Synthesis of stereocontrolled α,α-difluoro-β- hydroxycarbonyl materials

Article abstract of DOI:10.1016/j.jfluchem.2004.09.026

Synthesis and synthetic utilities of stereocontrolled α,α- difluoro-β-hydroxy-γ,δ-unsaturated carbonyl compounds via enzymatic resolution with lipase PS (Pseudomonas cepacia, Amano Pharmaceutical Co. Ltd.) or lipase MY (Candida rugosa, Meito Sangyo Co. Lt

Full text of DOI:10.1016/j.jfluchem.2004.09.026

Journal of Fluorine Chemistry 126 (2005) 17–26
www.elsevier.com/locate/fluor
Synthesis of stereocontrolled a,a-difluoro-b-hydroxycarbonyl materials
*
Takeshi Kaneda, Shinya Komura, Tomoya Kitazume
Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta,
Midori-ku, Yokohama 226-8501, Japan
Received 7 August 2004; received in revised form 9 September 2004; accepted 10 September 2004
Available online 2 December 2004
Abstract
Synthesis and synthetic utilities of stereocontrolled a,a-difluoro-b-hydroxy-g,d-unsaturated carbonyl compounds via enzymatic
resolution with lipase PS (Pseudomonas cepacia, Amano Pharmaceutical Co. Ltd.) or lipase MY (Candida rugosa, Meito Sangyo Co.
Ltd.) were described, and then the absolute configuration of obtained chiral materials was determined by the modified Mosher’s
method.
# 2004 Elsevier B.V. All rights reserved.
Keywords: Enzymatic resolution; Chiral fluorinated compounds
1. Introduction
those methods are not enough in a practical sense
if considering a large scale handling and/or high optical
purity.
The b-hydroxycarbonyl structure is frequently found in
natural products, and this framework is widely used as a key
intermediate in organic synthesis to afford highly functio-
nalized compounds [1-4]. Substitution of the two geminal
hydrogens attached to a-methylene group by fluorines
would inhibit such reactions because of the difficulty to
generate a fluorocation species, and would exert a
pronounced influence on its chemical property with no
significant effect on its geometry, which has possibility to
show unexpected biological properties [2-7]. Furthermore,
much attention has been paid to the b-hydroxycarbonyl
materials possessing fluorine(s) at the a-position due to the
remarkable ability of these materials to function as
biologically active materials, or optical devices [8]. The
synthesis of chiral difluorinated b-hydroxycarbonyl materi-
als have been based on asymmetric synthesis by chemical
processes and/or enzymatic resolution of racemates: (1) the
asymmetric synthesis using chiral aminoalcohol ligands in
Reformatsky-type reaction [9], (2) the asymmetric aldol
reaction of allyl acetals catalyzed by a chiral Lewis acid
[10], and a kinetic resolution by lipase OP [11]. However,
In our continuous study of stereocontrolled fluorinated
materials [12], we would like to describe a practical
enzymatic method for a,a-difluoro-b-hydroxy-g,d-unsatu-
rated carbonyl materials with high optical purity in a large
scale handling. The absolute configuration of the obtained
a,a-difluoro-b-hydroxy-g,d-unsaturated carbonyl materials
was determined by the modified Mosher’s method with
NMR spectral data. Furthermore, synthesis of several types
of stereocontrolled difluoromethylene compounds based on
the transformation of chiral unsaturated materials, is
described.
2. Results and discussion
2.1. Preparation of optically active a,a-difluoro-b-hydroxy
derivatives
Based on the recent impressive progress made on chiral
fluorinated materials, we designed a,a-difluoro-b-hydroxy-
g,d-unsaturated amides as a chiral building block with high
optical purity. For the purpose of the enzymatic resolution to
search for a practical route to chiral a,a-difluoro-b-
* Corresponding author. Fax: +81 45 924 5780.
E-mail address: tkitazum@bio.titech.ac.jp (T. Kitazume).
0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2004.09.026

18
T. Kaneda et al. / Journal of Fluorine Chemistry 126 (2005) 17–26
enantioselectivity by controlling the extent of hydrolysis
conversion.
The asymmetric hydrolysis of the ester rac-3e (R = n-
C5H11) with lipase PS (Pseudomonas cepacia, Amano
Pharmaceutical Co. Ltd.) produces the corresponding chiral
carbinol 2e (R = n-C5H11; 97% ee) at 47% conversion,
while 49% conversion of rac-3h (R = (E)-CH3CH=CH2)
afford 41 h in 95%ee. However, rac-3d (R = i-Bu), 3f (R =
Ph) and 3g (R = CH2Ph) was not hydrolysed under this
reaction condition after 1 week. Lipase MY (Candida
rugosa, Meito Sangyo Co. Ltd.) is a reasonable choice for
these cases to obtain the chiral carbinols (2d, 2f and 2g)
(Figs. 1–3).
Scheme 1. aCF2BrCO2Et, Zn, THF, 0 8C bpyrrolidine, toluene, reflux
cAc2O, pyridine, DMAP, CH2Cl2, 0 8C dlipase PS (P. cepacia, Amano
Pharmaceutical Co. Ltd.), phosphate, pH 7.4 buffer.
hydroxy-g,d-unsaturated amides prepared by synthetic
strategies shown in Scheme 1, we have examined following
methods; (1) the search of the carbon chain length to
enhance the enantioselectivity of asymmetric hydrolysis by
lipase, and (2) the modification of the structure a,a-difluoro-
b-hydroxy-g,d-unsaturated amides for the enzymatic trans-
formation.
The absolute configuration of the obtained chiral
secondary alcohols was confirmed by the Mosher’s method
[13]. This methodology has been widely accepted for
elucidating the absolute stereochemistries of various types
of materials. The Dd values (dS À dR) obtained for these
complexes are summarized in Fig. 3. It is evident from Figs.
1 and 2 that protons with Dd > 0 are located on the right side
of the MTPA plane, while those oriented on the left side of
MTPA plane are Dd < 0. Also, Dd values are almost
proportional to the distance between the protons and the
MTPA moiety.
The first synthetic strategy to obtain chiral a,a-difluoro-
b-hydroxy-g,d-unsaturated amides is the enzymatic route
based on the use of a wide range of lipases under the
different reaction conditions: (a) enzymatic resolution in
water, (b) organic medium, and (c) medium in phosphate pH
7.4 buffer. Since enzymatic resolution in water and/or
organic media was insufficient for practical resolution with
high optical purity, we examined various modification of the
substrate structures to increase enantio-selectivity of
enzymatic resolution in a buffer solution. The results shown
in Table 1 support that products would be obtained with high
These results suggest that the absolute configuration
of all alkanols shown in Fig. 3 is the R-configuration from
the model indicated by Fig. 2. Another trial to determine the
absolute configuration was the conversion from the acetate
of compound 2f to (+)-2,2-difluoro-1-hydroxy-1-phenyl-
heptan-3-one which was (S)-configuration in the literature
[14].
Table 1
Asymmetric hydrolysis of compound 3 with lipase MY or PS
Entry
R
Compound no.
Time (h)
Lipase
Conversiona (%)
Compound 2 (% ee)b
E value
[a]D (c, CHCl3)
1
2
Me
3a
3b
3c
51
PS
53
96 (R)
75 (R)
12 (R)
76 (R)
89 (R)
–
>200
14.3
1.4
À29.3 (c, 1.3)
À18.1 (c, 1.1)
C2H5
i-Pr
17
PS
48
3
72
MY
PS
47
4
330
36
31
10.2
31.7
–
À21.5 (c, 1.2)
5
i-Ba
3d
MY
PS
41
+2.9 (c, 0.3)
6
>150
47
No reaction
7
n-C5H11
3e
3f
PS
47
97 (R)
36 (R)
–
183
2.3
À12.6 (c, 1.4)
À17.2 (c, 0.3)
8
Ph
120
>150
60
MY
PS
20
9
No reaction
–
10
11
12
13
14
15
16
17
18
19
20
21
a
PhCH2
3g
3h
MY
PS
42
>99 (R)
–
>200
–
+5.8 (c, 0.3)
À19.9 (c, 1.0)
À65.3 (c, 1.1)
>150
12
No reaction
(E)-CH3CH=CH
MY
PS
49
49
49
32
58
48
38
38
49
36
85 (R)
95 (R)
>99 (R)
74 (R)
78 (R)
82 (R)
91 (R)
89 (R)
96 (R)
89 (R)
29.2
125
>200
9.2
41
(Z)-CH3CH=CH
CHBB C
3i
3j
24
MY
MY
PS
0.25
18
>20
22.1
30.5
30.5
125
34.1
+16.3 (c, 0.8)
+20.1 (c, 0.7)
+1.5 (c, 1.0)
CH3CBB C
(E)-CH3CH=C(CH3)
(E)-n-C3H7CH=CH
3k
3l
3m
12
MY
MY
MY
PS
6
6
41
À21.1 (c, 1.5)
À23.8 (c, 1.0)
n-C3H7CH=C(C2H5)
3n
24
MY
Determined by 19F NMR 99.5/0.5, 1.0 ml).
b
Determined by HPLC analysis (Daicel chiralpak OD-H, n-hexane/i-propanol.

