Fluorinated Radicamine A and B: Synthesis and Glycosidase Inhibition

Article abstract of DOI:10.1002/ejoc.201501453

Fluorinated derivatives of radicamine A and radicamine B have been synthesized from D-arabinose-derived cyclic nitrone. Structure-activity relationship studies showed that glycosidase inhibition of these fluorinated derivatives was significantly influenced by the position of the fluorine atom. C-7 or C-11 fluorination of the aromatic ring decreased α-glucosidase inhibition of the derivatives, whereas C-8 or C-10 fluorination preserved glycosidase inhibitory activities. Fluorinated derivatives of radicamine A and B have been synthesized from D-arabinose-derived cyclic nitrone. Structure-activity relationship studies revealed that glycosidase inhibition of these fluorinated derivatives was significantly influenced by the position of the fluorine atom.

Full text of DOI:10.1002/ejoc.201501453

DOI: 10.1002/ejoc.201501453
Full Paper
Drug Discovery
Fluorinated Radicamine A and B: Synthesis and Glycosidase
Inhibition
[
a]
[b]
[b]
[a]
[c,e]
Xuan Zhao,[a]
Yi-Xian Li, Ren Iwaki, Atsushi Kato,* Yue-Mei Jia, George W. J. Fleet,
[
d]
[a,e]
Min Xiao, and Chu-Yi Yu*
Abstract: Fluorinated derivatives of radicamine A and radic- nificantly influenced by the position of the fluorine atom. C-7 or
amine B have been synthesized from -arabinose-derived cyclic C-11 fluorination of the aromatic ring decreased α-glucosidase
D
nitrone. Structure–activity relationship studies showed that inhibition of the derivatives, whereas C-8 or C-10 fluorination
glycosidase inhibition of these fluorinated derivatives was sig- preserved glycosidase inhibitory activities.
Introduction
Radicamine A (1) and B (2) are representatives of naturally oc-
[
1]
curring polyhydroxylated pyrrolidines with an aromatic sub-
[
2]
stituent on the iminosugar ring (Figure 1). The compounds
were isolated from Lobelia chinensis LOUR (Campanulaceae) by
[
2d,2e]
Kusano and co-workers in 2001.
Absolute configurations
of radicamines were initially proposed as (2S,3S,4S,5S) and later
[
3]
revised to (2R,3R,4R,5R) by our group. Radicamines have at-
tracted extensive interest because of their potent inhibition of
[
2d,4]
α-glucosidase
and potential pharmaceutical applications.
On the basis of our continuing interest in 2,5-dideoxy-2,5-im-
[
3,5]
ino-
D
-mannitol (DMDP) related iminosugars,
we report a
study of the structure–activity relationship of radicamine A and
B.
Fluorine is one of the most powerful tools available for struc-
Figure 1. Radicamine A and B, and related fluorinated derivatives.
[
5c,6]
ture–activity relationship studies.
Moreover, incorporation
of fluorine into pharmaceutical and veterinary drugs has be- our previous study,[5c] hydroxyl groups on the DMDP moiety
come almost standard practice to enhance their pharmacologi- are important for interaction of the molecule with enzymes,
[
7]
[6b]
cal properties. According to the research of Stütz et al. and and should remain intact in structure modification. Based on
that assumption, we recently extended our studies to australine
and
tion of australine enhanced inhibition against α-glucosidase,
whereas replacement of side chain hydroxyl groups with fluor-
ide in -homoDMDP derivatives did not show any significant
L-homoDMDP, and found that fluorination at the C-7 posi-
[
a] Beijing National Laboratory for Molecular Science (BNLMS),
CAS Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences,
Beijing 100190, P. R. China
[
5f]
L
E-mail: yucy@iccas.ac.cn
[
5g]
influence on α-glucosidase inhibition. The above results pro-
moted our study of radicamines, which are a special class of
DMDP related iminosugars in which aryl groups constitute their
side chains. Herein, we report the synthesis of and glycosidase
inhibition by radicamine A and B derivatives with hydrogen or
hydroxyl groups on aromatic rings replaced by fluoride (Fig-
ure 1). The work could help further our understanding of the
SAR of 2-aryl polyhydroxylated pyrrolidines and DMDP-related
iminosugars.
http://yucy.iccas.ac.cn/
b] Department of Hospital Pharmacy, University of Toyama,
[
2
630 Sugitani, Toyama 930-0194, Japan
E-mail: kato@med.u-toyama.ac.jp
http://www.hosp.u-toyama.ac.jp/pharmacy/
c] Chemistry Research Laboratory, Department of Chemistry,
University of Oxford,
[
[
[
Mansfield Road, Oxford OX1 3TA, UK
d] State Key Laboratory of Microbial Technology and National
Glycoengineering Research Center, Shandong University,
Jinan 250100, P. R. China
e] National Engineering Research Center for Carbohydrate Synthesis, Jiangxi
Normal University,
Results and Discussion
Nanchang 330022, P. R. China
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201501453.
Different synthetic approaches to radicamines have been
[
3,4,8]
exploited,
1429
with syntheses starting from sugar-derived
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nitrones showing advantages in terms of establishing multiple and 18b in this step, the mixture of the two isomers was di-
chiral centers of radicamines and introducing aromatic sub- rectly brominated to 19 and 20, which were then separated
[
3,4,8a–8c]
stituents with high diastereoselectivity.
On the basis more easily (19/20, 2.6:1). Hydrolysis and benzylation gave
of our previous research on sugar-derived polyhydroxylated bromides 10 and 12, respectively.
[
3,5a–5e,9]
[13]
and 14[14] can also be
nitrones,
synthesis of radicamines derivatives 3–8 can
-arabinose-derived cyclic obtained from 2-fluorophenol (16) by successive methylation
with appropriate fluorinated aromatic bromides (or benzylation) and bromination, in 71 and 84 % total yields,
0–15 followed by simple reduction and deprotection. Thus, respectively (Scheme 2). Synthesis of bromides 11 and 15
synthesis of derivatives 3–8 relied on the preparation of fluorin- started from 3-fluorophenol (23). Benzylation and subsequent
Fluorinated aromatic bromides 13
be achieved by Grignard reactions of
nitrone 9
1
D
[
10]
[
15]
ated aromatic bromides 10–15 (Figure 2).
bromination gave product 15 in 89 % total yield (Scheme 2),
whereas 11 was prepared by a similar procedure with 10 and
1
2. 3-Fluorophenol (23) was converted into aldehydes accord-
[
11a]
ing to Hofsløkken's method,
ford 25
hyde (26) (in a ratio of 5.6:1). Compound 25 was brominated
which were methylated to af-
and a side product, 2-fluoro-6-methoxybenzalde-
[
16]
[
17]
[
18]
to 27,
Baeyer–Villiger oxidation, hydrolysis, and benzylation
Scheme 3).
which was then transformed into 11 by successive
(
Figure 2. Nitrone and fluorinated aromatic bromides for the synthesis of
radicamine derivatives.
Synthesis of Fluorinated Aromatic Bromides
Fluorinated aromatic bromides 10 and 12 were prepared from
2
-fluorophenol (16) (Scheme 1). Compound 16 was first con-
[
11]
verted into 3-fluorocatechol
and then acetylated to give a
Scheme 2. Synthesis of fluorinated aromatic bromides 13, 14, and 15.
pair of inseparable isomers 17a and 17b. The mixture of 17a
[
12]
and 17b was methylated to afford 18a and 18b, respectively,
as known compounds that could be partially separated by col-
umn chromatography. Given the difficulty of separating 18a
Scheme 3. Synthesis of fluorinated aromatic bromide 11.
Synthesis of Fluorinated Radicamine A and B
With fluorinated aromatic bromides 10–15 in hand, Grignard
reactions of bromides with nitrone 9 were performed according
to standard procedures to give the addition products 28–33 in
8
2–95 % yield (Figure 3). As an exception, the reaction of brom-
Scheme 1. Synthesis of fluorinated aromatic bromides 10 and 12.
ide 11 was very sluggish under typical Grignard conditions; ac-
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cordingly, magnesium powder, instead of magnesium strips,
was used to prepare the Grignard reagent.
Scheme 4. Synthesis of 3 and 3′ from hydroxylamine 28.
Glycosidase Inhibition
Naturally occurring radicamine A (1) and B (2) were also pre-
[
3]
pared and used as reference compounds in the glycosidase
assays of fluorinated derivatives 3–8 (Table 1). Radicamine A (1)
Figure 3. Addition products of nitrone 9 with bromides 10–15.
proved to be a potent inhibitor of yeast α-glucosidase (IC50
Under routine hydrogenation conditions, 28–33 were con- 5.5 μ ). This compound also showed weak inhibition of rice
verted into the final products 3–8 in MeOH in high yields. In and rat intestinal maltase, with IC50 values of 309 and 439 μ
=
M
M,
the synthesis of fluorinated derivative 3, the N-methylated side respectively. The replacement of C-10 hydrogen of radicamine A
product 3′ was also formed during hydrogenation, which may (1) by fluorine gave 3, with slightly enhanced yeast α-glucosid-
be attributed to trace amounts of formaldehyde in MeOH ase inhibition (IC50 = 1.4 μ
M). Furthermore, N-methylated deriv-
(
Scheme 4). ative 3′ improved the specificity of inhibition towards this en-
Table 1. Comparison of glycosidase inhibition of fluorinated derivatives 3–8 with radicamine A (1) and B (2).
[
a] NI: no inhibition (<50 % inhibition at 1000 μ
M). [b] Numbers in parentheses indicate percent inhibition at 1000 μ
M.
