Application of axially dissymmetric ligand recoverable with fluorous solvent as a chiral auxiliary

Article abstract of DOI:10.1016/j.jfluchem.2005.10.008

(Ra)-(R)₂-2,2′-Bis(1-hydroxy-1H-perfluorooctyl)biphenyl ((Ra)-(R)₂-1c), which is an axially dissymmetric ligand with two chiral centers, works as a good chiral auxiliary for asymmetric aldol reaction. Thus, the reaction of monopropan

Full text of DOI:10.1016/j.jfluchem.2005.10.008

Journal of Fluorine Chemistry 127 (2006) 74–78
www.elsevier.com/locate/fluor
Application of axially dissymmetric ligand recoverable
with fluorous solvent as a chiral auxiliary
*
Masaaki Omote, Yuji Nishimura, Kazuyuki Sato, Akira Ando , Itsumaro Kumadaki
*
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1, Nagaotoge-cho, Hirakata, Japan
Received 30 September 2005; received in revised form 17 October 2005; accepted 18 October 2005
Available online 28 November 2005
Abstract
(Ra)-(R)2-2,20-Bis(1-hydroxy-1H-perfluorooctyl)biphenyl ((Ra)-(R)2-1c), which is an axially dissymmetric ligand with two chiral centers,
works as a good chiral auxiliary for asymmetric aldol reaction. Thus, the reaction of monopropanoyl ester of 1c (2) with benzaldehyde in the
presence of triethylamine and titanium(IV) chloride gave (2R),(3S)- and (2R),(3R)-3-hydroxy-2-methyl-3-phenylpropanoic acid esters (3a) in
an approximate ratio of 4:1 in a total high yield. This result shows that stereoselectivity at 2-position is quite high, while that at 3-position is
moderate. Both isomers were easily separated by column chromatography. Methanolysis of the separated isomers gave nearly quantitative
recovery of 1c by extraction with a fluorous solvent without any loss of ee, while methyl (2R),(3S)- or (2R),(3R)-3-hydroxy-2-methyl-3-
phenylpropanoates were obtained by CH2Cl2 extraction quantitatively in >99% ee. Aldol reaction of 2 with various aldehydes gave similar
results.
# 2005 Elsevier B.V. All rights reserved.
Keywords: Aldol reaction; Axially dissymmetric ligand; Chiral auxiliary; Propanoic ester; Benzaldehyde; (Ra)-(R)2-2,20-Bis(1-hydroxy-1H-perfluorooctyl)bi-
phenyl; Fluorine; Perfluoroheptyl
1. Introduction
BINOL and that they might be recovered easily. (2) The
hydroxyl group is much more acidic than common alcohols due
to the electronic effect of the fluoroalkyl group. (3) The chiral
centers would control the axial chirality. This was confirmed in
the previous report [3b]. Thus, (Ra)-(R)2-isomers are much
more stable than (Sa)-(R)2- ones. Fortunately, the former were
found to work as a good chiral inducer for the reaction of
diethylzinc with benzaldehyde in the presence of Ti(OiPr)4,
while the latter did not work at all. (4) Perfluoroheptyl analog
(1c) can be extracted with a fluorous solvent after reaction and
used without purification again and again [4]. Thus, these are
quite eco-friendly ligands.
An asymmetric synthesis to provide an enantiomerically
pure product is of great importance for synthesis of biologically
active compounds. Recently, a number of chiral ligands have
been reported for the asymmetric synthesis, and new
methodologies using them have been developed. Among
these chiral ligands, 1,10-bi-2-naphthol (BINOL) is one of the
most widely used and well-studied chiral ligands with C2
symmetry [1]. Many outstanding reports on the asymmetric
reactions with BINOL and its derivatives have been published
[2].
We have synthesized axially dissymmetric ligands (1) with
chiral centers made of 1H-1-hydroxyperfluoroalkyl groups
(Fig. 1) [3]. Characteristics of our ligands are: (1) the hydroxyl
group on a carbon atom with a perfluoroalkyl substituent is
highly stable for hard reaction conditions. This means that the
ligands are much more stable than phenolic ligands such as
Another methodology for asymmetric synthesis is to use
chiral auxiliary. For example, Evans et al. used chiral
oxazolidone derivatives for asymmetric aldol reaction [5].
These auxiliary methods are very useful, but recovery of the
auxiliaries is not usually simple, since they are partly cleaved.
We expected that if our ligands could be used as chiral auxiliary,
it would be superior to the conventional one, since they were
recovered by simple extraction with fluorous solvents and
reused again and again. Another advantage that we expected
was that the space around the hydroxyl groups was rather
crowded and that one hydroxyl group would be esterified, while
* Corresponding authors.
