Efficient synthesis of optically pure 1,1,1-trifluoro-2-alkanols through lipase-catalyzed acylation in organic media

Article abstract of DOI:10.1021/jo951976a

Lipase-catalyzed esterification was successfully utilized for the optical resolution of 1,1,1-trifluoro-2-alkanol 1 when racemic 1 was treated with lipase from Candida antarctica in hexane in the presence of molecular sieves (4 A) to provide the corresponding (S)-acetate 2 in an optically pure state. Alkanol 1 is known as an important component of liquid crystal compounds which display remarkable ferroelectric liquid crystal (FLC) characteristics. Five types of optically pure alkanols, i.e., 1,1,1-trifluoro-2-octanol (1a), 1,1,1-trifluoro-2-nonanol (1b), 1,1,1-trifluoro-2-decanol (1c), 1,1,1-trifluoro-2-undecanol (1d), and 1,1,1-trifluoro-8-(benzyloxy)-2-octanol (1e), were thus obtained by the lipase-catalyzed acylation.

Full text of DOI:10.1021/jo951976a

2332
J . Org. Chem. 1996, 61, 2332-2336
Efficien t Syn th esis of Op tica lly P u r e 1,1,1-Tr iflu or o-2-a lk a n ols
th r ou gh Lip a se-Ca ta lyzed Acyla tion in Or ga n ic Med ia
Hiroki Hamada,†,* Mizuho Shiromoto,† Makoto Funahashi,† Toshiyuki Itoh,‡,* and
Kaoru Nakamura§,*
Department of Applied Science, Okayama University of Science, 1-1 Ridai-cho, Okayama 700, J apan;
Department of Chemistry, Faculty of Education, Okayama University, Okayama 700, J apan; and
Institute for Chemical Research, Kyoto University, Uji, Kyoto 611, J apan
Received November 7, 1995X
Lipase-catalyzed esterification was successfully utilized for the optical resolution of 1,1,1-trifluoro-
2-alkanol 1 when racemic 1 was treated with lipase from Candida antarctica in hexane in the
presence of molecular sieves (4 Å) to provide the corresponding (S)-acetate 2 in an optically pure
state. Alkanol 1 is known as an important component of liquid crystal compounds which display
remarkable ferroelectric liquid crystal (FLC) characteristics. Five types of optically pure alkanols,
i.e., 1,1,1-trifluoro-2-octanol (1a ), 1,1,1-trifluoro-2-nonanol (1b), 1,1,1-trifluoro-2-decanol (1c), 1,1,1-
trifluoro-2-undecanol (1d ), and 1,1,1-trifluoro-8-(benzyloxy)-2-octanol (1e), were thus obtained by
the lipase-catalyzed acylation.
In tr od u ction
Ferroelectric liquid crystals (FLC) are known to be
important high-speed switching devices,1 and their re-
sponse time strongly depends on the magnitude of their
spontaneous polarization (Ps). A recent study revealed
that chiral FLC compounds, which involve optically
active 1,1,1-trifluoroalkanols 1, possess remarkable char-
acteristics such as a wide temperature range of the Sc*
phase, a large spontaneous polarization, and a short
response time (Figure 1).1c Only three preparation
methods have been reported for optically active 1.2 The
first example is optical resolution through the lipase-
catalyzed hydrolysis of the corresponding racemic esters,
though high enantioselection was allowed for a limited
number of compounds.2a The second example is the
enantioselective reduction of trifluoromethyl ketones by
bakers’ yeast,2b or plant tissue cultures from Nicotiana
tabacum which we recently reported.2c The third method
is the classical resolution of racemic 1 as diastereomeric
esters using optically pure trans-2-benzamidocyclohex-
anoic acid.2d
F igu r e 1. Model structure of ferroelectric liquid crystals.1c
lective acylation in organic media using Candida ant-
arctica lipase.
Resu lts a n d Discu ssion
The racemic 1,1,1-trifluoroalkanols were prepared as
shown in Scheme 1. Initially, we prepared trifluorometh-
yl ketones 2 by a known method.2d The substitution
reaction of the magnesium bromide salt of trifluoroacetic
acid (TFA) with a Grignard reagent was attempted;
however, the reaction provided 2 in poor chemical yield
(20-30%), and also required an excess amount of the
reagent. We found that the one-pot procedure described
in Scheme 1 was superior to this method for synthesizing
trifluoromethyl ketones. TFA was first converted to the
corresponding lithium salt by hydrolysis with lithium
hydroxide.4 The salt was thoroughly dried under reduced
pressure prior to the next reaction and then treated with
1 equiv of the Grignard reagent to produce the desired
ketones 2. Ketones 2 were immediately subjected to
reduction with sodium borohydride (NaBH4) without
purification, because a significant loss of material, due
to the volatility of 2, was observed during the purification
process using silica gel flash column chromatography.
