Chemo-enzymatic synthesis of spiro type gem-difluorocyclopropane as core molecule candidate for liquid crystal compounds

Article abstract of DOI:10.1016/j.jfluchem.2009.06.007

The synthesis of a novel spiro type gem-difluorocyclopropane building block, 1,1,7,7-tetrafluoro-2,8-bis(hydroxymethyl)dispiro[2.2.2.2]decane (1), has been accomplished in optically pure form using chemo-enzymatic reaction protocol. Various types of diest

Full text of DOI:10.1016/j.jfluchem.2009.06.007

Journal of Fluorine Chemistry 130 (2009) 1157–1163
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Chemo-enzymatic synthesis of spiro type gem-difluorocyclopropane as core
molecule candidate for liquid crystal compounds
a
a
a
a
Toshiyuki Itoh a, , Manabu Kanbara , Shino Nakajima , Yusuke Sakuta , Shuichi Hayase ,
*
Motoi Kawatsura a, Takashi Kato b, Kazutoshi Miyazawa b, Hidemitsu Uno c
a Department of Chemistry and Biotechnology, Graduate School of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
b Chisso Petrochemical Corporation, Goi Research Center, Research Laboratory I, 5-1 Goikaigan, Ichihara-shi, Chiba 290-8551, Japan
c Department of Chemistry and Biology, Graduate School of Science and Engineering, Ehime University, Matsuyama 790-8577, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
The synthesis of a novel spiro type gem-difluorocyclopropane building block, 1,1,7,7-tetrafluoro-2,8-
bis(hydroxymethyl)dispiro[2.2.2.2]decane (1), has been accomplished in optically pure form using
chemo-enzymatic reaction protocol. Various types of diesters or dialkyl ether were prepared from diol
(+)-1 or (ꢀ)-1 in optically active form and their helical twisting power (HTP) was evaluated by addition of
1.0 wt% to a non-chiral nematic liquid crystal host. Although their HTP values were not significant, all
compounds showed liquid crystal property with SmC* phase when they were dissolved (20 wt%) in
achiral nematic host liquid crystal.
Received 12 May 2009
Received in revised form 9 June 2009
Accepted 9 June 2009
Available online 18 June 2009
Keywords:
Spiro compounds
ß 2009 Elsevier B.V. All rights reserved.
gem-Difluorocyclopropane
Lipase-catalyzed reaction
Helical twisting power
Liquid crystal
1. Introduction
helical twisting power [5a]. The synthesis of a spiro shaped
difluorocyclopropane derivative was reported by Miyazawa, de
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 a fluorine atom on an organic
molecule can alter the chemical reactivity due to the strong
electron-withdrawing nature of the fluorine, thus making it
possible to create a new molecule that exhibits unique physical
and biological properties [2]. Much attention has thus been paid to
Meijere and co-workers; it was established that the compound
showed ferroelectric liquid crystalline property [7]. We were
stimulated by the results and planned to synthesize spiro type
gem-difluorocyclopropane 1 and investigated its physical proper-
ties (Fig. 1).
2. Results and discussion
gem-difluorocyclopropane derivatives as
a source for novel
functional materials [3–5]. We have been synthesizing numerous
novel molecules that have gem-difluorocyclopropane moieties
through a chemo-enzymatic reaction strategy [4,5]. Development
of new materials that have good electrooptical properties for LCD
has now been recognized as a very important topic in the field of
organic synthesis [6]. We reported that gem-difluorocyclopropane
LC1 showed liquid crystal property (Fig. 1) [5d]. To gain insight into
designing novel liquid crystalline compounds based on the gem-
difluorocyclopropane molecules, we next designed difluorocyclo-
propane LC2 that has a benzene ring as a spacer unit between two
gem-difluorocyclopropane moieties. However, the compounds
showed no liquid crystalline property, while they had strong
2.1. Synthesis of optically active 1,1,7,7-tetrafluoro-2,8-
bis(hydroxymethyl)dispiro[2.2.2.2]decane (1) through chemo-
enzymatic reaction
Synthesis of a meso and dl mixture of spiro gem-difluorocy-
clopropane 1 was accomplished following Scheme 1. Diene 5 was
prepared using cyclohexane-1,4-dione as a starting material by
Horner–Wadsworth–Emmons reaction in 97% yield [8], and
subsequent diisobutylaluminum hydride (DIBAL) reduction of
the ethoxycarbonyl groups of 4 to give 5 in 79% yield as an
inseparable mixture [9]. Therefore, diol 5 was next converted to the
corresponding dibenzyl ether 6 in 96% yield. Compound 6 was then
subjected to the reaction with difluorocarbene produced from
pyrolysis of sodium chlorodifluoroacetate [5a]; dibenzyl ether of
1,1,7,7-tetrafluoro-2,8-bis(hydroxymethyl)dispiro[2.2.2.2]decane
was thus obtained and deprotection of the benzyl groups gave
* Corresponding author. Tel.: +81 857 31 5259; fax: +81 857 31 5259.
E-mail address: titoh@chem.tottori-u.ac.jp (T. Itoh).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.06.007

1158
T. Itoh et al. / Journal of Fluorine Chemistry 130 (2009) 1157–1163
Fig. 1. Design of a core molecule as candidate for a liquid crystalline compound.
desired diol 1 as a mixture of meso- and dl-form (ca. 1:1), and
separation of meso- and dl-isomers ((ꢁ)-1) of the diol was
accomplished by silica gel flash column chromatography. (Scheme 1).
Fortunately, we succeeded in obtaining a good crystal of
dibenzyl ether meso-7 by recrystallization from a mixed solvent of
acetone and hexane. As shown in Fig. 2 of the ORTEP view of meso-
7, the two difluorocyclopropane rings locate at the opposite side in
a very symmetrical manner [10].
