New axially dissymmetric ligand recoverable with fluorous solvent

Article abstract of DOI:10.1016/j.tet.2005.11.063

Axially dissymmetric ligands with perfluoroalkyl groups, (Ra)-2,2′-bis[(R)-1-hydroxy-1H-perfluorooctyl]biphenyl [(Ra)-(R) ₂-1c] and its enantiomer, have been synthesized successfully by the coupling reaction of the corresponding aryl bromide us

Full text of DOI:10.1016/j.tet.2005.11.063

Tetrahedron 62 (2006) 1886–1894
New axially dissymmetric ligand recoverable with fluorous solvent
*
Masaaki Omote, Yuji Nishimura, Kazuyuki Sato, Akira Ando and Itsumaro Kumadaki
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata 573-0101, Japan
Received 19 October 2005; revised 4 November 2005; accepted 9 November 2005
Available online 20 December 2005
Abstract—Axially dissymmetric ligands with perfluoroalkyl groups, (Ra)-2,20-bis[(R)-1-hydroxy-1H-perfluorooctyl]biphenyl [(Ra)-(R)2-1c]
and its enantiomer, have been synthesized successfully by the coupling reaction of the corresponding aryl bromide using Ni(COD)2. These
ligands showed much higher asymmetric induction in the reaction of various aldehydes with diethylzinc than the trifluoromethyl (1a) or
pentafluoroethyl (1b) analogues. Furthermore, 1c was recovered quantitatively by extraction with a fluorous solvent from the reaction
mixture due to its high fluorine content. The recovered ligand 1c was pure enough to be reused without purification. The efficiency of 1c as
the chiral ligand was not decreased at all even after seven times recycling.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
moisture to be recycled, or likely to be deactivated by
racemization.
The search for easily recoverable and efficient chiral ligand
for asymmetric synthesis is of major interest in modern
chemistry from ecological and environmental points of view.
One of the most interesting advances in this field is based on a
selective recovery of highly fluorinated compounds with
In our previous study, axially dissymmetric ligands with
short perfluoroalkyl (Rf) groups, (Ra)-2,20-bis[(R)-2,2,2-
trifluoro-1-hydroxyethyl]biphenyl [(Ra)-(R)2-1a], (Ra)-2,20-
bis[(R)-1-hydroxy-1H-perfluoropropyl]biphenyl [(Ra)-(R)2-
1b], and their enantiomers have been synthesized as chiral
ligands for Lewis metals (Fig. 1).11 The symbols (Ra) and
(Sa) represents the axial chirality. Titanium complex
prepared from 1a or 1b and Ti(OiPr)4 catalyzed asymmetric
addition reaction of diethylzinc to benzaldehyde much
better than the BINOL–Ti(OiPr)4 complex, and 1b showed
higher asymmetric induction than 1a. These suggested that
the electron-withdrawing Rf groups increased the Lewis
acidity of the titanium complex and that the bulkier
perfluoroalkyl groups might show the higher asymmetric
induction. Based on this observation, we designed a
perfluoroheptyl analogue (1c) whose fluorine content is
60%. We expected that large Rf groups and high fluorine
content of 1c would make it not only an excellent
asymmetric inducer but also a recoverable ligand with a
fluorous solvent. In our preliminary reports,1 the synthesis
of 1c and its application were presented. In this paper, we
would like to discuss in details a modified synthesis of 1c, its
applicability for asymmetric addition of diethylzinc to
perfluorocarbons, called fluorous solvents.2 Since the first
3
´
´
report by Horvath and Rabai, the fluorous recovering
technique has aroused a growing scientific and industrial
interest due to the simple procedure and use of a chemically
inert and low toxic fluorous solvent. The fluorous recovering
technique can be classified into two categories, liquid–liquid
partition4 and solid separation using fluorine-capped silica-
gel.5 The former is an economical and simple procedure but
introduction of long perfluoroalkyl chains into target
materials is essential for the efficient partition. On the other
hand, the latter can be applied to the recovery of partly
fluorinated molecules, but it is necessary to use a very
expensive fluorine-capped silica-gel. There are many reports
on recoverable chiral ligands by liquid–liquid fluorous
technique involving recoverable analogues of BINAP,6
BINOL,7 BOX,8 salen9 and chiral phase-transfer catalyst10
tethered with long perfluoroalkyl chains. These ligands have
the perfluoroalkyl chains far from the active centers, and their
activities are not improved by the introduction of perfluor-
oalkyl chains. These analogues exhibit their efficient
recoverabilities. However, there are few reports on their
recycling, since they are too labile toward oxygen and
Keywords: Axial dissymmetry; Chiral ligand; Fluorine; Fluorous solvent;
Recoverable; Reusable.
*
Corresponding author. Tel.: C81 72 866 3140; fax: C81 72 850 7020;
e-mail: kumadaki@pharm.setsunan.ac.jp
Figure 1. Structures of 1a to 1c.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.063

M. Omote et al. / Tetrahedron 62 (2006) 1886–1894
1887
various aldehydes, and its high reusability on recycling
using a fluorous solvent.
Results of the coupling reaction are summarized in
Table 1. The reaction of (R)-5c with Ni(COD)2 in DMF
at 60 8C gave 59% of (Ra)-(R)2-6c and 12% of the axial
isomer (Sa)-(R)2-6c after separation by a column chroma-
tography (entry 1). The latter was easily converted to (Ra)-
(R)2-1c after hydrolysis as mentioned later. This means that
the total yield of 6c is more than 70%. When NMP was
used as a solvent, the total yield was decreased to 30%
(entry 2). Raising the reaction temperature did not improve
the yield of the coupling reaction (entry 3). When
Ni(PPh3)4 was used, the total yield of 6c was decreased
to 6%, and a fairly large amount of 5c was recovered. This
suggested that the low reactivity might be due to a low
oxidative additivity of this nickel complex to aryl bromide.
The enantiomer (S)-5c was also coupled efficiently by the
same manner to give 6c in total 68% yield, 57% of (Sa)-
(S)2-6c and 11% of the axial isomer (Ra)-(S)2-6c (entry 5).
This coupling reaction using Ni(COD)2 in DMF gave much
higher yields of 6a or 6b than the former method11 (entries
6 and 7).
2. Results and discussion
The key step for the synthesis of the ligands (1a and 1b) was
the Ullmann type coupling reaction of the corresponding
aryl bromides using copper powder. The chiral substrate
(5c) for this coupling reaction was prepared according to the
same procedure as the previous route as shown Scheme 1.
Thus, enantioselective reduction of 3c12 with catecholbor-
ane in the presence of CBS catalyst13 gave 4c quantitatively
in a high ee. Interestingly, while (S)-4a was obtained with
(R)-CBS catalyst, (R)-4c was obtained with the same (R)
catalyst.14 This suggested that the order of steric bulkiness is
C7F15[C6H5[C2F5OCF3. The reduction of heptafluoro-
propyl analogue with the (R)-CBS catalyst gave the (S)
product only in 60% ee, which means that the bulkiness of
C3F7 is comparable to that of C6H5 on this reduction. After
protection of the hydroxyl groups, (R)-5c was used for the
next coupling reaction. The enantiomer (S)-5c was also
prepared efficiently by the same sequence.
Deprotection of (Ra)-(R)2-6a–c with TFA gave the desired
ligands (Ra)-(R)2-1a–c quantitatively. The axial isomers
(Sa)-(R)2-6a–c were also deprotected quantitatively to (Sa)-
(R)2-1a–c. The (Sa)-(R)2-ligands could be converted to the
corresponding (Ra)-(R)2-ligands by thermal equilibration
followed by separation. Namely, refluxing a solution of
each (Sa)-(R)2-ligand in toluene gave an equilibrium
mixture, where the corresponding (Ra)-(R)2-ligand pre-
dominated. The efficiency of the conversion depended on
each equilibrium constant (K) shown in Eq. 2. The
equilibrium mixture was separated by silica-gel column
chromatography to give a large amount of the desired (Ra)-
(R)2-ligand and a small amount of (Sa)-(R)2-ligand. The
large K values of 1b and 1c facilitated the conversion of
(Sa)-(R)2-1b or (Sa)-(R)2-1c to the corresponding (Ra)-
(R)2-isomers over 90% by only one equilibration followed
by separation. Compound (Sa)-(R)2-1a was also converted
into (Ra)-(R)2-1a in 93% yield by twice equilibration and
separation. Compound (Sa)-(S)2-1c was obtained similarly.
