Ring opening of sugar-derived epoxides by TBAF/KHF2: An attractive alternative for the introduction of fluorine into the carbohydrate scaffold

Article abstract of DOI:10.1016/j.cclet.2016.10.006

A stable and commercially available reagent mixture, composed of tetrabutylammonium bifluoride/potassium bifluoride (TBAF/KHF₂), was found to be effective for the nucleophilic ring opening reactions of sugar-derived epoxides with fluoride. Diff

Full text of DOI:10.1016/j.cclet.2016.10.006

G Model
CCLET 3841 1–5
Chinese Chemical Letters xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
5
Ring opening of sugar-derived epoxides by TBAF/KHF2: An attractive
alternative for the introduction of fluorine into the carbohydrate
scaffold
a,
Nan Yan a, Zhi-Wei Lei a, Jia-Kun Su b, Wei-Lin Liao a, , Xiang-Guo Hu
*
*
6
7
8
a National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, China
b Center of R&D, China Tobacco Jiangxi Industrial Co., Ltd., Nanchang 330096, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A stable and commercially available reagent mixture, composed of tetrabutylammonium bifluoride/
potassium bifluoride (TBAF/KHF2), was found to be effective for the nucleophilic ring opening reactions
of sugar-derived epoxides with fluoride. Different sugar-derived epoxide precursors, including 1-thio-
glycosides can be ring-opened to afford fluorinated carbohydrate products in high yields and in short
reaction times.
Received 17 June 2016
Received in revised form 12 September 2016
Accepted 23 September 2016
Available online xxx
ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Carbohydrate
Fluorinated carbohydrate
Fluoro-sugar
Organofluorine
Epoxide
9
10
1. Introduction
fluoride [8,9]. One major drawback associated with the aforemen- 29
tioned transformations is the unpredictable nature of stereochem- 30
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Fluorine is generally regarded as a remarkable element because
incorporation of fluorine into an organic molecule can dramatically
alter its physical, chemical and biological properties [1]. Carbohy-
drates play many key roles in biological systems and their
fluorinated counterparts have found a variety of applications in
life science. For example, fluorinated carbohydrates have been
used as biological probes for the structure elucidation of biological
targets [2]. They can also act as highly efficient enzymatic
inhibitors, which have broad applications in the treatment of
diseases such as viral infections and cancer [3]. In this regard, many
fluorinated nucleosides are marker drugs including sofosbuvir
[4]. Furthermore, they are also used as positron emission
tomography (PET) agents, with [18F] fluorodeoxyglucose being
the standard radiotracer for PET neuroimaging and as a cancer
diagnostic tool [5,6].
ical outcomes. Competing reactions involving anchimeric 31
assistance effects, rearrangement and SN1 pathways is often 32
difficult to control [10]. One important, yet under-developed 33
alternative is the nucleophilic ring-opening reactions of sugar- 34
derived epoxides with fluoride. Examples of this class of reactions 35
on sugar derived epoxides are limited to the use of KHF2 [11] and 36
Et3NÁ3HF [12]. However, these reagents have their own limitations. 37
For instance, KHF2 requires high temperature (up to 200 8C) and 38
prolonged reaction time, while Et3NÁ3HF is both corrosive and 39
toxic. Recently, the ring-opening reactions of sugar-derived 40
epoxides have been reported using tetrabutylammonium bifluor- 41
ide (TBABF/KHF2) under milder condition [13]. However, TBABF is 42
a viscous liquid and difficult to handle [13]. Furthermore, TBABF 43
needs to be prepared from tetrabutylammonium fluoride (TBAF) 44
and concentrated HF solution (highly toxic) coupled with an 45
extensive drying process prior to use [13]. Thus, ring opening of 46
sugar-derived epoxides under mild conditions with easy-to- 47
handle reagents is desirable for the synthesis of fluorinated 48
Typically, fluorinated carbohydrates [7] can be prepared via
deoxyfluorination of hydroxyl groups using DAST, deoxy-fluor or
via nucleophilic substitution of an activated hydroxyl group with
carbohydrates.
