Synthesis of optically active gem-difluorocyclopropanes through a chemo-enzymatic reaction strategy

Article abstract of DOI:10.1016/j.jfluchem.2004.01.010

The synthesis of a chiral difluorocyclopropane building block has been accomplished using lipase-catalyzed reaction; the prochiral diacetate of cis -1,3-bishydroxymethyl-2,2-difluorocyclopropane was converted to the corresponding chiral monoacetate by the Alcaligenes lipase (lipase QL)-catalyzed hydrolysis with >99% enantiomeric excess. Enantiomerically pure trans-1,3-bishydroxymethyl-2,2-difluorocyclopropane was also obtained through the Pseudomonas cepacia SL-25 lipase (lipase SL)-catalyzed reaction. The synthesis of the chiral trans, trans -bis- gem -difluorocyclopropane derivatives has been accomplished using the same lipase technology; trans, trans-1,6-bishydroxymethyl-2,2,5,5-tetrafluorobicyclopropane was obtained in optically active form using the lipase SL-catalyzed hydrolysis of the corresponding diacetate.

Full text of DOI:10.1016/j.jfluchem.2004.01.010

Journal of Fluorine Chemistry 125 (2004) 775–783
Synthesis of optically active gem-difluorocyclopropanes
through a chemo-enzymatic reaction strategy
Toshiyuki Itoha,*, Nanae Ishidab, Koichi Mitsukurab,1,
Shuichi Hayasea, Kazumasa Ohashia
aDepartment of Materials Science, Faculty of Engineering, Tottori University, Tottori 680-8552, Japan
bDepartment of Science Education, Graduate School of Okayama University,
Okayama 700-8530, Japan
Received 3 October 2003; received in revised form 7 January 2004; accepted 9 January 2004
Available online 6 March 2004
Abstract
The synthesis of a chiral difluorocyclopropane building block has been accomplished using lipase-catalyzed reaction; the prochiral
diacetate of cis-1,3-bishydroxymethyl-2,2-difluorocyclopropane was converted to the corresponding chiral monoacetate by the Alcaligenes
lipase (lipase QL)-catalyzed hydrolysis with >99% enantiomeric excess. Enantiomerically pure trans-1,3-bishydroxymethyl-2,2-difluor-
ocyclopropane was also obtained through the Pseudomonas cepacia SL-25 lipase (lipase SL)-catalyzed reaction. The synthesis of the chiral
trans,trans-bis-gem-difluorocyclopropane derivatives has been accomplished using the same lipase technology; trans,trans-1,6-bishydrox-
ymethyl-2,2,5,5-tetrafluorobicyclopropane was obtained in optically active form using the lipase SL-catalyzed hydrolysis of the corresponding
diacetate.
# 2004 Elsevier B.V. All rights reserved.
Keywords: gem-Difluorocyclopropane; Lipase-catalyzed reaction; Asymmetric synthesis
1. Introduction
undertook this project. The first is the diastereoselective
Michael addition of the enolate, and subsequent oxidative
cyclopropanation gave this compound with high diastereos-
electivity [7]. The second is the addition of difluorocarbene to
an olefin and HPLC separation of these two diastereo isomers
[8a]. These two methods are excellent but are difficult to
apply for large-scale preparation, so we developed a synthetic
methodology for preparing optically pure gem-difluorocy-
clopropanes [9,10]. We accomplished the synthesis of trans-
1,3-bishydroxymethyl-2,2-difluorocyclopropane (1), cis-(3-
hydroxymethyl-2,2-difluorocyclopropyl)methyl acetate (2)
and trans,trans-1,6-bishydroxymethyl-2,2,5,5-tetrafluorobi-
cyclopropane (3) and used as the core molecules for synthe-
sizing novel gem-difluorocyclopropane derivatives such as
the aminomethyl-substituted cyclopropane 4,2 oligo-gem-
difluorocyclopropanes 5 and 6 [9c,e], and diester 7 which
showed a liquid crystal property [10] (Fig. 1). We describe
here the full details of the synthesis of the optically pure
mono- and bis-gem-difluorocyclopropanes using lipase-tech-
nology [9–12].
The utility of cyclopropane derivatives in the construction
of a variety of cyclic and acyclic organic compounds has
been amply demonstrated [1]. The substitution of two
fluorine atoms on the cyclopropane ring is expected to alter
both its chemical reactivity and biological activity due to the
strong electron-withdrawing nature of the fluorine, and this
makes it possible to create new molecules that exhibit
unique biological activities or functionalities [2–4]. To
the best of our knowledge, the first synthesis of gem-difluor-
ocyclopropane was reported by Sargeant in 1970 [5] and
great attention has been paid to the chemistry of this unique
material of gem-difluorocyclopropanes [4,6–9]. The first
synthesis of an optically active gem-difluorocyclopropane
was reported by Taguchi et al. in 1994 [7] and only two
methods were reported for the synthesis of chiral difluoro-
cyclopropanes, both from the Taguchi group [7,8] when we
* Corresponding author. Tel.: þ81-85-731-5259; fax: þ81-82-731-5259.
E-mail address: titoh@chem.tottori-u.ac.jp (T. Itoh).
1 Present address: Department of Applied Chemistry, Faculty of
2 This compound has a potent DNA cleavage activity by photo
irradiation and paper is now on preparation.
Engineering, Gifu University, Gifu, Japan.
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.01.010

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T. Itoh et al. / Journal of Fluorine Chemistry 125 (2004) 775–783
Fig. 1. Core molecules for synthesizing various gem-difluorocyclopropane
derivatives.
Fig. 2. Determination of the stereochemistry of monacetate cis-2 obtained
by the lipase QL-catalyzed hydrolysis of prochiral diacetate cis-8.
Dd ¼ ðdS À dRÞ Â 103 ppm for (R)- and (S)-MTPA ester 9 (500 MHz,
1H NMR analysis). The optimized structure by semi-empirical (PM3)
calculation of (S)-MTPA ester 9 derived from (1R,2S)-cis-2.
