An efficient synthetic method for Z-fluoroalkene dipeptide isosteres: Application to the synthesis of the dipeptide isostere of Sta-Ala

Article abstract of DOI:10.1016/j.jfluchem.2005.11.016

Reaction of γ,γ-difluoro-α,β-enoates having a δ-hydroxyl group with trialkylaluminum (R₃Al) was found to be promoted by CuI·2LiCl and to proceed in SN2′ manner giving rise to the α-alkylated (Z)-γ-fluoro-β,γ-enoates, while reductive defluorination of γ,γ-difluoro-α,β-enoates with Me₂CuLi followed by reaction with alkyl halides provided the corresponding (Z)-α-alkylated products in high yields. The latter reaction was applied to the preparation of the dipeptide (Z)-fluoroalkene isostere of Sta-Ala, which is the central dipeptide unit in Pepstatin, a natural inhibitor of aspartate proteases.

Full text of DOI:10.1016/j.jfluchem.2005.11.016

Journal of Fluorine Chemistry 127 (2006) 627–636
www.elsevier.com/locate/fluor
An efficient synthetic method for Z-fluoroalkene dipeptide isosteres:
Application to the synthesis of the dipeptide isostere of Sta-Ala
Yuko Nakamura a, Midori Okada a, Minoru Koura b, Manabu Tojo b, Akio Saito b,
Azusa Sato a, Takeo Taguchi b,
*
a Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
b Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
Received 12 November 2005; accepted 16 November 2005
Available online 24 January 2006
Abstract
Reaction of g,g-difluoro-a,b-enoates having a d-hydroxyl group with trialkylaluminum (R3Al) was found to be promoted by CuIꢀ2LiCl and to
proceed in SN20 manner giving rise to the a-alkylated (Z)-g-fluoro-b,g-enoates, while reductive defluorination of g,g-difluoro-a,b-enoates with
Me2CuLi followed by reaction with alkyl halides provided the corresponding (Z)-a-alkylated products in high yields. The latter reaction was
applied to the preparation of the dipeptide (Z)-fluoroalkene isostere of Sta-Ala, which is the central dipeptide unit in Pepstatin, a natural inhibitor of
aspartate proteases.
# 2005 Elsevier B.V. All rights reserved.
Keywords: Fluoroalkene; Difuoroalkenoate; Organocopper; Dipeptide isostere; Pepstatin
1. Introduction
So far, extensive efforts to develop highly stereoselective
methods for the preparation of functionalized fluorinated
olefins have been reported [8–17]. We have been also working
in this field for a recent couple of years. A highly Z and 2,5-syn
selective allylic alkylation reaction of 5-hydroxy-4,4-difluor-
oallylic alcohol derivatives with a combination of trialkylalu-
minum and copper salt is one of our notable achievements
[18,19]. We have also communicated that using g,g-difluoro-
a,b-enoate derivatives 1 as the substrates, a-alkylated (Z)-g-
fluoro-b,g-enoate derivatives 2 can be prepared through
lithiocuprate (Me2CuLi) mediated reductive defluorination
followed by regioselective a-alkylation of the enolate inter-
mediate 5 with alkyl halide (Scheme 1) [20]. When g,g-
difluoro-a,b-enoate having a hydroxyl group at d-position (1,
Y = OH) was treated with trialkylaluminum in the presence of
Cu(I) salt, a direct alkyl-transfer reaction from trialkylalumi-
num proceeded to give the a-alkylated SN20 product (2,
Y = OH) (Scheme 1). Although the diastereoselectivity
(relative stereochemistry at C2 and C5) in these reactions
was low, due to the high product yield and a wide applicability
to a variety of substrates, we employed this lithiocuprate
mediated reaction for the synthesis of the dipeptide (Z)-
fluoroalkene isostere of Sta-Ala, which is the central dipeptide
unit of Pepstatin, a peptidic inhibitor of aspartate proteases such
It has been widely recognized that fluoroolefin (–CF CH–)
is an ideal mimic for an amide bond (–CO–NH–) due to their
similarities with respect to both steric and electronic properties.
Contrary to such similarities, fluoroolefin would be a
nonhydrolyzable bond both chemically and enzymatically,
and the lack of rotational freedom of this bond is also a different
property from that of an amide bond [1–4]. Due to these unique
properties, utilization of fluoroalkene dipeptide or depsipeptide
isosteres as nonhydrolyzable and/or conformationally
restricted replacements for the parent amide bonds has attracted
much attention in the field of medicinal chemistry [5–7]. To
develop synthetic methods for such fluoroalkene dipeptide
isosteres, a control of the olefin configuration (either Z or E) and
the relative stereochemistry of the two chiral centers at C2 and
C5 (either syn or anti) are major problems to be solved.
Furthermore, these molecules should be obtained in optically
pure forms (Fig. 1).
* Corresponding author. Tel.: +81 426 76 3257; fax: +81 426 76 3257.
E-mail address: taguchi@ps.toyaku.ac.jp (T. Taguchi).
0022-1139/$ – see front matter # 2005 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.11.016

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Y. Nakamura et al. / Journal of Fluorine Chemistry 127 (2006) 627–636
as pepsin, catepsin D or HIV proteases (Fig. 2) [21,22]. In this
paper, we report a detail of potential usefulness of g,g-difluoro-
a,b-enoate derivatives for the preparation of (Z)-fluoroalkene
dipeptide isosteres including a successful synthesis of the
dipeptide isostere Sta-c[(Z)-CF CH]-Ala.
2. Results and discussion
Fig. 1.
2.1. Copper mediated alkyl-transfer reaction of
trialkylaluminum
As the substrates, we chose g,g-difluoro-a,b-enoate deriva-
tives having a hydroxyl group (Y = OH, 1a, 1b) or an amino
group (Y = NHAnis, 1c) at the d-position as well as the
corresponding hydrogen derivative (Y = H, 1d) to examine the
reactivity of each substrate in organocopper mediated reactions
[17,23–25].
Firstly, results obtained by the reactions of difluoroenoate
2
derivatives 1a–d with trialkylaluminum (R3 Al) in the presence
of CuIꢀ2LiCl [26] are shown in Table 1. This reagent system
provided an excellent stereochemical outcome (Z and 2,5-syn
selective) with 4,4-difluoroallylic alcohol derivatives having a
Scheme 1.
Fig. 2.
Table 1
Copper mediated reaction of 1 with trialkylaluminum
Entry
1
R1
Y
R32Al
2
R2
Yield (%)a
Ratiob
3 Yield (%)a
4 Yield (%)a
1
1a
1a
1b
1b
1c
1d
Ph
OH
Me3Al
i-Bu3Al
Me3Al
i-Bu3Al
Me3Al
Me3Al
2a–1
2a–2
2b–1
2b–2
2c
Me
79
25
90
58
0
8:1
5.3:1
1:1
1.5:1
–
3a
3a
3b
3b
3c
3d
0
5
4a
4a
4b
4b
4a
–
0
2
Ph
OH
i-Bu
Me
18
Trace
10
0
3
PhCH2
PhCH2
Ph
OH
0
4
OH
i-Bu
Me
0
5
6c
NHAnis
H
41
15
Ph
2d
Me
0
–
a
Isolated yield.
Diastereomer ratio was determined by 1H and 19F NMR. Stereochemistries were not determined.
b
c
Recovery of 1d was 23%.