49
In the continued interest of developing novel fluorination 50
methodology[14], this study aims to demonstrate the feasibility of 51
substituting TBABF/KHF2 with the safe and commercially available 52
reagent mixture TBAF/KHF2, based on the work of Percy[15] and 53
*
Corresponding authors.
E-mail addresses: lmmtmmt@gmail.com (W.-L. Liao), huxiangg@iccas.ac.cn
(X.-G. Hu).
http://dx.doi.org/10.1016/j.cclet.2016.10.006
1001-8417/ß 2016 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: N. Yan, et al., Ring opening of sugar-derived epoxides by TBAF/KHF2: An attractive alternative for the
introduction of fluorine into the carbohydrate scaffold, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.006

G Model
CCLET 3841 1–5
2
N. Yan et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
54
55
56
57
58
Hu [14a]. The reactions described herein are the first application of
TBAF/KHF2 for the ring-opening of sugar-derived epoxides.
Different substrates including 1-thioglycoside can be ring-opened
to afford the corresponding fluorinated carbohydrates in high
yields and short reaction times.
59
2. Results and discussion
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
The investigation was initiated with D-arabinose derived
epoxide 1. Based on our previous work [14a], A neat solution of
1 in TBAF/KHF2 was heated at 100 8C for 24 h. To our delight, the
desired product 2 could be obtained as a single regioisomer,
although the yield was only 66% (Table 1, entry 1). Greater
conversion was achieved when the reaction was increased to
120 8C, affording fluorohydrin 2 in 84% yield (Table 1, entry 1).
Using this testablished conditions, TBAF/KHF2 was reacted with
other five epoxide substrates. For sugar-derived epoxides 3, 5, 7,
the C3 regioisomer was obtained as the only product in 73%-87%
yields (Table 1, entries 2-4). The regioselectivity is explained by the
model in Fig. 1. Ring-opening of epoxide at C3 is energetically
favorable over C2 attack which would incur an unfavourable twist
boat transition state. Similar regioselectivity was observed by Aube
[16] and Hu [14a] in ring-opening reactions of structurally related
substrates. For epoxides 9 and 12, both C2 and C3 regioisomers
were obtained in good combined yields (76%-80%, ratio ca. 2:1).
Fig. 1. Model of epoxide ring-opening (substituents are omitted for clarity).
Although the model described in Fig. 1 is able to predict the major
product of 12, it is unable to do so for epoxide 9 [17]. Among the
substrates tested, only a minimum amount of elimination product
77
78
79
80
81
82
83
84
85
86
87
88
was observed for epoxide
9 (Supporting information), thus
reflecting the mild basicity of the TBAF/KHF2 reagent. The
practicality of this method was demonstrated by reaction of
epoxide 12 on gram scale (entry 6, Table 1). The yields (57% and
28%) were slightly higher than those(54% and 26%) obtained from a
milligram scale reaction.
To compare the reactivity of the conventional fluorinating
reagents, reactions of all substrates with Et3NÁ3HF [2b,12] or
TBABF/KHF2 [13] were conducted, resulting in both reagents
Table 1
a
Ring-opening reactions of sugar-derived epoxides.
Entry
Substrates
Temperature
Products
and yieldb
1
100 8C
120 8C
130 8C
2
3
140 8C
4
5
140 8C
140 8C
6
130 8C
a
The reaction time is 2 h.
b
Isolated yield.
cYield after 24 h.
d1.12 g scale.
Please cite this article in press as: N. Yan, et al., Ring opening of sugar-derived epoxides by TBAF/KHF2: An attractive alternative for the
introduction of fluorine into the carbohydrate scaffold, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.006

G Model
CCLET 3841 1–5
N. Yan et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
3
balance of substituent electronic effects and the chemical 119
reactivity of sugar substrates.
120
3. Conclusion
121
TBAF/KHF2, a commercially available and stable reagent has 122
been demonstrated to be an effective fluorinating agent for the 123
ring-opening reactions of sugar-derived epoxides. Different sugar- 124
derived epoxides, including 1-thioglycoside substrates, can be 125
ring-opened to afford fluorinated carbohydrates in high yields and 126
in short reaction times. The availability, reactivity and easy-to- 127
handle nature of this reagent mixture makes it an attractive 128
alternative to TBABF/KHF2 and Et3NÁ3HF for the synthesis of 129
Fig. 2. X-ray crystal structure of compound 4.
