Design and concise synthesis of gem-difluoromethylenated analogue of 7-epi-castanospermine

Article abstract of DOI:10.1016/j.cclet.2014.04.018

A novel gem-difluoromethylenated castanospermine analogue B was designed and synthesized, starting from 3-bromo-3,3-difluoropropene and L-(-)-malic acid. The key steps involve substitution cyclization reaction and RCM reaction to construct the aza fused b

Full text of DOI:10.1016/j.cclet.2014.04.018

G Model
CCLET 2962 1–6
Chinese Chemical Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
Design and concise synthesis of gem-difluoromethylenated analogue
of 7-epi-castanospermine
Q1 Xin-Yi Jiang a, Xiu-Hua Xu a, Feng-Ling Qing a,b,
*
5
6
7
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai 200032, China
b College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A novel gem-difluoromethylenated castanospermine analogue B was designed and synthesized, starting
Received 20 February 2014
Received in revised form 8 April 2014
Accepted 10 April 2014
Available online xxx
from 3-bromo-3,3-difluoropropene and
L
-(À)-malic acid. The key steps involve substitution cyclization
reaction and RCM reaction to construct the aza fused bicyclic framework.
ß 2014 Feng-Ling Qing. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
reserved.
Keywords:
Indolizidine
Castanospermine
gem-Difluoromethylene
Cyclization
Dihydroxylation
8
9
1. Introduction
2006, our group found that introduction of a gem-difluoromethy- 30
lene group (CF2) into 1-deoxymannonojirimycin (DMJ) could 31
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Polyhydroxylated indolizidine alkaloids are widely found in
microorganisms, vertebrates, higher invertebrates, and plants [1].
Some of these aza fused bicyclic compounds, such as lentiginosine
[2], swainsonine [3], and castanospermine [4], have been reported
to exhibit good glycosidase inhibition activity, which makes them
potential therapeutic agents (Fig. 1). Among them, castanosper-
mine has attracted considerable attention. It is a strong inhibitor of
improve the inhibition selectivity of compound A [10]. As a part of 32
our interest in the synthesis of fluorinated iminosugars [10,11], we 33
designed a new gem-difluoromethylenated analogue B of 7-epi- 34
castanospermine. The strongly electron-withdrawing gem-difluor- 35
omethylene group would reduce the pKa value and might change 36
the stereoconfiguration, thus affecting the inhibition activity and 37
selectivity. In this paper, we present our results on the synthesis of 38
a
- and
b
-glucosidases [5] and has shown potential antitumor,
this novel castanospermine analogue.
39
antiviral, and immunomodulating activities [6]. Because of its
unique biological activities, a lot of efforts have been devoted into
the synthesis of castanospermine [7] as well as its analogues [8] to
study their structure-activity relationship (SAR).
2. Experimental
40
2.1. (3S,4R)-Methyl 3-(benzyloxy)-5,5-difluoro-4-hydroxyhept-6-
enoate (3a) and (4S,5S)-4-(benzyloxy)-5-(1,1-
difluoroallyl)dihydrofuran-2(3H)-one (3b)
41
42
43
The major drawback for castanospermine in clinical applica-
tions is the low inhibition selectivity between
glucosidases. In 1997, Tyler and co-workers reported that 7-epi-
castanospermine showed higher glucosidase selectivity than
castanospermine while retaining almost complete activity towards
-glucosidase (Scheme 1) [9]. To further improve the selectivity
a- and b-
a/b
To a stirring solution of (S)-O-benzylmalic acid dimethyl ester 2 44
(0.90 g, 3.57 mmol) in CH2Cl2 (50 mL) was added magnesium 45
bromide etherate (1.0 g, 4.0 mmol) at 0 8C. The solution was stirred 46
for 1 h at 0 8C and cooled to À90 8C. To the solution was added a 47
1.5 mol/L solution of diisobutylaluminum hydride in toluene 48
(3.0 mL, 4.5 mmol) via syringe pump over 90 min, then the 49
reaction mixture was stirred at À90 8C for 2 h. Methanol (4 mL) 50
was slowly added followed by saturated Rochelle salts (80 mL). 51
The mixture was warmed to room temperature and stirred for 52
12 h. The layers were separated and the aqueous phase was 53
a
and the potency of the inhibition of glycosidases, it is highly
desirable to develop new polyhydroxylated alkaloid analogues. In
*
Corresponding author at: Key Laboratory of Organofluorine Chemistry,
Q2
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, Shanghai
200032, China.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
http://dx.doi.org/10.1016/j.cclet.2014.04.018
1001-8417/ß 2014 Feng-Ling Qing. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Please cite this article in press as: X.-Y. Jiang, et al., Design and concise synthesis of gem-difluoromethylenated analogue of 7-epi-
castanospermine, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.04.018

G Model
CCLET 2962 1–6
2
X.-Y. Jiang et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
Na2SO4, and concentrated in vacuo. The residue was quickly
97
purified by silica gel column chromatography (petroleum ether/
98
ethyl acetate = 2/1) to afford compound 4 (0.28 g, 86%) as a clear
99
oil. [a]
20 = À17.01 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3):
d
100
101
102
103
104
105
106
107
108
109
110
D
7.35–7.25 (m, 5H), 6.10–5.93 (m, 1H), 5.73–5.68 (m, 1H), 5.50–5.47
(m, 1H), 4.52 (dd, 2H, J = 17.4 Hz, 11.4 Hz), 4.07–3.98 (m, 1H), 3.90–
3.63 (m, 3H), 2.96 (br, 2H), 2.02–1.92 (m, 2H); 19F NMR (282 MHz,
CDCl3):
d
À107.7 (dt, 1F, J = 251.5 Hz, 10.3 Hz), À109.3 (dt, 1F,
137.6, 130.9 (t,
Fig. 1. Polyhydroxylated indolizidines.