E-mail addresses: aando@pharm.setsunan.ac.jp (A. Ando),
kumadaki@pharm.setsunan.ac.jp (I. Kumadaki).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.10.008

M. Omote et al. / Journal of Fluorine Chemistry 127 (2006) 74–78
75
Fig. 1. Structure of (Ra)-(R)2-1a–c.
the other hydroxyl group would work as a ligand for Lewis acid.
Here, we would like to report our results on the aldol reaction of
propanoic ester of 1c which was carried out to verify above
expectations (Scheme 1).
2. Results and discussion
Reaction of 1c with propanoyl chloride in the presence of
DMAP gave monoester (2) quantitatively, as expected. This
means that the space around the hydroxyl groups is highly
crowded and only one propanoyl group is introduced.
First, we examined the reaction of 2 with benzaldehyde in
the presence of various Lewis acids and bases, where (2R,3S)-
and (2R,3R)-3-hydroxy-2-methyl-3-phenylpropanoic acid
esters of 2 ((2R,3S)- and (2R,3R)-3a) were obtained in an
approximate ratio of 4:1 irrespective of the kind of Lewis acids
or bases. The best result was obtained, when 1.3 equivalent of
TiCl4 and 2.6 equivalent of Et3N were used as shown in Scheme
1 (Scheme 2).
Fig. 2. Structures of (Z)- and (E)-forms of complexes.
The (Z)-form is less crowded and stable than the (E)-form.
The bottom face of the (Z)-form is hindered by the phenyl
group, and the carbonyl group of benzaldehyde would approach
from the top face of the (Z)-form to give (2R)-stereochemistry.
There would be a small repulsion between the phenyl group and
the methyl group, which might give the preference of (3S)-
stereochemistry to (3R)-stereochemistry.
(2R,3S)- and (2R,3R)-3a were easily separated by column
chromatography. Treatment of (2R,3S)-3a with NaOCH3 in
CH3OH was followed by quenching with 10% HCl and
The stereochemistries of 3a were determined after
methanolysis, which will be mentioned later.
When 1.5 equivalent of Et3N was used, the reaction hardly
proceeded. This suggests that 1 equivalent of base is used to
deprotonate the hydroxyl group on the formation of complex
from 2 and TiCl4, and the other deprotonates the propanoic
ester part to form the enolate.
Stereoselectivity at the 2-position is excellent, while at the 3-
position is moderate. We calculated the steric energies of (Z)-
and (E)-forms of the titanium complex of the enolate from 2.
The optimized structures for both forms are shown in Fig. 2.
Scheme 3.
Table 1
Aldol reaction of 2 with several aldehydes
Entry
R
3
Yield (%)a
(2R,3S)-3
(2R,3R)-3b
1
2
3
4
5
6
7
8
9
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
74
71
65
69
56
61
58
9
19
15
21
12
28
29
18
37
76
4-MeOPh
4-MePh
4-iPrPh
4-ClPh
Scheme 1.
2-FPh
4-CH3OCOPh
b,c
PhCH2CH2
PhCH CHc
14
a
Isolated yield.
b
The reaction was conducted with 1.5 equivalent TiCl4 and 3.0 equivalent
Et3N for 2 h.
c
Scheme 2.
The same stereochemical relation: (R,S) indication is inverted at 3-position.

76
M. Omote et al. / Journal of Fluorine Chemistry 127 (2006) 74–78
extraction with FC-72 (trade name of 3M, perfluorohexane),
then with CH2Cl2. (Ra)-(R)2-1c was recovered from FC-72
extract in 96% yield without any loss of ee. Methyl (2R,3S)-3-
hydroxy-2-methyl-3-phenylpropanoate ((2R,3S)-4a) was
recovered from the CH2Cl2 layer in 96% yield and >99% ee
(Scheme 3).
1752, 1214, 1150. LRMS (EI) m/z: 1006 (M+). HRMS (EI)
Calcd. for C31H16F30O3 (M+): 1006.062, Found: 1006.063.
4.2. Aldol reaction of 2 with benzaldehyde
In the atmosphere of Ar, TiCl4 (0.13 ml, 1.0 M in CH2Cl2,
0.13 mmol) was added to a solution of 2 (100 mg, 0.1 mmol) in
CH2Cl2 (0.5 ml) at 0 8C, and the solution was stirred for 5 min,
then Et3N (0.036 ml, 0.26 mmol) was added to this mixture.
