gem-Difluorocyclopropane as core molecule candidate for liquid crystal compounds

Article abstract of DOI:10.1016/j.jfluchem.2007.05.004

The synthesis of a novel chiral gem-difluorocyclopropane building block has been accomplished using chemo-enzymatic reaction protocol; the prochiral diol of 1,4-bis(2,2-difluoro-3-(hydroxymethyl)cyclopropyl)benzene (5) was converted to the corresponding c

Full text of DOI:10.1016/j.jfluchem.2007.05.004

Journal of Fluorine Chemistry 128 (2007) 1112–1120
www.elsevier.com/locate/fluor
gem-Difluorocyclopropane as core molecule candidate
for liquid crystal compounds
a
a
a
a
Toshiyuki Itoh a, , Manabu Kanbara , Masakazu Ohashi , Shuichi Hayase , Motoi Kawatsura ,
*
Takashi Kato b, Kazutoshi Miyazawa b, Yumiko Takagi c, Hidemitsu Uno d
a Department of Materials Science, Faculty of Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
b Chisso Petrochemical Corporation, Goi Research Center, Research Laboratory I, 5-1 Goi-kaigan, Ichihara-shi, Chiba 290-8551, Japan
c Department of Chemistry, Faculty of Education, Kagawa University, 1-1 Saiwai-cho, Taka-matsu 760-8522, Japan
d Integrated Center for Sciences, Ehime University, 2-5 Bunkyo-cho, Matsuyama 790-8577, Japan
Received 12 March 2007; received in revised form 4 May 2007; accepted 7 May 2007
Available online 13 May 2007
Abstract
The synthesis of a novel chiral gem-difluorocyclopropane building block has been accomplished using chemo-enzymatic reaction protocol; the
prochiral diol of 1,4-bis(2,2-difluoro-3-(hydroxymethyl)cyclopropyl)benzene (5) was converted to the corresponding chiral diacetate by
Pseudomonas lipase (lipase SL-25, Meito)-catalyzed transesterification with vinyl acetate as acyl donor with >99% enantiomeric excess.
Various types of diesters or dialkyl ether were prepared from the diol and their helical twisting power (HTP) was evaluated by addition of 1.0 wt%
to a non-chiral nematic liquid crystal host; the HTP was significantly dependent on the structure of ester or ether moieties and diester of diol 5 with
isopropylfumalic acid showed the largest HTP.
# 2007 Elsevier B.V. All rights reserved.
Keywords: gem-Diflurocyclopropane; Lipase-catalyzed reaction; Enantiomerically pure; Liquid crystal; Chiral dopant; Helical twisted power
1. Introduction
helically shaped compound which possesses a 7,7-difluorospiro
[2.0.2.1] heptane moiety has been reported by Miyazawa, de
Meijere and co-workers; it was established that the compound
showed ferroelectric liquid crystalline property [5]. We were
stimulated by the results and prepared 40-n-nonyloxybiphenyl
derivatives 3 and 4 and found that both compounds indeed
showed liquid crystalline properties with different modes;
compound 4 showed SmC* phase, while compound 3 showed
only SmA phase (Fig. 1) [4e]. Recently liquid crystal displays
(LCD) have become an inseparable part of our daily life.
Therefore, development of new materials that have good
electrooptical properties for LCD has now been recognized as
a very importanttopic in the filed of organic synthesis [6]. To gain
insight into designing novel liquid crystalline compounds based
on the gem-difluorocyclopropane molecules, we designed
difluorocyclopropane 6 that has a benzene ring as a spacer unit
between two gem-difluorocyclopropane moieties and is derived
from compound 5 (Fig. 1). In this paper we report the results of
the syntheses of novel gem-difluorocyclopropane compound 5 in
optically active form and investigation of properties of their
derivatives in liquid crystal chemistry.
Thesubstitution ofa fluorineatom onanorganicmoleculecan
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 properties
[1]. The utility of cyclopropane derivatives in the construction of
a variety of cyclic and acyclic organic compounds has been
amply demonstrated [2]. We have been synthesizing novel
molecules that have gem-difluorocyclopropane moieties [3]
usingouroriginalchiralgem-diflurocyclopropane1andbis-gem-
diflurocyclopropane 2 as building blocks [4]. CD spectroscopic
analysis of 9-anthracenecarboxylic acid diester of 2 showed that
the tetrafluorobicyclopropane group exists with a helical shape
configuration; this seems to suggest that a unique helically
shaped compound may be produced from gem-diflurocyclopro-
panes as building blocks [4h]. Recently, synthesis of a unique
* 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 # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.05.004

T. Itoh et al. / Journal of Fluorine Chemistry 128 (2007) 1112–1120
1113
ether was not appropriate for the protecting group because
significant decomposition of the difluorocyclopropane moieties
took place during the de-protection step of the benzyl group by
hydrogenation. So, diol 8 was converted to bis-methoxymethyl
(MOM) ether 9 which was subjected to the reaction with
difluorocarbene produced from pyrolysis of sodium chlorodi-
fluoroacetate; bis-gem-difluorocyclopropane 10 was thus
obtained and de-protection of the MOM ether groups gave
desired compound 5 in excellent yield (92% from 10) as a
mixture of meso- and DL-form (1:1). Fortunately, we succeeded
in obtaining a good crystal of meso-5 by recrystallization from a
mixed solvent of acetone and hexane. As shown in Fig. 2 of the
ORTEP view of meso-5, there was an interesting difference in
the crystalline structure found between 5 and 2: the two
difluorocyclopropane rings of 5 locate at the same plane, while
they locate at the opposite site for bis-gem-diflurocyclopropane
2 [3h].