Y. Nakamura et al. / Journal of Fluorine Chemistry 127 (2006) 627–636
629
hydroxyl group at C5 position [18,19]. Similarly, when g,g-
difluoro-a,b-enoate has a hydroxyl group at the d position such
as 1a or 1b, a direct alkyl transfer from the aluminum reagent
occurred at the a position giving rise to the desired a-alkyl-g-
fluoro-b,g-enoate derivative 2. Trimethylaluminum gave the a-
methylated product 2a–1 (79%) or 2b–1 (90%) in good yields
(entries 1 and 3). On the other hand, longer alkyl derivative (tri-
isobutylaluminum) gave the a-alkylated product 2a–2 (25%) or
2b–2 (58%) in moderate yields accompanying the formation of
reductive defluorination product 3 and/or dienoate derivative 4
to some extent (entries 2 and 4). In all cases, reaction proceeded
in completely Z selective manner. Regarding the diastereos-
electivity, moderate selectivity (dr = 8–5.3:1) was observed
with phenyl derivative 1a (entries 1 and 2), but almost
nonselective in the case of benzyl derivative 1b (entries 3 and
4). Since a complete recovery of the starting material was the
result, when 1a or 1b was treated with trialkylaluminum in
THF, Cu(I) is a crucial additive for the present alkyl-transfer
reaction [27,28].
Contrary to the above results, with theaminoderivative1cand
with the hydrogen derivative 1d a-alkylation did not occur under
similar conditions (Me3Al, CuIꢀ2LiCl in THF) (entries 5 and 6).
In both cases, reductive defluorination product 3 was detected in
low yield. Thus, a hydroxyl group at the d-position in the
substrate 1 seemed to be an essential functionality in the Cu(I)-
promoted alkyl-transfer reaction with trialkylaluminum R3Al.
Although mechanistic detail is not clear at this moment, it is
likely that formation of a five-membered complex A involving
fluorine–aluminum coordination is possibly the first step [29].
By forming complex A, one of the two fluorine atoms should be
activated as a leaving group and presumably the C–C double
bond becomes more electrophilic, thereby complex A showed
such reactivity toward copper reagent derived from R3Al and
CuIꢀ2LiCl [19].
Table 2
Me2CuLi mediated reduction and a-alkylation of 1
Entry
1
R1
Y
R2-X
Product
R2
Yield (%)a
Ratiob,c
1
1a
1a
1a
1b
1b
1c
1d
Ph
OH
–
3a
3a
2a–1
2b–1
2b–3
2c
70
64
93
75
78
92
95
–
2d
Ph
OH
–
–
3
Ph
OH
Mel
Mel
BnBr
Mel
Mel
Me
Me
Bn
1:1
6:1
5:1
1.4:1
–
4
PhCH2
PhCH2
Ph
OH
5
OH
6
NHAnis
H
Me
Me
7
Ph
2d
a
Isolated yield.
b
c
d
Diastereomer ratio was determined by 1H and 19F NMR.
Stereochemistries were not determined.
Me3Al (2 equiv) was added.
Scheme 2.

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Y. Nakamura et al. / Journal of Fluorine Chemistry 127 (2006) 627–636
2.2. Lithiocuprate mediated reaction
Next, results obtained by the reactions of 1a–d with
lithiocuprate are shown in Table 2. Reaction of 1a–d with
Me2CuLi (5 equiv) in THF followed by aqueous work-up gave
the corresponding reductive defluorination product 3 in high
yields without the formation of the desired a-methylated
product 2. For example, d-hydroxylated a,b-enoate 1a gave
(Z)-g-fluoro-b,g-enoate 3a in 70% yield (entry 1). Addition of
trimethylaluminum did not show any effect on the reaction
course obtaining 3a in 64% yield (entry 2). It would be likely
that the formation of the reductive defluorination product 3
involves the generation of the enolate intermediate 5 through
sequential two electron transfer from lithiocuprate and
elimination of fluoride anion [16,20,30]. Therefore, it was
expected that the desired a-alkylated g-fluoro-b,g-enoate 2 can
be obtained by treating the enolate intermediate 5 with an
appropriate alkylating reagent. In fact, treatment of 1a with
Me2CuLi (5 equiv) in THF at ꢁ20 8C for 15 min followed by
the reaction with methyl iodide (10 equiv) at 0 8C for 2 h gave
the a-methylated product 2a–1 in 93% yield (Table 2, entry 3).
As shown in Table 2, not only the d-hydroxylated derivatives 1a
or 1b, but also the amino derivative 1c and the substrate 1d
without an additional d-substituent provided the a-alkylated
(Z)-g-fluoro-b,g-enoate derivatives 2 in good yields without the
formation of a detectable amount of the reduction product 3
(entries 3–7). Moderate diastereoselective alkylation (dr = 5–
6:1) was observed only in the case of 1b (entries 4 and 5).
Although the above reactions provided the a-alkylated
products 2 in good yields, asymmetric control induced by C5-
chiral center (d-position) did not meet at a synthetically useful
level and the chromatographic separation of diastereomers thus
formed was quite difficult. Expecting a high level of chiral
induction at a position and an easy separation of diasteremers,
we next examined chiral auxiliary protocol using 8-phenyl-
menthyl ester 1e, camphorsultam derivative 1f and oxazolidi-
none derivative 1g [31–33].
Scheme 3.
mentioned above, at this moment we could not find out an
efficient chiral auxiliary or reaction conditions to obtain a-
alkylated product with satisfactory stereoselectivities and
chemical yield.
2.3. Preparation of the dipeptide (Z)-fluoroalkene isostere
of Sta-Ala
As an application of our method for the synthesis of
fluoroalkene dipeptide isosteres described above, we synthe-
sized N-Boc-Sta-c[CF CH]-Ala ethyl ester 16, which is
corresponding to a central Sta-Ala unit in Pepstatin, a natural
inhibitor of aspatate proteases including renin, pepsin, HIV-1
and HIV-2 proteases (see Fig. 2) [21,22]. From the inhibitory
activities in a cell-based AIDS anti-viral tests, Pepstatin is
considered to be moderately active. Therefore, a number of
Pepstatin analogs have been synthesized to find out a compound
having improved properties [22]. Among such analogs, a few
fluorinated compounds containing difluorostatin part [34] or a
trifluoromethyl group as a replacement of the statin isobutyl
side chain [35] have been reported. However, replacement of an
amide bond in the Pepstatin molecule with a fluoroalkene has
never been reported.
d-Hydroxy-g,g-difluro-a,b-enoate 11, one of the key
substrates for the lithiocuprate mediated reaction, was
synthesized in optically pure form using N-Boc leucinol 7 as
the starting material (Scheme 5). Thus, the Swern oxidation of
N-Boc leucinol 7 followed by the reaction of the crude aldehyde
with vinyl Grignard reagent gave a diastereomer mixture of the
allyl alcohol derivative 8 in 52% yield (syn/anti = 5.4:1), which
was purified by column chromatography [36]. The syn isomer
syn-8, having natural statin configuration, was converted to the
Reaction of E isomer of (1R,2S,5R)-8-phenylmenthyl ester
E–1e with Me2CuLi at 0 8C for 30 min and the subsequent
addition of methyl iodide at the same temperature gave the
methylated product 2e in 84% yield and in a highly Z selective
manner (Z/E = 18:1). Unfortunately, diastereomer ratio of the
major Z isomer was very low (dr = 1.5:1). Similar reaction
using Z isomer Z–1e gave much worse result. That is, we
obtained the desired methylated product 2e only in 33% yield as
a diastereomer mixture (dr = 1.8:1) along with the formation of
simply reduced product 3e in 31% yield (Scheme 2).
In the case of (1S)-2,10-camphorsultam derivative 1f,
relatively high diastereoselection was observed (dr = 19:1 for
the major Z isomer), although the low yield of the product 2f
(39% yield) due to the competitive formation of reduction
product 3f (31% yield) remained a problem (Scheme 3).