After the reduction of 2 with NaBH4, distillation under
reduced pressure provided the corresponding alcohol
Because the target compounds are FLC compounds,
large scale preparation is particularly desired. The
lipase-catalyzed reaction is obviously superior to the
others in total efficiency.3 We wish to report the highly
efficient enzymatic resolution of 1,1,1-trifluoroalkanols,
which have a long linear alkyl chain, through enantiose-
† Okayama University of Science.
‡ Okayama University.
§ Kyoto University.
X Abstract published in Advance ACS Abstracts, March 1, 1996.
(1) (a) Clark, N. A.; Lagerwal, S. T. Appl. Phys. Lett. 1980, 36, 899.
(b) Skarp, K.; Handschy, M. A. Mol. Cryst. Liq. Cryst. 1988, 165, 439.
(c) Nohira, H. J . Synth. Org. Chem., J pn. 1991, 49, 467 and references
cited therein.
(2) (a) Tain Lin. J .; Yamazaki, T.; Kitazume, T. J . Org. Chem. 1987,
52, 3211. (b) Kitazume, T.; Ishikawa, N. Chem. Lett. 1983, 237. (c)
Hamada, H.; Imura, M.; Okano, T. J . Biotechnology 1994, 32, 89. (d)
Ishizuka, T.; Miura, H.; Nohira, H. Nippon Kagaku Kaishi 1990, 1171.
(3) Transesterification-based enzymatic resolution of secondary
alcohols is now widely regarded as one of the best methods of choice
for the synthesis of an enantiomer of an alcohol with high enantiomeric
purity. For reviews see: (a) Santaniello, E.; Ferraboschi, P.; Grisenti,
P.; Manzocchi, A. Chem. Rev. 1992, 92, 1071. (b) Faber, K.; Riva, S.
Synthesis 1992, 895.
(4) The lithium salt of TFA could be kept at room temperature for
several months, though it was a deliquescent compound.
0022-3263/96/1961-2332$12.00/0 © 1996 American Chemical Society

Synthesis of Optically Pure 1,1,1-Trifluoro-2-alkanols
J . Org. Chem., Vol. 61, No. 7, 1996 2333
Sch em e 1
ester 3b with extremely high optical purity. As seen in
Table 1, CAL has the highest acylation efficiency of 1b
among all tested enzymes. It also catalyzed the acylation
with excellent enantioselectivity toward both 1b and 1f
(entries 11 and 12), though CCL and AY acylated 1f with
poor enantioselectivity (entries 8 and 10). It is particu-
larly interesting that CAL displayed completely the
opposite enantioselectivity to lipases AY and CCL, though
all three of these enzymes are obtained from Candida
species. A moderate effect on optical purity was observed
when the organic solvent was changed (entries 11, 13-
17).7 Obviously, hexane is the best solvent system in
which to obtain the optically pure alcohol 1b and acetate
3b based on a comparison of the reaction time and E
value (entry 11).8
(()-1 in 60-80% overall yield. Five types of (trifluoro-
methyl)alkanols, 1a -e, were thus successfully obtained
using these procedures from TFA.
The enantiomer favoritism of these enzymes is sum-
marized in Figure 2. The alcohol pair (S)-1b and (R)-1f,
or (R)-1b and (S)-1f, have the same geometry in the chiral
center, though they are assigned to the opposite config-
uration due to the sequence rule. As can be seen in the
figure, CAL catalyzed the acylation of alcohols 1b and
1f with the same enantiomer favoritism. CCL and AY
also displayed the same enantiomer favoritism during the
acylation of alcohols 1b and 1f. On the contrary, the
opposite enantiomer favoritism was observed during the
acylation of these substrates by lipases PS and AK,
though the selectivity was not an efficient one. It is
interesting that influenced favoritism in the geometry of
1b and 1f was observed in the reaction of lipases from
Pseudomonas species (PS and AK), whereas it was not
observed in the reaction of lipases from Candida species
(AY, CAL, and CCL). The lipase-catalyzed acylation has
been reported to proceed through a ping-pong mecha-
nism.9 Lively discussions have taken place about the
molecular structure of the active site of the lipase during
the hydrolysis of esters.10 On the other hand, there has
been no reputable theory offered for the mechanism of
enantiomer favoritism in the lipase-catalyzed acylation,
though two “pockets” of different sizes are generally
assigned for the active domain of a lipase in order to
explain the substrate selectivity and enantioselec-
tivity.7c,10,11 It is reported that Pseudomonas lipases all
have similar sequences.12 This fact may indicate the
presence of a special functional group, which is sensitive
to the electron rich trifluoromethyl group, such as the
hydroxyl group of the serine part, at the medium-sized
pocket or the large-sized pocket close to the active center
of the enzymes of the Pseudomonas species.13 Enzymes
from Candida species, on the other hand, seem to lack
such a functional group. Results of the present reaction
seem to offer a very interesting point from which to
consider the molecular structure of these enzymes.
