Design, synthesis and biological studies of coumarin based probes and tetrahydrolipstatin analogs

Trang 1

Appendices

Trang 2

Spectral data for Chapter 2

ju211017.2

O OH O

O

2.10a

Trang 3

O OH O

O

2.10a

Trang 4

O OH O

O

H3N

2.10b

COOH

Trang 5

O OH O

O

H3N

2.10b

COOH

Trang 6

O OH O

O

H3N

2.10c

COOH

Trang 7

O OH O

O

H3N

2.10c

COOH

Trang 8

O OH O

O

2.10d

H N O

COOH

H3N

Trang 9

171.3214 167.8012 136.6001 41.2510 40.5527 40.0000 39.4400

(ppm)

10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 190

O OH O

O

2.10d

H N O

COOH

H3N

Trang 10

O OH O

O

2.10e

H3N

Trang 11

O OH O

O

2.10e

H3N

Trang 12

N O

O

O N O

O

Trang 13

170.9978 167.2011 135.1294 40.1676 39.8397 33.1644 29.4843 25.8698

(ppm)

15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 140 145 150 155 160 165 170 175

2.11a

N O

O

O N O

O

Trang 14

N O

O

2.11b

O O N O

O

Trang 15

172.0335 169.5266 135.4508 41.0064 40.7660 40.5109 40.1757 37.1004 28.6689 26.3880 24.1872

(ppm)

5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 140 145 150 155 160 165 170 175

N O

O

2.11b

O O N O

O

Trang 16

1 1 1 1 1 1 1 1 1 1 1.

(ppm)

1.30 1.40 1.50 1.60 1.70 1.80

N O

O

O O N O

O

2.11c

Trang 17

170.7630 168.3217 134.0127 77.2587 76.7486 37.3968 30.7142 27.9669 25.7661 24.0099

(ppm)

5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 140 145 150 155 160 165 170 175

N O

O

O O N O

O

2.11c

Trang 18

N O

O

2.11d

O

O N O

O

Trang 19

N O

O

2.11d

O

O N O

O

Trang 20

O O

2.14

Trang 21

169.0095 161.6420 155.8381 152.8635 148.3906 125.1897 110.5419 108.3818 98.1996 77.4206 76.5696 61.4709 39.9792 14.0000

5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 140 145 150 155 160 165 170 175 180 185 190 195

N

O O

2.14

Trang 22

6.0 6.2 6.4 6.6 6.8 7.0 7.2 7.4 7.6

N

OH O

2.15

Trang 23

170.7631 160.6682 155.4026 152.7988 150.1878 125.9542 109.5826 108.0917 97.4367 40.3291 39.7764 39.5000 38.9400 37.2454

(ppm)

10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170

40.3291 40.0528 39.7764 39.5000 39.2236 38.9400 38.6636 37.2454

(ppm)

37.5 38.0 38.5 39.0 39.5 40.0 40.5

N

OH O

2.15

Trang 24

2.70 2.80 2.90 3.00 3.10 3.20 3.30 3.40 3.50 3.60 3.70 3.80

2

2.16

Trang 25

2.16

Trang 26

6 6 6 6 6.

(ppm)

6.40 6.50 6.60 6.70

(ppm)

3.20 3.30 3.40 3.50 3.60

N

N H

O

NHBoc O

2.17

2

Trang 27

168.3598 161.1307 156.0368 153.2530 126.4574 109.7547 108.6689 97.9273 78.0401 69.9074 69.4191 40.5903 40.3352 40.1676 39.8324 39.3150 28.6754

(ppm)

5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85 90 95 100 105 110 115 120 125 130 135 140 145 150 155 160 165 170 175 180 185 190 195

N

N H

O

NHBoc O

2.17

2

Trang 28

O N H

O N

Trang 29

O N H

O N

Trang 30

O N H

O N

O

N H

2

O

N O

O (1)

2.19

Trang 31

*** Current Data Parameters ***

O

O N H

O N

O

N H

2

O

N O

O (1)