Optical resolution of racemic 1 ((ꢁ)-1) was accomplished by
lipase technology [11] following Scheme 2 and the results are shown
in Table 1. Although we tested many commercial enzymes, only lipase
SL-25 and lipase QL gave moderate results (entries 2 and 3): the
highest E* value [12] obtained for lipase QL catalyzed reaction was
estimated to be 36 (entry 3). Although generally good results have
been obtained for lipase SL-25 for the optical resolution of gem-
Scheme 1. Synthesis of spiro type bis-gem-difluorocyclopropane.
Fig. 2. ORTEP view of (meso)-spiro-gem-difluorocyclopropane derivative 7. space group P21/c, R (reflections) = 0.0802 (1123).
Scheme 2. Optical resolution of (ꢁ)-1 using lipase-catalyzed enantioselective transesterification.

T. Itoh et al. / Journal of Fluorine Chemistry 130 (2009) 1157–1163
1159
Fig. 3. CD spectra of (+)- and (ꢀ)-8.
Scheme 3. Synthesis of LC compounds.
ylate 8 (Figs. 3 and 4). The CD spectrum of the ester (ꢀ)-8, which
was derived from (ꢀ)-3, exhibited a positive chirality on the large
Cotton effect [259.0 and 253.6 nm (De 4.16), CH3CN], while a
negative chirality on the Cotton effect was observed by the ester
(+)-8 derived from (+)-1 [259.0 and 253.8 nm (De 4.21), CH3CN]
(Fig. 3) [13,14]. This enantiofavoritism obtained from lipase QL in
the transesterification of (ꢁ)-1 was found to be the same as that of
LC2 (R55H) in Fig. 1 [5a] because the cyclohexane group between the
two gem-difluorocyclopropane rings seemed to cause no modifica-
tion in the enantiofavoritism of the enzymes.
Fig. 4. Assignment of the stereochemistry of (ꢀ)- and (+)-8 based on the Cotton
effect of CD spectra.
2.2. Helical twisting power and LC properties of spiro type gem-
difluorocyclopropane derivatives
difluorocyclopropane derivatives [5], the best enantioselectivity was
observed when lipase QL was used as catalyst for this spiro type
compound. In contrast, poor enantioselectivity was obtained for
Novozym 435 (entry 1), and no reaction took place when lipase PS
(entry 4) or lipase AY (entry 5) was employed as catalyst. Although
the enantioselectivity of lipase QL-catalyzed reaction was moderate,
since the lipase-catalyzed reaction was a kinetic resolution, we
succeeded in obtaining optically pure diol (+)-1 easily by repeating
the reaction, and thus we accomplished the preparation of both
enantiomers of diol 1 (Scheme 2).
There is great interest in the field of liquid crystals in the
application of chirality; chiral nematic (cholesteric) liquid crystals
having a macro-helical structure are currently used in liquid
crystal display devices [15]. The chiral nematic materials consist of
an achiral host mixture of nematic liquid crystals and a chiral
dopant with a large helical twisting power (HTP) [16]. Generally,
the chiral nematic materials that are used in good LCD devices
consist of an achiral host mixture of nematic liquid crystals and a
chiral dopant with a large helical twisting power (HTP). Therefore
it is very important to develop efficient chiral dopant materials
with large HTP. The syntheses of fluorinated compounds that have
The stereochemistry of the diol (+)-1 was assigned as (S,S), and
the diacetate (ꢀ)-3 was (R,R), based on the CD exciton chirality
method using the CD spectral results of bis-9-anthracenecarbox-
Table 1
Results of lipase-catalyzed transesterification of (ꢁ)-1.
Entry
Lipase
Time
%Yield of (ꢀ)-2 (% ee)
%Yield of (ꢀ)-3 (% ee)
%Yield of (+)-1 (% ee)
E*a
1
2
3
4
5
Novozym435
10 min
17 h
50 (22% ee)
10 (55% ee)
33 (49% ee)
29 (57% ee)
99 (0% ee)
6
10
–
SL-25
PS
34 (62% ee)
29 (69% ee)
4 days
40 min
4 days
0
0
QL
20 (65% ee)
0
28 (92% ee)
0
46 (41% ee)
100 (0% ee)
36
–
AY
a
Since the reaction included two processes, E* value was the result of two reactions. Here c* means conv. which was calculated by the formula: c* = ee3/(ee3 + ee1).
Therefore the present E* value is not the real E value [12] but a relative E value. E* = ln[(1 ꢀ c*)(1 + ee3)]/ln[(1 ꢀ c*)(1 ꢀ ee3)].

1160
T. Itoh et al. / Journal of Fluorine Chemistry 130 (2009) 1157–1163
obtained from compounds 9a–9e were inferior to the correspond-
ing ones derived from 1,4-bis(2,2-difluoro-3-(hydroxymethyl)cy-
clopropyl)benzene derivatives [5a]. The compound 9e with an
extended molecular shape exhibits a monotoropic SmA phase with
the transition temperatures of Cr 139.5 (SmA 130.2) Iso. On the
contrary, none of the showed liquid crystal property for 1,4-
bis(2,2,-difluoro-3-(hydroxymethyl)cyclopropyl)benzene deriva-
tives that we reported previously [5a]. We found that chiral 9a–
9e showed liquid crystal properties when they were dissolved
(20 wt%) in achiral nematic host liquid crystal (Cr 4 SmC 65 SmA 79
N 90 Iso (8C)). For example, the resulted mixture containing
compounds (ꢀ)-9d and (ꢀ)-9e exhibited SmC* phase at 50.9 and
50.0 8C, respectively. Because it is believed that two gem-
difluorocyclopropane rings of (ꢀ)-1 have a helical shape as
confirmed by CD spectroscopic analysis (see Fig. 3), this
conformation might be responsible for this unique physical
property of compound 1.
3. Conclusion
In summary, we accomplished the chemo-enzymatic synthesis
of chiral spiro type gem-difluorocyclopropane. The compounds
have interesting properties; in particular, the compound (ꢀ)-9e
with an extended molecular shape exhibits a monotoropic SmA
phase. Compounds (+)-9a, (ꢀ)-9b, (ꢀ)-9d and (ꢀ)-9e showed
liquid crystal property and exhibited SmC* phase when they were
dissolved in achiral nematic host liquid crystal. We are hopeful that
these unique properties might be identified allowing further
investigation of our novel gem-difluorocyclopropane compounds.