Initially several kinds of lipases were tested using
1,1,1-trifluoro-2-nonanol (1b) as the model substrate to
find a lipase that ensured high enantioselection. The
reaction was performed using the following procedure:
To a suspension of (()-1b in organic medium was added
the lipase (50 wt % of the alcohol), and the mixture was
then stirred at room temperature. Progress of the
reaction was monitored by GC analysis, and the reaction
was stopped when the peak of the produced acetate and
the unreacted alcohol reached the same intensity. Pu-
rification was carried out using silica gel flash column
chromatography. Optical purity of the produced acetate
3b and the remaining alcohol 1b was determined as the
acetate by capillary GC analysis using the chiral phase
of Chiraldex G-Ta. To identify the absolute configuration
of the produced acetate, authentic alcohol (S)-1b; [R]22
D
-19.0° (c 1.0, CHCl3), 75% ee, was derived from com-
mercial (S)-(trifluoromethyl)oxirane (75% ee). After com-
paring the value of the optical rotation of alcohol 1b,
[R]18D +17.8° (c 1.01, CHCl3), with the authentic sample,
the configuration of the 2-position of 1b remaining after
acylation was assigned as R, and the acetate 3d produced
was therefore assigned as S. From the diastereomeric
differences in retention time on GC analysis, the config-
uration was postulated. The results are summarized in
Table 1.
Preliminary experiments involving the acetylation of
1b (R ) Et, X ) F) showed that six types of lipases:
lipase PS, lipase AY, LPL, CAL, lipase AK, and CCL
catalyzed the acylation using vinyl acetate5 as an acyl
donor in hexane.6
Typical results are summarized in Table 1. In these
reactions, lipases from Pseudomonas sp. (PS, AK) were
not stereospecific to the acylation with 1,1,1-trifluoro-2-
nonanol (1b) (entries 1 and 3), though they catalyzed the
acylation of 2-nonanol (1f) with moderate enantioselec-
tivity (entries 2 and 5). Lipase from Candida rugosa
(AY), from Candida cylindracea (CCL), and from Can-
dida antarctica (CAL) were more promising than the
other tested enzymes (entries 7, 9, and 11), providing
(7) Examples, see: (a) Sakurai, T.; Margolin, A. L.; Russell, A. J .;
Klivanov, A. M. J . Am. Chem. Soc. 1988, 110, 7236. (b) Parida, S.;
Dordick, J . S. Ibid. 1991, 113, 2253. (c) Parida, S.; Dordick, J . S. J .
Org. Chem. 1993, 58, 3238. (d) Kamat, S. Biotechnol. Bioengin. 1992,
40, 158. (e) Arroyo, M.; Sinisterra, J . V. J . Org. Chem. 1994, 59, 4410.
(8) Chen, C.-S.; Fujimoto, Y.; Girdauskas, G.; Sih, C. J . J . Am. Chem.
Soc. 1982, 112, 7294.
(5) Vinyl acetate was found better as acyl donor than vinyl propi-
onate in enantioselectivity.
(6) List of lipases tested: Lipase PS (Pseudomonas cepacia), LPL
(Pseudomonas aeruginosa), Lipase AK (Pseudomonas sp.), CAL (Can-
dida antarctica), Lipase AY (Candida rugosa), CCL (Candida rugosa),
Immobilized Lipase from Pseudomonas fluorescence, Lipase CES
(Pseudomonas sp.) PPL (Porcine pancreas), PLE (Pig liver), Lipozyme
(Mucor miehei), Lipase L (Candida lipolytica), Lipase A (Aspergillus
niger), Lipase GC (Geotrichum candidum), Protease A, Lipase F
(9) Mitsuda, S.; Nabeshima, S. Recl. Trav. Chim. Pays-Bas 1991,
110, 151.
(10) For a recent example see: Cygler, M.; Grochulski, P.; Kazlaus-
kas, R. J .; Schrag, J . D.; Bouthillier, F.; Rubin, B.; Serreqi, A. N.; Gupta,
A. K. J . Am. Chem. Soc. 1994, 116, 3180. References cited therein.
(11) (a) Kazlauskas, R. J .; Weissfloch, A. N. E.; Rappaport, A. T.;
Cuccia, L. A. J . Org. Chem. 1991, 56, 2656. (b) Kim, M. J .; Cho, H. J .
Chem. Soc., Chem. Commun. 1992, 1411.