J = 251.8 Hz, 12.0 Hz); 13C NMR (100 MHz, CDCl3):
d
J = 25.4 Hz), 128.6, 128.1, 128.0, 120.4 (t, J = 9.5 Hz), 119.7 (t,
J = 243.1 Hz), 76.3, 73.8 (t, J = 27.9 Hz), 71.8, 58.9, 31.7; IR (thin
film, cmÀ1): 3392, 3033, 2928, 1664, 1056; MS (ESI): m/z 295.2
(M+Na+); HRMS Calcd. for C14H18O3F2Na: 295.1116; Found:
295.1120.
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
extracted three times with methylene dichloride. The combined
organic phase was dried with Na2SO4 and concentrated. The
mixture was separated by flash column chromatography (petro-
leum ether/ethyl acetate = 8/1) to yield 0.61 g (77%) of a colourless
oil. The colourless oil was dissolved in DMF (10 mL). After that,
indium (474 mg, 4.12 mmol) and 3-bromo-3,3-difluoropropane
2.3. (2R,3S)-1-Allyl-3-(benzyloxy)-2-(1,1-difluoroallyl)pyrrolidine
111
112
(5)
(420
mL, 4.20 mmol) was added. The reaction mixture was stirred
at room temperature for 24 h. The reaction mixture was then
quenched with 1 mol/L HCl and extracted with CH2Cl2. The
combined organic extract was washed with brine, dried over
anhydrous Na2SO4, and filtered. The solvent was removed in vacuo.
The residue was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 8/1) to give 255 mg (31% yield) of
compound 3a as a clear oil and 362 mg (44% yield) of compound 3b
as a clear oil.
To a solution of compound 4 (1.0 g, 3.68 mmol) in anhydrous
CH2Cl2 (12 mL), and NEt3 (3.4 mL, 23.8 mmol), MsCl (1.3 mL,
16.7 mmol) was added slowly at 0 8C. The reaction mixture was
then warmed to room temperature and stirred overnight. The
reaction was quenched with water. The resulting mixture was
extracted with CH2Cl2. The combined organic layer was washed
with brine, dried over anhydrous Na2SO4, and filtered. The solvent
was removed in vacuo. The residue was dissolved in allylamine
(6 mL). Then the reaction mixture was heated to 145 8C in the
sealed tub for 10 h. The allylamine was removed in vacuo and then
the residue was purified by silica gel column chromatography
(petroleum ether/ethyl acetate = 15/1) to give 870 mg (81%, yield,
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
3a: [
a
]
20 = À6.93 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3):
d
D
7.31–7.30 (m, 5H), 6.08–5.95 (m, 1H), 5.76–5.68 (m, 1H), 5.54–5.47
(m, 1H), 4.67–4.60 (m, 2H), 4.28–4.25 (m, 1H), 3.76–3.64 (m, 4H),
2.73–2.71 (m, 2H), 2.42 (br, 1H); 19F NMR (282 MHz, CDCl3):
d
À107.0 (dt, 1F, J = 253.0 Hz, 9.45 Hz), À111.5 (dt, 1F, J = 252.4 Hz,
two steps) of compound 5 as a clear oil. [
a
]
20 = À16.86 (c 1.10,
D
11.0 Hz); 13C NMR (100 MHz, CDCl3):
d
171.4, 137.4, 130.6 (t,
CHCl3); 1H NMR (300 MHz, CDCl3):
d 7.34–7.25 (m, 5H), 6.35–6.17
J = 25.7 Hz), 128.5, 128.1, 120.7 (t, J = 9.5 Hz), 119.4 (t,
J = 242.8 Hz), 74.1 (t, J = 29.6 Hz), 73.2, 72.9, 51.8, 37.3; IR (thin
film, cmÀ1): 3500, 3033, 2953, 1738, 1439; MS (ESI): m/z 301.3
(M+H+), 318.3 (M+NH4+); 323.2 (M+Na+); HRMS Calcd. for
C15H18O4F2Na: 323.1065; Found: 323.1073.
(m, 1H), 5.93–5.79 (m, 1H), 5.68–5.62 (m, 1H), 5.42–5.38 (m, 1H),
5.19–5.09 (m, 2H), 4.53 (s, 2H), 4.12 (q, 1H, J = 6.3 Hz), 3.57–3.51
(m, 1H), 3.18–3.00 (m, 3H), 3.17 (q, 1H, J = 8.7 Hz), 1.99–1.92 (m,
2H); 19F NMR (282 MHz, CDCl3):
(dt, 1F, J = 254.9 Hz, 13.25 Hz); 13C NMR (100 MHz, CDCl3):
d
À96.4 (d, 1F, J = 255.2 Hz), À97.3
138.2,
d
3b: [
a
]
20 = À15.17 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3):
134.8, 133.0 (t, J = 24.5 Hz), 128.3, 127.7, 127.6, 121.6 (t,
J = 239.9 Hz), 119.3 (t, J = 9.65 Hz), 117.4, 79.1 (d, J = 7.0 Hz),
72.1, 68.7 (dd, J = 30.3 Hz, 25.6 Hz), 58.2, 50.0 (d, J = 6 Hz), 30.4; IR
(thin film, cmÀ1): 3066, 2924, 2359, 1419, 1354, 1121, 738; MS
(ESI): m/z 298.4 (M+H+); HRMS Calcd. for C17H22OF2N: 294.1664;
Found: 294.1657.
