Synthesis of monofluorinated isofagomine analogues and evaluation as glycosidase inhibitors

Article abstract of DOI:10.1016/j.jfluchem.2011.05.031

The straightforward synthesis of monofluorinated isofagomine analogues 1-3 was described. The synthetic strategy featured that the chiral carbon center bearing fluorine atom was constructed stereoselectively via silicon-induced Reformatskii-Claisen rearra

Full text of DOI:10.1016/j.jfluchem.2011.05.031

Journal of Fluorine Chemistry 132 (2011) 838–845
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of monofluorinated isofagomine analogues and evaluation as
glycosidase inhibitors
Yi Yang a, Feng Zheng a, Mikael Bols b, Lavinia G. Marinescu b, Feng-Ling Qing a,
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
b Department of Chemistry, University of Copenhagen, Universitetsparken 5, Denmark
A R T I C L E I N F O
A B S T R A C T
Article history:
The straightforward synthesis of monofluorinated isofagomine analogues 1–3 was described. The
synthetic strategy featured that the chiral carbon center bearing fluorine atom was constructed
stereoselectively via silicon-induced Reformatskii–Claisen rearrangement of allyl bromofluoroacetate.
These compounds were tested for inhibition of five glycosidases. The 3S,4R,5R isomer 3 has been found to
Received 21 March 2011
Received in revised form 25 May 2011
Accepted 30 May 2011
Available online 12 June 2011
be a potent inhibitor against
b
-glucosidase from almonds with Ki value of 11.9
mM.
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
Iminosugar
Glycosidase inhibitor
Fluorinated compounds
1. Introduction
have been made on structure modification of leading iminosugars.
It is well known that the electronegative properties of fluorine
make it a near ‘isoelectronic’ replacement for the hydroxyl group.
Furthermore, the strong gauche and antiperiplanar effects of
fluorine atom due to its high electronegativity has profound
stereoelectronic effect on neighboring groups, thereby the fluorine
substituent can lead to a change in the preferred molecular
conformation, which could affect protein binding affinity and
selectivity at molecular level [5]. Several fluorinated iminosugars
have been studied [6]. Among them, the fluorinated analogue at C-
20 of Miglitol shows an inhibitory activity four times higher than
Iminosugars have received increasing attention among syn-
thetic chemists and biochemists in recent years because these
compounds and their derivatives have significant therapeutic
potential for the treatment of metabolic diseases, inhibition of
tumor metastasis and control of infections of fungi and viruses [1].
Two iminosugar-based drugs have successfully completed clinical
trials: GlysetTM (N-hydroxyethyl-DNJ) in 1996 for treatment of
complications associated with type II diabetes, and ZavescaTM (N-
butyl-1-DNJ) in 2003 as the first oral drug for Gaucher disease, a
severe lysosomal storage disorder (Fig. 1) [1e]. Isofagomine [2],
which mimics the transition state of glycoside cleavage in its
protonated form, exhibits potent inhibition to several glycosidases,
the parent compound for the
a-galactosidase from green coffee
beans and low cytotoxicity against a panel of human cell lines,
making it an promising candidate for further investigations [6a].
Recently, gem-4,4-difluoromethylated isofagomine analogues
have been investigated by our group [2a], and we found that
when a hydroxyl group is unessential it could be replaced by gem-
difluoro with minor change or even increase in the enzyme
inhibition. Since fluoromethylene group (CHF) and gem-difluor-
omethylene group (CF2) have distinct electron-withdrawing ability
[7], we suppose that 4-fluoroisofagomine will have an another
profile of glycosidases inhibition in comparison with gem-4,4-
difluoromethylated isofagomine analogues, which could give us a
deeper understanding of the fluorine effects on the bioactivity of
isofagomine analogues. On the basis of the above consideration
and our continuing interest in the fluorinated iminosugars [2a,8],
we described herein the synthesis and biological evaluation of
monofluorinated isofagomine analogues 1–3 (Fig. 2).
especially
b-glucosidase from sweet almond with Ki value of
0.11 M, and currently undergoes Phase I and II clinical trials
m
sponsored by Amicus Therapeutics. Moreover, the C-4 epimer of
isofagomine, isogalactofagomine, is also a strong glycosidase
inhibitor [3].
In spite of the initial potential shown by these molecules,
iminosugars as a therapeutic class have not been as promising as
expected. The main reason may be that many glycosidase
inhibitors are poor in clinical selectivity and cause unacceptable
side effects [4]. To overcome this limitation, considerable efforts
* Corresponding author. Fax: +86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.05.031

Y. Yang et al. / Journal of Fluorine Chemistry 132 (2011) 838–845
839
yield, respectively. Selective debenzylation of ethers 12 and 13 was
carried out in the presence of BCl3 in dichloromethane at 0 8C to
give triols 14 and 15, which were transformed to alcohols 16 and
17 through oxidation with NaIO4 and subsequent reduction with
NaBH4 in 72% and 73% yield over two steps, respectively. Finally, 4-
fluoroisofagomine analogues 1 and 2 were obtained by hydro-
genation of 16 and 17 in the presence of 20% Pd(OH)2/C (Scheme 2).
All the characterization data of compounds 10 and 11 were
identical to diols 100 and 110, which were prepared from our
reported compounds 18 and 19 [9] via benzylation, ozonolysis and
subsequent NaBH4 reduction. Therefore, the absolute configura-
tion of target molecules 1 and 2 at C-3 position generated by Luche
reduction could be determined as S and R according to the
configuration of compounds 18 and 19 (Scheme 3).
Fig. 1. Selected iminosugars as glycosidase inhibitors.
Diastereoisomer 3 of 4-fluoroisofagomines 1 and 2 was also
prepared by a similar procedure from compound 5 (Scheme 4).
The absolute configuration of 3 was determined by the X-ray
crystal structure of the p-nitrobenzoylated compound 26 (Fig. 3),
which was prepared from the reaction of triol 25 with 4-
nitrobenzoyl chloride (Scheme 4).
2. Results and discussion
2.1. Chemistry
Very recently, our group has developed the stereoselective
synthesis of monofluorinated synthons 4 and 5 by the Reformats-
2.2. Enzymology
kii–Claisen rearrangement of allyl bromofluoroacetate via a-fluoro
silyl ketene acetal (Scheme 1) [9]. Based on our reported synthetic
strategy to gem-4,4-difluoromethylated isofagomine analogues
[2a], we think that synthons 4 and 5 are the suitable precursors for
preparation of target molecules 1–3. Accordingly, treatment of
compound 4 with NaBH4 in the presence of cerium chloride
heptahydrate afforded two separable diastereoisomeric alcohols 6
and 7 in 81% and 11% yield, respectively. Then protection of
alcohols 6 and 7 to benzylic ethers 8 and 9, which are converted to
diols 10 and 11 via ozonolysis followed by NaBH4 reduction in situ,
respectively. Diols 10 and 11 are subjected to methylsulfonyl
chloride, followed by cyclization of corresponding mesylates with
neat benzylamine to afford piperidines 12 and 13 in 85% and 81%
The synthesized 4-fluoroisofagomine analogues 1–3 were
evaluated for their inhibitory activities toward five glycosidases
namely the
yeast, -galactosidases from Aspergillus orizae,
from Green Coffee beans, -mannosidases from Jack beans. All
b
-glucosidase from almonds,
a
-glucosidase from baker
b
a
-galactosidase
a
assays were performed at 25 8C and pH 6.8 using the corresponding
nitrophenyl glycoside substrates. The Ki value obtained are
summarized in Table 1.
Compounds 1 and 2 showed no or negligible inhibition toward
b
-glucosidase from almonds and
orizae, but displayed moderate inhibition of
baker yeast and -galactosidase from Green Coffee beans with a Ki
b
-galactosidases from Aspergillus
a
-glucosidase from
a
Fig. 2. Rational design of 4-fluoroisofagomine analogues.
