Novel fluorous prolinol as a pre-catalyst for catalytic asymmetric borane reduction of various ketones

Article abstract of DOI:10.1016/j.tet.2007.02.117

Novel prolinol carrying two perfluorohexylethyl groups at the α-position was prepared from l-proline as a starting chiral substrate. Catalytic asymmetric reduction of various ketones, including mono-, di-, and trifluoromethylated acetophenones, using fluo

Full text of DOI:10.1016/j.tet.2007.02.117

Tetrahedron 63 (2007) 4061–4066
Novel fluorous prolinol as a pre-catalyst for catalytic asymmetric
borane reduction of various ketones
*
Sakiko Goushi, Kazumasa Funabiki, Masaya Ohta, Keisuke Hatano and Masaki Matsui
Department of Materials Science and Technology, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
Received 15 January 2007; revised 26 February 2007; accepted 28 February 2007
Available online 2 March 2007
Abstract—Novel prolinol carrying two perfluorohexylethyl groups at the a-position was prepared from L-proline as a starting chiral substrate.
Catalytic asymmetric reduction of various ketones, including mono-, di-, and trifluoromethylated acetophenones, using fluorous oxazaborol-
idines derived from fluorous prolinol afforded the corresponding alcohols in good to excellent yields and with high enantioselectivities (up to
93.2% ee). The fluorous prolinol was recovered without any fluorous solvents or silica gel by simply cooling the organic phase and filtration.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
ordinary organic solvents, are needed in the liquid/liquid bi-
phasic system. Gladysz et al.,3 Ishihara et al.,4 and Mikami
et al.5 have independently reported the use of fluorous achiral
catalysts in a 1,4-addition reaction, direct amide condensa-
tion, and Friedel–Crafts reaction as well as in the recovery
of the catalysts without the use of fluorous solvents (Fig. 1).
Since the first report of a catalytic reaction using a organic/
fluorous liquid/liquid biphasic system (FBS) as an environ-
1
ꢀ
ꢀ
mentally benign recyclable system by Horvath and Rabai,
there have been many successful examples of catalytic asym-
metric reactions using a catalyst with fluorous ponytails as
well as the recovery of fluorous catalyst under a liquid/liquid
FBS system.2 However, this system has a serious drawback,
in that fluorous solvents, which are more expensive than
These reactions involve a new concept, i.e., temperature-
dependent organic/fluorous liquid/solid phase separation,
which has some advantages, such as the ability to use
homogeneous
Substrate
Product
Heat
Cool
or
micellar
solution
Fluorous
Catalyst
Fluorous
Catalyst
Filteration
Recycle and Reuse
Product
Friedel-Crafts Acylation
Reaction
1,4-Additional Reaction
Amide Condensation
C10F21
B(OH)2
C10F21
P[(CH2)2(CF2)7CF3]3
Yb[N(SO2C8F17)2]3
Gladysz (2001)
Ishihara (2001)
Mikami (2002)
Figure 1. Reported examples of synthesis using a liquid/solid biphasic system without fluorous solvent or silica gel.
* Corresponding author. E-mail: funabiki@gifu-u.ac.jp
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.117

4062
S. Goushi et al. / Tetrahedron 63 (2007) 4061–4066
(CF2)5CF3
(CF2)5CF3
ordinary organic solvents, no need for expensive fluorous
solvents or silica gel,6 and a significant decrease in the
number of steps. In particular, after the reaction with fluo-
rous catalyst is carried out under homogeneous or micellar
conditions at an elevated reaction temperature, the fluorous
catalyst can be recovered by simple cooling and filtration
of the precipitate. However, no report of a catalytic asymmet-
ric reaction using fluorous asymmetric catalyst based on this
concept has appeared in the literature.
NaOH
(+)-MTPA acid chloride
THF, rt, 1 h
N
H
OH
1
(CF2)5CF3
(CF2)5CF3
N
OH
F3C
O
Ph OMe
We describe here the synthesis of a novel fluorous solid
prolinol7,8 carrying two perfluorohexylethyl groups at the
a-position, the asymmetric borane reduction9 of a variety
of ketones including mono-, di-, and trifluoromethylated
acetophenones using this fluorous prolinol as a pre-catalyst,
and the recovery of fluorous pre-catalyst 1 without any
fluorous solvents or silica gel (Scheme 1).
4 (quant.)
Scheme 3. Transformation of fluorous prolinol 1 to Mosher amide.
insoluble in a small amount of ordinary organic solvent
and FC-72.