After the mixture was stirred for 10 min, PhCHO (0.015 ml,
0.15 mmol) was added. The mixture was stirred for 24 h at
room temperature, then quenched with 10% HCl, and extracted
with Et2O. After dried over MgSO4, the Et2O layer was
concentrated under vacuum, and the residue was separated by
column chromatography (SiO2, hexane/Et2O = 95/5–80/20) to
give (2R,3S)- and (2R,3R)-3-hydroxy-2-methyl-3-phenylpro-
panoic acid esters of 2 ((2R,3S)- and (2R,3R)-3a). (2R,3S)-3a:
Colorless waxy solid. 82 mg (74%), 1H NMR (CDCl3) d: 7.93
(1H, d, J = 7.8 Hz), 7.67 (1H, d, J = 7.4 Hz), 7.55 (1H, dd,
J = 7.8 Hz), 7.51–7.41 (3H, m), 7.37–7.27 (5H, m), 7.25 (1H,
m), 7.19 (1H, dd, J = 7.4, 3.3 Hz), 6.03 (1H, d, J = 22.0 Hz),
4.82 (1H, dd, J = 23.0, 4.9 Hz), 4.66 (1H, dd, J = 9.3, 3.4 Hz),
4.19 (1H, dd, J = 4.9, 3.9 Hz), 2.90 (1H, dq, J = 9.3, 6.9 Hz),
2.08 (1H, d, J = 3.4 Hz), 0.91 (3H, d, J = 6.9 Hz). 13C NMR
(2R,3R)-3a was cleaved similarly to (2R,3R)-4a. The
stereochemistries of (2R,3S)- and (2R,3R)-4a were determined
with comparison of spectral data of those reported in the
literatures [6,7]. We have synthesized (Sa)-(S)2-1c similarly
[3a]. Starting from this chiral auxiliary, (2S,3R)- and (2S,3S)-4a
would be obtained.
This reaction can be applied to several aldehydes. The
results are shown in Table 1.
The stereochemistry of the products is tentatively estimated
based on the results of 3a and the consideration of the stable
configuration of the transition state shown in Fig. 2.
3. Conclusion
(Ra)-(R)2-2,20-Bis(1-hydroxyl-1H-perfluorooctyl)biphenyl
((Ra)-(R)2-1c) was found to work as a chiral auxiliary for
asymmetric aldol reaction. Chirality on the 2-position is very
high, though that of the 3-position is moderate. However, both
diastereo isomers were separated easily and cleaved by
methanolysis to give enantiomerically pure methyl 3-
hydroxy-2-methyl-3-aryl- or alkyl-propanoates. The auxiliary
was recovered by fluorous solvent extraction quantitatively
without any loss of ee. Application of this auxiliary with other
carboxylic acids is now investigated. More detailed mechanism
on this reaction will be discussed with these results.
1
(CDCl3, H19F-COM) d: 174.9, 140.9, 140.4, 138.5, 134.2,
131.3, 130.4, 129.5, 129.3, 128.9, 128.9, 128.8, 128.7, 128.6,
128.5, 128.5, 126.7, 117.3, 117.2, 115.4, 114.2, 111.7, 111.3,
111.1, 111.0, 110.8, 110.7, 110.3, 108.5, 108.4, 68.1, 67.3, 47.5,
15.3, 14.0. IR (neat) cmꢁ1: 3548, 3076, 2948, 1740, 1460,
1164, 1018, 766, 704. LRMS (EI) m/z: 1112 (M+). HRMS (EI)
Calcd. for C38H22F30O4 (M+): 1112.104, Found: 1112.105.
(2R,3R)-3a: Colorless waxy solid. 21 mg (19%), 1H NMR
(CDCl3) d: 7.91 (1H, d, J = 7.8 Hz), 7.53 (1H, dd, J = 7.8,
7.8 Hz), 7.43–7.36 (2H, m), 7.29–7.17 (2H, m), 7.14–7.11 (7H,
m), 5.76 (1H, d, J = 23.0 Hz), 4.83 (1H, dd, J = 7.3, 3.4 Hz),
4.75 (1H, dd, J = 22.4, 4.8 Hz), 4.10 (1H, dd, J = 4.8, 2.9 Hz),
2.93 (1H, dq, J = 7.3, 7.3 Hz), 1.90 (1H, d, J = 3.4 Hz), 1.20
(3H, d, J = 7.3 Hz). 13C NMR (CDCl3, 1H19F-COM) d: 174.1,
141.2, 140.1, 138.2, 134.1, 131.1, 130.4, 129.2, 129.1, 128.9,
128.8, 128.6, 128.5, 128.5, 128.4, 127.7, 126.0, 117.2, 117.2,
115.4, 114.0, 111.7, 111.2, 111.2, 110.9, 110.8, 110.7, 110.4,
110.2, 108.5, 108.4, 74.7, 68.3, 67.2, 47.3, 12.3. IR
(neat) cmꢁ1: 3564, 1740, 1322, 1210, 1150, 1022, 760, 702.
LRMS (EI) m/z: 1112 (M+). HRMS (EI) Calcd. for
C38H22F30O4 (M+): 1112.104, Found: 1112.103.