T. Kaneda et al. / Journal of Fluorine Chemistry 126 (2005) 17–26
19
Table 2
Synthesis of chiral ketones
Entry R1
R2
n-Bu 74
Ph 84
E-C3H7CH=CH n-Bu 80
Ph 80
Yield (%)a o.p.(% ee)b [a]D (c, CHCl3)
Fig. 1. MTPA plane of an MTPA ester is shown. HA,B,C and HX,Y,Z are on
the left and right sides of the plane, respectively.
1
2
3
4
C5Hn
83
91
94
94
+ 7.6 (c, 0.6)
À3.7 (c,0.7)
À14.6 (c, 0.5)
À16.9 (c, 0.7)
a
Isolated yields.
b
Determined by HPLC analysis (Daicel chiralcel OD).
optical purity of obtained alkene decreased to 54% ee. The
transformations of chiral difluoromethylated materials to a
various kinds of functionalized fluorinated compounds were
carried out in the next step.
Fig. 2. Illustrations to determine the absolute configurations of secondary
alcohols.
As expected, the reaction of chiral amides 2 with a variety
of lithium compounds at À78 8C gave the corresponding
chiral ketones 4. Every instance in Table 2 showed good to
excellent chemical yields as well as very high optical purity
as expected.
In the next step, we examined a large scale process for
substrate 3e (13.4 g). Treatment with lipase PS at room
temperature gave the corresponding chiral alcohol 2e in
>97% ee and ester 3e after 51% conversion with 92%
recovered material balance as shown in Fig. 4.
Optically active epoxides have had much attention during
past few years [15–17]. However, the epoxidation in the field
of fluorinated materials with a strongly electron-with-
drawing group such as fluoromethyl groups is particularly
troublesome as traditional methods commonly employ
Synthetic applications of chiral compounds 2. The
transformation of the chiral compound 2m (96% ee) by
ozonolysis and the followed Wittig reaction successfully
proceeded to give the corresponding alkene. However, the
Fig. 3. Dd (dS À dR) values obtained for the MTPA esters of alkanols. Dd values are expressed in hertz (300 MHz).
Fig. 4. Large scale asymmetric hydrolysis.

20
T. Kaneda et al. / Journal of Fluorine Chemistry 126 (2005) 17–26
Table 3
Table 4
Diasteeomeric epoxidation
Diastereomeric ratios in the epoxidation
Entry R1 R2 R2 R3
Time Temperature Yield syn/antia
(h)
(8C)
(%)
1
2
3
4
5
6
7
8
9
Me
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
Et
H
H
H
Pyrrolidyl 72
0
64
67
85
80
80
76
85
82
79
>99/<1
94/6
Entry R
Oxidant
mCPBA
Temp (8C) Yield (%) syn/anti
H
72
15
48
72
15
0
1
2
3
4
5
6
H
rt
rt
rt
85
86/14
re-Pr
n-Pr
n-Pr
n-Pr
Me
rt
86/14
90/10
>99/<1
75/25
64/36
61/39
69/31
Ac
TBS
H
No reaction
No reaction
No reaction
Complex
Complex
0
À10
À10
À10
À10
À10
Ti(OPr6)4 (+)-DET/ TBHP À20
H
VO(acac)2/TBHP
H2O2
0
0
n-Bu
Ph
15
15
15
H
Me
Me
OEt
Determined by 1H and 19F NMR.
a
organic solvents and Lewis acid. Especially, the chiral
epoxidations of fluorinated allylic alcohols does not
proceed except the epoxidation with biocatalyst (Nocardia
corallina B-276) [18] or Darzens reaction [19]. One of the
reagents studied extensively to effect stereoselective
epoxidations is MCPBA. Therefore, we examined the
MCPBA epoxidation of chiral a, a-difluoro-b-hydroxy-g,d-
unsaturated carbonyl compounds at different reaction
temperatures. From the results shown in Table 3, we have
found that the reaction temperature affect the diastereomeric
ratios (Scheme 2).
alternative reaction to obtain the chiral difluorinated
materials in a large scale.
3. Experimental
3.1. General
All commercially available reagents were used without
1
further purification. Chemical shifts of H (300 MHz) and
Several epoxy alcohols with an amido group have been
prepared high stereoselectively starting from allyl alcohols
having a difluoromethylene group (Scheme 3). However,
a,a-difluoro-b-hydroxyketones and/or esters were not
obtained in high selectivity in the above epoxidation. In
those materials, the transformation of the corresponding
epoxyamide to epoxyketone is a reasonable way to obtain
the chiral materials (Table 4).
13C NMR (75 MHz) spectra were recorded in ppm b
downfield from the following internal standard (Me4Si, d
0.00) in CDCl3. The 19F (282 MHz) NMR spectra were
recorded in ppm downfield from internal standard C6F6 in
CDCl3 using a VXR 300 instrument.
3.2. General procedure: a,a-difluoro-b-hydroxyethylester
In conclusion, we have shown that asymmetric hydrolysis
of 2,2-difluoro-3-hydroxyamides is proved to be good
A suspension of activated zinc powder (1.3 equiv.) in
THF (0.5 mol/L) was cooled to 0 8C under an argon
atmosphere and the mixture was treated with a-bromo-a, a-
difluoroethylacetate (1.2 equiv.). The mixture was allowed
to warm carefully to room temperature or a hot bath
temperature to start a reaction. On a generation of heat, the
mixture was cooled to 0 8C and then the whole was treated
with an aldehyde (1.0 equiv.). After the whole was stirred for
2–3 h at room temperature, the mixture was quenched with
3N HCl and then the precipitates were removed by filtration.
Oily materials were extracted with ethyl acetate. The
organic layer was dried over MgSO4, concentrated under
vacuum. Products were purified by column chromatography
on silica gel using a mixture of hexane-ethyl acetate or a
distillation.
b
Scheme 2. aBz2O, pyr., DMAP/CH2Cl2, rt (i) O3/CH2Cl2, À78 8C (ii)
c
Me2S/CH2Cl2, À78 8C to rt Ph3PCHC(O)CH3/THF, rt.
3.3. General procedure: a,a-difluoro-b-
hydroxypyrrolidium amide
A mixture solution of a,a-difluoro-b-hydroxyester
(1 equiv.) and pyrrolidine (1.5 equiv.) in toluene was heated
at 110 8C under a nitrogen atmosphere. After heating for 2–
5 h, the mixture was quenched with aq. NH4Cl solution at
0 8C, and then the precipitates were removed by filtration.
Scheme 3.

T. Kaneda et al. / Journal of Fluorine Chemistry 126 (2005) 17–26
21
The solution was poured into 3N HCl, and then the organic
materials were extracted with diethyl ether. On removal of
the solvent, products were purified by column chromato-
graphy on silica gel using a mixture of hexane and ethyl
acetate (10:1).
3.64 (1 H, m), 3.74 (2 H, t, J = 6.6 Hz), 3.95–4.08 (1 H, m).
19F NMR (CDCl3): d 39.6 (dd, J = 19.8, 288.7 Hz), 50.9 (dd,
J = 2.6, 288.7 Hz). 13C NMR (CDCl3): d 10.0, 21.5 (dd,
J = 2.0, 3.7 Hz), 23.2, 26.3, 46.4 (dd, J=5.4, 7.4 Hz), 47.2,
72.8 (dd, J = 24.3, 28.1 Hz), 115.6 (dd, J = 256.5,
262.8 Hz), 162.3 (t, J = 29.5 Hz). IR (KBr): 3421, 1653,
1636 cmÀ1. Anal. Calcd. for C9H15F2NO2: C, 52.17; H,
7.30; N, 6.76. Found: C, 52.42; H, 6.88; N, 6.72.
3.4. Asymmetric hydrolysis
(a) A mixture of N-(2,2-difluoro-3-acetoxyoctanoyl)pyr-
rolidine (1 g) and lipase PS (1 g, P. cepacia, Amano
Pharmaceutical Co. Ltd.) in phosphate pH 7.4 buffer
(10 ml) was stirred at room temperature. After the
reaction, the whole was filtered over Celite pad in
vacuo. The organic materials were extracted with
diethyl ether, and then the extract was dried over
MgSO4. On removal of the solvent, the residues were
purified by column chromatography on silica gel,
eluting with a mixture of hexane-ethyl acetate, giving
N-(2,2-difluoro-3-hydroxyoctanoyl)-pyrrolidine (2a)
and N-(2,2-difluoro-3-acetoxyoctanoyl) pyrrolidine.
Optical purity was determined by HPLC analysis
(Daicel Chiralcel OD-H, n-hexane-i-propanol 99.5:
0.5; flow speed 1.0 ml/mim. tR (major), 26.1 min; tR
(minor), 28.9 min.
