
-(CH2)5-
n-Octyl
H
H
H
H
Et
i-Pr
Synthesis 2002, No. 3, 18 02 2002. Article Identifier:
1437-210X,E;2002,0,03,0427,0437,ftx,en;E08001SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
TBDMSOCH2
g

428
F. Bargiggia et al.
FEATURE ARTICLE
ditions the expected deconjugated isomer 4a without loss
of the fluorine atom (Scheme 4). This difference could be
explained by considering the strength of the C–Br and C–
F bonds.15 Furthermore, reductive cleavage of the carbon
bromide bond has been already observed for numerous
bromo derivatives under photochemical irradiation.16,17 In
order to generalize the photodeconjugation procedure ob-
served with fluoro derivative 2a, ethyl esters 2b–g were
irradiated and afforded the corresponding , -unsaturated
isomers 4b–g in similar chemical yields (Table 2).18
3) NaH
1) NaH
2) Br2
O
P
O
Br
4) Isobutyraldehyde
88%
OEt
EtO
OEt
EtO
O
1a
R1
F
O
O
OEt
P
R2
CHO
1) NaH
2)
EtO
EtO
OEt
O
R2
R1
F
64-88%
2a-f
Table 2 Irradiation of Ethyl Esters 2
F
CO2Et
Starting Material 2
Yield of Product 4 (%)
Ratio
>98/2
>98/2
>98/2
>98/2
>98/2
>98/2
O
P
O
O
Me2CuLi
Et2O
EtO
EtO
OEt
a
b
c
e
f
51
74
83
74
55
76
F
64%
2h
Scheme 3
Under irradiation at 254 nm, ethyl ester 1a (X = Br) un-
derwent a smooth degradation to reduced compound 3. In
contrast, ethyl ester 2a (X = F) gave under the same con-
g
Biographical Sketches
Frédéric Bargiggia was in 1997 in Dr Andrew the supervision of Prof.
born in Voiron (Isère), Greene's Laboratory un- Piva, devoted to the syn-
France, in 1974. He was der the guidance of Prof. thesis of Amphidinolide
a student at the Universi- Jean-Pierre Depres. He (R), a complex marine
ty Joseph Fourier of is currently completing natural product.
Grenoble, where he ob- his PhD work at the Uni-
tained his DEA degree versity of Lyon I under
Sylvia Dos Santos was Choplin and Prof. Denis the same University
born in Lyon, in 1971. In Sinou on allylic substi- working in the group of
1998, she obtained her tution catalyzed by sili- Olivier Piva. Since
PhD at the University ca-supported palladium 2000, she is a teacher in
Claude Bernard Lyon I, catalysts. In 1999, she Chambéry.
working with Dr Agnès was appointed ATER at
Olivier Piva was born in od. In 1989, he entered France, he continued to
Villers-Semeuse
(Ar- the CNRS as Chargé de develop his own re-
dennes) in 1960. He ob- recherche in Reims and search in Reims. Since
tained his PhD in 1988 at started a new research 1998, he is Professor of
the University of Reims, program on intramolecu- Chemistry at the Univer-
under the guidance of lar [2+2] photocycload- sity Claude Bernard
Prof. Jean-Pierre Pete. ditions. In 1994, he Lyon I. His research in-
From February 1988 to obtained his habilitation terests include the asym-
March 1989, he was a and moved for one year metric synthesis of
postdoctoral associate to Cambridge University natural products, photo-
with Prof. Dieter Enders (UK) working with Prof. chemistry and more re-
at the RWTH in Aachen, Steve Ley in the field of cently, tandem reactions.
working on the SAMP/ total synthesis of natural
RAMP hydrazone meth- products.
Back
to
Synthesis 2002, No. 3, 427–437 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Highly Stereoselective Synthesis of -Fluorocarboxylic Derivatives
429
hν
F
Br
H
F
Et2NH, CH2Cl2
OH
OEt
OEt
OEt
KOH, EtOH, ∆
27 %
O
O
O
O
76-96 %
R1
R2
R1
R2
1a
3
2a-d
6a-d
F
hν
R1
F
F
R*OH, DCC, DMAP
CH2Cl2, 0 °C
Et2NH, CH2Cl2
OEt
O-R*
OEt
R2
51-76 %
O
O
O
R1
68-87 %
R1
R2
H
R2
7a-d
2a-g
4a-g
Scheme 6
F
CO2Et
F
CO2Et
hν
Et2NH, CH2Cl2
Table 3 Preparation of Diacetone D-Glucose Esters 7
76 %
Ethyl Ester 2
Yield of Acid 6 (%) Yield of DAG ester 7
(%)
2h
4h
a
b
c
96
89
90
76
68
Scheme 4
83
87
While the deconjugation process appeared efficient with
ethyl esters 2, we decided to study the asymmetric proto-
nation of the prochiral photodienol intermediate. Our
enantioselective conditions6a were first tested. Ester 2c
was irradiated at 254 nm in dichloromethane at –40 °C in
the presence of N-benzylaminobornanol 5 (0.15 equiva-
lents). The deconjugation occurred and furnished ester 4c
in 86% yield (Scheme 5). The enantioselectivity was de-
d
77
tion. The -fluoro- , -unsaturated esters 8a–c were puri-
fied by column chromatography, isolated in good yields
and also high de (up to 95%). These selectivities are sim-
ilar to those obtained with -alkyl- , -unsaturated esters;
thus, presence of the fluorine atom seems to have no
strong influence on the asymmetric protonation step (Ta-
ble 4). Despite the presence of the allylic and highly acidic
proton on C-2, , -unsaturated isomers were surprisingly
stable and could be stored in the refrigerator for months
without any alteration or racemization of the new stereo-
genic center.
1
termined from the H NMR spectra in the presence of
small amounts of Eu(hfc)3 and the selectivity appeared
modest (40%).
hν,
CH2Cl2
NH-Bn
OH
F
F
5
OEt
OEt
hν
*
86% (ee = 40%)
F
R1
F
O
O
N
OH
OR*
*
OR*
2c
4c
R2
CH2Cl2, –40 °C
71-91 %
O
R1
R2
Scheme 5
O
7a-d
8a-d
It was then decided to turn back to the diastereoselective
process by using diacetone D-glucose derivatives. -Fluo-
ro ethyl esters 2a–d were conveniently saponified to un-
saturated acids 6a–d which were esterified19 with
diacetone D-glucose to furnish chiral compounds 7a–d
(Scheme 6, Table 3).
Scheme 7
Table 4 Photodeconjugation of Diacetone D-Glucose Esters 7
7
a
b
c
Yield of 8 (%) de (%)a
Yield of 9 (%) de (%)a
72
91
74
71
88
95
94
-
-
-
These esters were therefore irradiated at low temperature
(–40 °C) in dichloromethane in the presence of one equiv-
alent of dimethylaminoethanol which could act as base as
well as proton donor during the reketonization of the
prochiral intermediate (Scheme 7).9 In almost all cases,
-
-
-
-
d
91
95
1
the selectivity was conveniently determined from the H
a Determined from the crude 1H NMR spectra.
NMR spectra of the crude mixture obtained after irradia-
Synthesis 2002, No. 3, 427–437 ISSN 0039-7881 © Thieme Stuttgart · New York

430
F. Bargiggia et al.
FEATURE ARTICLE
R1
O
It should be noted that for compound 8d the presence of
the two E and Z isomers did not allow an easy determina-
tion of the diastereoselectivity. To overcome this prob-
lem, this ester was efficiently reduced by catalytic
hydrogenation of the carbon-carbon double bond over
PtO220 without significant cleavage of the C–F bond; the
de for the saturated ester 9d being similar to those of com-
pounds 8a–c (Scheme 8).
O
R2
R1
F
HO
F
F
OsO4, NMO
OEt
12b-c
acetone : H2O
R2
R1
R2
76-79 %
O
O
O
4b-c
HO
13b-c
H2, PtO2
H
F
F
Et2O
OR*
OR*
C8H17
C8H17
*
*
F
O
91 %
O
TMS-I, CH3CN
O
O
OEt
∆
8d
9d
37 %
O
F
4c
Scheme 8
14c
Scheme 10
Furthermore, the attribution of the (R) configuration to the
new stereogenic C-2 center has been made on the basis of
a model, we already proposed to explain the highly selec-
tive approach of the aminoalcohol toward one face of the
photodienol.9 Up to date, the main drawback of the photo-
deconjugation process was the difficulty to prepare esters
with opposite configuration on C-2. While L-glucose is
not commercially available or needs a multi-step se-
quence to be prepared, we have however demonstrated
that (S)-pantolactone can be used for this purpose.10f Acid
6b was therefore esterified with (S)-pantolactone to give
compound 10b. By irradiation under the same conditions
the deconjugated ester 11b, for which the (S) configura-
tion was assigned, was obtained in convenient yield and
selectivity (de = 83%) (Scheme 9).
lactone 14c by treatment of 4c with TMS-I24 but unfortu-
nately in a moderate yield.
In conclusion, we have demonstrated that photodeconju-
gation can be efficiently performed on -fluoro- , -un-
saturated esters. If the alkoxy group is a diacetone-D-
glucose moiety, high diastereoselectivities can also be ob-
tained. The -fluoro- , -unsaturated ethyl esters can also
be transformed into -fluorobutyrolactones according to
one single step procedure.
