A stereoselective preparation of 1-fluorocyclopropane-1-carboxylate derivatives through radical addition of fluoroiodoacetate to alkenes followed by intramolecular substitution reaction

Article abstract of DOI:10.1016/S0040-4020(01)00726-8

Triethylborane mediated iodine atom-transfer radical addition of fluoroiodoacetate to 1-alkene or cyclic alkene proceeded in a good yield to give the α-fluoro-γ-iodo esters in non-diastereoselective manner, while the subsequent cyclopropane formation via enolate of the α-fluoro ester provided the corresponding fluorocyclopropanecarboxylate in a highly cis- or F-endo-selective manner.

Full text of DOI:10.1016/S0040-4020(01)00726-8

TETRAHEDRON
Pergamon
Tetrahedron 57 42001) 7487±7493
A stereoselective preparation of 1-¯uorocyclopropane-1-
carboxylate derivatives through radical addition of
¯uoroiodoacetate to alkenes followed by intramolecular
substitution reaction
Akio Saito, Hisanaka Ito and Takeo Taguchip
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 11 June 2001; accepted 13 July 2001
AbstractÐTriethylborane mediated iodine atom-transfer radical addition of ¯uoroiodoacetate to 1-alkene or cyclic alkene proceeded in a
good yield to give the a-¯uoro-g-iodo esters in non-diastereoselective manner, while the subsequent cyclopropane formation via enolate of
the a-¯uoro ester provided the corresponding ¯uorocyclopropanecarboxylate in a highly cis- or F-endo-selective manner. q 2001 Elsevier
Science Ltd. All rights reserved.
1. Introduction
nated ole®n part was also reported, while there needs multi-
ple steps for the preparation of the precursor diazocarbonyl
compounds and stereoselective synthesis of ¯uorinated
ole®n part should be also required to achieve the stereo-
selective preparation of the corresponding cyclopropane
derivative.3,7
Organo¯uorine compounds are widely applied in bio- and
medicinal chemistry due to their unique properties.1 The
usefulness of the ¯uorinated cyclopropane moiety has
been demonstrated in modi®cation of biologically active
substances, in which the conformational restriction and
the alteration of chemical and physical properties of func-
tional groups are brought about by this unit.2±4 Forthe
synthesis of the ¯uorinated cyclopropane derivatives, in
particular 1-¯uorocyclopropane-1-carboxylate derivatives,
there remains several problems to be solved. For example,
the mercurial carbenoid reagent PhHgCXFCOOR 4XˆCl,
Br) is known as only one CFCOOR transfer reagent to elec-
tron-rich alkenes to give 1-¯uorocyclopropane-1-carboxy-
late derivatives, although high temperature and long
reaction time are required, the yields of the products
severely vary depending on the structure of alkenes, and
the toxicity of organomercurials is also disadvantage of
this reagent.5 Simmons±Smith reaction with ¯uoroallyl
alcohol derivatives proceeds in stereospeci®c manner,
although large excess of the zinc reagent is required to
obtain the cyclopropane in reasonable yield due to the low
reactivity of ¯uorinated ole®ns, and this reaction cannot be
applied to the preparation of 2,3-disubstituted 1-¯uoro-
cyclopropane derivatives including bicyclo[n.1.0] ring
systems.6 Intramolecular cyclopropanation reaction of
metal carbenoid derived from a-diazocarbonyl with ¯uori-
For the preparation 1-¯uorocyclopropane-1-carboxylate of
bicyclo[n.1.0] ring system, we examined the conjugate addi-
tion of bromo¯uoroacetate with cyclic enones followed by
enolate driven intramolecular cyclopropane formation
4Scheme 1). Thus, the reaction of ketene triethylsilylacetal
1,8 prepared in situ by treating dibromo¯uoroacetate with
triethylsilyl chloride and Zn in CH3CN, with cyclopente-
none gave the 1,4-adduct 2 in 61% yield as a diastereomeric
mixture 4ratio 1.5:1) accompanied by the formation of 1,2-
adduct 3 420% yield). After separation of the diastereomers
by silica gel column, each isomer4 2a, 2b) was treated with
DBU in DMF at room temperature to give the ¯uorocyclo-
propane carboxylate 4endo-4, exo-4)3 as a single isomerin
good yield, respectively. In this case, it is obvious that the
stereochemical outcome of this cis-fused ¯uorocyclopro-
pane carboxylate 4 4endo vs exo) depends on the diastereo-
selection in the 1,4-addition step, but unfortunately it was
almost non-selective with cyclopentenone and cyclohexe-
none.
As an alternative method for the preparation of 2-substituted
or2,3-disubstituted 1-¯uocryclooppr ane-1-cbaor xylate,
we have developed two-step procedure which involves
iodine atom-transfer radical addition of ¯uoroiodoacetate
to alkene followed by intramolecular substitution reaction
of the enolate of a-¯uoro ester. It would be expected that
Keywords: ¯uorocyclopropanes; radical reaction; triethylborane; ¯uoro-
iodoacetate.