3.7. N-(2,2-Difluoro-3-hydroxy-4-
methylpentanoyl)pyrrolidine (2c)
1H NMR (CDCl3): d 1.04–1.08 (6 H, m), 1.83–2.03 (4
H, m), 2.08–2.15 (1 H, m), 3.53 (2 H, t, J = 7.1 Hz), 3.60 (1
H, d, J = 4.7 Hz), 3.74 (2 H, t, J = 6.6 Hz), 3.87–3.99 (1 H,
ddd, J = 4.7, 9.1, 22.3 Hz). 19F NMR (CDCl3): d 41.7 (dd,
J = 22.4, 285.2 Hz), 54.0 (d, J = 285.2 Hz). 13C NMR
(CDCl3). d 17.4 (d, J = 2.6 Hz), 20.2, 23.1, 26.3, 27.9, 46.6
(dd, J = 4.9, 8.0 Hz), 47.3, 74.7 (dd, J = 22.9, 27.2 Hz),
116.7 (dd, J = 256.5, 264.5 Hz), 162.7 (t, J = 28.9 Hz). IR
(KBr): 3405, 1643 cmÀ1. Anal. Calcd. for C10H17F2NO2:
C, 54.29; H, 7.74; N, 6.33. Found: C, 54.02; H, 7.62; N,
6.21.
(b) To a solution of substrate (1 mmol) in phosphate buffer
(2 ml, pH 7.4), lipase MY (w/w = 1/2, C. rugosa,
Meito Sangyo Co. Ltd.) was added at room tempera-
ture. After the reaction, the whole was filtered with
Celite pad in vacuo. The solution was diluted with
ethyl acetate and then the separated aqueous phase was
extracted twice with ethyl acetate and the combined
organic layers were washed with brine, dried over
MgSO4, concentrated. The conversion ratio of crude
oil was determined by 19F NMR analysis. The residual
was subjected to column chromatography (hexane/
ethyl acetate). Optical purity was determined by HPLC
using a chiral column (DAICEL Chiralcel OD or
Chiralpac AD).
3.8. N-(2,2-Difluoro-3-hydroxy-5-
methylhexanoyll)pyrrolidine (2d)
1H NMR (CDCl3): d 0.94 (3 H, d, J = 6.6 Hz), 0.99 (3 H,
d, J = 6.6 Hz), 1.36–1.43 (1 H, m), 1.64 (1 H, s), 1.56–1.68
(1 H, m), 1.83–2.03 (5 H, m), 3.51–3.56 (2 H, m), 3.74 (2
H, t, J = 6.6 Hz), 4.12–4.26 (1 H, m). 19F NMR (CDCl3): d
39.6 (dd, J = 19.8, 288.4 Hz), 50.9 (d, J = 288.4 Hz). 13C
NMR (CDCl3): d 21.323.3, 23.7, 24.1, 26.4, 46.5 (dd,
J = 5.4, 7.2 Hz), 47.2, 69.8 (dd, J = 24.3, 28.1 Hz), 115.6
(dd, J = 256.8, 262.8 Hz), 162.5 (t, J = 29.5 Hz). IR (KBr):
3386, 1659 cmÀ1. Anal. Calcd. for C11H19F2NO2: C,
57.81; H, 8.49; N, 5.62. Found: C, 58.22; H, 8.89; N,
5.41. HPLC analysis: tR (major), 22.5 min; tR (minor),
21.4 min (Chiralpac AD, n-hexane/i-propanol: 98/2,
1.0 ml/min).
3.5. N-(2,2-Difluoro-3-hydroxybutanoyl)pyrrolidine (2a)
1H NMR (CDCl3): d 1.33 (3 H, d, J = 6.6 Hz), 1.85–2.03
(4 H, m), 2.18 (1 H, s), 3.54 (2 H, t, J = 7.1 Hz), 3.72-3.77
(2 H, m), 4.24–4.39 (1 H, m). 19F NMR (CDCl3): d 37.4
(dd, J = 19.0, 289.5 Hz), 50.7 (d, J = 288.7 Hz). 13C NMR
(CDCl3): d 14.2 (dd, J = 2.3, 4.6 Hz), 23.1, 26.2, 46.4 (dd,
J = 5.4, 7.2 Hz), 47.1, 67.4 (dd, J = 24.9, 29.2 Hz),
115.4 (dd, J = 256.2, 262.5 Hz), 162.1 (t, J = 29.2 Hz).
IR (KBr): 3406, 1644 cmÀ1. Anal. Calcd. for C8H13F2NO2:
C, 49.74; H, 6.78; N, 7.25. Found: C, 49.64; H, 7.01;
N, 7.19.
3.9. N-(2,2-Difluoro-3-hydroxyoctanoyl)pyrrolidine (2e)
1H NMR (CDCl3): d 0.89–0.92 (3 H, m), 1.29–1.42 (6
H, m), 1.60–1.67 (2 H, m), 1.84–2.02 (4 H, m), 3.52–3.56
(2 H, m), 3.74 (2 H, t, J = 6.8 Hz), 4.05–4.13 (1 H, m). 19
F
NMR (CDCl3): d 39.6(dd, J = 19.8, 289.2 Hz), 50.9 (d,
J = 288.4 Hz). 13C NMR (CDCl3): d 13.7, 22.3, 22.9, 24.9,
26.1, 28.1, 31.4, 46.3 (dd, J = 5.2, 7.5 Hz), 47.0, 71.0 (dd,
J = 24.3, 27.8 Hz), 115.6 (dd, J = 255.7, 262.0 Hz), 162.1
(t, J = 29.5 Hz). IR (KBr): 3412, 1636 cmÀ1. Anal. Calcd.
for C12H21F2NO2: C, 57.81; H, 8.49; N, 5.62. Found:
C, 58.22; H, 8.89; N, 5.41. [a]D À12.6 (c 1.4, CHCl3):
HPLC analysis: tR (major), 26.1 min; tR (minor),
28.9 min (Chiralcel OD-H, n-hexane/i-propanol 99.5/0.5,
1.0 ml).
3.6. N-(2,2-Difluoro-3-hydroxypentanoyl)pyrrolidine (2b)
1H NMR (CDCl3): d 1.08 (3 H, t, J = 7.4 Hz), 1.57–1.72
(2 H, m), 1.84–2.03 (4 H, m), 3.54 (2 H, t, J = 7.1 Hz), 3.62–

22
T. Kaneda et al. / Journal of Fluorine Chemistry 126 (2005) 17–26
3.10. N-(2,2-Difluoro-3-hydroxy-3-
phenylpropanoyl)pyrrolidine (2f)
13C NMR(CDCl3): d 13.74, 23.26, 26.35 (dd, J = 1.44,
2.00 Hz), 46.45 (dd, J = 5.30, 7.01 Hz), 47.22, 67.86 (dd,
J = 25.05, 29.35 Hz), 115.23 (dd, J = 257.09, 262.24 Hz),
123.85 (dd, J = 1.87, 3.30 Hz), 131,61, 162.38 (t,
J = 29.92 Hz). 19F NMR (CDCl3): d 42.12 (dd, J = 17.03,
288.66 Hz), 52.43 (dd, J = 5.22, 288.66 Hz); Anal. Calcd.
for C10H15F2NO2: C, 54.79; H, 6.90; N, 6.39. Found: C,
54.30; H, 7.25; N, 6.30. HPLC analysis: tR (major),
36.6 min; tR (minor), 34.6 min (Chiralpac AD, n-hexane/
i-propanol 98/2, 1.0 ml/min).
1H NMR (CDCl3): d 1.81–1.92 (4 H, m), 3.52–3.61 (4 H,
m), 4.35 (1 H, d, J = 3.9 Hz), 5.22–5.28 (1 H, m), 7.36–7.49
(Ar-H). 19F NMR (CDCl3): d 41.4 (dd, J = 19.8, 285.3 Hz),
53.7 (d, J = 285.3 Hz). 13C NMR (CDCl3): d 23.0, 26.2, 46.5
(dd, J = 5.2, 7.5 Hz), 47.3, 73.2 (dd, J = 23.5, 28.6 Hz),
114.8 (dd, J = 256.2, 264.0 Hz), 127.7, 127.8, 128.3, 134.8,
162.3 (t, J = 28.9 Hz). IR (KBr): 3406, 1774, 1648 cmÀ1
.
HPLC analysis: tR (major), 30.3 min; tR (minor), 28.5 min
(Chiralpac AD, n-hexane/i-propanol 98/2, 2.0 ml/min).