4. Experimental
4.1. (Ra)-(R)2-2,20-Bis(1-hydroxyl-1H-
perfluorooctyl)biphenyl monopropanoate (2)
Propanoyl chloride (0.208 ml, 2.4 mmol) was added to a
solution of (Ra)-(R)2-1c (1.90 g, 2.0 mmol) and 4-dimethyl-
aminopyridine (DMAP, 489 mg, 4.0 mmol) in CH2Cl2 (5.0 ml)
at 0 8C, and the solution was stirred at room temperature for 2 h.
The solution was poured into a mixture of 10% HCl and ice,
then extracted with Et2O. The Et2O layer was dried over
MgSO4. After MgSO4 was filtered off, the solution was
concentrated under vacuum, and the residue was purified by
column chromatography (SiO2, hexane/Et2O = 95/5) to give 2
25
(1.95 g, 97%). 2: Colorless needles (Et2O–hexane). ½aꢀD
4.3. Aldol reaction of 2 with other aldehydes
1
(CHCl3) +18.54. Mp 55.0–56.0 8C. H NMR (CDCl3) d: 7.92
(1H, d, J = 7.8 Hz), 7.63 (1H, d, J = 7.4 Hz), 7.53 (1H, dd,
J = 7.4, 7.4 Hz), 7.52–7.44 (1H, m), 7.41 (1H, dd, J = 7.8,
7.8 Hz), 7.25 (1H, m), 7.17 (1H, dd, J = 7.8, 3.9 Hz), 5.85 (1H,
d, J = 21.9 Hz), 4.81 (1H, dd, J = 23.5, 4.9 Hz), 4.17 (2H, dd,
J = 4.9, 2.9 Hz), 2.42 (2H, q, J = 7.5 Hz), 1.10 (3H, t,
Aldol reaction of 2 with other aldehydes was carried out as
with benzaldehyde. In each case, two diastereomers were
isolated. Spectral data of the products are shown below.
Stereochemistries of acid parts are estimated by the coupling
1
constants in H NMR.
1
J = 7.5 Hz). 13C NMR (CDCl3, H19F-COM) d: 173.8, 140.5,
138.3, 134.2, 131.5, 130.5, 129.6, 129.1, 128.9, 128.7, 128.5,
128.0, 117.3, 117.2, 115.4, 114.2, 111.6, 111.3, 111.1, 111.0,
110.8, 108.5, 108.4, 68.3, 67.3, 27.4, 8.6. IR (KBr) cmꢁ1: 3572,
4.3.1. With anisaldehyde
(2R,3S)-3b: Colorless crystals (Et2O–hexane). Mp 86.0–
87.0 8C. H NMR (CDCl3) d: 7.93 (1H, d, J = 8.6 Hz), 7.67
1

M. Omote et al. / Journal of Fluorine Chemistry 127 (2006) 74–78
77
(1H, d, J = 7.0 Hz), 7.54 (1H, dd, J = 7.0 Hz), 7.50–7.40 (3H,
m), 7.26–7.16 (4H, m), 6.87–6.83 (2H, m), 6.04 (1H, d,
J = 21.6 Hz), 4.82 (1H, dd, J = 23.2, 4.9 Hz), 4.62 (1H, d,
J = 9.2 Hz), 4.20 (1H, dd, J = 4.9, 2.4 Hz), 3.79 (3H, s), 2.87
(1H, dq, J = 9.2, 7.3 Hz), 1.97 (1H, s), 0.90 (3H, d, J = 7.3 Hz).
IR (KBr) cmꢁ1: 1744, 1248, 1212, 1152. LRMS (EI) m/z: 1142
(M+). HRMS (EI) Calcd. for C39H24F30O5 (M+): 1142.115,
Found: 1142.115.
(2R,3R)-3b: Colorless waxy solid. 1H NMR (CDCl3) d: 7.90
(1H, d, J = 7.5 Hz), 7.52 (1H, dd, J = 7.9, 7.9 Hz), 7.41–7.33
(2H, m), 7.23 (1H, dd, J = 7.5, 7.5 Hz), 7.17 (1H, dd, J = 7.5,
3.1 Hz), 7.12–7.09 (2H, m), 7.10 (2H, d, J = 8.5 Hz), 7.04 (1H,
d, J = 7.9 Hz), 6.70 (2H, d, J = 8.5 Hz), 5.70 (1H, d,
J = 24.0 Hz), 4.73 (1H, dd, J = 23.0, 4.8 Hz), 4.68 (1H, d,
J = 7.8 Hz), 4.12 (1H, dd, J = 4.8 Hz), 3.77 (3H, s), 2.91 (1H,
d, J = 2.9 Hz), 1.24 (3H, d, J = 7.8 Hz), 1.22 (3H, d,
J = 7.0 Hz), 1.19 (3H, d, J = 7.0 Hz). IR (KBr) cmꢁ1: 1720,
1242, 1214, 1150. LRMS (EI) m/z: 1154 (M+). HRMS (EI)
Calcd. for C41H28F30O4 (M+): 1154.151, Found: 1154.151.