Corresponding author. Tel./fax: 181-426-76-3257;
e-mail: taguchi@ps.toyaku.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020401)00726-8

7488
A. Saito et al. / Tetrahedron 57 ,2001) 7487±7493
Scheme 1.
while with cyclic alkenes such as cyclohexene the yield of
the adduct was not good and the stereoselectivity of this
reaction was not clear 4vide infra). It has been well docu-
mented that triethylborane 4in the presence of oxygen) is an
excellent radical initiator in the radical reaction of alkyl
halides or tinhydride since the ®rst report by Oshima et
al.12 To improve the yield of the adducts 6 as well as stereo-
selectivity in the cases of cyclic alkenes 4cis vs trans),
triethylborane mediated reaction of ¯uoroiodoacetate with
alkenes were conducted. Results are shown in Table 1. As
expected, reaction proceeded at room temperature within a
relatively short time to give the iodine containing adducts 6
in good yields. With 1-alkene 5a, 5b, diastereoselectivities
of the products was low 41.7:1 for 6a, 1.1:1 for 6b, respec-
tively) 4entries 1±4). Reaction with cyclic alkenes
proceeded smoothly to give the trans isomerpredominantly.
For example, when the reaction was carried out at room
temperature, cyclopentene gave the adduct 6c in 69%
yield with a ratio of trans/cisˆ5 4entry 5), 2,5-dihydrofuran
gave 6d in 43% yield with trans/cisˆ9.8 4entry 7) and
cyclohexene gave 6e in 69% yield with trans/cisˆ1.9
4entry 8). The use of Lewis acids in radical reactions with
alkenes were reported to improve the reactivity of atom-
transfer reactions of a-halo esters, amides, or oxazolidinone
imides.13±15 In ourcase, as shown in entries 6 and 9, by the
addition of Lewis acid 4Et2AlCl) the atom transfer reaction
proceeded at low temperature 42788C) within 1 h to give 6c
461% yield) and 6e 469 % yield), respectively, and increase
in trans-selectivity was observed in the case of 6c 4trans/
cisˆ8). The role of Et2AlCl should increase both the rate of
addition of the electrophilic a-carbonyl radical to the alkene
and also the iodine abstraction from ¯uoroiodoacetate by the
resulting nucleophilic carbon radical due to increasing the
electron-withdrawing nature of ester group by complexation
with Et2AlCl, thereby the reaction proceeded at low
temperature. The trans or cis stereochemistries of the adduct
6c, 6d, 6e were determined by NOE experiments of each
isomer after separation by MPLC. The diastereomer ratio of
trans-6c due to the ¯uorine-bearing chiral center was 1.2:1,
and 1.4:1 for cis-6c. Similarly, low diastereoselectivity was
observed in the case of cyclohexene 41.6:1 for trans-6e).
Thus, with cyclic alkenes, atom-transfer addition of ¯uor-
oiodoacetate mediated by triethylborane proceeded in a high
trans-selectivity with low diastereoselectivity with respect
to ¯uorine-bearing chiral center. It should be noted that
Scheme 2.
even if radical addition of ¯uoroiodoacetate with 1-alkene
proceeds in non-diastereoselective manner, relative stereo-
chemistry at the stereogenic center having ester group and
¯uorine atom can be neglected in the cyclization stage,
because this position is converted to an enolate form by
treating with base. Likewise, in the case of cyclic alkene,
while addition of ¯uoroiodoacetate forms an adduct having
consecutive three chiral centers, that is, which theoretically
consists of four diastereomers, two trans isomers of these
four isomers would be possibly cyclized through SN2 path-
way to give the cis-fused bicyclo[n.1.0] ring system
4Scheme 2). Therefore, trans-selectivity in the ®rst radical
addition step would be crucial for the ef®ciency of this
method. In this paper, we report the results with particular
emphasis on the stereochemical outcome in the cyclization
step.
2. Results and discussion
Radical addition of ¯uoroiodoacetate9 to alkenes have been
reported by two groups.10,11 Barton et al. reported that zinc
and nickel dichloride hexahydrate promote this addition
reaction to obtain the corresponding iodine-free a-¯uoro
esters.10 Later, Chen et al. reported the iodine atom-transfer
addition with electron-rich alkenes promoted by acid-
washed iron powder under THF re¯uxing conditions to
afford a-¯uoro-g-iodo esters.11 Underthe iorn powder
mediated conditions 4THF, re¯ux, 10±24 h), electron-rich
1-alkenes having a variety of functional groups reacted
smoothly to give the a-¯uoro-g-iodo esters in good yields,

A. Saito et al. / Tetrahedron 57 ,2001) 7487±7493
Table 1. Atom-transfer addition of ICFHCO2Et to alkene
7489
c
Entry
Alkene
Molar ratioa
Time 4h)
6
Yield 4%)b
Isomerratio
1
5a RˆBzO4CH2)3±
1:1.5:1
1:1.5:1
1:1.5:1
1:3:1
7
5
3
3
6a
6a
6b
6b
88
73
54
73
1.7:1
1.8:1
1.1:1
1.1:1
2d
3
5a
5b RˆTBDPSOCH2±
4
5b
5
6
5c
5c
4:1:1
8
1
6c
6c
69
61
t/cˆ5:1, trans 1.2:1, cis 1.4:1
t/cˆ8:1, trans 1.5:1, cis 4.3:1
4:1:1e
7
5d
4:1:1
1
6d
43
t/cˆ9.8:1, trans 1.1:1, cis 1.2:1
8
9
5e
5e
4:1:1
4:1:1e
4
1
6e
6e
69
69
t/cˆ1.9:1, trans 1.7:1, cis 1.9:1
t/cˆ1.7:1, trans 1.2:1, cis 2.2:1
a
Molarratio; alkene: ICFHCO 2Et/Et3B.