4. Experimental
4.1. General procedures
Reagents and solvents were purchased from common com-
mercial sources and were used as received or purified by
distillation from appropriate drying agents. Reactions requiring
anhydrous conditions were run under an atmosphere of dry argon.
Wako gel C-300 and Wako gel B5F were used for the flash column
chromatography and thin-layer chromatography (TLC). 1H NMR
(500 MHz), 13C NMR (125 MHz) and 19F NMR (470 MHz) spectra
were recorded in CDCl3 unless otherwise noted on a JEOL JNM MH-
500 spectrometer. Chemical shifts are expressed in
d value (ppm)
downfield from tetramethylsilane (TMS) as the internal reference.
The 19F NMR spectra were reported in ppm downfield from C6F6 as
the internal reference. IR spectra were obtained on SHIMADZU FT-
IR 8000 spectrometers and reported in cmꢀ1. CD spectra were
measured by a JASCO J-820 spectrometer using CH3CN as solvent.
Optical purity was determined by HPLC analysis using chiralcel
OD-H (Daicel). Helical twisted power of gem-difluorocyclopropane
derivatives was estimated by the distance between the stripes
appearing using a microscope in the Cano type wedge-shaped
cell when 1.0 wt% of gem-difluorocyclopropane was dissolved in
the achiral nematic host mixture consisting of cyanobenzene
compounds: 1-cyano-4-(trans-4-n-propylcyclohexyl)benzene, 1-
cyano-4-(trans-4-n-heptylcyclohexyl)benzene, 4-cyano-40-(trans-
4-n-heptylcyclohexyl)biphenyl (24:36:25:15 by weight). The
physical properties of the host mixture are TNI = 72.4 8C,
Fig. 5. HTP and LC properties of spiro-bis-gem-difluorocyclopropane derivatives.
large HTP have been reported by several groups [14]. Optically
pure diol (+)-1 was converted to bis-n-nonyl ether 9a and four
types of esters 9b, 9c, 9d, and 9e were prepared from (ꢀ)-1 (>99%
ee) (Scheme 3) and their liquid crystal properties were investigated
(Fig. 5). All of them had helical twisting power (HTP) when 1.0 wt%
was added to the achiral nematic liquid crystal [17]. The helical
pitches in the chiral nematic phases were measured using Cano
wedge cells [18]: the HTP can be calculated by (pc)ꢀ1, where p is the
pitch of the chiral nematic phase in mm and c is the mass fraction of
the chiral dopant [19]; the results are summarized in Fig. 5.
Among them, compounds 9a and 9d showed a somewhat high
HTP value, 9.8 and 9.5
than that of cholesteryl caprylate (HTP = 4.4
m
m
ꢀ1, respectively, values ca. 2-fold larger
De = 11.0, Dn = 0.137.
mm
ꢀ1). Although we
expected that high HTP power might be found for these
compounds, the results are not particularly impressive. In addition,
it was well established that introduction of isopropylfumalic acid
moiety was very effective to obtain high HTP values. However, no
significant enhancement was obtained by introduction of the
isopropylfumaroyl group to this compound. Further, HTP values
4.2. 1,4-Bis(carboethoxymethylene)cyclohexane 4 [8]
To a solution of sodium hydride in tetrahydrofuran (THF)
(9.0 ml) was added ethyl diethylphosphonoacetate (440 mg,
11 mmol) in THF (9.0 ml) at 0 8C via a cannula. After stirring for
1 h at rt, a solution of cyclohexane-1,4-dione (500 mg, 4.5 mmol)

T. Itoh et al. / Journal of Fluorine Chemistry 130 (2009) 1157–1163
1161
in THF (10 ml) was added via a cannula. After 30 min, the dark
brown colored mixture was quenched with saturated aq. NH4Cl
and 2 M HCl. The resulting mixture was extracted with ethyl
acetate, dried (MgSO4), concentrated, and purified using silica gel
flash column chromatography (ethyl acetate/hexane, 10:1) to give
4 (1.1 g, 97%) as a colorless oil as an inseparable mixture of E:Z
isomers in a ratio of ca. 1:1. Rf 0.48 (hexane/ethyl acetate = 7:1); 1H
(dd, JC-F = 295 Hz, 288 Hz), 127.7, 127.8, 128.4, 137.9; 19F NMR
(470 MHz, ppm, CDCl3) 13.8 (2F, d, J = 161 Hz), 24.3 (1F, dd,
d
J = 35.0 Hz, 17.3 Hz), 24.6 (1F, dd, J = 35.0 Hz, 17.3 Hz); IR (KBr,
cmꢀ1); 2860, 1458, 1447, 1236; Anal. Calcd for C26H28F4O2; C,
69.63; H, 6.29. Found: C, 69.56; H, 6.17.
dl-7: Rf 0.48 (ethyl acetate/hexane = 1:4); 1H NMR (500 MHz,
ppm, CDCl3)
m), 4.53–4.57 (2H, m), 7.28–7.38 (10H, m); 13C NMR (125 MHz,
ppm, CDCl3) 22.9, 29.5, 30.6–30.9 (m), 63.4 (d, JC-F = 3.8 Hz), 72.7,
116.0 (dd, JC-F = 289 Hz, 6.7 Hz), 127.67, 127.73, 128.4, 137.9; 19F
NMR (470 MHz, ppm, CDCl3, C6F6) 14.1 (2F, d, J = 161 Hz), 24.6
d 1.49–1.65 (8H, m), 3.56–3.62 (4H, m), 4.45–4.48 (2H,
NMR (500 MHz, ppm, CDCl3)
m), 2.98–3.02 (4H, m), 4.13–4.18 (4H, m), 5.69 (1H, s), 5.72 (1H, m);
13C NMR (125 MHz, ppm, CDCl3)
14.2, 28.8, 29.5, 35.9, 37.3, 59.6,
d 1.26–1.30 (6H, m), 2.37–2.40 (4H,
d
d
59.7, 114.5, 114.6, 159.5, 159.9, 166.4, 166.5. Spectroscopic data of
this compound were identical to those previously reported in the
literature [8].
d
(2F, dt, J = 127 Hz, 17.3 Hz); IR (KBr, cmꢀ1) 2860, 1458, 1236, 1194,
993, 741; Anal. Calcd for C26H28F4O2; C, 69.63; H, 6.29. Found: C,
69.56; H, 6.17.