D
d
7.40–7.30 (m, 5H), 6.04–5.87 (m, 1H), 5.80–5.74 (m, 1H), 5.63–
5.60 (m, 1H), 4.65–4.51 (m, 3H), 4.46–4.44 (m, 1H), 2.87–2.78 (m,
1H), 2.65–2.59 (m, 1H); 19F NMR (282 MHz, CDCl3):
À109.8 (ddd,
1F, J = 258.6 Hz, 12.7 Hz, 4.5 Hz), À113.0 (ddd, 1F, J = 258.9 Hz,
18.6 Hz, 10.6 Hz); 13C NMR (100 MHz, CDCl3):
174.2, 136.7, 128.8
d
d
(t, J = 25.8 Hz), 128.7, 128.3, 127.9, 122.9 (t, J = 9.5 Hz), 117.6 (t,
J = 242.7 Hz), 84.3 (t, J = 31.4 Hz), 73.4, 71.4, 34.9; IR (thin film,
cmÀ1): 3033, 2932, 1691, 1455, 1208; MS (ESI): m/z 286.2
(M+NH4+); HRMS Calcd. for C14H14O3F2Na: 291.0803; Found:
291.0811.
2.4. (1S,8aR)-1-(Benzyloxy)-8,8-difluoro-1,2,3,5,8,8a-
138
139
hexahydroindolizine (6)
To a solution of compound 5 (520 mg, 1.77 mmol) in anhydrous
toluene (50 mL) was added Grubbs’ II catalyst (70 mg,
0.0824 mmol). The reaction mixture was then warmed to 80 8C
and stirred for 10 h. After the solvent was evaporated, the crude
product was purified by flash silica gel column chromatography
(petroleum ether/ethyl acetate = 6/1) to give compound 6 (375 mg,
140
141
142
143
144
145
146
147
148
91
2.2. (3S,4S)-3-(Benzyloxy)-5,5-difluorohept-6-ene-1,4-diol (4)
92
93
94
95
96
To a suspension of LiAlH4 (91.2 mg, 2.4 mmol) in dry THF (5 mL)
was added a solution of 3b (0.36 g, 1.2 mmol) in dry THF at 0 8C.
The mixture was stirred for 3 h at 0 8C and quenched by careful
addition of water and then extracted with CH2Cl2. The combined
organic layer was washed with brine, dried over anhydrous
80%) as a clear oil. [
(300 MHz, CDCl3): 7.40–7.23 (m, 5H), 6.15–6.11 (m, 1H), 5.92–
5.86 (m, 1H), 4.66 (dd, 2H, J = 37.5 Hz, 12.3 Hz), 4.39–4.33 (m, 1H),
a]
D
20 = 98.66 (c 1.15, CHCl3); 1H NMR
d
Scheme 1. Design of target molecule B.
Please cite this article in press as: X.-Y. Jiang, et al., Design and concise synthesis of gem-difluoromethylenated analogue of 7-epi-
castanospermine, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.04.018

G Model
CCLET 2962 1–6
X.-Y. Jiang et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
3
149
150
151
152
153
154
155
156
157
3.61–3.55 (m, 1H), 3.28 (t, 1H, J = 8.6 Hz), 3.00–2.93 (m, 1H), 2.73–
2.64 (m, 1H), 2.36 (q, 1H, J = 8.4 Hz), 2.26–2.15 (m, 1H), 2.07–1.95
2.7. (3S,4R)-4-Azido-3-(benzyloxy)-5,5-difluorohept-6-en-1-ol (9)
211
(m, 1H); 19F NMR (282 MHz, CDCl3):
d
À98.3 (d, 1F, J = 270.4 Hz),
Compound 8 (0.87 g, 4.06 mmol) was dissolved in MeOH 212
(15 mL). After that, KOH (0.12 g) was added. The resulting mixture 213
was stirred for about 1 h. Water was added and the aqueous phase 214
was extracted with CH2Cl2. Then, the combined organic layers 215
were washed with brine. After the resultant solution was dried 216
over anhydrous Na2SO4 and filtered, the solvent was removed in 217
vacuo. The residue was purified by flash silica gel column 218
chromatography (petroleum ether/ethyl acetate = 6/1) to give 9 219
À100.5 (d, 1F, J = 269.3 Hz); 13C NMR (100 MHz, CDCl3):
d 138.7,
133.8 (t, J = 9.8 Hz), 128.3, 127.4, 127.3, 123.7 (dd, J = 30.3 Hz,
26.4 Hz), 117.7 (dd, J = 244.8 Hz, 229.7 Hz), 78.2, 72.2, 65.9 (d,
J = 20.7 Hz), 65.6 (d, J = 21.3 Hz), 51.6, 31.2; IR (thin film, cmÀ1):
3033, 2987, 1620, 1237, 987; MS (ESI): m/z 266.3 (M+H+); HRMS
Calcd. for C15H17OF2NNa: 288.1170; Found: 288.1164.