Isolated yield.
b
c
d
e
Determined by 1H and 19F NMR.
Solvent; hexane.
In this case, 1 equiv. of Et2AlCl was added and reaction was carried out at 2788C.
stereochemical assignments of 6c, 6e reported by Chen et
al.11 are wrong. Although they reported that the cis/trans
ratio of both 6c and 6e is almost 1:1, NMR data reported
are coincide with trans isomers, not with cis isomers in
comparison with our NMR data of all the isomers obtained
in pure forms after MPLC puri®cation. That is, the cis
isomerthey assigned should be anotherdiasteeromerof
trans isomer. In fact, we re-examined the reaction of ¯uoro-
iodoactate with cyclopentene underthe reported conditions
420 mol% iron powder, THF, re¯ux) to reveal that 6c was
obtained as a mixture of four isomers in a ratio of
2.3:2.0:1.6:1 and the former two isomers are trans-6c and
the lattertwo isomesr aer cis-6c. Underthe similarcondi-
tions, cyclohexene gave the adduct 6e in a ratio of trans-1/
trans-2/cis-1/cis-2ˆ4.6:5.5:1:3.6 4To specify each dia-
stereomer of trans-6 or cis-6, compound numbers trans-6-
1/trans-6-2 or cis-6-1/cis-6-2 are used on the basis of the
order of elution on MPLC as indicated in Section 3).
Next, we examined the cyclopropane formation of the iodo-
¯uoro esters 6 obtained by the above reaction. It was found
that LHMDS [LiN4SiMe3)2] is a suitable base forcyclo-
propane formation and regardless of the diastereomeric
ratio of the iodo¯uoro esters 6 reaction proceeds in a highly
Scheme 3.

7490
A. Saito et al. / Tetrahedron 57 ,2001) 7487±7493
Scheme 4.
stereoselective manner to give the cis-2-substituted 1-
¯uorocyclopropane-1-carboxylate 7a, 7b from 6a, 6b and
only F-endo-bicyclo[n.1.0] ring compound 7c±7e from
trans-6c±6e 4see Scheme 3). Forexample, eraction of a
diastereomeric mixture of 6a 41.7:1) was treated with
LHMDS 43.2 equiv.) in THF at 2788C for3 h to give the
cyclopropane 7a in 81% yield 4cis/transˆ5.8). The use of
LDA instead of LHMDS resulted in decrease in the yield of
7a 433% yield) along with the formation of b-elimination
product, 2-¯uoro-7-benzoyloxy-3-heptenoate, in 18% yield.
Similarly, treatment of 6b with LHMDS gave the cyclo-
propane 7b in quantitative yield 4cis/transˆ9). Although
relative stereochemistries were not determined, both
diastereomers of trans isomer derived from cyclopentene
4trans-6c-1, trans-6c-2) showed almost equal reactivity in
the cyclopropane formation to give only F-endo cyclo-
propane derivative 7c in good yield 479 and 75%, respec-
tively), while cis isomer4 cis-6c-1 or cis-6c-2) gave the b-
elimination product 8c. This F-endo selective formation of
the ¯uorocyclopropane carboxylate was also realized with
trans-6d and trans-6e as shown in Scheme 3.
obtained on a Hitachi M-80 orVG Auto spec. Medium
pressure liquid chromatography 4MPLC) was performed
using prepacked column 4silica gel, 50 mm) with UV or
RI detector.
3.1. General procedure of triethylborane mediated
addition of ethyl ¯uoroiodoacetate to alkenes: ethyl 2-
¯uoro-7-benzoyloxy-3-iodoheptanoate 6a
Under an argon atmosphere, to a mixture of 5a 4100 mg,
0.53 mmol) and ethyl ¯uoroiodoacetate9 4180 mg,
0.78 mmol) in dichloromethane 43 ml) was added triethyl-
borane 41 M hexane solution, 0.53 ml) at room temperature.
Then, to the mixture was injected air 45 ml) by a syringe.
After being stirred for 7 h at the same temperature, the
reaction mixture was quenched by the addition of water
and extracted with ether. The organic layer was washed
with brine, dried over MgSO4, then concentrated under
reduced pressure. The residue was chromatographed on
silica gel 4hexane/etherˆ20:1) to give 6a 4195 mg, 88%
1
yield, diastereomer ratio 1.7:1) as colorless oil. H NMR
4400 MHz, CDCl3) d; 8.05±8.01 42H, m), 7.59±7.53 41H,
m), 7.47±7.41 42H, m), 5.16 40.63H, ddd, Jˆ49.4, 10.8,
2.2 Hz, major-CFH), 5.09 40.37H, ddd, Jˆ48.6, 7.5,
5.0 Hz, minor-CFH), 4.39±4.23 43H, m), 4.26 42H, q,
Jˆ7.1 Hz), 2.65±1.85 46H, m), 1.31 43H, t, Jˆ7.1 Hz).
19F NMR 4376.5 MHz, CDCl3) d; 2127.6 40.37F, ddd,
Jˆ48.6, 37.5, 19.3 Hz, minor), 2131.9 40.63F, ddd,
Jˆ49.4, 37.5, 12.5 Hz, major). EI-MS m/z: 423 4M111).