4.3.4. With 4-chlorobenzaldehyde
(2R,3S)-3e: Colorless waxy solid. 1H NMR (CDCl3) d: 7.92
(1H, d, J = 7.6 Hz), 7.60 (1H, d, J = 6.9 Hz), 7.54 (1H, dd,
J = 7.6, 7.6 Hz), 7.51–7.43 (2H, dd, J = 7.6, 7.6 Hz), 7.43 (1H,
dd, J = 7.6, 7.6 Hz), 7.32–7.28 (2H, m), 7.26–7.20 (3H, m),
7.18 (1H, dd, J = 7.6, 3.9 Hz), 6.00 (1H, dd, J = 22.9 Hz), 4.81
(1H, dd, J = 22.9, 4.7 Hz), 4.66 (1H, dd, J = 8.8, 3.0 Hz), 4.11
(1H, dd, J = 4.9, 2.8 Hz), 2.86 (1H, dq, J = 8.8, 7.2 Hz), 2.15
(1H, d, J = 3.7 Hz), 0.93 (3H, d, J = 7.2 Hz). IR (neat) cmꢁ1
:
3532, 3067, 2936, 1746, 1496, 1370, 1322, 1164, 764. LRMS
(EI) m/z: 1146 (M+). HRMS (EI) Calcd. for C38H21ClF30O4
(M+): 1146.065, Found: 11146.065.
dq, J = 7.8, 7.2 Hz), 1.24 (3H, d, J = 7.2 Hz). IR (KBr) cmꢁ1
:
1738, 1244, 1208, 1150. LRMS (EI) m/z: 1142 (M+). HRMS
(EI) Calcd. for C39H24F30O5 (M+): 1142.115, Found: 1142.115.
(2R,3R)-3e: Colorless waxy solid. 1H NMR (CDCl3) d: 7.91
(1H, d, J = 8.0 Hz), 7.53 (1H, dd, J = 7.7, 7.7 Hz), 7.43 (1H, dd,
J = 7.3, 7.3 Hz), 7.40 (1H, dd, J = 7.3, 7.3 Hz), 7.34 (1H, dd,
J = 7.3, 7.3 Hz), 7.19 (1H, d, J = 7.7 Hz), 7.17–7.09 (5H, m),
7.06 (1H, d, J = 8.0 Hz), 5.71 (1H, d, J = 22.3 Hz), 4.75 (1H,
dd, J = 7.4 Hz), 4.75 (1H, d, J = 7.4 Hz), 4.08 (1H, dd, J = 4.8,
2.2 Hz), 2.88 (1H, dq, J = 7.4, 7.4 Hz), 1.95 (1H, s), 1.22 (3H, d,
J = 7.4 Hz). IR (neat) cmꢁ1: 3556, 2932, 1740, 1360, 1242,
1150, 1100, 762. LRMS (EI) m/z: 1146 (M+). HRMS (EI)
Calcd. for C38H21ClF30O4 (M+): 1146.065, Found: 11146.064.
4.3.2. With p-tolualdehyde
(2R,3S)-3c: Colorless waxy solid. 1H NMR (CDCl3) d: 7.93
(1H, d, J = 7.8 Hz), 7.68 (1H, d, J = 7.8 Hz), 7.54 (1H, dd,
J = 7.8, 7.8 Hz), 7.50–7.40 (3H, m), 7.26–7.22 (1H, m), 7.20–
7.12 (5H, m), 6.03 (1H, d, J = 21.8 Hz), 4.81 (1H, dd, J = 23.0,
4.9 Hz), 4.63 (1H, dd, J = 9.3, 2.5 Hz), 4.91 (1H, dd,
J = 4.9 Hz), 2.88 (1H, dq, J = 9.3, 7.2 Hz), 2.34 (3H, s), 1.92
(1H, d, J = 3.4 Hz), 0.89 (3H, d, J = 7.2 Hz). IR (neat) cmꢁ1
:
1746, 1234, 1072. LRMS (EI) m/z: 1126 (M+). HRMS (EI)
Calcd. for C39H24F30O4 (M+): 1126.120, Found: 1126.120.