2. Results and discussion
We employed the lipase-catalyzed reaction protocol as the
key process of our asymmetric synthesis for chiral difluor-
ocyclopropanes [9]. The asymmetric hydrolysis of the dia-
cetate cis-8 was carried out in a phosphate buffer solution
(0.1 M at pH 7.2) using acetone as co-solvent (Table 1). The
mixture of cis-8 and lipase QL (50 wt.% towards the sub-
strate) was stirred at 35 8C and the partly hydrolyzed alcohol
cis-2 was extracted with ethyl acetate and purified by silica
gel flash column chromatography. Twenty-eight commer-
cially available lipases were screened for their activity and
nine were found to have hydrolyzed diacetate cis-8 to afford
the monoacetate cis-2 with more than 60% ee; lipase QL
(Meito Sangyo Co. Ltd.) from Alcaligenes sp. provided the
corresponding monoacetate cis-2 in the highest enantiomeric
excess (Table 1, entry 5). Lipase PS, SL, and TL also gave
cis-2 with good enantiomeric excess with the same enantio-
favoritism of the lipase QL (Table 1, entries 1–3 and 5). The
absolute configuration was determined by the modified
Mosher method proposed by Kusumi and Ohtani [13]. Since
two protons on the cyclopropane ring of the MTPA ester
9 showed negative Dd values, and protons on the armed
methylene groups of 9 showed positive Dd values, we
tentatively assigned the stereochemistry of this compound
to be (S,R) based on the desirable conformer of 9 which was
suggested by a semi-empirical calculation [14] (Fig. 2),3
though no example has yet been reported of the Kusumi–
Ohtani method being applicable to this type of compound.
Table 1
Results of lipase-catalyzed enantioselective hydrolysis of prochiral
diacetate
Entry
Lipasea
Time
(h)
Yield of
cis-2 (%)b
% ee of
cis-2b
[a]D of
cis-2 (%)c
1
2
3
4
5
6
7
8
9
PS
8
4
97
62
58
71
81
49
45
83
53
85
97
þ12.5
þ16.0
þ15.4
þ12.5
þ15.5
þ4.2
SL
TL
6
90
AL
48
5
85
QL
>99
12
CRL
CAL
PLE
PPL
1
168
168
168
56
þ8.4
15
þ2.0
62
þ6.0
(1)
a PS: P. cepacia (Amano Enzyme Co. Ltd.); SL: P. cepacia SL-25
(Meito Sangyo Co. Ltd.); TL: P. cepacia sp.; AL: Acromobacter sp. lipase
(Meito Sangyo Co. Ltd.); QL: Alcaligenes sp.; CRL; Candida rugosa
(Meito Sangyo Co. Ltd.: Lipase OF); CAL: Candida antarctica; PLE: pig
liver esterase (Amano Enzyme Co. Ltd.); PPL: porcine liver lipase (Sigma
Type II).
The diacetate of trans-8 is not a prochiral but a racemic
form, so that optical resolution of (Æ)-trans-8 was per-
formed using the lipase-catalyzed reaction (Eq. (2)). The
enzymatic reactions were tentatively evaluated by the ‘‘EÃ
value’’ which was calculated by the results of enantiomeric
excesses of the monoacetate (þ)-2 and unreacted (À)-8
b Isolated yield. The reaction was carried out in 0.1 M potassium
phosphate buffer at pH 7.2, and the enantiomeric excess was determined
by capillary GC analysis using Chiraldex G-TA (f 0:25 mm  20 m; He;
70 or 100 8C).
c c ¼ ca: 1.0 in CHCl3.
3 MasSpartan Pro was employed for the semi-empirical calculation.

T. Itoh et al. / Journal of Fluorine Chemistry 125 (2004) 775–783
777
Table 2
Results of lipase-catalyzed enantioselective hydrolysis of diacetate (Æ)-trans-8
Entry
Lipasea
Time
Yield of 2 (% ee)b
Yield of 8 (% ee)b
[a]D of 8c
Conversion
EÃ valued
1
2
3
4
5
6
PCL
CAL
PPL
QL
20 min
20 min
3.5 h
10 min
1 h
74 (13)
55 (3)
14 (76)
7 (40)
À7.2
À4.2
0.85
0.93
0.82
0.80
0.67
0.63
2
1
72 (17)
51 (22)
53 (48)
59 (55)
10 (80)
11 (90)
36 (>99)
34 (92)
À8.0
3
À8.6
4
SL
SLe
À13.6
À10.0
>11
11
3 h
a The reaction was carried out in 0.1 M potassium phosphate buffer at pH 7.2.
b Isolated yield. The enantiomeric excess was determined by capillary GC analysis using Chiraldex G-TA (f 0:25 mm  20 m; He; 70 8C or 100 8C).
c c ¼ ca: 1.0 in CHCl3.
d Eà ¼ ln½ð1 À cÞð1 þ ee2Þꢀ=ln½ð1 À cÞð1 À ee2Þꢀ, where c means conversion which was calculated by the following formula: c ¼ ee8=ðee2 þ ee8Þ.
e The reaction was carried out at 0 8C.
according to the same method of the ‘‘E value’’ [15],
although it was the combined results of two enantioselective
enzymatic reactions such as initial hydrolysis of (Æ)-8 and
subsequent hydrolysis of the corresponding monoacetate 2.
In this reaction, the best result was recorded when (Æ)-trans-
8 was reacted with lipase SL (Pseudomonas cepacia SL-25,
Meito Sangyo Co. Ltd.), and the diacetate (À)-trans-8
remaining was obtained with >99% ee (‘‘E value’’ of the
reaction was estimated as >11) (Table 2, entry 5) [9a]. The
second result was obtained and 90% ee of (À)-8 was
obtained when the lipase QL-catalyzed reaction was stopped
for 10 min (Table 2, entry 4). We conducted the hydrolysis
reaction at 0 8C catalyzed by lipase SL, but no improvement
in the enantioselectivity was accomplished (Table 2, entry
6). Lipases QL and SL hydrolyzed the diacetate with the
same enantio-favoritism due to the comparison of the spe-
cific rotations of the produced monoacetate and remaining
diacetate (Table 2, entries 2 and 4). The CD spectrum of
79% ee of the bis-9-anthracenecarboxylic ester (À)-9 [16]
which was converted from 79% ee of (À)-trans-8 exhibited a
negative chirality on the Cotton effect (250.2 and 255.2 nm
(De 0.85), CH3CN:H2O ¼ 1:1), while (þ)-9 which was
converted from 85% ee of (þ)-trans-2 showed a positive
chirality on the Cotton effect (252.8 and 254.8 nm (De 2.9),
CH3CN:H2O ¼ 1:1) (Fig. 3). The stereochemistry of (À)-8
and (þ)-9 was thus determined as (R,R) for (À)-9 and (S,S)
for (þ)-9 based on the CD exciton chirality rule [16,17].