Anal. calcd forC 16H20FIO4: C, 45.51; H, 4.77. Found: C,
45.60; H, 4.82.
The following example indicates the ef®ciency of the
present two-step preparation of ¯uorocyclopropane carbox-
ylate. Triethylborane mediated atom-transfer radical addi-
tion of ¯uoroiodoacetate with 4-benzyloxycyclopentene 5f
proceeded at room temperature to give a isomeric mixture of
the adduct 6f in 76% yield. Without separation of isomers,
the adduct 6f was treated with LHMDS 45 equiv.) in THF at
2788C for2 h to give the cyclopropane 7f in 58% yield 42
steps) with complete F-endo selectivity 4Scheme 4).
In conclusion, we have developed a convenient stereoselec-
tive preparation of 1-¯uorocyclopropane-1-carboxylate
derivatives including bicyclo[n.1.0] ring system through
triethylborane mediated iodine atom-transfer radical addi-
tion of ¯uoroiodoacetate to 1-alkene or cyclic alkene
followed by the subsequent cyclopropane formation via
enolate of a-¯uoro ester.
3.1.1. Ethyl 5-,tert-butyldiphenylsiloxy)-2-¯uoro-4-iodo-
pentanoate 6b. 73% yield, diastereomer ratio 1.1:1. H
1
NMR 4400 MHz, CDCl3) d; 7.67±7.64 44H, m), 7.46±
7.39 46H, m), 5.13 40.52H, ddd, Jˆ49.5, 10.1, 3.1 Hz,
major-CFH), 5.05 40.48H, ddd, Jˆ48.6, 7.8, 5.1 Hz,
minor-CFH), 4.31±4.24 43H, m), 3.91±3.85 42H, m),
2.78±2.16 42H, m), 1.32 43H, t, Jˆ7.1 Hz), 1.09 49H, s).
19F NMR 4376.5 MHz, CDCl3) d; 2128.0 40.48F, ddd,
Jˆ48.6, 26.5, 18.5 Hz, minor), 2131.6 40.52F, ddd,
Jˆ49.5, 36.0, 14.5 Hz, major). EI-MS m/z: 529 4M111).
Anal. calcd forC 23H30FIO3Si: C, 52.27; H, 5.72. Found:
C, 52.07; H, 5.68.
3. Experimental
1H and 13C NMR spectra were taken on a Brucker AM400 or
a Varian Gemini-300 spectrometer, and chemical shifts
were reported in parts per million 4ppm) using CHCl3
47.26 ppm) in CDCl3 for 1H NMR, and CDCl3
477.01 ppm) for 13C NMR as an internal standard, respec-
tively. 19F NMR spectra were taken on a Brucker AM400
spectrometer, and chemical shifts were reported in parts per
million 4ppm) using benzotri¯uoride as a standard. Infrared
spectra 4IR) were recorded on a Perkin±Elmer FTIR-1710
infrared spectrophotometer. Mass spectra 4MS) were
3.1.2. Ethyl 2-¯uoro-2-,2-iodocyclopentyl)acetate 6c. In a
similar manner, reaction of cyclopentene 40.18 ml,
2.0 mmol) with ethyl ¯uoroiodoacetate 4120 mg,
0.52 mmol) in the presence of triethylborane 40.52 mmol)
and the subsequent puri®cation by column chromatography
on silica gel 4hexane/AcOEtˆ10:1) gave 6c as a diastereo-
meric mixture, which was further separated by MPLC 4hex-
ane/AcOEtˆ9:1, ¯ow rate 7.0 ml/min) to give trans-6c-1

A. Saito et al. / Tetrahedron 57 ,2001) 7487±7493
7491
449 mg, 32% yield), trans-6c-2 440 mg, 26% yield), cis-6c-1
46.6 mg, 4% yield) and cis-6c-2 49.6 mg, 6% yield) in the
order of elution. trans-6c-1: 1H NMR 4400 MHz, CDCl3) d;
5.11 41H, dd, Jˆ49.4, 2.5 Hz), 4.27 42H, q, Jˆ7.2 Hz), 4.02
41H, ddd, Jˆ9.5, 9.5, 7.1 Hz), 2.63 41H, dddd, Jˆ32.0, 17.6,
9.1, 2.5 Hz), 2.41±2.29 41H, m), 2.17±2.03 41H, m), 1.31
43H, t, Jˆ7.2 Hz). 19F NMR 4376.5 MHz, CDCl3) d;
2143.1 41F, dd, Jˆ49.4, 32.0 Hz). EI-MS m/z: 301
41H, dd, Jˆ47.7, 10.1 Hz), 4.59 42H, ddd, Jˆ4.8, 2.3,
2.3 Hz), 4.40 42H, d, Jˆ2.3 Hz),4.35±4.23 42H, m), 3.93
41H, dd, Jˆ8.5, 8.5 Hz), 3.84 4dd, Jˆ9.6, 8.5 Hz), 1.96
4ddddd, Jˆ10.1, 9.6, 8.7, 8.5, 4.8 Hz), 1.32 43H, t,
Jˆ7.2 Hz). 19F NMR 4376.5 MHz, CDCl3) d; 2125.7 41F,
dd, Jˆ47.7, 8.7 Hz). EI-MS m/z: 302 4M1). HRMS calcd for
C8H12FIO3: 301.9815 4M1), Found: 301.9804.