4.3. Diol 5 [9]
4.6. 1,1,7,7-Tetrafluoro-2,8-
To a solution of 4 (1.4 g, 5.5 mmol) in toluene (10 ml) was added
diisobutylaluminum hydride (DIBAL) (12 ml 1.5 M in toluene,
18 mmol) at ꢀ20 8C. After stirring for 3 h at rt, the reaction mixture
was diluted with diethyl ether (Et2O), and quenched with
potassium fluoride and water, then extracted with ethyl acetate,
dried (MgSO4), and concentrated. Purification using silica gel
column chromatography (ethyl acetate–hexane, 0:1 to 1:3) gave
diol 5 (530 mg, 79%) as an inseparable mixture of E:Z mixture (ca.
bis(hydroxymethyl)dispiro[2.2.2.2]decane ((ꢁ)-1)
Palladium carbon (20 wt%) (697 mg, 5 mol%) was added to a
methanol (200 ml) solution of a dl and meso mixture of dibenzyl
ether 7 (11.7 g, 26.2 mmol), which was then saturated with H2 gas.
After stirring for 15 h at rt, the reaction mixture was filtered
through a sintered glass filter with a Celite pad to remove Pd-C, and
the filtrate was concentrated, and purified using silica gel flash
column chromatography (ethyl acetate/hexane, 1:10 to 1:2) to give
meso-1 (2.4 g, 37%), dl-1 (2.6 g, 34%).
dl-(ꢁ)-1: Rf 0.08 (ethyl acetate/hexane = 1:2); m.p. 68–70 8C; 1H
NMR (500 MHz, ppm, CD3OD) d 1.57–1.64 (2H, m), 1.66–1.85 (8H, m),
3.75–3.80 (4H, m), 4.98 (2H, s, OH); 13C NMR (125 MHz, ppm, CD3OD)
d 23.8, 24.0, 30.6, 30.8, 32.1 (t, JC-F = 9.7 Hz), 34.1 (t, JC-F = 9.6 Hz), 56.3,
117.8 (dd, JC-F = 295 Hz, 287 Hz); 19F NMR (470 MHz, ppm, CD3OD) d
14.6 (2F, dd, J = 161 Hz, 17.4 Hz), 26.5 (2F, dt, J = 161 Hz, 17.4 Hz); IR
(KBr, cmꢀ1) 3337, 2864, 1560, 1508, 1236, 1188, 1132, 980.0; Anal.
Calcd for C12H16F4O2; C, 53.71; H, 6.01, Found: C, 52.50; H, 6.13.
meso-1: Rf 0.32 (ethyl acetate/hexane = 1:2); m.p. 70–72 8C; 1H
1:1). 1H NMR (500 MHz, ppm, acetone d6)
3.98–4.00 (4H, m), 4.76 (2H, s, OH), 5.28 (4H, t, J = 16 Hz, 9.0 Hz);
13C NMR (125 MHz, ppm, CD3OD)
29.8, 30.5, 38.0, 38.9, 58.6,
d 2.16–2.18 (4H, m),
d
123.0, 142.6, 142.7. Spectroscopic data of this compound are
identical to those previously reported in the literature [9].
4.4. Dibenzyl ether 6
A suspension of sodium hydride (NaH) (1.50 g, 9.0 mmol) in
20 ml of N,N-dimethylformamide (DMF) was cooled to 0 8C with
stirring and a DMF (20 ml) solution of diol 5 (500 mg, 3.0 mmol)
was added dropwise. To this mixture was added a DMF (10 ml)
solution of benzyl bromide (1.50 g, 9.0 mmol) and the mixture was
stirred at rt for 10 h, then the reaction was quenched by addition of
water and extracted with ethyl acetate. The combined organic
layers were washed with water and brine, dried (MgSO4), and
concentrated. Silica gel thin layer chromatography (TLC) (ethyl
acetate/hexane, 1:7) afforded dibenzyl ether 6 (1.00 g) in 96% yield.
Rf 0.48 (hexane/ethyl acetate = 7:1); 1H NMR (500 MHz, ppm,
NMR (500 MHz, ppm, CD3OD)
J = 7.8 Hz), 1.53–1.56 (6H, m), 1.60–1.68 (2H, m), 3.54–3.64 (4H,
m), 4.77 (2H, s, OH); 13C NMR (125 MHz, ppm, CD3OD)
24.2, 30.9
(t, JC-F = 9.0 Hz), 32.0 (t, JC-F = 9.1 Hz), 29.3, 34.2, 56.2, 117.9 (dd, JC-
F = 293 Hz, 285 Hz); 19F NMR (470 MHz, ppm, CD3OD)
14.7 (2F,
d 1.60 (1H, t, J = 7.3 Hz), 1.61 (1H, t,
d
d
dd, J = 161 Hz, 40.5 Hz), 26.6 (2F, dd, J = 156 Hz, 11.8 Hz); IR (KBr,
cmꢀ1) 3337, 2864, 1474, 1236, 1190, 1119, 1092, 968; Anal. Calcd
for C12H16F4O2; C, 53.73; H, 6.01. Found: C, 53.31; H, 5.86.