Scheme 1. Reagents and conditions: (a) (i) n-BuLi, THF–Et2O, K110 8C, (ii)
RfCOOEt; (b) catecholborane, THF, (R)- or (S)-2-methyl-5,5-diphenyl-3-4-
propano-1,3,2-oxazaborolidine, K78 to K30 8C; (c) NaH, MOMCl, THF.
The coupling reaction of 5c using copper powder hardly
proceeded probably due to the steric repulsion between the
large C7F15 groups. To solve this problem, tetrakis(triphenyl-
phosphine)nickel(0) or bis(1,5-cyclooctadiene)nickel(0)15
[Ni(COD)2], were examined in the place of the active copper
powder, since they were reported to have high reactivity on
oxidative addition to aryl bromide16 (see Eq. 1).
(2)
(1)
Ability of 1c as an asymmetric inducer was evaluated
by the reaction of diethylzinc with benzaldehyde in
the presence of a stoichiometric amount of Ti(OiPr)4
Table 1. Ni(0) mediated coupling reaction
Entry
Substrate
Catalyst
Product Yield (%)a
1
(R)-5c
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(PPh3)4
Ni(COD)2
Ni(COD)2
Ni(COD)2
(Ra)-(R)2-6c
59
25
55
5
57
56
69
(Sa)-(R)2-6c
12
5
10
1
11
36
11
2b
3c
4
5
6
7
(S)-5c
(R)-5a
(R)-5b
(Sa)-(S)2-6c
(Ra)-(R)2-6a
(Ra)-(R)2-6b
(Ra)-(S)2-6c
(Sa)-(R)2-6a
(Sa)-(R)2-6b
a Isolated yield.
b NMP was employed as a solvent.
c Reaction was carried out at 120 8C.

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M. Omote et al. / Tetrahedron 62 (2006) 1886–1894
Table 3. Asymmetric ethylation of other aldehydes (R-CHO)
(see Eq. 3).17,18
Entry
R
Ligand
Yield (%) ee (%) Config.a
96
94
97
98
73
89
95b
95b
96c
93c
80b
82d
(3)
1
2
3
4
5
6
p-Cl–C6H4
(Sa)-(S)-1c
(Sa)-(S)-1c
(Sa)-(S)-1c
(Sa)-(S)-1c
R
R
R
R
S
p-Me–C6H4
C6H5–CH]CH
1-Napthyl
The results are summarized with the results of 1a and 1b in
Table 2. The trifluoromethyl analogue 1a showed a good
asymmetric induction, as reported before:11a the product
was obtained in 85% ee using 5 mol% of 1a. The
pentafluoroethyl analogue 1b with bulkier pentafluoroethyl
groups showed higher asymmetric induction: ee of the
product increased to 91% with the same amount of 1b
as 1a. The highest asymmetric induction was achieved
by the perfluoroheptyl analogue 1c. A 5 mol% of 1c
catalyzed the reaction efficiently to give the product of
97% ee. Increasing the amount of 1c to 8 mol% resulted
in a further improvement of the ee. Only 1 mol% of
(Sa)-(S)2-1c gave the (R)-product in 88% ee. These results
suggest that the asymmetric induction depends signifi-
cantly on the size of perfluoroalkyl moieties of the ligands.
The larger perfluoroalkyl groups give the better asym-
metric induction. It was reported that 20 mol% of BINOL
showed 85% ee in the same reaction. This means that 1c is
more than twenty times effective than BINOL.
C6H5–CH2CH2CHO (Ra)-(R)-1c
n-C7H15 (Ra)-(R)-1c
S
a
Determined by comparing the optical rotation with the literature data. For
entries 1– and 5: Watanabe, M.; Araki, S.; Butsugan, Y. J. Org. Chem. 1991,
56, 2218. For entry 4: Dai, W.-M.; Zhu, H.-J.; Hao X.-J. Tetrahedron:
Asymmetry 2000, 11, 2315. For entry 6: Nakano, H.; Kumagai, N.; Matsuzaki,
H.; Kabuto, C.; Hongo, H. Tetrahedron Asymmetry 1997, 8, 1391.
b ee was determined by chiral GLC analysis.
c
ee was determined by chiral HPLC analysis.
d ee was determined by chiral HPLC analysis after derivatization to benzoyl
ester.
high enough to be recovered by the fluorous phase
separation technique. Partition of 1c between perfluoro-
hexane (FC-72) and some organic solvents was investigated
as follows. To a mixture of FC-72 and an organic solvent
(2 mL each), 50 mg of 1c was added. The mixture was
shaken vigorously enough to establish the partition. Both
layers were separated on ice-cooling, and the amount of 1c
dissolved in each solvent was determined by weighing each
residue after evaporation of the solvent. The results are
summarized in Table 4. The highest partition to FC-72 was
observed, when hexane was used. This may be due to the
fact that two hydroxyl groups of 1c lower the solubility in
nonpolar hexane. Dichloromethane was also found to be a
good solvent for this fluorous phase separation technique.
Other solvents, chloroform or ether, did not show sufficient
partition for fluorous extraction. This moderate partition of
1c in FC-72 is attributed to rather low content of fluorine
(60%) for fluorous extraction. This content is believed to be
the border whether the fluorous phase separation can be used
or not. While the introduction of more fluorine to 1c might
increase the solubility in a fluorous solvent, it would lower
the solubility in a common organic solvent. The solubility in
a common solvent, in which a reaction is carried out, is
crucial for a reaction to proceed. Thus, we expected that
60% of fluorine content of 1c would have not only its
recoverability by a fluorous solvent but also good solubility
in various solvents. To estimate the recoverability of 1c,
combination of FC-72 and dichloromethane was chosen as
the solvent system for extraction, since dichloromethane
would extract common organic materials better than
hexane.
Table 2. Asymmetric induction by la to lc
Ligand
Mol%
Yield (%)a ee (%)b
Config.c
(Sa)-(S)2-1a
(Ra)-(R)2-1a
2
2
3
5
10
1
2.5
5
10
1
3
5
95
97
92
94
97
97
99
96
99
92
93
97
96
91
97
81
82
81
85
85
63
90
91
93
88
94
96
97
98
85
R
S
S
S
S
S
S
S
S
R
R
R
S
S
S
(Ra)-(R)2-1b
(Sa)-(S)2-1c
(Ra)-(R)2-1c
5
8
20
(Sa)-BINOL
a Isolated yield.
b ee was determined by chiral GLC analysis.
c Determined by sign of optical rotation.
To investigate scope of applicability of 1c, the same
asymmetric reaction of other aromatic and aliphatic
aldehydes was examined. The results are summarized in
Table 3. Electron-withdrawing and donating substituents
had no significant effects on the asymmetric induction
(entries 1 and 2). The reaction could be applied to the
synthesis of labile chiral allyl alcohol as shown in entry 3. A
large aromatic aldehyde, 1-naphthaldehyde, also reacted,
while ee of the product was slightly decreased (entry 4).
This ligand was less effective for the reactions of aliphatic
aldehydes as shown in entries 5 and 6. These results suggest
that titanium complex of 1c is an effective chiral catalyst for
the reaction of diethylzinc with aromatic aldehydes
including conjugated ones.