(Rizopus javanicus), Lipase
R (Penicillium roqueforti), Lipase N
(Rhizopus niveus), Lipase CE (Humicola lanuginosa), Protease S,
Lipase M (Mucor javanicus), Protease P, Lipase G (Penicillium sp.),
and Lipase D (Rhizopus delemar).
(12) Gilbert, E. J . Enzyme Microb. Technol. 1993, 15, 634.
(13) Nakamura, K.; Kawasaki, M.; Ohno, A. Bull. Chem. Soc. J pn.
1994, 67, 3053.

2334 J . Org. Chem., Vol. 61, No. 7, 1996
Hamada et al.
Ta ble 1. En zym a tic Resolu tion of 1,1,1-Tr iflu or o-2-a lk a n ol 1 th r ou gh Lip a se-Ca ta lyzed Ester ifica tion Vin yl Aceta te a s
a n Acyl Don or a
entry
substrate
enzyme
solvent
time (h)
% conv
% ee of 3 (config)
E valueb
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
1b (R ) Et, X ) F)
1f (R ) Et, X ) H)
1b (R ) Et, X ) F)
1f (R ) Et, X ) H)
1b (R ) Et, X ) F)
1f (R ) Et, X ) H)
1b (R ) Et, X ) F)
1f (R ) Et, X ) H)
1b (R ) Et, X ) F)
1f (R ) Et, X ) H)
1b (R ) Et, X ) F)
1f (R ) Et, X ) H)
1b (R ) Et, X ) F)
1b (R ) Et, X ) F)
1b (R ) Et, X ) F)
1b (R ) Et, X ) F)
1b (R ) Et, X ) F)
PS
PS
AK
AK
LPL
LPL
CCL
CCL
AY
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
hexane
iPr2O
6
6
6
6
6
6
6
6
6
6
6
6
240
240
240
240
240
27
20
27
39
45
10
9
20
14
37
28
36
26
0
17 (S)
83 (S)
36 (S)
76 (S)
99 (S)
37 (R)
99 (R)
37 (S)
99 (R)
24 (S)
98 (S)
99 (R)
>99 (S)
0
2
13
2
12
15
2
322
2
255
2
118
350
>280
-
75
>220
130
AY
CAL
CAL
CAL
CAL
CAL
CAL
CAL
THF
Et2O
CHCl3
CH3CN
31
9
22
96 (S)
>99 (S)
98 (S)
a
b
Substrate 1 (1 mmol), vinyl acetate (1.5 equiv), solvent (5 mL), enzyme (50 wt %), reaction temperature 35 °C. Calculated by the
acylated conversion and % ee of the product, see reference 8. E ) ln[(1 - c)(1 - ee3)]/ln[(1 - c)(1 + ee3)], where c ) ee3/(ee3 + ee1).
the total amounts of product and substrate recovered
because of the high volatility of the product, hence the
reaction was stopped at the levels listed in the table. The
(trans)esterification reaction actually involves the reac-
tion of an alcohol with an acyl enzyme. Although we
tried to increase the reaction rate by applying several
acyl donors such as vinyl butyrate, vinyl chloroacetate,
or isopropenyl acetate, no acceleration of the esterifica-
tion was observed. The concentration of vinyl acetate
also did not affect the reaction rate. Because the reaction
rate was not influenced by the nature of the acyl donor
or concentration of the acyl donor, the slow speed of the
esterification seemed to depend on the low nucleophilicity
of the trifluoromethyl alkanols. We also tested the CAL-
catalyzed hydrolysis of the corresponding acetate (()-3d .
The present method was superior to the hydrolysis
method for two reasons, though the hydrolysis reaction
proceeded smoothly. The first is that we could not obtain
the alcohols in an optically pure form by the hydrolysis
method. This was probably due to the ease of hydrolysis
of the acetates of the trifluoromethyl alkanols under the
reaction conditions. Secondly, the total amount of prod-
uct and substrate recovered were worth more than that
of the (trans)esterification method. Trifluoromethyl al-
kanols are very volatile compounds. The simplicity of
the procedure is essential for obtaining products in good
yield during the reaction of such volatile compounds.
It should be emphasized that the present lipase resolu-
tion is the only method for preparing 1 in the optically
pure state.14 It is of particular importance that compound
1e was obtained in the optically pure state. Because 1e
possesses a benzyloxy group at the terminal position, this
compound is converted to various types of 1,1,1-trifluoro-
2-alkanols. The lipase-catalyzed reaction in organic
media can be used in large scale preparations, and the
present method offers a valuable technique for preparing
optically pure trifluoro-2-alkanol. Key compounds for
making ferroelectric liquid crystals are thus easily ob-
tained.
F igu r e 2. Map of favorite substrates of six types of lipases.