NMR spectra were recorded in CDCl3 using a Bruker AC 250, AC
300 or DRX 500 instrument. 19F NMR spectra are referenced
against internal CFCl3, H and 13C NMR spectra against internal
1
F
F
O
(S)-Pantolactone
TMS. FT-IR spectra were measured neat or in CHCl3 on a Perkin
Elmer SpectroOne spectrometer. Mass spectra were obtained on a
Finigan-MAT 95 XL apparatus. Optical rotations were measured on
a Perkin Elmer 243 spectrometer. Flash chromatography was per-
formed on SDS silica gel 60 (40–63 mesh). Solvents were distilled
before use according to standard procedures.25 Other reagents were
obtained from commercial sources and used as received. Compound
2h was prepared according to a literature procedure.13h
O
OH
DCC, DMAP
CH2Cl2, 0 °C
O
O
O
92 %
6b
10b
hν
F
O
Ethyl (2Z)-2-Bromo-4-methyl-pent-2-enoate (1a)11a
*
O
N
OH
O
To a suspension of NaH (0.48 g, 20 mmol) in Et2O (200 mL) was
added dropwise triethylphosphonoacetate (4.48 g, 20 mmol) at
0 °C. After one hour, Br2 (3.2g, 20 mmol) was carefully added. The
solution was stirred for an additional 3 h. NaH (0.48g, 20 mmol)
was added by portion. After 2 h, isobutyraldehyde (1.44g, 20 mmol)
in Et2O (20 mL) was added at r.t. and the resulting solution stirred
for 2 h at this temperature. After hydrolysis with brine, the aqueous
layer was extracted with Et2O (3 50 mL). The organic layer was
dried over MgSO4, filtered and concentrated. Purification by distil-
lation under reduced pressure afforded 1a (3.91g, 17.6 mmol) as a
pale yellow liquid (88%).
CH2Cl2, –40 °C
62 %
O
(2S)-11b
Scheme 9
The unsaturation in the acid chain of 4 and 8 potentially
allows further transformation into new and more function-
alized structures (Scheme 10). For example, esters 4b and
4c were submitted to osmylation conditions.4g,21,22 A di-
rect lactonization of the diol occurred, leading to the for-
mation of -fluoro- -hydroxybutyrolactones syn-12b,c
and anti-13b,c with a typical 7:3 ratio, easily determined
by measurement of coupling constants and comparison
with literature data.23 Finally we noticed the formation of
Bp11 65–67 °C.
IR (neat): 2960, 1700, 1605, 1375, 1220–1195, 1025 cm–1.
1H NMR (CDCl3, 250 MHz): (E isomer) = 1.02 (d, 6 H, J = 7.0
Hz), 1.33 (t, 3 H, J = 7.0 Hz), 3.24 (m, 1 H), 4.26 (q, 2 H, J = 7.0
Hz), 6.44 (d, 1 H, J = 10.0 Hz); (Z isomer) = 1.10 (d, 6 H, J = 7.0
Hz), 1.33 (t, 3 H, J = 7.0 Hz), 3.24 (m, 1 H), 4.26 (q, 2 H, J = 7.0
Hz), 7.09 (d, 1 H, J = 10.0 Hz).
Synthesis 2002, No. 3, 427–437 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Highly Stereoselective Synthesis of -Fluorocarboxylic Derivatives
431
MS (EI, 70 eV): m/z (%) = 222 (M+, 29), 220 (M, 27), 194 (39), 192
19F NMR (CDCl3, 235.36 MHz): = –125.2 (d, J = 22.8 Hz).
(39), 179 (22), 177 (30), 97 (34).
MS (EI, 70 eV): m/z (%) = 200 (M, 28), 172 (31), 119 (26), 91 (34),
UV (CH2Cl2): 229 = 5300; 254 = 760.
81 (100), 67 (83), 55 (59).
Anal. Calcd for C8H13O2Br: C, 43.45; H, 5.93. Found: C, 43.07; H,
5.83.
UV (CH2Cl2): 236 = 8170; 254 = 415.
Anal. Calcd for C11H17O2F: C, 65.97; H, 8.55. Found: C, 66.29; H,
8.71.
Preparation of Ethyl 2-Fluoro-2-alkenoates; Typical Procedure
To a solution of 2-fluoro-triethylphosphonoacetate (2.42g, 10
mmol) in THF (50 mL) was slowly added a hexane solution of n-
BuLi (1.6 M, 6.6 mL, 10.5 mmol) at 0 °C. The pale yellow solution
was stirred for 1 h and then cooled to –20 °C. The aldehyde (10
mmol) in THF (3 mL) was added dropwise to the resulting solution,
which was stirred overnight at r.t. Careful hydrolysis was performed
with a sat. NH4Cl solution. Small amounts of H2O were added in or-
der to dissolve the phosphate salts. After separation of the phases,
the aqueous layer was extracted with Et2O (2 50 mL) and the or-
ganic phase dried over MgSO4. After filtration and concentration
under vacuo, ethyl ester 4 was purified from the crude material by
flash chromatography on silica gel (eluent: EtOAc–hexanes, 5:95).
Ethyl (2E)-2-Fluorododec-2-enoate (2d)13e
Yield: 64%.
IR (film): 2925, 2855, 1730, 1665, 1465, 1375, 1350, 1325, 1225
cm–1.
1H NMR (CDCl3, 300 MHz): = 0.87 (t, 3 H, J = 7.5 Hz), 1.22–1.40
(m, 14 H), 1.34 (t, 3 H, J = 7.3 Hz), 2.49 (ddt, 2 H, J = 6.3, 8.0 Hz),
4.28 (q, 2 H, J = 7.3 Hz), 5.91 (dt, 1 H, J = 22.0, 8.0 Hz).
13C NMR (CDCl3, 50.32 MHz): = 14.0 (CH3), 14.1 (CH3), 22.6
(CH2), 25.4 (CH2), 25.5 (CH2), 29.2 (CH2), 29.25 (CH2), 29.3
(CH2), 29.4 (CH2), 29.5 (CH2), 31.9 (CH2), 61.2 (O-CH2), 123.7 (d,
J = 17.7 Hz, CH), 147.0 (d, J = 250.4 Hz, C), 161.1 (d, J = 36.0 Hz,
CO2R).*
Ethyl (2E)-2-Fluoro-4-methylpent-2-enoate (2a)13d
Yield: 88%.
19F NMR (CDCl3, 235.36 MHz): = –123.3 (d, J = 17.8 Hz).
IR (film): 2970, 2870, 1730, 1666, 1465, 1315, 1230, 1155 cm–1.
MS (EI, 70 eV): m/z (%) = 245 [(M + 1), 12], 241 (85), 223 (44),
185 (36), 173 (92), 167 (50), 155 (34), 149 (21), 119 (22).
1H NMR (CDCl3, 250 MHz): = 1.05 (d, 6 H, J = 6.6 Hz), 1.34 (t,
3 H, J = 7.2 Hz), 3.26–3.42 (m, 1 H), 4.27 (q, 2 H, J = 7.2 Hz), 5.72
(dd, 1 H, J = 10.4, 21.9 Hz).
13C NMR (CDCl3, 62.89 MHz): = 14.0 (CH3), 25.3 (CH), 61.2
(OCH2), 130.0 (d, J = 15.5 Hz, CH), 145.8 (d, J = 251.8 Hz, C),
161.0 (d, J = 35.5 Hz, CO2R).
19F NMR (CDCl3, 235.36 MHz): = –125.2 (d, J = 22.3 Hz).
MS (EI, 70 eV): m/z (%) = 160 (M+, 1), 153 (5), 140 (15), 125 (100),
Ethyl (2E)-2-Fluorohex-2-enoate (2e)26
Yield: 83%.
IR (film): 2960, 2915, 2895, 1730, 1665, 1465, 1405, 1380, 1345,
1280, 1220 cm–1.
1H NMR (CDCl3, 250 MHz): = 0.95 (t, 3 H, J = 7.3 Hz), 1.34 (t,
3 H, J = 7.2 Hz), 1.41–1.51 (m, 2 H), 2.48 (dt, 2 H, J = 8.0, 7.4 Hz),
4.28 (q, 2 H, J = 7.2 Hz), 5.90 (dt, 1 H, J = 21.8, 8.2 Hz).
13C NMR (CDCl3, 62.89 MHz): = 13.5 (CH3), 13.7 (CH3), 22.4
(CH2), 27.4 (CH2), 61.2 (CH2), 123.4 (d, J = 17.7 Hz, CH), 147.1 (d,
J = 251 Hz, C–F), 161.0 (d, J = 35.8 Hz, CO2R).
115 (53).
Ethyl (2E)-4-Ethyl-2-fluorohex-2-enoate (2b)
Yield: 84%.
19F NMR (CDCl3, 235.36 MHz): = –123.0 (d, J = 22.6 Hz).
IR (film): 2970, 1726, 1666, 1560, 1375, 1333, 1275, 1215, 1165,
1110, 1020 cm–1.
MS (EI, 70 eV): m/z (%) = 160 (M, 2), 131 (12), 110 (16), 85 (32),
71 (100).
1H NMR (CDCl3, 250 MHz): = 0.86 (t, 6 H, J = 7.4 Hz), 1.12–1.28
(m, 2 H), 1.34 (t, 3 H, J = 7.1 Hz), 1.48–1.60 (m, 2 H), 2.99 (m, 1
H), 4.29 (q, 2 H, J = 7.1 Hz), 5.57 (dd, 1 H, J = 11.0, 22.7 Hz).