2.2. Optimization of reaction conditions
(CF2)5CF3
(CF2)5CF3
We initially investigated the effects of boron reagents for
preparing oxazaborolidine as well as a stoichiometric reduc-
ing agent on the enantioselectivity and yield in the reduction
of acetophenone 2a using fluorous prolinol 1 as a pre-
catalyst. The results are summarized in Table 1.
N
H
1 (10 mol%)
pre-catalyst
OH
OH
R2
O
R1
R2
Borone reagent, toluene-d8, reflux to rt
R1
2
3
When borane–tetrahydrofuran (BH3$THF) complex was
used not only as a reagent to prepare the fluorous oxaza-
borolidine but also as a reducing agent, the corresponding al-
cohol 3a was obtained in 85% yield with 73.0% ee (entry 1).
Among other boron reagents examined, such as trimethoxy-
borane (B(OMe)3)10 and trimethylboroxine, in place of
BH3$THF as a reagent to prepare the oxazaborolidine,
B(OMe)3 gave the best enantioselectivity (93.2% ee, entry
2). Borane–dimethyl sulfide (BH3$SMe2) complex and
catecholborane11 as a reducing agent were not effective
compared to BH3$THF complex (entries 4 and 5).
Scheme 1. Asymmetric reduction of ketone using novel fluorous prolinol 1.
2. Results and discussion
2.1. Synthesis of fluorous prolinol
Fluorous prolinol 1 was synthesized as follows (Scheme 2).
Treatment of N-(tert-butoxycarbonyl)proline methyl ester
with perfluorohexylethyllithium, prepared by reacting
commercially available perfluorohexylethyl iodide (8,8,8,7,
7,6,6,5,5,4,4,3,3-tridecafluorooctyl iodide) and t-BuLi, pro-
duced N-Boc fluorous prolinol in 57% yield and subsequent
deprotection of N-Boc fluorous prolinol with trifluoroacetic
acid (TFA) led to the fluorous prolinol 1 in quantitative yield.
2.3. Catalytic asymmetric reduction of various ketones
Next, various ketones were investigated under the reaction
conditions using BH3$THF or B(OMe)3 as reagents to
prepare the oxazaborolidine and to reduce the ketones.
The results are summarized in Table 2.
(CF2)5CF3
(CF2)5CF3
a,b
CO2Me
Chiral oxazaborolidine (R¼H), derived from BH3$THF
complex, was not an effective catalyst in the enantioselective
reduction of some acetophenones carrying electron-donat-
ing or electron-withdrawing groups at the 4-position of the
phenyl group and gave the corresponding alcohols 3a–e
with lower enantioselectivities (71.0–74.4% ee, entries
1–4). On the other hand, as shown in Table 2, reduction using
B(OMe)3 as a reagent to prepare the oxazaborolidine
(R¼OMe) gave much better enantioselectivities. Reduction
of acetophenone 2a proceeded smoothly to give the best
enantioselectivity (93.2% ee, entry 6). Other acetophenones
2b–e carrying methyl, methoxy, chloro, and trifluoromethyl
groups at the 4-position on the phenyl group gave the prod-
ucts 3b–e with good to high enantioselectivities (entries
2–5). The reduction of 4-acetylpyridine 2f also proceeded
smoothly to give the corresponding alcohols 3f with 90.2%
ee (entry 11). a-Tetralone 2h also participated in the reduc-
tion to produce the alcohol 3h in 95% yield with high enan-
tioselectivity (entry 13). Unfortunately, however, pinacoline
N
N
H
Boc
OH
1
Reagents and conditions: (a) t-BuLi, CF3(CF2)5CH2CH2I,
Et2O, -78 to 0 ºC, 2 h, 57%; (b) CH2Cl2-CF3CO2H (v/v =
1/1), 0 ºC to rt, 1.5 h, quant.
Scheme 2. Preparation of fluorous prolinol 1.
As shown in Scheme 3, the enantiomeric purity of fluorous
prolinol 1 was determined to be >99% ee by 1H, 19F
NMR, and GC analyses of the crude reaction mixture of
(+)-a-methoxy-a-(trifluoromethyl)phenylacetic acid ((+)-
MTPA) amide derivative 4, prepared by reacting fluorous
prolinol 1 with (+)-a-methoxy-a-(trifluoromethyl)phenyl-
acetyl chloride in the presence of sodium hydroxide.
The content of the fluorine atoms in fluorous prolinol 1 is
62.27% and prolinol 1 can be classified as a heavy fluorous
compound. Fluorous prolinol 1 was a white solid that was

S. Goushi et al. / Tetrahedron 63 (2007) 4061–4066
Table 1. Screening of reagents for asymmetric reductiona
4063
1) Reagent 2 (1 eq.)
2)
O
Ph
(1 eq.)