Ta ble 2. Op tica l Resolu tion of 1,1,1-Tr iflu or o-2-a lk a n ols
1 th r ou gh Ca n d id a a n ta r ctica Lip a se-Ca ta lyzed
Ester ifica tion a
time
%
% ee of 3
entry
substrate
(days) conv % ee of 1 (config)
E
1
2
3
4
5
1a (R ) Me)
1b (R ) Et)
7
8
6
11
6
25
35
25
32
14
33 (R)
52 (R)
33 (R)
12 (R)
25 (R)
>99 (S)
96.6 (S)
>99 (S)
>99 (S)
>99 (S)
>274
97
>274
>317
>253
1c (R ) Pr)
1d (R ) Bu)
1e (R ) CH2OBn)
a
Reaction was carried out under the following conditions:
substrate 1 (1 g), vinyl acetate (1.5 equiv), hexane (5 mL), enzyme
(0.1 g), molecular sieves 4 Å (0.5 g), reaction temperature 18-20
°C.
The optical resolution of various types of 1,1,1-trifluoro-
2-alkanols using CAL are summarized in Table 2. Al-
though all entries of the reaction proceeded slowly, CAL
catalyzed the acylation of all compounds tested with
perfect enantioselectivity, affording optically pure 3.
Further prolongation of the reaction significantly reduced
Exp er im en ta l Section
(14) Preparation of optically active (trifluoromethyl)oxirane was
reported recently through enantioselective reduction of 1,1,1-trifluoro-
3-chloro-2-propanone by chlorodisiopinocamphenylborane. Various
types of 1,1,1-trifluoro-2-alkanols were derived from the oxirane,
though the optical purity was, at best, 96% ee: Ramachandran, P. V.;
Gong, B.; Brown, H. C. J . Org. Chem. 1995, 60, 41.
In str u m en t a n d Ma ter ia ls. Reagents and solvents were
purchased from a common commercial source and were used
as received following purification by distillation from appropri-
ate drying agents. Boiling points are uncorrected. Reactions
requiring anhydrous conditions were run under an atmosphere

Synthesis of Optically Pure 1,1,1-Trifluoro-2-alkanols
J . Org. Chem., Vol. 61, No. 7, 1996 2335
of dry argon. Silica gel (Wako gel C-300) was used for column
chromatography, and TLC analyses were done on Merck 60
F254 silica gel plates and Wako gel B5F. Chemical shifts are
expressed in δ value (ppm) downfield from tetramethylsilane
(TMS) in CDCl3 as an internal reference. 19F NMR spectra
were reported in ppm downfield from C6F6 as an internal
reference.
filter with a Celite pad, and the filtrate was chromatographed
on silica gel flash column, hexane/ethyl acetate ) 100:1 to 10:
1, and gave 3d ([R]17 +5.6° (c 1.09, Et2O); 1.29 g, 4.80 mmol;
D
32%) and unreacted 1d ([R]19 +8.16° (c 0.80, Et2O); 2.05 g,
D
9.06 mmol; 60%), respectively. The optical purity of the
produced acetate 3d was found to be >99% ee (S) by GPC
analysis using a capillary column on chiral phase. Optical
purity of the remaining alcohol 1d was measured by GPC
analysis to be 46.7% ee as the corresponding acetate 3d .
(()-1,1,1-Tr iflu or o-2-u n d eca n ol (1d ). To an ether (Et2O)
(83 mL) solution of TFA (82.8 mmol) was carefully added
lithium hydroxide (82.8 mmol) at 0 °C, and the mixture was
evaporated to dryness after neutralization was completed. The
residue was thoroughly dried under reduced pressure at room
temperature overnight and then diluted with 50 mL of Et2O.
To this solution was added a Et2O (100 mL) solution of
nonylmagnesium bromide (100 mmol) at 0 °C, and the mixture
was allowed to warm to rt with stirring for 14 h. The reaction
was quenched by addition of 2 M HCl and extracted with ether.
The combined organic layers were dried over MgSO4 and
evaporated to give 2d (22.5 g) as a colorless oil. To a methanol
(100 mL) solution of 2d was added NaBH4 (3.783 g, 100 mmol)
in several portions at 0 °C. After being stirred for 2 h at 0 °C,
solvent was evaporated off. Purification by silica gel flash
column chromatography (hexane:ethyl acetate ) 10:1) gave
1d (12.2 g, 53.8 mmol) in 65% yield: bp 65 °C/4 Torr
Using the same procedure, acetates 3a , 3b, 3c, and 3e were
prepared. Retention time on GC analyses and [R]D values of
the remaining alcohols are summarized as follows: tR of 3.