4M111). HRMS calcd forC H15FIO2: 301.0101 4M111),
3.1.4. Ethyl 2-¯uoro-2-,2-iodocyclohexyl)acetate 6e. A
diastereomeric mixture of the adduct 6e 4113 mg, 69%
yield, trans-6e-1: trans-6e-2/cis-6e-1/cis-6e-2ˆ3.5:5.8:1:
4.1) was separated by MPLC 4hexane/AcOEtˆ12:1, ¯ow
rate 7.0 ml/min) to give trans-6e-1 427 mg, 17% yield),
trans-6e-2 431 mg, 14% yield), trans-6e-2 and cis-6e-1
mixture 421 mg, 13% yield, trans-6e-2/cis-6e-1ˆ1.7:1)
and cis-6e-2 432 mg, 15% yield) in the order of elution.
9
1
Found: 301.0114. trans-6c-2: H NMR 4400 MHz, CDCl3)
d; 4.86 41H, dd, Jˆ48.3, 3.6 Hz), 4.30 42H, q, Jˆ7.2 Hz),
4.23 41H, ddd, Jˆ6.8, 6.8, 6.6 Hz), 2.88 41H, ddddd,
Jˆ27.1, 9.9, 6.6, 6.6, 3.6 Hz), 2.23 4ddd, Jˆ20.5, 6.8,
6.8 Hz), 2.21 4ddd, Jˆ20.5, 6.8, 6.8 Hz), 2.00±1.58 44H,
m), 1.33 43H, t, Jˆ7.2 Hz). 19F NMR 4376.5 MHz,
CDCl3) d; 2136.5 41F, dd, Jˆ48.3, 27.0 Hz). EI-MS m/z:
301 4M111). HRMS calcd forC 9H15FIO2: 301.0101
1
trans-6e-1: H NMR 4400 MHz, CDCl3) d; 5.27 41H, dd,
1
4M111), Found: 301.0121. cis-6c-1: H NMR 4400 MHz,
Jˆ46.5, 3.3 Hz), 4.50±4.19 43H, m), 2.58±2.50 41H, m),
2.28 41H, ddddd, Jˆ16.4, 11.4, 11.4, 3.5, 3.5 Hz), 2.10
41H, ddd, Jˆ25.2, 12.1, 3.7 Hz), 2.04±1.95 41H, m),
1.88±1.81 41H, m), 1.63±1.55 41H, m), 1.45±1.23 42H,
m), 1.34 43H, t, Jˆ7.2 Hz), 1.18±1.05 41H, m). 19F NMR
4376.5 MHz, CDCl3) d; 2130.7 41F, dd, Jˆ46.5, 16.4 Hz).
EI-MS m/z: 315 4M111). Anal. calcd forC 10H16FIO2: C,
CDCl3) d; 4.97 41H, dd, Jˆ48.1, 6.5 Hz), 4.40 41H, dd,
Jˆ9.2, 4.4 Hz), 4.23 42H, m), 2.31±2.24 42H, m), 2.05±
1.60 45H, m), 1.33 43H, t, Jˆ7.2 Hz). 19F NMR
4376.5 MHz, CDCl3) d; 2132.2 41F, dd, Jˆ48.1,
16.0 Hz). EI-MS m/z: 301 4M111). HRMS calcd for
1
C9H14FIO2: 300.0023 4M1), Found: 300.0023. cis-6c-2: H
1
38.23; H, 5.13. Found: C, 38.33; H, 5.13. trans-6e-2: H
NMR 4400 MHz, CDCl3) d; 4.76 41H, dd, Jˆ48.9, 9.7 Hz),
4.66 41H, dd, Jˆ4.2, 4.2 Hz), 2.36 41H, ddd, Jˆ14.6, 8.3,
1.6 Hz), 2.23 4dddd, Jˆ14.3, 9.6, 9.6, 4.2 Hz), 2.15±2.00
41H, m), 1.82±1.60 43H, m), 1.53±1.41 41H, m), 1.32 43H, t,
Jˆ7.2 Hz). 19F NMR 4376.5 MHz, CDCl3) d; 2123.0 41F,
dd, Jˆ48.9, 9.0 Hz). EI-MS m/z: 301 4M111). HRMS calcd
NMR 4400 MHz, CDCl3) d; 5.40 41H, dd, Jˆ48.6,
1.8 Hz), 4.28 42H, q, Jˆ7.2 Hz), 4.21 42H, ddd, Jˆ11.9,
11.9, 4.2 Hz), 2.68±2.59 41H, m), 2.27±2.08 42H, m),
1.91±1.83 41H, m), 1.62±1.23 45H, m), 1.32 43H, t,
Jˆ7.2 Hz). 19F NMR 4376.5 MHz, CDCl3) d; 2144.8 41F,
dd, Jˆ48.6, 3.1 Hz). EI-MS m/z: 315 4M111). HRMS calcd
forC H14FIO2: 300.0023 4M1), Found: 300.0017.
9
forC H3FNO3: 314.0179 4M1), Found: 314.0171. Anal.