158
159
2.5. (3S,4S)-3-(Benzyloxy)-5,5-difluoro-4-hydroxyhept-6-enyl
(713 mg, 96%) as a clear oil. [
NMR (400 MHz, CDCl3): d 7.37–7.27 (m, 5H), 6.09–5.96 (m, 1H), 221
a
]
20 = À49.66 (c 1.00, CHCl3); 1H 220
D
acetate (7)
5.77 (d, 1H, J = 17.2 Hz), 5.54 (d, 1H, J = 11.1 Hz), 4.62 (dd, 2H, 222
J = 36.8 Hz, 26.0 Hz), 4.02–3.98 (m, 1H), 3.73 (t, 2H, J = 5.6 Hz), 223
3.62–3.56 (m, 1H), 1.92 (q, 2H, J = 6.0 Hz), 1.73 (br, 1H); 19F NMR 224
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
To a solution of compound 4 (1.032 g, 3.79 mmol) in vinyl
acetate (15 mL) was added lipase AK (0.52 g). The solution was
stirred at room temperature. After 24 h, the solution was filtered
and volatiles were removed by reduced pressure. The crude
product was chromatographed (petroleum ether/ethyl ace-
(282 MHz, CDCl3):
d
À98.6 (dt, 1F, J = 253.5 Hz, 9.9 Hz), À105.24 225
137.5, 226
(dt, 1F, J = 251.5 Hz, 11.8 Hz); 13C NMR (100 MHz, CDCl3):
d
130.3 (t, J = 25.3 Hz), 128.5, 128.0, 127.9, 121.1 (t, J = 9.7 Hz), 119.5 227
(t, J = 244.2 Hz), 75.0 (d, J = 3.7 Hz), 73.2, 67.3 (t, J = 28.3 Hz), 59.1, 228
34.8 (d, J = 1.5 Hz); IR (thin film, cmÀ1): 3387, 2929, 2883, 2113, 229
989; MS (ESI): m/z 268.0 ([MÀN2ÀH]+); HRMS Calcd. for 230
tate = 8/1) to afford 7 (1.037 g, 87%) as a clear oil. [
35.71 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3):
a
]
20 = À35.71
D
d
7.35–7.25 (m,
5H), 6.05–5.92 (m, 1H), 5.69 (d, 1H, J = 17.2 Hz), 5.49 (d, 1H,
J = 11.2 Hz), 4.51 (dd, 2H, J = 34.4 Hz, 11.2 Hz), 4.23–4.12 (m, 2H),
4.03 (td, 1H, J = 11.2 Hz, 3.2 Hz), 3.77–3.74 (m, 1H), 2.04–1.91 (m,
C14H16O2F2N: 268.1149; Found: 268.1152.
231
5H); 19F NMR (282 MHz, CDCl3):
d
À107.5 (dt, 1F, J = 251.5 Hz,
2.8. 1-((2R,3S)-3-(Benzyloxy)-2-(1,1-difluoroallyl)pyrrolidin-1-
232
233
11.3 Hz), À109.4 (dt, 1F, J = 251.3 Hz, 11.3 Hz); 13C NMR
yl)prop-2-en-1-one (10)
(100 MHz, CDCl3):
d 171.1, 137.4, 130.5 (t, J = 25.3 Hz), 128.5,
128.1, 128.0, 120.6 (t, J = 9.7 Hz), 119.4 (dd, J = 241.2 Hz,
243.3 Hz), 74.6 (t, J = 1.5 Hz), 73.6 (t, J = 28.3 Hz), 72.0, 61.1,
28.7, 20.9; IR (thin film, cmÀ1): 3466, 3032, 2904, 1736, 819; MS
(ESI): m /z 315.0 (M+H+); HRMS Calcd. for C16H20O4F2NNa:
337.1222; Found: 337.1223.
A solution of compound 9 (3.897 g, 13.12 mmol) in dry CH2Cl2 234
(30 mL) was cooled to 0 8C. Et3N (3.975 g, 39.36 mmol), DMAP 235
(80 mg, 0.656 mmol), and MsCl (5 mL, 65.6 mmol) were added. 236
The mixture was stirred at room temperature for 12 h and then 237
quenched with water. The two layers were separated and the 238
aqueous layer was extracted with CH2Cl2. The combined organic 239
layer was dried over Na2SO4 and concentrated. The residue was 240
purified by silica gel column chromatography (petroleum ether/ 241
ethyl acetate = 6/1) to give methanesulfonate (4.543 g, 242
12.08 mmol) as a clear oil. To a solution of methanesulfonate in 243
THF (50 mL) was added Ph3P (4.75 g, 18.12 mmol) and water 244
(4 mL). The reaction mixture was warmed to 80 8C and stirred for 245
4 h and then the reaction mixture was monitored by TLC. When 246
the starting material was consumed, 10% NaOH (aq., 15 mL) was 247
added and the reaction mixture was stirred for 12 h at room 248
temperature. The reaction mixture extracted with ethyl acetate. 249
The combined organic layer was washed with water and dried 250
over Na2SO4. The residue was dissolved in CH2Cl2 (20 mL). Then, 251
K2CO3 (3.33 g, 24.16 mmol) and acryloyl chloride (2.18 g, 252
24.16 mmol) was added. The mixture was stirred at room 253
temperature for 12 h and then quenched with water. The two 254
layers were separated, and the aqueous layer was extracted with 255
CH2Cl2. The combined organic layer was dried over Na2SO4 and 256
concentrated. The residue was purified by silica gel column 257
chromatography (petroleum ether/ethyl acetate = 10/1) to give 258
178
179
2.6. (3S,4R)-4-Azido-3-(benzyloxy)-5,5-difluorohept-6-enyl acetate
(8)
180
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
Compound 7 (2.62 g, 8.34 mmol) was dissolved in dry CH2Cl2
(50 mL). After that, DMAP (2.03 g, 16.68 mmol) was added. The
resulting mixture was cooled to À35 8C. Then, Tf2O (2.10 mL,
12.52 mmol) was added dropwise to the solution with stirring.