when we undertook this project. (E,E)-Hexa-1,3-diyne-1,6-
diol, which was prepared from propargyl alcohol by a homo-
coupling reaction using copper nitrate [18], was converted to
the diene (E,E)-hexa-1,3-diene-1,6-diol by lithium aluminum
hydride (LAH) reduction and subsequent protection of the
hydroxyl groups as benzyl ethers. This dibenzyl ether is
treated with difluorocarbene [19,20] and allowed to achieve
the one pot preparation of trans,trans-1,6-bisbenzyloxy-
methyl-2,2,5,5-tetrafluorobicyclopropane (11); deprotection
and acetylation gave the diacetate trans,trans-12 in good
overall yield [9b]. The synthesis of trans,trans-tetrafluoro-
bicyclopropane was thus accomplished and both the diol
trans,trans-3 and diacetate trans,trans-12 were found to be
very stable compounds. On the contrary, cis,cis-3 and 12
were very unstable compounds; we attempted to prepare
cis,cis-12 through the same route using the (Z,Z)-hexa-1,3-
diene-1,6-diol as the starting compound, however, only poor
results were obtained from the preparation of cic,cis-tetra-
fluorobicyclopropane. In addition, cis,cis-12, which is a
(2)
The chiral trans,trans-1,6-bishydroxylmethyl-2,2,5,5-tet-
rafluorobicyclopropane (3) is a challenging target for syn-
thetic organic chemists because the computational chemistry
suggested a kinked form of two gem-difluorocyclopropane
groups for 3 [9c] (see footnote 3), however, no example of the
synthesis of even the racemic form of 3 has been reported
Fig. 3. Determination of the absolute configuration of (þ)-2 and (À)-8 by
CD spectrum analysis.

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T. Itoh et al. / Journal of Fluorine Chemistry 125 (2004) 775–783
mixture of the prochiral and dl forms, was easily decomposed
during the lipase-catalyzed reaction to form unidentified
products by opening the cyclopropane rings. Because the
unstable nature of the cis-types of the gem-difluorocyclopro-
pane was recently reported [20], we focused our effort on
synthesizing the optically active trans,trans-3.
The optical resolution of the diacetate, trans,trans-12,
which is a mixture of the dl and meso forms (1:1), was very
successfully achieved by the lipase SL-catalyzed reaction.
The lipase SL-catalyzed hydrolysis of the diacetate trans,-
trans-8 gave the meso monoacetate trans,trans-13 in 50%
yield, which corresponded to a perfect chemical yield, the
diol (þ)-trans,trans-3 in 17% yield with 91% ee, and the
unreacted diacetate (À)-trans,trans-12 was obtained in 14%
yield with over 99% ee. Although the synthesis of the
optically active bis-difluorocyclopropane was thus simply
accomplished, the enantiomeric excess of (þ)-3 was insuf-
ficient. Fortunately, we found that the dibenzyl ether of
meso-11 was preferentially crystallized from hexane; the dl-
rich 11 (dl:meso ¼ 7:3) was thus obtained in 68% yield by
removing the meso-isomer by a single recrystallization from
hexane and this mixture was converted to the corresponding
dl-rich diacetate 12. The lipase SL-catalyzed hydrolysis of
the dl-rich diacetate 12 (dl:meso ¼ 7:3) gave the diol
(S,R,R,S)-(þ)-3 in 30% yield with 99% ee, and the unreacted
diacetate (R,S,S,R)-(À)-12 in 24% yield with >99% ee. The
meso-isomer was obtained as the monoacetate 13 in 30%
yield. We thus succeeded in preparing both enantiomers of
(þ)-3 and (À)-3 with sufficient optical purity (Scheme 1).
The stereochemistry of the diol (þ)-trans,trans-3 was
assigned as (1S,3S,4R,6S), and the diacetate (À)-trans,-
trans-12 was (1R,3S,4S,6R), based on the CD exciton chir-
ality method using the CD spectral results of bis-9-
anthracenecarboxylate (12). The CD spectrum of the ester
14, which was derived from (þ)-3, exhibited a positive
chirality on the large Cotton effect (387.2 and 364.0 nm
(De 1.20), CH3CN), while a negative chirality on the
Cotton effect was observed by the ester 14 derived from
(À)-8 (387.4 and 366.6 nm (De 3.05), CH3CN) (Fig. 4).
Fig. 4. Determination of the stereochemistry of the lipase-catalyzed
reaction of bis-difluorocyclopropane by CD spectra.
These observed Cotton effects corresponded to the E2
absorption of the anthracene group (E2 lmax 375 nm
(e ¼ 28,756) [16]. Computer chemistry suggested that there
was a kinked form of two gem-difluorocyclopropane groups
for this compound (see footnote 3). This was confirmed by
these CD spectra on the large Cotton effect. An X-ray
crystallographic analysis of the dibenzyl ether, which was
derived from the monoacetate 13, was successful and the
stereochemistry of the monoacetate 13 was confirmed as the
meso form [9b].4
The enantio-favoritism of lipase SL against difluorocy-
clopropanes is summarized in Fig. 5. (þ)-trans-1 and (þ)-
trans,trans-3 are favorable isomers, hence, both acetyl
groups are hydrolyzed while (À)-trans-8 and (À)-trans,-
trans-12 are so unfavorable for the enzyme that neither
acetyl groups is hydrolyzed. The difluorocyclopropane
cis-2 was obtained as the optically active form and the meso
form of trans,trans-bicyclopropane was obtained as the
monoacetate trans,trans-13 because one of the acetyl groups
of these compounds had a favorable configuration while the
other was unfavorable to the enzyme. These results con-
cerning the enantio-favoritism for lipase SL were so clear
that we have now confidence in the results of the absolute
configuration of cis-2, though we initially felt a slight
ambiguity towards the absolute configuration assignment
F
F
F
F
OAc
H
H
AcO
F
H
F
H
H
H
H
AcO
H
OAc
F
F
(meso)-12
(dl)-12
dl-rich-diacetate 12 (dl: meso=7:3)
Lipase SL, pH 7.2, 35 ˚C 4 h
F
F
F F
F
F
H
OAc
H
OAc
HO
H
F
F
F
F
H
H
H
H
H
H
H
HO
H
AcO
H
OH
F
F
4 The authors have already deposited coordinates for structure meso-11
with the Cambridge Data Centre. The coordinate can be obtained, on
request, from the Director, Cambridge Crystallographic Data Centre,
12 Union Road, Cambridge CB2 1EZ, UK.
(meso)-13
(S,R,R,S)-(+)-3
(R,S,S,R)-(-)-12
Y= 30%
Y= 30% (99% ee) Y= 24% (>99% ee)
Scheme 1.

T. Itoh et al. / Journal of Fluorine Chemistry 125 (2004) 775–783
779
silane (TMS) in CDCl3 as the internal reference. The 19F
NMR spectra were reported in ppm downfield from C6F6 as
the internal reference.