3
calcd forC 10H16FIO2: C, 38.23; H, 5.13. Found: C, 38.41;
H, 5.15. cis-6e-1: 1H NMR 4400 MHz, CDCl3) d; 4.70 41H,
dd, Jˆ48.4, 8.3 Hz), 4.58 41H, br.s), 4.35±4.24 42H, m),
2.27±1.25 412H, m). 19F NMR 4376.5 MHz, CDCl3) d;
2133.4 41F, dd, Jˆ48.4, 11.5 Hz). EI-MS m/z: 315
4M111). HRMS calcd forC 9H14FIO2: 314.0179 4M1),
3.1.3. Ethyl 2-¯uoro-2-,4-iodotetrahydrofuran-3-yl)ace-
tate 6d. A mixture of diastereomers obtained from 5d
40.15 ml, 2.0 mmol), ethyl ¯uoroiodoacetate 4120 mg,
0.52 mmol) and triethylborane 40.52 mmol) was separated
by MPLC 4hexane/AcOEtˆ4:1, ¯ow rate 7.0 ml/min) to
give trans-6d-1 429 mg, 19% yield), trans-6d-2 431 mg,
20% yield), cis-6d-1 42.8 mg, 2% yield) and cis-6d-2
1
Found: 314.0168. cis-6e-2: H NMR 4400 MHz, CDCl3)
1
d; 4.90 41H, br.s), 4.60 41H, dd, Jˆ49.0, 9.8 Hz), 4.26
42H, q, Jˆ7.2 Hz), 2.24 4dddd, Jˆ14.1, 5.0, 2.5, 2.5 Hz),
1.83±1.57 44H, m), 1.48±1.23 43H, m), 1.32 43H, t,
Jˆ7.2 Hz), 1.07 41H, dddd, Jˆ19.0, 9.9, 4.0, 2.7 Hz). 19F
NMR 4376.5 MHz, CDCl3) d; 2130.6 41F, dd, Jˆ49.0,
9.9 Hz). EI-MS m/z: 315 4M111). HRMS calcd for
C9H14FIO2: 314.0179 4M1), Found: 314.0168.
43.6 mg, 2% yield) in the order of elution. trans-6d-1: H
NMR 4400 MHz, CDCl3) d; 5.01 41H, dd, Jˆ48.6, 4.3 Hz),
4.29 42H, q, Jˆ7.1 Hz), 4.24 41H, dd, Jˆ8.9, 7.6 Hz), 4.14
41H, dd, Jˆ15.1, 7.6 Hz), 3.96±3.82 43H, m), 2.97 41H,
dddd, Jˆ25.6, 15.1, 7.6, 4.3 Hz), 1.33 43H, t, Jˆ7.1 Hz).
19F NMR 4376.5 MHz, CDCl3) d; 2137.6 41F, dd, Jˆ48.6,
25.6 Hz). EI-MS m/z: 303 4M111). HRMS calcd for
C8H12FO3: 175.0770 4M12I), Found: 175.0768. trans-6d-
1
2: H NMR 4400 MHz, CDCl3) d; 4.87 41H, dd, Jˆ48.3,
3.2. General procedure of cyclopropane formation of
¯uoroiodo ester 6 with LHMDS: cis and trans ethyl 2-,3-
benzoyloxypropyl)-1-¯uorocyclopropane-1-carboxylate
,cis-7a and trans-7a)
4.5 Hz), 4.33 42H, q, Jˆ7.1 Hz), 4.28±4.17 42H, m), 4.06
41H, dd, Jˆ9.2, 8.3 Hz), 3.97 41H, dd, Jˆ9.3, 6.3 Hz), 3.85
4dd, Jˆ9.2, 5.7 Hz), 3.08 4dddd, Jˆ23.0, 10.1, 8.3, 4.5 Hz),
1.35 43H, t, Jˆ7.1 Hz). 19F NMR 4376.5 MHz, CDCl3) d;
2135.6 41F, dd, Jˆ48.3, 23.0 Hz). EI-MS m/z: 303
Under an argon atmosphere, to a solution of the ¯uoroiodo
ester 6a 4isomerartio 1.7:1, 100 mg, 0.24 mmol) in THF
42.5 ml) was added LHMDS 40.48 M THF-hexane solution,
1.6 ml, 0.76 mmol) prepared from n-BuLi and hexamethyl-
disilazane at 2788C. After being stirred for 3 h at the same
temperature, the reaction mixture was quenched by the addi-
tion of 1N HCl and extracted with ether. The organic layer
was washed with brine, dried over MgSO4, then concen-
trated under reduced pressure. The residue was chromato-
graphed on silica gel 4hexane/AcOEtˆ10:1) to give 7a as a
diastereomeric mixture. The mixture was separated by
4M111). HRMS calcd forC H12FO3: 175.0770 4M12I),
8
1
Found: 175.0766. cis-6d-1: H NMR 4400 MHz, CDCl3)
d; 5.12 41H, dd, Jˆ47.7, 6.4 Hz), 4.41 42H, dd, Jˆ11.2,
5.2 Hz), 4.36±4.26 43H, m), 4.14 41H, ddd, Jˆ9.6, 5.2,
2.8 Hz), 4.06 41H, dd, Jˆ8.4, 7.8 Hz), 3.97 4dd, Jˆ8.4,
7.8 Hz), 2.46 4ddddd, Jˆ19.4, 9.6, 7.8, 7.8, 6.4 Hz), 1.33
43H, t, Jˆ7.2 Hz). 19F NMR 4376.5 MHz, CDCl3) d;
2133.9 41F, dd, Jˆ47.7, 19.4 Hz). EI-MS m/z: 302 4M1).