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zyme; inhibition of rice and rat intestinal maltase was lost. Re- a FTIR spectrometer. High-resolution mass spectra (HRMS) were per-
1
13
formed with a LTQ/FT linear ion trap mass spectrometer. H,
C
placement of the C-8 hydroxyl group of radicamine A (1) by
fluorine afforded 6. Compound 6 was not only a potent yeast
and 19F NMR spectra were recorded with a magnetic resonance
spectrometer ( H at 300 MHz, C at 75 MHz, F at 376 MHz) using
CDCl (with TMS as internal standard) or D O (with H O as internal
1
13
19
α-glucosidase inhibitor (IC50 = 4.9 μ
of snail ꢀ-mannosidase (IC50 = 781 μ
mannosidase is rare. For fluorinated derivatives of radicamine B
2), the C-9 hydroxyl group was found to be an essential feature
M), but also a weak inhibitor
3
2
2
M); inhibition of snail ꢀ-
standard) as solvent.
Materials and Methods for the Enzyme Inhibition Assay: With
rat intestinal maltase as an exception, other enzymes were pur-
chased from Sigma–Aldrich Chemical Co. (St. Louis, Mo. USA). Brush
(
for recognition of E. coli ꢀ-glucuronidase, because none of the
radicamine A derivatives that have the C-9 methoxyl group,
showed inhibition.
On the basis of the above assays, fluorination of the aromatic
ring of radicamines has a significant effect on inhibition. The
border membranes, prepared from rat small intestine according to
[21]
a previous report,
were assayed at pH 6.8 for rat intestinal mal-
-glucose was determined colori-
metrically using the Glucose CII-test (Wako Pure Chemical Ind.,
tase using maltose. The released
D
decrease in α-glucosidase inhibition by fluorination of the C-7 Osaka, Japan). Other glycosidase activities were determined by us-
or C-11 position indicates the fluorine atom may form hydrogen ing an appropriate p-nitrophenyl glycoside as substrate in a buffer
[
19]
solution at the optimal pH value for each enzyme. The reaction was
stopped by addition of 400 m Na CO . The released p-nitrophenol
was measured spectrometrically at 400 nm.
bonds with the adjacent N-H.
Such bonding may affect the
M
interaction of N-H with the enzyme active site or change the
interfacial angle between the sugar ring and the aryl group,
2
3
thus influencing interaction of the molecules with enzymes. Synthesis of 3-Fluorocatechol: 2-Fluorophenol (20.0 g, 0.2 mol)
was dissolved in acetonitrile (500 mL, dried with CaH ) and purged
When the C-8 hydroxyl or C-10 hydrogen is replaced with
fluorine, these interactions will not occur. Moreover, fluorine
can act as a chemical isoster of either hydrogen or hydroxyl
2
with argon, anhydrous magnesium chloride (68.0 g, 0.72 mol) was
then added while stirring. A significant exotherm was observed. The
suspension was stirred for 5 min when triethylamine (150.0 mL,
[
20]
groups,
which leaves interaction of compounds with en-
1.08 mol) was added over 5 min. The reaction mixture was then
zymes less affected. These two reasons may account for similar
α-glucosidase inhibition of C-8 or C-10 fluorinated radicamines
to those of the natural products.
stirred for another 20 min. A significant exotherm was also ob-
served. Paraformaldehyde (42.0 g) was added in one batch, and the
reaction mixture was allowed to react at 60 °C for 6 h. TLC showed
unreacted 2-fluorophenol remained; further heating did not lead to
any further change. The reaction mixture was cooled in an ice-bath
to room temperature when aq. NaOH solution (22.8 g NaOH/80 mL
of H O) was added, and followed by dropwise addition of H O
Conclusions
2
2 2
Radicamine derivatives with fluorinated aryl substituents have
(30 %, 140 mL). Considerable heat was produced, and the tempera-
been synthesized efficiently through Grignard addition of fluor- ture should be maintained below 30 °C. The reaction mixture was
inated aromatic bromides 10–15 to the sugar-derived nitrone stirred at room temperature for 1.5 h, acidified with concd. aqueous
HCl to adjust the pH to 1–2, and then extracted with EtOAc (4 ×
00 mL). The EtOAc extracts were combined and stirred with satd.
aq. Na S O (200 mL) for 1 h. The organic phase was separated and
9
as the key step. Structure–activity relationship studies showed
1
that inhibition of glycosidases by these radicamine analogues
was significantly affected by fluorination of the aromatic ring.
This synthetic approach is versatile and gives general access
to radicamines and their analogues. The glycosidase inhibition
results observed herein may be valuable for further structure–
activity studies, as well as for the design and synthesis of more
potent glycosidase inhibitors.
2
2 3
the aqueous phase was extracted with EtOAc (100 mL). The EtOAc
extracts were combined, dried with MgSO4 and concentrated in
vacuo. The crude product was purified by flash column chromatog-
raphy (silica gel; petroleum ether/EtOAc, 15:1) to give 3-fluorocate-
chol (10.3 g, 45 % yield) as a yellow solid and recovered 2-fluoro-
[22]
phenol (4.3 g). Data for 3-fluorocatechol: m.p. 67–69 °C (ref.
71–
1
7
1.5 °C). H NMR (300 MHz, CDCl ): δ = 6.82–6.65 (m, 3 H, Ph), 5.44
3
(
br. s, 1 H, OH), 5.21 (br. s, 1 H, OH) ppm.
-Fluoro-2-hydroxyphenyl Acetate (17a) and 2-Fluoro-6-hydroxy-
phenyl Acetate (17b): To a solution of 3-fluorocatechol (14.6 g,
1.4 mmol) in dichloromethane (40 mL) was added acetic anhydride
Experimental Section
3
General Methods: All reagents were used as received from com-
mercial sources without further purification or prepared as de-
scribed in the literature. Tetrahydrofuran was dried with 4 Å molec-
ular sieve and then distilled from sodium and benzophenone
1
[
23]
(11.6 mL, 12.3 mmol) and one drop of triethylamine. The mixture
was stirred overnight when TLC showed completion of the reaction.
The reaction mixture was washed with water (2 × 50 mL) and the
aqueous extracts were combined and extracted with EtOAc (3 ×
immediately before use. Acetonitrile was distilled from CaH . Chro-
2
matographic purification of products was carried out by flash col-
umn chromatography on silica gel (200–300 mesh). Acidic ion ex-
5
0 mL). The organic phases were combined, dried with MgSO , and
4
+
concentrated in vacuo. The crude product was purified by flash
column chromatography (silica gel; petroleum ether/EtOAc, 10:1) to
give a pair of inseparable isomers 17a and 17b (16.6 g, 86 % yield)
as a yellow oil. The mixture was used directly in the next step.
change chromatography was performed on Dowex 50WX8–400, H
form. Analytical TLC was performed with 0.20 mm silica gel 60F
plates with 254 nm fluorescent indicator. TLC plates were visualized
by ultraviolet light or by treatment with I , a spray of Pancaldi rea-
2
gent [(NH ) MoO , Ce(SO ) , H SO , H O], or a 0.5 % solution of 3-Fluoro-2-methoxyphenyl Acetate (18a) and 2-Fluoro-6-
4
6
4
4 2
2
4
2
KMnO in acetone. Polarimetry measurements were conducted with
methoxyphenyl Acetate (18b): The mixture of 17a and 17b
4
a polarimeter with concentrations (c) given in gram per 100 mL. (14.3 g, 84.1 mmol) was dissolved in acetone (50 mL). K CO (29.7 g,
2
3
Melting points were measured with an electrothermal melting point
apparatus and are uncorrected. Infrared spectra were obtained with
0.22 mol) was added in one batch, followed by dropwise addition
of dimethyl sulfate (10.2 mL, 0.11 mmol). A significant exotherm
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was observed. The mixture was heated at 50 °C for 1 h, when TLC
showed completion of the reaction. Solid was removed from the
reaction mixture by filtration and then washed with EtOAc (3 ×
EtOAc (3 × 30 mL). The organic extracts were combined, dried with
MgSO , and concentrated in vacuo. The crude product was purified
4
by flash column chromatography (silica gel; petroleum ether/EtOAc,
5
0 mL). The EtOAc extracts were combined, dried with MgSO , and
20:1) to give target product 10 (6.0 g, 93 % yield for two steps) as
4
concentrated in vacuo to afford the crude product (15.0 g) as an a yellow oil. IR (film): ν˜ = 3031 (m), 2941 (m), 1731 (m), 1600 (s),
–
1
orange oil. A small portion of the crude product was purified by
flash column chromatography (silica gel; petroleum ether/EtOAc,
1496 (s), 1422 (s), 1236 (s), 1076 (s), 863 (m), 737 (m), 698 (m) cm .
1
H NMR (300 MHz, CDCl ): δ = 7.48–7.34 (m, 5 H, PhCH O), 6.96–
3
2
8
:1) to give the target products (18a and 18b, both as colorless oil)
6.93 (m, 2 H), 5.10 (s, 2 H, PhCH O), 3.94 (d, J = 0.6 Hz, 3 H,
2
for NMR confirmation. The remaining product was used directly in
the next step.
OMe) ppm. 13C NMR (75 MHz, CDCl ): δ = 156.2 (d, J = 247.7 Hz,
3
C,F
C3), 153.5 (d, J = 5.6 Hz), 137.3 (d, J = 13.0 Hz), 136.0, 128.7, 128.3,
1
2
27.4, 114.9 (d, J = 11.9 Hz), 113.5 (d, J = 3.0 Hz), 113.1 (d, J =
1
Data for 18a: H NMR (300 MHz, CDCl ): δ = 6.99–6.94 (m, 2 H, Ph),
3
3.0 Hz), 71.5 (PhCH O), 61.5 (d, J = 3.0 Hz, OMe) ppm. HRMS (ESI):
2
6
.84–6.80 (m, 1 H, Ph), 3.91 (d, J = 1.8 Hz, 3 H, OMe), 2.30 (s, 3 H,
79
+
+
BrFO Na [M + Na] 332.9897; found
[
12] 1
m/z calcd. for C14H
12
2
Ac) ppm [ref.
H NMR (400 MHz, CDCl ): δ = 6.97–7.02 (m, 2 H),
3
332.9898.