13C NMR (CDCl3, 62.89 MHz): = 11.5 (CH3), 14.0 (CH3), 27.9
(CH2), 38.7 (d, J = 3.4 Hz, CH), 61.2 (CH2), 127.7 (d, J = 15.6 Hz,
CH), 147.3 (d, J = 250.7 Hz, C), 161.1 (d, J = 35.2 Hz, CO2R).
Ethyl (2E)-2-Fluoro-5-methylhex-2-enoate (2f)27
Yield: 68%.
IR (film): 2960, 2870, 1730, 1666, 1465, 1380, 1215, 1155, 1055
cm–1.
1H NMR (CDCl3, 250 MHz): = 0.92 (d, 6 H, J = 7.0 Hz), 1.34 (t,
3 H, J = 7.0 Hz), 1.72 (m, 1 H), 2.42 (ddd, 2 H, J = 1.7, 8.4, 6.9 Hz),
4.29 (q, 2 H, J = 7.0 Hz), 5.92 (dt, 1 H, J = 22.0, 8.2 Hz).
13C NMR (CDCl3, 62.89 MHz): = 14.0 (CH3), 22.1 (CH3), 28.7
(CH2), 34.5 (CH), 61.1 (O-CH2), 122.3 (d, J = 17.8 Hz, CH), 147.3
(d, J = 250 MHz, C–F), 161.0 (d, J = 35.7 Hz, CO2R).
19F NMR (CDCl3, 235.36 MHz): = –125.0 (d, J = 22.8 Hz).
MS (EI, 70 eV): m/z (%) = 188 (M, 21), 160 (32), 159 (18), 132
(84), 113 (62), 85 (44), 70 (100).
UV (CH2Cl2): 229 = 7160; 254 = 290.
Anal. Calcd for C10H17O2F: C, 63.80; H, 9.10. Found: C, 64.20; H,
9.47.
19F NMR (CDCl3, 235.36 MHz): = –122.0 (d, J = 22.3 Hz).
MS (EI, 70 eV): m/z (%) = 174 (M, 13), 145 (15), 132 (16, 103 (43),
86 (66), 82 (100).
Ethyl (2E)-3-Cyclohexyl-2-fluoroacrylate (2c)
Yield: 87%.
IR (film): 2920, 2850, 1730, 1666, 1375, 1350, 1300, 1270, 1215,
1180, 1125, 1095 cm–1.
Ethyl (2E)-{[5-t-Butyl(dimethyl)silyl]oxy}-2-fluoropent-2-eno-
ate (2g)
1H NMR (CDCl3, 250 MHz): = 1.08–1.45 (m, 6 H), 1.35 (t, 3 H,
J = 7.0 Hz), 1.55 (m, 4 H), 3.02 (m, 1 H), 4.27 (q, 2 H, J = 7.0 Hz),
5.76 (dd, 1 H, J = 10.3, 22.0 Hz).
Yield: 80%.
IR (film): 2960, 2850, 1730, 1670, 1470, 1395, 1330, 1250, 1220,
1145, 1095 cm–1.
13C NMR (CDCl3, 62.89 MHz): = 13.9 (CH3), 25.2 (CH2), 25.4
(CH2), 25.7 (CH2), 31.9 (CH2), 34.5 (d, J = 3.4 Hz, CH), 61.1
(CH2), 128.6 (d, J = 15 Hz, CH), 145.9 (d, J = 251 Hz, C), 160.9 (d,
J = 36.4 Hz, CO2R).
1H NMR (CDCl3, 250 MHz): = 0.05 (s, 6 H), 0.89 (s, 9 H), 1.34
(t, 3 H, J = 7.3 Hz), 2.73 (ddt, 2 H, J = 1.7, 6.2, 7.9 Hz), 3.70 (dd, 2
H, J = 0.7, 6.1 Hz), 4.29 (q, 2 H, J = 7.3 Hz), 6.01 (dt, 1 H, J = 21.4,
7.9 Hz).
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13C NMR (CDCl3, 62.89 MHz): = –5.4 (CH3), 14.0 (CH3), 18.2
(C), 25.8 (CH3), 29.2 (CH2), 61.2 (CH2), 61.8 (CH2), 120.3 (d,
J = 19.5 Hz, CH), 147.6 (d, J = 252 Hz, C), 160.9 (d, J = 36.4 Hz,
CO2R).
IR (film): 2920, 2860, 1755, 1670, 1630, 1440, 1280, 1190, 1040,
850 cm–1.
1H NMR (CDCl3, 250 MHz): = 1.30 (t, 3 H, J = 7.0 Hz), 1.45–
1.72 (m, 6 H), 2.05–2.55 (m, 2 H), 2.26–2.40 (m, 2 H), 4.24 (q, 2 H,
J = 7.1 Hz), 5.29 (ddt, 1 H, J = 8.9, 10.2, 1.0 Hz), 5.52 (dd, 1 H,
J = 8.9, 48.5 Hz).
13C NMR (CDCl3, 62.85 MHz): = 14.0 (CH3), 25.4 (CH2), 26.3
(CH2), 27.6 (CH2), 28.2 (CH2), 29.7 (CH2), 61.4 (CH2), 84.6 (d,
J = 176 Hz, CH), 114.5 (d, J = 21.5 Hz, CH), 151.0 (d, J = 10.0 Hz,
C), 169.2 (d, J = 27 Hz, CO2R).
19F NMR (CDCl3, 235.36 MHz): = –121.6 (d, J = 22.1 Hz).
MS (EI, 70 eV): m/z (%) = 277 [(M + 1), 12], 261 (13), 219 (95),
191 (100), 145 (47), 89 (70), 77 (75), 75 (100).
Anal. Calcd for C13H25O3FSi: C, 56.48; H, 9.11. Found: C, 56.72;
H, 9.31.
Irradiation of Esters 1 and 2; General Procedure
19F NMR (CDCl3, 235.36 MHz): = –177.8 (d, J = 54.1 Hz).
A solution of ester 1a (or 2a–h) (10 mmol) and Et2NH (10 mmol)
(100 mL) was poured into quartz tubes and deoxygenated by bub-
bling with argon. The tubes were placed around a Quartz Dewar
containing a short wave length OSRAM lamp. The irradiation was
performed at 0–10 °C (external EtOH cooling bath). After disap-
pearance of the starting material (by TLC control), the solvent was
removed by concentration. Ester 3 (or 4a–h) was purified by flash
chromatography (eluent: EtOAc–pentane, 3:97).
MS (EI, 70 eV): m/z (%) = 200 (M, 9), 181 (18), 180 (67), 152 (27),
151 (39), 127 (64), 107 (65), 85 (69), 80 (100), 67 (54), 59 (62).
Ethyl (3Z)-2-Fluorohex-3-enoate (4e)
Yield: 74% (E/Z = 70/30).
IR (film): 2980, 1763, 1460, 1370, 1280, 1205, 1035 cm–1.
1H NMR (CDCl3, 250 MHz): (E isomer) = 1.03 (t, 3 H, J = 7.4
Hz), 1.30 (t, 3 H, J = 7.0 Hz), 2.03–2.25 (m, 2 H), 4.26 (q, 2 H,
J = 7.0 Hz), 5.20 (dd, 1 H, J = 3.7, 45.1 Hz), 5.50–5.65 (m, 1 H),
5.95–6.10 (m, 1 H); (Z isomer) = 1.04 (t, 3 H, J = 7.5 Hz), 1.29 (t,
3 H, J = 7.1 Hz), 2.15–2.35 (m, 2 H), 4.24 (q, 2 H, J = 7.1 Hz),
5.41–5.90 (m, 3 H).
Ethyl (2E)-4-Methylpent-2-enoate (3)
Yield: 27% (conversion 64%).
IR (film): 2950, 1695, 1640, 1375, 1360, 1290, 1265, 1140, 1025
cm–1.
13C NMR (CDCl3, 62.89 MHz): (E isomer) = 12.6 (CH3), 13.9
(CH3), 25.1 (CH2), 61.5 (OCH2), 88.6 (d, J = 181.1 Hz, C–F), 121.7
(CH), 140.5 (d, J = 10.9 Hz, CH), 169.0 (d, J = 9.9 Hz, CO2R). (Z
isomer) = 12.6 (CH3), 13.6 (CH3), 21.4 (CH2), 61.5 (OCH2), 84.3
(d, J = 178 Hz, C–F), 121.3 (CH), 140.2 (d, J = 10.5 Hz, CH), 168.6
(d, J = 8.3 Hz, CO2R).
1H NMR (CDCl3, 250 MHz): = 1.08 (d, 6 H, J = 7.0 Hz), 1.30 (t,
3 H, J = 7.0 Hz), 2.42 (quint, 1 H, J = 7.0 Hz), 4.20 (q, 2 H, J = 7.0
Hz), 5.75 (dd, 1 H, J = 16, 1.4 Hz), 6.92 (dd, 1 H, J = 16, 7.0 Hz).
MS (EI, 70 eV): m/z (%) = 142 (M, 29), 114 (48), 97 (100), 69 (95).
Anal. Calcd for C8H14O2: C, 67.57; H, 9.92. Found: C, 67.57; H,
10.04.
MS (EI, 70 eV): m/z (%) = 160 (M, 3), 129 (15), 111 (18), 87 (15),
71 (100).
Ethyl 2-Fluoro-4-methylpent-3-enoate (4a)
Yield: 51%.
Ethyl (3E)-5-{[t-Butyl(dimethyl)silyl]oxy}-2-fluoropent-3-
enoate (4g)
Yield: 55% (E/Z = 66/34).
IR (film): 2965, 2875, 1745, 1660, 1465, 1365, 1285, 1190, 1155
cm–1.