Scheme 1. Synthesis of key fluorinated synthons 4 and 5 via Reformatskii–Claisen rearrangement.

840
Y. Yang et al. / Journal of Fluorine Chemistry 132 (2011) 838–845
Scheme 2. Synthesis of target molecules 1–2 from compound 4.
Scheme 3. Assignment of the configuration of compounds 1–2.
value of 200
m
M approximately. Toward
a
-mannosidases from
M. Compound
-galactosidase from Green
-mannosidases from Jack beans similar to
compound 2, but inhibited -glucosidase from almonds potently
at 11.9 M.
almonds with literature values for isofagomine and its analogues
28–30 [2b], and gem-4,4-difluoromethylated isofagomine analo-
gues 31–33 [2a] (Fig. 4) show that the introduction of fluor-
omethylene group at C-4 site to compound 30 has a positive
influence on inhibition. Although analogues 1 and 2 have an
attenuated inhibition in contrast with difluoromethylated analo-
gues 31 and 32, compound 3 is 100 times more potent than both 30
and difluoromethylated analogue 33. This is highly remarkable.
Jack beans, compound 2 also gave a Ki value of 290
3 showed moderate inhibition to
Coffee beans and
m
a
a
b
m
It is known that the stereochemistry of an iminosugar is crucial
for its ability to bind the glycosidase, since hydroxyl groups are
involved in the binding, and epimerization of a single hydroxyl
group may change the inhibition level significantly [10]. Compari-
The relationship between pH and the inhibition of
dase from almonds by compound 3 was also established (Chart 1).
The data showed that 3 inhibits -glucosidase from almonds well
b-glucosi-
son of the Ki value of compounds 1–3 versus
b
-glucosidase from
b
Scheme 4. Synthesis of target molecule 3 from compound 5.

Y. Yang et al. / Journal of Fluorine Chemistry 132 (2011) 838–845
841
Fig. 3. X-ray crystal structure of compound 26.
0.10
0.08
0.06
0.04
0.02
0.00
Table 1
Inhibition constants of 4-fluoroisofagomine analogue 1–3 at 25 8C and pH 6.8.
Enzyme
Ki (mM)
1
2
3
b
a
b
a
a
-Glucosidasea
-Glucosidaseb
-Galactosidasec
-Galactosidased
-Mannosidasee
>1000
194
>1000
226
11.9
919
NDf
183
251
>1000
194
NDf
>1000
218
290
a
b
c
d
e
f
From almonds.
From baker yeast.
From Aspergillus orizae.
From Green Coffee beans.
From Jack beans.
4.8
5.0
5.2
5.4
5.6
5.8
6.0
6.2
6.4
6.6
6.8
7.0
Not determined.
pH
Chart 1. pH versus 1/Ki for 3 at 25 8C toward
b-glucosidase from almonds.
at neutral condition, but a sharp drop of inhibition takes place
when the solution turns to be acidic. This profile is identical to that
of gem-4,4-difluoromethylated isofagomine analogues [2a]. The
pKa of compound 3 is predicted to 8.8 using an empirical rule [11],
while compounds 30 and 33 are 9.2 and 7.6 respectively. The
significant variation in Ki value is thus explained by the large
difference in stereoelectronic effect between CF2, CHF, and CH(OH)
groups [12]. We speculate that the interactions of iminosugar 3
binding to glycosidases, have benefited from exploiting ‘polar
hydrophobic’ effect [13] of the C–F bond relative to C–OH, so the
inhibitory activity is enhanced greatly.
3. Conclusion
In summary, we described herein the design and synthesis of 4-
fluoroisofagomine analogues 1–3. The biological evaluation
showed that compound 3, despite having a wrong stereochemistry
at C-3, was a potent inhibitor of b-glucosidase from almonds. This
work shows that we can exploit the ‘polar hydrophobic’ effect of
the C–F bond relative to C–OH to modify iminosugar, in which the
basicity of the molecule will not be greatly altered.
4. Experimental
4.1. General
4.1.1. Chemistry
All reagents were used as received from commercial sources,
unless specified otherwise, or prepared as described in the
literature. THF was distilled from sodium and benzophenone.
Dichloromethane was distilled from calcium hydride. Petroleum
ether refers to the fraction of light petroleum ether with bp 60–
90 8C. 1H NMR and 13C NMR spectra were recorded on Bruker AM-
300, Bruker AM-400 or Varian Mercury-300 spectrometers. 19F
NMR was recorded on a Bruker AM-300 spectrometer (FCCl3 as
outside standard and low field is positive). Chemical shifts (d) are
reported in parts per million, and coupling constants (J) are in
hertz. Optical rotations were measured using a Perkin-Elmer 241
or 341 polarimeter. Crystallographic data were analyzed with
Rigaku FCR Diffractimer.
4.1.2. Enzyme inhibition
Each glycosidase assay was performed by preparing eight 2 mL
samples in cuvettes, containing 1 mL sodium phosphate buffer
(0.1 M) of right pH along with 0.04–0.80 mL of different substrates.
Fig. 4. Comparison of the inhibition constants of 4-fluoroisofagomine analogues
with 4-deoxy-4,4-difluoroisofagomine analogues and their parent molecules.

842
Y. Yang et al. / Journal of Fluorine Chemistry 132 (2011) 838–845
The concentration of the substrate was in the range of 0.25–
5 Km. The substrates used were 2-nitrophenyl- -galacto-
pyranoside, 4-nitrophenyl- -galactopyranoside, 4-nitrophe-
nyl- -glucopyranoside, 4-nitrophenyl- -glucopyranoside,
or 4-nitrophenyl- -mannopyranoside. Also added was 0.02–
0.1 mL of a solution of either the inhibitor or water, and finally
each cuvette was filled up to a total volume of 1.9 mL with
distilled water. Four of the samples contained the inhibitor at a
fixed concentration but with varying concentrations of nitro-
phenyl glycoside. The other four samples contained no inhibitor,
but also varying concentrations of nitrophenyl glycoside. Finally
the reaction was started by adding 0.1 mL of a diluted solution
of enzyme solution. The formation of 4- or 2-nitrophenol was
monitored for 2 min at 25 8C by measurement of the absorbance
at 400 nm. Initial velocities were calculated from the slopes
4.2.3. (4S,5S,6S,E)-6-((S)-1,2-Bis(benzyloxy)ethyl)-4-benzyloxy-5-
fluoroocta-2,7-diene (8)
b
-D
a
-
D
To a suspended solution of NaH (60% in oil, 186 mg, 4.46 mmol),
Bu4NI (80 mg, 0.21 mmol), and THF (8 mL) at 0 8C under nitrogen
atmosphere, a solution of compound 6 (920 mg, 2.4 mmol) in THF
(4 mL) was added dropwise. The mixture was stirred at rt for
30 min. BnBr (700 mg, 4.1 mmol) in THF (4 mL) was added
dropwise at 0 8C. The reaction mixture was stirred at rt for 2 h
and then quenched with saturated aqueous NH4Cl. The layers were
separated and the aqueous layer was extracted with ether. The
combined organic layer was dried over Na2SO4, and the solvent
was removed under reduced pressure. The residue was purified by
flash chromatography (petroleum ether: ethyl acetate = 30:1) to
give compound 8 (313 mg) as a light yellow oil in 95% yield.