After that, the reaction mixture was stirred for about 3 h at 0 8C.
Water and NaHCO3 solution were added successively after the
mixture was warmed to room temperature. Then the mixture
was extracted with CH2Cl2, dried over anhydrous Na2SO4. The
mixture was separated by flash column (petroleum ether/ethyl
acetate = 8/1) to yield a colourless oil. The colourless oil was
dissolved in DMF (20 mL). Then, sodium azide (2.7 g, 41.7 mmol)
was added carefully with stirring at 0 8C in an ice bath. The
reaction mixture was stirred overnight at room temperature.
Water was added to quench the reaction. The aqueous phase
was extracted with CH2Cl2. The combined organic layer was
washed with brine, dried over anhydrous Na2SO4, and concen-
trated in vacuo. The residue was quickly purified by silica gel
column chromatography (petroleum ether/ethyl acetate = 8/1)
compound 10 (2.54 g, 63%) as a clear oil. [
CHCl3); 1H NMR (400 MHz, CDCl3):
a
]
20 = À56.83 (c 2.00, 259
D
d
7.34–7.26 (m, 5H), 6.57–6.51 260
to afford compound
8
(1.95 g, 69% yield) as
a
clear oil.
(m, 0.5H), 6.41–6.37 (m, 1.5H), 6.23–6.07 (m, 1H), 5.74–5.66 (m, 261
2H), 5.44 (dd, 1H, J = 21.2, 11.2 Hz), 4.95–4.87 (m, 0.5H), 4.70– 262
4.63 (m, 1H), 4.55–4.49 (m, 1H), 4.45–4.38 (m, 0.5H), 4.25–4.08 263
(m, 1H), 3.74–3.64 (m, 1H), 3.57–3.46 (m, 1H), 2.37–2.12 (m, 2H); 264
[
a
]
20 = À45.97 (c 1.00, CHCl3); 1H NMR (300 MHz, CDCl3):
d
D
7.35–7.25 (m, 5H), 6.08–5.95 (m, 1H), 5.78 (dt, 1H, J = 17.4 Hz,
2.1 Hz), 5.49 (d, 1H, J = 11.1 Hz), 4.59 (dd, 2H, J = 39.3 Hz,
11.1 Hz), 4.24–4.08 (m, 2H), 3.92–3.86 (m, 1H), 3.58–3.49 (m,
19F NMR (376 MHz, CDCl3):
d
À96.2 (dd, 0.48F, J = 252.3 Hz, 265
1H), 2.03–1.97 (m, 5H); 19F NMR (282 MHz, CDCl3):
d
À97.98 (d,
10.9 Hz), À102.7 (dt, 0.52F, J = 249.3 Hz, 13.9 Hz), À102.8 (dt, 266
0.48F, J = 250.8 Hz, 10.9 Hz), À103.4 (dt, 0.52F, J = 249.3 Hz, 267
1F, J = 253.2 Hz), À104.70 (d, 1F, J = 251.3 Hz); 13C NMR
(100 MHz, CDCl3):
d
170.3, 136.9, 129.8 (t, J = 25.1 Hz), 128.0,
12.4 Hz); 13C NMR (100 MHz, CDCl3):
d 166.1, 137.5, 137.3, 268
127.6, 127.5, 120.7 (t, J = 9.6 Hz), 119.0 (dd, J = 244.7 Hz,
243.6 Hz), 73.8 (d, J = 2.7 Hz), 72.8, 66.7 (t, J = 28.3 Hz), 60.1,
31.0, 20.4; IR (thin film, cmÀ1): 3032, 2962, 2114, 1740, 1240,
989; MS (ESI): m /z 357.1 (M+NH4+); HRMS Calcd. for
C16H19O3F2N3Na: 362.1287; Found: 362.1287.
132.4 (t, J = 24.6 Hz), 131.9 (t, J = 24.6 Hz), 129.1, 128.5, 128.4, 269
128.2, 127.9, 127.8, 127.7, 127.6, 127.5, 120.7 (t, J = 11.1 Hz), 270
119.5 (t, J = 9.6 Hz), 118.3 (t, J = 245.3 Hz), 117.4 (t, J = 244.9 Hz), 271
77.8, 76.5, 72.7, 61.4 (t, J = 23.1 Hz), 58.1 (t, J = 26.8 Hz), 44.0, 43.1, 272
29.5, 27.5; IR (thin film, cmÀ1): 3030, 2896, 1655, 1614, 1421; MS 273
Please cite this article in press as: X.-Y. Jiang, et al., Design and concise synthesis of gem-difluoromethylenated analogue of 7-epi-
castanospermine, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.04.018

G Model
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X.-Y. Jiang et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
274
275
(ESI): m /z 308 (M+H+); HRMS Calcd. for C17H19O2F2NNa:
330.1276; Found: 330.1270.