6
.81–6.86 (m, 1 H), 3.93 (d, J = 1.6 Hz, 3 H), 2.33 (s, 3 H) ppm].
2
-(Benzyloxy)-4-bromo-3-fluoro-1-methoxybenzene (12): Prod-
1
Data for 18b: H NMR (300 MHz, CDCl ): δ = 7.15–7.07 (m, 1 H, Ph),
3
uct 12 (light yellow oil, 4.1 g, 89 % yield for two steps) was synthe-
sized from 20 (3.9 g, 14.9 mmol) as described for the preparation
of 10. IR (film): ν˜ = 3032 (m), 2941 (m), 1735 (m), 1578 (m), 1456
6
[
(
.79–6.71 (m, 2 H, Ph), 3.80 (s, 3 H, OMe), 2.33 (s, 3 H, Ac) ppm
H NMR (400 MHz, CDCl ): δ = 7.10–7.16 (m, 1 H), 6.73–6.79
m, 2 H), 3.83 (s, 3 H), 2.35 (d, J = 0.4 Hz, 3 H) ppm].
ref.[
12] 1
3
–1
(
s), 1296 (s), 1223 (s), 1092 (s), 982 (m), 793 (m), 741 (m), 697 (m) cm .
H NMR (300 MHz, CDCl ): δ = 7.52–7.49 (m, 2 H, PhCH O), 7.43–
1
5
2
-Bromo-3-fluoro-2-methoxyphenyl Acetate (19) and 3-Bromo-
-fluoro-6-methoxyphenyl Acetate (20): NBS (14.6 g, 89.6 mmol)
3
2
7.33 (m, 3 H, PhCH O), 7.20 (dd, J = 8.7, 7.5 Hz, 1 H, H5), 6.61 (dd,
2
was added to the crude mixture of 18a and 18b (15.0 g) in aceto- J = 9.0, 1.8 Hz, 1 H, H6), 5.12 (s, 2 H, PhCH O), 3.84 (s, 3 H,
2
OMe) ppm. 13C NMR (75 MHz, CDCl ): δ = 153.7 (d, J = 4.3 Hz),
nitrile (100 mL), and the reaction mixture was stirred at 100 °C for
h when TLC showed completion of the reaction. Solvent was re-
3
8
153.4 (d, JC,F = 244.0 Hz, C3), 137.1 (d, J = 14.3 Hz), 136.9, 128.43,
moved in vacuo, water (200 mL) was added, and the mixture was 128.40, 128.3, 126.68, 126.67, 108.5 (d, J = 3.2 Hz), 100.6 (d, J =
stirred for 10 min, then extracted with EtOAc (3 × 80 mL). The or-
ganic phases were combined, dried with MgSO and concentrated
19.8 Hz, C4), 75.8 (d, J = 2.9 Hz, PhCH O), 56.4 (OMe) ppm. HRMS
2
(ESI): m/z calcd. for C14H1279BrFO Na [M + Na] 332.9897; found
+
+
4
2
in vacuo again. The crude product was purified by flash column
chromatography (silica gel; petroleum ether/EtOAc, 20:1) to give
bromides 19 (10.0 g) and 20 (3.9 g) both as yellow oil (63 % total
yield for two steps).
332.9897.
1-Fluoro-2-methoxybenzene (21): To a solution of 2-fluorophenol
(4.0 g, 35.7 mmol) in acetone (30 mL) was added K CO3 (18.5 g,
2
0.13 mol) and dimethyl sulfate (4.2 mL, 44.3 mmol), TLC showed
Data for 19: IR (film): ν˜ = 2943 (w), 1741 (m), 1490 (s), 1238 (m), completion of the reaction after 1 h heating at 50 °C. The solid was
–
1 1
1
089 (m), 1008 (m), 880 (m), 777 (w) cm . H NMR (300 MHz,
removed from the reaction mixture by filtration and then washed
CDCl ): δ = 7.16 (dd, J = 10.5, 2.4 Hz, 1 H, Ph), 7.02–7.00 (m, 1 H, with EtOAc (3 × 20 mL). The EtOAc extracts were combined, dried
3
13
Ph), 3.89 (d, J = 1.8 Hz, 1 H, OMe), 2.31 (s, 3 H, Ac) ppm. C NMR
75 MHz, CDCl ): δ = 168.3 (Ac), 155.7 (d, JC,F = 249.4 Hz, C3), 144.5,
with MgSO , and concentrated in vacuo to afford 1-fluoro-2-meth-
4
(
oxybenzene (21) (3.74 g, 83 % yield) as a light-yellow oil. IR (film):
3
–1
1
39.7, 122.0, 118.2 (d, J = 22.8 Hz), 113.9 (d, J = 11.0 Hz), 61.2 (d, ν = 2925 (m), 2854 (w), 1253 (w), 1215 (m), 1062 (m), 759 (m) cm .
˜
1
J = 5.9 Hz, OMe), 20.4 (Ac) ppm. HRMS (ESI): m/z calcd. for
H NMR (300 MHz, CDCl ): δ = 7.07–6.84 (m, 4 H, Ph), 3.87 (s, 3 H,
3
C9H879BrFO Na [M + Na] 284.9533; found 284.9532.
+
+
[24] 1
3
OMe) ppm [ref.
.7 (s, 3 H) ppm].
H NMR (100 MHz, CDCl ): δ = 6.9–6.5 (m, 4 H),
3
3
Data for 20: IR (film): ν˜ = 2944 (m), 1774 (m), 1606 (m), 1492 (m),
–
1 1
1
297 (m), 1180 (m), 1086 (s), 1012 (s), 917 (m), 796 (m) cm .
H
4-Bromo-2-fluoro-1-methoxybenzene (13): To a solution of 1-
fluoro-2-methoxybenzene (1.0 g, 7.9 mmol) in acetonitrile (15 mL)
was added NBS (1.4 g, 8.7 mmol), and the solution was stirred at
NMR (300 MHz, CDCl ): δ = 7.34 (dd, J = 9.3, 7.5 Hz, 1 H, Ph), 6.66
3
(
dd, J = 9.0, 1.8 Hz, 1 H, Ph), 3.83 (s, 3 H, OMe), 2.35 (s, 3 H, Ac) ppm.
1
3
C NMR (75 MHz, CDCl ): δ = 167.8 (Ac), 152.3 (d, J = 3.4 Hz), 152.1 70 °C for 3 h. TLC showed completion of the reaction. Solvent was
3
(
1
d, JC,F = 246.1 Hz, C2), 129.4, 108.3 (d, J = 3.3 Hz), 100.3 (d, J =
9.3 Hz, C3), 56.4 (OMe), 20.2 (Ac) ppm. C NMR (Dept-135, 75 MHz,
removed in vacuo, water (30 mL) was added and the mixture was
stirred for 10 min, then extracted with EtOAc (3 × 20 mL). The or-
1
3
CDCl ): δ (positive) = 129.4, 108.3, 56.4, 20.2 ppm. HRMS (ESI): m/z ganic phases were combined, dried with MgSO , and concentrated
3
4
79
+
+
calcd. for C9H8 BrFO Na [M + Na] 284.9533; found 284.9530.
in vacuo again. The crude product was purified by flash column
3
chromatography (silica gel; pure petroleum ether) to afford bromide
1
-(Benzyloxy)-5-bromo-3-fluoro-2-methoxybenzene (10): To a
solution of bromide 19 (10.0 g, 38.2 mmol) in methanol/water
10 mL/10 mL) was added K CO (5.8 g, 42.0 mmol), and the solu-
1
3 (1.4 g, 86 % yield) as a light-yellow oil. IR (film): ν˜ = 2925 (m),
–1 1
1252 (m), 1214 (m), 1709 (s), 1035 (s) cm . H NMR (300 MHz,
(
2
3
CDCl ): δ = 7.24–7.16 (m, 2 H, H3 and H5), 6.82 (t, J = 8.7 Hz, 1 H,
3
tion was heated at 40 °C for 1 h, after which TLC showed the disap-
pearance of bromide 19. The solution was diluted with water
13
H6), 3.86 (s, 3 H, OMe) ppm. C NMR (75 MHz, CDCl ): δ = 152.3
3
(
d, JC,F = 249.0 Hz, C2), 147.1 (d, J = 10.4 Hz, C1), 127.2 (d, J = 4.0 Hz,
C5), 119.6 (d, J = 21.1 Hz, C3), 114.6 (d, J = 2.2 Hz, C6), 111.9 (d, J =
.2 Hz, C4), 56.4 (OMe) ppm. 13C NMR (Dept-135, 75 MHz, CDCl ): δ
(50 mL) and extracted with EtOAc (3 × 50 mL). The EtOAc extracts
were combined, dried with MgSO , and concentrated in vacuo to
4
8
(
3
give the hydrolysis product (9.9 g) as an orange oil. A solution of
the crude product (5.4 g) in THF (20 mL) was added dropwise to a
suspension of NaH (60 %, 1.3 g, 32.5 mmol) in THF (10 mL). The
reaction mixture was stirred for 5 min then a catalytic amount of
TBAI was added, followed by dropwise addition of BnBr (3.2 mL,
[
25] 1
positive) = 127.2, 119.6, 114.6, 56.4 ppm [ref.
H NMR (400 MHz,
CDCl ): δ = 7.20 (m, 2 H), 6.83 (t, J = 8.8 Hz, 1 H), 3.86 (s, 3 H) ppm].
3
1-(Benzyloxy)-4-bromo-2-fluorobenzene (14): 2-Fluorophenol
(5.0 g, 44.6 mmol) was dissolved in THF (20 mL), and added drop-
2
2
6.9 mmol) at 40 °C. TLC showed completion of the reaction after wise to a suspension of NaH (60 %, 2.3 g, 57.5 mmol) in THF (20 mL).