2.19

Trang 32

O

O N H

O N

O

N H

2

O

N O

O (1)

2.19

Trang 33

2.0 2.5 3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0 7.5 8.0

160 140 120 100 80 60 40 20

Current Data Parameters EXPNO 12

F2 - Acquisition Parameters Date_ 20061025 INSTRUM av500 PULPROG hmbcgplpndqf SOLVENT CDCl3

DS 16 SWH 5252.101 Hz

AQ 0.3900844 sec

RG 16384

DW 95.200 usec

TE 297.1 K CNST2 145.0000000 d0 0.00000300 sec d2 0.00344828 sec D16 0.00020000 sec

======== CHANNEL f1 ========

NUC1 1H P1 11.00 usec PL1 -2.00 dB SFO1 500.1320890 MHz

======== CHANNEL f2 ========

NUC2 13C P3 6.40 usec PL2 0.00 dB SFO2 125.7707030 MHz

====== GRADIENT CHANNEL =====

GPNAM1 SINE.100 GPNAM3 SINE.100 GPZ1 50.00 % GPZ3 40.10 % P16 1000.00 usec F1 - Acquisition parameters ND0 2 SFO1 125.7707 MHz FIDRES 80.541237 Hz

SW 163.938 ppm FnMODE QF F2 - Processing parameters

SI 2048

SF 500.1300000 MHz WDW SINE

O N

O

N H

2

O

N O

O (1)

2.19

Trang 34

110 100 90 80 70 60 50 40 30 20 10

DS 16 SWH 5252.101 Hz

AQ 0.3900844 sec

RG 16384

DW 95.200 usec

======== CHANNEL f1 ======== NUC1 1H P1 11.00 usec PL1 -2.00 dB SFO1 500.1320890 MHz

======== CHANNEL f2 ======== NUC2 13C P3 6.40 usec PL2 0.00 dB SFO2 125.7707030 MHz

====== GRADIENT CHANNEL ===== GPNAM1 SINE.100 GPNAM3 SINE.100 GPZ1 50.00 % GPZ3 40.10 % P16 1000.00 usec F1 - Acquisition parameters ND0 2 SFO1 125.7707 MHz FIDRES 80.541237 Hz

SI 2048

HMBC

O

O N H

O N

O

N H

2

O

N O

O (1)

2.19

Trang 35

5.5 6.0

6.5 7.0

7.5 8.0

110 100 90 80 70 60 50 40 30 20 10

DS 16 SWH 5252.101 Hz

AQ 0.3900844 sec

RG 16384

DW 95.200 usec

SI 2048

O N

O

N H

2

O

N O

O (1)

2.19

Trang 36

120 125 130 135 140 145 150 155 160 165 170 175

DS 16 SWH 5252.101 Hz

AQ 0.3900844 sec

RG 16384

DW 95.200 usec

SI 2048

HMBC

O

O N H

O N

O

N H

2

O

N O

O (1)

2.19

Trang 37

5.5 6.0

6.5 7.0

7.5 8.0

120 125 130 135 140 145 150 155 160 165 170 175

DS 16 SWH 5252.101 Hz

AQ 0.3900844 sec

RG 16384

DW 95.200 usec

SI 2048

O N

O

N H

2

O

N O

O (1)

2.19

Trang 38

1H normal range AC300 ma26nmh4085 mh4087b 2

Br

OH

9

5.10

Trang 39

Trang 40

OTBS

9

5.11

Trang 41

Trang 42

1.90 2.00 2.10 2.20

OTBS

9

TBDPS

5.12

Trang 43

OTBS

9

TBDPS

5.12

Trang 44

9

TBDPS

5.13

Trang 45

9

TBDPS

5.13

Trang 46

9 9.

(ppm) 9.75

2 2 2 2.

(ppm) 2.30 2.40

2.50

9

5.14

Trang 47

9

5.14

Trang 48

5 5 5 5.

(ppm) 5.80 5.90

5 5 5.

(ppm) 5.10 5.20

2 2 2 2 2 2 2 2 2.