1H NMR (CDCl3, 250 MHz): = 1.29 (t, 3 H, J = 7.1 Hz), 1.79 (s,
3 H), 1.81 (s, 3 H), 4.24 (q, 2 H, J = 7.1 Hz), 5.34 (dd, 1 H, J = 12.1,
9.0 Hz), 5.46 (dd, 1 H, J = 47.3, 9.0 Hz).
13C NMR (CDCl3, 62.89 MHz): = 14.0 (CH3), 18.6 (CH3), 25.8
(CH3), 60.4 (CH2), 85.2 (d, J = 177.3 Hz, CH), 117.8 (d, J = 22.0
Hz, CH=), 142.8 (d, J = 12.9 Hz, C=), 169.2 (CO2R).
IR (neat): 2960, 2935, 2860, 1769, 1480, 1250, 1115, 1030 cm–1.
1H NMR (CDCl3, 250 MHz): (E and Z isomers) = 0.05 and 0.06
(s, 6 H), 0.90 (s, 9 H), 1.28 and 1.29 (t, 3 H, J = 7.0 Hz), 4.10–4.50
(m, 4 H), 5.30 (ddd, 1 H, J = 1.25, 5.8, 42.3 Hz), 5.70–6.10 (m, 2H).
13C NMR (CDCl3, 62.89 MHz): (E and Z isomers) = –5.3 (CH3),
14.0 (CH3), 18.3 (C), 25.8 (CH3), 60.1 (CH2, Z isomer) and 61.6
(CH2, E isomer), 62.3 (OCH2), 84.6 (d, J = 179.2 Hz, CH–F, Z iso-
mer) and 88.0 (d, J = 183.1 Hz, CH–F, E isomer), 121.4 (d, J = 19.1
Hz, CH=, E isomer) and 121.9 (d, J = 22.4 Hz, CH=, Z isomer),
135.7 (d, J = 10.1 Hz, CH=, E isomer) and 137.6 (d, J = 8.3 Hz,
CH=, Z isomer), 168.4 (d, J = 28.0 Hz, CO2R).
19F NMR (CDCl3): = –177.9 (d, J = 46.5 Hz).
Ethyl 4-Ethyl-2-fluorohex-3-enoate (4b)
Yield: 74%.
IR (film): 2980, 2895, 1745, 1660, 1470, 1360, 1270, 1195, 1125
cm–1.
19F NMR (CDCl3, 235.36 MHz): (E isomer)
= –185.9 (dd,
J = 15.3, 48.2 Hz); (Z isomer): = –182.6 (dd, J = 13.9, 35.3 Hz).
1H NMR (CDCl3, 250 MHz): = 1.04 (t, 3 H, J = 7.3 Hz), 1.06 (t,
3 H, J = 7.3 Hz), 1.29 (t, 3 H, J = 7.0 Hz), 2.03–2.27 (m, 4 H), 4.24
(q, 2 H, J = 7.0 Hz), 5.30 (dd, 1 H, J = 9.1, 10.3 Hz), 5.51 (dd, 1 H,
J = 9.1, 48.6 Hz).
MS (EI, 70 eV): m/z (%) = 277 (M, 46), 275 (25), 257 (75), 219
(38), 211 (33), 173 (62), 145 (100), 97 (100), 63 (27).
Ethyl Fluoro(3,3,5,5-tetramethylcyclohex-1-en-1-yl)acetate
(4h)
Yield: 76%.
IR (film): 2948, 2860, 1755, 1455, 1365, 1280, 1205, 1055 cm–1.
13C NMR (CDCl3, 62.89 MHz): = 12.0 (CH3), 13.2 (CH3), 14.0
(CH3), 24.2 (CH2), 29.0 (CH2), 61.4 (CH2), 85.0 (d, J = 175.8 Hz,
CH), 115.7 (d, J = 21.0 Hz, CH), 154.6 (d, J = 11.9 Hz, C), 169.5
(d, J = 27.6 Hz, CO2R).
19F NMR (CDCl3, 235.36 MHz): = –177.0 (d, J = 44.2 Hz).
1H NMR (CDCl3, 250 MHz): = 0.88 (s, 3 H), 0.96 (s, 3 H), 1.02
(s, 3 H), 1.04 (s, 3 H), 1.27 (d, 1 H, J = 7.0 Hz), 1.29 (t, 3H, J = 7.0
Hz), 1.33 (d, 1 H, J = 6.4 Hz), 1.64 (d, 1 H, JAB = 16.6 Hz), 1.88 (d,
1 H, JAB = 16.6 Hz), 4.15–4.40 (m, 2 H), 5.13 (d, J = 48.5 Hz, 1 H),
5.67 (d, J = 2.0 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 189 [(M + 1), 12], 169 (43), 168 (44),
153 (38), 115 (58), 95 (100), 73 (100).
Ethyl 3-Cyclohexylidene-2-fluoropropanoate (4c)
Yield: 83%.
Synthesis 2002, No. 3, 427–437 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Highly Stereoselective Synthesis of -Fluorocarboxylic Derivatives
433
13C NMR (CDCl3, 62.89 MHz): = 14.1 (CH3), 29.4 (CH3), 29.7
(CH3), 30.2 (CIV), 30.8 (CH3), 31.0 (CH3), 32.8 (CIV), 36.9 (CH2),
49.4 (CH2), 61.4 (CH2), 92.0 (d, J = 182.2 Hz, C–F), 127.9 (d,
J = 19.2 Hz, CIV), 139.3 (d, J = 9.9 Hz), 168.6 (d, J = 27.5 Hz,
CO2).
(2E)-2-Fluorododec-2-enoic Acid (6d)
Yield: 76%.
IR (CHCl3): 3600–3000, 2925, 1705, 1650, 1440, 1260, 1115 cm–1.
1H NMR (CDCl3, 300 MHz): = 0.87 (t, 3 H, J = 6.2 Hz), 1.15–1.35
(m, 12 H), 1.36–1.48 (m, 2 H), 2.53 (ddt, 1 H, J = 1.8, 6.2, 8.1 Hz),
6.07 (dt, 1 H, J = 21.3, 8.1 Hz), 6.20–7.20 (m, 1 H).
19F NMR (CDCl3, 235.36 MHz): = –184.2 (d, J = 48.5 Hz).
MS (EI, 70 eV): m/z (%) = 242 (M, 12), 227 (15), 222 (82), 207
(100), 177 (26), 169 (24), 161 (37), 149 (67), 137 (69), 133 (41),
121 (57), 107 (47).
13C NMR (CDCl3, 50.32 MHz): = 14.0 (CH3), 22.7 (CH2), 25.7
(CH2), 29.1 (CH2), 29.2 (CH2), 29.3 (CH2), 29.4 (CH2), 29.7 (CH2),
31.9 (CH2), 127.1 (d, J = 17.4 Hz, CH), 146.1 (d, J = 246 Hz, C–F),
166.3 (d, J = 39.1 Hz, CO2H).
19F NMR (CDCl3, 188.31 MHz): = –123.7 (d, J = 20.8 Hz).
MS (CI): m/z (%) = 217 [(M+ + 1), 100], 195 (5).
Saponification of Ethyl Esters (2); Typical Procedure
Ethyl ester 2a–d (20 mmol) diluted in EtOH (5 mL) was added to a
solution of KOH (1.68 g, 30 mmol) in EtOH (95mL) and H2O
(5mL). The mixture was heated for 4 h at reflux, cooled to r.t., half-
concentrated under vacuum and acidified with 2 N H2SO4 solution.
After extraction with hexanes, the organic layers were dried over
MgSO4, filtered and concentrated. The resulting oil was purified by
flash chromatography over silica gel giving acids 6a–d.
Esterification of Acids 6 and Synthesis of Esters 7a–d
To a solution of acid 6 (20 mmol) in CH2Cl2 (20 mL) were succes-
sively added DMAP (40 mg) and diacetone D-glucose (5.46g, 21
mmol). The solution was cooled at 0 °C with an external ice-water
bath. DCC (4.12 g, 20 mmol), first dissolved into CH2Cl2 (2 mL),
was added dropwise. After 10 min at 0 °C, the cooling bath was re-
moved and the mixture stirred overnight at r.t. Urea was filtered off
and the solvent was removed by concentration. Ester 7 was purified
by flash chromatography (eluent: EtOAc–hexanes, 10:90).
(2E)-2-Fluoro-4-methylpent-2-enoic Acid (6a)12b
Yield: 96%.
IR (CHCl3): 3600–3100, 2970, 2870, 1705, 1655, 1440, 1305, 1240,
1165, 1105 cm–1.
1H NMR (CDCl3, 250 MHz): = 1.01 (d, 6 H, J = 7.0 Hz), 3.29–
3.45 (m, 1 H), 5.88 (ddd, 1 H, J = 0.5, 10.7, 21.3 Hz), 10.55–10.90
(m, 1 H).
13C NMR (CDCl3, 62.89 MHz): = 22.6 (CH3), 25.5 (CH), 133.0
(d, J = 15.1 Hz, CH), 144.9 (d, J = 247.3 Hz, C–F), 165.8 (d,
J = 37.3 Hz, CO2R).
19F NMR (CDCl3, 235.36 MHz): = –125.5 (d, J = 22.1 Hz).
MS (EI, 70 eV): m/z (%) = 132 (M+, 8), 117 (65), 91 (59), 87 (100),
(2E)-(1,2:5,6-Di-O-isopropylidene- -D-glucofuranose-3-O-yl) 2-
Fluoro-4-methylpent-2-enoate (7a)
Yield: 68%.