Table 2
fluorinated carbohydrates.
130
Synthesis of C-2 fluorinated 1-thioglycoside 16 and a comparison of TBAF/KHF2 and
other fluorinating reagents. .
4. Experimental
131
Entry
Condition
Product and yield
General procedure for the ring-opening of epoxides: TBAFÁ3H2O 132
(2 equiv.) and KHF2 (1 equiv.) was added to epoxide (1 equiv.) in a 133
glove box at room temperature, the reaction vessel was removed 134
from the glove box and stirred under argon for 2 h at the specified 135
temperature. The mixture was diluted with EtOAc (20 mL)/H2O 136
(5 mL), and saturated aqueous NaHCO3 was added to neutralize the 137
resulting HF. The organic layer was washed with saturated 138
aqueous NaCl (2 Â 10 mL) and concentrated under reduced 139
pressure. The crude product was purified by flash column 140
1
2
3
4
5
6
TBAF/KHF2, 70 8C, 2 h
TBABF/KHF2, 70 8C, 6 h
TBABF/KHF2, 90 8C, 6 h
TBABF/KHF2, 120 8C, 2 h
KHF2, glycol,120 8C, 6 h
TBAF, 70 8C, 6 h
16, 83%
-
16:17 = 8:1, total 42%
17, 80%
-
17, 40%
89
90
91
92
93
94
95
96
displaying inferior reactivity under identical condition (Supporting
information). A possible explanation for the lower yields obtained
from the TBABF/KHF2 reactions may be due to the instability of the
reagent mixture under high temperatures, which can not be
avoided for the ring opening of sugar epoxides. The chemical
structures of all the products obtained were determined by the
NMR spectroscopy and the X-ray structure of product 4 is provided
(Fig. 2) (Supporting information) [18].
chromatography.
141
Methyl-4, 6-O-benzylidene-3-deoxy-3-fluoro-
a
-D-altropyra- 142
noside (4): White solid (110.8 mg, 84%); Reaction temperature: 143
130 8C. Column chromatography (silica gel, petroleum ether/ 144
EtOAc: 7:1). Mp: 151–152 8C (recrystallized with petroleum ether/ 145
EtOAc 8:1 before measuring the Mp); [
(cmÀ1): 3450, 1462, 1388, 1139, 1043; 1H NMR (400 MHz, CDCl3): 147
7.51–7.35 (m, 5H), 5.60 (s, 1H, H7), 4.80 (ddd, 1H, J = 3.0, 3.0, 148
a]D +113.6 (c 1.0, CHCl3); IR 146
97
Having established the fluorination methodology, efforts were
directed towards the synthesis of fluorinated 1-thiogylcoside
derivatives, one kind of useful glycosylation donor [19]. Reaction of
15 with TBAF/KHF2 at 70 8C for 2 h furnished the C2 fluorinated
product 16 in 83% yield (Table 2, entry 1). In contrast, reaction of 15
with TBABF/KHF2 gave poorer reactivity and selectivity (Table 2,
entry 2-4) [20]. Furthermore, the use of TBAF/KHF2 is more
attractive from an operational perspective due to its easy-to-
handle nature. To verify the importance of this reagents
combination, TBAF and KHF2 were then tested separately for this
reaction. TBAF yielded completely the elimination product 17
along with recovery of starting material 15 at 70 8C, whereas KHF2
alone brought about no reaction even at 120 8C (Table 2, entry 5-6).