Table 4. Partition of 1c: FC-72/solvent
Solvent
mL
Amount (mg)
FC-72/hexane
2/2
2/1
2/2
2/1
2/2
2/1
2/2
2/1
2/2
2/1
37/13
47/3
30/20
42/7
26/23
35/15
20/29
32/17
13/37
23/26
FC-72/dichloromethane
FC-72/toluene
To apply the fluorous extraction methodology to a
compound, its partition between a fluorous solvent and a
common organic solvent is very important. We expected
that the high fluorine content of 1c would make its partition
FC-72/chloroform
FC-72/diethyl ether

M. Omote et al. / Tetrahedron 62 (2006) 1886–1894
1889
Table 5. Recycled use of 1c
The procedure for recovering 1c from the reaction of
diethylzinc with benzaldehyde is as follows: the titanium
complex of the catalyst was prepared by warming a solution
of 1c (34 mg, 0.036 mmol) and Ti(OiPr)4 (0.86 mmol) in
toluene (0.3 mL) at 50 8C for 30 min. The solution was
cooled to K78 8C and a solution of diethylzinc in hexane
(0.86 mmol) was added to the solution. To this solution, a
solution of benzaldehyde (0.72 mmol) in toluene (0.3 mL)
was added over 30 min. The temperature was raised to
K30 8C gradually and the reaction was followed by TLC.
After the completion of the reaction (within 5 h), the
reaction mixture was quenched with 2 mL of 10% aqueous
HCl. Dichloromethane (1 mL) and FC-72 (2 mL) were
added to the mixture for extraction. The mixture was shaken
vigorously to complete the partition. After separation of
FC-72 phase containing 1c, another FC-72 (2 mL) was
added to the remaining mixture for the next extraction.
Extraction with FC-72 (2 mL each) was performed three
times to recover almost all of 1c. Evaporation of combined
FC-72 layer under reduced pressure gave 1c in a recovery of
97% with an excellent purity of 98%. After the recovery of
1c from the reaction mixture, the product was extracted by
dichloromethane in three portions (1 mL!1C2 mL!2).
The yield and ee of the product were measured after
evaporation of the combined dichloromethane layers
followed by separation with silica-gel column
chromatography.
Product
ee (%)b
1c
Cycle
Yield (%)a
Recovery (%)
—
1
2
3
4
5
6
7
97
99
95
92
98
95
97
97
97
97
97
97
98
97
97
97
97
98
97
97
98
97
99
97
a Isolated yields.
b Ee were determined by chiral GLC analysis.
were adjusted based on the amount of recovered 1c for
the ratio to be constant (5 mol%) in every recycled use. The
results of recycling experiments are shown in Table 5. The
efficiency of 1c did not decrease at all even after seven times
recycling. This is well demonstrated by the fact that the
product from every cycle has high and constant ee and yield.
This means that the purity of recovered 1c is pure enough to
be used for the next reaction without purification.
In conclusion, we have succeeded in the synthesis of new
axially dissymmetric ligands, (Ra)-(R)2-1c and (Sa)-(S)2-1c
by coupling reaction of 5c using Ni(COD)2 in DMF. The
undesired axial diastereomer, (Sa)-(R)2-1c, was converted
efficiently into the desired ligand (Ra)-(R)2-1c by the
thermal equilibration and separation. This methodology
could be used for less bulky analogue to give better results
than the conventional Ullmann reaction using copper
powder. Compound (Ra)-(R)2-1c or (Sa)-(S)2-1c showed
very high asymmetric induction in the reaction of
diethylzinc with aldehydes to give up to 98% ee of the
products. Furthermore, the ligand 1c is recovered quanti-
tatively by fluorous phase separation technique using FC-72
directly from the reaction mixture. Evaporation of the
fluorous solvent under reduced pressure gives 1c in so high
purity enough to be reused in the next reaction. The activity
of 1c as an asymmetric inducer is not decreased even after
seven times recycled uses. These facts show that 1c is a very
stable and recyclable ligand with high asymmetric
induction. Further application of this ligand to other
asymmetric syntheses is now in progress.
By the simple procedure shown above, almost perfect
recovery of 1c was attained in high purity. This high purity
seemed to enable 1c to be recycled. For the effective
recycling of the ligand, its chemical stability during several
times recycling must be ensured. The chemical stability of
1c was estimated by subjecting it to a recycling procedure,
as shown by a flow chart in Figure 2. After the reaction
using 5 mol% of 1c (34 mg, 0.036 mmol), 1c was
partitioned into FC-72 as in the above procedure. Three
times extraction was necessary for almost all extraction of
1c. The combined FC-72 layer containing 1c was
evaporated to give 1c quantitatively and high purity as
shown above. The activity of recovered 1c was evaluated as
follows. The amounts of all other reagents and compounds
evaporation to dryness
without purification
3. Experimental
reaction (ligand 5 mol%)
3.1. General remarks
quenched by 10% HCl
CH Cl (1 mL)
All reactions were carried out under argon atmosphere
unless noted otherwise. Chemicals were prepared as
follows: THF, ether, and toluene were distilled from Na/
benzophenone; and other chemicals were used as received.
1H and 13C NMR spectra were recorded on 400 or 600 MHz
spectrometers and 19F NMR spectra were recorded on 60 or
600 MHz spectrometers at ambient probe temperature and
2
2
FC 72 (2mL each)
three times extraction
aqueous phase
1
referenced as follows: H and 13C, TMS; 19F, BTF. Mass
CH2Cl2 phase --product
FC 72 phase --(Ra)-(R)2-1
Figure 2. Recycled use of 1c.
spectra were recorded on EI method. Enantiomeric excess
was determined by GLC with GAMMA DEXe 225
Capillary Column (30 m!0.25 mm!0.25 mm) or HPLC
with Chiralcel OD-H (0.46f!25 cm, Daicel).

1890
M. Omote et al. / Tetrahedron 62 (2006) 1886–1894
3.2. Synthesis of chiral ligands
JC–FZ272.1, 32.8, 32.8 Hz), 110.5 (ttt, JC–FZ272.1, 32.8,
32.8 Hz), 108.7 (tqt, JC–FZ272.1, 40.1, 32.8 Hz), 70.4 (dd,
JC–FZ29.2, 20.7 Hz). 19F NMR (CDCl3) d: K18.0 (3F, s),
K53.6 (1F, d, JZ286.6 Hz), K58.3–K59.8 (6F, m),
K60.0 (2F, dd, JZ407.3, 297.4 Hz), K63.3 (2F, dd, JZ
411.6, 286.6 Hz), K64.1 (1F, d, JZ286.6 Hz). IR (KBr)
cmK1: 3395, 1244, 1210, 1148, 750. LRMS (EI) m/z: 554
(MC), 185 (MCKC7F15, base peak). HRMS (EI) Calcd for
C14H6O79BrF15 (MC): 553.936, found 553.937.
3.2.1. 1-Bromo-2-(perfluorooctanoyl)benzene (3c). A
solution of n-butyllithium (1.54 M in hexane, 40 mL,
62.0 mmol) was added to a solution of o-dibromobenzene
(6.8 mL, 56.4 mmol) in THF (250 mL) and Et2O (250 mL)
at K110 8C over 30 min. After stirring for 20 min, ethyl
perfluorooctanoate (29.5 g, 66.7 mmol) was added to the
solution at the same temperature. The mixture was stirred
for 1 h, and the reaction was quenched by adding 28 mL of a
cooled mixture of EtOH and concd HCl (ratioZ3:1). The
mixture was extracted with Et2O and organic layer was
washed with H2O and dried over MgSO4. After filtration of
MgSO4, the filtrate was concentrated under vacuum and the
residue was separated by a silica-gel column chromato-
graphy (Et2O/hexane, 5:95). The separated product was
purified by distillation under vacuum to give 3c (26.2 g,
84%). Compound 3c. A colorless oil. Bp 106–109 8C/
3.2.3. (S)-1-Bromo-2-(1-hydroxy-1H-perfluorooctyl)-
benzene ((S)-4c). Colorless crystals. Mp 43.5–44.5 8C.