complex (2.0 mol/L in THF, 3.0 mL, 6.0 mmol). After 30 min, the
cold bath was removed, and the reaction was heated to reflux and
then stirred for 20 h. The reaction was then quenched with MeOH
(1 mL) and concentrated under reduced pressure. The residue was
dissolved in MeOH (5 mL). Then, the reaction was heated to reflux
and stirred for 12 h. The mixture was concentrated under reduced
pressure and the residue purified by column chromatography on
silica gel (MeOH/CH2Cl2 = 1/50) to afford 13 (147 mg, 85%) as a
327
328
329
330
331
332
333
334
335
336
337
338
339
340
341
342
343
344
345
346
276
277
2.9. (1S,8aR)-1-(Benzyloxy)-8,8-difluoro-2,3,8,8a-
tetrahydroindolizin-5(1H)-one (11)
278
279
280
281
282
283
284
285
286
287
288
289
290
291
292
293
294
295
296
297
298
Compound 10 (643 mg, 0.31 mmol) and titanium isopropoxide
(180 mg, 0.643 mmol) in dry toluene (20 mL) was refluxed for 3 h
under an argon atmosphere. Then Grubbs’ II catalyst dissolved in
toluene (5 mL) was added dropwise to the mixture. The reaction
mixture was stirred at reflux for 10 h. The reaction mixture was
cooled to room temperature and concentrated under reduced
pressure. The residue was purified by silica gel column chroma-
tography (petroleum ether/ethyl acetate = 8/1) to give compound
white solid. [
CD3OD): 7.34–7.20 (m, 5H), 4.85 (s, 2H), 4.53 (dd, 2H, J = 11.1 Hz,
a]
D
20 = 18.06 (c 1.00, CD3OD); 1H NMR (400 MHz,
d
9.3 Hz), 4.28–4.25 (m, 1H), 3.93–3.84 (m, 2H), 3.14–3.10 (m, 1H),
2.93–2.90 (m, 1H), 2.66 (dd, 1H, J = 19.2 Hz, 3.3 Hz), 2.33 (t, 1H,
J = 8.4 Hz), 2.26–2.15 (m, 2H), 1.93–1.89 (m, 1H); 19F NMR
(376 MHz, CD3OD):
d
À114.5 (d, 1F, J = 253.5 Hz), À117.1 (dd,
138.5,
11 (450 mg, 78% yield) as a yellow oil. [
a
]
20 = À716.00 (c 0.51,
1F, J = 254.5 Hz, 26.0 Hz); 13C NMR (100 MHz, CD3OD):
d
D
CHCl3); 1H NMR (300 MHz, CDCl3):
d
7.33–7.24 (m, 5H), 6.52–6.47
127.6, 127.2, 127.0, 120.0 (t, J = 243.8 Hz), 76.9, 71.3, 70.9 (dd,
J = 32.6 Hz, 20.5 Hz), 66.6 (d, J = 6.8 Hz), 63.2 (dd, J = 30.4 Hz,
19.0 Hz), 51.9, 51.3, 30.8; IR (thin film, cmÀ1): 3531, 2952, 1116,
1049, 740; MS (ESI): m/z 300.0 (M+H+); HRMS Calcd. for
(m, 1H), 6.20 (d, 1H, J = 7.8 Hz), 4.63 (dd, 2H, J = 19.5 Hz, 9.0 Hz),
4.48 (d, 1H, J = 1.8 Hz), 3.97–3.88 (m, 1H), 3.77–3.65 (m, 2H), 2.21–
2.15 (m, 1H), 1.93–1.84 (m, 1H); 19F NMR (376 MHz, CDCl3):
d
À101.4 (dd, 1F, J = 254.9 Hz, 25.6 Hz), À106.4 (dt, 1F, J = 273.7 Hz,
C15H19O3F2NNa: 322.1225; Found: 322.1212.
8.3 Hz); 13C NMR (100 MHz, CDCl3):
d
161.0 (d, J = 3.3 Hz), 131.7,
133.7 (dd, J = 32.6 Hz, 24.3 Hz), 131.0 (dd, J = 11.3 Hz, 8.3 Hz),
128.4, 127.8, 127.5, 116.2 (dd, J = 251.3 Hz, 231.5 Hz), 77.85, 72.2
(d, J = 1.5 Hz), 62.8 (dd, J = 35.7 Hz, 24.3 Hz), 43.0, 29.9; IR (thin
film, cmÀ1): 2952, 1675, 1616, 1445, 1206; MS (ESI): m/z 302.0
(M+Na+), 280.0 (M+H+); HRMS Calcd. for C15H16O2F2N: 280.1144;
Found: 280.1154.
2.12. 7-epi-8,8-Difluorocastanospermine (B)
347
HCOOH (1.045 mL) was added to a mixture of compound 13
(25 mg, 0.084 mmol) and 10% Pd/C (334 mg) in MeOH (5 mL)
under an argon atmosphere. The suspension was stirred for 4 h and
then filtered through a short pad of celite. The filtrate was
concentrated under reduced pressure and the residue was
dissolved in water and passed through a column of ion-exchange
resin (Dowex 1 Â 8, OH-form) eluting with MeOH. The eluent was
concentrated under reduced pressure to give 7-epi-8,8-difluor-
348
349
350
351
352
353
354
355
356
357
358
359
360
361
362
363
364
365
366
299
300
2.10. (1S,6R,7S,8aR)-1-(Benzyloxy)-8,8-difluoro-6,7-
dihydroxyhexahydroindolizin-5(1H)-one (12)
301
302
303
304
305
306
307
308
309
310
311
312
313
314
315
316
317
318
319
320
321
322
To a solution of compound 11 (450 mg, 1.61 mmol) in acetone
(5 mL) was added NMNO (438 mg, 3.23 mmol), followed by
addition of water (10 mL) at room temperature with stirring.