Optical resolution of racemic 5 was accomplished by lipase
technology [9] and the results are shown in Table 1. Lipase SL-
25, Lipase PS, and Lipase QL gave good results (Entries 1–3).
With Lipase SL-25 being the best enzyme from the standpoint
of enantioselectivity among them. The highest E* value [10]
obtained for Lipase SL-25 catalyzed reaction was estimated to
be 55 (Entry 1). The most rapid reaction was observed when
lipase QL was used as catalyst, though the enantioselectivity
remained at a moderate level (Entry 3). In contrast, no
enantioselctivity was obtained for Novozym 435 (Entry 4), nor
did any reaction take place when lipase AY was employed as
catalyst (Entry 5). Since the lipase-catalyzed reaction was a
kinetic resolution, we succeeded in obtaining optically pure
diol (+)-5 easily, and thus handed both enantiomers of diol 5.
An interesting point was found in the enantiofavoritism of
the enzymatic reactions. (ꢀ)-Diacetate 12 and (+)-diol 5 were
obtained for three enzymatic reactions (Entries 1–3). Mono-
acetate 11 was converted to diol 5 and assigned to be the meso
form because the diol showed no specific rotation value and 1H
NMR spectra coincided with those of meso-5. According to the
sign of specific rotation value of diacetate 12, it was assumed
that the produced (ꢀ)-diacetate 12 was (R,S,S,R)-isomer, and
that, (+)-diol 12 unreacted was (S,R,R,S)-isomer [4d,4h]; these
three lipases prefer to react with the hydroxyl group that has
(R)-configuration. On the other hand, we had previously
established that the same enzymes, SL-25 and QL, reacted with
bis-gem-difluorocyclopropane 1 or 2 with (S)-enatiofavoritism
[4d,4h]. This seems to mean that the phenyl group between the
two gem-difluorocyclopropane rings seemed to cause a
modification in the enantiofavoritism of these enzymes.
Fig. 1. Core molecules for liquid crystals that have gem-difluorocyclopropane
moiety.
2. Results and discussion
2.1. Synthesis of optically active 1,4-bis(2,2-difluoro-3-
(hydroxymethyl)cyclopropyl)benzene (5) using chemo
enzymatic reaction
Synthesis of a racemic and DL mixture of gem-difluorocy-
clopropane 5 was accomplished following Scheme 1. (E,E)-
Diene 7 was prepared using terephthaldicarboxaldehyde as a
starting material by Horner-Wadsworth-Emmons reaction in
93% yield [6], and subsequent diisobutylalminum hydride
(DIBAL) reduction of the ethoxycarbonyl groups of 7 to give
1,4-bis((E)-2-hydroxy-1-propenyl)benzene (8) in 86% yield
[7]. We initially prepared benzyl ether derivative 9 (R = Ben-
zyl) and converted it to the gem-difluorocyclopropane; the
corresponding gem-difluorocyclopropane was obtained in
excellent yield, however, we soon recognized that benzyl
2.2. Helical twisting power of gem-diflurocyclopropane
derivatives
Optically pure diol 5 was converted to bis-n-nonyl ether 6a
and four types of esters 6b, 6c, 6d, and 6e and their liquid
crystal property was investigated. Although we expected that
liquid crystal properties might be found for these compounds,
none showed this property. Chiral nematic liquid crystals
having macro helical structure are currently used in LCD

1114
T. Itoh et al. / Journal of Fluorine Chemistry 128 (2007) 1112–1120
Scheme 1.
devices [6]; the chiral nematic materials consist of achiral host
mixtures of nematic liquid crystals and a chiral dopant with
helical twisting power [HTP][11]. Generally, the chiral nematic
materials that are used in good LCD devices consist of achiral
host mixture of nematic liquid crystals and a chiral dopnat with
a large helical twisting power (HTP). Therefore, it is very
important to develop efficient chiral dopant materials with
having large HTP. The syntheses of fluorinated compounds that
have large HTP have been reported by several groups [12–15].
So we investigated the HTP of our gem-difluorocyclopropane
compounds 6a–6e and found that all of them had helical
twisting power (HTP) when 1.0 wt% was added to the host
achiral nematic liquid crystal [16]. The helical pitches in the
chiral nematic phases were measured using Cano wedge cells
[17]: 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 [17], and the results are summarized in Fig. 3.
Fig. 2. ORTEP view of meso-5.

T. Itoh et al. / Journal of Fluorine Chemistry 128 (2007) 1112–1120
1115
Table 1
Results of lipase-catalyzed acylation of meso- and DL-5
Entry
Lipase
Time
Yield of 11a (meso)
Yield of 12a,b (% ee)
Yield of 5a,b (% ee)
c*c
E*c
1
2
3
4
5
Lipase SL-25
Lipase PS
105 min
180 min
20 min
5 min
43%
38%
41%
0%
29% (90% ee)
31% (75% ee)
47% (61% ee)
82% (0.8% ee)
0% (–)
28% (88% ee)
31% (80% ee)
3% (99% ee)
0% (–)
0.49
0.52
0.62
–
55
17
23
–
Lipase QL
Novozym435
Lipase AY
2 days
0%
99% (0% ee)
–
–
a
Isolated yield.
b
c
Determined by HPLC analysis using Chiralcel OD-H (hexane:i-PrOH = 4:1).
Since the reaction included two processes, E* value was the result of two reactions. E* = ln[(1 ꢀ c)(1 ꢀ ee12)]/ln[(1 ꢀ c)(1 + ee12)], here c* = ee5/(ee12 + ee5).