[a]2D4 K15.0 (c 0.96, CHCl3). 1H NMR (CDCl3) d: 7.67 (1H,
d, JZ7.8 Hz), 7.60 (1H, d, JZ7.8 Hz), 7.40 (1H, dd, JZ
7.8, 7.8 Hz), 7.26 (1H, ddd, JZ7.8, 7.8, 1.4 Hz), 5.89 (1H,
ddd, JZ19.9, 5.4, 2.5 Hz), 2.72 (1H, d, JZ5.4 Hz). 13C
1
NMR (CDCl3, H19F-COM) d: 134.0, 133.1, 131.1, 130.0,
128.0, 124.3, 117.3, 115.3, 111.9, 111.3, 111.0, 110.5,
1
1
4 mmHg. H NMR (CDCl3) d: 7.76–7.70 (1H, m), 7.56–
108.6, 70.3. 13C NMR (CDCl3, H-COM) d: 134.0, 133.1,
7.50 (1H, m), 7.49–7.41 (2H, m). 13C NMR (CDCl3, 1H19F-
COM) d: 186.8, 135.1, 134.6, 133.7, 129.1, 127.5, 120.8,
117.5, 111.5, 111.3, 111.1, 110.6, 109.7, 108.8. 13C NMR
(CDCl3, 1H-COM) d: 186.8 (t, JC–FZ27.8 Hz), 135.1,
134.6, 133.7, 129.1 (t, JC–FZ3.6 Hz), 127.5, 120.8, 117.5
(qt, JC–FZ289.0, 33.9 Hz), 111.5 (ttt, JC–FZ272.0, 32.6,
32.6 Hz), 111.3 (ttt, JC–FZ272.0, 32.6, 32.6 Hz), 111.1 (ttt,
JC–FZ272.0, 32.6, 32.6 Hz), 110.6 (ttt, JC–FZ272.0, 32.6,
32.6 Hz), 109.7 (tt, JC–FZ272.0, 32.6 Hz), 108.8 (tqt, JZ
287.0, 40.0, 32.6 Hz). 19F NMR (CDCl3) d: K18.0 (3F, s),
K51.7 (2F, s), K57.9 (2F, s), K58.3 (2F, s), K59.2 (2F, s),
K59.9 (2F, s), K63.3 (2F, s). IR (neat) cmK1: 1740, 1204,
1152. LRMS (EI) m/z: 552 (MC), 533 (MCKF), 183
(MCKC7F15, base peak). HRMS Calcd for C14H4O79BrF15
(MC): 551.921, found 551.921.
131.1, 130.0, 128.0, 124.3, 117.3 (qt, JC–FZ287.9,
32.8 Hz), 115.3 (ddt, JC–FZ267.3, 257.6, 30.8 Hz), 111.9
(ttt, JC–FZ270.9, 31.6, 31.6 Hz), 111.3 (ttt, JC–FZ272.1,
32.8, 32.8 Hz), 111.0 (ttt, JC–FZ272.1, 32.8, 32.8 Hz),
110.5 (ttt, JC–FZ272.1, 32.8, 32.8 Hz), 108.6 (tqt, JC–F
Z
272.1, 40.1, 32.8 Hz), 70.3 (dd, JC–FZ29.2, 20.7 Hz). 19F
NMR (CDCl3) d: K18.0 (3F, s), K53.6 (1F, d, JZ
284.5 Hz), K58.3–K59.8 (6F, m), K60.0 (2F, dd, JZ
409.5, 297.4 Hz), K63.3 (2F, dd, JZ411.6, 290.1 Hz),
K64.1 (1F, d, JZ284.5 Hz). IR (KBr) cmK1: 3395, 1242,
1210, 1150, 750. LRMS (EI) m/z: 554 (MC), 185 (MCK
C7F15, base peak). HRMS Calcd for C14H6O79BrF15 (MC):
553.936, found 553.935.
3.2.4. (R)-1-Bromo-2-(1-methoxymethoxy-1H-perfluoro-
octyl)benzene ((R)-5c). Compound 4c (20.0 g, 36.0 mmol)
was added slowly to the suspension of sodium hydride
(1.16 g, 54 mmol, 60% dispersion in mineral oil) in THF
(10 mL) under ice-cooling. To the mixture was added
chloromethyl methyl ether (4.35 g, 54.0 mmol) and stirred
for over night at room temperature. The reaction was
quenched by adding water and then the mixture was
extracted with Et2O. The organic layer was washed with
H2O and dried over MgSO4. After filtration of MgSO4, the
filtrate was concentrated under vacuum, and the residue was
purified by a silica-gel column chromatography (Et2O/
hexane, 5:95). The product was further purified by
distillation under vacuum to give 5c (19.8 g, 92%).
Compound (R)-5c. A colorless oil. Bp 123–125 8C/
3.2.2. (R)-1-Bromo-2-(1-hydroxy-1H-perfluorooctyl)-
benzene ((R)-4c). Catecholborane (7.30 g, 65.2 mmol)
was added to a solution of (R)-2-methyl-5,5-diphenyl-
3,4-propano-1,3,2-oxazaborolidine (1.00 g, 3.61 mmol) in
THF (150 mL) at room temperature and stirred for 30 min.
The solution was cooled to K78 8C and a solution of 3c
(20.0 g, 36.2 mmol) in THF (50 mL) was added over
30 min. The reaction mixture was stirred for over night at
K30 8C. The reaction was quenched by adding slowly
150 mL of a mixed solution of 30% H2O2 and 20% NaOH
(1:1) and the mixture was stirred for 2 h at room
temperature. The mixture was extracted with Et2O and
organic layer was washed with H2O and dried over MgSO4.
After filtration of MgSO4, the filtrate was concentrated
under vacuum, and the residue was separated by a silica-gel
column chromatography (Et2O/hexane, 10:90) to give 4c
(19.3 g, 96%). Compound (R)-4c. Colorless crystals. Mp
43.5–44.5 8C. [a]D24 C15.2 (c 0.92, CHCl3). 1H NMR
(CDCl3) d: 7.62 (1H, d, JZ7.8 Hz), 7.58 (1H, d, JZ7.8 Hz),
7.36 (1H, dd, JZ7.8, 7.8 Hz), 7.24 (1H, ddd, JZ7.8, 7.8,
1.4 Hz), 5.89 (1H, ddd, JZ19.8, 5.3, 2.5 Hz), 2.78 (1H, d,
JZ5.3 Hz). 13C NMR (CDCl3, 1H19F-COM) d: 134.1,
133.2, 131.2, 130.0, 128.0, 124.3, 117.4, 115.4, 111.9,
111.4, 111.1, 110.5, 108.7, 70.4. 13C NMR (CDCl3,
1H-COM) d: 134.1, 133.2, 131.2, 130.0, 128.0, 124.3,
117.4 (qt, JC–FZ287.9, 32.8 Hz), 115.4 (ddt, JC–FZ267.3,
257.6, 30.8 Hz), 111.9 (ttt, JC–FZ270.9, 31.6, 31.6 Hz),
111.4 (ttt, JC–FZ272.1, 32.8, 32.8 Hz), 111.1 (ttt,
1
8 mmHg. [a]2D4 C54.5 (c 1.05, CHCl3). H NMR (CDCl3)
d: 7.65 (1H, ddd, JZ7.8, 1.8, 1.8 Hz), 7.60 (1H, dd, JZ8.1,
1.2 Hz), 7.39 (1H, ddd, JZ7.8, 7.8, 1.2 Hz), 7.25 (1H, ddd,
JZ8.1, 7.8, 1.8 Hz), 5.90 (1H, dd, JZ20.3, 1.5 Hz), 4.64
(1H, dd, JZ7.2, 1.5 Hz), 4.52 (1H, d, JZ7.2 Hz), 3.34 (3H,
1
s). 13C NMR (CDCl3, H19F-COM) d: 133.2, 132.3, 131.2,
130.9, 127.9, 125.6, 117.5, 115.5, 111.9, 111.5, 111.1,
110.6, 108.7, 95.3, 73.2, 56.7. 13C NMR (CDCl3, 1H-COM)
d: 133.2, 132.3, 131.2, 130.9 (d, JC–FZ2.4 Hz), 127.9,
125.6, 117.5 (qt, JC–FZ287.9, 32.8 Hz), 115.5 (ddt, JC–F
Z
266.1, 253.9, 31.6 Hz), 111.9 (ttt, JC–FZ270.9, 31.6,
31.6 Hz), 111.5 (ttt, JC–FZ270.9, 31.6, 31.6 Hz), 111.1
(ttt, JC–FZ270.9, 31.6, 31.6 Hz), 110.6 (ttt, JC–FZ270.9,
31.6, 31.6 Hz), 108.7 (ttt, JC–FZ270.9, 38.9, 31.6 Hz), 95.3,
73.2 (dd, JC–FZ30.2, 19.4 Hz), 56.7. 19F NMR (CDCl3)

M. Omote et al. / Tetrahedron 62 (2006) 1886–1894
1891
d: K18.0 (3F, s), K53.2 (1F, d, JZ286.6 Hz), K58.1–K
59.9 (6F, m), K60.0 (2F, dd, JZ532.3, 303.8 Hz), K61.6
(1F, d, JZ286.6 Hz), K63.3 (2F, dd, JZ532.3, 295.3 Hz).