F
F
F
H
S
F
HO
F
F
HO
H
S
H
S
H
H
R
R
OH
S
H
OH
4.1. cis-3-Acetoxymethyl-2,2-difluorocyclopropylmethyl
acetate (8)
(+)-(trans)-1
(+)-(trans,trans)-3
favorable isomer
To a dry diglyme (40 ml) solution of (Z)-1,4-bisbenzy-
loxy-2-butene (10.7 g, 40 mmol) was dropwise added a
diglyme (80 ml) solution of sodium chlorodifluoroacetate
(30.5 g, 200 mmol) at 180 8C over 5 h with vigorous stirring.
After being kept at 180 8C for an additional 1 h, the reaction
mixture was allowed to cool to room temperature, then the
mixture was poured into ice water and extracted with hexane
and ethyl acetate. The combined organic layers were washed
with water, dried over MgSO4 and evaporated under reduced
pressure. Silica gel flash column chromatography (hexane/
ethyl acetate ¼ 20:1–10:1) gave 1,3-bisbenzyloxymethyl-
2,2-difluorocyclopropane (cis-15) (12.0 g, 37.7 mmol) in
94% yield. A methanol (20 ml) solution of cis-15 (6.02 g,
18.9 mmol) was added to palladium carbon (1.20 g,
20 wt.%) under H2 (1 atm) and the mixture was stirred at
room temperature for 24 h then filtered through a glass-
sintered filter on celite. cis-1,3-Bishydroxymethyl-2,2-
difluorocyclopropane (cis-1) was obtained in quantitative
yield as a colorless oil. To a dichloromethane (CH2Cl2)
(30 ml) solution of diol cis-1 was added pyridine (4.6 ml,
56.9 mmol) and a CH2Cl2 (10 ml) solution of acetyl chloride
(3.27 g 41.7 mmol) at 0 8C and the mixture was stirred at
room temperature for 3 h. The reaction was quenched by the
addition of crushed ice, then extracted with ethyl acetate,
dried over MgSO4 and evaporated. Silica gel flash column
chromatography (hexane/ethyl acetate ¼ 10:1) gave cis-8
(3.62 g, 16.3 mmol) in 86% yield; Rf 0.50 (hexane/ethyl
F
F
H
HO
F
F
R
SH
S
H
H
OAc
HO
R OAc
S
R
H
H
F
F
(cis)-2
(meso)-13
F
F
F
F
OAc
F
OAc
H
F
H
R
R
R
H
H
R
S
H
S
H
AcO
AcO
(-)-(trans,trans)-12
(-)-(trans)-8
unfavorable isomer
Fig. 5. Results of the enantio-favoritism of lipase SL against difluor-
ocyclopropane derivatives.
for this compound because there had been no example of
application of the Kusumi-Ohtani method to our type of
compound.
3. Conclusions
The synthesis of three types of bis-hydroxymethyl-gem-
difluorocyclopropane derivatives has been demonstrated
through a chemo-enzymatic reaction methodology. We
are now able to prepare chiral gem-difluorocyclopropanes
on a multi-gram scale. Results of the CD spectroscopic
analysis showed that tetrafluorobicyclopropane, trans,-
trans-3, exists with a helical shape configuration; this seems
to suggest that a unique helical-shaped polymeric compound
may be produced from trans,trans-3 as a monomer unit. We
are hopeful of synthesizing various types of gem-difluor-
ocyclopropanes such as amino acids, carboxylic acids,
polymeric compounds and hybrid types of difluorocyclo-
propanes using our compounds as building blocks.
1
acetate ¼ 2:1); bp 122 8C at 5 Torr (Kugelrohr); H NMR
(200 MHz, d, CDCl3, J in Hz): 2.03–2.18 (2H, m), 2.06 (6H,
s), 4.17–4.38 (4H, m); 13C NMR (50 MHz, d, CDCl3, J in
Hz): 20.68, 24.01 (t, JCÀF ¼ 10:7), 57.80 (d, JCÀF ¼ 5:9),
113.22 (dd, JCÀF ¼ 290:2, 282.7), 170.60; 19F NMR
(188 MHz, d, CDCl3, J in Hz): 10.32 (d, JFÀF ¼ 164:8),
36.29 (dt, JFÀF ¼ 165:1, JHÀF ¼ 12:1); IR (neat, cmÀ1):
2968, 1743, 1479, 1377, 1234, 1118, 1038, 837. Anal. calcd.
for C9H12F2O4: C, 48.65; H, 5.44. Found: C, 48.77; H, 5.72.
Using the same procedure, trans-8 was prepared from (E)-
1,4-bisbenzyloxy-2-butene [9d].
4. Experimental
4.1.1. cis-1,3-Bisbenzyloxymethyl-2,2-
difluorocyclopropane (15)
Reagents and solvents were purchased from common
commercial sources and were used as received or purified
by distillation from appropriate drying agents. Reactions
requiring anhydrous conditions were run under an atmo-
sphere of dry argon. Wako gel C-300 and Wako gel B5F
were used for the flash column chromatography and thin-
layer chromatography (TLC), respectively. Chemical shifts
are expressed in d value (ppm) downfield from tetramethyl-
Rf 0.36 (hexane/ethyl acetate ¼ 10:1); bp 175 8C at
1
2 Torr (Kugelrohr); H NMR (200 MHz, d, CDCl3, J in
Hz): 1.95–2.06 (2H, m), 3.50–3.69 (4H, m), 4.49 (4H, ABq,
J ¼ 11:8), 7.23–7.35 (10H, m); 13C NMR (50 MHz, d,
CDCl3, J in Hz): 24.84 (t, JCÀF ¼ 10:5), 63.07 (d,
JCÀF ¼ 5:1), 72.73, 114.18 (dd, JCÀF ¼ 289:7, 282.8),
127.71, 127.77, 128.43, 137.76; 19F NMR (188 MHz, d,
CDCl3, J in Hz): 11.03 (d, JFÀF ¼ 161:8), 36.57 (dt,

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T. Itoh et al. / Journal of Fluorine Chemistry 125 (2004) 775–783
JFÀF ¼ 161:8, JHÀF ¼ 12:9); IR (neat, cmÀ1): 3032, 2866,
1469, 1367, 1282, 1192, 1086, 1028, 912, 849, 742, 700.
Anal. calcd. for C19H20F2O2: C, 71.68; H, 6.33. Found: C,
73.63; H, 6.45.
(2.22 g, 9.99 mmol). After being stirred for 4 h at room
temperature, the reaction was quenched by addition of
crushed ice and NaCl powder and immediately extracted
with ethyl acetate. The organic layer was dried over MgSO4,
evaporated, and silica gel flash column chromatography
(hexane/ethyl acetate ¼ 4:1–2:1) gave monoacetate cis-2
(1.66 g, 9.21 mmol) in 81% yield.