Chiraldex G-Ta, L 0.25 mm × 20 m, carrier gas: He 40 mL/
min, temp: 100 °C, inlet pressure: 1.35 kg/cm2, amount 400
ng, detection: FID; 3a : tR(R) ) 1.6 min, tR(S) ) 1.9 min; 3b:
tR(R) ) 1.9 min, tR(S) ) 2.5 min; 3c: tR(R) ) 2.5 min, tR(S) ) 2.9
min; 3d : tR(R) ) 7.5 min, tR(S) ) 9.5 min; 3e: tR(R) ) 19.1 min,
tR(S) ) 20.0 min (oven temperature was 150 °C). [R]D values
of alcohols 1a -e; (R)-1a : [R]19 +8.0° (c 0.96, Et2O), 33% ee;
D
(R)-1b: [R]21 +17.8° (c 1.23, Et2O), 52% ee; (R)-1c: [R]19
D
D
+8.2° (c 0.97, Et2O), 34% ee; (R)-1d : [R]17 +11.3° (c 1.53,
D
Et2O), 47% ee; (R)-1e : [R]19 -0.11° (c 1.06, MeOH), 25% ee.
D
(S)-1,1,1-Tr iflu or ou n decan -2-yl acetate (3d): [R]17D +5.6°
(c 1.46, Et2O), >99% ee; bp 65 °C/4 Torr (Kugelrohr); Rf 0.60
1
1
(Kugelrohr); Rf 0.38 (hexane/ethyl acetate ) 10:1); H NMR
(hexane/ethyl acetate ) 10:1); H NMR (200 MHz, δ, CDCl3)
(200 MHz, δ, CDCl3) 0.88 (3H, t, J ) 6.4 Hz) 1.15-1.43 (14H,
m) 1.51-1.76 (2H, m) 2.57 (1H, OH, t, J ) 4.2 Hz) 3.78-4.00
(1H, m); 13C NMR (50 MHz, ppm, CDCl3) 14.04, 22.67, 24.91,
29.01, 29.28, 29.40, 29.45, 29.45, 29.50, 31.87, 70.52 (q, J C-F
) 30.8 Hz) 125.21 (q, J C-F ) 280.1 Hz); 19F NMR (188 MHz,
δ, CDCl3) 81.77 (d, J ) 6.2 Hz); IR (neat) 3350, 2970, 2860,
0.87 (3H, t, J ) 6.3 Hz) 1.17-1.41 (14H, m) 1.63-1.80 (2H,
m) 2.13 (3H, s) 5.28 (1H, dt, J ) 20.1 Hz, 6.8 Hz); 13C NMR
(50 MHz, ppm, CDCl3) 14.01, 20.37, 22.64, 24.52, 27.77, 29.05,
29.27, 29.41, 31.83, 69.54 (q, J C-F ) 32.0 Hz) 123.84 (q, J C-F
) 280.6 Hz); 19F NMR (188 MHz, δ, CDCl3) 84.57 (d, J ) 6.8
Hz); IR (neat) 2950, 2850, 1760(CO), 1460, 1220, 1020 cm-1
.
1460, 1270, 1170, and 1140 cm-1
.
Anal. Calcd for C13H23O2F3: C, 58.19; H, 8.64%. Found: C,
58.19; H, 8.77%.
1,1,1-Tr iflu or o-2-a lk a n ols 1a , 1b, 1c, and 1e were pre-
pared with a yield of 60-80% by the above procedure.
(S)-1,1,1-Tr iflu or oocta n -2-yl a ceta te (3a ): [R]18D +7.2° (c
0.9, Et2O), >99% ee; bp 45 °C/4 Torr (Kugelrohr); Rf 0.48
(()-1,1,1-Tr iflu or o-2-octa n ol (1a ): bp 45 °C/4 Torr (Kugel-
rohr); Rf 0.38 (hexane/ethyl acetate ) 10:1); 1H NMR (200
MHz, δ, CDCl3) 0.89 (3H, t, J ) 6.5 Hz) 1.12-1.48 (8H, m)
1.53-1.72 (2H, m) 2.38 (1H, OH, t, J ) 6.4 Hz) 3.79-4.00 (1H,
m); 13C NMR (50 MHz, ppm, CDCl3) 13.97, 22.52, 24.85, 28.85,
29.54, 31.56, 70.52 (q, J C-F ) 30.7 Hz) 125.21 (q, J C-F ) 280.3
Hz); 19F NMR (188 MHz, δ, CDCl3) 81.73 (d, J ) 6.6 Hz); IR
1
(hexane/ethyl acetate ) 10:1); H NMR (200 MHz, δ, CDCl3)
0.87 (3H, t, J ) 6.6 Hz) 1.14-1.43 (8H, m) 1.63-1.81 (2H, m)
2.14 (3H, s) 5.28 (1H, dt, J ) 20.1 Hz, 6.8 Hz); 13C NMR (50
MHz, ppm, CDCl3) 13.96, 20.46, 22.47, 24.48, 27.76, 28.72,
31.45, 69.56 (q, J C-F ) 31.7 Hz) 123.84 (q, J C-F ) 278.9 Hz);
19F NMR (188 MHz, δ, CDCl3) 84.48 (d, J ) 6.4 Hz); IR (neat)
(neat) 3350, 2925, 2850, 1450, 1270, 1170, and 1140 cm-1
.
