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Journal of Synthetic rganic Chemistry SUPPORTING INFORMATIONSYNTHESIS
Thieme
Supporting Information for DOI: 10.1055/s-0033-1340556
© Georg Thieme Verlag KG Stuttgart · New York 2013
Strategies for Large-Scale Synthesis of
Coelenterazine for in Vivo Applications
Tej B. Shrestha1,2*, Deryl L. Troyer2, Stefan H. Bossmann1*
TS-6-17-34gscale
9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shif t (ppm)
2.001.02
CHLOROFORM-d
5.05
7.27
8.05
N
NH2N
BrBr
TS-4-63-fr1-2-13C
192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shif t (ppm)
CHLOROFORM-d
76.6
977
.00
77.3
2
123.
6212
3.90
143.
12
151.
85
N
NH2N
BrBr
220 200 180 160 140 120 100 80 60 40 20 0 -20
Chloroform-d
152.
33
142.
6414
1.92 13
5.90
129.
2912
8.60
127.
5012
6.43
77.5
577
.23
76.9
2
40.9
2
TS-4-80-fr14-28
9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
2.202.025.940.99
CHLOROFORM-d8.00
7.31
7.29 7.
217.
20
4.49
4.06
)
BrN
NH2N
BrN
NH2N
TS-4-80-fr14-28
8.5 8.0 7.5 7.0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
5.940.99
CHLOROFORM-d8.00
7.31
7.29
7.27
7.25
7.22
7.21
7.20
TS-4-85
9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
6.009.211.941.931.906.042.010.92
CHLOROFORM-d
8.34 7.84
7.82
7.33 7.
32 7.28
7.27
6.95
6.93
4.37
4.19
1.02
0.24
TS-4-85-13C
200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shif t (ppm)
CHLOROFORM-d-4
.38
18.2
6
25.7
0
41.2
7
76.6
977.0
077
.31
120.
48
126.
9412
8.55
128.
9513
0.55
136.
8113
6.94
140.
4114
2.69
151.
22
155.
97
N
NH2N
OTBDMS
TS-4-85
8.5 8.0 7.5 7.0 6.5Chemical Shift (ppm)
0
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.45
0.50
No
rma
lize
d I
nte
nsi
ty
1.906.042.010.92
CHLOROFORM-d
8.3
4
7.8
47
.82
7.3
3 7.3
27
.28
7.2
7
6.9
56
.93
N
NH2N
OTBDMS
TS-6-18-2highvaccum
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5Chemical Shift (ppm)
5.959.342.022.01
CHLOROFORM-d
0.19
0.97
0.98
6.716.
73
7.27
7.31
7.34
Br
OTBDMS
TS-4-82-13C
220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
155.
06
132.
51
122.
12
113.
83
77.5
577
.23
76.9
1
25.8
6
18.4
2
-4.2
6
Br
OTBDMS
TS-6-8-3
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shif t (ppm)
2.052.092.002.274.30
CHLOROFORM-d
4.58
5.08
6.966.
987.
317.
34
7.43
TS-5-15new13C
200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shif t (ppm)
CHLOROFORM-d
46.2
5
70.0
5
76.6
877
.00
77.3
2
115.
05
127.
4312
8.6113
0.06
136.
74
158.
87
OBn
Cl
OBn
Cl
TS-5-15new13C
143 142 141 140 139 138 137 136 135 134 133 132 131 130 129 128 127 126 125 124 123Chemical Shif t (ppm)
12
7.4
3
12
8.0
3
12
8.6
1
12
9.9
61
30
.06
13
6.7
4
TS-6-8-3
8.3 8.2 8.1 8.0 7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1Chemical Shif t (ppm)
2.002.274.30
CHLOROFORM-d
6.966.
98
7.31
7.34
7.407.
43
TS-6-31
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)
6.002.032.002.010.922.032.012.014.98
CHLOROFORM-d
OOEt
OEt
BnO
TS-6-31-13C
220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20Chemical Shift (ppm)
CHLOROFORM-d
15.1
6
42.8
0
63.3
4
70.0
0
76.6
977
.00
77.3
1
102.
26
114.
88
126.
0012
7.45
130.
76
137.
03
157.
75
203.
50
OOEt
OEt
BnO
220 200 180 160 140 120 100 80 60 40 20 0 -20
Chloroform-d
204.
04
154.
81
131.
1212
5.85
115.
64
102.
40
77.5
477
.23
76.9
1
63.6
0
43.0
7
15.3
6
TS-5-23-columndry
8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)
6.461.971.992.081.001.002.012.00
OOEt
OEt
HO
OOEt
OEt
HO
NH
NN
OH
HOO
13 12 11 10 9 8 7 6 5 4 3 2 1 0 -1 -2Chemical Shift (ppm)
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Nor
mal
ized
Inte
nsity
2.001.681.99
METHANOL-d4
METHANOL-d4
7.13
27.
029
6.92
96.
806
6.79
16.
533
6.52
76.
511
6.34
66.
331
4.50
74.
044
3.71
83.
303
2.96
32.
959
8 11 1
N
NH2N
OTBDMS8
HO O
OEt
OEt
11
+HCl / ethanol, reflux
N
NN
OTBDMS
HO
OEtOEt
N
NN
OTBDMS
HO
OEtH
H
- H2O
OEt
ring closure
1) hydrolysis2) H-shift
NH
N
OH
N
OHO
1
coelenterazine
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