2a
(CF2)5CF3
(CF2)5CF3
(CF2)5CF3
rt, 1 h
1) Reagent 1
OH
Ph
3) NaHCO3 aq.
(10 mol%)
(CF2)5CF3
N
toluene-d8
toluene-d8
reflux, 1 h
N
H
O
B
3a
OH
1 (10 mol%)
R
R = H, OMe, Me
Entry
Reagent 1
Reagent 2
Yieldb (%)
Isomer ratioc (R/S)
eec (%)
Conversionb (%)
Recovery of 1d (%)
1
2
3
4
5
BH3$THFe
B(OMe)3
BH3$THFe
BH3$THFe
BH3$THFe
BH3$SMe2
85
78
83
83
51
86.5:13.5
96.6:3.4
81.6:18.4
81.9:18.1
69.3:30.7
73.0
93.2
63.2
63.8
38.6
>99
>99
>99
95
59
43
63
86
40
Trimethylboroxinee
BH3$THFe
e
BH3$THFe
Catecholboranee
66
a
The reaction was carried out with fluorous ligand 1 (0.1 mmol) and acetophenone 2a (1 mmol).
Determined by 1H NMR.
Determined by HPLC analysis with DAICEL Chiralcel OD-H column.
b
c
d
After quenching of the reaction, removal of the aqueous phase, and storage at ꢀ30 ꢁC for 40 h, the supernatant was removed via syringe and the fluorous
ligand was determined by weighing the residue.
THF solution (1.0 M) was used.
e
2g gave the product 3g with much lower enantioselectivity
(30.4% ee, entry 12).
cases, ligand 1 was recovered by filtration from the suspen-
sion in good yield (up to 84%).
Significantly, the enantioselectivities of the alcohols 3 using
the fluorous oxazaborolidine derived from B(OMe)3 are
much better than those using BH3$THF. These results can
be explained by an increase in the Lewis acidity of the boron
atom of the oxazaborolidine in the transition state.12 In all
To further expand the utility of this fluorous oxazaborol-
idine-catalyzed asymmetric reduction, three fluoromethyl-
ated ketones 5 were examined, as shown in Table 3.
a-Monofluorinated and difluorinated acetophenones 5a,b
participated in the reaction to give the corresponding
Table 2. Asymmetric reduction of various ketonesa
1) boron reagent (1 eq.)
2)
O
R1
R2
(1 eq.)
2
(CF2)5CF3
(CF2)5CF3
rt, 1 h
1) boron reagent
OH
R2
3) NaHCO3 aq.
(CF2)5CF3
(10 mol%)
(CF2)5CF3
N
R1
toluene-d8
toluene-d
8
N
O
B
3
H
OH
reflux, 1 h
R
1 (10 mol%)
R = H, OMe
Yieldb (%)
Entry
Boron reagents
Ketones 2
R1, R2
Isomer ratio (R/S)
ee (%)
Recovery of 1c (%)
1
2
3
4
5
6
7
8
BH3$THFd
BH3$THFd
BH3$THFd
BH3$THFd
BH3$THFd
B(OMe)3
B(OMe)3
B(OMe)3
B(OMe)3
B(OMe)3
B(OMe)3
B(OMe)3
B(OMe)3
2a
2b
2c
2d
2e
2a
2b
2c
2d
2e
2f
Me, Ph
85
82
>99
69
71
78
76
83
86.5:13.5e
87.2:12.8e
86.2:13.8e
85.5:14.5e
86.0:14.0e
96.6:3.4e
96.1:3.9e
94.4:5.6e
96.0:4.0e
93.0:7.0e
95.1:4.9f
65.2:34.8f
94.4:5.6f
73.0e
74.4e
72.4e
71.0e
72.0e
93.2e
92.2e
88.8e
92.0e
86.0e
90.2f
30.4f
88.8f
59
63
84
58
74
43
32
66
43
54
72
38
41
Me, 4-MeC6H4
Me, 4-MeOC6H4
Me, 4-ClC6H4
Me, 4-CF3C6H4
Me, Ph
Me, 4-MeC6H4
Me, 4-MeOC6H4
Me, 4-ClC6H4
Me, 4-CF3C6H4
Me, 4-Pyridyl
Me, t-Bu
9
88
91
10
11
12
13
50
2g
2h
>99g
95
a-Tetralone
a
The reaction was carried out with fluorous ligand 1 (0.1 mmol) and ketones 2 (1 mmol) in toluene-d8.
Determined by 1H NMR.
b
c
After quenching of the reaction, removal of the aqueous phase, and storage at ꢀ30 ꢁC for 40 h, the supernatant was removed via syringe and the fluorous
ligand was determined by weighing the residue.
THF solution (1.0 M) was used.