2950, 2850, 1755(CO), 1370, 1210, 1070 cm-1
. Anal. Calcd
for C10H17O2F3: C, 53.09; H, 7.57%. Found: C, 52.85; H,
7.65%.
(()-1,1,1-Tr iflu or o-2-n on an ol (1b): bp 52 °C/4 Torr (Kugel-
rohr); Rf 0.41 (hexane/ethyl acetate ) 10:1); 1H NMR (200
MHz, δ, CDCl3) 0.88 (3H, t, J ) 6.5 Hz) 1.16-1.43 (10H, m)
1.51-1.70 (2H, m) 2.52 (1H, OH, brs) 3.78-3.98 (1H, m); 13C
NMR (50 MHz, ppm, CDCl3) 14.00, 22.59, 24.90, 29.15, 29.33,
29.56, 31.72, 70.50 (q, J C-F ) 30.8 Hz) 125.21 (q, J C-F ) 281.8
Hz); 19F NMR (188 MHz, δ, CDCl3) 81.77 (d, J ) 6.6 Hz); IR
(S)-1,1,1-Tr iflu or on on a n -2-yl a ceta te (3b): [R]18D +3.69°
(c 1.42, Et2O), 96.6% ee; bp 55 °C/4 Torr (Kugelrohr); Rf 0.57
1
(hexane/ethyl acetate ) 10:1); H NMR (200 MHz, δ, CDCl3)
0.85 (3H, t, J ) 6.4 Hz) 1.12-1.40 (10H, m) 1.60-1.79 (2H,
m) 2.12 (3H, s) 5.26 (1H, dt, J ) 20.2 Hz, 6.7 Hz); 13C NMR
(50 MHz, ppm, CDCl3) 14.02, 20.48, 22.57, 24.53, 27.77, 28.94,
29.01, 31.65, 69.56 (q, J C-F ) 31.7 Hz) 123.84 (q, J C-F ) 276.3
Hz); 19F NMR (188 MHz, δ, CDCl3) 84.48 (d, J ) 6.6 Hz); IR
(neat) 3350, 2940, 2850, 1460, 1280, 1170, and 1140 cm-1
.
(()-1,1,1-Tr iflu or o-2-d eca n ol (1c):2a bp 60 °C/5 Torr
1
(Kugelrohr); Rf 0.37 (hexane/ethyl acetate ) 10:1); H NMR
(neat) 2910, 2850, 1775(CO), 1460, 1370, 1210, 1080 cm-1
.
(200 MHz, δ, CDCl3) 0.88 (3H, t, J ) 7.0 Hz) 1.16-1.45 (12H,
m) 1.51-1.80 (2H, m) 2.29 (1H, OH, brs) 3.78-3.99(1H, m);
13C NMR (50 MHz, ppm, CDCl3) 14.06, 22.64, 24.90, 29.19,
29.34, 29.56, 31.81, 70.54 (q, J C-F ) 30.8 Hz) 125.21 (q, J C-F
) 280.2 Hz); 19F NMR (188 MHz, δ, CDCl3) 81.68 (d, J ) 6.5
Hz); IR (neat) 3350, 2900, 2850, 1460, 1270, 1170, and 1130
Anal. Calcd for C11H19O2F3: C, 54.99; H, 7.97%. Found: C,
55.35; H, 7.98%.
(S)-1,1,1-Tr iflu or od eca n -2-yl a ceta te (3c): [R]19 +3.4°
D
(c 1.20, Et2O), >99% ee; bp 110 °C/42 Torr (Kugelrohr); Rf 0.54
1
(hexane/ethyl acetate ) 10:1); H NMR (200 MHz, δ, CDCl3)
cm-1
.