3.14. N-(2,2-Difluoro-3-hydroxy-4-pentynoyl)pyrrolidine
(2j)
3.11. N-(2,2-Difluoro-3-hydroxy-4-
phenylbutanoyl)pyrrolidine (2g)
1H NMR (CDCl3): d 1.88–2.03 (4 H, m), 2.56 (1 H, d,
J = 2.2 Hz), 3.54–3.59 (2 H, m), 3.74–3.78 (2 H, m), 4.86
(1 H, ddd, J = 2.2, 6.0, 12.1 Hz). 19F NMR (CDCl3): d 46.8
(dd, J = 12.1, 286.9 Hz), 51.9 (dd, J = 6.6, 287.0 Hz). 13C
NMR (CDCl3): d 23.2, 26.3, 46.5 (dd, J = 4.6, 7.4 Hz),
47.3, 64.0 (dd, J = 27.5, 31.2 Hz), 75.3, 77.5 (dd, J = 2.0,
5.2 Hz), 113.3 (dd, J = 260.0, 265.1 Hz), 161.4 (t,
J = 28.6 Hz). IR (KBr): 3300, 1649 cmÀ1. Anal. Calcd.
for C9H11F2NO2: C, 53.20; H, 5.46; N, 6.89. Found: C,
53.51; H, 5.09; N, 6.48.
1H NMR (CDCl3): d 1.83–2.02 (4 H, m), 2.87 (1 H, dd,
J = 9.9, 14.0 Hz), 3.05 (1 H, d, J = 14.3 Hz), 3.51 (2 H, t,
J = 6.9 Hz), 3.62 (1 H, d, J = 3.0 Hz), 3.76 (2 H, t,
J = 6.6 Hz), 4.33–4.43 (1 H, m), 7.21–7.35 (Ar–H). 19F
NMR (CDCl3): d 39.8 (dd, J = 19.0, 286.1 Hz), 51.3 (dd,
J = 2.6, 287.8 Hz). 13C NMR (CDCl3): d 23.1, 26.2, 34.9,
46.5 (dd, J = 4.9, 7.7 Hz), 47.2, 72.5 (dd, J = 23.8, 28.3 Hz),
115.5 (dd, J = 256.5, 263.7 Hz), 126.2, 128.0, 129.2, 137.5,
162.0 (t, J = 28.9 Hz). IR (KBr): 3418, 1648 cmÀ1. Anal.
Calcd. for C14H17F2NO2: C, 62.44; H, 6.36; N, 5.20. Found:
C, 62.39; H, 6.24; N, 5.15. HPLC analysis: tR (major),
23.0 min; tR (minor), 20.2 min (Chiralpac AD, n-hexane/i-
propanol: 98/2, 2.0 ml/min).
3.15. N-(2,2-Difluoro-3-hydroxy-4-hexynoyl)pyrrolidine
(2k)
1H NMR (CDCl3): d 1.86–1,93 (2 H, m), 1.89 (3 H, d,
J = 2.20 Hz), 1.95–2.04 (2 H, m), 3.52-3.59 (2 H, m), 3.72–
3.80 (2 H, m), 3.91 (1 H, d, J = 7.32 Hz), 4.84 (1 H, qdd,
J = 2.20, 5.98, 7.32, 13.30 Hz). 13C NMR (CDCl3): d 3.81,
23.29, 26.36 (dd, J = 1.43, 2.29 Hz), 46.49 (dd, J = 4.87,
7.44 Hz), 47.30, 64.34 (dd, J = 27.19, 30.92 Hz), 72.87
(dd, J = 2.29, 4.87 Hz), 83.84, 113.40 (dd, J = 259.09,
264.53 Hz), 161.43 (t, J = 28.92 Hz). 19F NMR (CDCl3): d
45.92 (dd, J = 13.30, 285.35 Hz), 52.12 (dd, J = 5.98,
285.35 Hz); Anal. Calcd. for C10H13F2NO2: C, 55.29; H,
6.03; N, 6.45. Found: C, 55.49; H, 5.68; N, 6.47. HPLC
analysis: tR (major), 22.6 min; tR (minor), 32.0 min
(Chiralpac AD, n-hexane/i-propanol: 98/2, 2.0 ml/min).
3.12. N-((E)-2,2-Difluoro-3-hydroxy-4-
hexenoyl)pyrrolidine (2h)
1H NMR (CDCl3): d 0.91 (3 H, t, J = 7.3 Hz), 1.40–1.48
(2 H, m), 1.85–1.91 (2 H, m), 1.95–2.01 (2 H, m), 2.05–
2.11 (2 H, m), 3.54 (2 H, t, J = 7.1 Hz), 3.73 (2 H, t,
J = 6.6 Hz), 4.56 (1 H, ddd, J = 6.1, 6.1, 17.1 Hz), 5.58 (1
H, dd, J = 7.1, 15.6 Hz), 5.60–5.89 (1 H, m). 19F NMR
(CDCl3): d42.6 (dd, J = 16.8, 285.3 Hz), 52.6 (d,
J = 287.2 Hz). 13C NMR (CDCl3): d 13.6, 21.9, 23.2,
26.3, 34.4, 46.5 (dd, J = 5.2, 7.2 Hz), 47.2, 72.9 (dd,
J = 24.9, 28.6 Hz), 114.8 (dd, J = 256.5, 262.2 Hz), 122.9,
137.1, 162.2 (t, J = 30.0 Hz). IR (KBr): 3403, 1644 cmÀ1
.
3.16. N-(2,2-Difluoro-3-hydroxy-4-methyl-4-
heptenoyl)pyrrolidine (2l)
Anal. Calcd. for C12H19F2NO2: C, 58.29; H, 7.74; N, 5.66.
Found: C, 58.19; H, 7.92; N, 5.52. HPLC analysis: tR
(major), 16.8 min; tR (minor), 14.6 min (Chiralpac AD,
n-hexane/i-propanol: 98/2, 2.0 ml/min).
1H NMR (CDCl3): d 1.00 (3 H, t, J = 7.45 Hz), 1.74 (3 H,
s), 1.85–1.91 (2 H, m), 1.94–2.00 (2 H, m), 2.11 (2 H, dq,
J = 7.33, 7.33 Hz), 3.54 (2 H, t, J = 7.04 Hz), 3.69–3.75 (2
H, m), 3.80 (1 H, dd, J = 0.67, 3.84 Hz), 4.56 (1 H, td,
J = 3.72, 11.97 Hz), 5.59 (1 H, dqt, J = 1.22, 1.34, 7.20 Hz);
13C NMR (CDCl3): d 12.66 (dd, J = 1.43, 3.15 Hz), 13.67,
20.98, 23.19, 26.36 (dd, J = 1.43, 2.29 Hz), 46.57 (dd,
J = 5.16, 7.44 Hz), 47.34, 75.83 (dd, J = 22.62, 28.92 Hz),
115.51 (dd, J = 255.80, 264.39 Hz), 128.57, 133.76 (d,
J = 0.57 Hz), 162.64 (dd, J = 29.20, 30.06 Hz). 19F NMR
(CDCl3): d 41.40 (dd, J = 11.75, 284.20 Hz), 53.86 (d,
3.13. N-((Z)-2,2-Difluoro-3-hydroxy-4-
hexenoyl)pyrrolidine (2i)
1H NMR (CDCl3): d 1.74 (3 H, dd, J = 1.92, 7.14 Hz),
1.83–2.03 (4 H, m), 3.54 (2 H, t, J = 6.87 Hz), 3.69 (1 H, d,
J = 5.49 Hz), 3.73 (2 H, t, J = 6.73 Hz), 4.96 (1 H, dtdd,
J = 1.10, 5.22, 8.79, 17.03 Hz), 5.56 (1 H, qdd, J = 1.92,
8.79, 10.99 Hz), 5.90 (1 H, dqd, J = 1.10, 7.14, 10.99 Hz).

T. Kaneda et al. / Journal of Fluorine Chemistry 126 (2005) 17–26
23
J = 284.20 Hz); Anal. Calcd. for C12H19F2NO2: C, 58.29; H,
7.74; N, 5.66. Found: C, 57.82; H, 7.87; N, 5.53. HPLC
analysis: tR (major), 26.7 min; tR (minor), 32.6 min
(Chiralcel OD, n-hexane/i-propanol 99/1, 1.0 ml/min).
4.07 (1 H, m). 19F NMR (CDCl3): d 36.7 (dd, J = 16.4,
276.6 Hz), 47.5 (dd, J = 6.6, 276.6 Hz). 13C NMR (CDCl3):
d 13.7 (d, J = 8.9 Hz), 13.9 (d, J = 8.6 Hz), 22.0 (d,
J = 4.3 Hz), 22.5, 24.5, 25.0, 28.9, 31.5, 37.5, 70.5–71.3
(m), 115.6 (t, J = 254.8 Hz), 202.9 (t, J = 30.3 Hz). IR
(KBr): 3448, 1741 cmÀ1. Anal. Calcd. for C12H22F2O2: C,
60.99; H, 9.38. Found: C, 60.64; H, 9.32. [a]D +7.6 (c 0.6,
CHCl3), 83% ee. HPLC analysis (Daicel Chiralcel OD-H,
n-hexane–i-propanol 99.5:0.5; flow speed 1.0 ml/mim. tR
(major), 15.4 min; tR (minor), 16.7 min.
