The synthesis of enantiomerically pure novel liquid crystal compounds containing the bis(trifluoromethyl)alkanediol moiety

Article abstract of DOI:10.1016/j.tetasy.2004.07.021

The synthesis of two types of novel liquid crystals, which possess the optically active bis(trifluoromethyl)alkanediol moiety has been accomplished using the lipase-catalyzed reaction and the Wittig reaction as key reactions.

Full text of DOI:10.1016/j.tetasy.2004.07.021

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 2591–2594
The synthesis of enantiomerically pure novel liquid crystal
compounds containing the bis(trifluoromethyl)alkanediol moiety
a
a
b
b
Yumiko Takagi,a, Fumi Yamana, Yousuke Sumino, Hideyuki Ito, Takashi Yoshida,
*
Takashi Kato,c Kazutoshi Miyazawac and Toshiyuki Itohd,
*
aDepartment of Chemistry, Faculty of Education, Kagawa University, Takamatsu, Kagawa 760-8522, Japan
bDepartment of Pharmacognosy, Faculty of Pharmaceutical Sciences, Okayama University, Okayama, 700-8530, Japan
cChisso Corporation, Co., Ltd, 5-1 Goi-kaigan, Ichihara, Chiba 290-8551, Japan
dDepartment of Materials Science, Faculty of Engineering, Tottori University, Tottori 680-8552, Japan
Received 10 May 2004; revised 28 June 2004; accepted 13 July 2004
Abstract—The synthesis of two types of novel liquid crystals, which possess the optically active bis(trifluoromethyl)alkanediol
moiety has been accomplished using the lipase-catalyzed reaction and the Wittig reaction as key reactions.
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. Result and discussion
Anti-ferroelectric liquid crystal compounds (AFLCs),
which possess a chiral 1,1,1-trifluoromethyl-2-alkanol
moiety, have been acknowledged as important sources
for high-speed switching devices.1 Hiyama et al.
reported unique AFLC molecules, which contain opti-
cally active bis(trifluoromethyl)alkanediols as the chiral
core units.2 It was shown that the anti-ferroelectric
properties of the compounds is dependent on the alkyl
chain length between the two hydroxyl groups. We were
interested by this report and hence decided to synthesize
novel analogues of the Hiyama-type AFLC compounds.
We anticipated that it might be possible to modify the
liquid crystalline property by the introduction of an aro-
matic group in the middle of the alkyl chain of the
bis(trifluoromethyl)alkanediol core, because aromatic
groups sometimes play an important role in the arrange-
ment of molecules by both the p–p interactions and the
planarity between the aromatic rings. We hence planned
to synthesise two types of such compounds as shown in
Scheme 1. We herein report the successful preparation
of enantiomerically pure novel bis(trifluoromethyl)-
alkanediols units using lipase technology and the synthe-
sis of novel Hiyama-type liquid crystalline compounds.
Since a cumbersome resolution technique using HPLC
with a chiral column was employed for the preparation
of the bis(trifluoromethyl)alkanediols by Hiyama et al.,2
we decided to refine the process of preparing the bis(tri-
fluoromethyl)alkanediols in their enantiomerically pure
forms using lipase technology. The lipase-catalyzed
reaction is well recognized as a useful method for pre-
paring optically active compounds in organic synthesis
while the value of the reaction has recently been
increased by its environmentally friendly nature.3 In
fact, we accomplished the synthesis of various types of
1,1,1-trifluoro-2-alkanols in their enantiomerically pure
forms using the lipase-catalyzed reaction.4,5
The results of the retro-synthetic analysis for our target
molecules are shown in Scheme 1. There are two key
points for our synthesis; the first is realizing the practical
resolution of the racemic 1,1,1-trifluoromethylalkane-
diol via the lipase-catalyzed reaction while the second
is the synthesis of a bis(trifluoromethyl)alkanediol that
possesses an aromatic ring in the center of the alkyl
chain using the Wittig reaction protocol.
Our synthesis started with the preparation of 1-benzyl-
oxy-8-bromooctane 5, which was easily prepared from
the partially benzyl protected 1,8-octanediol. Alcohol 5
was first converted to the corresponding mesylate and
*
Corresponding authors. Tel./fax: +81-87-832-1461; e-mail: ytakagi@
ed.kagawa-u.ac.jp
0957-4166/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.07.021