4.1.2. (Æ)-trans-15
Rf 0.33 (hexane/ethyl acetate ¼ 10:1); bp 160 8C at
2 Torr (Kugelrohr); 1H NMR (200 MHz, d, CDCl3, J in
Hz): 1.66–1.80 (2H, m), 3.45–3.70 (4H, m), 4.53 (4H, ABq,
J ¼ 11:9), 7.20–7.40 (10H, m); 13C NMR (50 MHz, d,
CDCl3, J in Hz): 26.45 (t, JCÀF ¼ 10:5), 65.93, 72.45,
114.78 (t, JCÀF ¼ 286:6), 127.63, 127.69, 128.37, 137.82;
19F NMR (188 MHz, d, CDCl3, J in Hz): 23.64; IR (neat,
cmÀ1): 3032, 2864, 1477, 1367, 1261, 1194, 1099, 1032,
741. Anal. calcd. for C19H20F2O2: C, 71.68; H, 6.33. Found:
C, 71.73; H, 6.43.
4.2.1. (1R,3S)-2,2-Difluoro-3-
hydroxymethylcyclopropylmethyl acetate (2)
23
½aꢀD þ 15:5ꢁ (c ¼ 1:20, CHCl3), >99% ee; Rf 0.22 (hex-
ane/ethyl acetate ¼ 2:1); bp 108 8C at 6.5 Torr (Kugelrohr);
1H NMR (200 MHz, d, CDCl3, J in Hz): 1.95–2.10 (2H, m),
2.06 (3H, s), 2.48 (1H, s), 3.67–3.90 (2H, m), 4.12–4.36 (2H,
m); 13C NMR (50 MHz, d, CDCl3, J in Hz): 20.76, 24.00 (t,
JCÀF ¼ 10:2), 27.63 (t, JCÀF ¼ 10:1), 55.91 (d, JCÀF ¼ 5:5),
58.06 (d, JCÀF ¼ 5:6), 113.71 (dd, JCÀF ¼ 290:7, 282.1),
170.94; 19F NMR (188 MHz, d, CDCl3, J in Hz): 10.57 (d,
JFÀF ¼ 164:8), 37.20 (dd, JFÀF ¼ 165:0, JHÀF ¼ 8:8); IR
(neat, cmÀ1): 3432, 2964, 1738, 1478, 1374, 1241, 1186,
1115, 1037, 907, 833, 719. Anal. calcd. for C7H10F2O3: C,
46.67; H, 5.60. Found: C, 47.05; H, 5.93. Enantiomeric
excess of cis-2 was determined by capillary GC analysis
using chiral column (Chiraldex G-TA): f 0:25 mm  20 m;
carrier gas, He 40 ml/min; temperature, 100 8C, inlet pres-
sure, 1.35 kg/cm2; amount, 400 ng; detection, FID. Rt of
(1R,3S)-2, 9.5 min; (1S,3R)-2, 11.3 min.
4.1.3. cis-1,3-Bishydroxymethyl-2,2-difluorocyclopropane
(1)
Rf 0.14 (hexane/ethyl acetate ¼ 1:1); bp 100 8C at 2 Torr
(Kugelrohr); 1H NMR (200 MHz, d, CDCl3, J in Hz): 2.01–
2.14 (2H, m), 3.61–3.78 (4H, m), 4.00 (2H, ddd, J ¼ 12:3,
5.9, 2.8); 13C NMR (50 MHz, d, CDCl3, J in Hz): 27.65 (t,
JCÀF ¼ 10:3), 55.68 (t, JCÀF ¼ 4:2), 114.40 (dd,
JCÀF ¼ 289:7, 284.1); 19F NMR (188 MHz, d, CDCl3, J
in Hz): 13.56 (1F, dd, J ¼ 164:7, 9.8), 39.17 (1F, dt,
J ¼ 164:8, 12.6); IR (neat, cmÀ1): 3334, 2898, 1477,
1284, 1175, 1026, 931. Anal. calcd. for C5H8F2O2: C,
43.48; H, 5.84. Found: C, 43.40; H, 6.01.
4.2.2. (S)-MTPA ester-9: (S)-(À)-MTPA ester of cis-2
1H NMR (500 MHz, d, CDCl3, J in Hz): 2.03–2.13 (2H,
m), 3.48 (3H, s), 4.04 (1H, dd, J ¼ 12:5, 6.5), 4.17 (1H, dd,
J ¼ 12:0, 6.5), 4.33 (1H, dd, J ¼ 12:5, 7.5), 4.46 (1H, dd,
J ¼ 12:5, 7.0) 7.31–7.36 (3H, m), 7.43–7.45 (2H, m); 19F
4.1.4. (Æ)-trans-1
Rf 0.14 (hexane/ethyl acetate ¼ 1:1); bp 100 8C at 2 Torr
(Kugelrohr); 1H NMR (200 MHz, d, CDCl3, J in Hz): 1.65–
1.88 (2H, m), 3.27 (2H, s), 3.50–3.66 (1H, m), 3.80–3.93
(1H, m); 13C NMR (50 MHz, d, CDCl3, J in Hz): 29.29 (t,
JCÀF ¼ 10:1), 59.21 (t, JCÀF ¼ 2:3), 114.40 (t,
JCÀF ¼ 295:27); 19F NMR (188 MHz, d, CDCl3, J in Hz):
23.56; IR (neat, cmÀ1): 3334, 2898, 1477, 1367, 1284, 1175,
1113, 1026, 931, 830. Anal. calcd. for C5H8F2O2: C, 43.48;
H, 5.84. Found: C, 43.42; H, 5.71.
NMR (188 MHz, d, CDCl3, J in Hz): 10.63 (d, JFÀF
166:2), 36.06 (dt, JFÀF ¼ 167:0, JHÀF ¼ 12:2).
¼
4.2.3. (R)-MTPA ester-9: (R)-(þ)-MTPA ester of cis-2
1H NMR (500 MHz, d, CDCl3, J in Hz): 2.07–2.24 (2H,
m), 3.56 (3H, s), 4.01 (1H, dd, J ¼ 12:0, 6.0), 4.17 (1H, dd,
J ¼ 12:0, 6.5), 4.34 (1H, dd, J ¼ 12:5, 7.5), 4.48 (1H, dd,
J ¼ 12:5, 7.5), 7.41–7.47 (3H, m), 7.50–7.52 (2H, m);
19F NMR (188 MHz, d, CDCl3, J in Hz): 10.68 (d,
JFÀF ¼ 165:8), 36.06 (dt, JFÀF ¼ 166:2, JHÀF ¼ 11:9).