b
-
D
a-D
a
-D
[a] d 7.31–7.19
25 = 33.88 (c 3.2, CHCl3); 1H NMR (300 MHz, CDCl3)
D
from each reaction and used to construct two Hanes plots ([S]/
v
(m, 15H), 5.71–5.59 (m, 3H), 5.06 (d, J = 9.9 Hz, 1H), 4.96 (d,
J = 9.9 Hz, 1H), 4.83–4.44 (m, 5H), 3.77 (dd, J = 28.8 Hz, 5.4 Hz, 1H),
3.58–3.47 (m, 2H), 3.05–3.02 (m, 1H), 1.77 (d, J = 3.9 Hz, 3H); 13C
NMR (100.7 MHz, CDCl3) d 139.2, 138.5, 138.4, 132.6, 132.5, 130.9,
128.4, 128.3, 128.3, 128.1, 128.1, 127.6, 127.5, 127.4, 120.3, 94.0 (d,
vs [S]), one with and one without inhibitor, which also was used
to check whether inhibition was competitive. From the two
Michaelis–Menten constants, Km and Km0, thus obtained, the
inhibition constant, Ki, was calculated. All assays were per-
formed at 25 8C. The inhibition constants (Ki) were obtained
J = 183.7 Hz), 78.2 (d, J = 17.0 Hz), 76.0, 76.0, 73.8, 73.2, 72.7, 70.1,
from the formula Ki = [I]/(KM0/KMꢀ1), where KM and KM
47.6 (d, J = 20.7 Hz); 19F NMR (282 MHz, CDCl3)
J = 45.7 Hz, 29.0 Hz, 1F); IR (KBr) ymax 3064, 3030, 2918, 2861,
1454, 1097, 735, 696 cmꢀ1; MS (ESI) m/z 492 (M+NH4)+; HRMS
Calcd for C31H35O3FNa: 497.2468; Found: 497.2462.
d
ꢀ202.4 (dd,
0
are Michaelis–Menten constants with and without inhibitor
present.
4.2. General procedure of the preparation of iminosugars 1–3
4.2.4. (4R,5S,6S,E)-6-((S)-1,2-Bis(benzyloxy)ethyl)-4-benzyloxy-5-
fluoroocta-2,7-diene (9)
4.2.1. (4S,5S,6S,E)-6-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluoroocta-2,7-
dien-4-ol (6)
Using the same condition as described for compound 8,
compound 9 (287 mg, 93% yield) was prepared as a light yellow
A
solution of compound 4 [8] (385 mg, 1.0 mmol) and
CeCl3ꢁ7H2O (745 mg, 2.0 mmol) in methanol (10 mL) was cooled
to 0 8C, and NaBH4 (77 mg, 2.0 mmol) was added in portions. The
solution remained at the temperature for 20 min and quenched
with saturated aqueous NH4Cl. The mixture was extracted
with EtOAc, dried over Na2SO4, and the solvent was removed
under reduced pressure. The residue was purified by flash
chromatography (petroleum ether: ethyl acetate = 9:1) to give
compound 6 (313 mg) and 7 (43 mg) as a clear oil in 81% and
11% yield, respectively. Data for compound 6: clear oil;
oil from compound 7 (250 mg, 0.65 mmol). [
a
]
25 = ꢀ6.58 (c 1.9,
D
CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.31–7.28 (m, 15H), 5.74–5.50
(m, 3H), 5.11–4.80 (m, 2H), 4.76–4.31 (m, 7H), 4.06 (t, J = 6.0 Hz,
1H), 3.85 (dd, J = 33.6 Hz, 8.7 Hz, 1H), 3.57–3.39 (m, 2H), 2.53 (dd,
J = 18.3 Hz, 9.6 Hz, 1H), 1.79 (d, J = 7.5 Hz, 3H); 13C NMR
(100.7 MHz, CDCl3)
d 138.9, 138.4, 138.4, 132.8, 132.6, 132.5,
128.4, 128.3, 128.3, 127.8, 127.7, 127.6, 127.5, 127.5, 125.1, 125.1,
120.1, 92.9 (d, J = 181.6 Hz), 80.0 (d, J = 18.7 Hz), 75.6 (d, J = 5.0 Hz),
73.7, 73.2, 71.7, 69.8, 48.5 (d, J = 19.5 Hz); 19F NMR (282 MHz,
[
a
]
25 = 20.08 (c 0.4, CHCl3); 1H NMR (300 MHz, CDCl3)
d
CDCl3)
d
ꢀ200.2 (ddd, J = 33.0 Hz, 26.2 Hz, 5.1 Hz, 1F); IR (KBr) ymax
D
7.72–7.58 (m, 10H), 6.15–5.96 (m, 3H), 5.60 (d, J = 6.0 Hz, 1H),
5.18–4.81 (m, 5H), 4.51–4.41 (m, 2H), 3.99–3.81 (m, 2H), 3.28
(dd, J = 17.4 Hz, 8.4 Hz, 1H), 2.07 (d, J = 6.3 Hz, 1H);13C NMR
3063, 3029, 2920, 2857, 1738, 1453, 1366, 1217, 1092, 735,
697 cmꢀ1; MS (ESI) m/z 492 (M+NH4)+, 497 (M+Na)+; HRMS Calcd
for C31H35O3FNa: 497.2468; Found: 497.2462.
(100.7 MHz, CDCl3)
d 138.9, 138.2, 132.5, 132.4, 130.1, 128.4,
128.3, 128.2, 127.6, 127.4, 120.7, 93.6 (d, J = 180.3 Hz), 76.7,
75.9, 75.9, 73.6, 73.3, 72.1, 71.1 (d, J = 19.1 Hz), 47.8 (d,
4.2.5. (2S,3S,4S)-2-(Benzyloxy)-4-((S)-1,2-bis(benzyloxy)ethyl)-3-
fluoropentane-1,5-diol (10)
J = 20.7 Hz), 17.8; 19F NMR (282 MHz, CDCl3)
d
ꢀ205.5 (ddd,
A solution of compound 8 (820 mg, 1.73 mmol) in dichloro-
methane and methanol (20 mL, V/V = 1:1) was cooled to ꢀ78 8C and
treated with ozone until the solvent appeared blue. Nitrogen was
bulbed inside until the bule color disappeared, and NaBH4 (660 mg,
1.74 mmol) was added in portions. The mixture was returned to
room temperature and stirred for 3 h, then be quenched with
saturated aqueous NH4Cl solution (30 mL). The mixture was
extracted with ethyl acetate, dried over Na2SO4. The solvent was
removed under reduced pressure, and the residue was purified by
flash chromatography (petroleum ether: ethyl acetate = 3:1) on
J = 34.1 Hz, 28.2 Hz, 6.8 Hz, 1F); IR (KBr) ymax 3589, 3449, 3030,
2917, 1496, 1454, 1365, 1090, 736, 697 cmꢀ1; MS (ESI) m/z 385
(M+H)+, 407 (M+Na)+; HRMS Calcd for C24H29O3FNa: 407.1998;
Found: 407.1993.
4.2.2. (4R,5S,6S,E)-6-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluoroocta-2,7-
dien-4-ol (7)
Data for compound 7: clear oil; [
NMR (300 MHz, CDCl3) 7.36–7. 21 (m, 10H), 5.76–5.52 (m, 3H),
a]
25 = 13.7? (c 2.1, CHCl3); 1H
D
d
5.17 (d, J = 10.8 Hz, 1H), 5.04 (d, J = 10.8 Hz, 1H), 4.87–4.43 (m, 5H),
4.17–4.02 (m, 2H), 3.60–3.41 (m, 2H), 2.54 (dd, J = 16.8 Hz, 5.4 Hz,
silica gel to give 10 as a clear oil (712 mg) in 88% yield. [a D
]
25 = ꢀ7.28
(c 2.3, CHCl3); 1H NMR (300 MHz, CDCl3)
d
7.36–7.25 (m, 15H), 4.96
1H), 1.70 (d, J = 15.0 Hz, 3H); 13C NMR(100.7 MHz, CDCl3)
d
138.7,
(dd, J = 46.2 Hz, 9.3 Hz, 1H), 4.83–4.49 (m, 6H), 4.21 (t, J = 4.5 Hz,
1H), 3.92–3.60 (m, 6H), 3.45 (d, J = 12.0 Hz, 1H), 2.99 (d, J = 12.3 Hz,
1H), 2.27 (t, J = 9.9 Hz, 2H); 13C NMR (100.7 MHz, CDCl3)
d 138.1,
137.9, 128.5, 128.5, 128.5, 128.0, 128.0, 127.9, 127.9, 127.8, 127.6,
91.9 (d, J = 174.6 Hz), 73.8, 73.4, 72.6, 71.4, 61.7 (d, J = 6.0 Hz), 59.7
(d, J = 9.1 Hz), 42.4 (d, J = 18.7 Hz); 19F NMR (282 MHz, CDCl3)
138.3, 132.3, 132.2, 130.9, 128.4, 128.3, 127.8, 127.6, 127.6, 127.6,
127.0, 126.9, 120.3, 94.0 (d, J = 179.4 Hz), 75.8, 73.7, 73.4, 73.3,
73.2, 71.5, 48.6(d, J = 19.9 Hz); 19F NMR (282 MHz, CDCl3)
d
ꢀ202.4
(ddd, J = 34.4 Hz, 26.5 Hz, 8.7 Hz, 1F); IR (KBr) ymax 3585, 3445,
3030, 2918, 2859, 1496, 1454, 1094, 736, 697 cmꢀ1; MS (ESI) m/z
407 (M+Na)+; HRMS Calcd for C24H29O3FNa: 407.1998; Found:
407.1993.
