synthesis - thieme-connect.de · ts-4-63-fr1-2-13c 192 184 176 168 160 152 144 136 128 120 112 104...
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![Page 1: SYNTHESIS - thieme-connect.de · 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 0 Chemical Shift (ppm) CHLOROFORM-d 77.00 76.69](https://reader030.vdocuments.net/reader030/viewer/2022041204/5d53d30f88c993cb2e8be550/html5/thumbnails/1.jpg)
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
![Page 2: SYNTHESIS - thieme-connect.de · 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 0 Chemical Shift (ppm) CHLOROFORM-d 77.00 76.69](https://reader030.vdocuments.net/reader030/viewer/2022041204/5d53d30f88c993cb2e8be550/html5/thumbnails/2.jpg)
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
![Page 3: SYNTHESIS - thieme-connect.de · 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 0 Chemical Shift (ppm) CHLOROFORM-d 77.00 76.69](https://reader030.vdocuments.net/reader030/viewer/2022041204/5d53d30f88c993cb2e8be550/html5/thumbnails/3.jpg)
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
![Page 4: SYNTHESIS - thieme-connect.de · 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 0 Chemical Shift (ppm) CHLOROFORM-d 77.00 76.69](https://reader030.vdocuments.net/reader030/viewer/2022041204/5d53d30f88c993cb2e8be550/html5/thumbnails/4.jpg)
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
![Page 5: SYNTHESIS - thieme-connect.de · 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 0 Chemical Shift (ppm) CHLOROFORM-d 77.00 76.69](https://reader030.vdocuments.net/reader030/viewer/2022041204/5d53d30f88c993cb2e8be550/html5/thumbnails/5.jpg)
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
![Page 6: SYNTHESIS - thieme-connect.de · 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 0 Chemical Shift (ppm) CHLOROFORM-d 77.00 76.69](https://reader030.vdocuments.net/reader030/viewer/2022041204/5d53d30f88c993cb2e8be550/html5/thumbnails/6.jpg)
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
![Page 7: SYNTHESIS - thieme-connect.de · 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 0 Chemical Shift (ppm) CHLOROFORM-d 77.00 76.69](https://reader030.vdocuments.net/reader030/viewer/2022041204/5d53d30f88c993cb2e8be550/html5/thumbnails/7.jpg)
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
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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
![Page 9: SYNTHESIS - thieme-connect.de · 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 0 Chemical Shift (ppm) CHLOROFORM-d 77.00 76.69](https://reader030.vdocuments.net/reader030/viewer/2022041204/5d53d30f88c993cb2e8be550/html5/thumbnails/9.jpg)
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
![Page 10: SYNTHESIS - thieme-connect.de · 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 0 Chemical Shift (ppm) CHLOROFORM-d 77.00 76.69](https://reader030.vdocuments.net/reader030/viewer/2022041204/5d53d30f88c993cb2e8be550/html5/thumbnails/10.jpg)
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
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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
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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