It is noted that oxazolidinone derivative such as 1g cannot be
used, because the formation of reduction product 3g and
deacylation determined by the isolation of ozazolidinone 6
were main reaction courses and only a trace amount of the
desired a-methylated product was detected (Scheme 4). As
Scheme 4.

Y. Nakamura et al. / Journal of Fluorine Chemistry 127 (2006) 627–636
631
Scheme 5. Reagents and conditions: (1) CICOCOCI, DMSO, Et3N; (2) CH2 CHMgBr (52%, 2 steps, syn/anti = 5.4:1); (3) silica gel column; (4) 2,2-
dimethoxypropane, PPTS (96%); (5) OsO4, NMO then NalO4 (96%); (6) Zn, BrCF2COOEt (92%, syn/anti = 3:1) then silica gel column; (7) DIBAL then
H2O; (8) NaH, (EtO)2P(O)CH2COOEt (72%).
Scheme 6.
protected aldehyde 9 in high yield through OsO4–NaIO4
cleavage of the vinyl group. The Reformatsky reaction of this
aldehyde 9 with bromodifluoroacetate gave a 3:1 diastereo-
meric mixture of the difluoro-b-hydroxy ester 10 in 92% yield,
which was separated by silica gel column chromatography.
DIBAL reduction of ester group of 10 (2,3-syn isomer) and the
subsequent olefination reaction with phosphonoacetate gave E
isomer of g,g-difluoro-a,b-enoate 11 in 76% yield (Scheme 5).
Since the enoate 11 has a d-hydroxyl group, we examined
CuIꢀ2LiCl mediated reaction using trimethylaluminum (see
Table 1). As expected, a-methylated g-fluoro-b,g-enoate 12
was isolated in 53% yield. The product 12 consisted of a
Scheme 7. Reagents and conditions: (1) thiocarbonyldiimidazole (93%); (2) Et3SiH, Bz2O2 (78%); (3) DIBAL then H2O; (4) NaH, (EtO)2P(O)CH2COOEt (60%);
(5) Me2CuLi then Mel (96%); (6) MPLC; (7) p-TsOH, MeOH.

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Y. Nakamura et al. / Journal of Fluorine Chemistry 127 (2006) 627–636
Z-isomer rich mixture (Z/E = 6:1), and the major Z isomer was
an almost 1:1 mixture of diastereomers. By employing so called
Barton–McCombie procedure (treatment of the alcohol 12 with
phenyl chlorothionoformate then Bu3SnH or thiocarbonyldii-
midazole then Et3SiH), radical deoxygenation of the d-
hydroxyl group was tried [37]. These reactions, however, gave
a complex mixture probably due to the lack of both regio- and
stereo-selectivity in a radical reaction of the allylic system
(Scheme 6).
4.2. General procedure for alkyl-transfer reaction of
difluoroenoate derivative with trialkylaliminum in the
presence of CuIꢀ2LiCl
Under an argon atmosphere, to a solution of 1a (0.5 mmol)
in THF at ꢁ78 8C was added tri-isobutylaluminium (5 mmol,
1 M hexane solution). After being stirred for 10 min, 0.5 M
THF solution of CuIꢀ2LiCl (1.25 mmol) [25] was added and the
reaction mixture was stirred for 4 h at 0 8C. Addition of 5%
HCl, filtration of precipitates through Celit pad and extractive
work-up of the filtrate (AcOEt for extraction) gave the crude
product, which was purified by silica gel column (hexane/
AcOEt = 10:1) to give 2a–2 in 25% yield as a diastereomer
mixture (ratio 5.3:1), 3a in 5% yield and 4a in 18% yield,
respectively (Table 1, entry 2).
To avoid this problematic allylic deoxygenation step, we
next used g,g-difluoro-a,b-enoate 15 lacking a d-hydroxyl
group in the lithiocuprate reaction. Thus, the g-hydroxyl group
in the Reformatsky product 10 (used as a diastereomer mixture)
was replaced with hydrogen via radical deoxygenation of
thioimidazolide derivative obtaining the difluoro ester 14 in
73% yield, which was converted to E isomer of g,g-difluoro-
a,b-enoate 15 by DIBAL reduction and the subsequent
condensation with phosphonoacetate. Since the substrate 15
does not posses a d-hydroxyl group, lithiocuprate mediated
reductive defluorination followed by methylation with methyl
iodide was conducted, and we obtained the desired a-
methylated product 13 in an excellent yield (96%). From the
NMR data of the product 13 and the structure determination of
the purified each isomer, the reaction proceeded in a moderate Z
selectivity (Z/E = 6.4:1), but without any diasteroselectivity
(dr = ca. 1:1 for the major Z isomer). Fortunately, separation of
the product mixture could be carried out by MPLC as shown in
Scheme 7, and finally deprotection of acetonide group gave the
Sta-Ala dipeptide isostere (2R)–16 and the corresponding Sta-
D-Ala isostere (2S)–16 along with the E isomer E-16 as their N-
Boc ethyl ester forms (Scheme 7).
4.2.1. Ethyl (Z)-4-fluoro-5-hydroxy-2-isobutyl-5-phenyl-3-
pentenoate (2a–2)
A diastereomer mixture (ratio 5.3:1). Colorless oil. IR
1
(CHCl3) n cmꢁ1; 3612, 1728. H NMR (400 MHz, CDCl3) d;
0.88 (3H, d, J = 6.5 Hz), 0.92 (0.48H, d, J = 6.5 Hz), 1.24
(0.48H, t, J = 7.1 Hz), 1.25 (2.52H, t, J = 7.1 Hz), 1.38–1.48
(1H, m), 1.52–1.67 (2H, m), 2.17 (0.16H, d, J = 4.9 Hz), 2.20
(0.84H, d, J = 5.1 Hz), 3.53–3.59 (1H, m), 4.13 (1.68H, q,
J = 7.1 Hz), 4.14 (0.32H, q, J = 7.1 Hz), 5.07 (0.16H, dd,
J = 35.8, 9.9 Hz), 5.09 (0.84H, dd, J = 35.8, 10.0 Hz), 5.22 (1H,
dd, J = 11.7, 4.8 Hz), 7.31–7.44 (5H, m). 13C NMR
(100.6 MHz, CDCl3) d; 14.1, 21.9, 22.7, 25.9, 39.0, 41.7,
60.7, 72.5 (d, J = 32.2 Hz), 105.6 (d, J = 11.8 Hz), 126.7, 128.5
(d, J = 15.9 Hz), 139.3, 159.6 (d, J = 259.5 Hz), 174.0. 19F
NMR (376.5 MHz, CDCl3) d; ꢁ56.7 (0.16F, dd, J = 36, 12 Hz),
ꢁ56.8 (0.84F, dd, J = 35, 12 Hz). EI-MS m/z; 294 (M+). Calcd.
for C17H23O3F: C, 69.36; H, 7.88. Found: C, 69.24; H, 7.71.
3. Conclusion
As shown here, lithiocuprate mediated reductive defluorina-
tion of g,g-difluoro-a,b-enoate derivative would provide a
promising method for the preparation of a variety of (Z)-
fluoroalkene modified dipeptide analogs. Currently, further
efforts to achieve higher stereoselectivity are being undertaken.
