Synthesis and biological evaluation of γ-fluoro-β,γ-unsaturated acids

Article abstract of DOI:10.1016/j.jfluchem.2006.02.016

Several γ-fluoro-β,γ-unsaturated acids, fluorine-containing analogues of N-acyl glycines, were synthesized via Julia-Lythgoe olefination. The antimicrobial activities of these compounds and synthetic intermediates were evaluated. Analogues with an octyl group showed in vitro antifungal activity agaist Penicillium chrysogenum IFO4626.

Full text of DOI:10.1016/j.jfluchem.2006.02.016

Journal of Fluorine Chemistry 127 (2006) 800–808
www.elsevier.com/locate/fluor
Synthesis and biological evaluation of g-fluoro-b,g-unsaturated acids
a
b
Noriaki Asakura a, Yoshinosuke Usuki a, , Hideo Iio , Toshio Tanaka
*
a Department of Material Science, Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
b Department of Biology, Graduate School of Science, Osaka City University, Sugimoto, Sumiyoshi, Osaka 558-8585, Japan
Received 8 February 2006; received in revised form 20 February 2006; accepted 28 February 2006
Available online 8 March 2006
Abstract
Several g-fluoro-b,g-unsaturated acids, fluorine-containing analogues of N-acyl glycines, were synthesized via Julia–Lythgoe olefination. The
antimicrobial activities of these compounds and synthetic intermediates were evaluated. Analogues with an octyl group showed in vitro antifungal
activity agaist Penicillium chrysogenum IFO4626.
# 2006 Elsevier B.V. All rights reserved.
Keywords: a-Fluoro sulfone; Julia–Lythgoe olefination; Monofluorinated building block; Antifungal activity
1. Introduction
Lythgoe coupling between a-fluorosulfone anions and carbonyl
compounds and their biological evaluation.
In the past few decades, interest in fluorinated compounds
has increased significantly due to the unique influence of the
fluorine substituent on the chemical, physical, and physiolo-
gical properties of these compounds [1]. Functionalized fluoro-
olefins are particularly important, with current applications in
the synthesis of biologically active materials such as peptide
isosteres [2]. Recently organocopper mediated construction of
(Z)-g-fluoro-b,g-enoates have been demonstrated by Otaka
et al. and Taguchi and co-workers [3,4]. Fluorine-containing
building blocks are thus required in order to establish versatile
synthetic methods of desired fluorinated compounds [5].
However, a literature survey revealed few reports on the
synthesis of fluoro-olefination via Julia–Lythgoe conditions
[6,7]. Julia and Paris reported a novel olefination in which b-
acyloxysulfones were reductively eliminated to the correspond-
ing alkenes in 1973 [8]. This olefin synthesis, known as the
Julia–Lythgoe olefination [9], has the benefits of utilizing
readily available a-sulfonyl carbanions, a tendency to afford
stereoselectively E-olefins [10]. Julia–Lythgoe olefination is a
prominent method amongst the numerous reported techniques
for the connective synthesis of alkenes. This report describes a
new synthesis of g-fluoro-b,g-unsaturated acids by Julia–
2. Results and discussion
2.1. Chemistry
Our synthesis commences with mono-alkylation of fluor-
omethyl phenyl sulfone 1, which is commercially available.
Treatment of 1 with n-BuLi (1 eq.) in THF at À78 8C and the
following addition of alkyl bromide afforded the corresponding
mono-alkylated products 2a–d in good yields (Scheme 1).
In order to optimize the reaction conditions, the synthesis of
5a was carried out under several conditions as shown in Scheme
2. First, treatment of 2a with n-BuLi (1 eq.) in DME at À78 8C
and the following addition of 3-benzyloxy-1-propanal [11]
afforded the desired product 3a as a 1:1 mixture of
diastereomers in 70% yield. The dr of 3a was determined by
19F NMR spectra. Acylation of 3a was achieved with acetyl
chloride or benzoyl chloride in pyridine to give 4aa or 4ab,
respectively, in moderate yields. Interestingly, treatment of 4aa
or 4ab with SmI2 resulted in the recovery of the starting
materials. Reductive desulfonylation of 4aa or 4ab proceeded
smoothly with 8 eq. of sodium amalgum and 40 eq. of
NaH2PO4 in THF–MeOH (1:1). The desired fluoro-olefin 5a
was obtained in 80% yield from 4aa and in 43% yield from 4ab
as a 1:3 mixture of E/Z isomers.
* Corresponding author. Fax: +81 6 6605 2522.
E-mail address: usuki@sci.osaka-cu.ac.jp (Y. Usuki).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2006.02.016

N. Asakura et al. / Journal of Fluorine Chemistry 127 (2006) 800–808
801
Scheme 1. Mono-alkylation of fluoromethyl phenyl sulfone 1.
The Z configurations of the major fluoro-olefin product was
established by the large coupling constant between the vinylic
proton and fluorine (3JHF = 50 Hz) on the 19F NMR spectrum
[12]. The mechanism of reductive elimination is not still known
with certainty. A possible mechanism of desulfonylation is
shown in Fig. 1. One-electron transfer from sodium amalgam to
b-acyloxysulfone and the following homolytic cleavage of C–S
bond generated the C-centered radical, which was converted to
the carbanion by an additional electron transfer from sodium
amalgam. b-Elimination of acyloxy group proceeded via a
sterically less hindered conformation to give the corresponding
fluoro-olefin Z-selectively.
Fig. 1. A possible mechanism of desulfonylation.
analysis suggested the formation of methyl sulfide B [13]. As
shown in Scheme 5, the carbanion, which was generated from
the desired b,g-unsaturated aldehyde by treatment with Et3N,
reacted with sulfinium cation derived from ‘‘activated Me2SO’’
to afford methyl sulfide B.
Then we applied 6a to Jones oxidation. Under acidic
condition, oxidation of 6a proceeded to give the corresponding
g-fluoro-b,g-unsaturated acid 7a in 16% yield. The desired
carboxylic acid 7b–d were synthesized in the same manner
(Scheme 6).
Fluoro-olefins 5b–d were synthesized in the same manner;
the results are summarized in Scheme 3. The lower solubilities
of 2d and 4d in polar solvents decreased the yields of 4d and 5d.
Treatment of 5b with lithium metal and ethanol in liquid
ammonia at À78 8C resulted in the formation of 6b as a 1:1
mixture of E/Z isomers in 20% yield in addition to the
defluorinated homoallyl alcohol A (17%). Removal of benzyl
group was achieved with sodium metal in liquid ammonia at
À33 8C to give the desired alcohol 6b in 79% yield. None of
defluorinated compound was generated under this condition.
Fluorinated homoallyl alcohols 6a, 6c and 6d were synthesized
in the same manner (Scheme 4).
2.2. Biological activity
As shown in Fig. 2, g-fluoro-b,g-unsaturated acids are
molecular mimics of N-acyl glycines by substituting a fluoro-
olefin (–CF CH–) for the amide bond (–CO–NH–). Protein N-
myristoylation, an irreversible protein modification, involves
covalent attachment, via an amide bond, of the C14 saturated
fatty acid, myristate, to the N-terminal glycine residue of
nascent eukaryotic cellular and viral proteins [14]. Myristoyl
Subjection of 6a under Swern oxidation condition resulted
1
in a complex mixture of the crude products, whose H NMR
Scheme 2. Synthesis of fluoro-olefin 5a.