(ppm)

2.00 2.10 2.20 2.30 2.40 2.50

9

s

5.15

Trang 49

5 5 5 5 5 5.

(ppm)

5.70 5.80 5.90

5.16 9

Trang 50

5.16 9

Trang 51

2 2 2 2.

(ppm)

2.3 2.4 2.5

5.17

Trang 52

5.17

Trang 53

5.17

Trang 54

5 5 5 5 5 5 5 5 5 5 5 5 5.

(ppm)

5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9

9

S-MTPA ester

O OCH3

CF3

Trang 55

5 5 5 5 5 5 5 5 5 5 5 5 5 5 4.

(ppm)

5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 6.0

Trang 56

N S

Trang 57

Trang 58

2 2 2 2 2.

(ppm) 2.2 2.4

N S

OTBS

C5H11

5.26

Trang 59

OTBS

C5H11

5.26

Trang 60

4 4 4 4 4 4 4 3 3.

(ppm)

3.8 3.9 4.0 4.1 4.2 4.3 4.4 4.5

3 3 3 3.

(ppm) 3.10 3.20

2 2 2 2 2 2.

(ppm) 2.30 2.40 2.50

(ppm)

1.30 1.40 1.50 1.60 1.70 1.80 1.90

9

C6H13O

5.30

Trang 61

C6H13O

5.30

Trang 62

4 4 4.

(ppm) 4.50

3 3 3.

(ppm) 3.20 3.30

(ppm)

0.80 0.90 1.00 1.10 1.20 1.30 1.40 1.50 1.60 1.70 1.80 1.90

9

C6H13O

5.31a

Trang 63

C6H13O

5.31a

Trang 64

1.9 2.0 2.1 2.2 2.3

OTBS

10

Trang 65

OTBS

10

Trang 66

1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3

OH

10

5.46

Trang 67

10

5.46

Trang 68

1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7

9

O H

Trang 69

O H

Trang 70

OH

5.47

R

Trang 71

5.48

9

Trang 72

5.49

Trang 73

(ppm) 9.8

4 4 4.

(ppm) 4.40

3 3.

(ppm) 3.84

3 3.

(ppm) 3.10 3.20

2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1.

(ppm)

1.20 1.30 1.40 1.50 1.60 1.70 1.80 1.90 2.00 2.10 2.20 2.30 2.40

9

C5H11O

Trang 74

C5H11

O

Trang 75

2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1.

(ppm)

1.20 1.30 1.40 1.50 1.60 1.70 1.80 1.90 2.00 2.10 2.20

9

C5H11O

5.51a

Trang 76

C5H11O

5.51a

Trang 77

5 5 5 5 5 5 5 5 5 5.

(ppm)

5.50 5.60 5.70 5.80 5.90

5 5 5 5 5 4.

(ppm)

4.9 5.0 5.1 5.2

2 2 2 2 2 1 1.

(ppm)

1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5

CF3OMe

9

(S)-MTPA ester

5.50S

Trang 78

5 5 5 5.

(ppm) 5.10 5.20

(ppm)

1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5 2.6

Trang 79

4.1 4.2 4.3 4.4 4.5 4.6 4.7 4.8 4.9 5.0

3 3 3.

(ppm) 3.20

9

C5H11O

5.1

O NHCHO

Trang 80

5 5 5 4 4 4 4 4 4 4 4 4 4.

(ppm)

4.3 4.4 4.5 4.6 4.7 4.8 4.9 5.0 5.1 5.2

3 3 3.

(ppm) 3.20

2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1.

(ppm)

1.10 1.20 1.30 1.40 1.50 1.60 1.70 1.80 1.90 2.00 2.10 2.20 2.30

9

C5H11O

5.53a

O NHCHO

Trang 81

C5H11O

5.53a

O NHCHO

Trang 82

5 5 4 4 4 4 4 4 4.

(ppm)

4.0 4.2 4.4 4.6 4.8 5.0 5.2

3 3 3.

(ppm) 3.2 3.3

2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0.