d
ꢀ206.4 (ddd, J = 40.9 Hz, 29.6 Hz, 11.3 Hz, 1F); IR (KBr)
ymax 3425,
2872, 1454, 1273, 1067, 1027, 737, 698 cmꢀ1; MS (ESI) m/z 469

Y. Yang et al. / Journal of Fluorine Chemistry 132 (2011) 838–845
843
(M+H)+, 491 (M+Na)+; HRMS Calcd for C28H33O5FNa: 491.2201;
Found: 491.2204.
atmosphere and BCl3 (1 M solution in dichloromethane, 3.7 mL,
3.7 mmol) was added dropwise. The reaction mixture remained at
this temperature for 3 h and then quenched with methanol (5 mL).
The solvent was removed under reduced pressure, and the residue
was purified by flash chromatography (dichloromethane: metha-
nol = 12:1) to give compound 14 (90 mg) as a foam in 90% yield.
4.2.6. (2R,3S,4S)-2-(Benzyloxy)-4-((S)-1,2-bis(benzyloxy)ethyl)-3-
fluoropentane-1,5-diol (11)
Using the same condition as described for compound 10,
compound 11 (790 mg, 89% yield) was prepared as a clear oil from
[a
]
D
25 = ꢀ24.88 (c 0.2, CH3OH); 1H NMR (300 MHz, CD3OD)
d 7.62–
compound 9 (900 mg, 1.90 mmol). [
a
]
25 = ꢀ19.38 (c 1.2, CHCl3);
7.50 (m, 5H), 4.54 (dt, J = 48.3, 9.0 Hz, 1H), 4.46 (d, J = 12.9 Hz, 1H),
4.38 (d, J = 12.9 Hz, 1H), 4.10–4.00 (m, 2H), 3.60–3.31 (m, 7H), 3.03
(dt, J = 61.5 Hz, 12.6 Hz, 2H), 2.39 (dd, J = 21.3 Hz, 10.2 Hz, 1H); 13
C
D
1H NMR (300 MHz, CDCl3)
d
7.31 (m, 15H), 4.98 (d, J = 47.1 Hz, 1H),
4.76–4.53 (m, 6H), 4.16 (m, 1H), 3.92–3.78 (m, 4H), 3.72–3.63 (m,
2H), 3.60 (t, J = 5.1 Hz, 1H), 2.84 (s, 1H), 2.10 (s, 1H); 13C NMR
NMR(75.5 MHz, CD3OD)
d 131.1, 130.0, 129.0, 129.0, 67.2, 63.4,
(100.7 MHz, CDCl3)
d
137.8, 137.7, 128.6, 128.5, 128.2, 128.1,
48.5, 48.3, 48.1, 47.9, 47.6; 19F NMR (282 MHz, CD3OD)
d
ꢀ195.3
128.0, 128.0, 127.8, 127.7, 91.5 (d, J = 174.9 Hz), 78.0 (d,
J = 17.9 Hz), 77.4 (t, J = 3.2 Hz), 77.1, 76.8, 73.6, 72.9, 72.5, 70.7,
61.4 (d, J = 7.6 Hz), 59.4 (d, J = 7.0 Hz), 43.1 (d, J = 30.8 Hz); 19F NMR
(m, 1F); IR (KBr) ymax 3337, 2926, 1475, 1287, 1217, 1044,
972 cmꢀ1; MS (ESI) m/z 270 (M+H)+; HRMS Calcd for C14H21O3FN:
270.1506; Found: 270.1500.
(282 MHz, CDCl3)
(KBr)
d
ꢀ200.9 (ddd, J = 38.6 Hz, 27.5 Hz, 6.9 Hz, 1F); IR
y
max 3432, 2872, 1454, 1278, 1069, 1027, 737 cmꢀ1; MS (ESI)
4.2.10. (S)-1-((3S,4S,5R)-1-Benzyl-4-fluoro-5-hydroxypiperidin-3-
yl)ethane-1,2-diol (15)
m/z 469 (M+H)+, 491 (M+Na)+; HRMS Calcd for C28H33O5FNa:
491.2210; Found: 491.2204.
Using the same condition as described for compound 14,
compound 15 (78 mg, 87% yield) was prepared as a clear oil from
4.2.7. (3S,4S,5S)-1-Benzyl-3-(benzyloxy)-5-((S)-1,2-
compound 13 (180 mg, 0.33 mmol).
CH3OH); 1H NMR (300 MHz, CD3OD)
[a]
25 = ꢀ35.18 (c 1.3,
D
bis(benzyloxy)ethyl)-4-fluoropiperidine (12)
d 7.66–7.60 (m, 5H), 4.58
A solution of compound 10 (203 mg, 0.434 mmol) in dry
dichloromethane (3 mL) was cooled to 0 8C. Et3N (0.31 mL,
2.22 mmol), DMAP (8 mg, 0.07 mmol), and MsCl (0.15 mL,
1.97 mmol) were added. The mixture was stirred at rt for 4 h
and then quenched with water. The two layers were separated and
the aqueous layer was extracted with dichloromethane. The
combined organic layer was dried over Na2SO4 and concentrated.
The crude product was dissolved in BnNH2 (1 mL) and heated for
18 h at 80 8C. Then the mixture was directly purified by flash
chromatography (petroleum ether: ethyl acetate = 15:1) to give
compound 12 (199 mg) as a light yellow oil in 85% yield for two
(d, J = 13.2 Hz, 1H), 4.40 (t, J = 4.5 Hz, 1H), 4.33 (d, J = 13.2 Hz, 1H),
4.06 (dd, J = 6.0 Hz, 3.9 Hz, 1H), 3.74–3.60 (m, 3H), 3.46–3.18 (m,
3H), 2.89 (t, J = 9.0 Hz, 1H); 13C NMR(100.7 MHz, CD3OD)
d
130.9,
129.8, 129.0, 117.0, 63.9, 63.7, 63.4, 59.9, 48.5; 19F NMR (282 MHz,
CD3OD) max 3348,
d
ꢀ195.3 (dd, J = 46.5 Hz, 20.6 Hz, 1F); IR (KBr)
y
1641, 1459, 1236, 1129, 1058, 983, 762, 702 cmꢀ1; MS (ESI) m/z
270 (M+H)+; HRMS Calcd for C14H21O3FN: 270.1506; Found:
270.1500.