Determined by HPLC analysis.
d
e
f
Determined by GC analysis using InertCap CHIRAMIX (GL Sciences).
Determined by GC.
g

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S. Goushi et al. / Tetrahedron 63 (2007) 4061–4066
Table 3. Asymmetric reduction of various a-fluorinated ketonesa
1) boron reagent (1 eq.)
2)
O
Rf
Ph
(1 eq.)
(CF2)5CF3
5
(CF2)5CF3
rt, 1 h
1) boron reagent
OH
Ph
(CF2)5CF3
3) NaHCO3 aq.
(10 mol%)
(CF2)5CF3
N
Rf
toluene
toluene
reflux, 1 h
N
H
O
B
6
OH
1 (10 mol%)
R
R = H, OMe
Entry
Boron reagents
Ketones 5
Rf
Yieldb (%)
Isomer ratio (R/S)
ee (%)
Recovery of 1c (%)
1
2
3
4
B(OMe)3
B(OMe)3
B(OMe)3
BH3$THFf
5a
5b
5c
5c
CH2F
CHF2
CF3
56
80
85
54
8.3:91.7d
11.8:88.2d
50.6:49.4e
51.6:48.6e
83.4d
76.4d
0.8e
38
31
40
58
CF3
3.2e
a
The reaction was carried out with fluorous ligand 1 (0.1 mmol) and ketones 5 (1 mmol).
Determined by 1H or 19F NMR.
b
c
After quenching of the reaction, removal of the aqueous phase, and storage at ꢀ30 ꢁC for 40 h, the supernatant was removed via syringe and the fluorous
ligand was determined by weighing the residue.
Determined by HPLC analysis.
Determined by GC analysis.
d
e
f
THF solution (1.0 M) was used.
alcohols 6a,b in good yields with high enantioselectivities
(entries 1 and 2). However, the reduction of trifluoroaceto-
phenone 5c resulted in a significant decrease in the enantio-
selectivity (entries 3 and 4). There are two possible
explanations for these results: (1) the carbonyl group of tri-
fluoroacetophenone 5c cannot coordinate to the boron atom
of the oxazaborolidine, since the oxygen atom in trifluoro-
acetophenone 5c is much less basic than those of other
acetophenone derivatives. (2) Uncatalyzed reduction with
BH3$THF could occur in the case of trifluoroacetophenone
5c, since the LUMO of ketone 5c is much lower than those
of other acetophenones.13 Fluorous prolinol 1 could be re-
covered in fair to moderate yields.
prolinol with two perfluorohexylethyl groups at the a-posi-
tion afforded the corresponding alcohols in good yields
and good to high enantioselectivities (up to 93.2% ee).
Moreover, up to 86% of the fluorous ligand 1 could be recov-
ered by filtration without the use of any fluorous solvents or
silica gel.
4. Experimental
4.1. General methods
1H (500 MHz) and 13C (126 MHz) NMR spectra were mea-
sured with a JEOL ECA-500 FTNMR spectrometer in deu-
terochloroform (CDCl3) solutions with tetramethylsilane
(Me4Si) as an internal standard. 19F NMR (471 MHz) spec-
tra were recorded on a JEOL ECA-500 FT NMR in CDCl3
solutions using trichlorofluoromethane (CFCl3) as an exter-
nal standard. Anhydrous tetrahydrofuran (THF) and diethyl
ether were purchased from Kanto Chemical Co., Inc. and
used directly without any treatment. Dichloromethane
(CH2Cl2) was distilled over calcium hydride under argon.
Toluene-d8 was purchased from Cambridge Isotope Labora-
tories, Inc. and used without any treatment. The ee values
of the products were determined by chiral HPLC or GC
analyses.
Finally, the reusability of the recovered fluorous prolinol 1
was investigated. After work-up in this reaction using
B(OMe)3 to prepare the oxazaborolidine, the fluorous ligand
1 was recovered from the suspension with a glass filter and
washed with a small amount of cold aq sodium hydrogen
carbonate as well as cold hexane, and dried under vacuum
at room temperature. Unfortunately, the second reduction
using the obtained fluorous ligand 1 gave a similar yield
(78%) of the product 3a but with lower enantioselectivity
(R/S¼68.4:31.6). Epimerization of the recovered fluorous
prolinol 1 did not occur in this reaction, because the enantio-
meric purity of the recovered fluorous prolinol 1 was also de-
termined to be >99% ee by 1H and 19F NMR analyses of the
crude reaction mixture of (+)-MTPA amide derivative 4, pre-
pared by reacting the recovered fluorous prolinol 1 with (+)-
a-methoxy-a-(trifluoromethyl)phenylacetyl chloride. While
the exact reason for the decrease in enantioselectivity is not
yet clear, it may be due to the presence of a small amount of
water14 or boric acid derivatives along with the recovered
fluorous prolinol 1.