3.17. N-(2,2-Difluoro-3-hydroxy-4-octenoyl)pyrrolidine
(2m)
1H NMR (CDCl3): d 5.60–5.89 (1 H, m), 5.58 (1 H, dd,
J = 7.1, 15.6 Hz), 4.56 (1 H, ddd, J = 6.1, 6.1, 17.1 Hz),
3.73 (2H, t, J = 6.6 Hz), 3.54 (2 H, t, J = 7.1 Hz), 2.11–2.05
(2 H, m), 2.01–1.95 (2 H, m), 1.91–1.85 (2 H, m), 1.48–
1.40 (2 H, m), 0.91 (3 H, t, J = 7.3 Hz); 13C NMR (CDCl3):
d 162.2 (t, J = 30.0 Hz), 137.1, 122.9, 114.8 (dd, J = 256.5,
262.2 Hz), 72.9 (dd, J = 24.9, 28.6 Hz), 47.2, 46.5 (dd,
J = 5.2, 7.2 Hz), 34.4, 26.3, 23.2, 21.9, 13.6; 19F NMR
(CDCl3): d 52.6 (d, J = 287.2 Hz), 42.6 (dd, J = 16.8,
285.3 Hz); IR (neat): 1738, 1644 cmÀ1; Anal. Calcd. for
C12H19F2NO2: C, 58.29; H, 7.74; N, 5.66. Found: C, 58.19;
H, 7.92; N, 5.52.
3.20. (R)-(À)-2,2-Difluoro-3-hydroxy-1-phenyloctan-
1-one (4b)
1H NMR (CDCl3): d 0.88–0.93 (3 H, m), 1.29–1.76 (8 H,
m), 2.48 (1 H, d, J = 6.3 Hz), 4.17–4.31 (1 H, m), 8.10–8.13
(Ar-H). 19F NMR (CDCl3): d 44.6 (dd, J = 17.2, 294.7 Hz),
53.9 (dd, J = 6.0, 294.7 Hz). 13C NMR (CDCl3): d 14.0,
22.5, 25.1, 28.2, 31.5, 71.6 (dd, J = 24.1, 27.2 Hz), 116.7
(dd, J = 256.5, 260.8 Hz), 128.5, 130.0 (t, J = 3.4 Hz),
132.2, 134.3, 190.5 (t, J = 29.5 Hz). IR (KBr): 3446,
1698 cmÀ1. Anal. Calcd. for C14H18F2O2: C, 65.61; H,
7.08. Found: C, 65.41; H, 7.02. [a]D –3.7 (c 0.7, CHCl3),
91% ee. HPLC analysis (Daicel Chiralcel AD-H, n-hexane–
i-propanol 98:2; flow speed 1.0 ml/min. tR (major),
18.8 min; tR (minor), 22.2 min.
3.18. N-(2,2-Difluoro-3-hydroxy-4-ethyl-4-
octenoyl)pyrrolidine (2n)
1H NMR (CDCl3): d 0.92 (3 H, t, J = 7.41 Hz), 1.03 (3 H,
t, J = 7.41 Hz), 1.42 (2 H, sex, J = 7.41 Hz), 1.82–2.02 (4 H,
m), 2.10 (2 H, sex, J = 7.42 Hz), 2.27 (2 H, qd, J=7.42,
13.73 Hz), 3.57 (2 H, t, J=6.60 Hz), 3.68–3.75 (2 H, m), 4.62
3.21. (R)-(-)-(E)-6,6-Difluoro-7-hydroxy-8-dodecen-
5-one (4c)
(1 H, dd, J = 3.76, 21.57 Hz), 5.62 (1 H, t, J=7.28 Hz). 13
C
NMR (CDCl3): d 13.89, 13.93 (d, J = 1.43 Hz), 21.45 (t,
J = 1.72 Hz), 22.73, 23.28, 26.43 (dd, J = 1.72, 2.29 Hz),
29.64, 46.64 (dd, J = 5.15, 7.44 Hz), 47.39, 74.43 (dd,
J = 22.62, 28.34 Hz), 115.32 (dd, J = 256.23, 264.53 Hz),
131.93, 135.06, 162.81 (t, J = 29.78 Hz). 19F NMR (CDCl3):
d 40.85 (dd, J = 15.51, 284.14 Hz), 54.16 (dd, J = 20.90,
284.14 Hz); Anal. Calcd. for C14H23F2NO2: C, 61.07; H,
8.42; N, 5.09. Found: C, 60.58; H, 8.16; N, 4.78. HPLC
analysis: tR (major), 20.0 min (95.4%); tR (minor), 24.6 min
(4.6%) (Chiralcel OD, n-hexane/i-propanol: 99/1, 1.0 ml/
min).
1H NMR (CDCl3): d 0.91 (3 H, t, J = 7.4 Hz), 0.92 (3 H, t,
J = 7.1 Hz), 1.28–1.49 (4 H, m), 1.54–1.65 (2 H, m), 2.08 (2
H, q, J = 6.9 Hz), 2.19 (1 H, J = 6.1 Hz), 2.70 (2 H, t,
J = 7.1 Hz), 4.45–4.57 (1 H, m), 5.52 (1 H, dd, J = 7.1,
15.4 Hz), 5.90 (1 H, td, J = 6.1, 15.4 Hz). 19F NMR
(CDCl3): d 38.6 (dd, J = 14.7, 271.4 Hz), 47.3 (dd, J = 7.8,
270.6 Hz). 13C NMR (CDCl3): d 13.6, 13.8, 21.9, 22.1, 24.5,
34.4, 37.7, 72.3 (dd, J = 24.9, 28.3 Hz), 114.9 (dd, J = 255.3,
259.4 Hz), 122.8 (dd, J = 2.3, 3.4 Hz), 138.1, 202.0 (dd,
J = 27.8, 30.6 Hz). IR (KBr): 3454, 1740 cmÀ1. Anal. Calcd.
for C12H20F2O2: C, 61.52; H, 8.60. Found: C, 61.36; H, 8.68.
[a]D –14.6 (c 0.5, CHCl3), 94% ee. HPLC analysis (Daicel
Chiralcel OD-H, n-hexane–i-propanol 99.5: 0.5; flow speed
1.0 ml/min. tR (major), 20.8 min; tR (minor), 22.4 min.
3.19. (R)-(+)-6,6-Difluoro-7-hydroxydodecan-5-one (4a)
Into a mixture of (R)-(À)-N-(2,2-difluoro-3-hydroxyoc-
tanoyl)pyrrolidine 2e (1.26 g, 5 mmol) in THF (20 ml)
under an atmosphere of nitrogen, butyl lithium (1 M in
hexane, 2.0 equiv.) was added at À78 8C. After 10 min of
stirring at that temperature, the mixture was quenched with
methanol at À78 8C, and the solution was poured into 3N
HCl and the organic materials were extracted with diethyl
ether. On removal of the solvent, the residue was purified by
column chromatography on silica gel, eluting with a mixture
of hexane-ethyl acetate, giving (R)-(+)-6,6-difluoro-7-
hydroxydodecan-5-one 4a in 83% yield.
3.22. (R)-(À)-(E)-2,2-Difluoro-3-hydroxy-1-phenyl-4-
octen-1-one (4d)
1H NMR (CDCl3): d 0.90 (3 H, t, J = 7.4 Hz), 1.43 (2 H,
dq, J = 7.4, 7.4 Hz), 2.09 (2 H, q, J = 6.9 Hz), 2.49 (1 H, d,
J = 6.0 Hz), 4.66–4.78 (1 H, m), 5.62 (1 H, dd, J = 6.9,
15.1 Hz), 5.94 (1 H, td, J = 6.0, 15.4 Hz), 7.46–8.12 (Ar-H).
19F NMR (CDCl3): d 46.4 (dd, J = 15.5, 290.4 Hz), 54.6 (dd,
J = 7.6, 291.2 Hz). 13C NMR (CDCl3): d 13.6, 21.9, 34.4,
72.7 (dd, J = 24.3, 27.8 Hz), 116.0 (dd, J = 256.8,
261.1 Hz), 122.8 (dd, J = 2.3, 3.4 Hz), 128.5, 130.0 (t,
1H NMR (CDCl3): d 0.90–0.95 (6 H, m), 1.32–1.68 (2 H,
m), 2.19 (1 H, d, J = 6.6 Hz), 2.72 (2 H, t, J = 7.1 Hz), 3.97–

24
T. Kaneda et al. / Journal of Fluorine Chemistry 126 (2005) 17–26
J = 3.2 Hz), 132.3, 134.3, 137.9, 190.3 (dd, J = 28.9,
30.6 Hz). IR (KBr): 3454, 1698 cmÀ1. Anal. Calcd. for
C14H16F2O2: C, 66.13; H, 6.34. Found: C, 66.39; H, 6.71.