IR (neat) cmK1: 2904, 1242, 1212, 1150, 1042, 752. LRMS
(EI) m/z: 598 (MC), 537 (MCKCH3OCH2O), 229 (MCK
C7F15, base peak). HRMS Calcd for C16H10O729BrF15 (MC):
597.963, found 597.962.
1044. LRMS (EI) m/z: 1038 (MC), 669 (MCKC7F15), 563
(base peak). HRMS Calcd for C32H20O4F30 (MC):
1038.088, found 1038.088. Compound (Sa)-(R)2-6c. Color-
less crystals. Mp 57.0–58.0 8C. [a]2D5 C41.7 (c 1.03,
CHCl3). 1H NMR (CDCl3) d: 7.85 (2H, m), 7.51–7.42
(6H, m), 5.83 (2H, d, JZ21.0 Hz), 4.73 (4H, d, JZ1.3 Hz),
1
3.30 (6H, s). 13C NMR (CDCl3, H19F-COM) d: 140.9,
131.4, 131.2, 130.2, 129.2, 128.4, 117.4, 115.0, 111.7,
111.2, 110.9, 110.4, 108.6, 94.8, 71.2, 56.0. 13C NMR
3.2.5. (S)-1-Bromo-2-(1-methoxymethoxy-1H-perfluoro-
octyl)benzene ((S)-5c). A colorless oil. Bp 123–125 8C/
8 mmHg. [a]2D4 K54.1 (c 0.98, CHCl3). 1H NMR (CDCl3) d:
7.65 (1H, ddd, JZ7.9, 1.8, 1.8 Hz), 7.60 (1H, dd, JZ8.2,
1.1 Hz), 7.39 (1H, ddd, JZ7.9, 7.9, 1.1 Hz), 7.26 (1H, ddd,
JZ8.2, 7.9, 1.8 Hz), 5.88 (1H, dd, JZ20.2, 1.3 Hz), 4.64
(1H, dd, JZ7.2, 1.3 Hz), 4.52 (1H, d, JZ7.2 Hz), 3.34 (3H,
(CDCl3, 1H-COM) d: 140.9, 131.4, 131.2, 130.2 (d, JC–F
Z
3.6 Hz), 129.2, 128.4, 117.4 (qt, JC–FZ287.8, 32.6 Hz),
115.0 (ddt, JC–FZ268.4, 252.7, 31.6 Hz), 111.7 (ttt, JC–F
Z
270.9, 31.6, 31.6 Hz), 111.2 (ttt, JC–FZ270.9, 31.6,
31.6 Hz), 110.9 (ttt, JC–FZ270.9, 31.6, 31.6 Hz), 110.4
(ttt, JC–FZ270.9, 31.6, 31.6 Hz), 108.6 (tqt, JC–FZ270.9,
38.7, 31.6 Hz), 94.8, 71.2 (dd, JC–FZ31.4, 17.0 Hz), 56.0.
19F NMR (CDCl3) d: K18.4 (3F, s), K49.5, (1F, d, JZ
288.8 Hz), K58.4–K60.0 (6F, m), K60.1 (2F, dd, JZ
422.4, 295.3 Hz), K63.2 (1F, d, JZ288.8 Hz), K63.6 (2F,
dd, JZ474.1, 295.3 Hz). IR (KBr) cmK1: 1246, 1210, 1152,
1046. LRMS (EI) m/z: 1038 (MC), 669 (MCKC7F15), 563
(base peak). HRMS Calcd for C32H20O4F30 (MC):
1038.088, found 1038.088. Compound (Sa)-(S)2-6c. Color-
less crystals. Mp 108.5–110.0 8C. [a]2D5 K1.7 (c 1.05,
CHCl3). 1H NMR (CDCl3) d: 7.83 (1H, d, JZ7.6 Hz), 7.46
(1H, dd, JZ7.6, 7.6 Hz), 7.34 (1H, dd, JZ7.6, 7.6 Hz), 7.11
(1H, dd, JZ7.6, 6.1 Hz), 5.22 (1H, d, JZ20.8 Hz), 5.06
(1H, d, JZ7.0 Hz), 4.58 (1H, d, JZ7.0 Hz), 3.12 (3H, s).
1
s). 13C NMR (CDCl3, H19F-COM) d: 133.2, 132.3, 131.2,
130.8, 127.9, 125.6, 117.5, 115.5, 111.9, 111.5, 111.1,
110.6, 108.8, 95.3, 73.2, 56.7. 13C NMR (CDCl3, 1H-COM)
d: 133.2, 132.3, 131.2, 130.8 (d, JC–FZ2.4 Hz), 127.9,
125.6, 117.5 (qt, JC–FZ287.9, 32.8 Hz), 115.5 (ddt, JC–F
Z
266.1, 253.9, 31.6 Hz), 111.9 (ttt, JC–FZ270.9, 31.6,
31.6 Hz), 111.5 (ttt, JC–FZ270.9, 31.6, 31.6 Hz), 111.1
(ttt, JC–FZ270.9, 31.6, 31.6 Hz), 110.6 (ttt, JC–FZ270.9,
31.6, 31.6 Hz), 108.8 (tqt, JC–FZ270.9, 38.9, 31.6 Hz),
95.3, 73.2 (dd, JC–FZ30.2, 19.4 Hz), 56.7. 19F NMR
(CDCl3) d: K18.0 (3F, s), K53.2 (1F, d, JZ288.8 Hz),
K58.1–K59.9 (6F, m), K60.0 (2F, dd, JZ530.2,
299.6 Hz), K61.6 (1F, d, JZ288.8 Hz), K63.3 (2F, dd,
JZ530.2, 291.0 Hz). IR (neat) cmK1: 2904, 1242, 1212,
1150, 1044, 752. LRMS (EI) m/z: 598 (MC), 537 (MCK
CH3OCH2O), 229 (MCKC7F15, base peak). HRMS Calcd
for C16H10O729BrF15 (MC): 597.963, found 597.963.