4.2. N-tert-Butoxycarbonyl-(2S)-bis(3,3,4,4,5,5,6,6,7,7,-
8,8,8-tridecafluorooctyl)(pyrrolidin-2-yl)methanol
A solution of 3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl
iodide (4.181 g, 8.82 mmol) in dry Et2O (24 ml) was cooled
to ꢀ78 ꢁC and t-BuLi (5.8 ml, 8.58 mmol) was added
slowly. The mixture was stirred for 20 min at ꢀ78 ꢁC. After
N-(tert-butoxycarbonyl)-(L)-proline methyl ester (0.338 g,
1.47 mmol) in dry Et2O (10 ml) was added slowly, the solu-
tion was stirred for 1 h at ꢀ78 ꢁC and then slowly warmed to
0 ꢁC with stirring. The mixture was poured into an ice solu-
tion of satd aq NH4Cl/10% aq HCl¼3:1 (80 ml), the organic
3. Conclusions
Catalytic asymmetric reduction of a variety of ketones using
fluorous oxazaborolidines derived from a novel fluorous

S. Goushi et al. / Tetrahedron 63 (2007) 4061–4066
4065
layer was separated, and the aqueous layer was extracted
with Et2O (2ꢂ50 ml). The combined organic layers were
washed with brine (50 ml) and dried over Na2SO4. After
Et2O was evaporated, the residue was purified by column
chromatography on silica gel (eluant: hexane/Et2O¼30:1)
to give N-tert-butoxycarbonyl-(2S)-bis(3,3,4,4,5,5,6,6,7,7,8,
8,8-tridecafluorooctyl)(pyrrolidin-2-yl)methanol (0.758 g,
0.849 mmol). Rf 0.13 (Hexane/Et2O¼30:1); [a]2D3 ꢀ22.4
(c 1.00, CHCl3); IR (KBr): 3292 (OH), 1662 (C]O)
cmꢀ1; mp 89.5 ꢁC; 1H NMR (CDCl3): d 1.47 (s, 9H),
1.52–1.89 (m, 8H), 2.05–2.22 (m, 3H), 2.30–2.54 (m, 1H),
3.13–3.20 (m, 1H), 3.71–3.76 (m, 1H), 3.99 (t, J¼7.81 Hz,
1H), 6.40 (s, 1H); 13C NMR (CDCl3): d 24.16 (s), 25.16
(s), 25.23 (t, J¼21.92 Hz), 25.29 (t, J¼21.09 Hz), 28.11
(s), 28.24 (s), 28.32 (s), 48.56 (s), 65.24 (s), 74.36 (s),
81.64 (s), 105.33–121.92 (m, 12C), 158.37 (s); 19F NMR
(CDCl3): d ꢀ48.49 to ꢀ48.41 (m, 4F), ꢀ45.68 (br s,
4F), ꢀ45.16 (br s, 4F), ꢀ44.17 (br s, 4F), ꢀ37.80 to
ꢀ36.11 (m, 4F), 3.12 (t, J¼9.92 Hz, 6F); HRMS (FAB+)
found: m/z 894.1496, calcd for C26H26F26NO3: M+H,
894.1498.
4:1) to give N-a-methoxy-a-(trifluoromethyl)phenylacetyl-
(2S)-bis(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)(pyrro-
lidin-2-yl)methanol (0.157 g, 0.198 mmol). Rf 0.6 (hexane/
EtOAc¼4:1); [a]2D3.0 +24.36 (c 0.67, CHCl3); IR (NaCl):
3304 (OH), 1628 (C]O) cmꢀ1; mp 98.0–102.0 ꢁC; 1H
NMR (CDCl3): d 1.40–1.66 (m, 5H), 1.77–1.89 (m, 2H),
2.04–2.18 (m, 4H), 2.45–2.62 (m, 2H), 3.66 (s, 3H), 4.04–
4.08 (m, 1H), 4.39 (t, J¼8.31 Hz, 1H), 6.37 (d, J¼1.72 Hz,
1H), 7.35–7.41 (m, 3H), 7.50–7.51 (m, 2H); 13C NMR
(CDCl3): d 24.65–25.44 (m, 4C), 25.18 (s, 2C), 27.12 (s,
2C), 48.43 (s, 1C), 55.98 (s, 1C), 75.17 (s, 1C), 85.18 (q,
J¼25.99 Hz, 1C), 108.13–124.70 (m, 12C), 126.67 (s, 2C),
128.56 (s, 2C), 129.64 (s, 1C), 133.38 (s, 1C), 168.63 (s,
1C); 19F NMR (CDCl3): d ꢀ126.12 (d, J¼14.09 Hz, 4F),
ꢀ123.39 to ꢀ123.19 (m, 4F), ꢀ122.84 (s, 4F), ꢀ121.82 (d,
J¼7.59 Hz, 4F), ꢀ115.45 to ꢀ113.72 (m, 4F), ꢀ80.81 (t,
J¼9.75 Hz, 3F), ꢀ80.83 (t, J¼10.12 Hz, 3F), ꢀ71.22 (s,
3F); HRMS (FAB+) found: m/z 1010.1364, calcd for
C31H25F29NO3: M+H, 1010.1371.