Fig. 3. Helical twisting power of various cyclopropane derivatives.

1116
T. Itoh et al. / Journal of Fluorine Chemistry 128 (2007) 1112–1120
Among them, compounds 6c, 6d, and 6e showed large HTP
by weight). The physical properties of the host mixture are
TNI = 72.4 8C, De = 11.0, Dn = 0.137.
values, 19.6, 16.7 and 17.2 mmꢀ1, respectively, values ca. four-
fold larger than that of cholesteryl caprylate (HTP = 4.4 mmꢀ1).
The HTP values were significantly dependent on the ester group,
and it was found that introduction of isopropylfumalic acid
moiety was very effective to obtain high HTP values.
4.2. (E)-Diethyl p-phenylenediacrylate (7) [7]
To a solution of the sodium hydride in tetrahydrofuran
(THF) (60 mL) was added ethyl diethylphosphonoacetetate
(17 g, 75 mmol) in THF (60 mL) at 0 8C and the mixture was
stirred for 2 h at rt, then terephthalaldehyde (4.0 g, 30 mmol) in
THF (60 mL) was added. After being stirred for 30 min at the
same temperature, the reaction was quenched by addition of
saturated aq. NH4Cl and 2 M HCl. Extraction with ethyl
acetate, dried over MgSO4, concentrated under vacuum, and
purified by silica gel flash column chromatography (ethyl
acetate–hexane, 0:1–1:5) gave (E)-diester 7 (3.3 g) in 93%
To gain insight in the role of the benzene ring between gem-
difluorcyclopropane for helical twisting power, we prepared
three types of bis-isopropylfumalate derivatives, (ꢀ)-13, (ꢀ)-
14, and (+)-15, but all these had smaller HTP values than 6e.
Flexibility of the gem-difluorocyclopropane moiety seems to
play an important part in determining the helical twisting
ability, and the rigid form of the core part of the molecule seems
to be important for obtaining high HTP, because the lowest HTP
value was obtained for (ꢀ)-13. It was thus established that gem-
difluorocyclopropane compound showed good property as a
chiral dopant that caused helical twisting of achiral host
mixture of nematic liquid crystal compounds.
1
yield: Rf 0.5 (hexane/ethyl acetate = 4:1); mp 114–116 8C; H
NMR (500 MHz, CDCl3) d 1.28 (6H, t, J = 7.3 Hz), 4.21–4.23
(4H, m), 6.40 (2H, d, J = 16.1 Hz), 7.47 (4H, s), 7.60 (2H, d,
J = 16.0 Hz); 13C NMR (125 MHz, CDCl3) d 14.18, 60.48,
119.21, 128.36, 136.01, 143.25, 166.55; IR (KBr, cmꢀ1) 3393,
1701, 1632, 1512, 1448, 1474, 1420, 1366, 1323, 1306; Anal.
Calcd for C12H14O2; C, 75.76; H, 7.42. Found: C, 70.22;
H, 7.23.
3. Conclusion
In summary, we accomplished the synthesis of various types
of unique diether or diester based on optically active bis-
hydroxymethyl-gem-difluorocyclopropane compounds as
building blocks. These compounds have interesting properties;
in particular, compounds (+)-6c, (+)-6d and (+)-6e acted caused
helical twisting 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.
4.3. 1,4-Bis(3-hydroxy-1-((E)-propenyl)benzene (8) [8]
To a solution of 7 (14 g, 50 mmol) in toluene (280 mL) was
added diisobutylaluminum hydride (230 mL, 1.5 M in toluene,
230 mmol) at ꢀ20 8C and the reaction mixture was stirred for
12 h allowed to RT. The reaction was quenched by addition of
potassium fluoride and water, then extracted with ethyl acetate,
dried over MgSO4, and concentrated under vacuum. Re-
crystallization in ether gaive diol 8 (8.2 g) in 86% yield: Rf
0.34 (hexane/ethyl acetate/methanol = 4:4:1); 1H NMR
(500 MHz, CDCl3 + D3COD) d 2.11 (2H, s), 4.27–4.29 (4H,
m), 6.33–6.37 (2H, m), 6.56–6.60 (2H, m), 7.35 (4H, s); 13C
NMR (125 MHz, D3COD) d 63.67, 127.64, 129.89, 131.18,
137.65; IR (KBr, cmꢀ1) 3751, 3726, 3269, 3024, 2839, 2718,
2446, 1911, 1655, 1541.
4. Experimental
4.1. General procedures
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 atmosphere of dry
argon. Wako gel C-300 and Wako gel B5F were used for the
flash column chromatography and thin-layer chromatography
4.4. 1,4-Bis((E)-3-(methoxymethoxy)prop-1-enyl)benzene
(9)
1
(TLC). H NMR spectra, 13C NMR spectra and 19F NMR
spectra were recoded on JEOL JNM MH-500 spectrometer.
Chemical shifts are expressed in d value (ppm) downfield from
tetramethylsilane (TMS) in CDCl3 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. Optical purity was
determined by HPLC analysis using chiralcel OD-H (Daicel).