Then a catalytic amount of OsO4 (5 mol %) solution in water (4%
solution) was added. After the reaction mixture was stirred at room
temperature for 48 h, it was quenched with saturated NaHSO3
solution and extracted with ethyl acetate. The combined organic
layer was washed with brine, dried over anhydrous Na2SO4, and
filtered. The solvent was removed in vacuo. The residue was
purified by silica gel column chromatography (petroleum ether/
ethyl acetate = 2/1) to give 402 mg (80% yield) of compound 12 as a
ocastanospermine (B) (16 mg, 92%) as
a colourless solid.
[a
]
D
20 = 20.52 (c 0.50, CD3OD); 1H NMR (400 MHz, CD3OD):
d
4.47 (s, 1H), 3.91–3.89 (m, 1H), 3.82 (s, 1H), 3.13 (t, 1H, J = 3.3 Hz),
2.93–2.91 (m, 1H), 2.51 (d, 1H, J = 12.0 Hz), 2.33–2.22 (m, 2H), 2.15
(q, 1H, J = 8.8 Hz), 1.77–1.69 (m, 1H); 19F NMR (376 MHz, CD3OD):
d
À112.6 (d, 1F, J = 251.9 Hz), À113.8 (dd, 1F, J = 250.3 Hz, 22.9 Hz);
13C NMR (100 MHz, CD3OD):
d
120.2 (t, J = 247.5 Hz), 70.8 (dd,
J = 32.6 Hz, 21.3 Hz), 69.3, 66.9 (d, J = 6.8 Hz), 63.8 (dd, J = 28.8 Hz,
19.0 Hz), 51.9, 51.1, 33.1; IR (thin film, cmÀ1): 3401, 3321, 2938,
1079, 1057; MS (ESI): m/z 209.9 (M+H+); HRMS Calcd. for
C8H14O3F2N: 210.0936; Found: 210.0946.
yellow oil. [
CDCl3): 7.37–7.27 (m, 5H), 4.63 (dd, 2H, J = 14.7 Hz, 9.0 Hz), 4.40–
a]
D
20 = 93.56 (c 1.00, CHCl3); 1H NMR (400 MHz,
d
3. Results and discussion
367
4.32 (m, 2H), 4.32 (s, 1H), 4.15 (d, 1H, J = 19.5 Hz), 3.69–3.65 (m,
2H), 2.21–2.15 (m, 1H), 1.97–1.92 (m, 1H); 19F NMR (376 MHz,
The retrosynthetic analysis of target molecule B is shown in
Scheme 2. Compound B could be prepared by substrate-controlled
cis-dihydroxylation of cycloalkene C. The six-member ring in
compound C could be constructed by ring-closing metathesis
(RCM) reaction from diene D, in which the pyrrolidine ring is easily
accessible by intermolecular cyclization of allylamine and
compound E. Compound E is expected to be obtained by coupling
of 3-bromo-3,3-difluoropropene and aldehyde F.
368
369
370
371
372
373
374
375
376
377
378
379
380
381
CDCl3):
d
À113.6 (dd, 1F, J = 256.0 Hz, 8.3 Hz), À117.7 (dd, 1F,
169.0, 137.7,
J = 256.0 Hz, 25.6 Hz); 13C NMR (100 MHz, CDCl3):
d
128.4, 127.8, 127.5, 118.6 (t, J = 248.6 Hz), 76.9, 71.9 (d, J = 1.5 Hz),
70.3 (dd, J = 32.8, 21.6 Hz), 69.1 (d, J = 8.2 Hz), 59.9 (dd, J = 37.2,
19.4 Hz), 43.4, 29.6; IR (thin film, cmÀ1): 3372, 2896, 1644, 1117,
1068; MS (ESI): m/z 314.0 (M+H+); HRMS Calcd. for C15H18O4F2N:
314.1198; Found: 314.1212.
Our initial route towards compound B commenced from the
323
324
2.11. (1S,6S,7S,8aR)-1-(Benzyloxy)-8,8-difluorooctahydroindolizine-
cheap and commercially available
L
-(À)-malic acid 1 (Scheme 3).
6,7-diol (13)
Esterfication of compound with SO2Cl2/MeOH and then
1
protection of the hydroxyl group under the condition of Ag2O/
BnBr gave compound 2 in high yield. Lewis acid mediated selective
reduction of compound 2 produced the desired aldehyde [12],
325
326
To a stirred, cooled (0 8C, ice bath) solution of 12 (185 mg,
0.585 mmol) in THF (3 mL) was added borane dimethylsulfide
Scheme 2. Retrosynthestic analysis of target molecule B.
Please cite this article in press as: X.-Y. Jiang, et al., Design and concise synthesis of gem-difluoromethylenated analogue of 7-epi-
castanospermine, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.04.018

G Model
CCLET 2962 1–6
X.-Y. Jiang et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
5
Scheme 3. Initial synthetic route.
Scheme 4. Modified synthetic route.