2592
Y. Takagi et al. / Tetrahedron: Asymmetry 15 (2004) 2591–2594
CF3
O
O
O
O
O
O
O
O
Ar
O
CF3
O
1a: Ar=Phenyl
1b: Ar=Biphenyl
Ar
Wittig reaction
OH
OH
OH
CF3
BnO
F3C
CF3
(S)-3
2a: Ar=Phenyl
2b: Ar=Biphenyl
Lipase-catalyzed reaction
OH
BnO
1,8-Octanediol
BnO
CF3
OH
4
( )-3
Scheme 1. Retrosynthetic analysis.
subsequent treatment with sodium bromide in a mixed
solvent of acetone with dimethylformamide (1:1) gave
5 in 85% yield (two steps). Bromide 5 was then con-
verted to the Grignard reagent, which was immediately
subjected to a reaction with 2-trifluoromethyloxirane
in the presence of 2mol% of copper iodide in THF at
0°C to form racemic 8-benzyloxy-1,1,1-trifluoro-
methyl-2-octanol 3, which was finally acetylated to pro-
vide acetate ( )-6 in 84% yield (three steps) (Scheme 2).
enantiomeric excess of the product alcohol and unre-
acted acetate was determined by capillary GC using a
chiral column (Chiraldex). As seen in Table 1, both
Novozym 435 and CAL-B worked nicely with an excel-
lent enantioselectivity being recorded. Also, remarkably
high E values7 were obtained for all the reactions.
Conversion to the bis(trifluoromethyl)alkanediol 10 was
accomplished using the Wittig reaction protocol
(Scheme 3): The benzyl protecting group of (S)-3 was
first converted to the tertiary butyl dimethylsilyl group
with the 2-hydroxyl group was protected as a benzyl
ether (94%), which was then converted to aldehyde
(S)-7 by Swern oxidation in 85% yield. Aldehyde (S)-7
was subjected to the Wittig reaction by treatment with
bisphosphoniumylide 8 to give the corresponding
diene (S,S)-10a in 62% yield. Diene (R,R)-10b was
also prepared using the same sequence in a 46% overall
yield.
With the substrate of the enzymatic reaction in hand, we
investigated the lipase-catalyzed hydrolysis reaction of
( )-6. We previously reported that Candida antarctica
lipase (CAL) catalyzed the trans-esterification of race-
mic 1,1,1-trifluoro-2-alkanols with perfect enantioselec-
tivity,4,5 although the reaction required a long time to
go to completion. Therefore, we tested the hydrolysis
of acetate 6 using two types of commercial Candida ant-
arctica lipases, Novozym 4356 and CAL-B. These were
immobilized using different supporting materials but
from the same origin of the enzyme. Typically, the reac-
tion was carried out as follows: to a mixture of ( )-6
(from 1,8-octanediol, 235mg, 0.68mmol) in a mixed sol-
vent of 6.8mL of 0.1M phosphate buffer (pH7.2) and
acetone (10:1) was added the Novozym (50wt% vs sub-
strate). The mixture was then stirred at rt. Extraction
with ethyl acetate and subsequent purification using sil-
ica gel flash chromatography gave (S)-3 and acetate (R)-
6 unreacted in 32% and 41%, respectively (entry 1). The
The syntheses of the optically active liquid crystals 1a and
1b were accomplished following by Scheme 4. The benzyl
protecting group of the 2-hydroxyl group of 10a was first
deprotected by hydrogenolysis and subjected to the este-
rification with p-benzyloxybenzoic acid to afford 11a in
89% yield. The 4-benzyloxy group of 11a was deprotected
with the final esterification with octyloxyphenylbenzoic
acid using EDC in the presence of DMAP as the base
in CH2Cl2 giving 1a in 67% yield (two steps).8 Compound
b
a
BnO
BnO
1,8-Octanediol
OH
Br
5
4
OAc
CF3
OH
d
BnO
c
BnO
CF3
( )-3
( )-6
Scheme 2. Reagents and conditions: (a) NaH, THF; BnBr, DMF; 54%; (b) MsCl, pyridine, CH2Cl2; NaBr, acetone–DMF; 84% (two steps); (c) Mg,
THF; 2-(trifluoromethyl)oxirane, CuI, THF; 84% (two steps); (d) AcCl, pyridine, CH2Cl2; quant.