4.1.5. (Æ)-trans-8
Rf 0.58 (hexane/ethyl acetate ¼ 2:1); bp 95 8C at 2.5 Torr
(Kugelrohr); 1H NMR (200 MHz, d, CDCl3, J in Hz): 1.74–
1.92 (2H, m), 2.02 (6H, s), 3.98–4.18 (4H, m); 13C NMR
(50 MHz, d, CDCl3, J in Hz): 20.70, 25.78 (t, JCÀF ¼ 10:8),
4.3. Preparation of optically active trans-8
60.00 (d, JCÀF ¼ 5:9), 113.95 (t, JCÀF ¼ 286:5), 170.61; 19
F
To a buffer solution (pH 7.2, 182 ml) was added 2.0 g of
lipase SL (Meito Sangyo Co. Ltd.) and diacetate (Æ)-trans-8
(8.07 g, 36.3 mmol). The mixture was stirred at room tem-
perature for 0.5 h. The reaction was quenched with crushed
ice and NaCl powder and extracted with ethyl acetate.
The combined organic layer was dried over MgSO4, evapo-
rated, and silica gel flash column chromatography (hexane/
ethyl acetate ¼ 7:1–1:1) gave monoacetate trans-2 (3.63 g,
20.2 mmol, 56%) and diacetate (À)-trans-8 (3.05 g,
13.7 mmol, 38%). Enantiomeric excess of diacetate
NMR (188 MHz, d, CDCl3, J in Hz): 23.35; IR (neat, cmÀ1):
2966, 1743, 1483, 1377, 1234, 1034. Anal. calcd. for
C9H12F2O4: C, 48.65; H, 5.44. Found: C, 49.33; H, 6.00.
4.2. Lipase-catalyzed reaction: preparation of
optically active cis-2
To a buffer solution (pH 7.2, 100 ml) was added lipase QL
powder (1.11 g, Meito Sangyo Co. Ltd.) and diacetate cis-8

T. Itoh et al. / Journal of Fluorine Chemistry 125 (2004) 775–783
781
23
(1R,3R)-8(½aꢀD À 9:6ꢁ (c ¼ 1:40, CHCl3)wasdeterminedby
and dl form (1:1) in 74% yield. Dehydration of 11 using Pd-
C/H2 in ethanol at room temperature gave diol trans,trans-3
in quantitative yield, and subsequent acetylation of 3 was
accomplished to afford trans,trans-12 in over 90%.
capillary GC analysis on chiral column (Chiraldex G-TA) as
>99% ee because only a single signal was detected.
4.3.1. (1S,3S)-(þ)-2
24
½aꢀD þ 14:9ꢁ (c ¼ 2:41, CHCl3), 51% ee; bp 100 8C at
4.4.1. meso-11
2.0 Torr (Kugelrohr); Rf 0.23 (hexane/ethyl acetate ¼ 2:1);
1H NMR (200 MHz, d, CDCl3, J in Hz): 1.64–1.88 (2H, m),
2.03 (3H, s), 3.02 (1H, s), 3.65 (1H, dd, J ¼ 6:3, 2.0),
4.00 (1H, dd, J ¼ 13:3, 6.6), 4.12–4.16 (1H, m); 13C
NMR (50 MHz, d, CDCl3, J in Hz): 20.65, 25.16
(t, JCÀF ¼ 10:8), 28.93 (t, JCÀF ¼ 10:2), 58.97 (d,
JCÀF ¼ 5:5), 60.85 (d, JCÀF ¼ 4:9), 114.56 (t,
JCÀF ¼ 286:3), 171.16; 19F NMR (188 MHz, d, CDCl3, J
in Hz): 22.35 (dd, JFÀF ¼ 164:3, JHÀF ¼ 12:2), 23.86 (dd,
JFÀF ¼ 164:3, JHÀF ¼ 13:2); IR (neat, cmÀ1): 3432, 2964,
1738, 1478, 1374, 1241, 1186, 1115, 1037, 907, 833, 719.
Anal. calcd. for C7H10F2O3: C, 46.67; H, 5.60. Found: C,
46.95; H, 5.83.
Optical purity of (1S,3S)-(þ)-2 was determined to be
51% ee by GC analysis using Chiraldex G-TA as diacetate
8. Results of GC analysis of 8: Chiraldex G-TA, f
0:25 mm  20 m; carrier gas, He 40 ml/min; temperature,
70 8C, inlet pressure, 1.35 kg/cm2; amount, 400 ng;detection,
FID. Rt of (À)-(1R,3R)-8, 42.8 min; (þ)-(1S,3S)-8, 45.3 min.
Rf 0.22 (hexane/ethyl acetate ¼ 10:1); mp 105–106 8C;
1H NMR (200 MHz, d, CDCl3, J in Hz): 1.21–1.41 (2H, m),
1.80 (2H, ddd, J ¼ 13:7, 13.6, 6.8), 3.51 (2H, ddd, J ¼ 19:3,
10.9, 1.6), 3.56–3.69 (2H, m), 4.52 (4H, ABq, J ¼ 12:0),
7.24–7.40 (10H, m); 13C NMR (50 MHz, d, CDCl3, J in Hz):
23.46 (dt, JCÀF ¼ 11:2, 3.8), 28.02 (t, J ¼ 9:8), 66.16 (d,
J ¼ 4:5), 72.58, 113.88 (ddd, JCÀF ¼ 290:3, 287.2, 2.8),
127.60, 127.76, 128.43, 137.76; 19F NMR (188 MHz, d,
CDCl3, J in Hz): 22.61 (dd, JFÀF ¼ 161:2, JHÀF ¼ 13:2),
24.60 (dd, JFÀF ¼ 161:1, JHÀF ¼ 13:6); IR (neat, cmÀ1):
3062, 3033, 2891, 1461, 1366, 1303, 1253, 1167, 1139,
1104, 972, 742. Anal. calcd. for C22H22F4O2: C, 67.00; H,
5.62. Found: C, 66.83; H, 5.75. Crystal and refinement data
for 11: C22H22F4O2, formula weight ¼ 394:41, monoclinic,
˚
space group P21(#4), a ¼ 8:6979 A, b ¼ 6:0163, c ¼
3
19:3163 A, V ¼ 1005:5700 A , Z ¼ 2, dcalc ¼ 1:30 g cmÀ3
,
˚
˚
I > 3:00 s and 253 valuable.