CDCl3)
s), 5.42 (2H, t, J = 7.3 Hz), 7.26–7.35 (10H, m); 13C NMR (125 MHz,
ppm, CDCl3) 28.9, 29.5, 36.7, 65.6, 65.6, 71.8, 71.9, 118.9, 119.0,
127.4, 127.6, 128.2, 138.3, 143.0, 143.1; IR (KBr, cmꢀ1); 3030, 2845,
1452, 1099, 1067, 1028, 736.8, 698.2; Anal. Calcd for C24H28O2; C,
82.72; H, 8.10. Found: C, 81.99; H, 8.28.
d 2.20 (4H, s), 2.23 (4H, s), 4.04 (4H, d, J = 6.8 Hz), 4.51 (4H,
4.7. Lipase-catalyzed optical resolution of (ꢁ)-1
d
To a solution of (ꢁ)-1 (90 mg, 0.34 mmol) and vinyl acetate
(86 mg, 1.0 mmol) in diisopropyl ether (i-Pr2O) (1.7 ml) was added
lipase QL (45 mg, 50 wt%) and the mixture was stirred at 35 8C for
40 min. The reaction course was monitored by silica gel TLC. The
reaction mixture was filtered through a sintered glass filter with a
Celite pad to remove the lipase, and the filtrate was concentrated.
Silica gel flash column chromatography (ethyl acetate–hexane, 4:1 to
1:0) to give diacetate 3 (34 mg, 28%), monoacetate 2 (21 mg, 20%), and
4.5. Dibenzyl ether of 1,1,7,7-tetrafluoro-2,8-
bis(hydroxymethyl)dispiro[2.2.2.2]decane 7
Toa dry diglyme(30 ml) solution of6 (9.1 g, 26 mmol) wasadded
a diglyme (60 ml) solution of sodium chlorodifluoroacetate (40 g,
260 mmol) at 190 8C during 4 h with vigorous stirring. After being
stirred at 190 8C for an additional 1 h, the reaction mixture was
allowed to cool to rt, then the mixture was poured into ice water and
extracted with hexane and ethyl acetate. The combined organic
layers were washed with brine and water, dried over MgSO4 and
evaporated to dryness. Separation of dl- and meso-7 was successful
and we obtained pure meso-7 by recrystallization from hexane.
meso-7: Rf 0.55 (ethyl acetate/hexane = 1:4); m.p. 70–72 8C; 1H
diol 1 (41 mg, 46%).
25
D
Diacetate (ꢀ)-3: 92% ee, [
a]
ꢀ7.18 (c 1.7, MeOH); Rf 0.72
(ethyl acetate/hexane = 1:1); 1H NMR (500 MHz, ppm, CD3OD)
1.65–1.75 (10H, m), 2.05 (6H, s), 4.15–4.21 (2H, m), 4.22–4.27 (2H,
m); 13C NMR (125 MHz, ppm, CD3OD)
20.8, 24.0, 30.3, 30.6–30.7
(m), 32.5 (t, JC-F = 9.6 Hz), 59.3 (d, JC-F = 4.8 Hz), 117.2 (dd, JC-
d
d
F = 293 Hz, 286 Hz); 19F NMR (470 MHz, ppm, CD3OD)
d 15.5 (2F, d,
J = 156 Hz), 26.4 (2F, dd, J = 161 Hz, 11.3 Hz); IR (KBr, cmꢀ1) 2963,
2868, 1744, 1448, 1369, 1232, 1194, 966.0; Anal. Calcd for
NMR (500 MHz, ppm, CDCl3)
d
1.50–1.71 (10H, m), 3.53–3.62 (4H,
C16H20F4O4; C, 57.83; H, 4.85. Found: C, 55.90; H, 4.53.
24
25
m), 4.46–4.60 (4H, m), 8.28–7.37 (10H, m); 13C NMR (125 MHz,
ppm, CDCl3); 23.3–23.4 (m), 29.8, 30.6–30.9 (m), 63.3, 72.8, 116.2
Monoacetate (ꢀ)-2: 65% ee, [
a
]
D
ꢀ2.20 (c 1.1, CHCl3), [
a]
D
ꢀ0.76 (c 1.0, MeOH); Rf 0.72 (ethyl acetate/hexane = 1:1); 1H NMR

1162
T. Itoh et al. / Journal of Fluorine Chemistry 130 (2009) 1157–1163
(500 MHz, ppm, CDCl3)
d
1.51–1.75 (10H, m), 2.09 (3H, s), 3.37–
(2H, m), 3.44–3.48 (2H, m), 3.52–3.56 (4H, m); 13C NMR (125 MHz,
ppm, CDCl3) 14.07, 22.67, 22.97 (d, JC-F = 4.8 Hz), 26.15, 29.29–
3.89 (2H, m), 4.19–4.20 (2H, m); 13C NMR (125 MHz, ppm, CDCl3)
d
d
20.9, 22.9–23.2 (m), 29.4–29.6 (m), 31.0 (dt, JC-F = 9.6 Hz, 2.9 Hz),
31.2 (t, JC-F = 9.6 Hz), 33.1 (t, JC-F = 9.6 Hz), 56.5 (t, JC-F = 4.8 Hz),
58.4 (t, JC-F = 3.4 Hz), 115.3 (dd, JC-F = 221.7 Hz, 72.9 Hz), 117.0 (dd,
29.67 (m), 30.73 (t, JC-F = 9.5 Hz), 31.88, 63.76 (d, JC-F = 4.8 Hz),
70.79, 116.13 (dd, JC-F = 294 Hz, 286 Hz); 19F NMR (470 MHz, ppm,
CDCl3) d 13.7 (2F, d, J = 161 Hz), 24.40 (2F, dd, J = 161 Hz, 17.4 Hz);
JC-F = 289 Hz, 73.0 Hz), 171.0; 19F NMR (470 MHz, ppm, CDCl3)
d
IR (KBr, cmꢀ1) 2926, 2856, 2804, 2743, 1474, 1414, 1375, 1261,
1236, 1194; Anal. Calcd for C30H52F4O2; C, 69.20; H, 10.07. Found:
C, 69.15; H, 10.51.
13.2 (1F, dd, J = 136 Hz, 40.0 Hz), 13.5 (1F, dd, J = 118 Hz, 35.0 Hz),
24.3 (1F, ddd, J = 159 Hz, 25 Hz, 12 Hz), 24.8 (1F, dd, J = 159 Hz,
12 Hz); IR (KBr, cmꢀ1) 2963, 2868, 1744, 1448, 1369, 1232, 1194,
966.0.