Helical twisted power of gem-difluorocyclopropane derivatives
were estimated by the distance between the stripes appeared
using a microscope in the Cano’s type wedge-shaped when
1.0 wt% of gem-diflurocyclopropane was dissolved in the
achiral nematic host mixture consisted of cyanobenzene
To dichloromethane (340 mL) solution of 8 (13 g, 68 mmol)
were added diisopropylethylamine (22 g, 170 mmol) and
chloromethoxymethane at 0 8C and the mixture was stirred
for 3 h at rt and extracted with ethyl acetate. The combined
organic layers were washed with water and brine, dried over
MgSO4, and concentrated. Silica gel flash column chromato-
graphy (ethyl acetate–hexane, 20:1–4:1) afforded di-MOM-
ether 9 (14 g) in 76% yield: Rf 0.30 (hexane/ethyl acet-
1
ate = 4:1); mp 65–67 8C; H NMR (500 MHz, CDCl3) d 3.34
(6H, s), 4.16–4.17 (4H, m), 4.64 (4H, s) 6.21–6.24 (2H, m),
6.53–6.56 (2H, m), 7.28 (4H, s); 13C NMR (125 MHz, CDCl3) d
55.20, 67.73, 95.59, 125.50, 126.63, 132.06, 136.03; IR
(KBr, cmꢀ1) 3854, 3751, 1653, 1558, 1508, 1458, 1381, 1211,
1146, 1097.
compopunds:
1-cyano-4-(trans-4-n-propylcyclohexyl)ben-
zene, 1-cyano-4-(trans-4-n-heptylcyclohexyl)benzene, 4-
cyano-40-(trans-4-n-heptylcyclohexyl)biphenyl (24:36:25:15

T. Itoh et al. / Journal of Fluorine Chemistry 128 (2007) 1112–1120
1117
4.5. 1,4-Bis(2,2-difluoro-3-
(methoxymethoxymethyl)cyclopropyl)benzene (5)
through a sintered glass filter with a Celite pad and the filtrate
was concentrated under vacuum. Silica gel TLC (acetone–
hexane, 2:1) gave (ꢀ)-diacetate 12 (23 mg, 29%), monoacetate
11 (32 mg, 48%), and (+)-diol 5 (22 mg, 28%):
To a dry diglyme (20 mL) solution of di-MOM-ether 9 (14 g,
52 mmol) was added 150 mL of diglyme solution of sodium
chlorodifluoroacetate (87 g, 570 mmol) drop wise at 190 8C
over 4 h with vigorous stirring. After being kept at 190 8C for
an additional 2 h, the reaction mixture was allowed to cool to
room temperature (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 under reduced pressure to
give di-MOM-ether 10. Since it was difficult to remove diglyme
at this stage, this was used for the nxet reaction without further
purification.
29
Monoacetate 11: ½aꢂD ꢀ 1:83 (c 1.2, MeOH), a mixture of
meso-11 and a small amount of (ꢀ)-11; Rf 0.32 (acetone/
hexane = 1:2); 1H NMR (500 MHz, CDCl3) d 1.70 (1H, s), 2.03
(3H, s) 2.11–2.19 (2H, m), 3.80–3.82 (1H, m), 3.81–3.90 (1H,
m), 4.15–4.20 (1H, m), 4.25–4.30 (1H, m), 7.12 (4H, d,
J = 2.8 Hz); 13C NMR (125 MHz, CDCl3) d 20.5, 27.8 (t, JC–
F = 9.6 Hz), 30.8 (t, JC–F = 11.6 Hz), 31.1 (t, JC–F = 8.6 Hz),
31.3 (t, JC–F = 10.6 Hz), 59.1 (d, JC–F = 3.9 Hz), 60.7 (d, JC–
F = 4.8 Hz), 113.2 (td, JC–F = 212, 77.8 Hz), 128.1 (d, JC–
F = 5.7 Hz), 131.9 (d, JC–F = 107 Hz), 171.2; 19F NMR
(470 MHz, CDCl3) d 24.34–26.44 (m); IR (neat, cmꢀ1
)
3854, 3751, 3690, 3676, 3398, 2891, 1707, 1560, 1524, 1508.
To the methanol (200 mL) solution of di-MOM-ether 10 was
added conc. hydrochloric acid drop wise and stirred under
reflux conditions for 2 h. After being cooled to rt, the mixture
was extracted with ethyl acetate. The combined organic layers
were washed with water and brine, dried over MgSO4, and
concentrated under reduced pressure. Silica gel flash column
chromatography (ethyl acetate–hexane, 5:1–4:1) afforded diol
5 (14 g) in 92% yield as a mixture of meso and DL mixture (2
steps): Rf 0.32 (hexane/ethyl acetate = 3:1); 1H NMR
(500 MHz, CDCl3) d 2.17 (2H, sex, J = 6.7 Hz), 2.54 (2H, q,
J = 7.4 Hz), 3.53 (6H, s), 3.74 (4H, d, J = 12.0 Hz), 4.65 (4H,
s), 7.18 (4H, s); 13C NMR (125 MHz, CDCl3) 29.13 (t, JC–
F = 95.4 Hz), 31.33 (t, JC–F = 105 Hz), 55.21, 63.91, 96.17,
4.6.1. Diacetate (ꢀ)-12
29
29
90% ee: ½aꢂD ꢀ 36:3 (c 1.2, MeOH), >99% ee: ½aꢂD ꢀ 40:3
(c 1.0, MeOH). Enantiomeric excess of (ꢀ)-12 was deyermined
by HPLC analysis using Chiralcel OD-H, hexane/2-propanol
(9:1), 35 8C. Rt (R,R) = 17 min, Rt (meso) = 11 min, and Rt
(S,S) = 9.3 min.; Rf 0.50 (acetone/hexane = 1:2); 1H NMR
(500 MHz, CDCl3) d 2.09 (6H, s), 2.23 (2H,s ex, J = 7.8 Hz),
4.10–4.25 (2H, m), 4.31–4.35 (2H, m), 7.17 (4H, s); 13C NMR
(125 MHz, CDCl3) d 20.5, 27.9 (t, JC–F = 9.6 Hz), 31.4 (t, JC–
F = 10.5 Hz), 60.6 (d, JC–F = 4.8 Hz), 112.8 (t, JC–F = 289 Hz),
128.2, 131.8, 170.7; 19F NMR (470 MHz, CDCl3) d 24.37–
26.49 (m); IR (neat, cmꢀ1) 3854, 3751, 3690, 3676, 3651, 2963,
1742, 1701, 1560, 1508.