4.5. Typical procedure for the asymmetric reduction of
ketones with fluorous prolinol 1 (Table 1, entry 2)
4.3. (2S)-Bis(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluoro-
octyl)(pyrrolidin-2-yl)methanol (1)
To a toluene-d8 (1 ml) solution of fluorous prolinol 1
(0.079 g, 0.100 mmol), was added trimethoxyborane
(B(OMe)3) (0.1 mmol, 0.01 ml) at room temperature under
an argon atmosphere. After being refluxed for 1 h, the reac-
tion mixture was cooled to room temperature. After the suc-
cessive addition of a THF solution of BH3$THF complex
(1.0 M tetrahydrofuran solution, 1.0 mmol, 1.0 ml) and a
toluene-d8 (8 ml) solution of acetophenone 2a (0.120 g,
1 mmol) over 3 h at room temperature, the reaction mixture
was stirred for an additional 1 h at the same temperature. The
reaction mixture was then quenched with MeOH (1 ml) and
satd aq NaHCO3 (3 ml), the aqueous phase was removed and
the mixture was held at ꢀ30 ꢁC for 40 h, the supernatant was
removed via syringe, and the fluorous ligand was determined
by weighing the residue (0.034 g, 43%). Measurement of
the organic phase by 1H NMR using anisole (0.104 g,
0.962 mmol) as an internal standard gave the corresponding
alcohol 3a in 78% yield (0.779 mmol).
A solution of N-tert-butoxycarbonyl-(L)-bis(3,3,4,4,5,5,
6,6,7,7,8,8,8-tridecafluorooctyl)(pyrrolidin-2-yl)methanol
(0.953 g, 1.07 mmol) in CH2Cl2 (6.3 ml) was cooled to 0 ꢁC
and TFA (6.3 ml) was added. The mixture was stirred for
1.5 h at room temperature. After the mixture was poured
into a satd aq Na2CO3 solution (60 ml), the organic layer
was separated, and the aqueous layer was extracted with
CH2Cl2 (2ꢂ60 ml). The combined organic layers were
washed with brine and dried over Na2SO4. CH2Cl2 was
evaporated to give (2S)-bis(3,3,4,4,5,5,6,6,7,7,8,8,8-trideca-
fluorooctyl)(pyrrolidin-2-yl)methanol (0.814 g, 1.21 mmol).
[a]2D3.5 ꢀ5.34 (c 0.374, CHCl3 and AK-225G); IR (KBr):
1
3101 (OH) cmꢀ1; mp 50.0–52.0 ꢁC; H NMR (CDCl3 and
AK-225G): d 1.64–1.94 (m, 8H), 1.98–2.33 (m, 6H), 2.84–
2.93 (m, 1H), 3.02–3.12 (m, 1H), 3.14–3.22 (m, 1H);
13C NMR (CDCl3 and AK-225G): d 24.98 (s), 25.76 (t, J¼
22.33 Hz), 25.89 (s), 27.61 (s), 46.96 (s), 63.98 (s), 72.13
(s), 107.14–125.80 (m, 12C); 19F NMR (CDCl3 and AK-
225G): d ꢀ126.55 to ꢀ126.30 (m, 4F), ꢀ123.52 (s, 4F),
ꢀ123.06 (s, 4F), ꢀ122.09 (s, 4F), ꢀ115.07 to ꢀ114.42 (m,
4F), ꢀ81.21 (t, J¼10.22 Hz, 6F); HRMS (FAB+) found:
m/z 794.0790, calcd for C21H18F26NO: M+H, 794.0973.
4.5.1. 1-Phenylethanol (3a).15,16 1H NMR (CDCl3): d 1.44
(d, J¼6.52 Hz, 3H), 3.89 (s, 1H), 4.52–4.85 (m, 1H), 7.26–
7.38 (m, 5H). Enantiomer separation of 3a: HPLC (Daicel
Chiralcel OD-H column, 0.4 ml/min, 254 nm, hexane/
i-PrOH¼95:5, t1 (R-isomer)¼16.6 min, t2 (S-isomer)¼
20.3 min).