4.10. Synthesis of (ꢀ)-9b
26
Diol (+)-1: 41% ee, [
a
]
+4.29 (c 2.1, MeOH); Rf 0.08 (ethyl
D
acetate/hexane = 1:2); m.p. 118–120 8C; 1H NMR (500 MHz, ppm,
CD3OD)
1.44–1.68 (10H, m), 3.62–3.70 (4H, m); 13C NMR
(125 MHz, ppm, CD3OD) 23.2 (d, JC-F = 4.8), 30.2 (d, JC-F = 4.8 Hz),
31.5 (t, JC-F = 9.5 Hz), 33.4 (t, JC-F = 9.5 Hz), 117.2 (dd, JC-F = 284 Hz,
Using the same method as described above, (ꢀ)-9b was
24
d
prepared in 86% yield starting from (ꢀ)-1 (>99% ee): [
a]
D
d
ꢀ5.49 (c 1.0, CHCl3); Rf 0.70 (ethyl acetate/hexane = 1:4); 1H NMR
(500 MHz, ppm, CDCl3)
d 0.88 (6H, t, J = 6.9 Hz), 1.27–1.29 (18H,
7.6 Hz); 19F NMR (470 MHz, ppm, CD3OD, C6F6)
J = 161 Hz), 26.4 (2F, dd, J = 161 Hz, 11.3 Hz); IR (KBr, cmꢀ1) 3337,
2864, 1560, 1508, 1236, 1188, 1132, 978. Optically pure (+)-1 was
d
14.6 (2F, d,
m), 1.55–1.65 (16H, m), 2.32 (4H, t, J = 7.6 Hz), 416–4.24 (4H, m);
13C NMR (125 MHz, ppm, CDCl3)
14.04, 22.61, 22.95 (d, JC-
d
F = 4.8 Hz), 24.90, 29.11–29.56 (m), 31.06 (t, JC-F = 9.5 Hz), 31.78,
34.20, 58.04 (d, JC-F = 5.7 Hz), 115.41 (dd, JC-F = 293 Hz, 286 Hz,),
obtained after recrystallization from methanol: [a]
23 +9.06 (c 1.1,
D
MeOH), >99% ee. Optical purity of diol 1 was determined by HPLC
analysis using chiralcel OD-H as diacetate 3, hexane/2-propanol
(9:1), 35 8C; Rt (R,R) = 17 min, Rt (meso) = 11 min, and Rt
(S,S) = 9.3 min.
173.56; 19F NMR (470 MHz, ppm, CDCl3)
d 13.55 (2F, d, J = 161 Hz),
24.32 (2F, dd, J = 161 Hz, 11.8 Hz); IR (KBr, cmꢀ1) 2934, 2860, 1747,
1474, 1283, 1198, 1140, 1123, 972; Anal. Calcd for C30H48F4O4; C,
65.67; H, 8.82. Found: C, 65.80; H, 8.66.
4.8. Preparation of (ꢀ)-8 and (+)-8 for CD spectroscopic analysis
4.11. Synthesis of (ꢀ)-9c
A mixture of (ꢀ)-1 (37.0 mg, 0.14 mmol, 96% ee) which was
prepared from (ꢀ)-3 by alkaline hydrolysis, 9-anthracene car-
boxylic acid (92 mg, 0.41 mmol), 1-(3-dimethylaminopropyl)-3-
ethylcarbodiimide hydrochloride (EDC) (79 mg, 0.41 mmol), 4-
(N,N-dimethylamino)pyridine (DMAP) (17 mg, 0.14 mmol) in
CH2Cl2 (3.0 ml) was stirred for 60 h at 50 8C. After being cooled
to rt, the solvent was removed by evaporation and the residue was
subjected on silica gel TLC (hexane/ethyl acetate = 2:1) to give (ꢀ)-
Using the same method as described above, (ꢀ)-9c was
23
prepared in 60% yield starting from (ꢀ)-1 (>99% ee): [
a]
D
ꢀ1.03 (c 1.4, CHCl3); Rf 0.55 (ethyl acetate/hexane = 4:1): 1H NMR
(500 MHz, ppm, CDCl3)
d 1.30 (12H, d, J = 6.0 Hz), 1.58–1.78 (10H,
m), 4.31–4.39 (4H, m), 5.21 (2H, sep, J = 6.5 Hz), 6.86 (4H, brs); 13
NMR (125 MHz, ppm, CDCl3) 21.70, 23.02 (d, JC-F = 3.8 Hz), 29.17
C
d
(t, JC-F = 9.6 Hz), 29.43 (d, JC-F = 3.8 Hz), 31.00 (t, JC-F = 9.6 Hz), 59.10
(d, JC-F = 3.8 Hz), 69.16, 115.18 (dd, JC-F = 293 Hz, 285 Hz), 132.43,
135.03, 164.21, 164.80; 19F NMR (470 MHz, ppm, CDCl3)
d 13.57
(2F, dd, J = 141 Hz, 47 Hz), 24.3 (2F, dd, J = 141 Hz, 47 Hz); IR (KBr,
cmꢀ1) 2986, 2943, 1715, 1645, 1472, 1456, 1389, 1375, 1352,
1298; Anal. Calcd for C26H32F4O8; C, 56.93; H, 5.88. Found: C,
57.02; H, 5.69.