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N. Asakura et al. / Journal of Fluorine Chemistry 127 (2006) 800–808
Scheme 3. Synthesis of fluoro-olefins 5b–d.
Scheme 4. Reductive removal of benzyl group on 5a–d.
Scheme 5. Formation of methyl sulfide B.
CoA:protein N-myristoyltransferase (NMT), which catalyses
this modification, could be an attractive drug target for human
pathogens such as Candida albicans and Candida neoformans,
if specific reagents selective for the pathogen rather than the
human enzyme can be developed. These isosteres are expected
to act as enzyme inhibitors.
For the preliminary biological evaluation, compounds 6b–d
and 7b–d were evaluated for in vitro antimicrobial activity.
Minimal inhibitory concentration (MIC) values were deter-
mined by the serial 2-fold broth dilution method [15] after 24 h
cultivation in 3% nutrient broth at 37 8C for bacteria, and in
YPD medium containing 1% yeast extract, 1% peptone, and 2%
Scheme 6. Synthesis of g-fluoro-b,g-unsaturated acids 7a–d.
Fig. 2. Molecular mimics of N-acyl glycines.

N. Asakura et al. / Journal of Fluorine Chemistry 127 (2006) 800–808
803
Table 1
Antimicrobial activities (MIC) of 6b–d and 7b–d
Test organism
MIC (mg/mL)
6b (n = 7)
6c (n = 12)
6d (n = 14)
7b (n = 7)
7c (n = 12)
7d (n = 14)
Yeast
C. albicans IFO1061
200
200
200
200
>400
>400
>400
>400
>400
>400
>400
>400
400
400
400
400
>400
>400
>400
>400
>400
>400
>400
>400
Rhodotorula mucilaginosa IFO0001
Saccharomyces cerevisiae IFO0203
Schizosaccharomyces pombe IFO0342
Fungi
Aspergillus niger ATCC6275
Mucor mucedo IFO7684
P. chrysogenum IFO4626
Rhizopus oryzae IFO4766
400
>400
100
>400
>400
>400
>400
>400
>400
>400
>400
100
>400
12.5
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
Bacteria
Escherichia coli IFO3545
Bacillus subtilis IFO3007
Micrococcus luteus IFO3333
>400
>400
>400
>400
>400
>400
>400
>400
>400
>400
400
>400
>400
>400
>400
>400
>400
>400
Table 2
Antifungal activities against P. chrysogenum IFO4626 of 7b, lauric acid (C) and b,g-unsaturated lauric acid (D)
Test organism
MIC (mg/mL)
P. chrysogenum IFO4626
12.5
25
12.5
glucose at 25 8C for yeasts and filamentous fungi. The results
are summarized in Table 1.
Julia–Lythgoe olefination. These compounds would be a basic
building block for the construction of more complex molecular
systems such as artificial lipopeptides.
Interestingly, 6b and 7b inhibited the growth of Penicillium
chrysogenum IFO4626, although all tested compounds, except
6b and 7b, did not show any growth inihibitions against the
microorganisms tested, even at concentrations up to 400 mM. In
order to evaluate the effect of fluorine substituion, the in vitro
antifungal activities of lauric acid (C) and b,g-unsaturated
lauric acid (D), non-fluorinated alkene analogue of 7b, against
P. chrysogenum IFO4626 were evaluated in the same manner.
As shown in Table 2, the MIC of lauric acid and b,g-
unsaturated lauric acid are 25 and 12.5 mg/mL, respectively. No
significant difference between fluorinated (7b) and non-
fluorinated (D) isosteres was observed in antifungal activity
against P. chrysogenum IFO4626. The length of alkyl chain has
some effect on the potency of the antifungal activity; Octyl
group provides suitable hydrophobicity for membrane perme-
ability to 7b and D. Introduction of double bond to fatty acid
caused an increase in antifungal activity.
4. Experimental
All air- and moisture-sensitive reactions were carried out in
flame-dried, argon-flushed, two-necked flasks sealed with
rubber septa, and the dry solvents and reagents were introduced
using a syringe. Tetrahydrofuran (THF) was fleshly distilled
under an argon atmosphere from sodium benzophenone ketyl.
Dichloromethane (CH2Cl2) was fleshly distilled from phos-
phoric pentaoxide (P2O5). Flash column chromatography was
carried out on a Kanto Chemical silica gel 60N (spherical,
neutral, 40–50 mm), and pre-coated Merck silica gel plates
(Art5715 Kieselgel 60F254, 0.25 mm) were used for thin-layer
chromatography (TLC). Unless mentioned otherwise, H, 13C
1
and 19F nuclear magnetic resonance (NMR) spectra were
recorded in CDCl3 on a JEOL JNM-LA400 or JEOL JNM-
LA300. Chemical shifts of 19F NMR were given by d relative to
that of an external trifluoroacetic acid (TFA). Mass spectra were
obtained on a JEOL JMS-700T or JEOL JMS-AX500
spectrometer. Infrared (IR) spectra were recorded on a JASCO
FT/IR-700.
3. Conclusion
In summary, g-fluoro-b,g-unsaturated acids, fluorine-con-
taining analogues of N-acyl glycines, were synthesized via

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N. Asakura et al. / Journal of Fluorine Chemistry 127 (2006) 800–808
4.1. Typical procedure for the mono-alkylation of
fluoromethyl phenyl sulfone 1
(FAB) calcd. for C20H34O2FS (M + H): 357.2264, found:
357.2271.
n-BuLi (1.60 M solution in hexane; 15 mL, 24.1 mmol) was
added to a solution of fluoromethyl phenyl sulfone 1 (4.11 g,
23.6 mmol) in THF (30 mL) under an argon atmosphere at
À78 8C. After stirring at this temperature for 30 min, to the
mixture was added dropwise a solution of n-butyl bromide
(4.51 g, 33.0 mmol) in THF (10 mL). The reaction mixture was
allowed to warm to room temperature and stirred overnight.
The resulting mixture was quenched with water (50 mL), and
the aqueous layer was extracted with diethyl ether. The
combined organic extracts were washed with brine, dried over
MgSO4. Filtration and concentration in vacuo afforded the
crude product, which was purified by a flash column
chromatography (10% EtOAc in hexane) to give 2a (4.23 g,
18.4 mmol; yield 78%).
4.1.4. 1-Fluoro-1-phenylsulfonylhexadecane (2d)
3
1H NMR (400 MHz) d 0.86 (t, JHH = 7.0 Hz, 3H), 1.19–
1.35 (m, 24H), 1.39–1.61 (m, 2H), 1.77–1.94 (m, 1H), 2.01–
2
3
2.25 (m, 1H), 5.07 (ddd, JHF = 48.3 Hz, JHH = 2.9, 9.9 Hz),
7.55–7.94 (m, 5H); 13C NMR (100 MHz) d 14.10, 22.68, 24.49
3
2
(d, JCF = 2.5 Hz), 27.50 (d, JCF = 19.8 Hz), 28.96, 29.19,
29.34, 29.40, 29.53, 29.60, 29.64, 29.66, 29.68, 31.91, 102.86
(d, 1JCF = 218.9 Hz), 129.25, 129.54, 134.48, 135.49; 19F NMR
2
3
(283 MHz) d À179.51 (ddd, JHF = 48.3 Hz, JHF = 13.8,
36.2 Hz); IR (methylene chloride) 2985, 2927, 2854, 1423,
1327, 1155, 1082 cmÀ1; MS (FAB) m/z 385 (M + H)+, HRMS
(FAB) calcd. for C22H37O2FS (M + H): 385.2577, found:
385.2592.