1
13C NMR (CDCl3, H19F-COM) d: 139.4, 133.0, 131.7,
129.0, 128.3, 128.0, 117.4, 115.3, 111.9, 111.3, 111.0,
110.5, 108.7, 97.2, 73.3, 56.4. 13C NMR (CDCl3, 1H-COM)
d: 139.4, 133.0 (d, JC–FZ7.3 Hz), 131.7, 129.0, 128.3,
128.0, 117.4 (qt, JC–FZ287.9, 32.8 Hz), 115.3 (ddt, JC–F
Z
3.2.6. Coupling reaction to 2,20-bis(1-methoxymethoxy-
1H-perfluorooctyl)biphenyl. A typical procedure is as
follows. To a suspension of Ni(COD)2 (633 mg, 2.3 mmol)
in anhydrous DMF (4 mL) was added (R)-5c (2.00 g,
3.3 mmol) at room temperature and the mixture was stirred
for 24 h at 60 8C. The reaction was quenched by adding
aqueous HCl (5%), and the mixture was extracted with
Et2O. The organic layer was concentrated after dehydration,
and the residue was separated by a silica-gel chromato-
graphy (Et2O/hexaneZ5:95–20:80) to give (Ra)-(R)2-6c
(1.01 g, 59%) and (Sa)-(R)2-6c (0.21 g, 12%). Compound
(Ra)-(R)2-6c. Colorless crystals. Mp 108.5–110.0 8C. [a]D25
C1.8 (c 1.07, CHCl3). 1H NMR (CDCl3) d: 7.84 (1H, d, JZ
7.6 Hz), 7.44 (1H, dd, JZ7.6, 7.6 Hz), 7.34 (1H, d, JZ7.6,
7.6 Hz), 7.12 (1H, dd, JZ7.6, 6.1 Hz), 5.25 (1H, d, JZ
20.9 Hz), 5.08 (1H, d, JZ7.0 Hz), 4.57 (1H, d, JZ7.0 Hz),
268.5, 255.1, 31.6 Hz), 111.9 (ttt, JC–FZ270.9, 31.6,
31.6 Hz), 111.3 (ttt, JC–FZ270.9, 31.6, 31.6 Hz), 111.0
(ttt, JC–FZ270.9, 31.6, 31.6 Hz), 110.5 (ttt, JC–FZ270.9,
31.6, 31.6 Hz), 108.7 (tqt, JC–FZ270.9, 38.9, 31.6 Hz),
97.2, 73.3 (dd, JC–FZ30.4, 19.4 Hz), 56.4. 19F NMR
(CDCl3) d: K18.0 (3F, s), K48.2 (1F, d, JZ284.5 Hz),
K58.4–K60.2 (6F, m), K59.9 (2F, dd, JZ491.4,
303.9 Hz), K62.6 (1F, d, JZ286.6 Hz), K63.3 (2F, dd,
JZ456.9, 295.3 Hz). IR (KBr) cmK1: 1242, 1210, 1150,
1044. LRMS (EI) m/z: 1038 (MC), 669 (MCKC7F15).
HRMS Calcd for C32H20O4F30 (MC): 1038.088, found
1038.088. Compound (Ra)-(S)2-6c. Colorless crystals. Mp
57.0–58.0 8C. [a]D25 K41.2 (c 1.03, CHCl3). 1H NMR
(CDCl3) d: 7.8 (2H, m), 7.51–7.42 (6H, m), 5.36 (2H, d, JZ
21.1 Hz), 4.73 (4H, d, JZ1.9 Hz), 3.30 (6H, s). 13C NMR
(CDCl3, 1H19F-COM) d: 140.9, 131.4, 131.2, 130.2, 129.2,
128.4, 117.4, 115.0, 111.7, 111.2, 110.9, 110.4, 108.6, 94.8,
1
3.11 (3H, s). 13C NMR (CDCl3, H19F-COM) d: 139.6,
133.1, 131.9, 129.1, 128.4, 128.0, 117.6, 115.2, 112.1,
111.5, 111.1, 110.7, 108.8, 97.4, 73.5, 56.5. 13C NMR
(CDCl3, 1H-COM) d: 139.6, 133.1 (d, JC–FZ7.3 Hz), 131.9,
129.1, 128.4, 128.0, 117.6 (qt, JC–FZ287.9, 32.8 Hz), 115.2
(ddt, JC–FZ268.5, 255.1, 31.6 Hz), 112.1, (ttt, JC–FZ270.9,
31.6, 31.6 Hz), 111.5 (ttt, JC–FZ270.9, 31.6, 31.6 Hz),
1
71.2, 56.0. 13C NMR (CDCl3, H-COM) d: 140.9, 131.4,
131.2, 130.2 (d, JC–FZ3.6 Hz), 129.2, 128.4, 117.4 (qt,
JC–FZ287.8, 32.6 Hz), 115.0 (ddt, JC–FZ268.4, 252.7,
31.6 Hz), 111.7 (ttt, JC–FZ270.9, 31.6, 31.6 Hz), 111.2 (ttt,
JC–FZ270.9, 31.6, 31.6 Hz), 110.9 (ttt, JC–FZ270.9, 31.6,
31.6 Hz), 110.4 (ttt, JC–FZ270.9, 31.6, 31.6 Hz), 108.6 (tqt,
JC–FZ270.9, 38.7, 31.6 Hz), 94.8, 71.2 (dd, JC–FZ31.4,
111.1 (ttt, JC–FZ270.9, 31.6, 31.6 Hz), 110.7 (ttt, JC–F
Z
270.9, 31.6, 31.6 Hz), 108.8 (tqt, JC–FZ270.9, 38.9,
31.6 Hz), 97.4, 73.5 (dd, JC–FZ30.4, 19.4 Hz), 56.5. 19F
NMR (CDCl3) d: K18.0 (3F, s), K48.2 (1F, d, JZ
284.5 Hz), K58.5–K60.1 (6F, m), K60.0 (2F, dd, JZ
491.4, 301.7 Hz), K62.9 (1F, d, JZ284.5 Hz), K63.4 (2F,
dd, JZ452.6, 293.1 Hz). IR (KBr) cmK1: 1242, 1209, 1150,
17.0 Hz), 56.0. IR (KBr) cmK1: 1244, 1210, 1150, 1044. 19
F
NMR (CDCl3) d: K18.3 (3F, s), K49.5, (1F, d, JZ
290.1 Hz), K58.3–K60.0 (6F, m), K60.1 (2F, dd, JZ
418.1, 306.0 Hz), K63.2 (1F, d, JZ290.1 Hz), K63.6 (2F,
dd, JZ476.3, 297.4 Hz). LRMS (EI) m/z: 1038 (MC), 669

1892
M. Omote et al. / Tetrahedron 62 (2006) 1886–1894
(MCKC7F15), 563 (base peak). HRMS Calcd for
JZ7.4, 7.4, 1.5 Hz), 7.24 (2H, d, JZ7.4 Hz), 4.87 (2H, ddd,
JZ19.0, 7.0, 7.0 Hz), 3.34 (2H, d, JZ7.0 Hz). 13C NMR
C32H20O4F30 (MC): 1038.088, found 1038.088.
1
(CDCl3, DMSO-d6, H19F-COM) d: 139.4, 133.6, 130.5,
128.7, 128.4, 128.2, 117.2, 115.5, 111.6, 111.2, 110.9,
3.2.7. Deprotection of 6c to 2,20-bis(1-hydroxy-1H-
perfluorooctyl)biphenyl and equilibration of the axial
isomers. Treatment of (Ra)-(R)2-6c (1.01 g, 0.97 mmol) by
TFA (5 mL) and water (0.5 mL) at room temperature for 3 h
followed by extraction with Et2O gave (Ra)-(R)2-1c
(894 mg, 0.94 mmol, 97%). Any impurities were not
detected by NMR and GLC. A similar treatment of (Sa)-
(R)2-6c (210 mg, 0.20 mmol) with TFA (1 mL) and water
(0.1 mL) gave its axial diastereomer (Sa)-(R)2-1c (183 mg,
0.19 mmol, 95%). Compound (Sa)-(R)2-1c (183 mg) was
converted to (Ra)-(R)2-1c by refluxing in toluene for 4 h.
The equilibrium mixture was separated by silica-gel
chromatography (Et2O/hexaneZ1:9–3:7) to give (Ra)-
(R)2-1c (166 mg, 91%). For further purification, (Ra)-(R)2-
1c was recrystallized from toluene, dissolving the crystals
under 60 8C so as to avoid the axial isomerization.