[a]D -16.9 (c 0.7, CHCl3), 94% ee. HPLC analysis (Daicel
Chiralcel AD-H, n-hexane–i-propanol 98: 2; flow speed
1.0 ml/min. tR (major), 22.8 min; tR (minor), 30.8 min.
In the above reaction, N-(3-benzyloxy-4,5-epoxy-2,2-
difluorooctanoyl)pyrrolidine (1 mmol) and n-BuLi (2.0 eq.)
in THF were used, and then worked up similarly, giving (E)-
6-benzyloxy-4,5-epoxy-7,7-difluorododecan-8-one in 81%
yield. 1H NMR (CDCl3): d 0.88 (3 H, t, J = 7.14 Hz), 0.97 (3
H, t, J = 7.14 Hz), 1.30 (2 H, sex, J = 7.14 Hz), 1.43–1.68 (6
H, m), 2.67 (2 H, tt, J=1.65, 7.14 Hz), 2.89 (1 H, m), 3.03 (1
H, dd, J = 2.20, 7.41 Hz), 3.52 (1 H, ddd, J = 6.32, 7.41,
16.76 Hz), 4.57 (1 H, d, J = 12.40 Hz), 4.84 (1 H, d,
J = 12.40 Hz), 7.25–7.38 (5 H, m). 13C NMR(CDCl3): d
13.81, 13.90, 22.02, 24.44, 33.51, 37.91, 54.66 (d,
J = 1.43 Hz), 55.97 (dd, J = 2.00, 4.58 Hz), 72.97, 79.80
(dd, J = 23.62, 29.63 Hz), 115.00 (dd, J = 254.80,
260.87 Hz), 127.92, 127.26, 128.23, 136.58, 201.20 (dd,
J = 25.48, 30.64 Hz). 19F NMR (CDCl3): d 39.59 (1 F, dd,
J = 16.37, 267.11 Hz), 52.46 (1 F, dd, J = 6.03, 267.11 Hz).
IR (neat): 1743 cmÀ1. Anal. Calcd. for: C, 67.04; H, 7.70.
Found: C, 66.72; H, 7.58.
3.23. (E)-5,5-Difluoro-4-hydroxy-2-decen-6-one (4e)
1H NMR (CDCl3): d 0.99 (3 H, t, J = 7.28 Hz), 1.34 (2 H,
sex, J = 7.28 Hz), 1.56–1.65 (2 H, m), 1.77 (3 H, ddd,
J = 0.82, 1.65, 6.59 Hz), 2.22 (1 H, br), 2.70 (2 H, tt,
J = 0.82, 7.28 Hz), 4.43–4.55 (1 H, m), 5.55 (1 H, qdd,
J = 1.65, 7.14, 15.38 Hz), 5.92 (1 H, dqd, J = 1.10, 6.59,
15.38 Hz). 13C NMR(CDCl3): d 13.54, 17.67, 21.87, 24.33,
37.64, 71.99 (dd, J = 25.10, 28.48 Hz), 115.06 (dd,
J = 254.99, 259.24 Hz), 123.58 (dd, J = 2.00, 3.44 Hz),
132.61, 202.17 (dd, J = 27.49, 30.64 Hz). 19F NMR
(CDCl3): d 38.47 (dd, J = 15.51, 271.43 Hz), 47.52 (dd,
J = 7.76, 271.4 Hz). Anal. Calcd. for C10H16F2O2: C, 58.24;
H, 7.82. Found: C, 57.84; H, 8.27.
3.26. General procedure for epoxide
To a solution of mCPBA (2.0 equiv., >65% assay) in
CH2Cl2 (0.1 M), allyl alcohol (1 equiv.) was added at
À10 8C under an argon atmosphere. After 72 h of stirring
at À10 8C, the reaction was quenched with 10% aq.
NaHSO3. The separated aqueous phase was extracted
twice with CH2Cl2 and the combined organic layers
were washed with saturated aq. NaHCO3, twice and
brine, dried over MgSO4, and concentrated. The resi-
dual was purified by column chromatography (hexane/
AcOEt).
3.24. (E)-2,2-Difluoro-3-hydroxy-1-phenyl-4-hexen-
1-one (4f)
Rf= (n-hexane:AcOEt=2:1). 1H NMR (CDCl3): d 1.78 (3
H, dd, J = 1.92, 6.59 Hz), 2.55 (1 H, br), 4.64–4.76 (1 H, m),
5.65 (1 H, qdd, J = 1.65, 7.14, 15.38 Hz), 5.97 (1 H, dqd,
J = 1.10, 6.59, 15.38 Hz), 7.48–7.54 (2 H, m), 7.62–7.68 (1
H, m), 8.08 (1 H, q, J = 1.10 Hz), 8.11 (1 H, q, J = 1.10 Hz).
13C NMR(CDCl3): d 17.89, 72.57 (dd, J = 24.48, 27.92 Hz),
116.13 (dd, J = 256.51, 260.81 Hz), 124.04 (dd, J = 2.15,
3.58 Hz), 128.41, 129.93 (t, J = 4.38 Hz), 132.35 (t,
J = 2.29 Hz), 132.84, 134.22, 190.32 (dd, J = 28.92,
30.63 Hz). 19F NMR (CDCl3): d 46.36 (dd, J = 15.89,
290.81 Hz), 54.81 (dd, J = 7.76, 290.81 Hz); Anal. Calcd.
for C12H12F2O2: C, 63.71; H, 5.35. Found: C, 63.50; H, 5.39.
3.27. (E)-5,5-Difluoro-4-hydroxy-2,3-epoxydecan-6-one
85% yield; IR (neat): 1743 cmÀ1. Anal. Calcd. for
C10H16F2O3: C, 54.05; H, 7.26. Found: C, 53.69; H, 7.48.
Major isomer; 1H NMR (CDCl3): d 0.93 (3 H, t,
J = 7.28 Hz), 1.32–1.40 (2 H, m), 1.38 (3 H, d,
J = 4.94 Hz), 1.57–1.68 (2 H, m), 2.73 (2 H, dt, J = 1.46,
7.28 Hz), 3.05 (1 H, dq, J = 2.68, 5.22 Hz), 3.08 (1 H, t,
3.25. (E)-6-Benzyloxy-4,5-epoxy-7,7-difluorododecan-
8-one
J = 2.61 Hz), 4.11 (1 H, ddd, J = 2.75, 5.77, 18.13 Hz). 13
C
N-(3-Benzyloxy-4,5-epoxy-2,2-difluorooctanoyl)pyrro-
lidine. 92% yield. 1H NMR (CDCl3): d 0.97 (3 H, t,
J = 7.14 Hz), 1.42–1.66 (4 H, m), 1.72–1.88 (4 H, m), 2.93
(1 H, dt, J = 2.72, 5.22 Hz), 3.09 (1 H, dd, J = 2.20,
7.42 Hz), 3.50–3.55 (2 H, m), 3.55–3.78 (2 H, m), 3.70 (1 H,
ddd, J = 7.01, 7.01, 16.76), 4.63 (1 H, d, J = 11.26 Hz), 4.87
(1 H, d, J = 11.54 Hz), 7.26–7.37 (5 H, m). 13C
NMR(CDCl3): d 13.86, 19.04, 23.21, 26.37 (dd, J = 1.43,
3.15 Hz), 33.49, 46.81 (dd, J = 4.58, 9.45 Hz), 47.77, 54.93
(dd, J = 0.86, 2.29 Hz), 56.19 (dd, J = 2.15, 4.73 Hz), 73.44,
80.44 (dd, J = 23.48, 29.49 Hz), 115.85 (dd, J = 253.37,
261.38 Hz), 127.72, 127.81, 128.10, 137.06, 161.22
(t, J = 27.77 Hz). 19F NMR (CDCl3): d 46.04 (1 F, dd,
J = 16.81, 268.41 Hz), 55.40 (1 F, dd, J = 6.47, 268.41 Hz).
NMR(CDCl3): d 13.72, 16.76, 21.98, 24.40, 37.61, 51.45,
56.12 (t, J = 3.72 Hz), 69.71 (dd, J = 24.48, 28.77 Hz),
114.98 (dd, J=255.66, 260.52 Hz), 201.30 (dd, J = 25.76,
30.92 Hz). 19F NMR (CDCl3): d 36.77 (dd, 1 F, J = 18.10,
274.88 Hz), 49.17 (dd, 1 F, J = 5.60, 274.88 Hz). Miner
isomer; 1H NMR (CDCl3): d 0.93 (3 H, t, J = 7.28 Hz), 1.32–
1.40 (2 H, m), 1.37 (3 H, d, J = 5.50 Hz), 1.57–1.68 (2 H, m),
2.74 (2 H, dt, J = 1.65, 7.14 Hz), 3.00 (1 H, dd, J = 2.75,
6.04 Hz), 3.12 (1 H, dq, J = 2.20, 5.22 Hz), 4.27 (1 H, ddd,
J = 3.44, 8.24, 14.13 Hz). 13C NMR(CDCl3): d 13.72, 16.76,
21.98, 24.40, 37.65, 51.55, 56.17 (t, J = 3.29 Hz), 68.90 (dd,
J = 25.06, 27.63 Hz), 115.25 (dd, J = 255.51, 258.95 Hz),
201.20 (t, J = 28.06 Hz). 19F NMR (CDCl3): d 40.26
(1 F, dd, J = 14.22, 273.15 Hz), 46.68 (1 F, dd, J = 7.76,
273.15 Hz).
IR (neat): 1659 cmÀ1
.