This method could also be applied for the synthesis C3
fluorinated 1-thioglycoside. As shown in Scheme 1, treatment of
18 with TBAF/KHF2 furnished fluorinated sugar 19 in 75% yield in
4 h. The regioselectivity in Table 2 and Scheme 1 is consistent with
both the results obtained in Table 1 and epoxide ring-opening
model in Fig. 1. It is worth noting that reaction of galactose-derived
epoxide 20 and TBAF/KHF2 failed to give the corresponding
fluorinated sugar (Scheme 1). The subtle structural differences
between 18 and 20 represents a good example of the delicate
d
98
99
49.9 Hz, H3e), 4.61 (s, 1H, H1), 4.36–4.25 (m, 2H, H5 and H6), 4.06 149
(ddd, 1H, J = 3.0, 6.5, 9.6 Hz, H2), 3.96 (ddd, 1H, J = 2.5, 9.6, 30.3 Hz, 150
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
H
4a), 3.79 (td, 1H, J = 1.4, 10.4 Hz, H6), 3.42 (s, 3H), 2.38 (d, 151
J = 5.6 Hz, OH); 13C NMR (100 MHz, CDCl3):
d
137.1 (CAr), 129.3 152
(CAr), 128.4 (CAr), 126.3 (CAr), 102.2 (C7), 101.4 (C1), 87.0 (d, 153
J = 185.3 Hz, C3), 74.8 (d, J = 16.9 Hz, C4), 69.2 (C6), 68.9 (d, 154
J = 25.5 Hz, C2), 58.4 (d, J = 3.0 Hz, C5), 55.7 (OCH3); 19F {1H} 155
NMR (376 MHz, CDCl3):
CDCl3): -205.1 (ddd, J = 6.5, 30.2, 49.9 Hz, 1F); HRMS (ESI): calcd. 157
for C14H17FNaO5 [M + Na]+ 307.0952, found 307.0940.
Methyl-4,6-O-benzylidene-3-deoxy-3-fluoro- -D-altropyra-
d
-205.1 (s, 1F); 19F NMR (376 MHz, 156
d
+
158
159
b
noside (8): White solid (82.4 mg, 0.290 mmol, 73%); Reaction 160
temperature: 140 8C; Column chromatography (silica gel, petro- 161
leum ether/EtOAc: 7:1); Mp: 166–168 8C; [
IR (cmÀ1): 3463, 2927, 1452, 1390, 1050; 1H NMR (400 MHz, 163
CDCl3): 7.52–7.34 (m, 5H), 5.58 (bs, 1H, H7), 5.00 (ddd, 1H, J = 1.9, 164
a]D -44.0 (c 1.1, CHCl3); 162
d
3.7, 49.9 Hz, H3), 4.75 (dd, 1H, J = 1.3, 2.8 Hz, H1), 4.39 (dd, 1H, 165
J = 4.9, 10.5 Hz, H5), 4.09–3.97 (m, 3H, H2, H6 and H4), 3.84–3.79 (m, 166
1H, H6), 3.59 (s, 3H, OCH3), 2.48 (bs, OH); 13C NMR (100 MHz, 167
CDCl3):
d 137.0 (CAr), 129.2 (CAr), 128.3 (CAr),, 126.2 (CAr), 102.5 168
(C7), 99.0 (C1), 87.8 (d, J = 177.3 Hz, C3), 75.2 (d, J = 16.5 Hz, C4), 69.3 169
(d, J = 27.7 Hz, C5), 69.0 (C6), 63.1 (d, J = 3.3 Hz, C2), 57.2 (OCH3); 19
{1H} NMR (376 MHz, CDCl3):
F
170
d
-208.6 (s, 1F); 19F NMR (376 MHz, 171
+
CDCl3):
d
-208.6 (m, 1F); HRMS (ESI): calcd. For C14H17FNaO5
172
173
174
[M + Na]+ 307.0952, found 307.0944.
Methyl-4,6-O-benzylidene-2-deoxy-2-fluoro-a-D-altropyra-
noside (13): Colorless oil (128 mg, 54%) and (684 mg, 57%); 175
Reaction temperatue:130 8C; Column chromatography (silica gel, 176
petroleum ether/EtOAc: 5:1); [
3446, 1452, 1378, 1045; 1H NMR (400 MHz, CDCl3):
a]
D +142.2 (c 1.0, CHCl3); IR (cmÀ1): 177
d
7.50 –7.35 178
(m, 5H, HAr), 5.64 (s, 1H, H7), 4.82 (d, 1H, J = 10.6 Hz, H7), 4.73 –4.61 179
(m, 1H, H2), 4.35 (dd, 1H, J = 5.2, 10.3 Hz, H6), 4.30 –4.20 (m, 2H, H3 180
Scheme 1. Synthesis of C-3 fluorinated 1-thioglycoside derivative 19.