HRMS calcd forC 8H12FO3: 175.0770 4M12I), Found:
1
175.0773. cis-6d-2: H NMR 4400 MHz, CDCl3) d; 4.91

7492
A. Saito et al. / Tetrahedron 57 ,2001) 7487±7493
MPLC 4hexane/AcOEtˆ6:1, ¯ow rate 7.0 ml/min) to give
trans-7a 48.5 mg, 12% yield) and cis-7a 448 mg, 69%
yield), respectively. trans-7a: H NMR 4400 MHz, CDCl3)
zane at 2788C. After being stirred for 2 h at 08C, the reac-
tion mixture was quenched by the addition of 1N HCl and
extracted with ether. The organic layer was washed with
brine, dried over MgSO4, then concentrated under reduced
pressure. 1H NMR spectrum of the residue using MeOH as
an internal reference consisted of 8c 445% yield) and the
recovery of cis-6c-2 45% yield). Puri®cation by chromato-
graphy 4SiO2, pentane/etherˆ50:1) gave 8c as a colorless
oil. In a similarmanne,r cis-6c-1 484 mg, 0.28 mmol)
provided 8c 420% yield) along with the recovery of cis-
1
d; 8.05±8.02 42H, m), 7.57±7.52 41H, m), 7.45±7.40 42H,
m), 4.34 42H, t, Jˆ6.4 Hz), 4.27 42H, q, Jˆ7.1 Hz), 1.87±
1.68 45H, m),1.57±1.46 42H, m), 1.38±1.25 41H, m), 1.31
43H, t, Jˆ7.1 Hz). 19F NMR 4376.5 MHz, CDCl3) d;
2124.2 41F, ddd, Jˆ20.0, 20.0, 9.0 Hz). EI-MS m/z: 295
4M111). Anal. calcd forC 16H19FO4: C, 65.29; H, 6.51.
Found: C, 65.16; H, 6.45. cis-7a: 1H NMR 4400 MHz,
CDCl3) d; 8.03±8.00 42H, m), 7.55±7.50 41H, m), 7.44±
7.39 42H, m), 4.35 42H, t, Jˆ6.4 Hz), 4.22 42H, q,
Jˆ7.1 Hz), 1.92 42H, tt, Jˆ6.8, 6.4 Hz), 1.79±1.58 41H,
m), 1.51 41H, ddd, Jˆ9.8, 8.5, 6.2 Hz), 1.05 41H, ddd,
Jˆ18.7, 7.7, 6.2 Hz), 1.31 43H, t, Jˆ7.1 Hz). 19F NMR
4376.5 MHz, CDCl3) d; 2148.5 41F, dd, Jˆ18.7, 8.5 Hz).
EI-MS m/z: 295 4M111). Anal. calcd forC 16H19FO4: C,
65.29; H, 6.51. Found: C, 65.43; H, 6.47.
1
6c-1 468% yield). H NMR 4400 MHz, CDCl3) d; 5.91
41H, br.s), 5.39 41H, d, Jˆ48.5 Hz), 4.25 42H, q,
Jˆ7.1 Hz), 2.49±2.25 44H, m), 1.97±1.85 42H, m), 1.29
43H, t, Jˆ7.1 Hz). 19F NMR 4376.5 MHz, CDCl3) d;
2120.8 41F, d, Jˆ48.5 Hz). EI-MS m/z: 172 4M1).
3.2.5. Ethyl 3-benzyloxy-6-¯uoro-bicyclo[3.1.0]hexane-
6-carboxylate 7f. Under an argon atmosphere, to a mixture
of 5f 4360 mg, 2.1 mmol) and ethyl ¯uoroiodoacetate
4120 mg, 0.52 mmol) in dichloromethane 42 ml) was
added triethylborane 41 M hexane solution, 0.53 ml) at
room temperature. Then, to the mixture was injected air
45 ml). After being stirred for 2 h at the same temperature,
the reaction mixture was quenched by the addition of water
and extracted with ether. The organic layer was washed with
brine, dried over MgSO4, then concentrated under reduced
pressure. The residue was chromatographed on silica gel
4hexane/etherˆ10:1) to give 6f 4160 mg, 76% yield, a dia-
stereomeric mixture) as colorless oil. Under an argon atmos-
phere, to a solution of the ¯uoroiodo ester 6f 4110 mg,
0.27 mmol) in THF 43 ml) was added LHMDS 40.48 M
THF±hexane solution, 2.9 ml, 1.4 mmol) prepared from n-
BuLi and hexamethyldisilazane at 2788C. Afterbeing stir-
red for 2 h at the same temperature, the reaction mixture was
quenched by the addition of 1N HCl and extracted with
ether. The organic layer was washed with brine, dried
3.2.1. Ethyl 2-,1-tert-butyldiphenylsiloxymethyl)-1-¯uoro-
cyclopropane-1-carboxylate 7b. Similarly, reaction of 6b
4130 mg, 0.25 mmol) with LHMDS 41.2 mmol) gave 7b as a
diastreomeric mixture, which was separated by MPLC 4hex-
ane/AcOEtˆ14:1, ¯ow rate 7.0 ml/min) to give trans-7b
49.4 mg, 10% yield) and cis-7b 489 mg, 90% yield), respec-
tively. trans-7b: 1H NMR 4400 MHz, CDCl3) d; 7.67±7.62
44H, m), 7.43±7.36 46H, m), 4.25 42H, q, Jˆ7.2 Hz), 3.87
41H, dd, Jˆ11.3, 6.4 Hz), 3.66 41H, dd, Jˆ11.3, 8.9 Hz),
1.99 41H, ddddd, Jˆ17.8, 11.1, 10.9, 8.9, 6.4 Hz), 1.48 41H,
ddd, Jˆ17.3, 10.9, 6.4 Hz), 1.35±1.26 41H, m), 1.29 43H, t,
Jˆ7.2 Hz), 1.03 49H, s). 19F NMR 4376.5 MHz, CDCl3) d;
2125.5 41F, ddd, Jˆ17.8, 17.3, 8.7 Hz). EI-MS m/z: 401
4M111). Anal. calcd forC 23H29FO3Si: C, 68.97; H, 7.30.