(2R,3R)-3c: Colorless crystals (Et2O–hexane). Mp 107.5–
4.3.5. With 2-fluorobenzaldehyde
(2R,3S)-3f: Colorless waxy solid. 1H NMR (CDCl3) d: 7.92
(1H, d, J = 7.8 Hz), 7.62–7.58 (1H, m), 7.55 (1H, dd, J = 7.8,
7.8 Hz), 7.48–741 (3H, m), 7.35 (1H, dd, J = 7.3, 7.3 Hz), 7.32–
7.22 (2H, m), 7.18 (1H, dd, J = 7.3, 3.9 Hz), 7.10 (1H, dd,
J = 7.3, 7.3 Hz), 7.04 (1H, dd, J = 7.8, 7.3 Hz), 6.00 (1H, d,
J = 21.6 Hz), 5.05 (1H, dd, J = 8.8, 4.8 Hz), 4.82 (1H, dd,
J = 23.0, 4.9 Hz), 4.10 (1H, dd, J = 4.9, 2.5 Hz), 2.99 (1H, dd,
J = 8.8, 6.9 Hz), 2.18 (1H, d, J = 4.8 Hz), 1.00 (3H, d,
J = 6.9 Hz). IR (neat) cmꢁ1: 3548, 3080, 2948, 1746, 1494,
1462, 1146, 1054, 760. LRMS (EI) m/z: 1130 (M+). HRMS (EI)
Calcd. for C38H21F31O4 (M+): 1130.195, Found: 1130.194.
(2R,3R)-3f: Colorless waxy solid. 1H NMR (CDCl3) d: 7.92
(1H, d, J = 7.9 Hz), 7.53 (1H, dd, J = 7.9, 7.9 Hz), 7.45–7.36
(4H, m), 7.33 (1H, dd, J = 7.4, 7.4 Hz), 7.29–7.21 (2H, m), 7.07
(1H, dd, J = 7.9, 7.9 Hz), 6.96 (1H, dd, J = 7.9, 7.4 Hz), 5.85
(1H, d, J = 22.0 Hz), 5.23 (1H, dd, J = 5.8, 4.8 Hz), 4.76 (1H,
dd, J = 23.0, 4.8 Hz), 4.01 (1H, dd, J = 5.4, 3.0 Hz), 3.05 (1H,
qd, J = 7.4, 5.4 Hz), 2.00 (1H, d, J = 4.8 Hz), 1.14 (3H, d,
J = 7.4 Hz). IR (neat) cmꢁ1: 3568, 3080, 2928, 1742, 1494,
1164, 1022, 762. LRMS (EI) m/z: 1130 (M+). HRMS (EI)
Calcd. for C38H21F31O4 (M+): 1130.195, Found: 1130.194.
1
108.5 8C. H NMR (CDCl3) d: 7.90 (1H, d, J = 8.3 Hz), 7.52
(1H, dd, J = 7.8, 7.8 Hz), 7.41–7.36 (2H, m), 7.24 (1H, dd,
J = 7.8, 7.8 Hz), 7.18 (1H, dd, J = 7.8, 3.4 Hz), 7.15–6.96 (6H,
m), 5.74 (1H, d, J = 22.0 Hz), 4.75 (1H, d, J = 7.1 Hz), 4.73
(1H, dd, J = 22.0 Hz), 4.11 (1H, dd, J = 4.9, 3.9 Hz), 2.99 (1H,
dq, J = 7.1, 7.1 Hz), 2.33 (3H, s), 1.86 (1H, s), 1.21 (3H, d,
J = 7.1 Hz). IR (KBr) cmꢁ1: 1738, 1242, 1212, 1152. LRMS
(EI) m/z: 1126 (M+). HRMS (EI) Calcd. for C39H24F30O4 (M+):
1126.120, Found: 1126.120.
4.3.3. With cuminaldehyde
(2R,3S)-3d: Colorless waxy solid. 1H NMR (CDCl3) d: 7.93
(1H, d, J = 7.8 Hz), 7.70 (1H, d, J = 7.3 Hz), 7.55 (1H, dd,
J = 7.8, 7.8 Hz), 7.51–7.40 (3H, m), 7.26–7.16 (6H, m), 6.04
(1H, d, J = 21.9 Hz), 4.82 (1H, dd, J = 23.0, 5.0 Hz), 4.63 (1H,
dd, J = 9.3, 3.4 Hz), 4.21 (1H, dd, J = 5.0, 2.9 Hz), 2.90 (1H,
dq, J = 9.3, 6.9 Hz), 2.90 (1H, sep, J = 6.9 Hz), 1.90 (1H, d,
J = 3.4 Hz), 1.24 (6H, d, J = 6.9 Hz), 0.90 (3H, d, J = 6.9 Hz).
IR (neat) cmꢁ1: 1746, 1248. LRMS (EI) m/z: 1154 (M+).
HRMS (EI) Calcd. for C41H28F30O4 (M+): 1154.151, Found:
1154.151.