113.25 (t,
J
C–F = 288 Hz), 128.14, 132.19; 19F NMR
(470 MHz, CDCl3) 11.49–11.59 (m), 36.45 (d, J = 35.2 Hz);
IR (neat, cmꢀ1) 3854, 3651, 2889, 2827, 1524, 1474, 1389,
1271, 1219, 1180.
4.6.2. Diol (+)-5
29
29
Recrystallization from acetone and hexane gave pure meso-5
and X-ray crystallographic analysis was successfully carried
out.
88% ee: ½aꢂD þ 18:9 (c 1.1, MeOH), >99% ee: ½aꢂD þ 22:5
(c 1.0, MeOH). Enantiomeric excess of (+)-5 was determined
by HPLC analysis using Chiralcel OD-H, hexane/2-propanol
(4:1), 35 8C. Rt (R,R) = 8.8 min, Rt (meso) = 11 min, and Rt
(S,S) = 10.0 min; Rf 0.14 (acetone/hexane = 1:2); mp 118–
120 8C; 1H NMR (500 MHz, CDCl3) d 1.63 (2H, s), 2.15–2.17
(2H, m), 2.56–2.59 (2H, m), 3.81–3.86 (2H, m), 3.90–3.95 (2H,
m), 7.17 (4H, s); 13C NMR (125 MHz, CDCl3) d 31.60 (t, JC–
F = 11.4 Hz), 32.09 (t, JC–F = 9.54 Hz), 59.12, 115.19 (t, JC–
F = 286 Hz), 128.93, 133.38; 19F NMR (470 MHz, CDCl3) d
24.65–25.68 (m); IR (neat, cmꢀ1) 3906, 3854, 3751, 3690,
3676, 3651, 3368, 2893, 1701, 1647; Anal. Calcd for
C14H14F4O2; C, 57.93; H, 4.86. Found: C, 57.77; H, 4.84.
(meso)-5: Rf 0.14 (acetone/hexane = 1:2); mp 158–160 8C;
1H NMR (500 MHz, CDCl3) d 2.19 (2H, sex. d, J = 5.5,
2.3 Hz), 2.63–2.67 (2H, m), 3.71–3.75 (2H, m), 3.77–3.81 (2H,
m), 7.21 (4H, s); 13C NMR (125 MHz, CDCl3) d 32.2 (q,
J = 10.6 Hz), 59.6 (d, JC–F = 3.8 Hz), 115.2 (t, JC–F = 289 Hz),
129.2, 133.7; 19F NMR (470 MHz, CDCl3) d 23.3 (qd, J = 144,
69, 11.5 Hz); IR (KBr, cmꢀ1); 3269, 3032, 2914, 2853, 2613,
1526, 1477, 1414, 1250, 1177; Anal. Calcd for C14H14F4O2; C,
57.93; H, 4.86. Found: C, 57.77; H, 4.81.
Crystal and refinement data for meso-5: C14H14F4O2,
formula weight = 394.41, triclinic, space group P11 (#2),
3
a = 5.6338 A, b = 8.9410, c = 13.133 A, V = 629.87 A , Z = 2,
˚
˚
˚
4.7. Results of lipase PS-catalyzed reaction
d
calc = 1.53 g cmꢀ3, R(Rw) = 0.0536 for 2795 diffraction data
with I > 3.00s (I) and 182 valuable.
28
Diacetate 12: 75% ee, ½aꢂD ꢀ 32:9 (c 1.1, MeOH), Y = 31%.
28
28
Monoacetate 11: ½aꢂD þ 2:00 (c 1.0, MeOH), Y = 46%.
4.6. Lipase-catalyzed optical resolution of (ꢁ)-5
Diol 5: 80% ee, ½aꢂD þ 13:2 (c 1.3, MeOH), Y = 24%.
To solution of 5 (60 mg, 0.21 mmol, racemic:meso = 1:1)
and vinyl acetate (36 mg, 0.42 mmol) in diisopropyl ether
(1.1 mL) was added Lipase SL-25 (30 mg, 50 wt%) and the
mixture was stirred at 35 8C for 1.8 h. The reaction course was
monitored by silica gel TLC. Lipase was removed by filtration
4.8. Results of lipase QL-catalyzed reaction
28
Diacetate 12: 61% ee, ½aꢂD ꢀ 42:3 (c 1.0, MeOH), Y = 47%.
28
Monoacetate 11: ½aꢂD28þ 13:1 (c 0.9, MeOH), Y = 41%.
Diol 5: >99% ee, ½aꢂD þ 29:0 (c 0.2, MeOH), Y = 3%.

1118
T. Itoh et al. / Journal of Fluorine Chemistry 128 (2007) 1112–1120
4.9. Results of Novozyme 435-catalyzed reaction
4.12. (+)-6c
25
Diacetate 12: 0.8% ee, ½aꢂD ꢀ 1:2 (c 1.0, MeOH), Y = 82%.