4 h. The reaction was quenched by aq. NH Cl and extracted with The reaction mixture was stirred for 5 min, after which a catalytic
4
Eur. J. Org. Chem. 2016, 1429–1438
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1433
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
amount of TBAI was added, followed by dropwise addition of BnBr
Data for 25: M.p. 46–48 °C (ref.[16] 53 °C). IR (film): ν˜ = 1687 (s),
(7.3 mL, 61.4 mmol) at 40 °C. TLC showed completion of the reac- 1607 (s), 1466 (m), 1280 (s), 1197 (m), 1152 (m), 1099 (m), 955 (m),
–
1 1
tion after 0.5 h. The reaction was quenched by addition of aq. NH Cl
840 (m) cm . H NMR (300 MHz, CDCl ): δ = 10.4 (s, 1 H, HC=O),
4
3
and the mixture was extracted with EtOAc (2 × 30 mL). The organic
7.85 (dd, J = 8.4, 6.9 Hz, 1 H, H6), 6.75–6.67 (m, 2 H, H3 and H5),
phases were combined, dried with MgSO , and concentrated in
3.93 (s, 3 H, OMe) ppm. 13C NMR (75 MHz, CDCl ): δ = 188.2 (HC=
4
3
vacuo to afford the crude product (11.9 g) as a colorless oil. To a
solution of the crude product in acetonitrile (50 mL) was added
NBS (7.3 g, 44.8 mmol), and the reaction mixture was stirred at
O), 167.7 (d, JC,F = 254.5 Hz, C4), 163.6 (d, J = 11.0 Hz, C2), 130.9 (d,
J = 11.6 Hz, C6), 121.6 (d, J = 2.7 Hz, C1), 108.1 (d, J = 22.1 Hz, C5),
99.7 (d, J = 25.7 Hz, C3), 56.0 (OMe) ppm. 13C NMR (Dept-135,
7
0 °C for 3 h when TLC showed completion of the reaction. Solvent
75 MHz, CDCl ): δ (positive) = 188.2, 130.9, 108.1, 99.7, 56.0 ppm.
3
was removed in vacuo, water (50 mL) was added, and the mixture
was stirred for 15 min then extracted with EtOAc (3 × 30 mL). The
Data for 26: M.p. 60–61 °C (ref.[17] 60–61 °C). H NMR (300 MHz,
1
CDCl ): δ = 10.3 (s, 1 H, HC=O), 7.41 (dd, J = 15.0, 8.4 Hz, 1 H, H4),
.71–6.61 (m, 2 H, H3 and H5), 3.85 (s, 3 H, OMe) ppm. C NMR
75 MHz, CDCl ): δ = 187.4 (d, J = 3.4 Hz, HC=O), 163.3 (d, J
60.5 Hz, C2), 162.2 (d, J = 5.4 Hz, C6), 136.2 (d, J = 12.0 Hz, C4),
3
organic extracts were combined, dried with MgSO , and concen-
4
13
6
trated in vacuo. The crude product was purified by flash column
chromatography (silica gel; pure petroleum ether) to afford bromide
(
=
3
C,F
2
1
3
(
(
(
1
4 as an oil that slowly gave a light-yellow solid (10.5 g, 84 % yield
14.0 (d, J = 8.7 Hz, C1), 108.6 (d, J = 21.3 Hz, C3), 107.3 (d, J =
[14]
1
for two steps), m.p. 63–65 °C (ref.
65–67 °C). H NMR (300 MHz,
.5 Hz, C5), 56.3 (OMe) ppm. 13C NMR (Dept-135, 75 MHz, CDCl ): δ
3
CDCl ): δ = 7.46–7.35 (m, 5 H, PhCH O), 7.27 (dd, J = 10.5, 2.4 Hz, 1
3
2
[17] 1
positive) = 187.4, 136.2, 108.6, 107.3, 56.3 ppm [ref.
500 MHz, CDCl ): δ = 10.44 (s, 1 H), 7.47–7.50 (m, 1 H), 6.72–6.80
m, 2 H), 3.95 (s, 3 H) ppm. C NMR (125 MHz, CDCl ): δ = 187.2,
64.4, 162.4, 162.2, 162.1, 136.0, 135.9, 114.3, 114.2, 108.7, 108.6,
07.3, 107.2, 56.4 ppm].
H NMR
H), 7.16 (dt, J = 8.7, 2.0 Hz, 1 H), 6.88 (t, J = 3.9 Hz, 1 H), 5.13 (s, 2
13
3
H, PhCH O) ppm. C NMR (75 MHz, CDCl ): δ = 152.9 (d, JC,F
=
2
3
13
3
2
1
2
49.5 Hz, C2), 146.2 (d, J = 10.6 Hz, C1), 136.2, 128.8, 128.4, 127.5,
1
1
27.3 (d, J = 3.9 Hz, C5), 120.0 (d, J = 21.3 Hz, C3), 117.0 (d, J =
[
14] 1
.1 Hz, C6), 112.7 (d, J = 8.3 Hz, C4), 71.6 (PhCH O) ppm [ref.
H
2
NMR (400 MHz, CDCl ): δ = 7.41 (m, 5 H), 7.27 (dd, J = 6.4 Hz, 2.2 Hz, 5-Bromo-4-fluoro-2-methoxybenzaldehyde (27): To a solution of
3
1
H), 7.26 (dt, J = 4.3 Hz, 2.0 Hz, 1 H), 6.89 (t, J = 8.8 Hz, 1 H), 5.13
aldehyde 25 (21.5 g, 0.14 mol) in acetonitrile (100 mL) was added
NBS (27.0 g, 0.17 mol), and the reaction mixture was stirred over-
night at 70 °C when TLC showed completion of the reaction. Sol-
vent was removed in vacuo, water (200 mL) was added, and the
mixture was stirred for 15 min then extracted with EtOAc (3 ×
(s, 2 H) ppm].
1
-(Benzyloxy)-4-bromo-3-fluorobenzene (15): Product 15 (light-
yellow oil, 11.1 g, 89 % yield for two steps) was synthesized from
1 (5.0 g, 44.6 mmol) as described for the preparation of 14. 1
NMR (300 MHz, CDCl ): δ = 7.37–7.30 (m, 5 H, PhCH O), 7.21 (t, J =
2
H
50 mL). The organic extracts were combined, dried with MgSO4,
3
2
and concentrated in vacuo. The crude product was purified by flash
column chromatography (silica gel; PE/EtOAc, 15:1) to afford brom-
ide 27 (30.7 g, 95 % yield) as a light-yellow solid, m.p. 80–82 °C
8
.7 Hz, 1 H, H5), 6.73 (dd, J = 10.8, 2.7 Hz, 1 H, H2), 6.68–6.64 (m, 1
1
3
H, H6), 4.96 (s, 2 H, PhCH O) ppm. C NMR (75 MHz, CDCl ): δ =
2
3
1
58.6 (d, J = 9.7 Hz), 158.5 (d, JC,F = 246.4 Hz, C3), 136.1, 130.6 (d,
J = 1.0 Hz), 128.8, 128.6, 128.5, 128.4, 127.8, 127.5, 112.6 (d, J =
7.9 Hz), 111.7 (d, J = 3.3 Hz), 103.9 (d, J = 24.2 Hz), 70.6
[18]
1
(ref. 86.5–87 °C). H NMR (300 MHz, CDCl ): δ = 10.2 (s, 1 H, HC=
3
O), 7.96 (d, J = 8.1 Hz, 1 H, H6), 6.72 (d, J = 10.2 Hz, 1 H, H3), 3.86
1
(s, 3 H, OMe) ppm.
[15a] 1
(PhCH O) ppm [ref.
H NMR (400 MHz, CDCl ): δ = 7.42–7.32 (m,
2
3
1-(Benzyloxy)-5-bromo-4-fluoro-2-methoxybenzene (11): To a
6
1
H), 6.77 (dd, J = 8 Hz, 4 Hz, 1 H), 6.69 (ddd, J = 10 Hz, 8 Hz, 4 Hz,
H), 5.05 (s, 2 H) ppm].
solution of bromide 27 (30.5 g, 0.13 mol) in dichloromethane
100 mL) was added mCPBA (40.0 g, 0.23 mol). The reaction mixture
(
4
-Fluoro-2-methoxybenzaldehyde (25) and 2-Fluoro-6-meth- was stirred overnight at 40 °C when TLC showed completion of the
oxybenzaldehyde (26): 3-Fluorophenol (20.0 g, 0.2 mol) was dis- reaction. Solid (mCPBA and mCBA) was removed from the reaction
solved in acetonitrile (500 mL, dried with CaH ) and purged with mixture by filtration and then washed with PE/EtOAc (1:5; 3 ×
argon. Anhydrous magnesium chloride (102.0 g, 1.1 mol) was then 50 mL). The organic phases were combined, concentrated in vacuo,
2
added to the stirred reaction mixture. A significant exotherm was
observed. The suspension was stirred for 5 min, then triethylamine
and most of the remaining mCPBA and mCBA in the crude product
was removed by crystallization from petroleum ether/EtOAc (1:10)
three times. The mother liquor was combined and concentrated in
(225.0 mL, 1.6 mol) was added over 5 min and the mixture was
stirred for another 30 min. Considerable heat was also produced. vacuo to afford a wine-red oil. The crude product was dissolved in
Paraformaldehyde (63.0 g) was added in one batch and the reaction THF (100 mL), and aq. NaOH was added to adjust the pH to ca. 12.
mixture was allowed to react at 50 °C for 3 h when TLC showed
completion of the reaction. The reaction mixture was cooled to
room temperature, acidified with concd. aqueous HCl to pH ca. 4,
The reaction mixture was heated at 40 °C for 1 h, acidified with
concd. aqueous HCl to adjust the pH to ca. 2, and then extracted
with EtOAc (3 × 50 mL). The organic extracts were combined, dried
and then extracted with EtOAc (3 × 150 mL). EtOAc extracts were with MgSO , and concentrated in vacuo to give the crude product
4
combined, dried with MgSO , and concentrated in vacuo to afford
a dark-red crude product (49.9 g). To the solution of the crude alde-
(53.4 g) as a brown solid. A solution of the crude product (27.6 g)
in THF (60 mL) was added dropwise to a suspension of NaH (60 %,
4
hyde in acetone (200 mL) was added K CO (81.2 g, 0.6 mol) and 6.4 g, 0.16 mmol) in THF (70 mL). The reaction mixture was stirred
2
3
dimethyl sulfate (25.4 mL, 0.3 mol); TLC showed completion of the
for 5 min, then a catalytic amount of TBAI was added, followed by
reaction after heating overnight at 40 °C. Solid was removed from dropwise addition of BnBr (9.2 mL, 77.4 mmol) at 40 °C. TLC showed
the reaction mixture by filtration and the solution was then washed
with EtOAc (3 × 100 mL). The organic phases were combined, dried
completion of the reaction after 2 h. The reaction was quenched
by the addition of aq. NH Cl and extracted with EtOAc (3 × 50 mL).