4.2.11. (3S,4S,5S)-1-Benzyl-4-fluoro-5-(hydroxymethyl)piperidin-3-
ol (16)
steps. [
a]
D
25 = ꢀ11.68 (c 3.9, CHCl3); 1H NMR (300 MHz, CDCl3)
d
A solution of compound 14 (74 mg, 0.275 mmol) in methanol
(2 mL) was added saturated aqueous NaIO4 solution (1.0 mL)
dropwise. The mixture was stirred strongly for 15 min at rt and
then cooled to 0 8C. NaBH4 (72 mg, 1.9 mmol) was added in
portions. The mixture was stirred for 30 min at rt and quenched
with saturated aqueous NH4Cl solution. The resulting mixture was
extracted with ethyl acetate. The combined organic layer was dried
over Na2SO4 and concentrated. The residue was purified by flash
chromatography (petroleum ether: ethyl acetate = 2:1) on silica
7.36–7.26 (m, 20H), 4.76–4.42 (m, 7H), 4.01 (dd, J = 7.8 Hz, 6.0 Hz,
1H), 3.61–3.51 (m, 1H), 3.49–3.43 (m, 4H), 3.05 (t, J = 5.1 Hz, 1H),
2.83 (d, J = 8.4 Hz, 1H), 2.28–1.94 (m, 3H); 13C NMR (75.5 MHz,
CDCl3)
d 138.8, 138.7, 138.4, 138.3, 129.2, 129.1, 129.1, 128.7,
128.6, 128.6, 128.5, 128.0, 127.9, 127.9, 127.9, 127.9, 127.4, 127.3,
95.2 (d, J = 135.4 Hz), 78.0, 77.8, 77.5, 75.0, 74.0, 73.6, 72.9, 71.3,
62.4, 57.3, 55.7 (d, J = 7.3 Hz), 51.1 (d, J = 6.7 Hz), 43.2 (d,
J = 12.8 Hz); 19F NMR (282 MHz, CDCl3)
1F); IR (KBr)
737, 697 cmꢀ1; MS (ESI) m/z 540 (M+H)+; HRMS Calcd for
35H39O3FN: 540.2914; Found: 540.2909.
d
–190.0 (d, J = 48.5 Hz,
y
max 3062, 3029, 2911, 1495, 1453, 1241, 1126, 984,
gel to give 16 as a foam (53 mg) in 80% yield. [
a
]
25 = ꢀ13.78 (c 0.7,
D
CH3OH); 1H NMR (300 MHz, CD3OD)
d
7.35–7.25 (m, 5H), 4.11 (dt,
C
J = 52.2 Hz, 8.4 Hz, 1H), 3.84–3.53 (m, 5H), 3.03–2.99 (m, 2H),
2.05–1.88 (m, 3H); 13C NMR (100.7 MHz, CD3OD)
137.2, 129.1,
d
4.2.8. (3R,4S,5S)-1-Benzyl-3-(benzyloxy)-5-((S)-1,2-
128.0, 127.1, 95.0 (d, J = 179.1 Hz), 69.7 (d, J = 17.9 Hz), 61.7, 59.8,
57.3 (d, J = 9.1 Hz), 54.0 (d, J = 9.0 Hz), 42.6 (d, J = 17.3 Hz); 19F NMR
bis(benzyloxy)ethyl)-4-fluoropiperidine (13)
Using the same condition as described for compound 12,
compound 13 (291 mg, 81% yield) was prepared as a clear oil from
(282 MHz, CD3OD)
d
ꢀ194.3 (d, J = 48.5 Hz, 1F); IR (KBr)
ymax 3394,
2931, 1453, 1389, 1215, 1023, 920 cmꢀ1; MS (ESI) m/z 240 (M+H)+;
compound 11 (312 mg, 0.67 mmol). [
a]
25 = ꢀ17.88 (c 1.6, CHCl3);
HRMS Calcd for C13H19O2FN: 240.1400; Found: 240.1394.
D
1H NMR (300 MHz, CDCl3)
d
7.31–7.25 (m, 20H), 4.76–4.41 (m, 6H),
3.95 (dd, J = 10.2 Hz, 5.1 Hz, 1H), 3.72 (d, J = 13.8 Hz, 1H), 3.64–3.33
(m, 5H), 2.77 (d, J = 6.0 Hz, 2H), 2.57–2.44 (m, 1H), 2.39 (d,
4.2.12. (3R,4S,5S)-1-Benzyl-4-fluoro-5-(hydroxymethyl)piperidin-3-
ol (17)
J = 9.3 Hz, 1H), 2.16 (d, J = 9.3 Hz, 1H); 13C NMR (75.5 MHz, CDCl3)
d
Using the same condition as described for compound 16,
compound 17 (60 mg, 84% yield) was prepared as a foam from
138.7, 138.5, 138.2, 138.1, 129.1, 128.4, 128.3, 128.2, 127.8, 127.8,
127.7, 127.6, 127.6, 127.5, 127.1, 127.0, 90.5 (d, J = 192.4 Hz), 75.3,
compound 15 (82 mg, 0.30 mmol). [
a
]
25 = ꢀ25.68 (c 1.1, CH3OH);
D
73.4, 73.3, 71.4, 62.3, 53.3, 50.4, 40.7; 19F NMR (282 MHz, CDCl3)
d
1H NMR (300 MHz, CD3OD)
d 7.78–7.66 (m, 5H), 4.86 (dd,
ꢀ196.5 (m, 1F); IR (KBr) ymax 2923, 2853, 1307, 1241, 1130, 984,
J = 49.2 Hz, 8.7 Hz, 1H), 4.41 (d, J = 12.6 Hz, 1H), 4.12–3.97 (m,
4H), 3.27 (d, J = 31.2 Hz, 2H), 2.86–2.65 (m, 3H); 13C NMR
746, 698 cmꢀ1; MS (ESI) m/z 540 (M+H)+; HRMS Calcd for
C
35H39O3FN: 540.2914; Found: 540.2909.
(100.7 MHz, CD3OD)
J = 179.5 Hz), 65.8 (d, J = 17.8 Hz), 61.5, 60.2, 55.6 (d, J = 6.2 Hz),
52.6, 38.9 (d, J = 19.0 Hz); 19F NMR (282 MHz, CD3OD)
ꢀ198.1 (m,
d 136.1, 129.2, 128.0, 127.3, 90.7 (d,
4.2.9. (S)-1-((3S,4S,5S)-1-Benzyl-4-fluoro-5-hydroxypiperidin-3-
yl)ethane-1,2-diol (14)
A solution of compound 12 (200 mg, 0.37 mmol) in dry
dichloromethane (3 mL) was cooled to 0 8C under nitrogen
d
1F); IR (KBr) y
max 3394, 2925, 2815, 1454, 1034, 761, 700 cmꢀ1; MS
(ESI) m/z 240 (M+H)+; HRMS Calcd for C13H19O2FN: 240.1400;
Found: 240.1394.

844
Y. Yang et al. / Journal of Fluorine Chemistry 132 (2011) 838–845
4.2.13. (3S,4S,5S)-4-Fluoro-5-(hydroxymethyl)piperidin-3-ol (1)
A solution of compound 16 (40 mg, 0.17 mmol) in methanol
(4 mL) was hydrogenated in the presence of 20% Pd(OH)2/C
(4 mg) at atmospheric pressure and at rt. After stirring for 8 h, the
reaction mixture was filtrated and concentrated. The residue was
purified by flash chromatography (dichloromethane: metha-
nol = 4:1) to give compound 1 (19 mg) as a foam in 75% yield.