T. Kaneda et al. / Journal of Fluorine Chemistry 126 (2005) 17–26
25
3.28. N-((E)-2,2-Difluoro-3-hydroxy-4,5-
epoxyhexanoyl)pyrrolidine (5a)
46.60 (dd, J = 4.29, 9.02 Hz), 47.47, 60.18 (d,
J = 2.86 Hz), 62.49, 74.28 (dd, J = 23.05, 27.06 Hz),
115.80 (dd, J = 256.38, 264.39 Hz), 162.09 (t,
1H NMR (CDCl3): d 1.37 (3 H, d, J = 4.97 Hz), 1.84–1.93
(2 H, m), 1.95–2.04 (2 H, m), 3.05–3.11 (2 H, m), 3.40 (1 H,
br), 3.55 (2 H, t, J = 7.01 Hz), 3.75 (2 H, t, J = 6.73 Hz), 4.13
(1 H, ddd, J = 3.85, 8.24, 15.38 Hz). 13C NMR(CDCl3): d
16.93, 23.18, 26.34 (dd, J = 1.43, 2.29 Hz), 46.91 (dd,
J = 5.15, 7.44 Hz), 47.39, 51.22, 56.26 (t, J = 3.87 Hz),
70.94 (dd, J = 24.05, 27.49 Hz), 115.34 (dd, J = 257.08,
262.24 Hz), 161.34 (t, J = 28.49 Hz). 19F NMR (CDCl3): d
44.78 (dd, J = 15.51, 286.93 Hz), 51.07 (dd, J = 8.19,
286.93 Hz). Anal. Calcd. for C10H15F2NO3: C, 51.06; H,
6.43; N, 5.95. Found: C, 51.26; H, 6.04; N, 5.67.
J = 28.77 Hz). 19F NMR (CDCl3):
d
44.39 (dd,
J = 19.82, 282.63 Hz), 54.91 (dd, J = 5.60, 282.63 Hz).
IR: 1652 cmÀ1. Anal. Calcd. for C14H23F2NO3: C, 57.72;
H, 7.96; N, 4.81. Found: C, 57.96; H, 8.21; N, 5.12. Minor
1
isomer: H NMR (CDCl3): d 0.99 (3 H, t, J = 7.42 Hz),
1.07 (3 H, t, J = 7.41 Hz), 1.42–2.20 (10 H, m), 2.96 (1 H,
br), 3.17 (1 H, dt, J = 1.37, 6.05 Hz), 3.51–3.59 (2 H, m),
3.67–3.78 (2 H, m), 4.43 (1 H, dd, J = 4.40, 19.23 Hz). 13
C
NMR(CDCl3): d 8.62, 13.88, 19.56, 21.61 (dd, J = 1.72,
2.29 Hz), 23.17, 26.39 (t, J = 2.86 Hz), 29.67, 46.60 (dd,
J = 4.01, 9.02 Hz), 47.60, 60.02 (d, J = 3.15 Hz), 61.37 (d,
J = 1.72 Hz), 69.05 (dd, J = 24.34, 29.49 Hz), 116.39 (dd,
J = 252.51, 263.39 Hz), 161.60 (t, J = 28.34 Hz). 19F NMR
(CDCl3): d 44.28 (dd, J = 18.96, 270.57 Hz), 54.15 (d,
J = 269.70 Hz).
3.29. N-((Z)-2,2-Difluoro-3-hydroxy-4,5-
epoxyhexanoyl)pyrrolidine (5b)
Major isomer:1H NMR (CDCl3): d 1.38 (3 H, d,
J = 5.61 Hz), 1.87–1,92 (2 H, m), 1.97–2.02 (2 H, m),
3.22 (1 H, dq, J = 4.28, 5.61 Hz), 3.28 (1 H, dd, J = 4.37,
6.83 Hz), 3.53 (1 H, br), 3.56 (2 H, t, J = 7.12 Hz), 3.76 (1 H,
t, J = 7.72 Hz), 4.09 (1 H, m). 13C NMR(CDCl3): d 13.92
(dd, J = 0.57, 2.00 Hz), 23.20, 26.33 (dd, J = 1.14, 2.29 Hz),
46.48 (dd, J = 4.87, 7.44 Hz), 47.38, 53.01, 54.74 (dd,
J=3.15, 4.87 Hz), 69.80 (dd, J = 4.05, 29.20 Hz), 115.31
(dd, J = 256.80, 262.81 Hz), 161.30 (t, J = 28.63 Hz). 19F
NMR (CDCl3): d 43.25 (dd, J = 15.26, 289.92 Hz), 51.44
(dd, J = 3.05, 289.92 Hz).
3.32. (E)-5,5-Difluoro-4-hydroxy-2,3-epoxydecan-6-one
(5e)
Major isomer; 1H NMR (CDCl3): d 0.93 (3 H, t,
J = 7.28 Hz), 1.32–1.40 (2 H, m), 1.38 (3 H, d,
J = 4.94 Hz), 1.57–1.68 (2 H, m), 2.73 (2 H, dt,
J = 1.46, 7.28 Hz), 3.05 (1 H, dq, J = 2.68, 5.22 Hz),
3.08 (1 H, t, J = 2.61 Hz), 4.11 (1 H, ddd, J = 2.75, 5.77,
18.13 Hz). 13C NMDCl3): d 13.72, 16.76, 21.98, 24.40,
37.61, 51.45, 56.12 (t, J = 3.72 Hz), 69.71 (dd, J = 24.48,
28.77 Hz), 114.98 (dd, J = 255.66, 260.52 Hz), 201.30 (dd,
J = 25.76, 30.92 Hz). 19F NMR (CDCl3): d 36.77 (dd,
J = 18.10, 274.88 Hz), 49.17 (dd, J = 5.60, 274.88 Hz).
Anal. Calcd. for C10H16F2O3: C, 54.05; H, 7.26. Found: C,
53.69; H, 7.48.
Miner isomer; 1H NMR (CDCl3): d 0.93 (3 H, t,
J = 7.28 Hz), 1.32–1.40 (2 H, m), 1.37 (3 H, d, J = 5.50 Hz),
1.57–1.68 (2 H, m), 2.74 (2 H, dt, J = 1.65, 7.14 Hz), 3.00 (1
H, dd, J = 2.75, 6.04 Hz), 3.12 (1 H, dq, J = 2.20, 5.22 Hz),
4.27 (1 H, ddd, J = 3.44, 8.24, 14.13 Hz). 13C NMR
(CDCl3): d 13.72, 16.76, 21.98, 24.40, 37.65, 51.55, 56.17 (t,
J = 3.29 Hz), 68.90 (dd, J = 25.06, 27.63 Hz), 115.25 (dd,
J = 255.51, 258.95 Hz), 201.20 (t, J = 28.06 Hz). 19F NMR
(CDCl3): d 40.26 (dd, J = 14.22, 273.15 Hz), 46.68 (dd,
J = 7.76, 273.15 Hz).
3.30. N-((E)-2,2-Difluoro-3-hydroxy-4,5-
epoxyoctanoyl)pyrrolidine (5c)
1H NMR (CDCl3): d 0.97 (3 H, t, J = 7.26 Hz), 1.43–1.53
(2 H, m), 1.55–1.60 (2 H, m), 1.86–1.91 (2 H, m), 1.96–2.02
(2 H, m), 3.01 (1 H, dt, J = 2.28, 5.61 Hz), 3.11 (1 H, dd,
J = 2.38, 3.85 Hz), 3.51–3.60 (2 H, m), 3.75 (2 H, t,
J = 6.60 Hz), 4.13 (1 H, ddd, J = 3.90, 7.82, 15.87 Hz). 13
C
NMR (CDCl3): d 13.75, 19.00, 23.12, 26.28 (dd, J = 1.43,
2.29 Hz), 33.29, 46.47 (dd, J = 5.16, 7.73 Hz), 47.33, 55.04,
55.35 (t, J = 3.87 Hz), 71.14 (dd, J = 24.05, 27.49 Hz),
115.37 (dd, J = 257.59, 262.23 Hz), 161.30 (t,
J = 28.49 Hz). 19F NMR (CDCl3): d 44.71 (dd, J = 15.52,
286.94 Hz), 51.32 (dd, J = 7.76, 286.94 Hz). Anal. Calcd.
for C12H19F2NO3: C, 54.74; H, 7.27; N, 5.32. Found: C,
54.62; H, 7.04; N, 4.99.