(ppm)

0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3

9

C5H11O

5.53b

O NHCHO

Trang 84

4.3 4.4 4.5 4.6 4.7 4.8 4.9 5.0 5.1

3 3 3.

(ppm) 3.15 3.20 3.25

2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1.

(ppm)

1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3

Trang 86

5 5 5.

(ppm) 5.10 5.20

4 4 4 4 4 4 4.

(ppm)

4.0 4.1 4.2 4.3 4.4

2 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 0 0.

(ppm)

0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3 2.4 2.5

Trang 88

3 3 3 3.

(ppm) 3.20 3.30

9

C5H11O

Trang 89

2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1.

(ppm)

1.21.4

1.61.8

2.02.2

2.4

9

C5H11O

5.57

Trang 90

102030405060708090100110120130140150160170

9

C5H11O

5.57

Trang 91

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 4.

(ppm)

5.0 5.2 5.4 5.6 5.8 6.0 6.2

CF3OMe

9

(S)-MTPA ester

Trang 92

7 7 7 7 7 7 7.

(ppm)

7.4 7.5 7.6 7.7

5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 5 4.

(ppm)

5.0 5.2 5.4 5.6 5.8 6.0 6.2

Trang 93

C5H11O

5.58

O NHCHO

Trang 94

10

5.60

Trang 95

10

5.60

Trang 96

1 1 1 1 1 1 1 0 0 0.

(ppm)

0.8 1.0 1.2 1.4 1.6 1.8

OH

10

5.62a

Trang 97

OH

10

5.62a

Trang 98

5 5 5 5 5.

(ppm) 5.70 5.80 5.90

3 3 3.

(ppm)

3.60 3.65 3.70 3.75

2 2 2 2.

(ppm) 2.20

OTBS

10

5.63a

Trang 99

OTBS

10

5.63a

Trang 100

4 4 4 4 4.

(ppm)

4.00 4.10 4.20 4.30

2 2.

(ppm) 2.45 2.50 2.55 2.60

TBSO

10

5.64a

O

Trang 101

TBSO

10

5.64a

O

Trang 102

10

5.64a

O

Trang 103

1 1 1 1 1 1 1 1 1 1 1 1.

(ppm)

1.40 1.50

1.60 1.70 1.80

OH O TMS

5.66

Trang 104

S O TMS

N

5.67

Trang 105

1.0000 1.0490 1.0110 1.0448 1.0354 4.8714 8.7746 9.5922 8.3103 6.0808

8.4231 8.4206 8.4130 8.4105 7.5633 7.5595 7.5481 7.5444 7.5330 7.5292 7.3288 7.3124 7.2607 7.0098 6.9985 6.9947 6.9859 6.9833 5.4087 5.3948 5.3797 2.2669 2.2531 2.2392 2.2241 2.2203 2.2089 2.1951 2.1800 1.6013 1.5710 1.5572 1.5508 1.5420 1.5345 1.5282 1.5206 1.5143 1.5105 1.5042 1.4966 0.8764 0.1489 0.0808

S TBSO TMS

N

5.68

Trang 106

TMS

Trang 107

TMS

Trang 108

TMS

Trang 109

TMS

Trang 110

4 4 4 4 4 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3.

(ppm)

3.2 3.4 3.6 3.8 4.0 4.2 4.4 4.6

C11H23

5.69

Trang 111

5.69

Trang 112

5.2

O NHCHO

Trang 113

5.2

O NHCHO

Trang 114

4 4 4 4 4 4 4 4 3.

(ppm) 4.2

C11H23

5.71a

O NHCHO

Trang 115

5.71b

O NHCHO

Trang 116

5.71b

O NHCHO

Trang 117

5.71c

O NHCHO

Trang 118

5.71c

O NHCHO

Trang 119

5 5 5 5 5 5 5 5.

(ppm) 5.00 5.10

Trang 120

5.71d

O NHCHO

Trang 121

4.3 4.4 4.5 4.6 4.7 4.8 4.9 5.0 5.1

2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1.