382
383
384
385
386
387
388
389
390
391
392
393
394
395
396
397
which reacted with 3-bromo-3,3-difluoropropene in the presence
of indium affording two diastereoisomers 3a and 3b. Interestingly,
compound 3b was obtained in the form of lactone. It was converted
into diol 4 in high yield by reduction with LiAlH4. Reaction of both
of the hydroxyl groups in diol 4 with MsCl and subsequent
intramolecular cyclization with allylamine afforded the RCM
reaction precursor 5. The RCM reaction of compound 5 with
Grubbs’ II catalyst proceeded smoothly to afford alkene 6 in 80%
yield. To our disappointment, the dihydroxylation of alkene 6
could not be achieved, despite trying many different reaction
systems [13]. The failure of the dihydroxylation reaction might be
ascribed to the coordination of nitrogen atom to the catalyst OsO4
[14].
protection of the primary hydroxyl group in compound 4 with 398
vinyl acetate and Pseudomonas (AK) [15] gave the secondary 399
alcohol 7 in 87% yield. Reaction of alcohol 7 with Tf2O in presence 400
of DMAP afforded the corresponding triflate, which then reacted 401
with NaN3 to give azide 8. Cleavage of the O-Ac group in a 402
methanolic solution of 1% KOH afforded the desired alcohol 9. 403
Mesylation of the hydroxyl group in compound 9 gave the 404
corresponding methanesulfonate. Reduction of azide group with 405
triphenylphosphine and subsequent intramolecular substitution 406
cyclization afforded the pyrrolidine intermediate, which then was 407
directly treated with acryloyl chloride to give diene 10 in 63% 408
overall yield. Considering the high electron-deficient properties of 409
diene 10, we performed the ring-closing metathesis (RCM) 410
reaction under the reaction conditions developed by our group 411
[16], with Grubbs’ II catalyst and co-catalyst Ti(i-PrO)4, affording 412
To reduce the coordination ability of nitrogen to osmium, we
decided to connect an electron-withdrawing group to the nitrogen
atom. The modified synthetic route is shown in Scheme 4. Selective
the desired a,b-unsaturated lactam 11 in 78% yield. Dihydroxyla- 413
tion of lactam 11 catalyzed by OsO4 proceeded well giving diol 12 414
as a single isomer. The high diastereoselectivity can be explained 415
by the steric hindrance of benzyl ether. Subsequent reduction of 416
lactam 12 with borane dimethyl sulfide complex gave indolizidine 417
13 in 85% yield. The absolute configuration of 13 was confirmed by 418
single-crystal X-ray diffraction analysis (Fig. 2). Finally, removal of 419
the benzyl group, via hydrogenolysis in the presence of 10% Pd/C, 420
provided the target molecule 7-epi-8,8-difluorocastanospermine 421
B.
422
The synthesized 7-epi-8,8-difluorocastanospermine
evaluated for its inhibitory activities against
baker’s yeast and -glucosidase from almonds. Unfortunately no 425
B
was 423
a-glucosidase from 424
b
significant inhibitory activity was observed.
426
427
4. Conclusion
In conclusion, we have designed and prepared a novel gem- 428
difluoromethylenated castanospermine analogue B. Intramolecu- 429
lar cyclization reaction was applied to construct pyrrolidine ring, 430
while RCM reaction was used to achieve the desired bicyclic 431
Fig. 2. X-ray crystallographic structures of compound 13.
Please cite this article in press as: X.-Y. Jiang, et al., Design and concise synthesis of gem-difluoromethylenated analogue of 7-epi-
castanospermine, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.04.018

G Model
CCLET 2962 1–6
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X.-Y. Jiang et al. / Chinese Chemical Letters xxx (2014) xxx–xxx
oligosaccharide processing inhibitor, reduces membrane expression of adhe-
sion molecules and prolongs heart allograft survival in rats, Transpl. Immunol. 4
(1996) 275–285.
493
494
495
496
497
498
499
500
501
502
503
504
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507
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509
510
511
512
513
514
515
516
517
518
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
536
537
538
539
540
541
542
543
544
545
546
547
548
549
550
551
552
553
554
555
556
557
558
559
560
561
432
433
434
435
436
437
438
framework. Comparing the two synthetic routes, it was found that
amide 11 showed much better reactivity than amine 6 in the
dihydroxylation reaction. Thus, the introduction of an electron-
withdrawing group to the nitrogen atom was the highlight of the
modified route. The synthesis of other difluoromethylenated
castanospermine isomers as well as evaluation of their biological
activity are currently on progress.
[7] (a) T. Machan, A.S. Davis, B. Liawruangrath, S.G. Pyne, Synthesis of castanosper-
mine, Tetrahedron 64 (2008) 2725–2732;
(b) T. Jensen, M. Mikkelsen, A. Lauritsen, et al., A concise synthesis of castanos-
permine by the use of
8886–8889;
a transannular cyclization, J. Org. Chem. 74 (2009)
(c) J. Ceccon, G. Danoun, A.E. Greene, J.F. Poisson, Asymmetric synthesis of (+)-
castanospermine through enol ether metathesis–hydroboration/oxidation, Org.
Biomol. Chem. 7 (2009) 2029–2031;
(d) G. Liu, T.J. Wu, Y.P. Ruan, P.Q. Huang, Asymmetric total syntheses of (+)-
castanospermine, (+)-7-deoxy-6-epi-castanospermine, and (+)-1-epi-castanos-
permine, Chem, Eur. J. 16 (2010) 5755–5768;
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439
Acknowledgments
440 Q3
441
442
We thank the National Natural Science Foundation of China
(Nos. 21272036, 21332010) and the National Basic Research
Program of China (No. 2012CB21600) for funding this work.
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(b) N.B. Kalamkar, V.G. Puranik, D.D. Dhavale, Synthesis of C1- and C8a-epimers
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444
445
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Please cite this article in press as: X.-Y. Jiang, et al., Design and concise synthesis of gem-difluoromethylenated analogue of 7-epi-
castanospermine, Chin. Chem. Lett. (2014), http://dx.doi.org/10.1016/j.cclet.2014.04.018