Please cite this article in press as: N. Yan, et al., Ring opening of sugar-derived epoxides by TBAF/KHF2: An attractive alternative for the
introduction of fluorine into the carbohydrate scaffold, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.006

G Model
CCLET 3841 1–5
4
N. Yan et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
and H5), 3.90 (dt, 1H, J = 3.2, 9.8, Hz, H4), 3.82 (t, 1H, J = 10.3 Hz, H6),
3.46 (s, 3H, OMe), 2.77 (dd, 1H, J = 1.5, 5.5 Hz, OH); 13C NMR
(100 MHz, CDCl3): d 137.1 (CAr), 129.3 (CAr), 128.3 (CAr), 126.2 (CAr),
X-ray crystal structure data of 4. Dr. Thanh Le is also acknowledged
for the proof reading.
243
244
102.3 (C7), 98.9 (d, J = 33.1 Hz, C1), 87.7 (d, J = 173.9 Hz, C2), 76.1 (d,
J = 1.7 Hz, C4), 69.1 (C6), 66.5 (d, J = 27.9 Hz, C3), 58.1 (C5), 56.0
References
245
(OCH3); 19F {1H} NMR (376 MHz, CDCl3):
d
-194.0 (s, 1F); 19F NMR
[1] (a) D. O’Hagan, Understanding organofluorine chemistry. An introduction to the
C-F bond, Chem. Soc. Rev. 37 (2008) 308–319;
246
247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
299
300
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
(376 MHz, CDCl3):
d
-194.0 (m, 1F); HRMS (ESI): calcd. For
C14H17FNaO5 [M + Na]+ 307.0952, found 307.0956.
Methyl-4,6-O-benzylidene-3-deoxy-3-fluoro- -D-glucopyra-
+
(b) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Fluorine in medicinal
chemistry, Chem. Soc. Rev. 37 (2008) 320–330;
a
(c) E.P. Gillis, K.J. Eastman, M.D. Hill, D.J. Donnelly, N.A. Meanwell, Applications of
fluorine in medicinal chemistry, J. Med. Chem. 58 (2015) 8315–8359.
[2] (a) H.A. Chokhawala, H.Z. Cao, H. Yu, X. Chen, Enzymatic synthesis of fluorinated
mechanistic probes for sialidases and sialyltransferases, J. Am. Chem. Soc. 129
(2007) 10630–10631;
noside (14): White soild (61.7 mg, 26%) and (335 mg, 28%);
Reaction temperatue:130 8C; Column chromatography (silica gel,
petroleum ether/EtOAc: 5:1); Mp: 164–166 8C; [
1.0, CHCl3); IR (cmÀ1): 3452, 1450, 1385, 1052; 1H NMR (400 MHz,
CDCl3): 7.51–7.49 (m, 2H), 7.39–7.35 (m, 3H), 5.55 (s, 1H, H7),
a] +172.68 (c
D
(b) C.D. Brown, M.S. Rusek, L.L. Kiessling, Fluorosugar chain termination agents as
probes of the sequence specificity of a carbohydrate polymerase, J. Am. Chem. Soc.
134 (2012) 6552–6555.
d
4.83 (dd, 1H, J = 2.7, 4.1 Hz, H1), 4.69 (ddd, 1H, J = 8.7, 8.7, 54.7 Hz,
H3a), 4.34–4.30 (m, 1H, H6), 3.88–3.68 (m, 4H, H5, H6, H4 and H2),
3.45 (s, 3H), 2.43 (d, J = 9.7 Hz, 1H, OH); 13C NMR (100 MHz,
[3] (a) J.H. Kim, R. Resende, T. Wennekes, et al., Mechanism-based covalent neur-
aminidase inhibitors with broad-spectrum influenza antiviral activity, Science
340 (2013) 71–75;
CDCl3):
d 136.8 (CAr), 129.3 (CAr), 128.3 (CAr), 126.2 (CAr), 101.7
(b) K.E. van Straaten, J.R.A. Kuttiyatveeti, C.M. Sevrain, et al., Structural basis of
ligand Binding to UDP-galactopyranose mutase from mycobacterium tuberculo-
sis using substrate and tetrafluorinated Substrate Analogues, J. Am. Chem. Soc.
137 (2015) 1230–1244.