1
Rf 0.50 (ethyl acetate/hexane = 1:4); H NMR (500 MHz,
CDCl3) d 0.888 (6H, t, J = 7.3), 1.26–1.37 (16H, m), 1.44–1.47
(4H, m), 1.80, (4H, quin, J = 6.9 Hz), 2.36 (2H, sex,
J = 6.4 Hz), 2.73 (2H, dd, J = 14.2, 7.3 Hz), 4.01 (4H, t,
J = 6.4 Hz), 4.45–4.49 (2H, m), 4.54–4.58 (2H, m), 6.91 (4H, d,
J = 9.2 Hz), 7.20 (4H, s), 7.99 (4H, d, J = 8.71 Hz); 13C NMR
(125 MHz, CDCl3) d 14.0, 22.6, 25.9, 28.3 (t, JC–F = 9.6 Hz),
29.2 (t, JC–F = 13.4 Hz), 31.5 (t, JC–F = 11.5 Hz), 31.7, 60.8,
68.2, 113.0 (t, JC–F = 289 Hz), 114.1, 121.7, 128.3, 131.7,
132.0, 163.2, 166.1; 19F NMR (470 MHz, CDCl3) d 25.6 (ddd,
J = 587, 155, 17.3 Hz); IR (KBr, cmꢀ1); 3854, 3651, 2924,
2849, 1707, 1609, 1514, 1254, 1105, 1009.
4.10. Synthesis of (+)-6a
To a DMF (1.0 mL) suspension of sodium hydride (110 mg,
0.38 mmol) was added a DMF (2.0 mL) solution of diol (+)-5
(110 mg, 0.38 mmol, >99% ee) at 0 8C and the mixture was
stirred for 5 h at rt. To this mixture was added water and
extracted with Et2O. The combined organic layers were
washed with water and brine, dried over MgSO4, evaporated
and purified by silica gel flash column chromatography (ethyl
acetate:hexane = 1:20) gave (+)-6a (160 mg) in 78% yield:
24
½aꢂD þ 19:4 (c 1.0, CHCl3); Anal. Calcd for C44H54F4O6;
24
½aꢂD ꢀ 36:6 (c 1.0, CHCl3); Rf 0.56 (ethyl acetate/hex-
C, 70.01; H, 7.21. Found: C, 69.27; H, 7.16.
ane = 1:7); 1H NMR (500 MHz, CDCl3) d 0.880 (6H, t,
J = 7.33 Hz), 1.26–1.36 (20H, m), 1.56–1.61 (4H, m), 2.13
(2H, sex, J = 7.3 Hz), 2.53 (2H, dd, J = 14.7, 7.8 Hz), 3.41–
3.46 (2H, m), 3.48–3.53 (2H, m), 3.59–3.63 (2H, m), 3.69–
3.73 (2H, m), 7.18 (4H, s); 13C NMR (125 MHz, CDCl3) d
14.1, 22.7, 26.1, 29.3 (t, JC–F = 10.6 Hz), 29.4, 29.5, 29.7, 31.1
(t, JC–F = 11.5 Hz), 31.9, 66.7 (d, JC–F = 3.84 Hz), 70.8, 113.4
(t, JC–F = 289 Hz), 128.2, 132.3; 19F NMR (470 MHz, CDCl3)
d 25.4 (ddd, J = 726, 144, 11.5 Hz); IR (KBr, cmꢀ1) 3906,
2926, 2856, 1686, 1647, 1560, 1508, 1375, 1267, 1111; Anal.
Calcd for C30H50F4O2; C, 70.82; H, 9.29. Found: C, 70.28;
H, 9.00.
4.13. (+)-6d
1
Rf 0.42 (ethyl acetate/hexane = 1:4); H NMR (500 MHz,
CDCl3) d 0.878–0.905 (6H, m), 1.25–1.39 (20H, m), 1.81 (4H,
q, J = 7.8 Hz), 2.39 (2H, sex, J = 7.3 Hz), 2.76 (2H, dd, J = 15,
7.8 Hz), 4.00 (4H, t, J = 6.4 Hz), 4.50–4.54 (2H, m), 4.59–4.62
(2H, m), 6.87 (4H, d, J = 8.7 Hz), 7.22 (4H, s), 7.56 (4H, d,
J = 8.7 Hz), 7.63 (4H, d, J = 8.7 Hz), 8.09 (4H, d, J = 8.7 Hz);