3.33. (E)-2,2-Difluoro-3-hydroxy-1-phenyl-4,5-
epoxyhexan-1-one (5f)
3.31. N-((E)-2,2-Difluoro-3-hydroxy-4-ethyl-4,5-
epoxyoctanoyl)pyrrolidine (5d)
82% yield. IR (neat): 1699 cmÀ1. major isomer; 1H NMR
(CDCl3): d 1.38 (3 H, d, J = 5.22 Hz), 2.78 (1 H, d,
J = 7.96 Hz), 3.06–3.21 (2 H, m), 4.25–4.37 (1 H, m), 7.48–
Major isomer:1H NMR (CDCl3): d 0.99 (3 H, t,
J = 7.42 Hz), 1.06 (3 H, t, J = 7.70 Hz), 1.42–2.20 (10 H,
m), 3.06–3.10 (1 H, m), 3.53 (2 H, t, J = 6.59 Hz), 3.67–
3.78 (2 H, m), 3.82 (1 H, d, J = 5.50 Hz), 4.10–4.22 (1 H,
m). 13C NMR(CDCl3): d 9.58, 13.93, 19.75, 21.71 (dd,
J = 1.43, 4.01 Hz), 23.11, 26.37 (t, J = 2.87 Hz), 29.63,
7.54 (2 H, m), 7.62–7.69 (1 H, m), 8.09–8.14 (2 H, m); 13
C
NMR(CDCl3): d 16.65, 16.67, 51.37, 51.55, 56.20, 56.25,
69.37 (t, J = 25.48 Hz), 70.26 (dd, J = 24.05, 27.20 Hz),
116.41 (dd, J = 257.37, 261.67 Hz), 116.62 (t,
J = 258.66 Hz), 128.36, 128.43, 129.80, 129.85, 129.89,

26
T. Kaneda et al. / Journal of Fluorine Chemistry 126 (2005) 17–26
[2] P.V. Ramachandran (Ed.), Asymmetric Fluoroorganic Chemistry, ACS
Symposium Series 746, ACS, Washington, DC, 1999.
[3] T. Kitazume, T. Yamazaki, Topics in Current Chemisty, vol. 193, pp.
91–130.
129.94, 134.20, 134.28, 189.37 (dd, J = 28.06, 29.48 Hz),
189.50 (t, J = 28.49 Hz). 19F NMR (CDCl3): d 47.23 (dd,
J = 16.37, 292.11 Hz), 54.44 (dd, J = 7.75, 292.11 Hz);
Anal. Calcd. for C12H12F2O3: C, 59.50; H, 4.99. Found: C,
59.26; H, 5.15.
Miner isomer; 1H NMR (CDCl3): d 1.37 (3 H, d,
J = 5.22 Hz), 2.71 (1 H, br), 3.06–3.21 (2 H, m), 4.40–4.51
(1 H, m), 7.48–7.54 (2 H, m), 7.62–7.69 (1 H, m), 8.09–8.14
(2 H, m). 19F NMR (CDCl3): d 47.85 (dd, J = 15.89,
291.24 Hz), 53.48 (dd, J = 7.75, 291.24 Hz).
[4] K. Iseki, Tetrahedron 54 (1998) 13887–13914.
[5] Y.A.I. Abdel-Aal, B.D. Hammock, Science 223 (1986) 1073–1076.
[6] K. Fearon, A. Spaltenstein, P.B. Hopkins, M.H. Gelb, J. Med. Chem.
30 (1987) 1617–1622.
[7] B. Imperiali, R.H. Abeles, Biochemistry 26 (1987) 4474–4477.
[8] T. Hiyama, Organofluorine Compounds: Chemistry and Applications,
Springer, Berlin, 2000.
[9] M. Braun, A. Vonderhagen, D. Waldmu¨ler, Liebigs Ann. Chem. (1995)
1447–1450.
J.M. Andres, M.A. Martinez, R. Pedrosa, A. Perez-Encabo, Synthesis
(1996) 1070–1072.
3.34. (E)-Ethyl 5,5-difluoro-4-hydroxy-2,3-epoxyhexanate
(5g)
[10] K. Iseki, Y. Kuroki, D. Asada, Y. Kobayashi, Tetrahedron Lett. 38
(1997) 1447–1448.
K. Iseki, Y. Kuroki, D. Asada, M. Takahashi, S. Kishimoto, Y.
Kobayashi, Tetrahedron 53 (1997) 10271–10280.
K. Iseki, Y. Kuroki, Y. Kobayashi, Tetrahedron Lett. 38 (1997) 7209–
7210.
79% yield, major isomer: 1H NMR (CDCl3): d 1.37 (3 H,
t, J = 7.14 Hz), 1.38 (3 H, d, J = 5.22 Hz), 2.65 (1 H, br),
3.06 (1 H, dq, J = 2.20, 5.22 Hz), 3.10 (1 H, t, J = 2.20 Hz),
4.08–4.21 (1 H, m), 4.38 (2 H, q, J = 7.14 Hz). 13C NMR
(CDCl3): d 13.74, 16.62, 51.21, 55.96 (t, J = 3.87 Hz), 63.21,
70.01 (t, J = 26.63 Hz), 113.73 (dd, J = 253.93, 257.97 Hz),
162.29 (dd, J = 30.35, 32.06 Hz). 19F NMR (CDCl3): d
39.05 (ddd, J = 6.03, 16.94, 267.12 Hz), 48.67 (dd, J = 6.03,
267.12 Hz). IR: 1762 cmÀ1. Anal. Calcd. for C8H12F2O4: C,
45.72; H, 5.75. Found: C, 45.54; H, 6.15.
minor isomer: 1H NMR (CDCl3): d 1.371 (3 H, d,
J = 5.22 Hz), 1.374 (3 H, t, J = 7.14 Hz), 2.56 (1 H, br), 3.02
(1 H, dd, J = 2.48, 3.57 Hz), 3.18 (1 H, dq, J = 2.20,
5.22 Hz), 4.27 (1 H, ddd, J = 3.58, 8.52, 13.46 Hz), 4.38 (2
H, q, J = 7.14 Hz). 13C NMR (CDCl3): d 13.74, 16.65, 51.59,
55.80 (t, J = 3.44 Hz), 63.16, 69.61 (t, J = 25.91 Hz), 113.90
(t, J = 254.94 Hz), 162.29 (dd, J = 30.35, 32.06 Hz). 19F
NMR (CDCl3): d 41.75 (dd, J = 13.79, 266.26 Hz), 46.71
(dd, J = 8.62, 266.26 Hz).
[11] H. Fukuda, M. Tetsu, T. Kitazume, Tetrahedron 52 (1996) 157–164,
and references cited therein.
[12] T. Sakamoto, K. Takahashi, T. Yamazaki, T. Kitazume, J. Org. Chem.
65 (2000) 9467–9474, and references cited therein.
T. Yamazaki, M. Ando, T. Kitazume, T. Kubota, M. Omura, Org. Lett.
1 (1999) 905–906.
Y. Komatsu, T. Sakamoto, T. Kitazume, J. Org. Chem. 64 (1999)
8369–8374.
[13] I. Ohtani, T. Kusumi, Y. Kashman, H. Kakisawa, J. Am. Chem. Soc.
113 (1991) 4092–4096.
[14] K. Iseki, Y. Kuroki, D. Asada, Y. Kobayashi, Tetrahedron Lett. 40
(1999) 85–89.
K. Iseki, D. Asada, Y. Kuroki, J. Fluorine Chem. 38 (1997) 1447–1448.
[15] M. Bougauchi, S. Watanabe, T. Arai, H. Sasai, M. Shibasaki, J. Am.
Chem. Soc. 119 (1997) 2329–2330.
S. Watanabe, Y. Kobayashi, T. Arai, H. Sasai, M. Bougauchi, M.
Shibasaki, Tetrahedron Lett. 39 (1998) 7353–7356.
E.N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive
Asymmetric Catalysis, vol. 2, Springer, Berlin, 1999, p. 649.
[16] K.D. Daikai, M. kamaura, J. Inanaga, Tetrahedron Lett. 39 (1998)
7321–7322.
[17] R. Chen, C. Qian, J.G. de Vries, Tetrahedron Lett. 42 (2001) 6919–
6921.
References
[18] O. Takahashi, K. Furuhashi, M. Fukumasa, T. Hirai, Tetrahedron Lett.
31 (1990) 7031–7034, and references cited therein.
[19] P.V. Ramachandran, B. Gong, H.C. Brown, J. Org. Chem. 60 (1995)
41–46.
[1] I. Ojima, J.R. McCarthyl, J.T. Welch (Eds.), Biomedical Frontiers of
Fluorine Chemistry, ACS Symposium Series 639, ACS, Washington,
DC, 1996.