(C7), 101.1 (d, J = 9.9 Hz,C1), 91.8 (d, J = 186.6 Hz, C3), 79.2 (d,
J = 17.1 Hz, C4), 71.5 (d, J = 17.9 Hz, C2), 68.8 (C6), 61.9 (d,
J = 7.5 Hz, C5), 55.7(OCH3); 19F {1H} NMR (376 MHz, CDCl3):
d -
[4] P.Y. Wang, B.K. Chun, S. Rachakonda, et al., An efficient and diastereoselective
synthesis of psi-6130: a clinically efficacious inhibitor of HCV NS5B polymerase, J.
Org. Chem. 74 (2009) 6819–6824.
[5] G.R. Morais, R.A. Falconer, I. Santos, Carbohydrate-based molecules for molecular
imaging in nuclear medicine, Eur. J. Org. Chem. (2013) 1401–1414.
[6] P. Som, H.L. Atkins, D. Bandoypadhyay, et al., A fluorinated glucose analog, 2-
fluoro-2-deoxy-D-glucose (F-18): nontoxic tracer for rapid tumor detection, J.
Nuc.l Med. 21 (1980) 670–675.
[7] (a) Y. Cheng, A.L. Guo, D.S. Guo, Recent progress in synthesis and applications of
fluorinated carbohydrates, Curr. Org. Chem. 14 (2010) 977–999;
(b) K. Dax, M. Albert, J. Ortner, B.J. Paul, Synthesis of deoxyfluoro sugars from
carbohydrate precursors, Carbohydr. Res. 327 (2000) 47–86.
[8] (a) P.A. Champagne, J. Desroches, J.D. Hamel, M. Vandamme, J.F. Paquin, Mono-
fluorination of organic compounds: 10 years of innovation, Chem. Rev. 115 (2015)
9073–9174;
200.0 (s, 1F); 19F NMR (376 MHz, CDCl3):
d -200.0 (m, 1F); HRMS
(ESI): calcd. For C14H17FNaO5 [M + Na]+ 307.0952, found
+
307.0960.
p-Tolyl-2-deoxy-2-fluoro-4,6-O-benzylidene-1-thio-b-D-altro-
pyranoside 16: White solid (109.1 mg, 0.290 mmol, 83%); Reaction
temperatue: 70 8C. Column chromatography (silica gel, petroleum
ether/EtOAc: 10:1); Mp: 164–165 8C; [
IR (cmÀ1): 3419, 2913, 1493, 1456, 1387, 1115; 1H NMR (400 MHz,
CDCl3): 7.48–7.37 (m, 6H), 7.15 (d, J = 7.9 Hz, 2H), 5.64 (s, 1H),
a
]D = À23.2 (c 1.0, CHCl3);
d
5.18 (bd, J = 32.3 Hz, 1H, H1), 4.87 (dd, 1H, J = 3.6, 44.5 Hz, H2),
4.39–4.34 (m, 2H, H6 and H3), 4.02–3.92 (m, 2H, H4 and H5), 3.89–
(b) X.Y. Yang, T. Wu, R.J. Phipps, F.D. Toste, Advances in catalytic enantioselective
fluorination, mono-, di-, and trifluoromethylation, and trifluoromethylthiolation
reactions, Chem. Rev. 115 (2015) 826–870;
3.84 (m, 1H, H6), 2.42 (d, 1H, J = 1.5 Hz, OH), 2.35 (s, 3H, CH3); 13
C
NMR (100 MHz, CDCl3):
d 138.1(CAr), 136.9 (CAr), 132.1(CAr), 129.9
(c) N. Al-Maharik, D. O’Hagan, Organofluorine chemistry: deoxyfluorination
reagents for C-F bond synthesis, Aldrichim Acta 44 (2011) 65–75.
[9] J.P. Card, Synthesis of fluorinated carbohydrates, J. Carbohydr. Chem. 4 (1985)
451–487.