[ ]D21 –31.0 (c 1.0, CH2Cl2).
IR (CHCl3): 2985, 2965, 1743, 1673, 1525, 1455, 1372, 1315, 1255,
1220, 1080, 1025 cm–1.
1H NMR (CDCl3, 250 MHz): = 1.07 (d, 6 H, J = 6.7 Hz), 1.30 (s,
3 H), 1.31 (s, 3 H), 1.41 (s, 3 H), 1.53 (s, 3 H), 3.26–3.43 (m, 1 H),
3.98–4.30 (m, 4 H), 4.56 (d, 1 H, J = 3.7 Hz), 5.37 (d, 1 H, J = 2.4
Hz), 5.80 (dd, 1 H, J = 10.5, 21.5 Hz), 5.91 (d, 1 H, J = 5.9 Hz).
13C NMR (CDCl3, 62.89 MHz): = 22.6 (CH3), 25.0 (CH3), 25.1
(CH3), 25.2 (CH3), 26.1 (CH3), 26.6 (CH3), 67.1 (CH2), 73.4 (CH),
76.9 (CH), 79.7 (CH), 83.1 (CH), 105.0 (CH), 109.2 (C), 112.2 (C),
131.4 (d, J = 14.5 Hz, CH), 144.9 (d, J = 253.2 Hz, C–F), 159.5 (d,
J = 36.0 Hz, CO2R).
69 (75).
(2E)-4-Ethyl-2-fluorohex-2-enoic Acid (6b)
Yield: 89%.
IR (CHCl3): 3600–3100, 2960, 2885, 1705, 1655, 1440, 1230, 1115
cm–1.
1H NMR (CDCl3, 250 MHz): = 0.89 (t, 6 H, J = 7.3 Hz), 1.18–1.39
(m, 2 H), 1.45–1.63 (m, 2 H), 2.92–3.13 (m, 1 H), 5.80 (dd, 1 H,
J = 11.3, 22.2 Hz), 9.30–9.70 (m, 1 H).
13C NMR (CDCl3, 62.89 MHz): = 11.5 (CH3), 27.9 (CH2), 39.0
(CH), 131.1 (d, J = 15.5 Hz, CH), 146.5 (d, J = 247 Hz, C–F), 166.2
(d, J = 37.5 Hz, CO2H).
19F NMR (CDCl3, 235.36 MHz): = –125.7 (d, J = 21.9 Hz).
MS (CI): m/z (%) = 375 [(M+ + 1), 24], 339 (10), 317 (100), 273
(31), 259 (10), 185 (11).
UV (CH2Cl2): 236 = 10300.
19F NMR (CDCl3, 235.36 MHz): = –122.4 (d, J = 21.6 Hz).
MS (EI, 70 eV): m/z (%) = 160 (M+, 18), 145 (8), 131 (100), 119
Anal. Calcd for C18H27O7F: C, 57.74; H, 7.27. Found: C, 57.27; H,
7.37.
(32).
(2E)-(1,2:5,6-Di-O-isopropylidene- -D-glucofuranose-3-O-yl) 4-
Ethyl-2-fluorohex-2-enoate (7b)
Yield: 83%.
[ ]D21 –31.0 (c 1.0, CH2Cl2).
IR (CHCl3): 2960, 2870, 1745, 1666, 1454, 1380 cm–1.
(2E)-3-Cyclohexyl-2-fluoroacrylic Acid (6c)
Yield: 90%.
IR (KBr): 3600–3100, 2930, 2850, 1710, 1660, 1440, 1305, 1130,
980 cm–1.
1H NMR (CDCl3, 250 MHz): = 0.87 (t, 3 H, J = 7.4 Hz), 0.88 (t,
3 H, J = 7.4 Hz), 1.20 1.40 (m, 2 H), 1.30 (s, 3 H), 1.32 (s, 3 H),
1.41 (s, 3 H), 1.45 1.65 (m, 2 H), 1.53 (s, 3 H), 2.90–3.10 (m, 1 H),
3.98–4.28 (m, 4 H), 4.54 (d, 1 H, J = 3.7 Hz), 5.40 (d, 1 H, J = 2.5
Hz), 5.70 (dd, 1 H, J = 11.2, 22.3 Hz), 5.91 (d, 1 H, J = 3.7 Hz).
13C NMR (CDCl3, 62.89 MHz): = 11.5 (CH3), 25.1 (CH3), 26.2
(CH3), 26.7 (CH3), 27.8 (CH2), 27.9 (CH2), 38.3 (CH), 67.2 (CH2),
72.5 (CH2), 77.0 (CH2), 79.8 (CH2), 83.2 (CH2), 105.1 (CH), 109.3
(C), 112.4 (C), 129.3 (d, J = 14.7 Hz, CH=), 146.6 (d, J = 251.9 Hz,
C–F), 159.7 (d, J = 37.8 Hz, CO2R).
1H NMR (CDCl3, 250 MHz): = 1.05–1.52 (m, 6 H), 1.63–1.85 (m,
4 H), 2.90–3.15 (m, 1 H), 5.91 (dd, 1 H, J = 10.5, 21.7 Hz), 7.30–
8.00 (m, 1 H).
13C NMR (CDCl3, 62.89 MHz): = 25.3 (CH2), 25.7 (CH2), 32.7
(CH2), 34.7 (CH), 131.6 (d, J = 15.1 Hz, CH), 144.6 (d, J = 250 Hz,
C–F), 165.5 (d, J = 36.2 Hz, CO2H).
19F NMR (CDCl3, 235.36 MHz): = –125.1 (d, J = 21.1 Hz).
MS (EI, 70 eV): m/z 172 (M+, <5), 143 (25), 130 (22), 95 (28), 81
(59), 69 (100).
Synthesis 2002, No. 3, 427–437 ISSN 0039-7881 © Thieme Stuttgart · New York

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FEATURE ARTICLE
19F NMR (CDCl3, 235.36 MHz): = –122.1 (d, J = 22.1 Hz).
IR (CHCl3): 2970, 2930, 2880, 1800, 1740, 1660, 1460, 1370, 1210,
1150, 1110 cm–1.
MS (EI, 70 eV): m/z (%) = 402 (M, 1), 388 (40), 387 (100), 329
(22), 269 (20), 243 (16), 185 (15), 143 (32), 127 (34), 113 (70), 101
(100).
1H NMR (CDCl3, 300 MHz): = 5.78 (dd, 1 H, J = 22.2, 11.3 Hz),
5.47 (s, 1 H), 4.09 (d, 1 H, J = 9.0 Hz), 4.06 (d, 1 H, J = 9.0 Hz),
2.99 (dp, 1 H, J = 11.3, 2.8 Hz), 1.45–1.64 (m, 2 H), 1.24–1.38 (m,
2 H), 1.25 (s, 3 H), 1.16 (s, 3 H), 1.05 (t, 3 H, J = 7.5 Hz), 1.03 (t, 3
H, J = 7.5 Hz).
Anal. Calcd for C20H31O7F: C, 59.69; H, 7.76. Found: C, 59.73; H,
8.02.
(2E)-(1,2:5,6-Di-O-isopropylidene- -D-glucofuranose-3-O-yl) 3-
Cyclohexyl-2-fluoroprop-2-enoate (7c)
Yield: 87%.
[ ]D21 –32.6 (c 1.0, CH2Cl2).
13C NMR (CDCl3, 75.45 MHz): = 11.2 (CH3), 11.3 (CH3), 19.8
(CH3), 22.6 (CH3), 27.6 (2 CH2), 38.6 (CH), 40.1 (C), 75.6 (CH),
75.9 (CH2), 129.7 (d, JCF = 15.5 Hz, CH), 146.0 (d, JCF = 250.4 Hz),
159.7 (d, JCF = 37.9 Hz), 171.3 (C).
19F NMR (CDCl3, 282 MHz): = – 122.4 (d, J = 22.2 Hz).
MS (CI, 70 eV): m/z (%) = 273 [(M+ + 1), 100], 161 (4), 115 (12).
IR (CHCl3): 2995, 2935, 2860, 1745, 1666, 1455, 1380, 1305, 1215,
1080, 1030 cm–1.
1H NMR (CDCl3, 250 MHz): = 1.00–1.35 (m, 6 H), 1.28 (s, 3 H),
1.29 (s, 3 H), 1.38 (s, 3 H), 1.50 (s, 3 H), 1.59–1.80 (m, 4 H), 2.89–
3.09 (m, 1 H), 3.96–4.28 (m, 4 H), 4.52 (d, 1 H, J = 3.7 Hz), 5.33
(d, 1 H, J = 2.1 Hz), 5.79 (dd, 1 H, J = 10.4, 21.5 Hz), 5.87 (d, 1 H,
J = 3.7 Hz).
13C NMR (CDCl3, 62.89 MHz): = 25.1 (CH3), 25.3 (CH2), 25.6
(CH2), 26.1 (CH3), 26.6 (CH3), 26.7 (CH3), 32.4 (CH2), 34.2 (CH),
66.8 (CH2), 72.4 (CH), 76.9 (CH), 79.3 (CH), 82.8 (CH), 105.0
(CH), 109.3 (C), 112.3 (C), 130.0 (d, J = 15.0 Hz, CH), 145.2 (d,
J = 252.1 Hz, C–F), 159.6 (d, J = 36.1 Hz, CO2R).
HMRS: m/z [M + H+] calcd for C14H21O4F: 273.1502; found:
273.1505.