Y. Takagi et al. / Tetrahedron: Asymmetry 15 (2004) 2591–2594
Table 1. Resolution of 1,1,1-trifluoro-2-undecanol by CAL-catalyzed hydrolysis reaction
2593
OH
CF3
OAc
CF3
OAc
CF3
Lipase
(1)
BnO
+
BnO
n
BnO
n
n
Buffer-acetone
(10:1)
( )-6
(S)-3
(R)-6
Entry
n (substrate)
Lipasea
Time (h)
Conv. (%)
Ee of (S)-3
Ee of (R)-6
E
1
2
3
4
n = 8 (from 1,8-octanediol)
n = 6 (from 1,6-hexanediol)
Novozym 435
CAL B
6
18
6
26
45
>99
>99
84
69
84
>990
>530
Novozym 435
CAL B
40>99
44
>530
45
4
>99
>260
a Candida antarctica lipase.
OBn
CF3
OH
CF3
a,b
H
BnO
-
+
PPh3Br
+
-
O
(S)-3
(S)-7
BrPh3P
8
OBn
OBn
CF3
c
+
PPh3Br
-
F3C
F3C
8
-
(S,S)-10a
(S,S)-10b
+
(S)-7
BrPh3P
9
OBn
OBn
CF3
c
9
Scheme 3. Reagents and conditions: (a) H2, Pd/C, ethanol; TBSCl, imidazole, DMAP, CH2Cl2; 94% (two steps); (b) 1, NaH, THF; BnBr, DMF; 2,
TBAF, THF; 3, Swern Oxi. 85% (three steps); (c) n-BuLi, THF; then 8 or 9; 10a 62%, 10b 58%.
CF3
CF3
O
O
O
O
HO
HO
b
a
O
O
(S,S)-10a
CF3
(S,S)-11a
CF3
(S,S)-2a
CF3
O
O
O
O
O
O
O
O
O
c
CF3
CF3
O
1a
O
O
O
O
O
O
O
(S,S)-10b
O
O
O
CF3
n-C8H17
O
COOH
1b
12
Scheme 4. Reagent and conditions: (a) H2, Pd/C, ethanol; BCl3, THF; 90% (two steps); (b) BnOC6H4COOH, DCC, DMAP, CH2Cl2 89%; (c) H2,
Pd/C, ethanol; EDC, DMAP, CH2Cl2; 67% (two steps).
1a showed only the SmA phase at 135°C; unfortunately,
no desired anti-ferroelectric property was observed.
Compound 1b was also synthesized from 10b through
the same reaction sequences as illustrated in Scheme 4.