1
Found: C, 68.97; H, 7.29. cis-7b: H NMR 4400 MHz,
CDCl3) d; 7.71±7.67 44H, m), 7.46±7.36 46H, m), 4.28
42H, q, Jˆ7.1 Hz), 3.91 41H, dd, Jˆ11.2, 5.7 Hz), 3.76
41H, dd, Jˆ11.2, 8.0 Hz), 1.93 41H, dddd, Jˆ10.5, 8.2,
8.1, 5.7 Hz), 1.48 41H, ddd, Jˆ10.5, 8.7, 6.4 Hz), 1.14
41H, ddd, Jˆ19.1, 8.2, 6.4 Hz), 1.32 43H, t, Jˆ7.1 Hz),
1.06 49H, s). 19F NMR 4376.5 MHz, CDCl3) d; 2147.9
41F, dd, Jˆ19.1, 8.7 Hz). EI-MS m/z: 401 4M111).
HRMS calcd forC 19H20FO3Si: 343.1166 4M12C4H9),
Found: 343.1184.
overMgSO , then concentrated under reduced pressure.
4
The residue was chromatographed on silica gel 4hexane/
AcOEtˆ10:1) to give 7f as a diastreomeric mixture. Further
puri®cation by MPLC 4hexane/AcOEtˆ6:1, ¯ow rate
7.0 ml/min) gave 7f-1 423 mg, 30% yield) and 7f-2
1
434 mg, 45% yield), respectively. 7f-1: colorless oil. H
NMR 4400 MHz, CDCl3) d; 7.34±7.26 45H, m), 4.45 42H,
s), 4.23 42H, q, Jˆ7.1 Hz), 4.04±3.96 41H, m), 2.33 42H, dd,
Jˆ13.5, 7.1 Hz), 2.20±2.08 44H, m), 1.30 43H, t, Jˆ7.1 Hz).
19F NMR 4376.5 MHz, CDCl3) d; 2153.9 41F, s). EI-MS
m/z: 279 4M111). HRMS calcd forC 16H20FO3: 279.1396
3.2.2. Ethyl 6-¯uoro-bicyclo[3.1.0]hexane-6-carboxylate
7c. Colorless oil. 79% yield. H NMR 4400 MHz, CDCl3)
1
d; 4.23 42H, q, Jˆ7.2 Hz), 2.15±1.95 45H, m), 1.81±1.59
43H, m), 1.30 43H, t, Jˆ7.2 Hz). 19F NMR 4376.5 MHz,
CDCl3) d; 2157.0 41F, s). EI-MS m/z: 172 4M1). HRMS
calcd forC 9H13FO2: 172.0900 4M12C4H9), Found:
172.0902.
1
4M111), Found: 279.1394. 7f-2: colorless oil. H NMR
4400 MHz, CDCl3) d; 7.34±7.26 45H, m), 4.46 42H, s),
4.36 41H, ddd, Jˆ16.5, 8.3, 8.3 Hz), 4.25 42H, q,
Jˆ7.1 Hz), 2.53±2.31 42H, m), 2.03±1.93 42H, m), 1.77
42H, dd, Jˆ14.0, 8.3 Hz), 1.31 43H, t, Jˆ7.1 Hz). 19F
NMR 4376.5 MHz, CDCl3) d; 2153.7 41F, s). EI-MS m/z:
279 4M111). HRMS calcd forC 16H19FO3: 278.1318 4M1),
Found: 278.1332.
3.2.3. Ethyl 6-¯uoro-3-oxabicyclo[3.1.0]hexane-6-car-
boxylate 7d and ethyl 7-¯uoro-bicyclo[4.1.0]heptane-7-
carboxylate 7e. 1H and 19F NMR spectra of these
compounds were identical with those reported by Seyferth
et al.5a
3.2.4. Ethyl cyclopent-1-yl-¯uoroacetate 8c. Underan
argon atmosphere, to a solution of the ¯uoroiodo ester cis-
6c-2 4334 mg, 1.11 mmol) in THF 420 ml) was added
LHMDS 40.48 M THF-hexane solution, 9.3 ml,
4.46 mmol) prepared from n-BuLi and hexamethyldisila-
Acknowledgements
The authors are grateful to Dr Atsuro Nakazato, Taisho
1
Pharmaceutical Co. for providing H and 19F NMR spectra
of compound F-endo-4 and F-exo-4.

A. Saito et al. / Tetrahedron 57 ,2001) 7487±7493
7493
6. Morikawa, T.; Sasaki, H.; Mori, K.; Shiro, M.; Taguchi, T.
Chem. Pharm. Bull. 1992, 40, 3189.
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