4.2.17. (4S,5R,6R,E)-6-((S)-1,2-Bis(benzyloxy)ethyl)-4-benzyloxy-5-
fluoroocta-2,7-dienel (22)
Using the same condition as described for compound 8,
compound 22 (231 mg, 95% yield) was prepared as a clear
oil from compound 21 (197 mg, 0.51 mmol). [
2.9, CHCl3); 1H NMR (300 MHz, CDCl3)
a
]
25 = ꢀ27.98 (c
D
d
7.32–7.27 (m, 15H),
5.90–5.77 (m, 1H), 5.69–5.57 (m, 1H), 5.34 (dd, J = 15.3 Hz,
9.0 Hz, 1H), 5.19 (d, J = 10.5 Hz, 1H), 5.08 (d, J = 17.7 Hz, 1H),
4.69–4.28 (m, 7H), 3.81–3.70 (m, 1H), 3.62 (s, 2H), 2.84–2.69 (m,
[
a
]
25 = ꢀ9.58 (c 0.4, CH3OH); 1H NMR (300 MHz, CD3OD)
d 4.20
D
(dt, J = 52.2 Hz, 9.9 Hz, 1H), 3.77–3.59 (m, 3H), 3.34 (d,
J = 11.4 Hz, 1H), 3.16–3.10 (m, 2H), 2.52–2.33 (m, 2H); 13C
1H), 1.73 (d, J = 6.0 Hz, 3H); 13C NMR (100.7 MHz, CDCl3)
d 138.7,
NMR (100.7 MHz, CD3OD)
d
94.8 (d, J = 170.5 Hz), 59.1, 48.3, 48.0,
ꢀ198.1 (d,
138.4, 138.3, 133.3, 133.3, 132.1, 128.4, 128.4, 128.3, 128.0,
127.9, 127.8, 127.6, 126.7, 126.6, 119.7, 94.1 (d, J = 179.5 Hz),
79.6, 79.4, 78.6, 78.5, 73.4, 72.5, 71.2, 70.0, 47.0 (d, J = 19.5 Hz),
47.8, 47.4, 46.0; 19F NMR (282 MHz, CD3OD)
d
J = 64.6 Hz, 1F); IR (KBr) ymax 3394, 2925, 2815, 1454, 1034, 761,
700 cmꢀ1; MS (ESI) m/z 150 (M+H)+; HRMS Calcd for C6H13O2FN:
18.0; 19F NMR (282 MHz, CDCl3)
d
ꢀ202.4 (ddd, J = 44.6 Hz,
150.0930; Found: 150.0925.
26.2 Hz, 17.5 Hz, 1F); IR (KBr) ymax 3064, 3030, 2916, 2864,
1496, 1454, 1097, 735, 696 cmꢀ1; MS (ESI) m/z 492 (M+NH4)+,
497 (M+Na)+; HRMS Calcd for C31H35O3FNa: 497.2468; Found:
497.2462.
4.2.14. (3R,4S,5S)-4-Fluoro-5-(hydroxymethyl)piperidin-3-ol (2)
Using the same condition as described for compound 1,
compound 2 (19 mg, 80% yield) was prepared as a foam from
compound 17 (38 mg, 0.16 mmol). [
1H NMR (300 MHz, CD3OD)
a]
25 = ꢀ47.18 (c 0.7, CH3OH);
4.2.18. (2S,3R,4R)-2-(Benzyloxy)-4-((S)-1,2-bis(benzyloxy)ethyl)-3-
fluoropentane-1,5-diol (23)
D
d
4.56 (dd, J = 34.2 Hz, 9.9 Hz, 1H), 4.04
(d, J = 7.2 Hz, 1H), 3.74–3.58 (m, 2H), 3.14–2.51 (m, 3H), 2.39–2.12
(m, 2H); 13C NMR (100.7 MHz, CD3OD)
90.6 (d, J = 180.8 Hz), 65.7
(d, J = 17.8 Hz), 65.2 (d, J = 17.4 Hz), 60.1, 59.5, 58.3, 48.5 (d,
J = 83.6 Hz), 45.5 (d, J = 5.8 Hz), 44.3, 39.0 (d, J = 17.9 Hz); 19F NMR
Using the same condition as described for compound 10,
compound 23 (212 mg, 84% yield) was prepared as a clear oil
d
from compound 22 (256 mg, 0.54 mmol). [
CHCl3); 1H NMR (300 MHz, CDCl3)
a
]
25 = ꢀ19.58 (c 4.8,
D
d
7.30–7.24 (m, 15H), 4.88 (d,
(282 MHz, CD3OD)
d
–192.5 (m, 1F); IR (KBr) ymax 3394, 2925,
J = 46.5 Hz, 1H), 4.67–4.38 (m, 6H), 3.91–3.62 (m, 7H), 3.41 (dt,
J = 18.6 Hz, 4.5 Hz, 1H), 2.43 (br, 2H), 2.25 (d, J = 16.5 Hz, 1H);
13C NMR (100.7 MHz, CDCl3)
d 137.8, 137.8, 137.8, 128.6, 128.5,
2815, 1454, 1034, 761, 700 cmꢀ1; MS (ESI) m/z 150 (M+H)+; HRMS
Calcd for C6H13O2FN: 150.0930; Found: 150.0925.
128.3, 128.1, 128.0, 128.0, 127.9, 127.7, 92.5 (d, J = 175.3 Hz),
78.1, 77.9, 77.4, 73.5, 72.8, 72.5, 70.7, 61.4 (d, J = 7.5 Hz), 59.4 (d,
4.2.15. (5R,6R,E)-6-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluoroocta-2,7-
dien-4-one (5)
J = 6.9 Hz), 43.1 (d, J = 19.5 Hz); 19F NMR (282 MHz, CDCl3)
d
Using the same condition as described for compound 4 [8],
compound 5 (318 mg, 77% yield) was prepared as yellow oil from
compound 20 (400 mg, 1.08 mmol, containing trace amount of
ꢀ204.5 (m, 1F); IR (KBr) ymax 3483, 3031, 2924, 2872, 1454,
1071, 1028, 738, 698 cmꢀ1; MS (ESI) m/z 469 (M+H)+, 491
(M+Na)+; HRMS Calcd for C28H33O5FNa: 491.2210; Found:
491.2204.
other isomers) over three steps. [
NMR(300 MHz, CDCl3) 7.34–7.04 (m, 10H), 6.98 (dt, J = 22.2 Hz,
a]
25 = 13.58 (c 4.5, CHCl3); 1H
D
d
6.9 Hz, 1H), 6.41 (d, J = 15.3 Hz, 1H), 5.81 (dt, J = 17.1 Hz, 9.3 Hz,
1H), 5.23–5.06 (m, 3H), 4.71 (d, J = 11.4 Hz, 1H), 4.60 (d, J = 11.4 Hz,
1H), 4.54 (s, 2H), 3.82 (dd, J = 9.9 Hz, 5.1 Hz, 1H), 3.65 (d, J = 4.8 Hz,
2H), 3.09–2.93 (m, 1H), 1.87 (d, J = 6.9 Hz, 3H); 13C NMR
4.2.19. (3S,4R,5R)-1-Benzyl-3-(benzyloxy)-5-((S)-1,2-
bis(benzyloxy)ethyl)-4-fluoropiperidine (24)
Using the same condition as described for compound 12,
compound 24 (125 mg, 79% yield) was prepared as a yellow oil
(100.7 MHz, CDCl3)
d
196.3 (d, J = 22.0 Hz), 145.6, 145.5, 138.5,
from compound 23 (138 mg, 0.29 mmol). [
a
]
25 = ꢀ12.58 (c 7.2,
D
138.2, 131.5, 131.5, 128.4, 128.3, 127.7, 127.7, 127.6, 126.1, 120.5,
CHCl3); 1H NMR (300 MHz, CDCl3)
d 7.35–7.24 (m, 20H), 4.70 (d,
94.3 (d, J = 187.9 Hz), 78.4, 76.8, 73.4, 72.6, 70.7, 48.8 (d,
J = 54.6 Hz, 1H), 4.71–4.42 (m, 6H), 3.75–3.46 (m, 6H), 2.96 (d,
J = 10.8 Hz, 1H), 2.88 (d, J = 12.0 Hz, 1H), 2.61 (d, J = 37.5 Hz, 1H),
J = 19.1 Hz), 18.6; 19F NMR (282 MHz, CDCl3)
d –199.2 (dd,
J = 49.4 Hz, 28.5 Hz, 1F); IR (KBr) ymax 3064, 3030, 2916, 2863,
1695, 1627, 1496, 1454, 1094, 736, 698 cmꢀ1; MS (ESI) m/z 383
(M+H)+, 400 (M+NH4)+, 405 (M+Na)+; HRMS Calcd for
2.27–2.13 (m, 2H), 2.10–1.86 (m, 1H); 13C NMR (75.5 MHz, CDCl3)
d
138.6, 138.4, 138.3, 138.1, 129.3, 129.0, 128.4, 128.3, 128.3, 127.9,
127.6, 127.6, 127.5, 127.1, 87.9 (d, J = 174.5 Hz), 77.8, 76.8, 73.4,
73.2, 73.0, 72.4, 71.0, 70.3, 62.9, 51.2, 50.6, 38.8 (d, J = 17.8 Hz); 19
F
C
24H27O3FNa: 405.1842; Found: 405.1836.