4.2. Typical procedure for the aldol condensation of 2 with
3-benzyloxypropanal 6
4.1.1. 1-Fluoro-1-phenylsulfonylpentane (2a)
3
1H NMR (400 MHz) d 0.92 (t, JHH = 7.3 Hz, 3H), 1.30–
1.66 (m, 4H), 1.81–1.95 (m, 1H), 2.01–2.24 (m, 1H), 5.09 (ddd,
n-BuLi (1.60 M solution in hexane; 1.36 mL, 2.08 mmol)
was added to a solution of sulfone 2a (0.46 g, 2.0 mmol) in
DME (4 mL) under an argon atmosphere at À78 8C. After
stirring at this temperature for 30 min, to the mixture was added
dropwise a solution of aldehyde 6 (0.35 g, 2.0 mmol) in DME
(1.5 mL). The reaction mixture was allowed to warm to room
temperature and stirred overnight. The resulting mixture was
quenched with sat aq NH4Cl (10 mL), and the aqueous layer
was extracted with diethyl ether. The combined organic extracts
were washed with brine, dried over MgSO4, and evaporated
under the reduced pressure. The crude product was purified by a
flash column chromatography (20% EtOAc in hexane) to give
3a (0.55 g, 1.4 mmol; yield 70%, d.r. = 1:1).
2JHF = 48.3 Hz, 3JHH = 2.9, 10.0 Hz, 1H), 7.60 (t,
3
3JHH = 7.6 Hz, 2H), 7.71 (t, JHH = 7.6 Hz, 1H), 7.95 (d,
3JHH = 7.6 Hz, 2H); 13C NMR (100 MHz) d 13.64, 22.08, 26.52
3
2
(d, JCF = 1.7 Hz), 27.20 (d, JCF = 19.8 Hz), 102.83 (d,
1JCF = 218.3 Hz), 129.23, 129.50, 134.48, 135.43; 19F NMR
2
3
(283 MHz) d À179.55 (ddd, JHF = 48.3 Hz, JHF = 15.5,
37.9 Hz); IR (methylene chloride) 2964, 2937, 2871, 1423,
1327, 1155, 1084 cmÀ1; MS (FAB) m/z 231 (M + H)+, HRMS
(FAB) calcd. for C11H16O2FS (M + H): 231.0855, found:
231.0858.
4.1.2. 1-Fluoro-1-phenylsulfonylnonane (2b)
3
1H NMR (400 MHz) d 0.88 (t, JHH = 7.0 Hz, 3H), 1.23–
1.68 (m, 10H), 1.76–1.98 (m, 2H), 2.02–2.28 (m, 2H), 5.08
4.2.1. 1-Benzyloxy-4-fluoro-4-phenylsulfonyl-octane-3-ol
(3a)
3
(ddd, JHH = 2.7, 9.9 Hz, JHF = 48.6 Hz, 1H), 7.60 (t,
2
3JHH = 7.8 Hz, 2H), 7.71 (t, JHH = 7.8 Hz, 1H), 7.94 (d,
1H NMR (400 MHz) d 0.84–0.94 (m, 3H), 1.22–1.37 (m,
2H), 1.37–1.52 (m, 2H), 1.85–1.99 (m, 2H), 2.04–2.28 (m, 2H),
3
3JHH = 7.8 Hz, 2H); 13C NMR (100 MHz) d 14.39, 22.94, 24.83
3
(d, JCF = 2.5 Hz), 27.85 (d, JCF = 19.9 Hz), 29.30, 29.40,
2
3
3
2.90 (d, JHH = 5.1 Hz, 0.5H), 3.37 (d, JHH = 3.6 Hz, 0.5H),
1
29.49, 32.07, 103.22 (d, JCF = 218.9 Hz), 129.60, 129.87,
3.61–3.76 (m, 2H), 4.30–4.38 (m, 1H), 4.45–4.54 (m, 2H),
7.22–7.37 (m, 5H), 7.46–7.74 (m, 3H), 7.91–7.96 (m, 2H); 13
C
134.83, 135.85; 19F NMR (283 MHz) d À179.53 (ddd,
2JHF = 48.6 Hz, 3JHF = 15.5, 38.2 Hz); IR (methylene chloride)
2958, 2929, 2858, 1423, 1327, 1155, 1084 cmÀ1; MS (FAB) m/
z 287 (M + H)+, HRMS (FAB) calcd. for C15H23O2FS (M + H):
287.1481, found: 287.1481.
NMR (100 MHz)
d
13.69, 23.06, 23.10, 24.70 (d,
3JCF = 2.4 Hz), 24.76 (d, 3JCF = 1.7 Hz), 28.7 (d,
2JCF = 20.6 Hz), 29.8 (d, 2JCF = 19.8 Hz), 31.0 (d,
3JCF = 3.3 Hz), 31.3 (d, JCF = 2.5 Hz), 67.36, 67.53, 69.58
3
2
(d, JCF = 48.8 Hz), 69.81 (d, JCF = 46.2 Hz), 73.10, 73.16,
2
1
1
4.1.3. 1-Fluoro-1-phenylsulfonyltetradecane (2c)
3
109.56 (d, JCF = 223.8 Hz), 110.52 (d, JCF = 223.1 Hz),
127.55, 127.68, 127.71, 128.38, 128.42, 128.85, 129.00,
130.24, 134.23, 134.46; 19F NMR (283 MHz) d À158.29 (dt,
1H NMR (400 MHz) d 0.88 (t, JHH = 6.8 Hz, 3H), 1.21–
1.39 (m, 20H), 1.41–1.62 (m, 2H), 1.81–1.94 (m, 1H), 2.06–
2
2.23 (m, 1H), 5.09 (ddd, JHF = 48.8 Hz, JHH = 3.0, 10.0 Hz,
3
3
3JHF = 13.9, 20.6 Hz, 0.5F), À156.80 (td, JHF = 7.1, 18.8 Hz,
0.5F); MS (FAB) m/z 395 (M + H)+, HRMS (FAB) calcd. for
C21H28O4FS (M + H): 395.1692, found: 395.1675.
3
1H), 7.60 (t, JHH = 7.4 Hz, 2H), 7.72 (t, JHH = 7.4 Hz, 1H),
3
3
7.95 (d, JHH = 7.4 Hz, 2H); 13C NMR (100 MHz) d 14.12,
3
2
22.69, 24.51 (d, JCF = 2.5 Hz), 27.53 (d, JCF = 19.1 Hz),
28.98, 29.22, 29.35, 29.42, 29.55, 29.62, 29.63, 29.66, 31.92,
1
102.90 (d, JCF = 218.9 Hz), 129.27, 129.56, 134.50, 135.54;
4.2.2. 1-Benzyloxy-4-fluoro-4-phenylsulfonyl-dodecane-3-
ol (3b)
2
3
19F NMR (283 MHz) d À179.51 (ddd, JHF = 48.8 Hz,
1H NMR (400 MHz) d 0.87 (t, JHH = 6.4 Hz, 3H), 1.19–
3JHF = 15.3, 37.9 Hz); MS (FAB) m/z 357 (M + H)+, HRMS
3
1.47 (m, 12H), 1.85–2.28 (m, 4H), 2.89 (d, JHH = 5.0 Hz,

N. Asakura et al. / Journal of Fluorine Chemistry 127 (2006) 800–808
805
0.5H), 3.35 (d, 3JHH = 3.5 Hz, 0.5H), 3.47–3.62 (m, 2H), 4.31–
4.38 (m, 1H), 4.48 (s, 2H), 7.25–7.35 (m, 5H), 7.48–7.73 (m,
3H), 7.91–7.96 (m, 2H); 19F NMR (283 MHz) d À158.39 (m,
0.5F), À156.90 (m, 0.5F); MS (EI) m/z 492 (M)+, HRMS (EI)
calcd. for C27H37O5FS (M+): 492.2372, found: 492.2359.