(2R,3R)-3d: Colorless crystals (Et2O–hexane). Mp 107–
109 8C. 1H NMR (CDCl3) d: 7.90 (1H, d, J = 7.8 Hz), 7.52 (1H,
dd, J = 7.8, 7.8 Hz), 7.43–7.35 (2H, m), 7.30–7.08 (8H, m),
5.78 (1H, d, J = 22.5 Hz), 4.83 (1H, dd, J = 7.0, 1.5 Hz), 4.72
(1H, dd, J = 23.0, 4.9 Hz), 4.09 (1H, dd, J = 4.9, 2.9 Hz), 2.94
(1H, dq, J = 7.0, 7.0 Hz), 2.88 (1H, sep, J = 7.0 Hz), 1.82 (1H,
4.3.6. With methyl 4-formylbenzoate
(2R,3S)-3g: Colorless crystals (Et2O–hexane). Mp 107.5–
108.5 8C. H NMR (CDCl3) d: 8.00 (2H, d, J = 8.2 Hz), 7.93
(1H, d, J = 7.6 Hz), 7.63–7.60 (1H, m), 7.55 (1H, dd, J = 7.8,
7.8 Hz), 7.48–7.41 (3H, m), 7.38–7.35 (2H, d, J = 8.2 Hz),
7.26–7.22 (1H, m), 7.18 (1H, dd, J = 7.6, 6.8 Hz), 6.01 (1H, d,
1

78
M. Omote et al. / Journal of Fluorine Chemistry 127 (2006) 74–78
J = 22.0 Hz), 4.81 (1H, dd, J = 23.0, 4.8 Hz), 4.74 (1H, d,
J = 9.0 Hz), 4.09 (1H, dd, J = 4.8, 2.5 Hz), 3.92 (3H, s), 2.90
(1H, dq, J = 9.0, 7.4 Hz), 2.26 (1H, s), 0.94 (1H, d, J = 7.4 Hz).
IR (KBr) cmꢁ1: 1748, 1706, 1240, 1214, 1150. LRMS (EI) m/z:
1170 (M+). HRMS (EI) Calcd. for C40H24F30O6 (M+):
1170.109, Found: 1170.110.
J = 22.9, 4.9 Hz), 4.48 (1H, ddt, J = 6.8, 5.8, 2.5 Hz), 4.09 (1H,
dd, J = 4.9, 2.9 Hz), 2.83 (1H, dq, J = 7.2, 5.8 Hz), 1.72 (1H, d,
J = 4.0 Hz), 1.20 (3H, d, J = 7.2 Hz). IR (neat) cmꢁ1: 3564,
3076, 2928, 1740, 1208, 1150, 1018, 762. LRMS (EI) m/z: 1138
(M+). HRMS (EI) Calcd. for C40H24F30O4 (M+): 1138.120,
Found: 1138.119.
(2R,3R)-3g: Colorless waxy solid. 1H NMR (CDCl3) d:
7.93–7.87 (2H, m), 7.89 (1H, d, J = 7.3 Hz), 7.53 (1H, dd,
J = 7.8, 7.8 Hz), 7.53 (1H, dd, J = 7.8, 7.8 Hz), 7.40 (1H, dd,
J = 7.8, 7.8 Hz), 7.38 (1H, dd, J = 7.5, 7.5 Hz), 7.28 (1H, d,
J = 7.3 Hz), 7.26–7.14 (3H, m), 7.12 (1H, dd, J = 7.8, 4.4 Hz),
5.78 (1H, d, J = 22.7 Hz), 4.92 (1H, d, J = 6.6 Hz), 4.76 (1H,
dd, J = 22.5, 4.5 Hz), 4.03 (1H, dd, J = 4.5, 2.9 Hz), 3.94 (3H,
s), 2.92 (1H, qd, J = 6.9, 6.6 Hz), 2.13 (1H, s), 1.18 (3H, d,
J = 6.9 Hz). IR (KBr) cmꢁ1: 1738, 1242, 1214, 1152. LRMS
(EI) m/z: 1170 (M+). HRMS (EI) Calcd. for C40H24F30O6 (M+):
1170.109, Found: 1170.109.