(ppm)

1.2 1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3

C11H23

5.71e

O NHCHO

Trang 122

5.71e

O NHCHO

Trang 123

TMS

Trang 124

TMS

Trang 125

3 3 3 3 3 3 3 3 3 3 3 3.

(ppm)3.203.30

3.40

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1

(ppm)

1.41.6

1.82.0

2.2

C11H23

TMS

Trang 126

102030405060708090100110120130140150160170

C11H23

TMS

Trang 127

2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1.

(ppm)

1.51.61.71.81.92.02.12.22.32.4

C11H23

5.72

Trang 128

5.72

Trang 129

5 5 5 5 5.

(ppm) 5.70 5.80

5 5 5 5.

(ppm) 5.00 5.10 5.20

C11H23

CF3OMe

(S)-MTPA ester

Trang 130

5 5 5 4.

(ppm)

4.90 5.00 5.10 5.20

Trang 131

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1.

(ppm)

1.51.61.71.81.92.02.12.22.32.4

C11H23

5.73a

O NHCHO

Trang 132

5.73a

O NHCHO

Trang 133

2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1.

(ppm)

1.51.61.71.81.92.02.12.22.32.42.5

C11H23

5.73b

O NHCHO

Trang 134

5.73b

O NHCHO

Trang 135

5 4 4 4 4 4 4.

(ppm)

4.3 4.4 4.5 4.6 4.7 4.8 4.9 5.0 5.1

2 2 2 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0.

(ppm)

0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2

C11H23

5.73c

O NHCHO

Trang 136

C11H23

C6H13O

5.74

Trang 140

2 2 2 2 2 2 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1.

(ppm)

1.21.31.41.51.61.71.81.92.02.12.22.32.42.5

C11H23

C6H13O

5.3

O

H N O

Trang 141

C6H13O

5.3

O

H N O

Trang 142

2 2 2 2 2 2 2 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1.

(ppm)

1.21.31.41.51.61.71.81.92.02.12.22.3

C11H23

C6H13O

5.76

O

H N O

5

Trang 143

C6H13O

5.76

O

H N O

5

Trang 144

OH

7.15

Trang 145

5 5 5.

(ppm) 5.00 5.10

3 3 3.

(ppm) 3.80 3.90

(ppm)

1.3 1.4 1.5 1.6 1.7 1.8 1.9 2.0 2.1 2.2 2.3

OTBS

Trang 147

83.6061 68.9439 66.6848 50.7036 36.1434 25.7370 14.4270

102030405060708090100110120130140150160170

OTBS

O

7.16

Trang 148

O TBSO

O

TMS

4

7.18

Trang 149

171.0764 106.6196 84.9979 83.7664 77.2588 77.0037 76.7486 74.7665 68.8637 67.4281 56.2055 41.9296 36.2964 31.5815 28.2075 27.3257 26.0285 25.8391 25.8026 25.6423 22.6472 19.6011 18.0270 13.9825 0.1438 -4.4108 -4.6950

0102030405060708090100110120130140150160170

O TBSO

O

TMS

4

7.18

Trang 150

O HO

O

TMS

4

7.19

Trang 151

171.1135 106.7004 84.9986 83.3736 77.2522 77.0044 76.7493 75.2846 69.6004 67.6474 56.5123 41.7044 35.8818 28.1207 27.2389 25.9053 19.5508 14.8577 0.1299

0102030405060708090100110120130140150160170

O HO

O

TMS

4

7.19

Trang 152

2.2795 2.2745 2.2656 2.2581 2.2442 2.2316 2.2139 2.1976 2.1837 2.1673 2.1522 2.1156 2.1068 2.0980 2.0853 2.0765 2.0677 2.0021 1.9971 1.9921 1.9668 1.9542 1.9378 1.9252 1.9088 1.8962 1.8723 1.8635 1.8584 1.8483 1.8433 1.8345 1.8206 1.8092 1.7021 1.6895 1.6857 1.6756 1.6643 1.6580

(ppm)

1.61.7

1.81.9

2.02.1

2.22.3

2.4

O

TMS

O O

O OHCHN

7.20

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