4.4. N-a-Methoxy-a-(trifluoromethyl)phenylacetyl-
(2S)-bis(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl)-
(pyrrolidin-2-yl)methanol (4)
4.5.2. 1-(4-Methylphenyl)ethanol (3b).15,16 1H NMR
(CDCl3): d 1.33 (d, J¼6.34 Hz, 3H), 2.23 (s, 3H), 2.39 (s,
1H), 4.69 (q, J¼6.34 Hz, 1H), 7.03 (d, J¼7.81 Hz, 2H),
7.12 (d, J¼7.81 Hz, 2H). Enantiomer separation of 3b: GC
(InertCap CHIRAMIX (GL Sciences), 40–180 ꢁC, program-
ming rate¼2.0, t1 (R-isomer)¼54.7 min, t2 (S-isomer)¼
56.2 min).
To a solution of (L)-bis(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluoro-
octyl)(pyrrolidin-2-yl)methanol (0.158 g, 0.199 mmol) in
THF (4 ml) was added 1.0 M aq NaOH (1.0 M, 0.2 ml,
0.200 mmol). The mixture was stirred, (+)-MTPA acid chlo-
ride (0.101 g, 0.400 mmol) was added, and the mixture was
stirred for 1 h at room temperature. After the mixture was
poured into brine (50 ml), the organic layer was separated,
and the aqueous layer was extracted with Et2O (2ꢂ50 ml).
The combined organic layers were dried over Na2SO4. After
the solution was evaporated, the residue was purified by
column chromatography on silica gel (hexane/ethyl acetate¼
4.5.3. 1-(4-Methoxyphenyl)ethanol (3c).15,16 1H NMR
(CDCl3): d 1.49 (s, 3H), 1.83 (s, 1H), 3.80 (s, 3H), 4.86 (s,
1H), 6.88–7.31 (m, 4H). Enantiomer separation of 3c: GC
(InertCap CHIRAMIX (GL Sciences), 40–180 ꢁC, program-
ming rate¼2.0, t1 (R-isomer)¼66.2 min, t2 (S-isomer)¼
67.0 min); HPLC (Daicel Chiralcel OD column, 0.3 ml/min,

4066
S. Goushi et al. / Tetrahedron 63 (2007) 4061–4066
hexane/i-PrOH¼95:5, t1 (R-isomer)¼36.8 min, t2 (S-iso-
mer)¼41.8 min).
Acknowledgements
We thank Professors and T. Ishihara, T. Konno and H. Yama-
naka of the Kyoto Institute of Technology for the HRMS
measurements. K.F. also gratefully acknowledges the AZI-
NOMOTO Award in Synthetic Organic Chemistry, Japan.
4.5.4. 1-(4-Chlorophenyl)ethanol (3d).15,16 1H NMR
(CDCl3): d 1.43 (d, J¼6.34 Hz, 3H), 2.34 (s, 1H), 4.82 (q,
J¼6.34 Hz, 1H), 7.25–7.30 (m, 4H). Enantiomer separation
of 3d: HPLC (Daicel Chiralcel OD column, 0.4 ml/min,
254 nm, hexane/i-PrOH¼95:5, t1 (R-isomer)¼30.0 min, t2
(S-isomer)¼28.9 min).
References and notes
4.5.5. 1-(4-Trifluoromethylphenyl)ethanol (3e).16 1H
NMR (CDCl3): d 1.51 (d, J¼6.10 Hz, 3H), 1.97 (s, 1H),
4.97 (q, J¼6.10 Hz, 1H), 7.49 (d, J¼8.06 Hz, 2H), 7.61 (d,
J¼8.06 Hz, 2H). Enantiomer separation of 3e: GC (InertCap
CHIRAMIX (GL Sciences), 40–180 ꢁC, programming
rate¼2.0, t1 (R-isomer)¼54.7 min, t2 (S-isomer)¼56.7 min).
4.5.6. 1-(4-Pyridyl)ethanol (3f).17 1H NMR (CDCl3):
d 1.41–1.45 (m, 3H), 2.69 (s, 1H), 4.80–4.94 (m, 1H),
7.21–7.44 (m, 2H), 8.35–8.43 (m, 2H). Enantiomer separa-
tion of 3f: HPLC (Daicel Chiralcel AS-H column, hexane/
i-PrOH¼95:5, 254 nm, 0.5 ml/min, t1 (S-isomer)¼71.4 min,
t2 (R-isomer)¼83.9 min).