[10] (a) K. Dax, M. Albert, J. Ortner, B.J. Paul, Synthesis of deoxyfluoro sugars from
carbohydrate precursors, Carbohydr. Res. 327 (2000) 47–86;
(CAr), 129.4 (CAr), 128.4 (CAr), 126.1(CAr), 102.2 (C7), 90.9 (d,
J = 176.5 Hz, C2), 84.2 (d, J = 18.4 Hz, C1), 76.2 (C4), 68.9 (C6), 67.2
(d, J = 29.5 Hz, C3), 66.4 (C5), 21.1(CH3); 19F {1H} NMR (376 MHz,
CDCl3):
d d -201.3 (m,
-201.3 (s, 1F); 19F NMR (376 MHz, CDCl3):
1F); HRMS (ESI): calcd. For C20H21FNaO4S+ [M + Na]+ 399.1037,
found 399.1042
(b) X.G. Hu, L. Hunter, Stereoselectively fluorinated N-heterocycles:
survey, Beilstein J. Org. Chem. 9 (2013) 2696–2708.
a brief
[11] (a) Y. Nishida, J. Thiem, Convenient synthetic approach towards C-3 modified
methyl beta-lactone, Carbohydr. Res. 263 (1994) 295–301;
Iso-propyl-4,6-O-benzylidene-3-deoxy-3-fluoro-1-thio-b-D-
Idopyranose 19: White soild (30.2 mg, 0.092 mmol, 75%); Reaction
temperatue: 80 8C; Column chromatography(silica gel, petroleum
(b) J.M. Chen, A.X. Huang, R.L. Mackman, et al., Nucleoside analogs for antiviral
treatment, PCT Int. Appl., 2008100447
(c) JA. Wright, N.F. Taylor, Flourocarbohydrates: Part XVIII. 9-(3-deoxy-3-flouro-
b-D-xylofuranosyl)adenine and 9-(3-deoxy-3-flouro-a-D-arabinofuranosyl)ade-
nine, Carbohydr. Res. 6 (1968) 347–354.
ether/EtOAc: 5:1); Mp: 172–174 8C; [
(cmÀ1): 3372, 2920, 1493, 1464, 1380; 1H NMR (400 MHz, CDCl3):
7.48–7.36 (m, 5H, HAr), 5.54 (s, 1H, H7), 4.97 (d, 1H, J = 4.0 Hz, H1),
a
]
D
-33.8 (c 1.0, CHCl3); IR
d
[12] (a) M. Bols, I. Lundt, Preparation of 2,3-epoxyaldonolactones and their conver-
sion into 2-fluoro-2-deoxy-aldonolactones and 2-fluoro-2-deoxy-sugars, Acta
Chem. Scand. 44 (1990) 252–256.
[13] (a) Y. Akiyama, T. Fukuhara, S. Hara, Regioselective synthesis of fluorohydrines
via SN2-type ring-opening of epoxides with TBABF-KHF2, Synlett (2003)
1530–1532;
4.83 (dt, 1H, J = 3.3, 43.6 Hz, H3), 4.40 (dd, 1H, J = 1.6, 12.7 Hz, H6),
4.21–4.18 (m, 1H, H2), 4.10 (dd, 1H, J = 1.8, 12.7 Hz, H6), 3.87 (ddd,
1H, J = 3.1, 6.5, 10.7 Hz, H4), 3.72 (t, 1H, J = 1.9 Hz, H5), 3.24
(quintet, 1H, J = 6.7 Hz, CH-), 3.17 (dd, 1H, J = 1.9, 12.5 Hz, OH),
1.37–1.34 (m, 6H); 13C NMR (100 MHz, CDCl3):
d 136.9 (CAr), 129.4
(b) Y. Akiyama, C. Hiramatsu, T. Fukuhara, S. Hara, Selective introduction of a
fluorine atom into carbohydrates and a nucleoside by ring-opening fluorination
reaction of epoxides, J Fluorine. Chem. 127 (2006) 920–923;
(c) M. Mastihubova, P. Biely, Deoxy and deoxyfluoro analogues of acetylated
methyl (-D-xylopyranoside—substrates for acetylxylan esterases, Carbohydr. Res.
339 (2004) 2101–2110.