4.4. Methanolysis of 3: recovery of the chiral auxiliary and
the chiral hydroxyl esters
A solution of MeONa (8.5 mg, 0.15 mmol) in MeOH
(0.2 ml) was added to a solution of (2R,3S)-3a (81.9 mg,
0.074 mmol) in MeOH (0.2 ml). After the solution was
stirred for 10 min at room temperature, 10% HCl (1.0 ml),
CH2Cl2 (1.0 ml) and FC-72 (1.0 ml) were added, and the
whole mixture was shaken vigorously, then the bottom FC-72
layer was separated. The top H2O layer and middle CH2Cl2
were extracted with FC-72 two more times. Then, the CH2Cl2
layer was separated from the H2O layer, and the H2O layer
was extracted with CH2Cl2 two more times. The FC-72
extract was dried over MgSO4 and concentrated under
vacuum to give (Ra)-(R)2-1c (67.9 mg, 97%), which did not
show any loss of optical purity. The CH2Cl2 layer was dried
over MgSO4 and concentrated under vacuum to give (ꢁ)-
4.3.7. With dihydrocinnamaldehyde
(2R,3R)-3h: Colorless waxy solid. 1H NMR (CDCl3) d: 7.91
(1H, d, J = 7.9 Hz), 7.64 (1H, d, J = 7.1 Hz), 7.54 (1H, dd,
J = 7.9, 7.9 Hz), 7.48–7.39 (3H, m), 7.30–7.1.4 (6H, m), 7.12
(1H, d, J = 7.1 Hz), 5.98 (1H, d, J = 21.9 Hz), 4.78 (1H, dd,
J = 22.9, 4.8 Hz), 4.01 (1H, dd, J = 4.8, 2.8 Hz), 3.74–3.66 (1H,
m), 2.80–2.72 (1H, m), 2.66 (1H, qd, J = 7.1, 7.1 Hz), 2.66–
2.58 (1H, m), 1.81–1.72 (2H, m), 1.65–1.55 (1H, m), 1.12 (3H,
d, J = 7.1 Hz). LRMS (EI) m/z: 1140 (M+). HRMS (EI) Calcd.
for C40H26F30O4 (M+): 1140.135, Found: 1140.135.
methyl
(2R,3S)-3-hydroxy-2-methyl-3-phenylpropanonate
[6], (2R,3S)-4 (13.8 mg, 96%), which was purified by
column chromatography (SiO2, hexane/Et2O = 70/30) for
spectral identification with the authentic sample. (2R,3S)-4:
1H NMR (CDCl3) d: 7.40–7.28 (5H, m), 4.76 (1H, dd,
J = 8.6, 2.9 Hz), 3.74 (3H, s), 2.93 (1H, d, J = 2.9 Hz), 2.83
(1H, dq, J = 8.6, 7.2 Hz), 1.02 (3H, d, J = 7.2 Hz). Similar
reaction of (2R,3R)-3 gave (+)-methyl (2R,3R)-3-hydroxy-2-
methyl-3-phenylpropanonate [7]. (2R,3R)-4: 1H NMR
(CDCl3) d: 7.38–7.24 (5H, m), 5.12 (1H, d, J = 4.1 Hz),
3.69 (3H, s), 2.92 (1H, br), 2.80 (1H, qd, J = 7.1, 4.1 Hz),
1.13 (3H, d, J = 7.1 Hz).
1
(2R,3S)-3h: H NMR (CDCl3) d: 7.91 (1H, d, J = 7.9 Hz),
7.61–7.51 (2H, m), 7.48–7.37 (3H, m), 7.30–7.14 (8H, m), 7.11
(1H, d, J = 7.3 Hz), 5.92 (1H, d, J = 22.0 Hz), 4.77 (1H, dd,
J = 23.0, 4.9 Hz), 3.99 (1H, dd, J = 4.9, 2.9 Hz), 3.88–3.82 (1H,
m), 2.81–2.72 (1H, m), 2.63 (1H, qd, J = 7.2, 4.9 Hz), 2.63–
2.55 (1H, m), 1.75–1.55 (3H, m), 1.15 (3H, d, J = 7.2 Hz).
LRMS (EI) m/z: 1122 (M+–H2O). HRMS (EI) Calcd. for
C40H24O3F30 (M+–H2O): 1122.125, Found: 1122.125.
4.3.8. With cinnamaldehyde
(2R,3R)-3i: Colorless crystals (Et2O–hexane). Mp 91.5–
92.5 8C. H NMR (CDCl3) d: 7.92 (1H, d, J = 7.8 Hz), 7.68
References
1
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3129–3131.
(1H, d, J = 7.3 Hz), 7.54 (1H, t, J = 7.8 Hz), 7.45–7.37 (3H, m),
7.35–7.21 (6H, m), 7.17 (1H, dd, J = 7.8, 4.0 Hz), 6.59 (1H, d,
J = 16.1 Hz), 6.07 (1H, dd, J = 16.1, 7.9 Hz), 6.02 (1H, d,
J = 22.0 Hz), 4.81 (1H, dd, J = 23.1, 4.9 Hz), 4.33 (1H, ddd,
J = 7.9, 7.9, 2.4 Hz), 4.13 (1H, dd, J = 4.9, 3.0 Hz), 2.76 (1H,
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1212, 1020, 764. LRMS (EI) m/z: 1138 (M+). HRMS (EI)
Calcd. for C40H24F30O4 (M+): 1138.120, Found: 1138.119.
(2R,3S)-3i: Colorless waxy solid. 1H NMR (CDCl3) d: 7.92
(1H, d, J = 7.8 Hz), 7.57 (1H, d, J = 7.8 Hz), 7.54 (1H, dd,
J = 7.8, 7.8 Hz), 7.41 (1H, dd, J = 7.3, 7.3 Hz), 7.35 (1H, dd,
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