4
with MgSO , and concentrated in vacuo. The crude product was
The organic phases were combined, dried with MgSO , and concen-
4
4
purified by flash column chromatography (silica gel; petroleum trated in vacuo. The crude product was purified by flash column
ether/EtOAc, 15:1) to give 4-fluoro-2-methoxybenzaldehyde (25;
5.8 g) and 2-fluoro-6-methoxybenzaldehyde (26; 2.8 g) both as
light-yellow solids (68 % total yield for two steps).
chromatography (silica gel; PE/EtOAc, 20:1) to afford bromide 11
1
(16.8 g, 80 % yield for three steps) as a light-yellow solid, m.p. 82–
1
85 °C. H NMR (300 MHz, CDCl ): δ = 7.41–7.27 (m, 5 H, PhCH O),
3
2
Eur. J. Org. Chem. 2016, 1429–1438
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1434
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
7
.00 (d, J = 6.6 Hz, 1 H, H6), 6.67 (d, J = 9.9 Hz, 1 H, H3), 5.02 (s, 2 IR (film): ν˜ = 3032 (w), 2940 (w), 1603 (m), 1498 (m), 1450 (m), 1284
1
3
–1 1
H, PhCH O), 3.80 (s, 3 H, OMe) ppm. C NMR (75 MHz, CDCl ): δ = (m), 1222 (m), 1077 (s), 1010 (m), 741 (m), 696 (m) cm . H NMR
2
3
1
54.0 (d, JC,F = 238.8 Hz, C4), 150.2 (d, J = 8.6 Hz, C2), 145.0 (d, J =
(300 MHz, CDCl ): δ = 7.23–6.98 (m, 20 H, PhCH O), 6.83 (d, J =
3
2
2
.9 Hz, C1), 136.4, 128.7, 128.2, 127.6 (PhCH O), 118.2 (C6), 101.1 (d, 6.9 Hz, 1 H), 6.45 (d, J = 11.4 Hz, 1 H), 4.91–4.73 (m, 2 H), 4.48 (t,
2
J = 27.5 Hz, C3), 97.4 (d, J = 22.4 Hz, C5), 72.0 (PhCH O), 56.3 J = 6.8 Hz, 1 H), 4.44–4.31 (m, 4 H), 4.19 (dd, J = 25.8, 12.0 Hz, 2 H),
2
(
1
OMe) ppm. 13C NMR (Dept-135, 75 MHz, CDCl ): δ (positive) = 3.99–3.94 (m, 2 H), 3.72–3.66 (m, 4 H), 3.58 (t, J = 6.9 Hz, 1 H), 3.41
3
28.7, 128.2, 127.6, 118.2, 101.1, 56.3; δ (negative) = 72.0 ppm. (t, J = 3.2 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl ): δ = 156.3 (d,
3
7
9
BrFO Na [M + Na]+ 332.9897; JC,F = 239.6 Hz, C11), 150.1 (d, J = 10.1 Hz, C9), 144.2 (d, J = 2.3 Hz,
+
HRMS (ESI): m/z calcd. for C H
1
4
12
2
found 332.9899.
C8), 138.3, 138.2, 137.9, 137.0, 128.7, 128.5, 128.4, 128.3, 128.0,
1
27.9, 127.82, 127.75, 127.67, 127.64, 115.8 (d, J = 13.9 Hz, C6), 114.4
General Procedures for Grignard Reaction of Nitrone 9 and
Bromides 10–15 (with Bromide 11 as an Exception): To a three-
neck flask was added magnesium scraps (5–12 equiv.) and a particle
(d, J = 5.0 Hz, C7), 100.0 (d, J = 28.5 Hz, C10), 86.3, 83.6, 73.4, 71.9,
13
7
7
1
5
1.7, 71.3 (PhCH O), 69.3, 67.0, 66.0, 56.1 ppm. C NMR (Dept-135,
2
5 MHz, CDCl ): δ (positive) = 128.5, 128.4, 128.3, 128.0, 127.9,
3
of I , then the flask was purged with argon. Freshly distilled THF
2
27.82, 127.75, 127.67, 127.64, 114.4, 100.0, 86.3, 83.6, 69.3, 66.0,
(1 mL) was added and the mixture was heated at 50 °C for 10 min.
6.1; δ (negative) = 73.4, 71.9, 71.7, 71.3, 67.0 ppm. HRMS (ESI): m/z
Two drops of 1,2-dibromoethane was added to induce the reaction,
and a solution of bromides (3–5 equiv.) in THF was added slowly
+
+
calcd. for C H FNO [M + H] 650.2912; found 650.2909.
40
41
6
by using a syringe. A significant exotherm was observed. The mix- Hydroxylamine 30: According to the general procedure, nitrone 9
ture was reacted at 50 °C for 30 min. Nitrone 9 (1 equiv.) was dis- (0.20 g, 0.48 mmol) and the Grignard reagent from bromide 12
solved in THF and cooled to 0 °C, and the above Grignard reagent
(0.74 g, 2.39 mmol) afforded hydroxylamine 30 (0.28 g, 90 % yield)
2
0
was added by using a syringe. After 5 min, the reaction was as a light-yellow syrup. [α] = +5.9 (c = 0.34, CH Cl ). IR (film): ν˜ =
D
2
2
quenched by the addition of aq. NH Cl solution, and extracted 3031 (m), 2941 (m), 1610 (m), 1498 (m), 1455 (m), 1291 (m), 1214
4
–
1 1
three times with EtOAc. The organic extracts were combined, dried
(m), 1091 (s), 1011 (m), 741 (m), 699 (m) cm . H NMR (300 MHz,
with MgSO , and concentrated in vacuo. The crude product was
CDCl ): δ = 7.45 (d, J = 6.9 Hz, 2 H, PhCH O), 7.33–7.18 (m, 16 H,
4
3
2
purified by flash column chromatography (silica gel; PE/EtOAc) to
afford the target hydroxylamine.
PhCH O), 7.12–7.06 (m, 3 H, PhCH O and H11), 6.60 (d, J = 8.7 Hz,
2
2
1 H, H10), 6.16 (br. s, 1 H, OH), 5.05 (s, 2 H, PhCH O), 4.57–4.28 (m,
2
7
3
H), 4.17 (dd, J = 6.9, 3.3 Hz, 1 H), 4.09 (t, J = 3.5 Hz, 1 H), 3.85–
Hydroxylamine 28: According to the general procedure, nitrone 9
1
3
.76 (m, 4 H), 3.67 (t, J = 8.3 Hz, 1 H), 3.57–3.52 (m, 1 H) ppm.
C
(
(
0.40 g, 0.96 mmol) and the Grignard reagent from bromide 10
1.48 g, 3.55 mmol) afforded hydroxylamine 28 (0.59 g, 95 % yield)
NMR (75 MHz, CDCl ): δ = 155.7 (d, J = 246.1 Hz, C7), 153.5 (d,
J = 5.0 Hz, C9), 138.3, 138.1, 137.9, 137.4, 135.8 (d, J = 14.1 Hz, C8),
3
C,F
2
0
as a light-yellow syrup. [α]D = +43.6 (c = 0.14, CH Cl ). IR (film): ν˜ =
2
2
1
1
28.4, 128.31, 128.27, 128.1, 128.0, 127.8, 127.72, 127.68, 127.61,
27.58, 123.7 (d, J = 5.0 Hz, C11), 119.1 (d, J = 12.1 Hz, C6), 107.3
3
(
031 (w), 2932 (w), 1587 (m), 1497 (m), 1453 (m), 1242 (m), 1075
–
1 1
s), 1004 (m), 738 (m), 698 (m) cm . H NMR (300 MHz, CDCl ): δ =
3
(C10), 86.4, 83.6, 75.6 (d, J = 2.6 Hz, PhCH O), 73.4, 71.9, 71.7
2
7
6
4
.39–7.20 (m, 19 H, PhCH O), 7.10–7.07 (m, 2 H, PhCH O, H7), 6.82–
2 2
13
(PhCH O), 69.2, 67.2, 66.7, 56.2 ppm. C NMR (Dept-135, 75 MHz,
2
.79 (m, 1 H, H11), 5.59 (br. s, 1 H, OH), 4.99 (s, 2 H, PhCH O), 4.65–
2
CDCl ): δ (positive) = 128.4, 128.31, 128.27, 128.1, 128.0, 127.8,
3
.30 (m, 6 H, PhCH O), 4.11–4.07 (m, 2 H), 3.95–3.88 (m, 4 H), 3.81
2
1
5
27.72, 127.68, 127.61, 127.58, 123.7, 107.4, 86.4, 83.6, 69.2, 66.7,
6.2; δ (negative) = 75.6, 73.4, 71.9, 71.7, 67.2 ppm. HRMS (ESI): m/z
(
dd, J = 9.0, 4.5 Hz, 1 H), 3.71 (t, J = 8.1 Hz, 1 H), 3.64–3.62 (m, 1
13
H) ppm. C NMR (75 MHz, CDCl ): δ = 156.0 (d, J = 243.7 Hz,
3
C,F
+
+
calcd. for C H FNO [M + H] 650.2912; found 650.2911.