UV (CH2Cl2): 240 = 2270.
Irradiation of Diacetone D-Glucose Esters 7a–d and 10b
A solution of esters 7 (or 10) (2.5 mmol) and N,N-dimethylamino-
ethanol (0.22g, 2.5 mmol) in CH2Cl2 (250 mL) was poured into
quartz tubes. After deoxygenation with argon, the tubes were placed
around a quartz Dewar in which was placed a 254 nm wavelength
OSRAM lamp. The tubes were cooled at –40 °C and irradiation was
performed until complete conversion. After concentration under re-
duced pressure, the selectivity was determined from 1H NMR spec-
tra of the crude material before any purification. The deconjugated
esters 8 (or 11) were isolated by flash chromatography on silica gel
(eluent: EtOAc–hexanes, 15:85).
19F NMR (CDCl3, 235.36 MHz): = –125.3 (d, J = 22.6 Hz).
MS (EI, 70 eV): m/z (%) = 414 (M, 1), 399 (55), 341 (7), 281 (9),
255 (6), 155 (14), 135 (12), 127 (18), 113 (54), 101 (100).
UV (CH2Cl2): 238 = 9610.
Anal. Calcd for C21H31O7F: C, 60.85; H, 7.54. Found: C, 60.83; H,
7.74.
(1,2:5,6-Di-O-isopropylidene- -D-glucofuranose-3-O-yl) 2-
Fluoro-4-methylpent-3-enoate (8a)
(2E)-(1,2:5,6-Di-O-isopropylidene- -D-glucofuranose-3-O-yl) 2-
Yield: 72% (de = 88%).
Fluoro-2-dodec-2-enoate (7d)
]
21 –99.6 (c 1.0, CH2Cl2).
D
Yield: 77%.
[ ]D21 –26.0 (c 1.0, CH2Cl2).
IR (CHCl3): 2990, 2940, 1770, 1672, 1375, 1265, 1215, 1165
cm–1.
1H NMR (CDCl3, 300 MHz): (major diastereoisomer) = 1.29 (s, 3
H), 1.31 (s, 3 H), 1.40 (s, 3 H), 1.52 (s, 3 H), 1.81 (s, 3 H), 1.83 (s,
3 H), 3.96–4.21 (m, 4 H), 4.52 (d, 1 H, J = 3.7 Hz), 5.32–5.34 (m, 1
H), 5.37 (d, 1 H, J = 3.7 Hz), 5.50 (dd, 1 H, J = 8.8, 47.8 Hz), 5.90
(d, 1 H, J = 3.7 Hz); (minor diastereoisomer, characteristic signal)
= 4.46 (d, 1 H, J = 3.8 Hz).
13C NMR (CDCl3, 62.89 MHz): = 18.6 (CH3), 18.7 (CH3), 25.2
(CH3), 25.8 (CH3), 26.2 (CH3), 26.7(CH3), 26.8 (CH3), 67.4 (CH2),
72.3 (CH2), 76.7 (CH), 80.0 (CH), 83.1 (CH), 84.9 (d, J = 171.2 Hz,
CH), 105.1 (CH), 109.4 (C), 112.5 (C), 117.4 (d, J = 20.7 Hz, CH=),
144.2 (d, J = 10.3 Hz, C=), 168.0 (d, J = 28.2 Hz, CO2R).
IR (CHCl3): 2980, 2925, 2860, 1735, 1665, 1455, 1375, 1345, 1215,
1165 cm–1.
1H NMR (CDCl3, 300 MHz): = 0.88 (t, 3 H, J = 6.0 Hz), 1.15–1.40
(m, 15 H), 1.29 (s, 3 H), 1.31 (s, 3 H), 1.41 (s, 3 H), 1.52 (s, 3 H),
2.46–2.54 (m, 2 H), 3.90–4.30 (m, 4 H), 4.55 (d, 1 H, J = 3.7 Hz),
5.36 (d, 1 H, J = 2.5 Hz), 5.90 (d, 1 H, J = 3.7 Hz), 5.98 (dt, 1 H,
J = 21.3, 8.1 Hz).
13C NMR (CDCl3, 50.23 MHz): = 14.1 (CH3), 22.6 (CH2), 25.2
(CH2), 26.2 (CH3), 26.7 (CH2), 26.8 (CH3), 29.1 (CH2), 29.2 (CH2),
29.3 (CH2), 29.4 (CH2), 29.5 (CH2), 31.9 (CH2), 67.2 (CH2), 72.5
(CH), 76.9 (CH), 79.7 (CH), 83.2 (CH), 105.1 (CH), 109.3 (C),
112.4 (C), 125.3 (d, J = 17.0 Hz, CH), 146.3 (d, J = 251 Hz, C–F),
159.7 (d, J = 36.1 Hz, CO2R).
19F NMR (CDCl3, 235.36 MHz): = –178.1 (d, J = 53.2 Hz).
MS (EI, 70 eV): m/z (%) = 374 (M, 8), 360 (18), 359 (100), 113
(18), 101 (55), 87 (32).
19F NMR (CDCl3, 188.31 MHz): = –123.7 (d, J = 22.0 Hz).
MS (EI, 70 eV): m/z (%) = 459 [(M+ + 1), 16], 401 (58), 261 (13),
HMRS: m/z calcd for C18H27O7F: 374.1740; found: 374.1742.
245 (16), 119 (72), 85 (100), 69 (90).
(1,2:5,6-Di-O-isopropylidene- -D-glucofuranose-3-O-yl) 4-
Ethyl-2-fluorohex-3-enoate (8b)
Yield: 91% (de = 95%).
[ ]D21 –96.1 (c 1.0, CH2Cl2).
HMRS: m/z [M + H+] calcd for C24H40O7F: 459.2758; found:
459.2759.
UV (CH2Cl2): 238 = 9610.
IR (CHCl3): 2985, 1755, 1666, 1465, 1365, 1265, 1215, 1065 cm–1.
4,4-Dimethyl-2-oxotetrahydrofuran-3-yl (2E)-4-Ethyl-2-
fluorohex-2-enoate (10b)
Prepared from acid 6b and (S)-(+)-pantolactone according a proce-
dure similar to the synthesis of esters 7a–d. Yield: 92% (E/Z = 98/
2).
1H NMR (CDCl3, 250 MHz): (major diastereoisomer) = 1.04 (t, 3
H, J = 7.3 Hz), 1.06 (t, 3 H, J = 7.3 Hz), 1.28 (s, 3 H), 1.32 (s, 3 H),
1.40 (s, 3 H), 1.51 (s, 3 H), 2.05–2.22 (m, 4 H), 3.90–4.22 (m, 4 H),
4.51 (d, 1 H, J = 3.7 Hz), 5.35 (t, 1 H, J = 9.5 Hz), 5.37 (d, 1 H,
J = 3.7 Hz), 5.52 (dd, 1 H, J = 9.5, 48.5 Hz), 5.87 (d, 1 H, J = 3.7
[ ]D21 –7.7 (c 0.1, CH2Cl2).
Synthesis 2002, No. 3, 427–437 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Highly Stereoselective Synthesis of -Fluorocarboxylic Derivatives
435
Hz); (minor diastereoisomer, characteristic signal) = 4.45 (d, 1 H,
J = 3.7 Hz).
IR (CHCl3): 2970, 2930, 2880, 1790, 1770, 1470, 1380, 1160, 1010
cm–1.
13C NMR (CDCl3, 62.89 MHz): = 11.9 (CH3), 13.3 (CH3), 24.2
(CH2), 25.1 (CH3), 26.1 (CH3), 26.6 (CH3), 26.7 (CH3), 29.7 (CH2),
67.2 (CH2), 72.2 (CH), 76.6 (CH), 80.0 (CH), 83.2 (CH), 84.4 (d,
J = 178.4 Hz, CH), 105.1 (CH), 109.3 (C), 112.3 (C), 114.9 (d,
J = 20.7 Hz, CH=), 154.9 (d, J = 9.9 Hz, C=), 167.7 (d, J = 28.0 Hz,
CO2R).
1H NMR (CDCl3, 300 MHz): (major diastereoisomer) = 1.05 (t, 3
H, J = 7.7 Hz), 1.06 (t, 3 H, J = 7.7 Hz), 1.13 (s, 3 H), 1.24 (s, 3 H),
2.06–2.27 (m, 5 H), 4.03 (d, 1 H, J = 9.0 Hz), 4.06 (d, 1 H, J = 9.0
Hz), 5.38 (s, 1 H), 5.66 (dd, 1 H, J = 48.4, 9.2 Hz); (minor diastere-
oisomer) = 1.05 (t, 3 H, J = 7.7 Hz), 1.06 (t, 3 H, J = 7.7 Hz), 1.13
(s, 3 H), 1.24 (s, 3 H), 2.06–2.27 (m, 5 H), 4.03 (d, 1 H, J = 9.0 Hz),
4.06 (d, 1 H, J = 9.0 Hz), 5.43 (s, 1 H), 5.70 (dd, 1 H, J = 48.2, 9.6
Hz).