(FAB) m/z 499 (M + H)+, HRMS (FAB) calcd. for C28H32O5FS
(M + H): 499.1955, found: 499.1981.
4.3.3. 3-Acetoxy-1-benzyloxy-4-fluoro-4-
phenylsulfonyldodecane (4b)
1H NMR (400 MHz) d 0.86–0.90 (m, 3H), 1.18–1.41 (m,
10H), 1.49–1.73 (m, 3.5H), 1.92 (m, 1.5H), 2.02–2.23 (m, 2H),
2.26–2.49 (m, 1H), 3.28–3.40 (m, 1H), 3.45–3.64 (m, 2H),
4.3. Typical procedure for the acylation of a-fluoro-b-
hydroxy sulfone 3
3
4.37–4.47 (m, 2H), 5.74 (t, JHH = 8.8 Hz, 1H), 5.61 (t,
3JHH = 9.2 Hz, 1H), 7.21–7.67 (m, 8H), 7.86–7.93 (m, 2H); 13
Acetyl chloride (0.39 g, 5.0 mmol) was added to a solution
of alcohol 3a (1.92 g, 5.0 mmol) in pyridine (8 mL) under an
argon atmosphere at room temperature. The reaction
mixture was stirred at room temperature for 2 h. The resulting
mixture was quenched with a mixture of aq 3 M HCl (15 mL)
and Et2O (15 mL), and the aqueous layer was extracted with
diethyl ether. The combined organic extracts were dried over
Na2SO4, and evaporated under the reduced pressure. The
crude product was purified by a flash column chromatography
(20% EtOAc in hexane) to give 4aa (1.66 g, 3.7 mmol; yield
74%).
C
3
NMR (100 MHz) (selected data) d 30.34 (d, JCF = 3.2 Hz),
30.47 (d, 3JCF = 4.9 Hz), 65.92, 66.09, 68.83 (d,
2
2JCF = 19.8 Hz), 69.01 (d, JCF = 23.1 Hz), 73.12, 73.08,
1
1
108.77 (d, JCF = 226.3 Hz), 109.55 (d, JCF = 223.0 Hz); 19F
NMR (283 MHz) d À155.70 (m, 0.5F), À156.85 (m, 0.5F); IR
(methylene chloride) 3055, 2929, 2858, 1751, 1604, 1373,
1311, 1082 cmÀ1; MS (EI) m/z 492 (M)+, HRMS (EI) calcd. for
C27H37O5FS (M)+: 492.2372, found: 492.2359.
4.4. Typical procedure for the preparation of 4c and 4d
through one-pot acetylation
4.3.1. 3-Acetoxy-1-benzyloxy-4-fluoro-4-
phenylsulfonyloctane (4aa)
n-BuLi (1.60 M solution in hexane; 2.1 mL, 3.4 mmol) was
added to a solution of sulfone 2c (1.14 g, 3.2 mmol) in DME
(6 mL) under an argon atmosphere at À10 8C. After stirring
at this temperature for 30 min, to the mixture was added
dropwise a solution of aldehyde 6 (0.55 g, 3.4 mmol) in
DME (2 mL). The reaction mixture was allowed to warm to
room temperature and stirred overnight. Acetic anhydride
(0.51 g, 5.0 mmol) was added to the reaction mixture, and
the resulting mixture was stirred at room temperature for 4 h.
The resulting mixture was quenched with water (10 mL),
and the aqueous layer was extracted with diethyl ether.
The combined organic extracts were dried over MgSO4,
and evaporated under the reduced pressure. The crude
product was purified by a flash column chromatography
(5% EtOAc in hexane) to give 4c (1.10 g, 2.0 mmol; yield 83%,
d.r. = 1:1).
1H NMR (400 MHz) d 0.84–0.94 (m, 3H), 1.19–1.66 (m,
4H), 1.86–1.98 (m, 3H), 2.04–2.45 (m, 4H), 3.28–3.76 (m, 2H),
4.31–4.52 (m, 2H), 5.53–5.57 (m, 0.5H), 5.66–5.71 (m, 0.5H),
7.23–7.72 (m, 5H), 7.89–7.96 (m, 5H); 13C NMR (100 MHz) d
3
13.72, 20.20, 20.61, 23.00, 23.05, 24.29 (d, JCF = 4.1 Hz),
2
3
24.52 (d, JCF = 4.9 Hz), 28.68 (d, JCF = 20.6 Hz), 29.07 (d,
2JCF = 19.7 Hz), 30.39 (d, 3JCF = 3.2 Hz), 30.51 (d,
3JCF = 5.0 Hz), 65.96, 66.15, 68.81 (d, JCF = 16.6 Hz),
2
2
69.03 (d, JCF = 19.8 Hz), 73.19, 108.79 (d, JCF = 226.3 Hz),
1
1
109.60 (d, JCF = 223.0 Hz), 127.59, 127.62, 127.69, 127.91,
128.30, 128.34, 128.84, 129.00, 130.26, 130.33, 130.44,
134.14, 134.51, 138.04, 138.08, 169.47; 19F NMR
3
(283 MHz) d À156.91 (td, JHF = 8.8, 20.6 Hz, 0.5F), d
À155.73 (m, 0.5F); IR (methylene chloride) 3055, 2985,
2835, 1672, 1601, 1115, 1074 cmÀ1; MS (FAB) m/z 437
(M + H)+, HRMS (FAB) calcd. for C23H30O5FS (M + H):
437.1798, found: 437.1825.