13C NMR (125 MHz, CDCl3) d 14.1, 22.6, 26.0, 28.2, (t, JC–
F = 9.6 Hz), 29.2, 29.3, 31.6 (t, JC–F = 9.6 Hz), 31.8, 61.2, 68.1,
113.0 (t, JC–F = 290 Hz), 115.3, 126.5, 127.6, 128.3, 128.4,
130.2, 132.0 (d, JC–F = 2.9 Hz), 145.6, 159.5, 166.3; 19F NMR
4.11. Synthesis of (ꢀ)-6b
(470 MHz, CDCl3) d 24.7–26.7 (m); IR (KBr, cmꢀ1); 3854,
26
3427, 2928, 2854, 1719, 1605, 1474, 1267, 1180, 1109; ½aꢂD
þ
To a mixture of (ꢀ)-5 (220 mg, 0.69 mmol, >99% ee),
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide ethylene
dichloride (EDC) (63 mg, 0.33 mmol), nonanoic acid
(380 mg, 2.1 mmol), and 4-N,N0-dimethylaminopyridine
(DMAP) (270 mg, 2.2 mmol) in 10 mL of dichloromethane
(CH2Cl2) was added 0.25 mL of triethylamine (Et3N) at 0 8C
and the mixture was stirred for 5 h at 60 8C, then cooled to rt
and was extracted with Et2O. The combined organic layers
were washed with water and 2 M HCl, dried over MgSO4,
evaporated, and purified by silica gel flash column
chromatography (ethyl acetate–hexane, 1:50–1:6) to give
13:8 (c 0.90, CHCl3); Anal. Calcd for C56H62F4O6; C, 74.15; H,
6.89. Found: C, 75.09; H, 6.68.
4.14. (+)-6e
23
½aꢂD þ 31:0 (c 1.0, CHCl3); Rf 0.36 (ethyl acetate/
1
hexane = 1:4); H NMR (500 MHz, CDCl3) d 1.30 (12H, d,
J = 6.3 Hz), 2.29 (2H, sex, J = 7.3 Hz), 2.69 (2H, q,
J = 7.3 Hz), 4.39 (2H, m), 4.48 (2H, m), 5.12 (2H, seq,
J = 6.0 Hz), 6.87 (4H, d, J = 1.8 Hz), 7.19 (4H, s); 13C NMR
(125 MHz, CDCl3) d 21.8 (d, JC–F = 3.8 Hz), 27.9 (t, JC–
F = 10.6 Hz), 31.7 (t, JC–F = 10.6 Hz), 61.6 (d, JC–F = 4.7 Hz),
69.2 (d, JC–F = 7.7 Hz), 112.8 (t, JC–F = 290 Hz), 128.4, 131.9,
132.4 (t, JC–F = 3.8 Hz), 135.1 (t, JC–F = 2.9 Hz), 164.2, 164.8;
19F NMR (470 MHz, CDCl3) d 25.5 (ddd, J = 720, 144,
11.6 Hz); IR (KBr, cmꢀ1) 3414, 2856, 1734, 1481, 1393, 1267,
1175, 1034, 964; Anal. Calcd for C28H30F4O4; C, 67.35;
H, 8.12. Found: C, 67.27; H, 7.89.
28
diester (ꢀ)-6b (350 mg) in 90% yield: ½aꢂD ꢀ 52:6 (c 1.0,
CHCl3); Rf 0.58 (ethyl acetate/hexane = 4:1); 1H NMR
(500 MHz, CDCl3) d 0.860–0.889 (6H, m), 1.25–1.35 (20H,
m), 1.60–1.66 (4H, m), 2.24 (2H, quin, J = 7.8 Hz), 2.34 (4H,
t, J = 7.3 Hz), 2.64 (2H, dd, J = 14.6, 7.8 Hz), 4.23–4.27 (2H,
m), 4.33–4.36 (2H, m), 7.18 (4H, s); 13C NMR (125 MHz,
CDCl3) d 14.0, 22.6, 24.9, 28.1 (t, JC–F = 10.5 Hz), 29.0, 29.1,
31.5 (t, JC–F = 11.5 Hz), 31.7, 34.1, 60.4 (d, JC–F = 18.2 Hz),
112.9 (t, JC–F = 289 Hz), 128.3, 131.9, 173.7; 19F NMR
(470 MHz, CDCl3) d 24.4–26.6 (m); IR (KBr, cmꢀ1); 2928,
2856, 1736, 1719, 1707, 1524, 1458, 1221, 1161, 1111; Anal.
Calcd for C28H30F4O4; C, 67.35; H, 8.12. Found: C, 67.44;
H, 8.58.
4.15. Synthesis of (ꢀ)-13
4.15.1. Synthesis of 1,4-bis(2,2-difluoro-(3-t-butyldiphenyl-
silyloxymethyl)cyclopropylmethoxymethyl)benzene (ꢀ)-16
To a suspension of NaH (23 mg, 0.57 mmol, 60% in mineral
oil) in 1.0 mL of THF was added 2,2-difluoro-3-(t-butyldiphe-
nylsiliyoxymethyl)cyclopropylmethanol (143 mg, 0.38 mg,
Compounds (+)-6c, (+)-6d, and (+)-6e were prepared using
optically pure diol (+)-5 following to the similar method.

T. Itoh et al. / Journal of Fluorine Chemistry 128 (2007) 1112–1120
1119
>99% ee) [4d] at 0 8C under argon atmospheric conditions and
the mixture was stirred for 1 h at the same temperature. To this
mixture was added 1,4-di(bromomethyl)benzen (50 mg,
0.19 mmol) and the resulting mixture was stirred for 15 h at
rt. The reaction was quenched by the addition of several pieces
of ice and was extracted with ether. The combined organic
layers were dried over MgSO4 and evaporated and purified by
silica gel flash chromatography to give (ꢀ)-16 (135 mg,
0.7 (hexane/ethyl acetate = 4:1; 1H NMR (270 MHz, CDCl3) d
0.97 (18H, s), 1.48–1.62 (4H, m), 3.37–3.51 (4H, m), 3.68 (4H,
d, J = 6.0 Hz), 4.44 (4H, dd, J = 18.5, 11.5 Hz), 7.21–7.60
(24H, m); 13C NMR (125 MHz, CDCl3) d 19.13, 25.98 (t, JC–
F = 10.6 Hz), 26.73, 28.46 (t, JC–F = 10.0 Hz), 60.15 (d, JC–
F = 4.3 Hz), 66.04 (d, JC–F = 4.3 Hz), 72.10, 114.20 (t, JC–
F = 287.0 Hz), 127.71, 129.77, 133.20, 133.30, 133.53, 137.42;
19F NMR (471 MHz, CDCl3) d 22.91 (dd, J = 161.3, 14.4 Hz),
24.05 (dd, J = 161.2, 14.4 Hz); IR (neat, cmꢀ1) 2858, 1474,
1427, 1396, 1362, 1259, 1192, 1092, 102, 802.