8 (11.0 mg, 0.01 mmol) in 12% yield. Since reactivity of (ꢀ)-1 was
21
very poor, 80% of starting diol (ꢀ)-1 was recovered: [
a
]
D
ꢀ2.60 (c
1.00 CHCl3); Rf 0.80 (hexane/ethyl acetate = 2/1); 1H NMR
(500 MHz, ppm, CDCl3) 1.26–1.27 (4H, s), 1.59–1.88 (6H, m),
d
4.61–4.65 (2H, m), 4.76 (2H, dd, J = 12.2 Hz, 8.2 Hz), 7.44–7.47 (8H,
m), 7.51–7.54 (8H, m), 7.96 (8H, dd, J = 9.8 Hz, 8.2 Hz), 8.50 (2H, d,
J = 5.7 Hz); 13C NMR (125 MHz, ppm, CDCl3)
d
20.3, 23.1–23.4 (m),
4.12. Synthesis of (ꢀ)-9d
29.2–29.7 (m), 31.0–31.9 (m), 54.8, 58.1, 59.5, 60.4, 77.0 (t, JC-
F = 31.7 Hz), 115.4 (t, JC-F = 288 Hz), 124.7, 125.5, 127.1, 128.6,
128.7, 130.9, 141.7, 141.8, 142.3, 169.4; 19F NMR (470 MHz, ppm,
Using the same method as described above, (ꢀ)-9d was
22
prepared in 50% yield starting from (ꢀ)-1 (>99% ee): [
a]
D
CDCl3)
d
24.0 (1F, dd, J = 43.0 Hz, 12.0 Hz), 24.3 (2F, d, J = 34.0 Hz),
ꢀ8.43 (c 0.83, CHCl3); Rf 0.63 (ethyl acetate/hexane = 1:4); m.p.
24.6 (1F, dd, J = 26.0 Hz, 12.0 Hz); IR (neat, cmꢀ1) 2963, 2926, 2874,
1719, 1449, 13350 1333, 1227, 1194, 1055, 739; HRMS (MALDI-
TOF MS, matrix: SA) found 676.2238 (C42H32F4O6, calcd:
676.2200). Using (+)-1 (94% ee) as a starting material, (+)-8 was
44–45 8C; 1H NMR (500 MHz, ppm, CDCl3)
d
0.888 (6H, t,
J = 6.9 Hz), 1.24–1.83 (34H, m), 3.96 (4H, t, J = 6.7 Hz), 4.34–4.38
(2H, m), 4.46–4.50 (2H, m), 6.85 (4H, d, J = 9.2 Hz), 7.94 (4H, d,
J = 8.7 Hz); 13C NMR (125 MHz, ppm, CDCl3)
d 14.06, 22.63, 23.07,
obtained in a similar yield: [
a
]
D
21 +3.60 (c 1.00 CHCl3). CD spectra
25.97, 29.09–29.59 (m), 31.18 (t, JC-F = 9.5 Hz), 31.78, 58.43 (d, JC-
F = 4.8 Hz), 68.21, 114.17, 115.55 (dd, JC-F = 296 Hz, 289 Hz),
121.75, 131.51, 163.18, 166.10; 19F NMR (470 MHz, ppm, CDCl3)
13.77 (2F, d, J = 161 Hz), 24.52 (2F, ddd, J = 172 Hz, 161 Hz,
11.3 Hz); IR (KBr, cmꢀ1) 2926, 2856, 1719, 1607, 1578, 1510,
1474, 1421, 1389, 1256, 997; Anal. Calcd for C42H56F4O6; C, 68.83;
H, 7.70. Found: C, 68.94; H, 7.42.
of (ꢀ)-8 or (+)-8 was measured as CH3CN solution (8.87 ꢂ 10ꢀ4 M)
at 15 8C using 1.00 cm cell.
4.9. Synthesis of (+)-9a
To a suspension of NaH (48 mg, 1.2 mmol) in DMF (2.0 ml) was
added a DMF (1.0 ml) solution of (+)-1 (>99% ee) at 0 8C, then a
DMF (1.0 ml) solution of n-nonylbromide (250 mg, 1.2 mmol) was
added and the mixture was stirred at rt for 12 h. The reaction was
quenched by addition of water and extracted with diethyl ether.
The combined organic layers were washed with water and brine,
dried (MgSO4), and purified by silica gel flash column chromato-
4.13. Synthesis of (ꢀ)-9e
Using the same method as described above, (ꢀ)-9e was
24
prepared in 73% yield starting from (ꢀ)-1 (>99% ee): [
a]
D
ꢀ2.91 (c 1.5, CHCl3); Rf 0.34 (ethyl acetate/hexane = 7:1); 1H NMR
graphy (ethyl acetate/hexane, 0:1 to 1:10) to afford (+)-9a
(500 MHz, ppm, CDCl3) d 0.893 (6H, t, J = 6.9 Hz), 1.26–1.85 (30H,
23
(170 mg) in 80% yield: [
a
]
+2.74 (c 0.96, CHCl3); Rf 0.53 (ethyl
0.88 (6H,
t, J = 6.9 Hz), 1.27–1.31 (24H, m), 1.54–1.66 (14H, m), 3.33–3.38
m), 3.97 (4H, t, J = 6.6 Hz), 4.37–4.41 (2H, m), 4.55–4.59 (2H, m),
6.92 (4H, d, J = 8.7 Hz), 7.45 (4H, d, J = 8.7 Hz), 7.52 (4H, d,
J = 8.3 Hz), 8.02 (4H, d, J = 8.3 Hz); 13C NMR (125 MHz, ppm, CDCl3)
D
acetate/hexane = 1:7); 1H NMR (500 MHz, ppm, CDCl3)
d

T. Itoh et al. / Journal of Fluorine Chemistry 130 (2009) 1157–1163
1163
(d) T. Itoh, N. Ishida, M. Ohashi, R. Asep, H. Nohira, Chem. Lett. 32 (2003) 494–
495;
(e) T. Itoh, N. Ishida, K. Mitsukura, K. Uneyama, J. Fluorine Chem. 112 (2001) 63–
68;
d
14.08, 22.65, 23.12, 26.04, 29.24–29.69 (m), 31.27 (t, JC-
F = 9.1 Hz), 31.81, 58.75 (d, JC-F = 4.8 Hz), 68.10, 114.86, 115.52
(dd, J = 296 Hz, 289 Hz), 126.47, 127.59, 128.26, 130.00, 131.81,
145.56, 159.47, 166.29; 19F NMR (470 MHz, ppm, CDCl3); 13.91
(2F, d, J = 161 Hz), 24.62 (2F, ddd, J = 173 Hz, 161 Hz, 11.8 Hz); IR
(KBr, cmꢀ1) 2924, 2855, 1713, 1605, 1524, 1499, 1474, 1310, 1277,
1244; Anal. Calcd for C54H64F4O6; C, 73.28; H, 7.29. Found: C,
73.81; H, 7.75.