4.4.2. (Æ)-11
Rf 0.20 (hexane/ethyl acetate ¼ 10:1); mp 82 8C; 1H
NMR (200 MHz, d, CDCl3): 1.39–1.56 (2H, m), 1.57–
1.79 (2H, m), 3.53 (4H, d, J ¼ 7:1), 4.51 (4H, ABq,
J ¼ 11:9), 7.22–7.40 (10H, m); 13C NMR (50 MHz, d,
CDCl3, J in Hz): 22.89 (dt, JCÀF ¼ 11:0, 3.7), 27.54 (t,
J ¼ 9:7), 66.08 (d, J ¼ 4:1), 72.56, 114.05 (dd,
JCÀF ¼ 290:5, 286.7), 127.58, 127.77, 128.44, 137.76;
19F NMR (188 MHz, d, CDCl3, J in Hz): 23.88 (dd,
JFÀF ¼ 160:2, JHÀF ¼ 12:0), 25.20 (dd, JFÀF ¼ 160:7,
JHÀF ¼ 12:6); IR (neat, cmÀ1): 3033, 2891, 1460, 1101,
973. Anal. calcd. for C22H22F4O2: C, 67.00; H, 5.62. Found:
C, 66.86; H, 5.65.
4.3.2. (R,R)-(À)-3-(9-anthracenecarbonyl)methyl-2,2-
difluorocyclopropylmethyl-9-anthracenecarboxylate (10)
24
½aꢀD À 69ꢁ (c ¼ 1:06, CHCl3), 79% ee; Rf 0.32 (hexane/
ethyl acetate ¼ 4:1); mp 168–171 8C (recrystallized from
hexane/ethyl acetate ¼ 10:1); 1H NMR (200 MHz, d,
CDCl3, J in Hz): 2.30–2.50 (2H, m), 4.62–4.88 (4H, m),
7.31–7.59 (8H, m), 7.90–8.10 (8H, m), 8.47 (2H, s); 13C
NMR (50 MHz, d, CDCl3, J in Hz): 26.34 (t, JCÀF ¼ 10:7),
61.38, 113.97 (t, JCÀF ¼ 286:9), 124.67, 125.36, 125.44,
127.04, 128.47, 128.51, 129.77, 130.78, 169.23; 19F NMR
(188 MHz, d, CDCl3, J in Hz): 23.54 (d, JHÀF ¼ 7:1); IR
(neat, cmÀ1): 3053, 2960, 1722, 1478, 1202, 1005, 732.
Anal. calcd. for C35H24F2O4: C, 76.91; H, 4.43. Found: C,
77.06; H, 4.38.
4.4.3. meso-3
1
Rf 0.20 (hexane/ethyl acetate ¼ 1:1); mp 88–89 8C; H
NMR (200 MHz, d, acetone-d6, J in Hz): 1.40–1.60 (2H, m),
1.87 (2H, ddd, J ¼ 14:4, 14.3, 6.6), 2.96 (2H, s), 3.48–3.82
(4H, m); 13C NMR (50 MHz, d, acetone-d6, J in Hz):
23.46 (dt, JCÀF ¼ 13:7, 2.2), 30.73 (d, J ¼ 2:5), 58.78 (d,
J ¼ 5:5), 115.57 (ddd, JCÀF ¼ 289:2, 285.9, 3.0); 19F NMR
(188 MHz, d, acetone-d6, J in Hz): 23.55 (dd, JFÀF ¼ 160:1,
JHÀF ¼ 13:6), 26.7 (dd, JFÀF ¼ 160:2, JHÀF ¼ 14:3); IR
(neat, cmÀ1): 3321, 2923, 1452, 1250, 1127, 965, 890. Anal.
calcd. for C8H10F4O2: C, 44.87; H, 4.71. Found: C, 44.75;
H, 4.68.
4.4. Synthesis of optically active 1,6-bishydroxymethyl-
2,2,5,5-tetrafluorobicyclopropane (3)
To a dry diglyme (20 ml) solution of (E,E)-1,6-bisbenzy-
loxy-2,4-hexadiene [19,21] (6.23 g, 21.2 mmol) was added
dropwise a diglyme (65 ml) solution of sodium chlorodi-
fluoroacetate (32.3 g, 212 mmol) at 180 8C over 5 h with
vigorous stirring. After being stirred for additional 1 h at the
same temperature, the mixture was allowed to cool to room
temperature. The reaction mixture was poured into ice water
and extracted with hexane and ethyl acetate, and the com-
bined organic layers were washed with water, dried over
MgSO4 and evaporated. Silica gel flash column chromato-
graphy(elution hexane/ethyl acetate ¼ 40:1–5:1) gave
dibenzyl ether 11 (6.20 g, 15.7 mmol) as a mixture of meso
4.4.4. dl-3
Rf 0.10 (hexane/ethyl acetate ¼ 1:1); bp 140 8C at
1
6.5 Torr (Kugelrohr); H NMR (200 MHz, d, CDCl3, J in
Hz): 1.41–1.78 (4H, m), 2.16 (2H, s), 3.65–3.85 (4H, m); 13
C
NMR (50 MHz, d, CDCl3, J in Hz): 23.00 (dt, JCÀF ¼ 11:4,

782
T. Itoh et al. / Journal of Fluorine Chemistry 125 (2004) 775–783
24
ꢂ (1R,3S,4S,6R)-12: ½aꢀD À 30:3ꢁ (c ¼ 1:11, CHCl3)
21
3.8), 29.60 (d, J ¼ 9:1), 59.24 (d, J ¼ 5:0), 114.41 (dd,
JCÀF ¼ 290:4, 286.3); 19F NMR (188 MHz, d, CDCl3, J in
Hz): 23.38 (dd, JFÀF ¼ 162:4, JHÀF ¼ 13:0), 25.53 (dd,
JFÀF ¼ 162:1, JHÀF ¼ 13:6); IR (neat, cmÀ1): 3332, 2944,
1463, 1253, 1169, 1008, 718. Anal. calcd. for C8H10F4O2: C,
44.87; H, 4.71. Found: C, 44.69; H, 5.68.
(>99% ee).
ꢂ (1S,3R,4R,6S)-3: ½aꢀD þ 70:8ꢁ (c ¼ 1:70, CHCl3) (>99%
21
ee).
ꢂ (1R,3S,4S,6R)-3: ½aꢀD À 70:3ꢁ (c ¼ 1:40, CHCl3) (>99%
ee).
4.4.5. meso-12
4.5.1. meso-13
Rf 0.63 (hexane/ethyl acetate ¼ 10:1); mp 68–69 8C; 1H
NMR (200 MHz, d, CDCl3, J in Hz): 1.32–1.48 (2H, m),
1.88 (2H, ddd, J ¼ 13:8, 13.4, 7.8), 2.06 (6H, s), 4.00–4.25
(4H, m); 13C NMR (50 MHz, d, CDCl3, J in Hz): 23.89 (dt,
JCÀF ¼ 11:0, 3.7), 27.16 (t, J ¼ 9:9), 60.29 (d, J ¼ 4:6),
113.37 (ddd, JCÀF ¼ 290:3, 286.9, 2.4), 170.81; 19F NMR
(188 MHz, d, CDCl3, J in Hz): 22.51 (dd, JFÀF ¼ 162:9,
JHÀF ¼ 13:2), 24.26 (dd, JFÀF ¼ 162:61, JHÀF ¼ 13:2); IR
(neat, cmÀ1): 2950, 1741, 1465, 1371, 1235, 1036, 742.