13C NMR (CDCl3, 75.45 MHz): (major diastereoisomer) = 12.0
(CH3), 13.3 (CH3), 19.7 (CH3), 22.8 (CH3), 24.3 (CH2), 29.0 (CH2),
40.1 (C), 75.6 (CH), 76.0 (CH2), 84.5 (d, J = 177.6 Hz, CH), 114.9
(d, J = 20.7 Hz, CH), 155.6 (d, J = 10.4 Hz, C), 168.4 (d, J = 28.7
Hz, CO2R), 171.2 (CO2R); (minor diastereoisomer) = 11.9 (CH3),
13.2 (CH3), 19.6 (CH3), 22.8 (CH3), 24.2 (CH2), 28.9 (CH2), 40.2
(C), 75.5 (CH), 76.0 (CH2), 84.4 (d, J = 178.2 Hz, CH), 115.1 (d,
J = 20.7 Hz, CH), 155.5 (d, J = 10.4 Hz, C), 168.5 (d, J = 28.2 Hz,
CO2R), 171.5 (CO2R).
19F NMR (CDCl3, 235.36 MHz): = –176.2 (d, J = 46.1 Hz).
MS (EI, 70 eV): m/z 403 [(M + 1), 11], 388 (26), 387 (81), 367 (29),
185 (19), 123 (26), 113 (59), 101 (100), 85 (28), 73 (63).
(1,2:5,6-Di-O-isopropylidene- -d-glucofuranose-3-O-yl) 3-
Cyclohexylidene-2-fluoropropanoate (8c)
Yield: 74% (de = 94%).
[ ]D21 – 96.8 (c 1.0, CH2Cl2).
IR (CHCl3): 2990, 2940, 2865, 1774, 1674, 1448, 1385, 1260, 1225,
1170, 1085, 1020 cm–1.
19F NMR (282 MHz, CDCl3): (major diastereoisomer) = –177.2;
(minor diastereoisomer) = –178.2.
MS (CI, 70 eV): m/z (%) = 273 [(M+ + 1), 12], 253 (100).
HMRS: m/z [M + H+] calcd for C14H21O4F: 273.1502; found:
273.1231.
1H NMR (CDCl3, 250 MHz): (major diastereoisomer) = 1.29 (s, 3
H), 1.31 (s, 3 H), 1.40 (s, 3 H), 1.52 (s, 3 H), 1.55–1.70 (m, 6 H),
2.05–2.22 (m, 2 H), 2.25–2.40 (m, 2 H), 3.95–4.25 (m, 4 H), 4.51
(d, 1 H, J = 3.7 Hz, major diastereoisomer), 5.31 (t, 1 H, J = 9.2
Hz), 5.38 (d, 1 H, J = 2.8 Hz), 5.55 (dd, 1 H, J = 9.2, 48.4 Hz), 5.89
(d, 1 H, J = 3.7 Hz); (minor diastereoisomer, characteristic signal)
= 4.46 (d, 1 H, J = 3.7 Hz)
UV (CH2Cl2): 229 = 860.
13C NMR (CDCl3, 62.85 MHz): = 24.7 (CH3), 25.7 (CH3), 25.8
(CH2), 26.3 (CH3), 27.1 (CH2), 27.7 (CH2), 29.2 (CH2), 36.5 (CH2),
66.9 (CH2), 71.7 (CH), 76.1 (CH), 79.9 (CH), 82.9 (CH), 83.6 (d,
J = 177 Hz, CH), 104.9 (CH), 109.0 (C), 112.0 (C), 113.9 (d,
J = 20.9 Hz, C), 168.0 (d, J = 27.2 Hz, CO2R).
(1,2:5,6-Di-O-isopropylidene- -D-glucofuranose-3-O-yl) 2-
Fluorododecanoate (9d)
Ester 8d (0.141 g, 0.3 mmol) in Et2O (5 mL) was placed under H2
(1 atm) in the presence of a catalytic amount of PtO2. After 3 h and
complete disappearance of the starting material (TLC monitoring),
the solution was filtered off over a small pad of celite®. After con-
centration of the solvent and chromatography on silica gel, ester 9d
was isolated as a pure compound (0.126g).
19F NMR (CDCl3, 235.36 MHz): = –177.2 (d, J = 40.2 Hz).
MS (EI, 70 eV): m/z (%) = 414 (M, 7), 400 (29), 399 (100), 379
(35), 278 (6), 235 (10), 185 (12), 135 (18), 127 (26), 101 (37).
Yield: 91% (de = 95%).
HMRS: m/z calcd for C21H31O7F: 414.2053; found: 414.2066.
[ ]D21 – 27.4 (c 1.0, CH2Cl2).
IR (CHCl3): 2985, 2885, 1770, 1455, 1375, 1255, 1215, 1185 cm–1.
(1,2:5,6-Di-O-isopropylidene- -D-glucofuranose-3-O-yl) 2-
Fluorododec-3-enoate (8d)
Yield: 71%.
IR (CHCl3): 2985, 1772, 1670, 1455, 1375, 1165 cm–1.
1H NMR (CDCl3, 300Hz): (major diastereoisomer: = 0.87 (t, 3 H,
J = 5.9 Hz), 1.15–1.60 (m, 28 H), 1.75–2.00 (m, 2 H), 3.95–4.25 (m,
4 H), 4.52 (d, 1 H, J = 3.7 Hz) 4.91 (dt, 1 H, J = 48.5, 6.6 Hz), 5.34
(d, 1 H, J = 3.0 Hz), 5.89 (d, 1 H, J = 3.7 Hz); (minor diastereoiso-
mer, characteristic signal) = 4.50 (d, 1 H, J = 3.7 Hz).
13C NMR (CDCl3, 50.32 MHz): = 14.0 (CH3), 22.7 (CH2), 24.2
(CH2), 25.2 (CH3), 26.2 (CH3), 26.8 (CH3), 29.2 (CH2), 29.3 (CH2),
29.5 (CH2), 29.6 (CH2), 32.2 (CH2), 32.3 (CH2), 32.6 (CH2), 67.6
(CH2), 72.3 (CH), 76.8 (CH), 80.0 (CH), 83.2 (CH), 88.7 (d,
J = 184.7 Hz, CH), 105.1 (CH), 109.4 (C), 112.5 (C), 169.0 (d,
J = 24.7 Hz, CO2R).
1H NMR (CDCl3, 250 MHz): (mixture of E and Z isomers) = 0.87
(t, 3 H, J = 6.0 Hz), 1.15–1.35 (m, 15 H), 1.40 (s, 3 H), 1.52 (s, 3 H),
1.57 (s, 3 H), 1.90–2.25 (m, 2 H), 3.95–4.30 (m, 4 H), 4.51 (d, 1 H,
J = 3.7 Hz), 5.22 (dd, 1 H, J = 6.6, 47.8 Hz), 5.37 and 5.38 (d, 1 H,
J = 2.9 Hz), 5.45–6.15 (m, 2 H), 5.90 (d, 1 H, J = 3.7 Hz).
13C NMR (CDCl3, 62.85 MHz): = 14.1 (CH3), 22.7 (CH2), 24.2
(CH2), 25.2 (CH3), 26.7 (CH3), 26.8 (CH3), 28.5 (CH2), 28.6 (CH2),
29.2 (CH2), 29.25 (CH2), 29.4 (CH2), 29.5 (CH2), 29.6 (CH2), 31.9
(CH2), 32.2 (CH2), 32.3 (CH2), 32.6 (CH2), 67.6 (CH2), 72.4 (CH),
76.8 (CH), 79.9 (CH), 83.3 (CH), 88.7 (d, J = 184 Hz, CH), 105.2
(CH), 109.5 (C), 112.5 (C), 121.9 (d, J = 19.7 Hz, CH), 139.9 (d,
J = 10.7 Hz, CH), 168.8 (d, J = 24.7 Hz, CO2R), 167.4 (d, J = 13.6
Hz, CO2R).
19F NMR (CDCl3, 188.31 MHz): = –192.4 (dt, J = 49.4, 26.7 Hz).
MS (EI, 70 eV): m/z (%) = 461 [(M+ + 1), 100], 459 (22), 403 (72),
381 (12), 345 (8).
Osmylation of Esters 4b and 4c
19F NMR (CDCl3, 188.3 MHz): = –180.6, –180.8.
To an acetone–H2O solution (9:1, 13.5 mL) of ester 4 (2 mmol) was
added NMO (4.3 mmol) at 0 °C, followed by a 4% aq soln of OsO4
(0.4 mL). The resulting mixture was stirred for 8 h. H2O (2 mL) was
added and the two layers were separated. The aqueous layer was ex-
tracted with CH2Cl2 (3 15 mL). The organic layers were com-
bined, dried over MgSO4, filtered off and concentrated under vacuo.
The butyrolactones 12 and 13 were separated and isolated in pure
form by flash chromatography on silica gel (eluent: EtOAc–hex-
anes, 25:75).
MS (EI, 70 eV): m/z (%) = 458 (M+, 2), 443 (86), 187 (7), 101 (100).
HMRS: m/z calcd for C24H39O7F: 458.2679; found: 458.2676.
4,4-Dimethyl-2-oxotetrahydrofuran-3-yl 4-Ethyl-2-fluorohex-
3-enoate (11b)
Yield: 62% (de = 83%).
[ ]D21 +63 (c 0.1, CH2Cl2).
Synthesis 2002, No. 3, 427–437 ISSN 0039-7881 © Thieme Stuttgart · New York

436
F. Bargiggia et al.
FEATURE ARTICLE
(syn)-4-Ethyl 2-Fluoro-3-hydroxy-4-hexanolide (12b)
Yield: 54%.
mixture was stirred for 10 min at r.t. Ester 4c (2.5 mmol) in CH3CN
(1 mL) was added and the solution was heated at 60 °C until com-
plete conversion. After cooling, the solution was hydrolyzed with
brine, extracted with CH2Cl2. The organic layers were dried over
MgSO4, concentrated and product 14c was purified by flash chro-
matography.