4.2.2. Ethyl (Z)-4-fluoro-5-hydroxy-5-phenyl-3-pentenoate
(3a)
Colorless oil. IR (neat) n cmꢁ1; 3612, 3250–3550,1728. 1H
NMR (400 MHz, CDCl3) d; 1.26 (3H, t, J = 7.1 Hz), 3.17 (2H,
d, J = 7.1 Hz), 4.14 (2H, q, J = 7.1 Hz), 5.21 (1H, dt, J = 35.9,
7.1 Hz), 5.23 (1H, d, J = 11.2 Hz), 7.28–7.47 (5H, m). 13C
NMR (100.6 MHz, CDCl3) d; 14.1, 29.2 (d, J = 5.1 Hz), 61.0,
72.4 (d, J = 31.6 Hz), 99.5 (d, J = 12.0 Hz), 126.7, 128.5 (d,
J = 14.5 Hz), 139.2, 160.5 (d, J = 160.4 Hz), 171.2. 19F NMR
(376.5 MHz, CDCl3) d; ꢁ56.0 (1F, dd, J = 36, 11 Hz). EI-MS
m/z; 238 (M+). HRMS. Calcd. for C13H15FO3Na: 261.0903.
Found: 261.0945.
4. Experimental
4.1. General
1
All reactions were carried out under argon atmosphere. H
and 13C NMR spectra were taken on a Bruker dpx400
spectrometer, and chemical shifts were reported in parts per
million (ppm) using CHCl3 (7.26 ppm) in CDCl3 for 1H NMR,
and CDCl3 (77.01 ppm) for 13C NMR as an internal standard,
respectively. 19F NMR spectra were taken on a Bruker dpx400
spectrometer, and chemical shifts were reported in parts per
million using benzotrifluoride as a standard. Infrared (IR)
spectra were recorded on a JASCO FT/IR-620 infrared
spectrophotometer. Mass spectra (MS) were obtained on a
VG Auto Spec. Medium pressure liquid chromatography
(MPLC) was performed using prepacked column (silica gel,
50 mm) with RI detector.
4.2.3. Ethyl-4-fluoro-5-phenyl-penta-2,4-dienoate (4a)
Colorless solid, mp 41–41.5 8C. IR (CHCl3) n cmꢁ1; 1712,
1624. 1H NMR (400 MHz, CDCl3) d; 1.33 (3H, t, J = 7.1 Hz),
4.25 (2H, q, J = 7.1 Hz), 6.01 (1H, d, J = 36.7 Hz), 6.25 (1H, d,
J = 15.4 Hz), 7.16 (1H, dd, J = 26.7, 15.4 Hz), 7.29–7.43 (3H,
m), 7.57–7.63 (2H, m). 13C NMR (100.6 MHz, CDCl3) d; 14.3,
60.7, 117.0 (d, J = 9.0 Hz), 119.0, 128.7, 129.6 (d, J = 7.9 Hz),
132.7, 136.2 (d, J = 23.1 Hz), 153.8, 156.4, 166.3. 19F NMR
(376.5 MHz, CDCl3) d; ꢁ55.2 (dd, J = 36.7, 26.7 Hz). EI-MS

Y. Nakamura et al. / Journal of Fluorine Chemistry 127 (2006) 627–636
633
m/z; 220 (M+). Calcd. for C13H15O2F: C, 70.90; H, 5.95. Found:
C, 70.63; H, 6.08.
ꢁ58.5 (1F, dd, J = 36, 12 Hz). EI-MS m/z; 308 (M+). HRMS.
Calcd. for C18H25FO3: 308.1788. Found: 308.1782.
1
anti-2b-2: Colorless oil. IR (neat) n cmꢁ1; 3610, 1728. H
4.2.4. Ethyl (2R*,3Z,5S*)- and (2R*,3Z,5R*)-4-fluoro-5-
hydroxy-2-methyl-6-phenyl-3-hexenoate (syn-2b-1) and
(anti-2b-1)
A 75% yield as a diastereomer mixture (ratio 6:1), which
was separated by MPLC (hexane/AcOEt = 5:1) to give syn-2b-
1 and anti-2b-1 in the order of elution.
NMR (400 MHz, CDCl3) d; 0.84 (3H, d, J = 4.4 Hz), 0.85
(3H, d, J = 4.3 Hz), 1.25 (3H, t, J = 7.1 Hz), 1.24–1.36 (2H,
m), 1.46–1.56 (1H, m), 1.92 (1H, d, J = 5.4 Hz), 2.95 (1H,
dd, J = 13.6, 7.3 Hz), 3.02 (1H, dd, J = 13.6, 6.4 Hz), 3.47–
3.55 (1H, m), 4.12 (2H, q, J = 7.1 Hz), 4.29–4.39 (1H, m),
4.82 (1H, dd, J = 36.4, 10.1 Hz), 7.19–7.32 (5H, m). 13C
NMR (100.6 MHz, CDCl3) d; 14.2, 21.8, 22.8, 25.5, 39.0 (d,
J = 3.8 Hz), 40.4, 41.7, 60.7, 71.6 (d, J = 30.3 Hz), 105.8 (d,
J = 11.9 Hz), 126.8, 128.5, 129.5, 136.6, 159.3 (d,
J = 260.1 Hz), 174.0. 19F NMR (376.5 MHz, CDCl3) d;
ꢁ60.7 (1F, dd, J = 36.4, 15.6 Hz). EI-MS m/z; 308 (M+).
HRMS. Calcd. for C18H25FO3: 308.1788. Found: 308.
1787.
syn-2b-1: Colorless oil. IR (CHCl3) n cmꢁ1; 3608, 3448,
1724. 1H NMR (400 MHz, CDCl3) d; 1.24 (3H, t,
J = 7.1 Hz), 1.24 (3H, d, J = 7.2 Hz), 1.86 (1H, dd,
J = 5.3, 2.9 Hz), 2.90 (1H, dd, J = 13.8, 7.8 Hz), 3.04
(1H, dd, J = 13.8, 5.0 Hz), 3.54 (1H, dq, J = 9.5, 7.2 Hz),
4.12 (2H, q, J = 7.1 Hz), 4.29–4.38 (1H, m), 4.97 (1H, dd,
J = 9.5, 36.6 Hz), 7.21–7.33 (5H, m). 13C NMR
(100.6 MHz, CDCl3) d; 14.1, 17.9, 35.0 (d, J = 4.3 Hz),
40.5, 60.8, 71.0 (d, J = 31.2 Hz), 106.2 (d, J = 11.7 Hz),
126.9, 128.5, 129.5, 136.6, 159.3 (d, J = 259.9 Hz), 174.2.
19F NMR (376.5 MHz, CDCl3) d; ꢁ59.2 (1F, dd, J = 37,
13 Hz). EI-MS m/z: 266 (M+). Anal. Calcd. for C15H19FO3:
C, 67.65; H, 7.19. Found: C, 67.68; H, 7.08.
anti-2b-1: Colorless oil. IR (CHCl3) n cmꢁ1; 3676, 3608,
1730. 1H NMR (400 MHz, CDCl3) d; 1.18 (3H, t,
J = 7.1 Hz), 1.25 (3H, d, J = 7.2 Hz), 1.93 (1H, dd,
J = 5.3, 2.4 Hz), 2.92 (1H, dd, J = 13.6, 5.8 Hz), 3.03
(1H, dd, J = 13.6, 5.8 Hz), 3.53 (1H, dq, J = 9.5, 7.1 Hz),
4.13 (2H, q, J = 7.2 Hz), 4.28–4.34 (1H, m), 4.93 (1H, dd,
J = 36.6, 9.5 Hz), 7.20–7.33 (5H, m). 13C NMR
(100.6 MHz, CDCl3) d; 14.2, 18.0, 35.0 (d, J = 4.5 Hz),
40.5, 60.8, 71.4 (d, J = 30.5 Hz), 106.5 (d, J = 11.7 Hz),
126.9, 128.5, 129.5, 136.7, 156.0 (d, J = 259.9 Hz), 174.2.