Anal. calcd. for C12H14F4O4: C, 48.33; H, 4.73. Found: C,
49.06; H, 5.75.
Rf 0.26 (hexane/ethyl acetate ¼ 2:1); bp 145 8C at 5 Torr
(Kugelrohr); 1H NMR (200 MHz, d, CDCl3, J in Hz): 1.28–
1.50 (2H, m), 1.68–1.88 (2H, m), 2.06 (3H, s), 2.56 (1H, s),
3.58–3.83 (2H, m), 4.00–4.24 (2H, m); 13C NMR (50 MHz,
d, CDCl3, J in Hz): 20.57, 22.96 (dt, JCÀF ¼ 11:1, 4.1),
24.06 (dt, J ¼ 11:1, 4.9), 27.02 (t, J ¼ 10:5), 30.19 (t,
J ¼ 10:1), 59.18 (d, J ¼ 5:5), 60.38 (d, J ¼ 5:0), 113.64
(ddd, JCÀF ¼ 298:7, 291.4, 2.1), 113.64 (ddd, JCÀF ¼ 289:7,
286.8, 2.7), 171.03; 19F NMR (188 MHz, d, CDCl3, J in Hz):
22.08 (ddd, JFÀF ¼ 218:6, 162.6, JHÀF ¼ 11:9), 24.54 (dd,
JFÀF ¼ 162:8, JHÀF ¼ 13:2); IR (neat, cmÀ1): 3423, 3033,
2961, 2894, 1739, 1462, 1378, 1241, 1173, 1035, 865, 715.
Anal. calcd. for C10H12F4O3: C, 46.88; H, 4.72. Found: C,
46.24; H, 5.14.
4.4.6. (Æ)-12
Rf 0.63 (hexane/ethyl acetate ¼ 10:1); bp 138 8C at
7 Torr (Kugelrohr); 1H NMR (200 MHz, d, CDCl3, J in
Hz): 1.39–1.56 (2H, m), 1.57–1.79 (2H, m), 3.53 (4H, d,
J ¼ 7:1), 4.51 (4H, ABq, J ¼ 11:9), 7.22–7.40 (10H, m);
13C NMR (50 MHz, d, CDCl3, J in Hz): 22.89 (dt,
JCÀF ¼ 11:0, 3.7), 27.54 (t, J ¼ 9:7), 66.08 (d, J ¼ 4:1),
72.56, 114.05 (dd, JCÀF ¼ 290:5, 286.7), 127.58, 127.77,
128.44, 137.76; 19F NMR (188 MHz, d, CDCl3, J in Hz):
23.88 (dd, JFÀF ¼ 160:2, JHÀF ¼ 12:0), 25.20 (dd,
JFÀF ¼ 160:7, JHÀF ¼ 12:6). IR (neat, cmÀ1): 2965, 1743,
1465, 1376, 1235, 1038, 872.
4.5.2. (Æ)-trans,trans-6-(9-anthracenecarbonyl)methyl-
2,2,5,5-tetrafluorobicyclopropylmethyl-9-
anthracenecarboxylate (14)
mp 185–186 8C (recrystallized from CH2Cl2); Rf 0.36
(hexane/ethyl acetate ¼ 4:1); 1H NMR (200 MHz, d,
CDCl3, J in Hz): 1.70–2.10 (2H þ 2H, m), 4.48–4.76
(4H, m), 7.38–7.58 (8H, m), 7.85–8.10 (4H, m), 8.52
(2H, s); 13C NMR (50 MHz, d, CDCl3, J in Hz): 23.54
(dt, JCÀF ¼ 11:2, 3.6), 26.31 (t, J ¼ 11:1), 61.37, 61.46,
113.36 (t, JCÀF ¼ 290:4), 124.64, 125.47, 127.17, 128.53,
128.64, 129.88, 130.86, 169.11; 19F NMR (188 MHz, d,
CDCl3, J in Hz): 23.88 (dd, JFÀF ¼ 162:4, JHÀF ¼ 10:9),
25.11 (dd, JFÀF ¼ 162:4, JHÀF ¼ 11:2); IR (neat, cmÀ1):
3050, 1719, 1203, 1004, 734. Anal. calcd. for C38H26F4O4:
C, 73.31; H, 4.21. Found: C, 72.43; H, 4.53.
4.5. Lipase-catalyzed reaction of trans,trans-6-
acetoxymethyl-2,2,5,5-tetrafluorobicyclopropylmethyl
acetate (12)
To a buffer solution (pH 7.2, 150 ml) was added lipase SL
powder (1.13 g, Meito Sangyo Co. Ltd.) and diacetate 12
(dl:meso ¼ 7:3, 4.52 g, 15.2 mmol) and the mixture was
stirred at room temperature for 4 h. The reaction was
quenched with crushed ice and addition of NaCl powder
and extracted with ethyl acetate. Silica gel flash column
chromatography (hexane/ethyl acetate ¼ 7:1–1:1) gave
monoacetate 13 (1.17 g, 4.56 mmol, 47%), diol (þ)-3
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (No. 283, ‘‘Innovative Synthetic
Reactions’’) from The Ministry of Education, Science,
Sports and Culture of Japan. The authors also thank Meito
Sangyo Co. Ltd., and Amano Enzyme Co. Ltd., for provid-
ing the lipases.
(976 mg, 4.56 mmol, 30%) and
a
diacetate (À)-12
(1.09 g, 1.52 mmol, 24%). Enantiomeric excess of diacetate
12 was determined by capillary GC analysis on chiral
column (Chiraldex G-TA): f 0:25 mm  20 m; carrier
gas, He 40 ml/min; temperature, 100 8C, inlet pressure,
1.35 kg/cm2; amount, 400 ng; detection, FID. Rt of
(1R,3S,4S,6R)-12, 25.2 min; (1S,3R,4R,6S)-7, 26.2 min;
meso-diacetate 12, 38.6 min.
References
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931–1648;
27
ꢂ (1S,3R,4R,6S)-12: ½aꢀD þ 31:5ꢁ (c ¼ 0:75, CHCl3)
(b) M.J. Tozer, T.F. Herpin, Tetrahedron 52 (1996) 8619–8683.
(>99% ee).

T. Itoh et al. / Journal of Fluorine Chemistry 125 (2004) 775–783
783
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