(CAr), 128.4 (CAr), 126.0 (CAr), 101.6 (C7), 86.4 (d, J = 175.2 Hz, C3),
81.8 (d, J = 1.4 Hz, C1), 72.1 (d, J = 30.5 Hz, C2), 69.6 (C6), 68.4 (d,
J = 26.0 Hz, C4), 68.2 (C5), 35.1(CH-), 23.8 (CH3-), 23.7(CH3-); 19F
NMR (376 MHz, CDCl3):
d
-197.1 (m, 1F); 19F {1H} NMR (376 MHz,
[14] (a) N. Yan, Z. Fang, Q.Q. Liu, X.H. Guo, X.G. Hu, Conformation-induced regiose-
lective and divergent opening of epoxides by fluoride: facile access to hydroxyl-
ated fluoro-piperidines, Org. Biomol. Chem. 14 (2016) 3469–3475;
(b) X.G. Hu, A. Lawer, M.B. Peterson, et al., Diastereoselective synthesis and
conformational analysis of (2R)- and (2S)-fluorostatines: an approach based on
CDCl3):
d
-197.1 (s, 1F); HRMS (ESI): calcd. for
C16H21FNaO4S+[M + Na]+ 351.1037, found 351.1044.
238
Acknowledgment
organocatalytic fluorination of
662–665;
a chiral aldehyde, Org. Lett. 18 (2016)
(c) X.G. Hu, D.S. Thomas, R. Griffith, L. Hunter, Stereoselective fluorination alters
the geometry of a cyclic peptide: exploration of backbone-fluorinated analogues
of unguisin A, Angew. Chem. Int. Edit. 53 (2014) 6176–6179.
239
240
241
242
We thank the National Natural Science Foundation of China (No.
21502076) for the financial support. Dr. Mohan M. Bhadbhade and
Dr. Thanh Le from the University of New South Wales (UNSW)
are acknowledged for their help in solving problems related to the
[15] J.M. Percy, R. Roig, K. Singh, Fluorinated analogues of amicetose and rhodinose -
novel racemic and asymmetric routes, Eur. J. Org. Chem. (2009) 1058–1071.
Please cite this article in press as: N. Yan, et al., Ring opening of sugar-derived epoxides by TBAF/KHF2: An attractive alternative for the
introduction of fluorine into the carbohydrate scaffold, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.006

G Model
CCLET 3841 1–5
N. Yan et al. / Chinese Chemical Letters xxx (2016) xxx–xxx
5
322
323
324
325
326
327
328
329
330
331
[16] T.C. Coombs, G.H. Lushington, J. Douglas, J. Aube, 1,3-allylic strain as a strategic
diversification element for constructing libraries of substituted 2-arylpiperidines,
Angew. Chem. Int. Edit 50 (2011) 2734–2737.
[17] M. Miljkovic, Electrostatic and Stereoelectronic Effects in Carbohydrate
Chemistry, Springer, 2014.
[18] The crystal structure of 4 has been deposited at the Cambridge Crystallographic
Data Centre and allocated the deposition number: CCDC 1473829.
[19] (a) M. Salvado, B. Amgarten, S. Castillon, G.J.L. Bernardes, O. Boutureira, Synthesis
of fluorosugar reagents for the construction of well-defined fluoroglycoproteins,
Org. Lett. 17 (2015) 2836–2839;
(b) L.M. Chauvigne-Hines, L.N. Anderson, H.M. Weaver, et al., Suite of Activity- 332
Based Probes for Cellulose-Degrading Enzymes, J. Am. Chem. Soc. 134 (2012) 333
20521–20532;
334
(c) D. Crich, L.F. Li, 4,6-O-benzylidene-directed (-mannopyranosylation and 335
(-glucopyranosylation: The 2-deoxy-2-fluoro and 3-deoxy-3-fluoro series of 336
donors and the importance of the O2-C2-C3-O3 interaction, J. Org. Chem. 72 337
(2007) 1681–1690.
[20] Y. Wang, Q. Li, S.H. Cheng, et al., Base-promoted rearrangement of sugar epoxides 339
to unsaturated sugars, Org. Lett. 7 (2005) 5577–5579.
338
340
Please cite this article in press as: N. Yan, et al., Ring opening of sugar-derived epoxides by TBAF/KHF2: An attractive alternative for the
introduction of fluorine into the carbohydrate scaffold, Chin. Chem. Lett. (2016), http://dx.doi.org/10.1016/j.cclet.2016.10.006