(f) T. Itoh, K. Mitsukura, N. Ishida, K. Uneyama, Org. Lett. 2 (2000) 1431–1434;
(g) K. Mitsukura, S. Korekiyo, T. Itoh, Tetrahedron Lett. 40 (1999) 5739–5742;
(h) T. Itoh, K. Mitsukura, M. Furutani, Chem. Lett. (1998) 903–904.
[6] For a good review see: B. List, A. Doehring, F.M.T. Hechavarria, A. Job, T.R. Rios,
Tetrahedron, 62 (2005) 476–482.
[7] K. Miyazawa, D.S. Yufit, J.A.K. Howard, A. de Meijere, Eur. J. Org. Chem. (2000)
4109.
[8] P.S. Engel, R.L. Allgren, W.-K. Chae, R.A. Leckonby, N.A. Marron, J. Org. Chem. 44
(1979) 4233–4239.
[9] G.H. Posner, S.H.T. Lee, H.J. Kim, S. Peleg, P. Dolanc, T.W. Kenslerc, Bioorg. Med.
Chem. 13 (2005) 2959–2966.
Acknowledgments
This work was supported in part by a Grant-in-Aid for Scientific
Research from the Ministry of Education, Culture, Sports, Science,
and Technology, Japan. The authors are grateful to Meito Sangyo
Co., Ltd., for providing the lipase.
[10] Crystallographic data for compound 7 have been deposited to the Cambridge
Crystallographic Data Centre as supplementary publication number CCDC
731672. Copies of the data can be obtained free of charge, on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax: +44(1223)336033 or e-mail:
data_request@ccdc.cam.ac.uk.
[11] For a nice recent review on lipase technology in organic syntheses see:, T.
Matsuda (Ed.), Future Directions in Biocatalysis, Elsevier Bioscience, The Nether-
lands, 2007.
References
[12] We used E* value for evaluating the lipase enantioselectivity because the reaction
included two steps (monoester formation and subsequent rapid formation of
diacetate). For the E value see: C.-S. Chen, Y. Fujimoto, G. Girdauskas, C.J. Sih, J. Am.
Chem. Soc. 102 (1982) 7294–7298.
[13] (a) S. Egusa, M. Sisido, Y. Imanishi, Bull. Chem. Soc. Jpn. 59 (1986) 3175–3178;
(b) B. Weckerle, P. Schreier, H.-U. Humpf, J. Org. Chem. 66 (2001) 8160–8164.
[14] For CD exciton theory, see: N. Harada, K. Nakanishi, Circular Dichroic Spectro-
scopy-Exciton Coupling in Organic Stereochemistry, University Science Books/
Oxford University Press, Mill Valley, CA/Oxford, 1983.
[15] For a good review see: P. Kirsch, M. Bremer, Angew. Chem. Int. Ed. 39 (2000)
4216–4235.
[16] A.N. Collins, G.N. Sheldrake, J. Crosby, Chirality in Industry II, John Wiley and Sons,
Ltd., Chichester, UK, 1997 (Chapter 13).
[1] For a review see: A. de Meijere (Ed.), Cyclopropanes and Related Rings, Chem. Rev.
103 (2003) 931–1648.
[2] Reviews see:
(a) I. Ojima (Ed.), Fluorine in Bioorganic and Medicinal Chemistry, Wiley–Black-
well, London, UK, 2009;
(b) K. Uneyama, Organofluorine Chemistry, Blackwell Publishing, London, 2006;
(c) V.A. Soloshonok (Ed.), Fluorine-Containing Synthons, ACS Symposium Series
911, Oxford University Press/American Chemical Society, Washington, DC, 2005;
(d) T. Hiyama, Organofluorine Compounds Chemistry and Applications,
Springer-Verlag, Berlin, Heidelberg, 2000.
[3] Reviews for the synthesis of gem-difluorocyclopropanes see:
(a) M.J. Tozer, T.F. Herpin, Tetrahedron 52 (1996) 8619–8683;
(b) M. Fedorynski, Chem. Rev. 103 (2003) 1099–1132.
[4] For our most recent review see:
(a) T. Itoh, in: I. Ojima (Ed.), Fluorine in Bioorganic and Medicinal Chemistry,
Wiley–Blackwell, London, UK, 2009 , pp. 313–355 (Chapter 12).
[5] (a) T. Itoh, M. Kanbara, M. Ohashi, S. Hayase, M. Kawatsura, T. Kato, K. Miyazawa,
H. Uno, J. Fluorine Chem. 128 (2007) 1112–1120;
[17] (a) Y. Aoki, K. Matsushima, T. Taroura, T. Hirose, H. Nohira, Mol. Cryst. Liq. Cryst.
398 (2003) 189–193;
(b) K. Tojo, Y. Aoki, M. Yasutake, T. Hirose, J. Fluorine Chem. 127 (2006) 620–626;
(c) P. Kirsch, T. Mergner, J. Fluorine Chem. 127 (2006) 146–149;
(d) T. Yamaguchi, T. Inagaw, H. Nakazumi, S. Irie, M. Irie, Chem. Mater. 12 (2000)
869–871;
(b) K. Ninomiya, K. Tanimoto, N. Ishida, D. Horii, M. Sisido, T. Itoh, J. Fluorine
Chem. 127 (2006) 651–656;
(c) T. Itoh, N. Ishida, K. Mitsukura, S. Hayase, K. Ohashi, J. Fluorine Chem. 125
(2004) 775–783;
(e) M. Acimis, E.B. Karaman, J. Colloid Interface Sci. 300 (2006) 1–6.
[18] T. Kato, M. Ushioda, K. Miyazawa, Liq. Cryst. 33 (2006) 543–548.
[19] R. Cano, Bull. Soc. Fr. Miner. Crystallogr. 91 (1968) 20–27.