NMR (282 MHz, CDCl3)
d
ꢀ200.8 (d, J = 33.0 Hz, 1F); IR (KBr) ymax
4.2.16. (4S,5R,6R,E)-6-((S)-1,2-Bis(benzyloxy)ethyl)-5-fluoroocta-
2,7-dien-4-ol (21)
3086, 3062, 3029, 2867, 1495, 1453, 1363, 1098, 735, 698 cmꢀ1
;
MS (ESI) m/z 540 (M+H)+; HRMS Calcd for C35H39O3FN: 540.2914;
Using the same condition as described for compound 6,
compound 21 (138 mg, 60% yield, the other isomer can not get
purely by flash chromatography) was prepared as a clear oil from
Found: 540.2909.
4.2.20. (S)-1-((3R,4R,5S)-1-Benzyl-4-fluoro-5-hydroxypiperidin-3-
yl)ethane-1,2-diol (25)
Using the same condition as described for compound 14,
compound 25 (71 mg, 86% yield) was prepared as a foam from
compound 24 (165 mg, 0.31 mmol). [
1H NMR (300 MHz, CD3OD)
7.59–7.51 (m, 5H), 4.72–4.31 (m, 3H),
4.13 (s, 1H), 3.71 (s, 4H), 3.33–3.13 (m, 4H), 2.71 (d, J = 33.0 Hz,
1H); 13C NMR (100.7 MHz, CD3OD)
131.2, 130.0, 129.0, 128.6,
86.2 (d, J = 176.4 Hz), 69.6, 63.3, 63.2, 63.0, 60.5, 51.8, 50.2, 36.0 (d,
J = 18.0 Hz), 48.5, 40.1; 19F NMR (282 MHz, CD3OD)
J = 47.9 Hz, 37.5 Hz, 1F); IR (KBr) ymax 3308, 2941, 1459, 1220,
1106, 1002, 936 cmꢀ1; MS (ESI) m/z 270 (M+H)+; HRMS Calcd for
C14H21O3FN: 270.1506; Found: 270.1500.
compound 5 (230 mg, 0.60 mmol). [
a
]
25 = ꢀ9.48 (c 10.1, CHCl3);
D
1H NMR (300 MHz, CDCl3)
d
7.32–7.22 (m, 10H), 5.90–5.68 (m, 2H),
5.38 (dd, J = 14.7 Hz, 6.6 Hz, 1H), 5.22 (d, J = 9.9 Hz, 1H), 5.10 (d,
J = 17.4 Hz, 1H), 4.72–4.42 (m, 5H), 4.18–4.08 (m, 1H), 3.76–3.63
a]
25 = 0.28 (c 5.9, CH3OH);
D
(m, 3H), 2.80–2.65 (m, 1H), 1.70 (s, 1H), 1.69 (d, J = 6.6 Hz, 3H); 13
C
d
NMR (100.7 MHz, CDCl3) d 138.5, 138.2, 133.0, 132.9, 130.6, 128.4,
128.4, 128.1, 128.0, 127.9, 127.7, 120.0, 95.2 (d, J = 176.7 Hz), 79.1,
79.0, 76.8, 73.4, 72.8, 72.6, 70.7, 47.0 (d, J = 19.1 Hz), 18.0; 19F NMR
d
(282 MHz, CDCl3)
IR (KBr) max 3578, 3442, 3030, 2917, 2860, 1496, 1454, 1098, 736,
698 cmꢀ1 MS (ESI) m/z 407 (M+Na)+; HRMS Calcd for
C24H29O3FNa: 407.1998; Found: 407.1993.
d
ꢀ205.5 (ddd, J = 44.0 Hz, 29.3 Hz, 15.5 Hz, 1F);
d
ꢀ202.6 (dd,
y
;

Y. Yang et al. / Journal of Fluorine Chemistry 132 (2011) 838–845
845
References
4.2.21. (S)-1-((3R,4R,5S)-1-Benzyl-4-fluoro-5-(4-
nitrobenzoyloxy)piperidin-3-yl)ethane-1,2-diyl bis(4-nitrobenzoate)
(26)
[1] (a) G. Horne, F.X. Wilson, J. Tinsley, D.H. Williams, R. Storer, Drug Dis. Today 16
(2011) 107–118;
Compound 25 (22 mg, 0.082 mmol), DMAP (3 mg, 0.0246 mmol)
was dissolved in dry pyridine (1 mL), cooled to 0 8C, then p-
NO2C6H4COCl (200 mg, 1.08 mmol) in CH2Cl2 (0.3 mL) was added
dropwise. The mixture was returned to room temperature and
stirred for 12 h, then at 50 8C for another 12 h. The mixture was
cooled to room temperature, CH2Cl2 (10 mL) was added in. The
organic phase was washed with saturated sodium bicarbonate,
brine, dried over Na2SO4 and the solvent was removed under
reduced pressure. The residuewas purified by flashchromatography
(petroleum ether: ethyl acetate = 4:1) on silica gel to give 26 as a
(b) B.G. Winchester, Tetrahedron: Asymmetry 20 (2009) 645–651;
(c) B.G. Davis, Tetrahedron: Asymmetry 20 (2009) 652–671;
(d) P. Compain, V. Chagnault, O.R. Martin, Tetrahedron: Asymmetry 20 (2009)
672–711;
(e) P. Compain, O.R. Martin (Eds.), Iminosugars: From Synthesis to Therapeutic
Applications, Wiley, West Sussex, 2007;
(f) M.S.M. Pearson, M. Mathe´-Allainmat, V. Fargeas, J. Lebreton, Eur. J. Org. Chem.
2005 (2005) 2159–2191;
(g) T. Ayad, Y. Genisson, M. Baltas, Curr. Org. Chem. 8 (2004) 1211–1233;
(h) L. Cipolla, B.L. Ferla, F. Nicotra, Curr. Top. Med. Chem. 3 (2003) 485–511;
(i) J. Alper, Science 291 (2001) 2339;
(j) N. Asano, R.J. Nash, R.J. Molyneux, G.W.J. Fleet, Tetrahedron: Asymmetry 11
(2000) 1645–1680;
(k) A.E. St1tz (Ed.), Iminosugars as Glycosidase Inhibitors: Nojirimycin and
Beyond, Wiley-VCH, Weinheim, 1999.
light yellow solid (37 mg, 80% yield). m.p. 226 8C; [a D
CH3OH); 1H NMR (300 MHz, CDCl3)
8.32–8.02 (m, 12H), 5.75 (s,
]
25 = 6.68 (c 2.3,
d
[2] (a) R.-j. Li, M. Bols, C. Rousseau, X.-g. Zhang, R.-w. Wang, F.-L. Qing, Tetrahedron
65 (2009) 3717–3727;
1H), 5.40 (s, 1H), 4.96–4.86 (m, 2H), 4.70–4.64 (m, 2H), 3.64 (d,
J = 13.5 Hz, 1H), 3.50 (d, J = 13.2 Hz, 1H), 2.96–2.56 (m, 5H); 13C NMR
(b) N. Asano, K. Ikeda, L. Yu, A. Kato, K. Takebayashi, I. Adachi, I. Kato, H. Ouchi, H.