19F NMR (376.5 MHz, CDCl3) d; ꢁ60.1 (1F, dd, J = 37,
15 Hz). EI-MS m/z: 267 (M+ + 1), 266 (M+). Anal.
Calcd. for C15H19FO3: C, 67.65; H, 7.19. Found: C,
67.57; H, 7.07.
4.2.6. Ethyl (Z)-4-fluoro-5-(4-methoxyanilino)-5-phenyl-3-
pentenoate (3c)
A 41% yield. Colorless oil. IR (neat) n cmꢁ1; 3385, 1734. 1H
NMR (400 MHz, CDCl3) d; 0.99 (3H, t, J = 7.1 Hz), 2.92–3.00
(2H, m), 3.48 (3H, s), 3.59 (1H, brs), 3.88 (2H, q, J = 7.1 Hz),
4.66 (1H, d, J = 11.2 Hz), 4.98 (1H, dt, J = 36.1, 7.3 Hz), 6.34
(2H, d, J = 8.8Hz), 6.51 (2H, d, J = 8.8Hz), 7.03–7.16 (3H, m),
7.16–7.27 (2H, m). 13C NMR (100.6 MHz, CDCl3) d; 14.2, 29.4
(d, J = 5.4 Hz), 55.7, 60.4 (d, J = 31.7 Hz), 60.8, 100.1 (d,
J = 12.3 Hz), 114.8, 114.9, 127.4, 128.2, 128.9, 139.0, 140.7,
152.7, 159.5 (d, J = 260 Hz), 171.0. 19F NMR (376.5 MHz,
CDCl3) d; ꢁ53.20 (1F, dd, J = 36, 11 Hz). EI-MS m/z; 343
(M+). HRMS. Calcd. for C20H22NO3F: 343.1584. Found:
343.1552.
4.3. General procedure for Me2CuLi mediated reduction
followed by alkylation with alkyl halide
Under an argon atmosphere, to a solution of Me2CuLi
prepared from CuI (2.5 mmol) and methyllithium (1.14 M
diethylether solution, 5 mmol) in THF (3 ml) at 0 8C was added
1a (0.5 mmol) and the mixture was stirred for 15 min at the
same temperature, which was then treated with methyl iodide
(5 mmol) for 1 h. Addition of 5% HCl, filtration of precipitates
through Celit pad and extractive work-up of the filtrate (AcOEt
for extraction) gave crude product, which was purified by silica
gel column (hexane/AcOEt = 1:1) to give 2a–1 in 93% yield as
a diastereomer mixture (ratio 1:1).
4.2.5. Ethyl (2R*,3Z,5S*)- and (2R*,3Z,5R*)-4-fluoro-5-
hydroxy-2-isobutyl-6-phenyl-3-hexenoate (syn-2b-2) and
(anti-2b-2)
A 58% yield as a diastereomer mixture (ratio 1.5:1), which
was separated by MPLC (hexane/AcOEt = 4:1) to give syn-2b-
2 and anti-2b-2 in the order of elution.
syn-2b-2: Colorless oil. IR (neat) n cmꢁ1; 3610, 3454, 1719.
1H NMR (400 MHz, CDCl3) d; 0.89 (3H, d, J = 6.5 Hz),
0.90 (3H, d, J = 6.6 Hz), 1.24 (3H, t, J = 7.2 Hz), 1.32–1.41
(1H, m), 1.41–1.52 (1H, m), 1.52–1.62 (1H, m), 1.90 (1H, d,
J = 5.4 Hz), 2.90 (1H, dd, J = 13.8, 7.6 Hz), 3.04 (1H, dd,
J = 13.8, 5.0 Hz), 3.54 (1H, ddd, J = 10.0, 8.6, 6.6 Hz), 4.11
(2H, q, J = 7.2 Hz), 4.30–4.39 (1H, m), 4.87 (1H, dd,
J = 36.6, 10.0 Hz), 7.20–7.33 (5H, m). 13C NMR
(100.6 MHz, CDCl3) d; 14.2, 21.9, 22.7, 25.7, 38.9 (d,
J = 3.8 Hz), 40.5, 41.7, 60.6, 71.0 (d, J = 31.6 Hz), 105.1 (d,
J = 11.6 Hz), 126.8, 128.5, 129.5, 136.6, 159.8 (d,
J = 259.6 Hz), 174.0. 19F NMR (376.5 MHz, CDCl3) d;
4.3.1. Ethyl 4-fluoro-5-hydroxy-2-methyl-5-phenyl-3-
pentenoate (2a–1)
Colorless oil. IR (neat) n cmꢁ1; 3620, 3495, 1730. 1H NMR
(400 MHz, CDCl3) d; 1.25 (0.5H, t, J = 7.1 Hz), 1.25 (1.5H, d,
J = 7.1 Hz), 1.29 (0.5H, d, J = 7.2 Hz), 1.29 (1.5H, d,
J = 7.2 Hz), 2.25 (0.5H, d, 2.29, J = 4.9 Hz), 2.29 (0.5H, d,
J = 4.9 Hz), 3.56 (1H, dq, J = 9.3, 7.2 Hz), 4.14 (2H, q,
J = 7.1 Hz), 5.16 (0.5H, dd, J = 36.2, 9.2 Hz), 5.17 (0.5H, dd,
J = 35.8, 9.3 Hz), 5.22 (1H, d, J = 16.5 Hz), 7.28–7.47 (5H, m).
13C NMR (100.6 MHz, CDCl3) d; 14.1, 17.9, 35.1 (d,
J = 4.3 Hz), 60.8, 72.3 (d, J = 31.9 Hz), 106.6 (d,

634
Y. Nakamura et al. / Journal of Fluorine Chemistry 127 (2006) 627–636
J = 11.6 Hz), 126.7 (d, J = 9.2 Hz), 128.4 (d, J = 17.2 Hz),
139.3, 159.3 (d, J = 260 Hz), 174.3. 19F NMR (376.5 MHz,
CDCl3) d; ꢁ56.9 (0.5F, dd, J = 36, 11 Hz), ꢁ57.3 (0.5F, dd,
J = 36, 12 Hz). EI-MS m/z; 252 (M+). Anal. Calcd. for
C14H18O3F: C, 66.65; H, 6.79. Found: C, 66.59; H, 6.71.
Calcd. for C14H18FO2 (M+ + 1): 237.1291. Found: 237.1303.
Anal. Calcd. for C14H17O2F: C, 71.16; H, 7.25. Found: C,
71.24; H, 7.22.
4.3.5. tert-Butyl (4S,5R)-5-(3-ethoxy-2,2-difluoro-1-
hydroxy-3-oxopropyl)-4-isobutyl-2,2-dimethyl-1,3-
oxazolidine-3-carboxylate (10)
4.3.2. Ethyl (Z)-2-benzyl-4-fluoro-5-hydroxy-6-phenyl-3-
hexenoate (2b–3)
A 75% yield as a diastereomer mixture (ratio 5:1). Colorless
After a mixture of the amino alcohol syn-8 (167 mg), 2,2-
dimethoxypropane (1 ml) and pyridinium p-toluenesulfonate
(5 mg) in toluene (5 ml) was stirred at 80 8C for 1.5 h, the
residue obtained by evaporation of the solvent was purified by
silica gel column (hexane/AcOEt = 20:1) to give N,O-
isopropylidene compound (183 mg, 94% yield) [36]. A mixture
of this 1,3-oxazolidine derivative (1.08 g, 3.8 mmol), 4-
methylmorpholine-N-oxide (2.23 g, 19 mmol), OsO4 (48 mg,
0.2 mmol) in acetone and water (15 ml/3 ml) was stirred at
room temperature for 17 h. Then, the reaction mixture was
extracted with AcOEt after addition of Na2SO3 solution. The
extracts were concentrated under reduced pressure to leave the
crude diol, which was used without further purification. To a
solution of NaIO4 (1.67 g, 7.6 mmol) in hot water (3.5 ml) was
added silica gel (Merck Art 9385, 7.6 g) and the whole was
vigorously mixed. After cooling, to this was added CH2Cl2
(12 ml), then the crude diol dissolved in CH2Cl2 (5 ml) at 0 8C
and the mixture was stirred for 1 h. Purification of the reaction
mixture by silica gel column (hexane/AcOEt = 2:1) gave the
aldehyde 9 (1.04 g, 3.64 mmol, 96% yield), which was used
immediately for the following reaction. To Zn powder (0.95 g,
14.5 mmol) in refluxing THF (10 ml) was added a THF solution
(15 ml) of ethyl bromodifluoroacetate (2.83 g, 14.0 mmol) and
the above aldehyde 9 (1.66 g, 5.82 mmol) and the mixture was
stirred for further 30 min. Addition of saturated NH4Cl
solution, extractive work-up (AcOEt for extraction) and
purification by silica gel column (hexane/AcOEt = 5:1) gave
the difluoro ester 10 (2.19 g, 92% yield) as a diastereomer
mixture (ratio 3:1), which was separated by MPLC (hexane/
AcOEt = 5:1).