J = 6.2 Hz), 1.92–1.99 (2H, m), 4.19–4.32 (4H, m), 5.05–5.14
(2H, m), 6.81 (4H, d, J = 1.9 Hz); 13C NMR (125 MHz, CDCl3)
d 21.64, 25.60 (t, JC–F = 10.6 Hz), 60.78, 69.08, 112.93 (t, JC–
F = 287.0 Hz), 132.18, 135.11, 164.08, 164.62; 19F NMR
(471 MHz, CDCl3) d 23.42 (s); IR (KBr, cmꢀ1) 2984, 1717,
1647, 1456, 1377, 1224, 1157, 1109, 988; Anal. Calcd for
C19H24F2O8; C, 54.54; H, 5.78. Found: C, 53.97; H, 5.72.
18
0.16 mmol) in 83% yield: ½aꢂD ꢀ 4:0 (c 1.0, CHCl3); Rf
4.16.2. (+)-(15)
27
½aꢂD þ 20:2 (c 1.0, CHCl3); Rf 0.4 (hexane/ethyl acet-
1
ate = 4:1); mp 90–95 8C; H NMR (270 MHz, CDCl3) d 1.30
(12H, d, J = 6.2 Hz), 1.67–1.75 (4H, m), 4.18–4.33 (4H, m),
5.07–5.16 (2H, m), 6.83 (4H, d, J = 2.0 Hz); 13C NMR
(125 MHz, CDCl3) d 21.70, 22.92 (t, JC–F = 10.6 Hz), 25.91 (t,
J
C–F = 10.4 Hz), 60.73 (d, JC–F = 3.9 Hz), 69.16, 112.38 (t, JC–
F = 288.0 Hz), 132.19, 135.13, 164.19, 164.71; 19F NMR
(471 MHz, CDCl3) d 24.32 (dd, J = 163.0, 10.1 Hz), 24.90 (dd,
J = 162.7, 12.9 Hz); IR (KBr, cmꢀ1); 1713, 1643, 1456, 1265,
1173, 1109, 986, 779, 426; Anal. Calcd for C22H26F4O8; C,
53.44; H, 5.30. Found: C, 53.28; H, 5.32.
4.15.2. Synthesis of (ꢀ)-13
To a 4.1 mL of THF solution of (ꢀ)-16 (347 mg, 0.41 mmol)
was added a 1.0 mL THF solution of tetrabutylammonium
fluoride (1.01 mmol) at rt and the mixture was stirred for 15 h at
rt, then the solvent was removed by evaporation under vacuum
conditions to give diol (ꢀ)-17 (127 mg) which was subjected to
the next esterification without further purification. To a mixture
of EDC (130 mg, 0.68 mmol), fumalic acid monoisopropyl ester
(108 mg, 0.68 mmol) and (ꢀ)-17 (127 mg, 0.34 mmol, crude) in
CH2Cl2 (2.4 mL) was added DMAP (17 mg, 0.14 mmol) at one
portion under argon at 0 8C. The mixture was stirred for 4 h at rt,
then removed the solvent by evaporation and the residue was
extracted with ethyl acetate. The combined organic layers were
washed with water, dried over MgSO4, and evaporated. Silica gel
flash column chromatography (hexane/ethyl acetate = 20:1–4:1)
gave (ꢀ)-13 (120 mg, 0.18 mmol) in 54 % yield (two steps):
1H NMR (270 MHz, CDCl3) d 1.23 (12H, d, J = 6.0 Hz), 1.73–
1.82 (4H, m), 3.43–3.53 (4H, m), 4.10–4.32 (4H, m), 4.44 (4H,
dd, J = 18.0, 11.5 Hz), 5.00–5.09 (2H, m), 6.77 (4H, s), 7.23 (4H,
s); 13C NMR (125 MHz, CDCl3) d 21.62, 24.99 (t, JC–
F = 10.8 Hz), 26.76 (t, JC–F = 10.0 Hz), 60.23, 65.51, 69.02,
72.25, 113.46(t, JC–F = 287 Hz), 127.65, 132.41, 134.85, 137.27,
164.15, 164.65; 19F NMR (471 MHz, CDCl3) d 23.49 (t,
J = 168 Hz); IR (neat, cmꢀ1) 2872, 1717, 1645, 1456, 1261,
1157, 1107, 989, 777; Anal. Calcd for C32H38F4O10; C, 58.35; H,
5.82. Found: C, 58.29; H, 5.72.
Acknowledgment
This work was supported in part by the Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
References
[1] (a) Reviews see: K. Uneyama, Organofluorine Chemistry, Blackwell
Publishing, London, 2006;
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22
½aꢂD ꢀ 12:0 (c 1.3, CHCl3); Rf 0.2 (hexane/ethyl acetate = 4:1;
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(2001) 63–68;
The syntheses of (ꢀ)-14 and (+)-15 were accomplished
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20
½aꢂD ꢀ 13:2 (c 1.0, CHCl3); Rf 0.4 (hexane/ethyl acet-
ate = 4:1); 1H NMR (270 MHz, CDCl3) d 1.28 (12H, d,

1120
T. Itoh et al. / Journal of Fluorine Chemistry 128 (2007) 1112–1120
[6] A good review see: P. Kirsch, M. Bremer, Angew. Chem. Int. Ed. 39
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´
[17] R. Cano, Bull. Soc. Fr. Miner. Cristallogr. 91 (1968) 20–27.
[10] We use E* value for evaluating the lipase enantioselectivity because the
reaction included two steps (monoester formation and subsequent rapid