4.4.1. 3-Acetoxy-1-benzyloxy-4-fluoro-4-
phenylsulfonylheptadecane (4c)
4.3.2. 3-Benzoyloxy-1-benzyloxy-4-fluoro-4-
1H NMR (400 MHz) d 0.87–0.90 (m, 3H), 1.19–1.37 (m,
20H), 1.46–1.71 (m, 3.5H), 1.92 (s, 1.5H), 2.03–2.19 (m, 2H),
2.24–2.49 (m, 1H), 3.30–3.40 (m, 1H), 3.45–3.59 (m, 2H),
4.40–4.48 (m, 2H), 5.56 (ddd, 3JHH = 1.6, 9.7 Hz,
phenylsulfonyloctane (4ab)
1H NMR (400 MHz) d 0.84–0.97 (m, 3H), 1.24–1.42 (m,
2H), 1.52–1.78 (m, 2H), 2.04–2.36 (m, 4H), 3.38–3.58 (m, 2H),
4.35–4.44 (m, 2H), 5.85 (br t, 3JHF = 8.8 Hz, 0.4H), 5.98–6.03
(m, 0.6H), 7.20–7.64 (m, 11H), 7.79–8.00 (m, 4H); 13C NMR
3
3JHF = 7.8 Hz, 0.5H), 5.69 (ddd, JHH = 2.6, 10.3 Hz,
3JHF = 7.8 Hz, 0.5H), 7.25–7.33 (m, 5H), 7.42–7.46 (m, 1H),
3
(100 MHz) d 13.72, 23.03, 23.08, 24.56 (d, JCF = 5.0 Hz),
7.53–7.57 (m, 1H), 7.61–7.67 (m, 1H), 7.89–7.96 (m, 2H); 13
C
3
24.87 (d, JCF = 4.9 Hz), 28.98 (d, JCF = 82.3 Hz), 29.82 (d,
2
3
NMR (100 MHz) (selected data) d 30.37 (d, JCF = 3.3 Hz),
30.49 (d, 3JCF = 5.0 Hz), 65.94, 66.12, 68.83 (d,
3
2JCF = 78.73 Hz), 30.71 (d, JCF = 4.8 Hz), 30.76 (d,
3JCF = 4.9 Hz), 66.00 (d, 2JCF = 32.2 Hz), 66.07 (d,
2JCF = 19.0 Hz), 69.01 (d, JCF = 23.2 Hz), 73.13 (d,
2
4
2JCF = 18.2 Hz), 69.24 (d, JCF = 2.5 Hz), 69.46, 73.17,
4JCF = 1.6 Hz), 73.15 (d, 4JCF = 2.5 Hz), 108.78 (d,
1
73.19,
109.10
(d,
1JCF = 226.3 Hz),
109.33
(d,
1JCF = 226.3 Hz), 109.58 (d, JCF = 223.0 Hz), 127.53,
1JCF = 223.8 Hz), 127.63, 127.80, 128.24, 128.27, 128.30,
129.00, 129.03, 129.83, 129.87, 130.29, 130.33, 130.35,
133.23, 133.26, 134.25, 165.04, 165.41; 19F NMR
(283 MHz) d À156.61 (m, 0.4F), À155.90 (m, 0.6F); MS
127.56, 127.65, 127.85, 128.25, 128.29, 128.77, 128.94,
130.28, 130.40, 134.06, 134.42, 134.90, 136.60, 138.00,
138.05, 169.39, 169.41; 19F NMR (283 MHz) d À156.67 (dt,
3
3JHF = 7.8, 20.6 Hz, 0.5F), À155.50 (ddd, JHF = 7.8, 14.6,

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N. Asakura et al. / Journal of Fluorine Chemistry 127 (2006) 800–808
2
26.05, 27.81 (d, JCF = 28.9 Hz), 28.76, 29.16, 31.69 (d,
21.6 Hz, 0.5F); MS (FAB) m/z 563 (M + H)+, HRMS
(FAB) calcd. for C32H48O5FS (M + H)+: 563.3206, found:
563.3193.
4
3JCF = 2.4 Hz), 69.52 (d, JCF = 1.7 Hz), 72.51, 100.91 (d,
2JCF = 15.6 Hz), 127.24, 127.33, 128.08, 138.39, 160.60 (d,
1JCF = 254.4 Hz); 19F NMR (283 MHz) d À108.42 (dt,
3JHF = 17.2, 37.8 Hz); IR (methylene chloride) 3055, 2929,
2858, 1707, 1362, 1155, 1099 cmÀ1; MS (EI) m/z 292 (M)+,
HRMS (EI) calcd. for C19H29OF (M)+: 292.2202, found:
292.2186. Isomer E: (selected data) 1H NMR (400 MHz) d 5.02
4.4.2. 3-Acetoxy-1-benzyloxy-4-fluoro-4-
phenylsulfonylnonadecane (4d)
1H NMR (300 MHz) d 0.85–0.89 (m, 3H), 1.16–1.35 (m,
24H), 1.48–1.68 (m, 3.5H), 1.92 (s, 1.5H), 1.99–2.21 (m, 2H),
2.23–2.51 (m, 1H), 3.26–3.40 (m, 1H), 3.45–3.56 (m, 2H),
4.35–4.50 (m, 2H), 5.54 (m, 0.5H), 5.68 (m, 0.5H), 7.28–7.65
(m, 8H), 7.88–7.95 (m, 2H); 19F NMR (283 MHz) d À156.88
(dt, 3JHH = 8.1 Hz, 3JHF = 21.3 Hz, 1H); 13C NMR (100 MHz)
4
31.95, 69.82 (d, JCF = 3.3 Hz), 72.73, 101.55 (d,
d
1
2JCF = 24.0 Hz), 161.29 (d, JCF = 247.8 Hz); 19F NMR
3
3
(ddd, JHF = 6.0, 18.9, 20.6 Hz, 0.5F), À155.71 (ddd,
(283 MHz) d À103.18 (q, JHF = 21.3 Hz).
3JHF = 8.5, 13.8, 20.6 Hz, 0.5F); MS (EI) m/z 590 (M)+,
HRMS (FAB) calcd. for C34H51O5FS: 590.3441, found:
590.3436.
4.5.3. 1-Benzyloxy-4-fluoro-3-heptadecene (5c)
Isomer Z: 1H NMR (400 MHz) d 0.86–0.90 (m, 3H), 1.18–
1.38 (m, 20H), 1.43–1.59 (m, 2H), 2.09–2.41 (m, 4H),
3.47 (t, 3JHH = 6.8 Hz, 2H), 4.49–4.63 (m, 3H), 7.24–7.34 (m,
5H); 13C NMR (100 MHz) (selected data) d 69.72 (d,
4.5. Typical procedure for the preparation of 5 through
reductive desulfonylation
2
4JCF = 1.6 Hz), 72.73, 101.02 (d, JCF = 15.7 Hz), 127.48,
127.59, 128.31, 138.51, 160.88 (d, 1JCF = 254.4 Hz); 19F NMR
(283 MHz) d À108.28 (dt, 3JHF = 17.2, 38.2 Hz); MS (FAB) m/
z 361 (M À H)+, HRMS (FAB) calcd. for C24H39OF (M À H):
3-Acetoxy-1-benzyloxy-4-fluoro-4-phenylsulfonyloctane
4aa (0.44 g, 1.0 mmol) was dissolved in methanol–THF (1:1;
30 mL) under an argon atmosphere. After addition of
anhydrous sodium hydrogen phosphate (4.80 g, 40.0 mmol),
the reaction mixture was cooled to À10 8C. The 5% sodium
amalgam (3.75 g, 8.0 mmol) was added in several portions
with vigorous stirring. The reaction mixture was allowed to
warm to room temperature and stirred overnight. The resulting
mixture was decanted from the solid residue, which was
extracted with diethyl ether. The combined organic extracts
were washed with water, dried over MgSO4, and evaporated
under the reduced pressure. The crude product was purified by a
flash column chromatography (5% EtOAc in hexane) to give 5a
(0.19 g, 0.8 mmol; yield 80%, E:Z = 1:3).
361.2907, found: 361.2910. Isomer E: (selected data) 1H NMR
3
3.44 (t, JHH = 7.0 Hz, 2H), 5.02 (dt,
(400 MHz)
d
3
3JHH = 7.8 Hz, JHF = 22.4 Hz, 1H); 13C NMR (100 MHz) d
4
70.03 (d, JCF = 2.5 Hz), 72.97, 101.67 (d, JCF = 23.9 Hz),
2
1
127.55, 127.57, 128.35, 138.35, 161.56 (d, JCF = 247.8 Hz);
3
19F NMR (283 MHz) d À103.36 (q, JHF = 22.4 Hz).