Compound (Ra)-(R)2-1c. Colorless crystals. Mp 82.0–
110.2, 108.4, 66.4. 13C NMR (CDCl3, DMSO-d6, 1H-COM)
d: 139.4, 133.6, 130.5, 128.7, 128.4, 128.2, 117.2 (qt, JC–F
287.8, 32.6 Hz), 115.5 (ddt, JC–FZ266.0, 255.1, 30.2 Hz),
111.6 (ttt, JC–FZ293.8, 30.2, 30.2 Hz), 111.2 (ttt, JC–F
Z
Z
270.9, 31.6, 31.6 Hz), 110.9 (ttt, JC–FZ270.9, 31.6,
31.6 Hz), 110.2 (ttt, JC–FZ270.9, 31.6, 31.6 Hz), 108.4
(tqt, JC–FZ270.9, 39.9, 32.6 Hz), 66.4 (dd, JC–FZ30.2,
20.6 Hz). 19F NMR (CDCl3) d: K18.0 (3F, s), K53.6 (1F, d,
JZ281.9 Hz), K58.1–K60.0 (6F, m), K60.0 (2F, dd, JZ
310.3, 310.3 Hz), K62.0 (1F, d, JZ281.9 Hz), K63.4 (2F,
dd, JZ310.3, 310.3 Hz). IR (KBr) cmK1: 3376, 1214, 1150.
LRMS (EI) m/z: 950 (MC), 669 (MCKC7F15), 563 (base
peak). HRMS Calcd for C28H12O2F30 (MC): 950.036, found
950.035. Compound (Ra)-(S)2-1c. Colorless crystals. Mp
99.0–100.0 8C. [a]D25 K31.9 (c 0.99, CHCl3). 1H NMR
(CDCl3) d: 7.84 (2H, d, JZ7.5 Hz), 7.53 (2H, ddd, JZ7.5,
7.5, 1.4 Hz), 7.49 (2H, ddd, JZ7.5, 7.5, 1.4 Hz), 7.33 (2H,
dd, JZ7.5, 1.4 Hz), 5.17 (2H, dd, JZ21.3, 7.5 Hz), 2.38
83.0 8C. [a]2D5 C13.6 (c 0.99, CHCl3). H NMR (CDCl3)
1
d: 7.76 (2H, d, JZ7.5 Hz), 7.53 (2H, ddd, JZ7.5, 7.5,
1.5 Hz), 7.48 (2H, ddd, JZ7.5, 7.5, 1.5 Hz), 7.24 (2H, d,
JZ7.5 Hz), 4.88 (2H, dd, JZ19.1, 7.0, 7.0 Hz), 3.34 (2H, d,
1
(2H, d, JZ7.5 Hz). 13C NMR (CDCl3, DMSO-d6, H19F-
COM) d: 140.3, 134.0, 130.8, 128.8, 128.7, 128.4, 117.2,
115.9, 111.5, 111.0, 110.7, 110.3, 108.4, 67.1. IR (neat)
cmK1: 3460, 1242, 1208, 1150. 13C NMR (CDCl3, DMSO-
1
JZ7.0 Hz). 13C NMR (CDCl3, DMSO-d6, H19F-COM) d:
139.7, 132.7, 130.3, 129.6, 129.0, 127.5, 117.3, 115.7,
111.8, 111.2, 111.0, 110.2, 108.4, 67.4. 13C NMR (CDCl3,
DMSO-d6, H-COM) d: 139.7, 132.7, 130.3, 129.6, 129.0,
1
d6, H-COM) d: 140.3, 134.0, 130.8, 128.8, 128.7, 128.4,
117.2 (qt, JC–FZ289.0, 33.4 Hz), 115.9 (ddt, JC–FZ266.0,
257.5, 31.6 Hz), 111.5 (ttt, JC–FZ293.8, 30.2, 30.2 Hz),
1
127.5, 117.3 (qt, JC–FZ287.8, 32.6 Hz), 115.7 (ddt, JC–F
Z
266.0, 255.1, 30.2 Hz), 111.8 (ttt, JC–FZ293.8, 30.2,
30.2 Hz), 111.2 (ttt, JC–FZ270.9, 31.6, 31.6 Hz), 111.0
(ttt, JC–FZ270.9, 31.6, 31.6 Hz), 110.2 (ttt, JC–FZ270.9,
31.6, 31.6 Hz), 108.4 (tqt, JC–FZ270.9, 39.9, 32.6 Hz), 67.4
(dd, JC–FZ30.2, 20.6 Hz). 19F NMR (CDCl3) d: K18.1 (3F,
s), K53.6 (1F, d, JZ282.8 Hz), K58.1–K60.0 (6F, m),
K60.0 (2F, dd, JZ305.2, 305.2 Hz), K62.0 (1F, d, JZ
282.8 Hz), K63.4 (2F, dd, JZ305.2, 305.2 Hz). IR (KBr)
cmK1: 3376, 1212, 1149. LRMS (EI) m/z: 950 (MC), 669
(MCKC7F15), 563 (base peak). HRMS Calcd for
C28H12O2F30 (MC): 950.036, found 950.036. Compound
(Sa)-(R)2-1c. Colorless crystals. Mp 99.0–100.0 8C. [a]D25
C31.5 (c 1.0, CHCl3). 1H NMR (CDCl3) d: 7.84 (2H, d, JZ
7.5 Hz), 7.54 (2H, ddd, JZ7.5, 7.5, 1.4 Hz), 7.49 (2H, ddd,
JZ7.5, 7.5, 1.4 Hz), 7.33 (2H, dd, JZ7.5, 1.4 Hz), 5.17
(2H, dd, JZ21.3, 7.5 Hz), 2.40 (2H, d, JZ7.5 Hz). 13C
111.0 (ttt, JC–FZ270.9, 31.6, 31.6 Hz), 110.7 (ttt, JC–F
Z
270.9, 31.6, 31.6 Hz), 110.3 (ttt, JC–FZ270.9, 31.6,
31.6 Hz), 108.4 (tqt, JC–FZ270.9, 38.7, 31.6 Hz), 67.1
(dd, JC–FZ30.2, 19.3 Hz). 19F NMR (CDCl3) d: K18.2 (3F,
s), K51.9 (1F, d, JZ283.6 Hz), K58.1–K60.8 (8F, m),
K63.2 (1F, d, JZ284.5 Hz), K63.6 (2F, dd, JZ303.9,
303.9 Hz). IR (KBr) cmK1: 3460, 1242, 1208, 1150. LRMS
(EI) m/z: 950 (MC), 669 (MCKC7F15), 563 (base peak).
HRMS Calcd for C28H12O2F30 (MC): 950.036, found
950.035.
3.3. Asymmetric reaction of diethylzinc with an aldehyde
Typical procedure is as follows. Ti(OiPr)4 (254 mL,
0.86 mmol) was added to a solution of (Ra)-(R)2-1c
(34 mg, 0.036 mmol) in anhydrous toluene (0.3 mL) at
room temperature and the mixture was stirred for 30 min at
50 8C. To the mixture was added a solution of diethylzinc
(1.0 mol/L in hexane, 0.86 mL, 0.86 mmol) at K78 8C and
stirred for 30 min. Then a solution of benzaldehyde (73 mL,
0.72 mmol) in anhydrous toluene (0.3 mL) was added to the
mixture at the same temperature. The mixture was allowed
to warm up to K30 8C over 1 h and stirred at this
temperature for another 4 h to complete the reaction. The
reaction was quenched by 10% HCl, and the mixture was
extracted with Et2O. The organic layer was concentrated
after dehydration, and the residue was purified by a column
chromatography (Et2O/hexaneZ5:95–10:90) to give (S)-1-
phenylpropanol (95 mg, 97%).