IR (CHCl3): 3600–3250, 2985, 2950, 2885, 1755, 1466, 1280,
1115, 930 cm–1.
1H NMR (CDCl3, 250 MHz): = 0.93–1.03 (m, 6 H), 1.55–1.72 (m,
2 H), 1.91 (t, 1 H, J = 7.5 Hz), 1.94 (t, 1 H, J = 7.7 Hz), 2.20–2.55
(m, 1 H, OH), 4.31 (d, 1 H, J = 4.9 Hz), 5.29 (dd, 1 H, J = 4.95, 49.2
Hz).
3-Fluoro-1-oxaspiro[4.5]decan-2-one (14c)
Yield: 37%.
13C NMR (CDCl3, 62.89 MHz): = 7.3 ( (CH3), 7.5 (CH3), 23.2
(CH2), 27.3 (CH2), 70.6 (d, J = 13.9 Hz, CH), 86.7 (d, J = 196.8 Hz,
C), 90.8, 170.0 (d, J = 22.1 Hz, CO2).
19F NMR (CDCl3, 235.36 MHz): = –215.7 (d, J = 48.7 Hz).
MS (EI, 70 eV): m/z (%) = 177 [(M+ + 1), 3], 159 (11), 147 (26),
IR (CHCl3): 2938, 2875, 1788, 1455, 1311, 1270, 1220, 1160, 1105
cm–1.
1H NMR (CDCl3, 250 MHz): = 1.40–2.00 (m, 10 H), 2.21 (ddd, 1
H, J = 7.0, 13.8, 25.6 Hz), 2.53 (ddd, 1 H, J = 8.2, 13.8, 22.1 Hz),
5.24 (ddd, 1 H, J = 7.0, 8.2, 51.4 Hz).
13C NMR (CDCl3, 62.85 MHz): = 22.2 (CH2), 22.4 (CH2), 24.3
(CH2), 36.9 (CH2), 37.6 (CH2), 39.7 (d, J = 18.8 Hz, CH2), 84.6 (C),
86.7 (d, J = 188 Hz, CH), 171.0 (d, J = 19.5 Hz, CO2R).
103 (15), 87 (92).
Anal. Calcd for C8H13O3F: C, 54.54; H, 7.43. Found: C, 54.77; H,
7.63.
19F NMR (CDCl3, 235.36 MHz): =–191.8 (m).
MS (EI, 70 eV): m/z 173 [(M+ + 1), 58], 155 (7), 129 (56), 82 (85),
(anti)-4-Ethyl 2-Fluoro-3-hydroxy-4-hexanolide (13b)
Yield: 22%.
1H NMR (CDCl3, 250 MHz): = 0.93–1.00 (m, 6 H), 1.63–1.92 (m,
4 H), 2.80–3.40 (s, 1 H, OH), 4.46 (dd, 1 H, J = 7.9, 21.7 Hz), 5.20
(dd, 1 H, J = 7.9, 51.6 Hz).
67 (61).
Acknowledgements
13C NMR (CDCl3, 62.89 MHz): = 7.35 (CH3), 7.5 (CH3), 25.8
(CH2), 29.9 (CH2), 76.8 (d, J = 19.4 Hz, CH), 88.2 (d, J = 8 Hz, C),
91.8 (d, J = 193.6 Hz, C–F), 169.2 (d, J = 21.4 Hz, CO2).
19F NMR (CDCl3, 235.36 MHz): = –202.1 (dd, J = 29.5, 52.0 Hz).
MS (CI, 70 eV): m/z (%) = 177 [(M+ + 1), 3], 159 (100), 139 (8).
F.B. thanks M.R.S. for financial support. O.P. acknowledges CNRS
and Région Rhône-Alpes for substantial funding, respectively AIP
Jeune Equipe and Programme Emergence.
References
HMRS: m/z [M + H+] calcd for C8H13O3F: 177.0926; found:
177.0928.
(1) (a) Payani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3146.
(b) O’Hagan, D.; Rzepa, H. S. Chem. Commun. 1997, 645.
(c) Schlosser, M. Angew. Chem. Int. Ed. 1998, 37, 1496.
(d) Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
(2) (a) Wilkinson, J. A. Chem. Rev. 1992, 92, 505. (b) Hayashi,
T.; Soloshonok, V. A. Tetrahedron: Asymmetry 1994, 5,
955. (c) Biomedical Frontiers of Fluorine Chemistry;
Ojima, I.; Mc Carthy, J. R.; Welch, J. T., Eds.; ACS:
Washingthon DC, 1996, 228. (d) Iseki, K. Tetrahedron
1998, 54, 13887. (e) Taylor, S. D.; Kotoris, C. C.; Hum, G.
Tetrahedron 1999, 55, 12431.
(3) By electrophilic fluorination: (a) Davis, F. A.; Han, W.
Tetrahedron Lett. 1992, 33, 1153. (b) Davis, F. A.; Zhou,
P.; Murphy, C. K. Tetrahedron Lett. 1993, 34, 3971.
(c) Siddiqui, M. A.; Marquez, V. E.; Driscott, J. S.; Barchi,
J. J. Jr. Tetrahedron Lett. 1994, 35, 3263. (d) Davis, F. A.;
Qi, H. Tetrahedron Lett. 1996, 37, 4345. (e) Davis, F. A.;
Kau, P. V. N. Tetrahedron Lett. 1998, 39, 6135. (f) Less, S.
L.; Handa, S.; Millburn, K.; Leadlay, P. F.; Dutton, C. J.;
Staunton, J. Tetrahedron Lett. 1996, 37, 3515. (g) Poss, A.
J.; Shia, G. A. Tetrahedron Lett. 1995, 36, 4721. (h)Mohar,
B.; Baudoux, J.; Plaquevent, J.-C.; Cahard, D. Angew.
Chem. Int. Ed. 2001, 40, 4214. (i) By nucleophilic
(syn)-4-Pentamethylene-2-fluoro-3-hydroxybutyrolactone (12c)
Yield: 48%.
IR (CHCl3): 3600 3200, 2985, 2875, 1770, 1465, 1285, 1215 cm–1.
1H NMR (CDCl3, 250 MHz): = 1.42–2.00 (m, 10 H), 2.77 (s, 1 H,
OH), 4.34 (d, 1 H, J = 4.8 Hz), 5.29 (dd, 1 H, J = 4.9, 48.9 Hz).
13C NMR (CDCl3, 62.89 MHz): = 21.6 (CH2), 22.3 (CH2), 24.7
(CH2), 30.2 (CH2), 34.7 (CH2), 70.9 (d, J = 14.1 Hz, CH), 86.7 (d,
J = 198.3 Hz, CH), 87.2 (C), 170.1 (d, J = 21.4 Hz, CO2R).
MS (CI, 70 eV): m/z (%) = 189 [(M+ + 1), 10], 171 (100), 151 (85).
HMRS: m/z [M + H+] calcd for C9H13O3F: 189.0927; found:
189.0937.
(anti)-4-Pentamethylene-2-fluoro-3-hydroxybutyrolactone
(13c)
Yield: 31%.
1H NMR (CDCl3, 250 MHz): = 1.50–2.00 (m, 10 H), 2.65–3.15
(m, 1 H, OH), 4.23 (dd, 1 H, J = 8.0, 19.5 Hz), 5.17 (dd, 1 H,
J = 8.0, 51.7 Hz).
13C NMR (CDCl3, 62.89 MHz): = 21.1 (CH2), 21.8 (CH2), 24.8
(CH2), 30.6 (CH2), 35.5 (CH2), 78.5 (d, J = 19.0 Hz, CH), 86.4 (C),
91.3 (d, J = 195.0 Hz, C–F), 169.8 (CO2).
substitution of -hydroxy acid derivatives: Hann, G. L.;
Sampson, P. J. Chem. Soc., Chem. Commun. 1989, 1650.
(j) See also: Shiozaki, M.; Kobayashi, Y.; Arai, M.
Tetrahedron 1991, 47, 7021. (k) See also: Fritz-Langhals,
E.; Schütz, G. Tetrahedron Lett. 1993, 34, 293. (l) See also:
Fritz-Langhals, E. Tetrahedron: Asymmetry 1994, 5, 981.
(m) From chiral -ketoesters: Ihara, M.; Taniguchi, N.; Kai,
T.; Satoh, K.; Fukumoto, K. J. Chem. Soc., Perkin Trans 1
1992, 221. (n) See also: Iwaoka, T.; Murohashi, T.; Sato,
M.; Kaneko, C. Tetrahedron: Asymmetry 1992, 3, 1025.
MS (CI, 70 eV): m/z (%) = 189 [(M+ + 1), 14], 171 (100), 151 (64).
HMRS: m/z [M + H+] calcd for C9H13O3F: 189.0926; found:
189.0932.
Lactonisation of Ester 4c Induced by TMS-I
To a suspension of anhyd NaI (3 mmol) in freshly distilled CH3CN
(5 mL) was added under argon (CH3)3SiCl (3 mmol). The resulting
Synthesis 2002, No. 3, 427–437 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
Highly Stereoselective Synthesis of -Fluorocarboxylic Derivatives
437
(4) (a) Behnen, W.; Mehler, T.; Martens, J. Tetrahedron:
Asymmetry 1993, 4, 1413. (b) Ventalon, F. M.; Faure, R.;
Laurent, E. G.; Marquet, B. S. Tetrahedron: Asymmetry
1994, 5, 1909. (c) Enders, D.; Pothoff, M.; Raabe, G.;
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