40
41
6
C10), 152.6 (d, J = 5.3 Hz, C8), 138.1, 138.0, 137.8, 137.1 (d, J =
1
1
4.6 Hz, C9), 136.7, 134.9 (d, J = 8.4 Hz, C6), 128.5, 128.4, 128.3, Hydroxylamine 31: According to the general procedure, nitrone 9
28.1, 128.0, 127.84, 127.76, 127.73, 127.70, 127.5, 109.6 (C7), 109.4 (0.32 g, 0.77 mmol) and the Grignard reagent from bromide 13
(
7
d, J = 20.5 Hz, C11), 87.2, 83.6, 73.52 (PhCH O), 73.48, 72.1, 71.7,
(0.44 g, 2.16 mmol) afforded hydroxylamine 31 (0.36 g, 86 % yield)
2
13
20
1.1 (PhCH O), 68.9, 66.9, 61.5 (d, J = 3.1 Hz, OMe) ppm. C NMR as an off-white solid, m.p. 107–109 °C. [α]D = +10.8 (c = 0.74,
2
(
Dept-135, 75 MHz, CDCl ): δ (positive) = 128.6, 128.4, 128.3, 128.1, CH Cl ). IR (film): ν˜ = 3386 (m), 3063 (m), 2866 (m), 1519 (m), 1275
3
2
2
–
1 1
1
8
6
6
28.0, 127.85, 127.79, 127.76, 127.73, 127.70, 127.5, 109.5, 109.2,
(m), 1097 (s), 1028 (s), 738 (m), 698 (m) cm . H NMR (300 MHz,
7.2, 83.5, 73.48, 68.9, 61.5; δ (negative) =73.52, 72.1, 71.7, 71.1, CDCl ): δ = 7.29–7.21 (m, 13 H, PhCH O), 7.16–7.04 (m, 4 H, PhCH O,
3
2
2
+
+
6.9 ppm. HRMS (ESI): m/z calcd. for C H FNO [M + H]
50.2912; found 650.2900.
H10 and H11), 6.83 (t, J = 8.6 Hz, 1 H, H7), 6.28 (br. s, 1 H, OH),
4.58–4.42 (m, 4 H, PhCH O), 4.34 (s, 2 H, PhCH O), 4.12–4.02 (m, 3
4
0
41
6
2
2
H), 3.81 (s, 3 H, OMe), 3.76 (dd, J = 9.3, 4.2 Hz, 1 H), 3.65 (t, J =
.3 Hz, 1 H), 3.55 (t, J = 3.3 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 152.2 (d, JC,F = 243.8 Hz, C8), 147.2 (d, J = 10.7 Hz, C9), 138.2,
Hydroxylamine 29: To a three-neck flask was added magnesium
8
powder (0.20 g, 8.3 mmol) and a particle of I , and the flask was
2
then purged with argon. Newly distilled THF (1 mL) was added and
the mixture was heated at 50 °C for 10 min. 1-Bromo-2-methylpro-
pane (0.1 mL) was added to induce the reaction, then a solution of
bromide 11 (0.80 g, 2.6 mmol) in THF (5 mL) was added slowly by
using a syringe. Considerable heat was produced. The reaction mix-
ture was reacted at 50 °C for 30 min. Nitrone 9 (0.18 g, 0.43 mmol)
was dissolved in THF (10 mL) and cooled to 0 °C, then the above
Grignard reagent was added by using a syringe. After 5 min, the
1
1
8
38.1, 137.8, 132.1 (d, J = 5.7 Hz, C6), 128.4, 128.3, 128.1, 127.74,
27.72, 127.67, 127.6, 124.5, 116.2 (d, J = 18.6 Hz, C7), 113.0, 87.1,
3.6, 73.4 (PhCH O), 73.0, 72.1, 71.6 (PhCH O), 69.1, 67.0, 56.2
2
2
(
OMe) ppm. 13C NMR (Dept-135, 75 MHz, CDCl ): δ (positive) =
3
1
8
28.4, 128.3, 128.1, 127.74, 127.72, 127.67, 127.6, 124.6, 116.2, 113.1,
7.1, 83.6, 73.0, 69.1, 56.2; δ (negative) = 73.4, 72.1, 71.6, 67.0 ppm.
+
+
HRMS (ESI): m/z calcd. for C H FNO [M + H] 544.2494; found
33
35
5
544.2492.
reaction was quenched by addition of aq. NH Cl solution and the
4
mixture was extracted with EtOAc (3 × 20 mL). The organic phases
Hydroxylamine 32: According to the general procedure, nitrone 9
were combined, dried with MgSO , and concentrated in vacuo. The (0.23 g, 0.55 mmol) and the Grignard reagent from bromide 14
4
crude product was purified by flash column chromatography (silica
(0.52 g, 1.86 mmol) afforded hydroxylamine 32 (0.29 g, 85 % yield)
2
0
gel; PE/EtOAc, 5:1) to afford the target hydroxylamine 29 (0.23 g, as an off-white solid, m.p. 142–144 °C. [α] = –18.9 (c = 0.95,
D
2
0
8
2 % yield) as a light-yellow syrup. [α]D = +22.6 (c = 0.53, CH Cl ). CH Cl ). IR (film): ν˜ = 3031 (m), 2867 (m), 1515 (m), 1274 (m), 1215
2
2
2
2
Eur. J. Org. Chem. 2016, 1429–1438
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
–
1
(
m), 1111 (s), 1026 (s), 736 (s), 697 (s) cm . 1H NMR (300 MHz,
1 H, H3), 3.62–3.59 (m, 4 H, OMe and H5), 3.56–3.45 (m, 2 H, H1),
CDCl ): δ = 7.43–7.15 (m, 19 H, PhCH O), 7.10–7.02 (m, 3 H, PhCH O, 3.03 (dd, J = 11.1, 6.0 Hz, 1 H, H2) ppm. 13C NMR (75 MHz, D O):
3
2
2
2
H7 and H11), 6.90 (d, J = 8.4 Hz, 1 H, H10), 5.76 (br. s, 1 H, OH), 5.09
δ = 156.0 (d, JC,F = 242.1 Hz, C10), 153.1 (d, J = 5.0 Hz, C8), 135.8
(
s, 2 H, PhCH O), 4.59–4.44 (m, 4 H, PhCH O), 4.34 (s, 2 H, PhCH O),
(d, J = 9.0 Hz, C6), 135.2 (d, J = 12.3 Hz, C9), 112.0 (C7), 104.6 (d,
2
2
2
4
3
.13–4.06 (m, 2 H), 4.02–3.99 (m, 1 H), 3.79 (dd, J = 9.3, 4.2 Hz, 1 H),
J = 20.1 Hz, C11), 81.8 (C4), 77.0 (C3), 63.4, 62.0 (C1), 61.5, 61.2 (d,
.68 (t, J = 8.3 Hz, 1 H), 3.59 (d, J = 3.0 Hz, 1 H) ppm. 13C NMR
J = 3.2 Hz, OMe) ppm. C NMR (Dept-135, 75 MHz, D O): δ (posi-
13
2
(
75 MHz, CDCl ): δ = 152.7 (d, JC,F = 244.7 Hz, C8), 146.3 (d, J =
tive) = 112.0, 104.6, 81.8, 77.0, 63.4, 61.5, 61.2; δ (negative) =
3
1
1
1
0.7 Hz, C9), 138.2, 138.0, 137.8, 136.6, 132.8 (d, J = 5.8 Hz, C6), 62.0 ppm. 19F NMR (376 MHz, D O): δ = –128.3 (s, 1 F) ppm. HRMS
2
+
+
28.6, 128.40, 128.38, 128.28, 128.09, 128.06, 127.72, 127.65, 127.5,
(ESI): m/z calcd. for C H FNO [M + H] 274.1085; found 274.1084.
12 17 5
24.3 (C11), 116.3 (d, J = 18.9 Hz, C7), 115.3 (C10), 87.2, 83.5, 73.4
Data for 3′: M.p. 54–57 °C. [α]2
0
= +24.4 (c = 0.99, MeOH). IR (film):
D
13
(
PhCH O), 73.1, 72.1, 71.7, 71.4 (PhCH O), 69.0, 66.9 (C1) ppm.
C
2
2
ν˜ = 3329 (s), 2927 (m), 1501 (m), 1440 (m), 1317 (m), 1236 (m), 1043
NMR (Dept-135, 75 MHz, CDCl ): δ (positive) = 128.6, 128.40, 128.38,
3
–
1 1
(
s), 1007 (s) cm . H NMR (300 MHz, D O): δ = 6.97–6.93 (m, 2 H,
2
1
8
28.28, 128.10, 128.06, 127.72, 127.65, 127.5, 124.4, 116.3, 115.3,
H7 and H11), 3.94 (dd, J = 8.7, 7.5 Hz, 1 H, H4), 3.84 (d, J = 7.5 Hz,
1 H, H3), 3.78 (d, J = 9.3 Hz, 1 H, H5), 3.72 (s, 3 H, OMe), 3.67–3.54
7.2, 83.5, 73.1, 69.0; δ (negative) = 73.4, 72.1, 71.7, 71.4, 66.9 ppm.
HRMS (ESI): m/z calcd. for C H FNO [M + H]+ 620.2807; found
+
3
9
39
5
1
3
(m, 2 H, H1), 3.17–3.11 (m, 1 H, H2), 2.13 (s, 3 H, NMe) ppm.
C
6
20.2800.
NMR (75 MHz, D O): δ = 155.3 (d, J = 243.3 Hz, C10), 144.4 (d, J =
2
C,F
Hydroxylamine 33: According to the general procedure, nitrone 9
11.1 Hz, C9), 135.5 (d, J = 7.1 Hz, C8), 133.6 (C6), 125.0 (d, J = 2.5 Hz,
(
(
0.60 g, 1.44 mmol) and the Grignard reagent from bromide 15
1.21 g, 4.32 mmol) afforded hydroxylamine 33 (0.79 g, 89 % yield)
C7), 112.9 (d, J = 19.9 Hz, C11), 81.7 (C4), 76.9 (C3), 63.1, 61.9 (C1),
13
61.6, 61.1 (d, J = 4.1 Hz, OMe), 14.9 (d, J = 2.6 Hz, NMe) ppm.