Takahata, G.W.J. Fleet, Tetrahedron: Asymmetry 16 (2005) 223–229;
(c) H.H. Jensen, A. Jensen, R.G. Hazell, M. Bols, J. Chem. Soc., Perkin Trans. 1 (2002)
1190–1198;
(d) H.H. Jensen, M. Bols, J. Chem. Soc., Perkin Trans. 1 (2001) 905–909;
(e) A. Bulow, I.W. Plesner, M. Bols, J. Am. Chem. Soc. 122 (2000)
8567–8568;
(f) M.J. Tina, D. Wenling, R.S. Michael, S. Troels, L. Inge, B. Mikael, Angew. Chem.
Int. Ed. 33 (1994) 1778–1779;
(g) T.M. Jespersen, M. Bols, M.R. Sierks, T. Skrydstrup, Tetrahedron 50 (1994)
13449–13460.
(100.7 MHz, CDCl3)
128.3, 128.2, 128.1, 126.1, 125.8, 124.8, 121.1, 120.1, 69.2, 59.5, 47.2,
36.4; 19F NMR (282 MHz, CD3OD)
d 161.5, 160.9, 148.3, 148.1, 134.7, 132.2, 132.0,
d
ꢀ200.0 (m, 1F); IR (KBr) ymax
3003, 1716, 1530, 1359, 1268, 1223, 1102, 721 cmꢀ1; MS (ESI) m/z
150 (M+H)+; HRMS Calcd for C6H13O2FN: 150.0930; Found:
150.0925; Crystal data have been deposited at the Cambridge
Crystallographic Data Center with reference number: CCDC 815092.
[3] Y. Ichikawa, Y. Igarashi, Tetrahedron Lett. 36 (1995) 4585–4586.
[4] P. Sears, C.-H. Wong, Angew. Chem. Int. Ed. 38 (1999) 2300–2324.
[5] (a) K. Mu¨ ller, C. Faeh, F. Diederich, Science 317 (2007) 1881–1886;
(b) D. O’Hagan, H.S. Rzepa, Chem. Commun. (1997) 645–652;
(c) L.H. Takahashi, R. Radhakrishnan, R.E. Rosenfield, E.F. Meyer, D.A. Trainor, J.
Am. Chem. Soc. 111 (1989) 3368–3374;
(d) P. Murray-Rust, W.C. Stallings, C.T. Monti, R.K. Preston, J.P. Glusker, J. Am.
Chem. Soc. 105 (1983) 3206–3214.
[6] (a) E. Prell, C. Korb, R. Kluge, D. Stro¨hl, R. Csuk, Arch. Pharm. 343 (2010)
583–589;
4.2.22. (3S,4R,5R)-1-Benzyl-4-fluoro-5-(hydroxymethyl)piperidin-3-
ol (27)
Using the same condition as described for compound 16,
compound 27 (59 mg, 83% yield) was prepared as a foam from
compound 25 (80 mg, 0.30 mmol). [
1H NMR (300 MHz, CD3OD)
a
]
25 = ꢀ2.38 (c 0.6, CH3OH);
D
d
7.43–7.31 (m, 5H), 4.60 (d,
J = 46.5 Hz, 1H), 3.92 (s, 1H), 3.82–3.57 (m, 4H), 2.83–2.72 (m,
3H), 2.54–2.34 (m, 2H); 13C NMR (100.7 MHz, CD3OD)
129.4,
128.1, 127.6, 65.2 (d, J = 22.5 Hz), 61.5, 59.5, 54.1, 50.5, 38.1; 19F
d
(b) E. Prell, R. Csuk, Bioorg. Med. Chem. Lett. 19 (2009) 5673–5674;
(c) S.M. Andersen, M. Ebner, C.W. Ekhart, G. Gradnig, G. Legler, I. Lundt, A.E. Stu¨ tz,
S.G. Withers, T. Wrodnigg, Carbohydr. Res. 301 (1997) 155–166;
NMR (282 MHz, CD3OD)
d
ꢀ202.5 (m, 1F); IR (KBr) ymax 3390,
(d) D.-K. Kim, G. Kim, Y.-W. Kim, J. Chem. Soc., Perkin Trans.
803–808;
1 (1996)
2929, 1706, 1495, 1455, 1058, 759, 701 cmꢀ1; MS (ESI) m/z 240
(M+H)+; HRMS Calcd for C13H19O2FN: 240.1340; Found: 240.1394.
(e) A. Arnone, P. Bravo, A. Donadelli, G. Resnati, Tetrahedron 52 (1996) 131–142;
(f) A. Kilonda, F. Compernolle, G.J. Hoornaert, J. Org. Chem. 60 (1995) 5820–5824;
(g) C.K. Lee, H. Jiang, L.L. Koh, Y. Xu, Carbohydr. Res. 239 (1993) 309–315;
(h) A. Arnone, P. Bravo, A. Donadelli, G. Resnati, J. Chem. Soc., Chem. Commun.
(1993) 984–986;
(i) J.L. Reymond, A.A. Pinkerton, P. Vogel, J. Org. Chem. 56 (1991) 2128–2135;
(j) T. Kajimoto, K.K.C. Liu, R.L. Pederson, Z. Zhong, Y. Ichikawa, J.A. Porco, C.H.
Wong, J. Am. Chem. Soc. 113 (1991) 6187–6196.
4.2.23. (3S,4R,5R)-4-Fluoro-5-(hydroxymethyl)piperidin-3-ol (3)
Using the same condition as described for compound 1,
compound 3 (19 mg, 77% yield) was prepared as a foam from
compound 27 (40 mg, 0.17 mmol). [
NMR (300 MHz, CD3OD) 4.71 (d, J = 3.6 Hz, 1H), 4.17 (s, 1H), 3.74–
3.55 (m, 2H), 3.46–3.23 (m, 3H), 2.93 (t, J = 12.6 Hz, 2H), 2.64–2.42
(m, 1H); 13C NMR (100.7 MHz, CD3OD)
94.8 (d, J = 170.5 Hz), 59.1,
48.3, 48.0, 47.8, 47.4, 46.0; 19F NMR (282 MHz, CD3OD)
ꢀ204.3
a]
25 = 5.6? (c 0.3, CH3OH); 1H
D
[7] (a) G.M. Blackburn, D.A. England, F. Kolkmann, J. Chem. Soc. Chem. Commun.
(1981) 930–932;
d
(b) G.M. Blackburn, M.J. Parratt, J. Chem. Soc., Perkin Trans.
1425–1430.
1 (1986)
d
[8] (a) R.-W. Wang, X.-L. Qiu, M. Bols, F. Ortega-Caballero, F.-L. Qing, J. Med. Chem. 49
(2006) 2989–2997;
d
(dd, J = 47.1 Hz, 34.4 Hz, 1F); IR (KBr) ymax 3351, 2963, 2933, 2793,
(b) R.-W. Wang, F.-L. Qing, Org. Lett. 7 (2005) 2189–2192.
[9] Y. Yang, F. Zheng, F.-L. Qing, Tetrahedron 67 (2011) 3388–3394.
[10] V.H. Lillelund, H.H. Jensen, X. Liang, M. Bols, Chem. Rev. 102 (2002) 515–554.
[11] (a) H.H. Jensen, M. Bols, Acc. Chem. Res. 39 (2006) 259–265;
(b) H.H. Jensen, L. Lyngbye, A. Jensen, M. Bols, Chem. – Eur. J. 8 (2002) 1218–
1226;
1453, 1390, 1050, 917 cmꢀ1; MS(ESI) m/z 150 (M+H)+; HRMS Calcd
for C6H13O2FN: 150.0930; Found: 150.0925.
Acknowledgment
(c) M. Bols, X. Liang, H.H. Jensen, J. Org. Chem. 67 (2002) 8970–8974.
[12] D. O’Hagan, Chem. Soc. Rev. 37 (2008) 308–319.
[13] J.C. Biffinger, H.W. Kim, S.G. DiMagno, ChemBioChem 5 (2004) 622–627.
We thank National Natural Science Foundation of China
(21072028, 20832008) for funding this work.