1
NMR (CDCl3, DMSO-d6, H19F-COM) d: 140.4, 134.3,
130.9, 129.0, 128.6, 128.2, 117.2, 116.0, 111.5, 111.1,
110.7, 110.3, 108.4, 67.0. 13C NMR (CDCl3, DMSO-d6, 1H-
COM) d: 140.4, 134.3, 130.9, 129.0, 128.6, 128.2, 117.2 (qt,
JC–FZ289.0, 33.4 Hz), 116.0 (ddt, JC–FZ266.0, 257.5,
31.6 Hz), 111.5 (ttt, JC–FZ293.8, 30.2, 30.2 Hz), 111.1 (ttt,
JC–FZ270.9, 31.6, 31.6 Hz), 110.7 (ttt, JC–FZ270.9, 31.6,
31.6 Hz), 110.3 (ttt, JC–FZ270.9, 31.6, 31.6 Hz), 108.4 (tqt,
JC–FZ270.9, 38.7, 31.6 Hz), 67.0 (dd, JC–FZ30.2,
19.3 Hz). 19F NMR (CDCl3) d: K18.2 (3F, s), K51.9 (1F,
d, JZ283.6 Hz), K58.1–K60.8 (8F, m), K63.2 (1F, d, JZ
284.5 Hz), K63.6 (2F, dd, JZ303.9, 303.9 Hz). IR (KBr)
cmK1: 3460, 1242, 1209, 1146. LRMS (EI) m/z: 950 (MC),
669 (MCKC7F15), 563 (base peak). HRMS Calcd for
C28H12O2F30 (MC): 950.036, found 950.036. Compound
(Sa)-(S)2-1c. Colorless crystals. Mp 82.0–83.0 8C. [a]D25
K13.9 (c 1.0, CHCl3). 1H NMR (CDCl3) d: 7.76 (2H, d, JZ
7.4 Hz), 7.53 (2H, ddd, JZ7.4, 7.4, 1.5 Hz), 7.48 (2H, ddd,
Results of other aldehydes are shown in Table 3. All the
products were identified with the samples obtained
according to the references shown in the note of Table 3.

M. Omote et al. / Tetrahedron 62 (2006) 1886–1894
1893
3.4. Recycling of the ligand
References and notes
3.4.1. Recovery of 1c from reaction mixture. After
completion of the reaction using 34 mg (0.036 mmol) of
1c, the reaction was quenched by adding 2 mL of 10%
aqueous HCl. Dichloromethane (1 mL) and FC-72 (2 mL)
were added to the mixture for extraction. The mixture
was shaken vigorously to complete the partition. After
separation of FC-72 phase containing 1c, another FC-72
(2 mL) was added to the remaining mixture for the next
extraction. Extraction with FC-72 (2 mL each) was
performed three times to recover almost all of 1c.
Evaporation of combined FC-72 layer under reduced
pressure gave 1c in a recovery of 97% with an excellent
purity of 98%. After the recovery of 1c from the reaction
mixture, the product was extracted by dichloromethane in
three portions (1 mL!1C2 mL!2). The yield and ee of
the product were measured after evaporation of the
combined dichloromethane layers followed by separation
with silica-gel column chromatography.
1. Preliminary communications: (a) Omote, M.; Nishimura, Y.;
Sato, K.; Ando, A.; Kumadaki, I. Tetrahdedron Lett. 2005, 46,
319–322. (b) Omote, M.; Nishimura, Y.; Sato, K.; Ando, A.;
Kumadaki, I. J. Fluorine Chem. 2005, 127, 407–409.
2. (a) Zhu, D. W. Synthesis 1993, 10, 953–954. (b) Meinert, H.;
Geister, U. J. Fluorine Chem. 1994, 68, 221–226. (c)
Chambers, R. D.; Sandford, G.; Shah, A. Synth. Commun.
1996, 26, 1861–1866. (d) Pozzi, G.; Montanari, F.; Rispens,
M. T. Synth. Commun. 1997, 27, 447–452. (e) Sandford, G.
Tetrahedron 2003, 59, 437–454.
´
3. (a) Horvath, I. T.;Rabai, J. Science 1994, 266, 72. (b) Horvath, I.;
´
´
´ ´
Rabai, J. U.S. Patent 5,463,082, 1995. (c) Horvath, I. T.; Kiss,
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G.; Cook, R. A.; Bond, J. E.; Stevens, P. A.; Rabai, J.;
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3.4.2. Recycling procedure. The asymmetric ethyl addition
and recovery of the ligand was performed as mentioned
above. The ligand recovered was used in the next reaction
without purification. First reaction carried out with 34.0 mg
(0.036 mmol) of (Ra)-(R)2-1c, 0.86 mmol of Ti(OiPr)4,
0.86 mmol of diethylzinc and 0.72 mmol of benzaldehyde
to give the product in 97% yield and 97% ee with 33.0 mg of
the ligand (97% recovering). The second reaction carried
out with 33.0 mg of the ligand recovered, 0.84 mmol of
Ti(OiPr)4, 0.84 mmol of diethylzinc and 0.70 mmol of
benzaldehyde to give the product in 99% yield and 97% ee
with 32.3 mg (0.034 mmol) of the ligand (98% recovery).
The third reaction carried out with 32.3 mg (0.034 mmol) of
the ligand recovered, 0.81 mmol of Ti(OiPr)4, 0.81 mmol of
diethylzinc and 0.68 mmol of benzaldehyde to give the
product in 95% yield and 97% ee with 31.3 mg
(0.033 mmol) of the ligand (97% recovery). The fourth
reaction carried out with 31.3 mg (0.033 mmol) of the
ligand recovered, 0.79 mmol of Ti(OiPr)4, 0.79 mmol of
diethylzinc and 0.66 mmol of benzaldehyde to give the
product in 92% yield and 97% ee with 30.4 mg
(0.032 mmol) of the ligand (97% recovery). The fifth
reaction carried out with 30.4 mg (0.032 mmol) of the
ligand recovered, 0.76 mmol of Ti(OiPr)4, 0.76 mmol of
diethylzinc and 0.64 mmol of benzaldehyde to give the
product in 98% yield and 98% ee with 29.8 mg
(0.031 mmol) of the ligand (98% recovery). The sixth
reaction carried out with 29.8 mg (0.031 mmol) of the
ligand recovered, 0.74 mmol of Ti(OiPr)4, 0.74 mmol of
diethylzinc and 0.62 mmol of benzaldehyde to give the
product in 95% yield and 97% ee with 28.9 mg
(0.030 mmol) of the ligand (97% recovery). The seventh
reaction carried out with 28.9 mg (0.030 mmol) of the
ligand recovered, 0.72 mmol of Ti(OiPr)4, 0.72 mmol of
diethylzinc and 0.60 mmol of benzaldehyde to give the
product in 97% yield and 97% ee with 28.6 mg
(0.030 mmol) of the ligand (99% recovery). The eighth
reaction carried out with 28.6 mg (0.030 mmol) of the
ligand recovered, 0.72 mmol of Ti(OiPr)4, 0.72 mmol of
diethylzinc and 0.60 mmol of benzaldehyde to give the
product in 97% yield and 97% ee with 27.7 mg
(0.029 mmol) of the ligand (97% recovery).
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14. Absolute configurations of 4c were determined by converting
them to (S)-methoxyphenyl(trifluoromethyl)acetic acid esters.
The a-proton of the ester from (R)-4c was observed at
6.98 ppm, while that of the ester from (S)-isomer at 7.07 ppm.
Structure optimization by MOPAC calculation suggested that

1894
M. Omote et al. / Tetrahedron 62 (2006) 1886–1894
4c has large substituents and the Mosher rule could not be
15. Semmelhack, M. F. Org. React. 1972, 19, 178.
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simply applied. By this opimization, the former proton is near
the benzene ring of MTP acid, while the latter is far from it.
These results support the configurations shown in the text. The
results of asymmetric synthesis using these ligands are
comparable to the results of 1a, the structure of which was
determined by X’ray analysis.10a
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