0.87 (3H, t, J ) 6.4 Hz) 1.17-1.42 (12H, m) 1.62-1.83 (2H,
m) 2.14 (3H, s) 5.28 (1H, dt, J ) 20.1 Hz, 6.8 Hz); 13C NMR
(50 MHz, ppm, CDCl3) 14.04, 20.46, 22.61, 24.51, 27.74, 29.04,
29.10, 29.22, 31.76, 69.55 (q, J C-F ) 31.9 Hz) 123.83 (q, J C-F
) 278.5 Hz); 19F NMR (188 MHz, δ, CDCl3) 84.48 (d, J ) 6.6
Hz); IR (neat) 2920, 2850, 1760(CO), 1460, 1280, 1220, 1080
(()-1,1,1-Tr iflu or o-8-(ben zyloxy)-2-octa n ol (1e): bp 160
°C/5 Torr (Kugelrohr); Rf 0.12 (hexane/ethyl acetate ) 10:1);
1H NMR (200 MHz, δ, CDCl3) 1.20-1.46 (4H, m) 1.46-1.75
(4H, m) 2.53 (1H, brs, OH) 3.47 (2H, t, J ) 6.5 Hz) 3.81 (1H,
dt, J ) 3.4 Hz, 16.2 Hz) 4.50 (2H, s), 7.20-7.40 (5H, m); 13C
NMR (50 MHz, ppm, CDCl3) 24.78, 25.89, 28.92, 29.46, 29.58,
70.34 (q, J C-F ) 30.7 Hz), 72.84, 125.2 (q, J C-F ) 282.0 Hz),
127.54, 127.66, 128.03, 128.34, 138.42; 19F NMR (188 MHz, δ,
CDCl3) 81.77 (d, J ) 6.4 Hz); IR (neat) 3375, 3000, 1450, 1270,
cm-1
. Anal. Calcd for C12H21O2F3: C, 56.68; H, 8.32%.
Found: C, 56.54; H, 8.28%.
(S)-1,1,1-Tr iflu or o-8-(ben zyloxy)octa n -2-yl a ceta te (3e):
[R]26 +2.7° (c 1.25, MeOH), >99% ee; bp 135 °C/2 Torr
D
1140 cm-1
.
1
(Kugelrohr); Rf 0.36 (hexane/ethyl acetate ) 10:1); H NMR
Lip a se-Ca ta lyzed Acyla tion s. P r ep a r a tion of (S)-1,1,1-
Tr iflu or ou n d eca n -2-yl Aceta te (3d ). Alcohol (()-1d (3.432
g, 15 mmol), vinyl acetate (12.9 g, 150 mmol), lipase CAL (787
mg, Novo Nordisk Co., Ltd.,) in hexane (150 mL), and 4 Å
molecular sieves (3.75 g) were stirred at room temperature
for 11 days. The mixture was filtered through a glass sintered
(200 MHz, δ, CDCl3) 1.15-1.42 (6H, m) 1.42-1.75 (4H, m) 2.05
(3H, s) 3.38 (2H, t, J ) 6.5 Hz) 4.42 (2H, s) 5.11-5.31 (1H, m)
7.12-7.35 (5H, m); 13C NMR (50 MHz, ppm, CDCl3) 20.41,
24.44, 25.85, 27.70, 28.83, 29.53, 69.30 (q, J C-F ) 32.0 Hz),
70.18, 72.85, 123.82 (q, J C-F ) 278.1 Hz), 127.45, 127.57,
128.30, 138.57, 169.40; 19F NMR (188 MHz, δ, CDCl3) 84.56

2336 J . Org. Chem., Vol. 61, No. 7, 1996
Hamada et al.
(d, J ) 6.8 Hz); IR (neat) 3375, 3000, 1450, 1270, 1140 cm-1
.
Ack n ow led gm en t. This work was supported by a
Grant-in-Aid for Scientific Research No. 07554066 from
the Ministry of Education, Science and Culture of
J apan. The authors are grateful to Novo Nordisk Co.,
Ltd., and Amano Pharmaceutical Co., Ltd., for providing
lipases. They also thank the SC-NMR Laboratory of
Okayama University for the NMR measurements.
Anal. Calcd for C17H23O3F3: C, 61.43; H, 6.98%. Found: C,
61.45; H, 6.97%.
P r ep a r a tion of (S)-1,1,1-Tr iflu or o-2-d eca n ol ((S)-1c).
To a solution of CuI (114 mg, 0.6 mmol) in a mixed solvent of
THF (13 mL) and dimethyl sulfide (1.0 mL) was added a THF
(2 mL) solution of (S)-1,1,1-trifluoropropene oxide (336 mg, 3.0
mmol) and a THF (4.4 mL) solution of hexylmagnesium
bromide (3.6 mmol) at -15 °C under argon, and then the
mixture was stirred for 7 h at the same temperature. The
reaction was quenched by addition of 2 M HCl and was
extracted with ether. The combined organic layers were
washed with brine, dried over anhydrous MgSO4, and evapo-
rated to dryness. Purification using Kugelrohr distillation
under reduced pressure gave (S)-1c (362 mg) as a colorless
Su p p or tin g In for m a tion Ava ila ble: IR, 1H NMR, 19F
NMR, and 13C NMR spectra for 1b-e and 3a -e (36 pages).
These materials are contained in libraries on microfiche,
immediately follow this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
liquid in 61% yield: [R]22 -19.0° (c 1.0, CHCl3), 75.4% ee.
J O951976A
D