1
oil. IR (neat) n cmꢁ1; 3610, 3460, 1725. H NMR (400 MHz,
CDCl3) d; 1.16 (3H, t, J = 7.1 Hz), 1.79 (0.17H, d, J = 5.1 Hz),
1.83 (0.83H, d, J = 5.4 Hz), 2.76–2.99 (4H, m), 3.77 (1H, dt,
J = 9.8, 7.4 Hz), 4.07 (2H, q, J = 7.1 Hz), 4.23–4.33 (1H, m),
4.94 (0.83H, dd, J = 36.2, 9.8 Hz), 4.98 (0.17H, dd, J = 36.1,
10.0 Hz), 7.06–7.33 (10H, m). 13C NMR (100.6 MHz, CDCl3)
d; 14.1, 38.8, 40.5 (d, J = 10.0 Hz), 42.5, 60.8, 71.3 (d,
J = 30.3 Hz), 104.7 (d, J = 11.6 Hz), 126.5, 126.9, 128.3, 128.6,
129.0, 129.5, 136.6, 138.1, 159.7 (d, J = 261.1 Hz), 172.9. 19
F
NMR (376.5 MHz, CDCl3) d; ꢁ58.7 (0.83F, dd, J = 36, 15 Hz),
ꢁ57.3 (0.17F, dd, J = 36, 12 Hz). EI-MS m/z: 342 (M+). Anal.
Calcd. for C21H23FO3: C, 73.66; H, 6.77. Found: C, 73.38; H,
6.82.
4.3.3. Ethyl (Z)-4-fluoro-5-(4-methoxyanilino)-2-methyl-5-
phenyl-3-pentenoate (2c)
A 92% yield as a diastereomer mixture (ratio 3:2). Colorless
oil. 1H NMR (400 MHz, CDCl3) d; 1.22 (1.74H, t, J = 7.1 Hz),
1.25 (1.74H, d, J = 7.1 Hz), 1.26 (1.26H, t, J = 7.1 Hz), 1.26
(1.26 H, d, J = 7.1 Hz), 3.52–3.62 (1H, m), 3.74 (1.26H, s), 3.74
(1.74H, s), 4.11 (0.84H, q, J = 7.1 Hz), 4.13 (1.16 H, q,
J = 7.1 Hz), 4.88 (0.58H, d, J = 10.5 Hz), 4.89 (0.42H, d,
J = 12.5 Hz), 5.15 (0.42H, dd, J = 36.3, 9.9 Hz), 5.17 (0.58H,
dd, J = 36.3, 9.9 Hz), 6.58–6.63 (2H, m), 6.74–6.79 (2H, m),
7.30–7.40 (3H, m), 7.41–7.46 (2H, m). 13C NMR (100.6 MHz,
CDCl3) d; 14.3, 17.9, 35.2 (0.58C, d, J = 4.5 Hz), 35.2 (0.42C,
d, J = 4.5 Hz), 55.7, 60.4 (0.58C, d, J = 32.1 Hz), 60.5 (0.42C,
d, J = 34.3 Hz), 107.2 (0.58C, d, J = 12.0 Hz), 107.5 (0.42C, d,
J = 12.1 Hz), 114.8, 114.9 (0.58C), 115.2 (0.42C), 127.3
(0.42C), 127.5 (0.58C), 128.2 (0.42C), 128.2 (0.58C), 128.8,
139.0 (0.42C), 139.0 (0.58C), 140.7 (0.58C), 140.7 (0.42C),
152.7 (0.58C), 152.8 (0.42C), 158.3 (1C, d, J = 260.8 Hz),
174.1 (0.42C), 174.2 (0.58C). 19F NMR (376.5 MHz, CDCl3) d;
ꢁ54.0 (0.58F, d, J = 36, 10.5 Hz), ꢁ54.5 (0.42F, d, J = 36,
12 Hz). Anal. Calcd. for C21H22O2F: C, 70.57; H, 6.77; N, 3.92.
Found: C, 70.56; H, 6.82; N, 3.91.
10-less polar: Colorless oil. IR (neat) n cmꢁ1; 3426, 1761,
1700. 1H NMR (400 MHz, CDCl3) d; 0.93 (3H, d,
J = 6.3 Hz), 0.94 (3H, d, J = 6.5 Hz), 1.35 (3H, t,
J = 7.2 Hz), 1.46 (9H, s), 1.48 (3H, s), 1.51 (3H, s), 1.50–
1.63 (3H, m), 4.00–4.13 (2H, m), 4.13–4.23 (1H, m), 4.25–
4.35 (2H, m). 13C NMR (100.6 MHz, CDCl3) d; 13.8, 21.1,
23.9, 25.5, 28.5, 43.2, 58.1, 63.0, 71.7 (t, J = 23.2 Hz), 78.3,
80.3, 95.3, 114.4 (t, J = 256.1 Hz), 151.6, 163.6 (t,
J = 30.9 Hz). 19F NMR (376.5 MHz, CDCl3, 50 8C) d;
ꢁ54.6 (2F, m). EI-MS m/z; 432 (M+ + Na). HRMS. Calcd.
for C19H33F2NO6Na (M+ + Na): 432.2174. Found:
432.2212.
10-more polar: Colorless oil. IR (neat) n cmꢁ1; 3448, 1701.
1H NMR (400 MHz, CDCl3) d; 0.94 (3H, d, J = 6.1 Hz), 0.94
(3H, d, J = 6.5 Hz), 1.36 (3H, t, J = 7.1 Hz), 1.47 (9H, s), 1.51
(3H, s), 1.50–1.57 (2H, m), 1.60 (3H, s), 1.63–1.75 (1H, m),
2.99 (1H, d, J = 6.1 Hz), 3.90–4.03 (2H, m), 4.14 (1H, dd,
J = 5.4, 3.5 Hz), 4.35 (2H, q, J = 7.1 Hz). 13C NMR
(100.6 MHz, CDCl3) d; 13.9, 21.1, 24.2, 25.0, 27.3, 28.4,
4.3.4. Ethyl (Z)-4-fluoro-2-methyl-5-phenyl-3-pentenoate
(2d)
1
95% yield. Colorless oil. IR (CHCl3) n cmꢁ1; 1735. H
NMR (400 MHz, CDCl3) d; 1.25 (3H, t, J = 7.1 Hz), 1.25 (3H,
d, J = 7.1 Hz), 3.28 (2H, d, J = 17.5 Hz), 3.55 (1H, qd, J = 9.3,
7.1 Hz), 4.13 (2H, q, J = 7.1 Hz), 4.78 (1H, dd, J = 35.7,
9.3 Hz), 7.19–7.34 (5H, m). 13C NMR (100.6 MHz, CDCl3) d;
14.5, 18.5, 35.7 (d, J = 4.5 Hz), 38.8 (d, J = 28.4 Hz), 61.0,
107.0 (d, J = 13.7 Hz), 127.3, 128.9, 129.2, 136.5, 159.3 (d,
J = 258.0 Hz), 175.0. 19F NMR (376.5 MHz, CDCl3) d; ꢁ43.2
(1F, d, J = 35, 17.5 Hz). EI-MS m/z; 237 (M+ + 1). HRMS.

Y. Nakamura et al. / Journal of Fluorine Chemistry 127 (2006) 627–636
635
43.4, 57.9, 63.2, 71.4 (t, J = 26.8 Hz), 77.0, 80.3, 94.8, 113.9
(dd, J = 260.1, 252.6 Hz), 151.3, 162.9 (t, J = 31.4 Hz). 19F
NMR (376.5 MHz, CDCl3, 50 8C) d; ꢁ47.6 (1F, d,
J = 265 Hz), ꢁ58.5 (1F, dd, J = 265, 14 Hz). EI-MS m/z;
432 (M+ + Na), 348, 310. HRMS. Calcd. for C19H33F2NO6Na
(M+ + Na): 432.2174. Found: 432.2172.
6.87 (1H, ddd, J = 15.8, 12.4, 11.2 Hz). 13C NMR (100.6 MHz,
CDCl3) d; 14.1, 21.3, 23.9, 25.5, 28.5, 42.4, 43.5 (t,
J = 24.9 Hz), 61.1, 61.3, 74.9, 78.0, 94.2 (d, J = 61.5 Hz),
119.4 (t, J = 240.8 Hz), 124.7 (t, J = 8.1 Hz), 139.4 (t,
J = 26.7 Hz), 151.6, 165.0. 19F NMR (376.5 MHz, CDCl3,
50 8C) d; ꢁ43.4 (2F, d, J = 258 Hz). EI-MS m/z; 442 (M+ + Na),
420. HRMS. Calcd. for C21H35F2NO5Na (M+ + Na): 442.2381.
Found: 442.2380. Anal. Calcd. for C21H35F2NO5: C, 60.12; H,
8.41; N, 3.34. Found: C, 60.31; H, 8.30; N, 3.39.
4.3.6. tert-Butyl (4S,5S)-5-(3-ethoxy-2,2-difluoro-3-
oxopropyl)-4-isobutyl-2,2-dimethyl-1,3-oxazolidine-3
carboxylate (14)
After the b-hydroxy ester 10 (a mixture of diastereomers,
2.47 g, 6.1 mmol) and 1,10-thiocarbonyldiimidazole (3.23 g,
18.2 mmol) in CH2Cl2 (30 ml) was stirred at room
temperature for 19 h, the reaction mixture was purified by
silica gel column (hexane/AcOEt = 3:1) to give the thioimi-
dazolide (2.92 g, 93% yield). The thioimidazolide, triethylsi-
lane (1.5 ml) and benzoyl peroxide (10 mg) in dioxane
(30 ml) was refluxed for 1.5 h and then stood at room
temperature for 20 h. Purification of the reaction mixture by
silica gel column (hexane/AcOEt = 3:1) gave 14 (1.78 g, 78%
4.3.8. tert-Butyl (4S,5S)-5-[(Z)-5-ethoxy-2-fluoro-4-
methyl-5-oxo-2-pentenyl]-4-isobutyl-2,2-dimethyl-1,3-
oxazolidine-3-carboxylate [(2S)–13]
In a similar manner for the preparation of 2a–1 by the
reaction of 1a with Me2CuLi (5 equiv) followed by with MeI
(10 equiv), the difluoroenoate 15 (635 mg, 1.5 mmol) gave a
isomer mixture of 13 (601 mg, 96% yield, Z:E=6.4:1, almost
1:1 diastereomer mixture for Z isomer), which was purified by
MPLC (hexane/AcOEt = 15:1) to give Z-anti isomer (2S)–13 in
a pure form and an inseparable mixture of Z-syn isomer (2R)–
13 and E-13.
1
yield). Colorless oil. IR (neat) n cmꢁ1; 1770, 1701. H NMR
(400 MHz, CDCl3) d; 0.92 (6H, d, J = 5.0 Hz), 1.34 (3H, t,
J = 7.1 Hz), 1.46 (12H, s), 1.54 (3H, s), 1.41–1.60 (3H, m),
2.22–2.38 (1H, m), 2.39–2.58 (1H, m), 3.74 (1H, m), 4.10–
4.18 (1H, m), 4.23–4.37 (2H, m). 13C NMR (100.6 MHz,
CDCl3) d; 13.8, 21.3, 24.0, 25.4, 27.9, 28.4, 40.9 (t,
J = 22.3 Hz), 42.3, 43.5, 61.1, 62.9, 74.6, 80.0, 94.6, 114.9
(dd, J = 252.3, 249.5 Hz), 151.6, 163.8 (t, J = 32.2 Hz). 19F
NMR (376.5 MHz, CDCl3, 50 8C) d; ꢁ44.7 (1F, m), ꢁ39.2
(1F, dt, J = 263, 13 Hz). EI-MS m/z; 416 (M+ + Na), 360.
HRMS. Calcd. for C19H33F2NO5Na (M+ + Na): 416.2224.
Found: 416.2239. Anal. Calcd. for C19H33F2NO5: C, 58.00;
H, 8.45; N, 3.56. Found: C, 57.95; H, 8.50; N, 3.59.
(2S)–13: Colorless solid, mp 48–49 8C. IR (neat) n cmꢁ1
;
1
1737, 1701. H NMR (400 MHz, CDCl3) d; 0.90 (6H, d,
J = 6.0 Hz), 1.22 (3H, t, J = 7.1 Hz), 1.23 (3H, d,
J = 7.1 Hz), 1.46 (9H, s), 1.48 (3H, s), 1.56 (3H, s), 1.41–
1.62 (3H, m), 2.34–2.54 (2H, m), 3.51 (1H, dq, J = 9.4,
7.4 Hz), 3.73 (1H, m), 4.04–4.14 (1H, m), 4.10 (2H, q,
J = 7.1 Hz), 4.80 (1H, dd, J = 36.5, 9.4 Hz). 13C NMR
(100.6 MHz, CDCl3) d; 14.1, 18.2, 21.2, 23.9, 25.6, 28.5,
35.3 (d, J = 4.6 Hz), 38.9 (d, J = 25.5 Hz), 43.3, 60.3, 60.6,
77.7, 79.7, 94.3, 107.8 (d, J = 13.0 Hz), 151.7, 156.7 (d,
J = 256.6 Hz), 174.3. 19F NMR (376.5 MHz, CDCl3, 50 8C)
d; ꢁ44.7 (1F, m). EI-MS m/z; 438 (M+ + Na), 416 (M+), 358.
HRMS. Calcd. for C22H39FNO5 (M+): 416.2812. Found:
416.2798.
4.3.7. tert-Butyl (4S,5S)-5-[(E)-5-ethoxy-2,2-difluoro-5-
oxo-3-phenyl]-4-isobutyl-2,2-dimethyl-1,3-oxazoline-3-
carboxylate (15)
A solution of difluoro ester 14 (602 mg, 1.53 mmol) in THF
(10 ml) was added DIBAL (0.95 M hexane solution, 4.8 ml,
4.60 mmol) at ꢁ78 8C and then this mixture was stirred at 0 8C
for 15 min. The reaction mixture was stirred for 10 min after
addition of water and the supernatant was decanted. The residue
was washed with AcOEt several times. The combined organic
layers were dried over anhydrous Na2SO4 and then concen-
trated under reduced pressure. The residue dissolved in THF
(4 ml) was added to a reaction mixture of sodium hydride (60%
in oil, 74 mg, 1.84 mmol) and triethyl phosphonoacetate
(344 mg, 1.53 mmol) in THF (6 ml) at ꢁ30 8C and the whole
was stirred at the same temperature for 35 min. Addition of
saturated NH4Cl solution, extractive work-up (AcOEt for
extraction) and purification by silica gel column (hexane/
AcOEt = 3:1) gave the difluoroenoate 15 (239 mg, 60% yield)
as colorless oil. IR (neat) n cmꢁ1; 1730, 1701. 1H NMR
(400 MHz, CDCl3) d; 0.92 (6H, d, J = 5.6 Hz), 1.29 (3H, t,
J = 7.1 Hz), 1.46 (9H, s), 1.48 (3H, brs), 1.55 (3H, brs), 1.42–
1.60 (3H, m), 2.17–2.38 (2H, m), 3.75 (1H, m), 4.10–4.17 (1H,
m), 4.23 (2H, q, J = 7.1 Hz), 6.25 (1H, dd, J = 15.8, 2.2 Hz),
4.3.9. Ethyl (2S,3Z,6S,7S)-7-[(tert-
Butoxycarbonyl)amino]-4-fluoro-6-hydroxy-2,9-dimethyl-
3-decenoate [(2S)–16]
The Z-anti isomer (2S)–13 (189 mg, 0.46 mmol) and p-
TsOH (10 mg) in MeOH (15 ml) was stirred at room
temperature for 2 h. After addition of 5% NaOH and extractive
work-up (AcOEt for extraction), the extract was purified by
silica gel column (hexane/AcOEt = 3:1) to give (2S)–16
(158 mg, 92% yield) as colorless oil. IR (neat) n cmꢁ1
;
3444, 3387, 1736, 1715, 1686. 1H NMR (400 MHz, CDCl3) d;
0.90 (6H, d, J = 6.6 Hz), 1.23 (3H, t, J = 7.1 Hz), 1.24 (3H, d,
J = 7.2 Hz), 1.27–1.36 (1H, m), 1.42 (9H, s), 1.44–1.54 (1H,
m), 1.55–1.70 (1H, m), 2.22–2.45 (2H, m), 2.68 (1H, d,
J = 3.8 Hz), 3.51 (1H, dq, J = 9.2, 7.2 Hz), 3.53–3.63 (1H, m),
3.75–3.84 (1H, m), 4.12 (2H, q, J = 7.1 Hz), 4.70–4.79 (1H, br),
4.80 (1H, dd, J = 36.7, 4.8 Hz). 13C NMR (100.6 MHz, CDCl3)
d; 14.1, 18.1, 22.1, 23.1, 24.8, 28.3, 35.3 (d, J = 4.5 Hz), 37.6 (d,
J = 25.8 Hz), 41.4, 52.4, 60.8, 70.3, 79.2, 107.6 (d,
J = 13.7 Hz), 157.5 (d, J = 263.1 Hz), 156.2, 174.5. 19F
NMR (376.5 MHz, CDCl3, 50 8C) d; ꢁ43.7 (1F, ddd, J = 38,

636
Y. Nakamura et al. / Journal of Fluorine Chemistry 127 (2006) 627–636
23, 16 Hz). EI-MS m/z; 398 (M+ + Na), 376 (M+ + 1), 320.
HRMS. Calcd. for C19H35FNO5 (M+ + 1): 376.2499. Found:
376.2517.
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butoxycarbonyl)amino]-4-fluoro-6-hydroxy-2,9-dimethyl-3-
decenoate (E-16)
Similar to the preparation of (2S)–16 from (2S)–13 by
deprotection and chromatographic purification, a mixture of
(2R)–13 and E–13 (147 mg, 0.35 mmol) gave the deprotected
(2R)–16 and E–16 in the order of elution in MPLC purification
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(2R)–16: Colorless oil. IR (neat) n cmꢁ1; 3445, 3395, 1740,
1715. 1H NMR (400 MHz, CDCl3) d; 0.90 (6H, d,
J = 6.5 Hz), 1.20–1.29 (6H, m), 1.29–1.37 (1H, m), 1.42
(9H, s), 1.44–1.56 (1H, m), 1.56–1.70 (1H, m), 2.19–2.46
(2H, m), 2.73 (1H, brs), 3.46–3.57 (1H, m), 3.55–3.70 (1H,
m), 3.70–3.87 (1H, m), 4.11 (2H, qd, J = 7.1, 1.0 Hz), 4.78
(1H, dd, J = 36.4, 8.7 Hz), 4.69–4.79 (1H, br). 13C NMR
(100.6 MHz, CDCl3) d; 14.1, 17.8, 22.2, 23.0, 24.8, 28.3,
35.3 (d, J = 4.5 Hz), 37.8 (d, J = 25.7 Hz), 41.9, 51.9, 60.8,
69.9, 79.1, 108.0 (d, J = 13.6 Hz), 157.4 (d, J = 261.8 Hz),
156.1, 174.6. 19F NMR (376.5 MHz, CDCl3, 50 8C) d;
ꢁ44.1 (1F,ddd, J = 37, 26, 15 Hz). EI-MS m/z; 398
(M+ + Na), 376 (M+ + 1), 320. HRMS. Calcd. for
C19H35FNO5 (M+ + 1): 376.2499. Found: 376.2464. Anal.
Calcd. for C19H35FNO5: C, 60.78; H, 9.13; N, 3.73. Found:
C, 60.72; H, 9.06; N, 3.73.
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E-16: Colorless oil. IR (neat) n cmꢁ1; 3444, 1740, 1714. 1H
NMR (400 MHz, CDCl3) d; 0.93 (3H, d, J = 6.6 Hz), 0.93
(3H, d, J = 6.5 Hz), 1.26 (3H, d, J = 6.9 Hz), 1.27 (3H, t,
J = 7.1 Hz), 1.35 (1H, ddd, J = 13.6, 8.0, 5.6 Hz), 1.45 (9H,
s), 1.53 (1H, ddd, J = 13.8, 9.4, 5.6 Hz), 1.58–1.74 (1H, m),
2.34–2.62 (2H, m), 2.97 (1H, d, J = 2.7 Hz), 3.06–3.19 (1H,
m), 3.56–3.69 (1H, m), 3.78–3.90 (1H, m), 4.16 (2H, q,
J = 7.1 Hz), 4.69 (1H, d, J = 9.5 Hz), 5.17 (1H, dd, J = 20.3,
10.5 Hz). 13C NMR (100.6 MHz, CDCl3) d; 14.1, 17.5, 22.3,
23.1, 24.8, 28.4, 34.6 (d, J = 26.4 Hz), 37.2 (d, J = 9.8 Hz),
42.0, 52.5, 61.4, 70.03, 79.2, 108.8 (d, J = 25.6 Hz), 156.2,
159.0 (d, J = 250.1 Hz), 174.7. 19F NMR (376.5 MHz,
CDCl3, 50 8C) d; ꢁ37.8 (1F, m). EI-MS m/z; 398 (M+ + Na),
376 (M+ + 1), 320. HRMS Calcd. for C19H35FNO5 (M+ + 1):
376.2499. Found: 376.2528. Anal. Calcd. for C19H35FNO5:
C, 60.78; H, 9.13; N, 3.73. Found: C, 60.97; H, 8.91; N, 3.45.
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