4.5.7. 3,3-Dimethyl-2-butanol (3g).18 1H NMR (CDCl3):
d 0.82 (s, 9H), 1.04 (d, J¼6.52 Hz, 3H), 2.52 (s, 1H), 3.62
(q, J¼6.52 Hz, 1H). Enantiomer separation of 3g: GC
(CP-Chirasil-Dex CB (VARIAN), 40–225 ꢁC, programming
rate¼2.0, t1 (R-isomer)¼18.7 min, t2 (S-isomer)¼20.3 min).
4.5.8. 1,2,3,4-Tetrahydronaphthalen-1-ol (3h).18 1H NMR
(CDCl3): d 1.79–2.00 (m, 5H), 2.68–2.86 (m, 2H), 4.77 (t,
J¼4.83 Hz, 1H), 7.09–7.11 (m, 1H), 7.17–7.22 (m, 2H),
7.40–7.43 (m, 1H). Enantiomer separation of 3h: HPLC
(Daicel Chiralcel AS-H column, hexane/i-PrOH¼95:5,
254 nm, 0.2 ml/min, t1 (R-isomer)¼42.7 min, t2 (S-isomer)¼
34.9 min).
ꢀ
1. Horvath, I. T.; Rabai, J. Science 1994, 266, 72.
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2. (a) Gladysz, J. A.; Curran, D. P. Tetrahedron 2002, 58, 3823 and
the following articles in this special issue entitled ‘Fluorous
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ꢀ
Gladysz, J. A., Horvath, I. T., Curran, D. P., Eds.; Wiley-
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3. (a) Wende, M.; Meier, R.; Gladysz, J. A. J. Am. Chem. Soc.
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7. For a,a-diphenylprolinols carrying the perfluoroalkyl group on
€ €
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11. Gilmore, N. J.; Jones, S. Tetrahedron: Asymmetry 2003, 14,
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4.5.9. 2-Fluoro-1-phenylethanol (6a).19 1H NMR (CDCl3):
d 2.53 (s, 1H), 4.59–4.34 (m, 2H), 5.05–4.99 (m, 1H),
7.38–7.42 (m, 5H). Enantiomer separation of 6a: HPLC
(Daicel Chiralcel OD column, 0.8 ml/min, 254 nm, hex-
ane/i-PrOH¼95:5, t1 (S-isomer)¼15.1 min, t2 (R-isomer)¼
18.9 min).
12. Farfan, N.; Contreras, R. J. Chem. Soc., Perkin Trans. 2 1987,
771.
13. Asao, N.; Asano, T.; Yamamoto, Y. Angew. Chem., Int. Ed.
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14. For the effect of water on the enantioselectivities, see: (a) Jones,
T. K.; Mohan, J. J.; Xavier, L. C.; Blacklock, T. J.; Mathre, D. J.;
Sohar, P.; Jones, E. T. T.; Reamer, R. A.; Roberts, F. E.;
Grabowski, E. J. J. J. Org. Chem. 1991, 56, 763; For the effect
of anions on the the enantioselectivities, see: (b) Xu, J.; Wei, T.;
Zhang, Q. J. Org. Chem. 2004, 69, 6860.
4.5.10. 2,2-Difluoro-1-phenylethanol (6b).19 1H NMR
(CDCl3): d 2.43 (s, 1H), 4.83 (dt, J¼10.08, 4.75 Hz, 1H),
5.77 (dt, J¼56.02, 4.75 Hz, 1H), 7.42–7.36 (m, 5H). Enan-
tiomer separation of 6b: HPLC (Daicel CHIRALPAK
AS-H, hexane/i-PrOH¼95:5, 0.8 ml/min, 254 nm, t1 (S-iso-
mer)¼12.0 min, t2 (R-isomer)¼12.7 min).
4.5.11. 2,2,2-Trifluoro-1-phenylethanol (6c).19 1H NMR
(CDCl3): d 2.65 (s, 1H), 5.02 (q, J¼6.68 Hz, 1H), 7.47–
7.41 (m, 5H). Enantiomer separation of 6c: GC (CP-Chira-
sil-Dex CB (VARIAN), 50–160 ꢁC, programming rate¼2.0,
t1 (S-isomer)¼43.5 min, t2 (R-isomer)¼44.2 min).
15. Kobayashi, Y.; Kodama, K.; Saigo, K. Org. Lett. 2004, 6, 2941.
€
€
16. Hedberg, C.; Kallstrom, K.; Arvidsson, P.; Andersson, P. G.;
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Lattes, A.; Thion, L. J. Am. Chem. Soc. 2001, 123, 5956.
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18. Puigjaner, C.; Vidal-Ferran, A.; Moyano, A.; Pericas, M. A.;
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19. Nakamura, K.; Yamanaka, R. Tetrahedron: Asymmetry 2002,
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