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Y. Takagi et al. / Tetrahedron: Asymmetry 15 (2004) 2591–2594
3. For reviews, see, (a) Wong, C.-H.; Whitesides, G. M.
Enzymes in Synthetic Organic Chemistry; Pergamon:
Oxford, 1994; (b) Bornscheuer, U. T.; Kazlauskas, R. J.
Hydrolases in Organic Synthesis: Regio- and Stereoselective
Biotransformations; John Wiley & Sons, 1999.
4. Hamada, H.; Shiromoto, M.; Funabiki, M.; Itoh, T.;
Nakamura, K. J. Org. Chem. 1996, 61, 2332–2336.
5. Itoh, T.; Shiromoto, M.; Inoue, H.; Hamada, H.; Naka-
mura, K. Tetrahedron Lett. 1996, 37, 5001–5002.
6. Novozym435 (Candida antarctica) is now commercially
available as CHIRAZYME 2, c.-f., C2, Iyo from Roche
Molecular Biochemicals.
Compound 1b also showed no desired anti-ferroelectric
property, though it showed the SmA phase at 170°C.9
Since our molecules, 1a and 1b, should be less flexible,
due to the existing aromatic ring at the center part of
the core molecule, than the Hiyama-type liquid crystal
molecules, it was concluded that the flexibility of the core
part contributed causing antiferroelectric property of this
type of liquid crystal molecule.
3. Conclusion
7. Chen, C. S.; Fujimoto, Y.; Girdauskas, G.; Sih, C. J. J. Am.
Chem. Soc. 1982, 112, 7294–7298.
In summary, we have synthesized two novel types of liq-
uid crystalline compounds using lipase technology and
the Wittig reaction as the key steps. Although the prod-
ucts showed only the SmA phase, we are still expecting
that unique properties might be obtained by modifica-
tion of the central aromatic group and proper combina-
tion of the side chain part. Further investigation into the
synthesis of compounds, which possess the spirobicyclo-
butane moiety at the center of the molecules, are cur-
rently underway.
25
8. Selected spectra data for 1a: ½aŠ ¼ ꢀ30:0 (c 1.0, CHCl3);
1H NMR (400MHz, CDCl3, dD) 0.82 (6H, t, J = 6.1Hz),
1.17–1.22 (44H, m), 1.33–1.40(4H, m), 1.50(4H, d,
J = 2.44Hz), 1.70–1.83 (8H, m), 2.47 (4H, t, J = 7.8Hz),
3.94 (4H, t, J = 6.3Hz), 5.45–5.50(2H, m), 6.93 (4H, d,
J = 8.3Hz), 7.00 (4H, s), 7.28 (4H, d, J = 8.3Hz), 7.52 (8H,
d, J = 8.3Hz), 7.62 (4H, d, J = 8.3Hz), 8.10(4H, d,
J = 8.3Hz), 8.15 (4H, d, J = 8.3Hz); 13C NMR (100MHz,
CDCl3, d) 14.08, 22.64, 24.53, 26.03, 28.00, 29.07, 29.22,
29.35, 29.41, 29.45, 31.55, 31.80, 35.54, 70.07, 115.00,
122.07, 126.64, 128.19, 128.37, 130.81, 131.68, 140.02,
146.34, 155.31, 159.67, 164.34, 164.50; 19F NMR
(188MHz, CDCl3, d) 84.76 (s); IR (neat, NaCl) 3860,
2920, 1730, 1600, 1160 and 890 cmꢀ1. Anal. Calcd for
C86H104F6O10: C, 73.17; H, 7.43. Found: C, 73.20; H, 7.49.
HRMS (FABMS): 1411.7612 (calcd for C86H104F6O10
1411.730).
Acknowledgements
We are grateful for the financial support from the Min-
istry of Education, Culture, Sports, Science and Tech-
nology, Japan.
25
9. Selected spectra data for 1b: ½aŠ ¼ ꢀ45:3 (c 1.0, CHCl3);
1H NMR (400MHz, CDCl3, dD) 0.82 (6H, t, J = 6.5Hz),
1.19–1.23 (48H, m), 1.51–1.57 (4H, m), 1.71–1.76 (4H, m),
1.78–1.84 (4H, m), 2.54 (4H, t, J = 7.8Hz), 3.94 (4H, t,
J = 6.6Hz), 5.46–5.41 (2H, m), 6.93 (4H, d, J = 8.3Hz) 7.14
(4H, d, J = 7.8Hz), 7.41 (8H, d, J = 8.3Hz), 7.52 (4H, d,
References
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J = 8.8Hz), 8.10(4H, d,
J = 8.8Hz), 8.15 (4H, d,
J = 8.3Hz); 13C NMR (100MHz, CDCl3, d) 14.10, 22.65,
24.53, 26.04, 27.07, 29.23, 29.35, 29.41, 29.46, 31.49, 31.82,
35.59, 68.16, 70.40, 115.01, 122,07, 126.31, 126.64, 126,77,
128.39, 128.72, 130.82, 131.69, 131.76, 138.46, 141.72,
146.39, 155.32, 159.67, 164.36, 164.52; 19F NMR
(188MHz, CDCl3, d) 84.71 (s); IR (neat, NaCl) 3390, 2930,
1730, 1600, 1160 and 880cmꢀ1
.
Anal. Calcd for
C92H108F6O10Æ2H2O: C, 72.51; H, 7.41. Found: C, 74.10;
H, 7.66. HRMS (FABMS): 1487.7973 (calcd for
C86H104F6O10 1487.826).
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