C
2
0
as a light-yellow solid, m.p. 81–84 °C. [α]D = +73.1 (c = 0.22, CH Cl ).
2
2
NMR (Dept-135, 75 MHz, D O): δ (positive) = 125.0, 112.9, 81.7, 76.9,
2
IR (film): ν˜ = 3246 (w), 3031 (m), 2867 (m), 1625 (m), 1508 (m), 1286
19
6
3.2, 61.6, 61.1, 14.9; δ (negative) = 61.9 ppm. F NMR (376 MHz,
–
1 1
(
m), 1101 (s), 1027 (s), 736 (s), 697 (s) cm . H NMR (300 MHz,
D O): δ = –129.0 (d, J = 10.9 Hz, 1 F) ppm. HRMS (ESI): m/z calcd.
2
CDCl ): δ = 7.37–7.19 (m, 19 H, PhCH O), 7.12–7.09 (m, 2 H, PhCH O
and H11), 6.71–6.59 (m, 2 H, H8 and H10), 4.95 (s, 2 H, PhCH O),
+
+
3
2
2
for C H FNO [M + H] 288.1242; found 288.1239.
13 19 5
2
4
1
3
2
1
1
1
7
7
1
8
.58–4.31 (m, 7 H), 4.20 (dd, J = 6.9, 3.3 Hz, 1 H), 4.08 (t, J = 3.5 Hz,
Data for 11-Fluoro-radicamine A (4): According to the general
H), 3.74 (dd, J = 9.6, 4.5 Hz, 1 H), 3.62 (t, J = 8.3 Hz, 1 H), 3.51– procedure, hydrogenation of hydroxylamine 29 (0.10 g, 0.15 mmol)
13
.45 (m, 1 H) ppm. C NMR (75 MHz, CDCl ): δ = 162.4 (d, J
=
gave 11-fluoro-radicamine A (4) (38.3 mg, 91 % yield) as a yellow
3
C,F
2
0
46.1 Hz, C7), 159.5 (d, J = 11.2 Hz, C9), 138.3, 138.2, 137.9, 136.5, solid, m.p. 109–112 °C. [α]
30.6 (d, J = 5.6 Hz, C11), 128.7, 128.4, 128.3, 128.2, 128.0, 127.8,
3316 (s), 2939 (m), 1630 (m), 1512 (m), 1446 (s), 1275 (m), 1193 (s),
27.72, 127.69, 127.62, 127.59, 127.55, 117.8 (d, J = 13.1 Hz, C6), 1125 (m), 1034 (s), 869 (m) cm . H NMR (300 MHz, D
10.8 (d, J = 2.8 Hz, C10), 102.3 (d, J = 26.2 Hz, C8), 86.2, 83.6, 73.4, (d, J = 6.9 Hz, 1 H), 6.70 (d, J = 12.0 Hz, 1 H), 4.10–4.02 (m, 2 H),
= +20.4 (c = 0.69, MeOH). IR (film): ν˜ =
D
–
1 1
O): δ = 6.78
2
1
3
1.9, 71.7, 70.3 (PhCH O), 69.3, 67.2, 66.2 ppm. C NMR (Dept-135, 3.83 (t, J = 9.9 Hz, 1 H), 3.70 (s, 3 H, OMe), 3.74–3.55 (m, 2 H), 3.15
2
(dd, J = 10.8, 5.4 Hz, 1 H) ppm. 13C NMR (75 MHz, D
(d, JC,F = 236.3 Hz, C11), 147.8 (d, J = 10.4 Hz, C9), 141.1 (C8), 116.8
O): δ = 154.8
2
5 MHz, CDCl ): δ (positive) = 130.6, 128.7, 128.4, 128.3, 128.2, 128.0,
3
27.77, 127.72, 127.69, 127.62, 127.59, 127.55, 110.8, 102.3, 86.2,
3.6, 69.3, 66.2; δ (negative) = 73.4, 71.9, 71.7, 70.3, 67.2 ppm. HRMS (d, J = 15.5 Hz, C6), 113.9 (d, J = 5.0 Hz, C7), 100.5 (d, J = 28.1 Hz,
+
+
13
(ESI): m/z calcd. for C H FNO [M + H] 620.2807; found 620.2801.
C10), 80.7, 76.9, 61.8, 61.5, 57.5, 55.8 ppm. C NMR (Dept-135,
5 MHz, D O): δ (positive) = 113.9, 100.5, 80.7, 76.9, 61.5, 57.5, 55.8;
39
39
5
7
2
General Procedures for Hydrogenation of Hydroxylamines 28–
3
3
19
δ (negative) = 61.8 ppm. F NMR (376 MHz, D O): δ = –123.1 (t,
J = 8.6 Hz, 1 F) ppm. HRMS (ESI): m/z calcd. for C H FNO [M +
H] 274.1085; found 274.1086.
2
3 to Afford Fluorinated Radicamines 3–8: Hydroxylamines 28–
3 (1 equiv.) were dissolved in methanol/dichloromethane (3:1)
+
12
17
5
+
(15–30 mL), and 10 % Pd/C (10–20 wt.-%) and 1
N
aqueous HCl (4–
6
mL) were added. The suspension was stirred under a hydrogen
Data for 7-Fluoro-radicamine A (5): According to the general pro-
cedure, hydrogenation of hydroxylamine 30 (0.18 g, 0.28 mmol)
gave 7-fluoro-radicamine A (5) (67.4 mg, 89 % yield) as a yellow
atmosphere for 16–48 h, when TLC showed completion of the reac-
tion. Hydrogen was replaced by nitrogen, and the catalyst was re-
moved from the reaction mixture by filtration and washed with
MeOH (3 × 30 mL). The filtrate was concentrated in vacuo and neu-
tralized with concd. NH and concentrated again. The residue was
then purified by an acidic ion exchange column (Dowex 5WX8–400,
20
solid, m.p. 100–104 °C. [α]D = +29.5 (c = 0.48, MeOH). IR (film): ν˜ =
3
317 (s), 2936 (m), 1618 (m), 1501 (m), 1460 (m), 1294 (m), 1082 (s),
–1 1
3
924 (m) cm . H NMR (300 MHz, D O): δ = 6.73 (s, 2 H, H10 and
2
H11), 4.23–4.11 (m, 2 H), 3.89 (t, J = 7.5 Hz, 1 H), 3.75 (s, 3 H, OMe),
+
H
form, Aldrich, column size: 1.3 × 14 cm), eluting with distilled
NH OH (50 mL), to afford the target
13
3
.69–3.61 (m, 2 H), 3.25 (dd, J = 12.4, 5.7 Hz, 1 H) ppm. C NMR
water (100 mL) and then 1
fluorinated radicamines 3–8.
N
4
(75 MHz, D O): δ = 151.1 (d, J = 236.5 Hz, C7), 150.0 (d, J = 6.4 Hz,
2 C,F
C9), 135.6 (d, J = 14.8 Hz, C8), 118.0 (d, J = 11.1 Hz, C6), 116.8 (C11),
1
3
1
07.6 (C10), 79.8, 76.4, 61.4, 61.1 (C1), 58.3, 56.1 ppm. C NMR
1
0-Fluoro-Radicamine A (3) and N-Methyl-10-fluoro-radicamine
(
5
–
Dept-135, 75 MHz, D O): δ (positive) = 116.8, 107.6, 79.7, 76.3, 61.4,
A (3′): According to the general procedure, hydrogenation of
hydroxylamine 28 (0.47 g, 0.72 mmol) gave a mixture of 10-fluoro-
radicamine A (3) and N-methyl-10-fluoro-radicamine A (3′), which
were first separated by flash column chromatography (silica gel;
MeOH/EtOAc, 5:1) and then purified by an acidic ion exchange col-
umn, to provide 3 (0.15 g) and 3′ (25.3 mg) both as light-yellow
solids in 76 and 12 % yield, respectively.
2
19
8.3, 56.1; δ (negative) = 61.1 ppm. F NMR (376 MHz, D O): δ =
2
+
138.4 (s, 1 F) ppm. HRMS (ESI): m/z calcd. for C H FNO [M +
12 17
5
+
H] 274.1085; found 274.1083.
Data for 8-Deoxy-8-fluoro-radicamine A (6): According to the
general procedure, hydrogenation of hydroxylamine 31 (0.30 g,
0
.55 mmol) gave 8-deoxy-8-fluoro-radicamine A (6) (0.14 g, 99 %
Data for 3: M.p. 105–108 °C. [α]2 = +91.5 (c = 1.47, MeOH). IR yield) as a light-yellow solid, m.p. 122–123 °C. [α]D = +38.8 (c =
0
20
D
(
(
(
film): ν˜ = 3329 (s), 2926 (m), 1585 (m), 1482 (m), 1429 (m), 1214 1.39, MeOH). IR (film): ν˜ = 3293 (s), 2919 (m), 1522 (s), 1445 (m),
–
1
1
–
1
1
m), 1047 (s), 993 (m) cm . H NMR (300 MHz, D O): δ = 6.45–6.39 1278 (s), 1131 (m), 1025 (s), 812 (m), 762 (m) cm . H NMR