4.5.4. 1-Benzyloxy-4-fluoro-3-nonadecene (5d)
Isomer Z: 1H NMR (300 MHz) d 0.86–0.90 (m, 3H), 1.17–
1.34 (m, 24H), 1.42–1.52 (m, 2H), 2.08–2.41 (m, 4H), 3.47 (t,
3
3JHH = 6.6 Hz, 2H), 4.51 (s, 2H), 4.56 (dt, JHH = 7.3 Hz,
3JHF = 37.9 Hz, 1H), 7.24–7.34 (m, 5H); 19F NMR (283 MHz)
4.5.1. 1-Benzyloxy-4-fluoro-3-octene (5a)
Isomer Z: 1H NMR (400 MHz) d 0.90 (t, 3JHH = 7.3 Hz, 3H),
1.25–1.39 (m, 2H), 1.42–1.51 (m, 2H), 2.09–2.18 (m, 2H),
3
d À108.48 (dt, JHF = 18.1, 37.9 Hz); MS (CI) m/z 391
(M + H)+, HRMS (CI) calcd. for C26H43OF (M + H): 391.3376,
found: 391.3371. Isomer E: (selected data) 1H NMR
3
2.20–2.40 (m, 2H), 3.46 (t, JHH = 6.6 Hz, 2H), 4.50 (s, 2H),
3
3.44 (t, JHH = 7.1 Hz, 2H), 5.02 (dt,
3
3
(300 MHz)
d
4.56 (dt, JHH = 7.3 Hz, JHF = 37.8 Hz, 1H), 7.21–7.33 (m,
5H); 13C NMR (100 MHz) d 13.81, 22.02, 24.33, 28.33, 31.70
3
3JHH = 7.9Hz, JHF = 21.4 Hz, 1H); 19F NMR (283 MHz) d
3
2
(d, JCF = 27.3 Hz), 69.73 (d, JCF = 2.4 Hz), 101.11 (d,
4
À103.37 (dt, JHF = 21.4, 22.3 Hz).
2JCF = 15.7 Hz) 127.52, 127.59, 127.63, 128.53, 138.55,
1
160.84 (d, JCF = 254.4 Hz); 19F NMR (283 MHz)
d
4.6. Typical procedure for the reductive removal of benzyl
group on 5
3
À108.59 (dt, JHF = 17.2, 37.8 Hz). Isomer E: (selected data)
1H NMR (400 MHz) d 0.89 (t, JHH = 7.3 Hz, 3H), 3.43 (t,
3
3JHH = 6.8 Hz, 2H), 5.03 (dt, JHH = 8.1, 22.3 Hz, 1H); 13C
A solution of 5b (0.264 g, 0.90 mmol) in THF (4 mL) was
cooled to À78 8C and liquid ammonia (ꢀ10 mL) was added.
An adequate amount of sodium was added in small pieces.
After stirring for 45 min at À33 8C, excess metal was
consumed by a careful addition of sat aq NH4Cl. The resulting
mixture was allowed to warm to room temperature, stirred
for 2 h and then extracted with diethyl ether. The organic layer
was washed with brine, dried over MgSO4. Filtration and
concentration in vacuo afforded the crude product, which
was purified by a flash column chromatography (15% EtOAc
in hexane) to give 6b (0.144 g, 0.71 mmol; yield 79%,
E:Z = 1:3).
3
2
NMR (100 MHz) d 22.12, 24.38, 27.75 (d, JCF = 28.9 Hz),
28.55, 70.03 (d, 4JCF = 2.5 Hz), 72.98, 101.76 (d,
2JCF = 23.9 Hz), 161.53 (d, JCF = 247.8 Hz); 19F NMR
1
3
(283 MHz) d À103.44 (q, JHF = 22.3 Hz).
4.5.2. 1-Benzyloxy-4-fluoro-3-dodecene (5b)
Isomer Z: 1H NMR (400 MHz) d 0.86–0.90 (m, 3H), 1.21–
1.37 (m, 10H), 1.39–1.49 (m, 2H), 2.03–2.41 (m, 4H), 3.40–
3
3.47 (m, 2H), 4.48 (s, 2H), 4.55 (dt, JHH = 7.3 Hz,
3JHF = 37.8 Hz, 1H), 7.20–7.31 (m, 5H); 13C NMR
3
(100 MHz) d 13.86, 15.03, 22.49, 24.17 (d, JCF = 3.1 Hz),

N. Asakura et al. / Journal of Fluorine Chemistry 127 (2006) 800–808
807
4.6.1. 4-Fluoro-oct-3-en-1-ol (6a)
Isomer Z: 1H NMR (400 MHz) d 0.88 (t, 3JHH = 7.3 Hz, 3H),
1.27–1.37 (m, 2H), 1.41–1.51 (m, 2H), 1.97–2.46 (m, 4H),
2835, 1649, 1602 cmÀ1; MS (FAB) m/z 299 (M À H)+, HRMS
(FAB) calcd. for C19H36OF (M À H): 299.2750, found:
1
299.2754. Isomer E: (selected data) H NMR (400 MHz) d
3
3
3
3
3.56–3.61 (m, 2H), 4.51 (dt, JHH = 7.3 Hz, JHF = 37.9 Hz,
1H); 13C NMR (100 MHz) d 13.77, 22.00, 27.32 (d,
4.92 (dt, JHH = 8.0 Hz, JHF = 21.7 Hz, 1H); 13C NMR
(100 MHz)
d
62.42 (d, 4JCF = 2.4 Hz), 101.25 (d,
2
1
3JCF = 4.1 Hz), 30.31, 31.71 (d, JCF = 27.2 Hz), 62.32 (d,
2JCF = 23.9 Hz), 162.41 (d, JCF = 249.5 Hz); 19F NMR
2
3
4JCF = 2.5 Hz), 100.50 (d, JCF = 15.7 Hz), 161.74 (d,
(283 MHz) d À103.35 (dt, JHF = 21.7, 24.2 Hz).
1JCF = 255.3 Hz); 19F NMR (283 MHz) d À107.99 (dt,
3JHF = 17.2, 37.9 Hz). Isomer E: (selected data) 1H NMR
4.7. Typical procedure for the Jones oxidation of 6
3
0.89 (t, JHH = 7.3 Hz, 3H), 4.97 (dt,
(400 MHz)
d
3
3JHH = 8.0 Hz, JHF = 21.5 Hz, 1H); 13C NMR (100 MHz) d
13.79, 22.13, 32.06 (d, 2JCF = 28.1 Hz), 62.37 (d,
To a solution of 6b (0.107 g, 0.53 mmol) in acetone (4 mL)
at 0 8C was added dropwise Jones reagent until a persistent
orange color was observed. After the mixture was stirred
for 30 min at room temperature, an excess of Jones reagent was
quenched by dropwise addition of 2-propanol (adequate
amount) with cooling in an ice bath. The reaction mixture
was partitioned between AcOEt and water. The aqueous phase
was extracted with AcOEt. The combined organic extracts
were washed with water and brine, dried over MgSO4,
concentrated under the reduced pressure. The crude product
was purified by a flash column chromatography (20% EtOAc in
hexane) to give 8b (90.7 mg, 0.42 mmol; yield 79%,
E:Z = 1:3).
2
4JCF = 3.3 Hz), 101.25 (d, JCF = 23.2 Hz); 19F NMR
3
(283 MHz) d À101.86 (q, JHF = 21.5 Hz).
4.6.2. 4-Fluoro-dodec-3-en-1-ol (6b)
1
Isomer Z: (selected data) H NMR (400 MHz) d 0.85–0.90
(m, 3H), 1.18–1.27 (m, 10H), 1.42–1.52 (m, 2H), 2.10–2.34 (m,
4H), 3.59–3.64 (m, 2H), 4.52 (dt, 3JHH = 7.3 Hz,
3JHF = 38.0 Hz, 1H); 13C NMR (100 MHz) d 15.27, 22.68,
3
26.51, 27.36 (d, JCF = 4.1 Hz), 27.92, 29.08, 29.23, 29.36,
32.07 (d, 2JCF = 27.3 Hz), 62.38 (d, 4JCF = 3.2 Hz), 101.57 (d,
1
2JCF = 15.8 Hz), 161.75 (d, JCF = 254.4 Hz); 19F NMR
3
(283 MHz) d À107.89 (dt, JHF = 18.9, 38.0 Hz); MS (EI) m/
z 202 (M+), HRMS (EI) calcd. for C12H23OF (M+): 202.1733,
found: 202.1726. Isomer E: (selected data) 1H NMR
4.7.1. 4-Fluoro-oct-3-enoic acid (8a)
1
Isomer Z: (selected data) H NMR (400 MHz) d 0.90–0.94
(m, 3H), 1.30–1.40 (m, 2H), 1.45–1.55 (m, 2H), 2.15–2.27 (m,
3
(400 MHz) d 4.98 (dt, JHH = 8.0 Hz, JHF = 21.7 Hz, 1H);
3
2
3
3
13C NMR (100 MHz) d 62.31, 101.32 (d, JCF = 23.1 Hz),
2H), 3.18 (d, JHH = 7.1 Hz, 2H), 4.73 (dt, JHH = 7.1 Hz,
3JHF = 36.3 Hz, 1H); 19F NMR (283 MHz) d À105.46 (dt,
3JHF = 19.2, 36.3 Hz); MS (FAB) m/z 159 (M À H)À, HRMS
(FAB) calcd. for C8H12O2F (M À H): 159.0822, found:
1
162.33 (d, JCF = 248.7 Hz); 19F NMR (283 MHz) d À101.72
3
(q, JHF = 21.7 Hz).
1
4.6.3. 4-Fluoro-heptadec-3-en-1-ol (6c)
Isomer Z: 1H NMR (400 MHz) d 0.84–0.87 (m, 3H), 1.17–
1.35 (m, 20H), 1.40–1.52 (m, 2H), 1.85 (br s, 1H), 2.09–2.32
159.0796. Isomer E: (selected data) H NMR (400 MHz) d
3
3
3.02 (d, JHH = 7.8 Hz, 2H), 5.19 (dt, JHH = 7.8 Hz,
3JHF = 20.0 Hz, 1H); 19F NMR (283 MHz) d À100.41 (q,
3JHF = 20.0 Hz).
3
3
(m, 4H), 3.59 (t, JHH = 6.5 Hz, 2H), 4.51 (dt, JHH = 7.5 Hz,
3JHF = 37.9 Hz); 13C NMR (100 MHz) d 14.03, 22.64, 26.19,
3
27.24, 28.97 (d, JCF = 9.8 Hz), 29.32, 29.60, 29.62, 29.65,
4.7.2. 4-Fluoro-dodec-3-enoic acid (8b)
Isomer Z: 1H NMR (400 MHz) d 0.86 (t, 3JHH = 6.8 Hz, 3H),
1.17–1.36 (m, 10H), 1.40–1.66 (m, 2H), 2.08–2.41 (m, 2H),
32.01 (d, 2JCF = 23.1 Hz), 62.20 (d, 4JCF = 1.7 Hz), 100.48 (d,
1
2JCF = 15.7 Hz), 161.65 (d, JCF = 255.2 Hz); 19F NMR
3
3
3
(283 MHz) d À107.64 (dt, JHF = 17.2, 37.9 Hz); MS (FAB)
3.16 (d, JHH = 7.0 Hz, 2H), 4.70 (dt, JHH = 7.0 Hz,
3JHF = 36.1 Hz, 1H); 13C NMR (100 MHz) d 15.20, 22.69,
m/z 271 (M À H)+, HRMS (FAB) calcd. for C17H32OF
(M À H)+: 271.2437, found: 271.2429. Isomer E: (selected
3
26.02 (d, JCF = 1.7 Hz), 27.99, 28.94, 29.22, 29.31, 31.81 (d,
3
2
data) 1H NMR (400 MHz) d 4.92 (dt, JHH = 8.1 Hz,
3JCF = 12.4 Hz), 31.94 (d, JCF = 14.1 Hz), 96.41 (d,
3JHF = 23.0 Hz); 13C NMR (100 MHz) d 22.60, 26.44, 27.28,
2JCF = 14.9 Hz), 162.16 (d, JCF = 257.7 Hz), 177.26; 19F
1
3
27.84, 28.13, 29.04 (d, JCF = 9.0 Hz), 29.34, 29.50, 31.70 (d,
3
NMR (283 MHz) d À105.47 (dt, JHF = 17.2, 36.1 Hz); MS
4
2JCF = 29.8 Hz), 62.28 (d, JCF = 2.5 Hz), 101.23 (d,
(FAB) m/z 215 (M À H)À, HRMS (FAB) calcd. for C12H20O2F
(M À H): 215.1447, found: 215.1458. Isomer E: (selected data)
1
2JCF = 23.9 Hz), 162.21 (d, JCF = 248.7 Hz); 19F NMR
3
3
(283 MHz) d À101.41 (q, JHF = 23.0 Hz).
1H NMR (400 MHz) d 2.99 (d, JHH = 7.9 Hz, 2H), 5.16 (dt,
3
3JHH = 7.9 Hz, JHF = 20.0 Hz, 1H); 13C NMR (100 MHz) d
4.6.4. 4-Fluoro-nonadec-3-en-1-ol (6d)
1
Isomer Z: (selected data) H NMR (400 MHz) d 0.79–0.83
97.87 (d, 2JCF = 28.9 Hz), 162.83 (d, 1JCF = 250.3 Hz), 176.94;
3
19F NMR (283 MHz) d À100.42 (dt, JHF = 20.0, 24.0 Hz).
(m, 3H), 1.16–1.26 (m, 24H), 1.32–1.48 (m, 2H), 2.05–2.29 (m,
4H), 3.52–3.60 (m, 2H), 4.47 (dt, 3JHH = 7.5 Hz,
3JHF = 37.9 Hz, 1H); 13C NMR (100 MHz) d 62.36 (d,
4.7.3. 4-Fluoro-heptadec-3-enoic acid (8c)
Isomer Z: 1H NMR (400 MHz) d 0.86–0.90 (m, 3H), 1.25–
1.32 (m, 20H), 1.46–1.65 (m, 2H), 2.14–2.32 (m, 2H), 3.18 (d,
2
4JCF = 2.5 Hz), 100.50 (d, JCF = 15.8 Hz), 161.83 (d,
1JCF = 255.2 Hz); 19F NMR (283 MHz) d À108.47 (dt,
3JHH = 7.1 Hz, 2H), 4.72 (dt, JHH = 7.1 Hz, JHF = 36.3 Hz);
3
3
3JHF = 17.2, 37.9 Hz); IR (methylene chloride) 3055, 2985,
13C NMR (100 MHz) d 14.10, 22.68, 25.96 (d, 3JCF = 1.6 Hz),

808
N. Asakura et al. / Journal of Fluorine Chemistry 127 (2006) 800–808
28.90, 29.30, 29.35, 29.50, 29.61, 29.67, 31.82 (d,
2
References
2JCF = 26.4 Hz), 96.17 (d, JCF = 14.9 Hz), 162.22 (d,
1JCF = 257.7 Hz), 177.76; 19F NMR (283 MHz) d À105.21
(dt, 3JHF = 18.2, 36.3 Hz); MS (FAB) m/z 287 (M + H)+, HRMS
(FAB) calcd. for C17H32OF (M + H)+: 287.2387, found:
[1] R. Filler, Y. Kobayashi, L.M. Yagupolskii (Eds.), Organofluorine Com-
pounds in Medicinal Chemistry and Biomedical Applications, Elsevier,
Amsterdam, 1993;
T. Hiyama, Organofluorine Compounds, Chemistry and Applications,
Springer, Berlin, 2000.
1
287.2390. Isomer E: (selected data) H NMR (400 MHz) d
3.02 (d, 3JHH = 7.8 Hz), 5.18 (dt, 3JHH = 7.8 Hz,
3JHF = 20.0 Hz); 13C NMR (100 MHz) d 24.66, 26.09, 30.98
(d, 2JCF = 10.7 Hz), 34.01, 97.64 (d, 2JCF = 29.7 Hz), 162.88 (d,
1JCF = 250.3 Hz), 177.53; 19F NMR (283 MHz) d À100.21 (dt,
3JHF = 20.0, 22.5 Hz).
[2] I. Ojima, J.R. McCarthy, J.T. Welch (Eds.), Biomedical Frontiers of
Fluorine Chemistry, ACS Symposium Series 639, American Chemical
Society, Washington, DC, 1996.
[3] A. Otaka, H. Watanabe, E. Mitsuyama, A. Yukimasa, H. Tamamura, N.
Fujii, Tetrahedron Lett. 42 (2001) 285–287.
[4] M. Okada, Y. Nakamura, A. Saito, A. Sato, H. Horikawa, T. Taguchi,
Chem. Lett. 49 (2002) 28–29.
[5] A. Fujii, Y. Usuki, H. Iio, T. Tokoroyama, Synlett (1994) 725–726;
N. Asakura, Y. Usuki, H. Iio, J. Fluorine Chem. 124 (2003) 81–88.
[6] M. Shimizu, A. Ohno, S. Yamada, Chem. Pharm. Bull. 49 (2001) 312–317.
[7] S. Pazenok, J.P. Demoute, S. Zard, T. Lequeux, WO Patent 0,240,459
(2002).
4.7.4. 4-Fluoro-nonadec-3-enoic acid (8d)
Isomer Z: 1H NMR (300 MHz) d 0.79–0.83 (m, 3H), 1.09–
1.30 (m, 24H), 1.36–1.45 (m, 2H), 2.06–2.30 (m, 2H), 3.11 (d,
3JHH = 7.1 Hz, 2H), 4.65 (dt, JHH = 7.1 Hz, JHF = 36.2 Hz,
1H); 13C NMR (100 MHz) d 14.11, 22.69, 25.96 (d,
3JCF = 1.6 Hz), 28.90, 28.96, 29.30, 29.32, 29.36, 29.51,
3
3
S. Pazenok, J.P. Demoute, S. Zard, T. Lequeux, Chem. Abstr. 136 (2002)
386131;
3
D. Chevrie, T. Lequeux, J.P. Demoute, S. Pazenok, Tetrahedron Lett. 44
(2003) 8127–8130.
29.61, 29.65, 29.67, 29.69, 31.81 (d, JCF = 23.1 Hz), 31.83
2
2
(d, JCF = 26.5 Hz), 96.17 (d, JCF = 14.1 Hz), 162.23 (d,
1JCF = 257.6 Hz), 177.54; 19F NMR (283 MHz) d À105.41 (dt,
3JHF = 17.2, 36.2 Hz); MS (CI) m/z 315 (M + H)+, HRMS (CI)
calcd. for C19H35O2F: 315.2699, found: 315.2713. Isomer E:
[8] M. Julia, J.M. Paris, Tetrahedron Lett. 14 (1973) 4833–4836.
[9] For reviews, see: M. Julia, Pure Appl. Chem. 57 (1985) 763–768;
P. Kocienski, Phosphorus Sulfur Silicon Relat. Elem. 24 (1985) 477–507.
[10] P.J. Kocienski, B. Lythgoe, I. Waterhouse, J. Chem. Soc., Perkin Trans. 1
(1980) 1045–1050.
1
3
(selected data) H NMR (300 MHz) d 2.95 (d, JHH = 7.9 Hz,
3
[11] A.P. Kozikowski, P.D. Stein, J. Org. Chem. 49 (1984) 2301–2309.
[12] N.M. Sergeev, N.N. Shapet’ko, G.V. Timofeyuk, Z. Strukturnoi Khim. 8
(1967) 43–50.
3
2H), 5.12 (dt, JHH = 7.9 Hz, JHF = 20.3 Hz, 1H); 13C NMR
(100 MHz)
d
30.94 (d, 2JCF = 11.5 Hz), 97.64 (d,
1
2JCF = 29.7 Hz), 162.88 (d, JCF = 251.1 Hz), 177.31; 19F
[13] Spectral data for B. 1H NMR (400 MHz) d 0.91 (t, JHH = 7.1 Hz, 3H),
3
3
1.24–1.43 (m, 4H), 1.72–2.01 (m, 2H), 2.18 (s, 3H), 2.86 (d,
3
NMR (283 MHz) d À100.40 (dt, JHF = 20.3, 22.5 Hz).
3JHF = 18.3 Hz, 2H), 6.36 (dd, JHH = 7.6, 15.6 Hz, 1H), 6.77 (dd,
3
3
3JHH = 15.6 Hz, JHF = 21.2 Hz, 1H), 9.62 (d, JHH = 7.6 Hz, 1H); 13C
4.8. Antimicrobial activity
4
NMR (100 MHz) d 13.85, 17.64 (d, JCF = 2.1 Hz), 22.73, 25.25 (d,
3JCF = 4.1 Hz), 37.29 (d, JCF = 22.3 Hz), 42.30 (d, JCF = 24.7 Hz),
2
2
1
3
Minimal inhibitory concentration (MIC) values were
determined by the serial 2-fold broth dilution method [15]
after 24 h cultivation in 3% nutrient broth at 37 8C for bacteria,
and in YPD medium containing 1% yeast extract, 1% peptone,
and 2% glucose at 25 8C for yeasts and filamentous fungi.
98.31 (d, JCF = 181.7 Hz), 131.37 (d, JCF = 8.2 Hz), 155.26 (d,
2JCF = 21.5 Hz), 192.60; 19F NMR (283 MHz) d À156.58 (m).
[14] J.I. Gordon, R.J. Duronio, D.A. Rudnick, S.P. Adams, G.W. Gokel, J. Biol.
Chem. 266 (1991) 8647–8650.
[15] M.S. Shafi, J. Clin. Pathol. 28 (1975) 989–992.