2
m, 2 H, H7 and H11), 3.82 (t, J = 8.0 Hz, 1 H, H4), 3.73 (t, J = 7.2 Hz,
(300 MHz, D O): δ = 7.03–6.95 (m, 2 H), 6.84 (t, J = 8.6 Hz, 1 H), 3.89
2
Eur. J. Org. Chem. 2016, 1429–1438
www.eurjoc.org
1436
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
(
3
t, J = 8.0 Hz, 1 H), 3.82 (t, J = 7.1 Hz, 1 H), 3.77 (d, J = 8.7 Hz, 1 H),
Keywords: Azasugars · Iminosugar · Fluorine · Inhibitors ·
Structure–activity relationships · Drug design
.64 (s, 3 H, OMe), 3.62–3.53 (m, 2 H), 3.10 (dd, J = 11.1, 6.0 Hz, 1
13
H) ppm. C NMR (75 MHz, D O): δ = 151.7 (d, J = 241.4 Hz, C8),
2
C,F
1
3
6
46.2 (d, J = 10.5 Hz, C9), 133.0 (d, J = 5.8 Hz, C6), 123.4 (d, J =
.2 Hz, C10), 114.4 (d, J = 18.5 Hz, C7), 113.6 (C11), 82.1, 77.3, 63.2,
1
3
2.2 (C1), 61.7, 55.9 ppm. C NMR (Dept-135, 75 MHz, D O): δ (posi-
[1] a) P. Compain, O. R. Martin, in: Iminosugars: From Synthesis to Therapeutic
Applications, 1st edition, Wiley-VCH, Chichester, UK, 2007; b) N. Asano,
R. J. Nash, R. J. Molyneux, G. W. J. Fleet, Tetrahedron: Asymmetry 2000,
11, 1645–1680; c) A. A. Watson, G. W. J. Fleet, N. Asano, R. J. Molyneux,
R. J. Nash, Phytochemistry 2001, 56, 265–295; d) T. M. Wrodnigg, Monatsh.
Chem. 2002, 133, 393–426; e) P. Compain, O. R. Martin, Curr. Top. Med.
Chem. 2003, 3, 541–560; f) W. Zou, Curr. Top. Med. Chem. 2005, 5, 1363–
1391; g) B. L. Stocker, E. M. Dangerfield, A. L. Win-Mason, G. W. Haslett,
M. S. M. Timmer, Eur. J. Org. Chem. 2010, 1615–1637.
2
tive) = 123.4, 114.4, 113.6, 82.1, 77.3, 63.2, 61.7, 55.9; δ (negative) =
6
F) ppm. HRMS (ESI): m/z calcd. for C H FNO [M + H] 258.1136;
found 258.1134.
2.2 ppm. 1 F NMR (376 MHz, D O): δ = –133.1 (t, J = 10.5 Hz, 1
9
2
+
+
1
2
17
4
Data for 8-Fluoro-radicamine B (7): According to the general pro-
cedure, hydrogenation of hydroxylamine 32 (0.24 g, 0.39 mmol)
gave 8-fluoro-radicamine B (7) (83.5 mg, 89 % yield) as a yellow
2
0
[2] a) B. A. Sobin, F. W. J. Tanner, J. Am. Chem. Soc. 1954, 76, 4053–4053; b)
S. F. Matkhalikova, V. M. Malikov, S. Y. Yunusov, Khim. Prir. Soedin. 1969,
solid, m.p. 89–92 °C. [α]D = +40.3 (c = 0.65, MeOH). IR (film): ν˜ =
3
1
1
313 (s), 2935 (m), 1603 (m), 1523 (m), 1504 (m), 1294 (s), 1117 (s),
036 (s), 820 (m) cm . H NMR (300 MHz, D O): δ = 7.10 (d, J =
2.3 Hz, 1 H), 6.98 (d, J = 7.8 Hz, 1 H), 6.86 (t, J = 8.6 Hz, 1 H), 4.06
5
, 30–32; c) S. F. Matkhalikova, V. M. Malikov, S. Y. Yunusov, Khim. Prir.
–
1 1
2
Soedin. 1969, 5, 606–607; d) M. Shibano, D. Tsukamoto, A. Masuda, Y.
Tanaka, G. Kusano, Chem. Pharm. Bull. 2001, 49, 1362–1365; e) M. Shib-
ano, D. Tsukamoto, G. Kusano, Heterocycles 2002, 57, 1539–1553; f) S.
Ishida, M. Okasaka, F. Ramos, Y. Kashiwada, Y. Takaishi, O. K. Kodzhimatov,
O. Ashurmetov, J. Nat. Med. 2008, 62, 236–238; g) T.-H. Tsai, L.-C. Lin,
Chem. Pharm. Bull. 2008, 56, 1546–1550; h) D. Wakana, N. Kawahara, Y.
Goda, Chem. Pharm. Bull. 2013, 61, 1315–1317.
(
(
t, J = 8.1 Hz, 1 H), 3.90 (t, J = 7.5 Hz, 2 H), 3.77–3.62 (m, 2 H), 3.24
s, 1 H) ppm. 13C NMR (75 MHz, D O): δ = 152.1 (d, JC,F = 237.7 Hz,
2
C8), 146.1 (d, J = 12.7 Hz, H9), 127.9 (C6), 124.0 (C11), 118.7 (C10),
14.9 (d, J = 19.1 Hz, H7), 80.6, 76.3, 63.0, 61.4, 61.2 (C1) ppm. 13
NMR (Dept-135, 75 MHz, D O): δ (positive) = 124.0, 118.7, 114.9,
1
C
2
1
9
[3] C.-Y. Yu, M.-H. Huang, Org. Lett. 2006, 8, 3021–3024.
8
0.6, 76.3, 63.0, 61.4; δ (negative) = 61.2 ppm. F NMR (376 MHz,
[
4] E.-L. Tsou, S.-Y. Chen, M.-H. Yang, S.-C. Wang, T.-R.-R. Cheng, W.-C. Cheng,
Bioorg. Med. Chem. 2008, 16, 10198–10204.
D O): δ = –134.1 (t, J = 19.6 Hz, 1 F) ppm. HRMS (ESI): m/z calcd.
for C H FNO [M + H] 244.0980; found 244.0978.
2
+
+
11
15
4
[
5] a) X.-G. Hu, Y.-M. Jia, J.-F. Xiang, C.-Y. Yu, Synlett 2010, 982–986; b) J.-K.
Su, Y.-M. Jia, R.-R. He, P.-X. Rui, N.-Y. Han, X.-H. He, J.-F. Xiang, X. Chen, J.-
H. Zhu, C.-Y. Yu, Synlett 2010, 1609–1616; c) Y.-X. Li, M.-H. Huang, Y.
Yamashita, A. Kato, Y.-M. Jia, W.-B. Wang, G. W. J. Fleet, R. J. Nash, C.-Y.
Yu, Org. Biomol. Chem. 2011, 9, 3405–3414; d) W. Zhang, K. Sato, A. Kato,
Y.-M. Jia, X.-G. Hu, F. X. Wilson, R. van Well, G. Horne, G. W. J. Fleet, R. J.
Nash, C.-Y. Yu, Org. Lett. 2011, 13, 4414–4417; e) H. Zhao, A. Kato, K. Sato,
Y.-M. Jia, C.-Y. Yu, J. Org. Chem. 2013, 78, 7896–7902; f) Y.-X. Li, Y. Shi-
mada, K. Sato, A. Kato, W. Zhang, Y.-M. Jia, G. W. J. Fleet, M. Xiao, C.-Y.
Yu, Org. Lett. 2015, 17, 716–719; g) Y.-X. Li, Y. Shimada, I. Adachi, A. Kato,
Y.-M. Jia, G. W. J. Fleet, M. Xiao, C.-Y. Yu, J. Org. Chem. 2015, 80, 5151–
5158.
Data for 7-Fluoro-radicamine B (8): According to the general pro-
cedure, hydrogenation of hydroxylamine 33 (0.36 g, 0.58 mmol)
gave 7-fluoro-radicamine B (8) (0.13 g, 92 % yield) as a yellow solid,
2
0
m.p. 89–91 °C. [α]D = +40.7 (c = 0.30, MeOH). IR (film): ν˜ = 3342 (s),
628 (m), 1512 (m), 1466 (m), 1303 (m), 1154 (m), 1035 (s), 967
1
–1 1
(m) cm . H NMR (300 MHz, D O): δ = 7.19 (t, J = 8.6 Hz, 1 H), 6.59
2
(d, J = 8.7 Hz, 1 H), 6.54 (d, J = 12.9 Hz, 1 H), 4.19–4.07 (m, 2 H),
3
1
.86 (t, J = 7.5 Hz, 1 H), 3.70–3.58 (m, 2 H), 3.18 (dd, J = 11.1, 5.4 Hz,
H) ppm. 13C NMR (75 MHz, D O): δ = 161.7 (d, JC,F = 243.5 Hz,
2
C7), 158.3 (d, J = 11.6 Hz, C9), 129.5 (d, J = 5.3 Hz, C11), 115.7 (d,
J = 12.8 Hz, C6), 112.0 (C10), 103.5 (d, J = 24.0 Hz, C8), 80.1, 76.6,
6
[6] a) T. Kajimoto, K. K. C. Liu, R. L. Pederson, Z. Zhong, Y. Ichikawa, J. A.
Porco, C. H. Wong, J. Am. Chem. Soc. 1991, 113, 6187–6196; b) S. M.
Andersen, M. Ebner, C. W. Ekhart, G. Gradnig, G. Legler, I. Lundt, A. E.
Stütz, S. G. Withers, T. Wrodnigg, Carbohydr. Res. 1997, 301, 155–166; c)
F. M. D. Ismail, J. Fluorine Chem. 2002, 118, 27–33; d) R.-W. Wang, X.-L.
Qiu, M. Bols, F. Ortega-Caballero, F.-L. Qing, J. Med. Chem. 2006, 49, 2989–
1
3
1.43, 61.39, 57.8 ppm. C NMR (Dept-135, 75 MHz, D O): δ (posi-
2
tive) = 129.5, 112.1, 103.5, 80.1, 76.6, 61.39, 57.8; δ (negative) =
1.43 ppm. 1 F NMR (376 MHz, D O): δ = –114.1 (s, 1 F) ppm.
9
6
2
HRMS (ESI): m/z calcd. for C H FNO [M + H]+ 244.0980; found
+
1
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Published Online: February 4, 2016
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim