Design and Synthesis of Amidine-type Peptide Bond · PDF fileS1 Supplementary Information Design and Synthesis of Amidine-type Peptide Bond Isostere: Application of Nitrile Oxide Derivatives

S1

Supplementary Information

Design and Synthesis of Amidine-type Peptide Bond Isostere:

Application of Nitrile Oxide Derivatives as Active Ester Equivarents to Peptide and Peptidomimetics Synthesis

Eriko Inokuchia, Ai Yamadaa, Kentaro Hozumib, Kenji Tomitaa, Shinya Oishia, Hiroaki

Ohnoa, Motoyoshi Nomizub, and Nobutaka Fujiia,*

a Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan.

b School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

Table of Contents Experimental Section ···························································································· S2 NMR spectra ········································································································· S3 FAB-mass spectra································································································· S25

Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is (c) The Royal Society of Chemistry 2011

S2

Synthesis of an epimer of compound 15: tert-Butyl (S)-2-[(R)-2-tertbutoxy-carbonylamino-3-methylbutyrylamino]-3-phenylpropionate (epi-15). To a solution of N-Boc-D-valine (92 mg, 0.42 mmol) and H-Phe-OtBu (100 mg, 0.42 mmol) in CH2Cl2 were added HOBt (79 mg, 0.59 mmol), HBTU (O-Benzotriazole- N,N,N’,N’-tetramethyluroniumhexafluoro-phosphate) (142 mg, 0.44 mmol) and DIEA (293 mL, 1.68 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was washed with 5% citric acid, saturated NaHCO3 and brine and dried over Na2SO4. Concentration under reduced pressure followed by flash chromatography over silica gel with CHCl3/MeOH (95/5) gave the title compound epi-15 (95 mg, 54%) as a white solid: mp 125.0–126.0 °C; [α]24

D +35.9 (c 0.31, CHCl3); δH (500 MHz, DMSO-d6, Me4Si) 0.82 (3H, d, J 6.8), 0.89 (3H, d, J 6.6), 1.39 (9H, s), 1.43 (9H, s), 2.04–2.16 (1H, m), 3.07 (2H, d, J 6.1), 3.97 (1H, br s), 4.76 (1H, dd, J 13.5 and 6.1), 4.96 (1H, br s), 6.36 (1H, d, J 7.6) and 7.10–7.31 (5H, m); δC (125 MHz, DMSO-d6, Me4Si) 17.2, 19.2, 27.9 (3C), 28.3 (3C), 30.8, 38.3, 53.4, 82.2 (2C), 127.0 (2C), 128.4 (3C), 129.4 (2C), 136.1, 170.4 and 171.0; HRMS (FAB) m/z calcd for C23H37N2O5 ([M+H]+) 421.2702, found 421.2705.


S3

PPM

108

64

20DF

ILE

Boc-Val-aldoxime c

is DMSO　

COMNT

DATIM

Thu Jan 29 21:21:40 2009

OBNUC

1HEXMOD

NON

OBFRQ

399.65 MHz

OBSET

124.00 KHz

OBFIN

10500.00 Hz

POINT

131072

FREQU

7992.01 Hz

SCANS

8

ACQTM

16.4004 sec

PD 2.9000 sec

PW1

5.50 usec

IRNUC

1HCTEMP

21.2 c

SLVNT

DMSO

EXREF

2.49 ppm

BF 0.12 Hz

RGAIN

14

\\Corelabo\17.inokuchi\Inokuchi NMR\LE\LE1-50\Boc-Val-aldoxime cis DMSO　1H.als

0.974

1.0000.784

1.003

1.085

8.978

5.891

10.650

10.625

10.632

7.157.147

7.0

6.9746.952

3.8

3.7

3.7993.7803.7603.741

1.8

1.7

1.7951.7781.7611.7441.7271.709 1

.401.35

1.366

0.8

0.809

0.792

H

NOH

NHBoc

9a


S4

PPM

200

175

150

125

100

7550

25

DFILE

Boc-Val-aldoxime cis DMSO

1COMNT

DATIM

Thu Jan 29 21:48:25 2009

OBNUC

13C

EXMOD

BCM

OBFRQ

100.40 MHz

OBSET

125.00 KHz

OBFIN

10500.00 Hz

POINT

32768

FREQU

27118.64 Hz

SCANS

512

ACQTM

1.2083 sec

PD 1.7920 sec

PW1

5.10 usec

IRNUC

1HCTEMP

22.4 c

SLVNT

DMSO

EXREF

39.50 ppm

BF 0.12 Hz

RGAIN

24

\\Corelabo\17.inokuchi\Inokuchi NMR\LE\LE1-50\Bo

c-Val-aldoxime cis DMSO 13C.als

155.046

148.978

77.741

55.438 40.126 39.920 39.714 39.500 39.294 39.080 38.874 30.930 28.172 18.770 18.605

H

NOH

NHBoc

9a


S5

PPM

10

86

42

0DFILE

Boc-Val Aldoxime trans DMS

OCOMNT

single_pulse

DATIM

30-01-2009 16:20:09

OBNUC

1HEXMOD

single_pulse.ex2

OBFRQ

500.16 MHz

OBSET

2.41 KHz

OBFIN

6.01 Hz

POINT

52428

FREQU

7507.39 Hz

SCANS

8

ACQTM

6.9835 sec

PD 5.0000 sec

PW1

6.35 usec

IRNUC

1HCTEMP

24.1 c

SLVNT

DMSO

EXREF

2.49 ppm

BF 0.12 Hz

RGAIN

36

single_pulse


c-Val Aldoxime trans DMSO 1H.als

0.951

0.851

0.946

0.787

0.987

9.000

5.724

10.9

10.856

7.0

6.9

6.9566.938

6.5

6.5136.499

4.6

4.5

4.548

4.531

4.516

1.8

1.8181.8041.7911.777

1.35

1.366

0.8

0.810

0.796

H

NOH

NHBoc

9b


S6

PPM

200

175

150

125

100

7550

25

DFILE

Boc-Val Aldoxime trans DMS

OCOMNT

single pulse decoupled gat

eDATIM

30-01-2009 16:44:55

OBNUC

13C

EXMOD

single_pulse_dec

OBFRQ

125.77 MHz

OBSET

7.87 KHz

OBFIN

4.21 Hz

POINT

26214

FREQU

31446.06 Hz

SCANS

512

ACQTM

0.8336 sec

PD 2.0000 sec

PW1

3.50 usec

IRNUC

1HCTEMP

24.6 c

SLVNT

DMSO

EXREF

39.50 ppm

BF 0.12 Hz

RGAIN

60

single pulse decoupled gated NOE


c-Val Aldoxime trans DMSO 13C.als

155.228

149.887

77.701

50.202 39.996 39.834 39.672 39.500 39.338 39.166 39.004 30.658 28.197 18.697 18.277

H

NOH

NHBoc

9b


S7

PPM

10

86

42

0

DFILE

LE44c BocVF isostere DMSO

1COMNT

single_pulse

DATIM

04-02-2009 15:24:57

OBNUC

1HEXMOD

single_pulse.ex2

OBFRQ

500.16 MHz

OBSET

2.41 KHz

OBFIN

6.01 Hz

POINT

52428

FREQU

7507.39 Hz

SCANS

8

ACQTM

6.9835 sec

PD 5.0000 sec

PW1

6.35 usec

IRNUC

1HCTEMP

22.1 c

SLVNT

DMSO

EXREF

2.50 ppm

BF 0.12 Hz

RGAIN

40

single_pulse

C:\Documents and Settings\Eriko Inok

uchi\デス

クト

ップ

\oxime isostere NMR\LE\LE44c BocVF is

ostere DMSO 1H.als

0.778

5.582

0.840

1.100

0.846

0.811

2.175

1.129

8.064

9.099

2.6043.000

9.35

9.361

7.3

7.2

7.278

7.263

7.238 6.7

6.6746.655

5.45.393

5.372

4.5

4.4874.4684.454

3.73.696

3.6782.9

2.9152.9032.8952.880

1.8

1.8161.8031.7861.773 1

.375

1.350

1.374 1.351.30

1.321 0.750.70

0.733 0.650.60

0.639

N H

NOH

NHBoc 13

Ot Bu

O

Bn


S8

PPM

200

175

150

125

100

7550

25

DFILE

LE44c BocVF isostere DMSO

1COMNT


eDATIM

04-02-2009 15:44:15

OBNUC

13C

EXMOD

single_pulse_dec

OBFRQ

125.77 MHz

OBSET

7.87 KHz

OBFIN

4.21 Hz

POINT

13107

FREQU

31446.06 Hz

SCANS

466

ACQTM

0.4168 sec

PD 2.0000 sec

PW1

3.50 usec

IRNUC

1HCTEMP

22.7 c

SLVNT

DMSO

EXREF

39.50 ppm

BF 0.12 Hz

RGAIN

60



uchi\デス

クト

ップ

\oxime isostere NMR\LE\LE44c BocVF is

ostere DMSO 13C.als

171.434

155.276

150.545

137.897136.982129.504129.103128.035126.451126.261

80.629 79.962 77.882 77.806

56.116 55.009 40.015 39.843 39.786 39.672 39.500 39.347 39.176 39.004 29.790 28.168 27.577 27.501 19.775 18.783 18.382

N H

NOH

NHBoc 13

Ot Bu

O

Bn


S9

PPM

86

42

0

DFILE

LJ33 1H rt DMSO.als

COMNT

single_pulse

DATIM

26-10-2010 21:35:17

OBNUC

1HEXMOD

single_pulse.ex2

OBFRQ

500.16 MHz

OBSET

2.41 KHz

OBFIN

6.01 Hz

POINT

52428

FREQU

7507.39 Hz

SCANS

8

ACQTM

6.9835 sec

PD 5.0000 sec

PW1

6.35 usec

IRNUC

1HCTEMP

25.6 c

SLVNT

DMSO

EXREF

0.00 ppm

BF 0.12 Hz

RGAIN

42

single_pulse


uchi\デス

クト

ップ

\oxime isostere NMR\LJ\LJ33\LJ33 1H rt DMSO.als

1.173

0.036

0.158

0.349

0.161

1.3441.520

1.000

7.2

7.245

7.237

7.228

7.222

4.25

4.261

3.8

3.7763.764

2.9

2.943

2.929

2.915

2.901

1.857

1.844 1.400

1.375

1.380 1.300

1.275

1.283 0.8

0.784

0.770

N H

NH

NHBoc 14

Ot Bu

O

Bn


S10

PPM

200

175

150

125

100

7550

25

DFILE

LJ33TLC 13C rt DMSO-1.als

COMNT


eDATIM

02-11-2010 17:08:10

OBNUC

13C

EXMOD

single_pulse_dec

OBFRQ

125.77 MHz

OBSET

7.87 KHz

OBFIN

4.21 Hz

POINT

26214

FREQU

31446.06 Hz

SCANS

1000

ACQTM

0.8336 sec

PD 2.0000 sec

PW1

10.50 usec

IRNUC

1HCTEMP

22.4 c

SLVNT

DMSO

EXREF

39.50 ppm

BF 0.12 Hz

RGAIN

58



uchi\デス

クト

ップ

\oxime isostere NMR\LJ\LJ33\LJ33TLC 13C rt DMSO-1.als

171.186

155.171

138.059

129.246127.920127.863126.137

79.876 77.844

59.521 40.006 39.834 39.672 39.500 39.338 39.166 39.004 37.840 31.030 28.159 27.539 19.260 18.001

N H

NH

NHBoc 14

Ot Bu

O

Bn


S11

PPM

86

42

0

DFILE

Boc-VF-OtBu amide 1H rt CD

CCOMNT

single_pulse

DATIM

01-11-2010 18:09:60

OBNUC

1HEXMOD

single_pulse.ex2

OBFRQ

500.16 MHz

OBSET

2.41 KHz

OBFIN

6.01 Hz

POINT

52428

FREQU

7507.39 Hz

SCANS

8

ACQTM

6.9835 sec

PD 5.0000 sec

PW1

6.35 usec

IRNUC

1HCTEMP

25.5 c

SLVNT

CDCL3

EXREF

0.00 ppm

BF 0.12 Hz

RGAIN

36

single_pulse


uchi\デス

クト

ップ

\Inokuchi\paper\100104\NMR\Boc-VF-OtBu amide 1H rt CDCl3-1.als

5.815

0.754

0.815

1.105

0.875

2.074

1.054

9.390 8.959

3.000 2.030

7.2

7.274

7.267

7.170

6.3

6.3196.306

5.0

5.0515.036

4.7

4.747

4.732

3.9

3.916

3.902

3.13.080

3.067

2.1172.1042.091 1

.451.446 1.375

1.383 0.925

0.939 0.900.884

N H

O

NHBoc 15

Ot Bu

O

Bn


S12

PPM

200

175

150

125

100

7550

25

0

DFILE

Boc-VF-OtBu amide 13C rt C

DCOMNT


eDATIM

01-11-2010 18:58:56

OBNUC

13C

EXMOD

single_pulse_dec

OBFRQ

125.77 MHz

OBSET

7.87 KHz

OBFIN

4.21 Hz

POINT

32768

FREQU

39308.18 Hz

SCANS

1024

ACQTM

0.8336 sec

PD 2.0000 sec

PW1

3.50 usec

IRNUC

1HCTEMP

25.9 c

SLVNT

CDCL3

EXREF

77.00 ppm

BF 0.12 Hz

RGAIN

56


F:\Boc-VF-OtBu amide 13C rt CDCl3-1.jdf

170.972170.256

136.004129.470128.364126.943

82.303 79.757 77.258 77.000 76.742

59.879

53.536

38.169

30.911 28.269 27.878

19.160 17.643

N H

O

NHBoc 15

Ot Bu

O

Bn


S13

PPM

86

42

0

DFILE

LE58 1H.als

COMNT

DATIM

Fri Jan 28 18:27:23 2011

OBNUC

1HEXMOD

NON

OBFRQ

399.65 MHz

OBSET

124.00 KHz

OBFIN

10500.00 Hz

POINT

32768

FREQU

7992.01 Hz

SCANS

8

ACQTM

4.1001 sec

PD 2.9000 sec

PW1

5.50 usec

IRNUC

1HCTEMP

23.6 c

SLVNT

CDCL3

EXREF

0.00 ppm

BF 0.12 Hz

RGAIN

16

\\Seizo-win28\seizo\inokuchi\LJ1-\LE58 1H.als

5.417

0.891

0.6460.887

0.804

1.937

0.980

16.763

6.000

7.25

7.271

7.266

7.253

7.168

6.46.367

6.348

5.04.964

4.84.7

4.752

4.03.973

3.0

3.080

3.0652.00

2.127

2.113

2.096

1.50

1.4351.3951.3521.275 1

.00

0.75

0.9610.9020.8850.8250.808

N H

O

NHBoc epi-15

Ot Bu

O

Bn


S14

PPM

200

175

150

125

100

7550

25

DFILE

authentic epi-15 13C.als

COMNT

DATIM

Fri Jan 28 18:43:40 2011

OBNUC

13C

EXMOD

BCM

OBFRQ

100.40 MHz

OBSET

125.00 KHz

OBFIN

10500.00 Hz

POINT

32768

FREQU

27118.64 Hz

SCANS

256

ACQTM

1.2083 sec

PD 1.7920 sec

PW1

5.10 usec

IRNUC

1HCTEMP

25.0 c

SLVNT

CDCL3

EXREF

77.00 ppm

BF 0.12 Hz

RGAIN

26


uchi\デス

クト

ップ

\Inokuchi\paper\100104\NMR\authentic epi-15 13C.als

170.935170.392

136.094

129.409128.413126.956

82.343 77.313 77.206 77.000 76.679

53.446

38.298

30.765 28.287 27.917

19.239 17.198

N H

O

NHBoc epi-15

Ot Bu

O

Bn


S15

PPM

108

64

20

DFILE

22 LJ25 1H rt DMSO-1.als

COMNT

single_pulse

DATIM

22-10-2010 23:54:45

OBNUC

1HEXMOD

single_pulse.ex2

OBFRQ

500.16 MHz

OBSET

2.41 KHz

OBFIN

6.01 Hz

POINT

52428

FREQU

7507.39 Hz

SCANS

8

ACQTM

6.9835 sec

PD 5.0000 sec

PW1

6.35 usec

IRNUC

1HCTEMP

25.5 c

SLVNT

DMSO

EXREF

0.00 ppm

BF 0.12 Hz

RGAIN

44

single_pulse


uchi\デス

クト

ップ

\Inokuchi\paper\100104\NMR\22 LJ25 1H rt DMSO-1.als

0.698

0.190

0.6760.190

1.3330.1500.184

0.564 0.569

7.311

0.675 0.187

0.787 0.649 0.1780.737 0.300

0.5890.2570.681

1.3242.053

0.5162.967 3.083

-0.783

6.7048.921

3.204 3.000

9.659.630 9.175

9.150

9.166

8.45

8.4608.447 8

.358.308.2

8.1348.119

7.857.757.50

7.499

7.45

7.463

7.2

7.2657.2507.2177.2037.191

5.35.280

5.260

5.154.64.582

4.563

4.50

4.505

4.492

4.4

4.24.208

4.154.10

4.124

4.003.95

3.990

3.976

3.853.854

3.83.799

3.785 3.053.00

3.0113.000

2.95

2.959

2.602.584

2.45

2.466 2.425

2.400

2.413

1.95

1.988

1.40

1.407 1.351.347

0.7350.722

0.654

0.641

N HNH

H NO

O

N H

NOH

HN

O O

Phe

Asp

Val

Arg

22Gly

t BuO

Pbf


S16

PPM

200

175

150

125

100

7550

25

0

DFILE

22 LJ25 13C rt DMSO 101026

-COMNT


eDATIM

26-10-2010 08:25:19

OBNUC

13C

EXMOD

single_pulse_dec

OBFRQ

125.77 MHz

OBSET

7.87 KHz

OBFIN

4.21 Hz

POINT

26214

FREQU

31446.06 Hz

SCANS

12288

ACQTM

0.8336 sec

PD 2.0000 sec

PW1

3.50 usec

IRNUC

1HCTEMP

25.5 c

SLVNT

DMSO

EXREF

39.50 ppm

BF 0.12 Hz

RGAIN

58



uchi\デス

クト

ップ

\Inokuchi\paper\100104\NMR\22 LJ25 13C rt DMSO 101026-1.als

172.397172.235171.177170.690169.269

157.460156.030148.876137.258136.953134.177131.430129.265129.113129.046128.187128.101126.461124.334116.274

86.305 80.257 79.733 60.274 59.769 54.990 52.558 51.967 42.476 40.006 39.834 39.672 39.500 39.338 39.166 39.004 36.305 28.788 28.312 27.739 27.672 21.110 19.126 19.040 18.945 17.915 17.848 17.571 17.314 12.268 12.087

N HNH

H NO

O

N H

NOH

HN

O O

Phe

Asp

Val

Arg

22Gly

t BuO

Pbf


S17

PPM

86

42

0

DFILE

LJ30 amidine 1H rt MeOH-1.

aCOMNT

single_pulse

DATIM

30-10-2010 17:36:09

OBNUC

1HEXMOD

single_pulse.ex2

OBFRQ

500.16 MHz

OBSET

2.41 KHz

OBFIN

6.01 Hz

POINT

52428

FREQU

7507.39 Hz

SCANS

8

ACQTM

6.9835 sec

PD 5.0000 sec

PW1

6.35 usec

IRNUC

1HCTEMP

24.4 c

SLVNT

CD3OD

EXREF

0.00 ppm

BF 0.12 Hz

RGAIN

42

single_pulse


uchi\デス

クト

ップ

\oxime isostere NMR\LJ\LJ30\LJ30 amidine 1H rt MeOH-1.als

6.871

0.737

0.470 0.815 0.607

0.930

0.743

0.9940.7222.303 0.7320.905

4.135 3.894

3.9920.457

1.415

0.90813.947

6.000

7.2

7.2607.2457.2247.221 4

.704.678

4.404.35

4.355 4.304.264

3.85

3.860 3.553.50

3.511

3.15

3.157

3.053.024 3.0002.991 2.952.956 2.802.75

2.761

2.550

2.559 2.500

2.497 2.075

2.050

2.071

1.95

1.964

1.91.890

1.6

1.6171.598

1.450

1.425

1.433

0.7

0.760

0.746

N HNH

H NO

O

N H

NH

HN

O O

Phe

Asp

Val

Arg

23b

Gly

t BuO

Pbf


S18

PPM

200

175

150

125

100

75

5025

0

DFILE

LJ30 amidine 13C rt MeOH-1.

COMNT


eDATIM

31-10-2010 03:17:03

OBNUC

13C

EXMOD

single_pulse_dec

OBFRQ

125.77 MHz

OBSET

7.87 KHz

OBFIN

4.21 Hz

POINT

26214

FREQU

31446.06 Hz

SCANS

12288

ACQTM

0.8336 sec

PD 2.0000 sec

PW1

3.50 usec

IRNUC

1HCTEMP

26.3 c

SLVNT

CD3OD

EXREF

0.00 ppm

BF 0.12 Hz

RGAIN

60



uchi\デス

クト

ップ

\oxime isostere NMR\LJ\LJ30\LJ30 amidine 13C rt MeOH-1.als

174.294174.246173.893173.607173.293171.957159.891158.127

139.431137.991134.414133.537132.459130.408129.616127.928126.040118.466 87.705 82.631 62.505 56.429 54.063 49.666 49.552 49.494 49.380 49.208 49.046 48.874 48.846 48.731 48.703 48.665 48.550 48.531 44.019 38.430 37.858 30.885 29.588 28.749 28.424 28.367 19.716 19.592 18.705 18.428 12.533 0.000

N HNH

H NO

O

N H

NH

HN

O O

Phe

Asp

Val

Arg

23b

Gly

t BuO

Pbf


S19

PPM

86

42

0

DFILE

LJ31 1H rt DMSO.als

COMNT

single_pulse

DATIM

Wed Jul 15 16:31:09 2009

OBNUC

1HEXMOD

NON

OBFRQ

399.65 MHz

OBSET

124.00 KHz

OBFIN

10500.00 Hz

POINT

32768

FREQU

7992.01 Hz

SCANS

128

ACQTM

4.1001 sec

PD 2.9000 sec

PW1

5.50 usec

IRNUC

1HCTEMP

23.7 c

SLVNT

DMSO

EXREF

0.00 ppm

BF 0.12 Hz

RGAIN

20

single_pulse


uchi\デス

クト

ップ

\NMR\LJ\LJ31 RGD amide\LJ31 1H rt DMSO.als

0.866

1.784

1.969

1.081

6.922

1.498

1.9560.965

2.6821.834

3.1500.7710.830

3.837 3.1431.082

3.1890.9690.913

7.03710.386

6.000

8.4

8.366

8.0

8.0728.054

7.9587.938 7

.8

7.7617.7407.732

7.4

7.4787.459

7.2

7.2427.2247.1787.159

4.6

4.5944.576 4

.14.0

4.059

4.040 3.85

3.80

3.819 3.33.2

3.282

3.266

3.0

3.010

2.9

2.959

2.941

2.8

2.827

2.811

2.6

2.6612.6212.600

2.45

2.464

2.40

2.411

2.3

2.3882.373

2.02.002

1.8

1.8421.825

1.401.407 1.351.341

0.6

0.7390.7230.6720.655

N HNH

H NO

O

N H

OHN

O O

Phe

Asp

Val

Arg

23a

Gly

t BuO

Pbf


S20

PPM

200

175

150

125

100

7550

250

DFILE

LJ31 amide 13C rt DMSO-1.a

lCOMNT


eDATIM

28-10-2010 08:24:50

OBNUC

13C

EXMOD

single_pulse_dec

OBFRQ

125.77 MHz

OBSET

7.87 KHz

OBFIN

4.21 Hz

POINT

26214

FREQU

31446.06 Hz

SCANS

12288

ACQTM

0.8336 sec

PD 2.0000 sec

PW1

3.50 usec

IRNUC

1HCTEMP

26.0 c

SLVNT

DMSO

EXREF

39.50 ppm

BF 0.12 Hz

RGAIN

58



uchi\デス

クト

ップ

\NMR\LJ\LJ31 RGD amide\LJ31 amide 13C rt DMSO-1.als

171.119171.033170.757169.851169.441169.059157.432156.011

137.373131.402130.314129.036128.101126.241124.296119.775116.255

86.285 79.981 60.103 53.931 52.243 48.924 43.144 42.466 39.834 39.758 39.672 39.500 39.338 39.166 37.096 36.362 29.666 28.397 28.292 27.615 25.803 19.193 18.926 18.172 17.562 12.259

N HNH

H NO

O

N H

OHN

O O

Phe

Asp

Val

Arg

23a

Gly

t BuO

Pbf


S21

PPM

108

64

20

DFILE

LJ35 RGD amidine deprotect

eCOMNT

single_pulse

DATIM

02-11-2010 22:55:57

OBNUC

1HEXMOD

single_pulse.ex2

OBFRQ

500.16 MHz

OBSET

2.41 KHz

OBFIN

6.01 Hz

POINT

52428

FREQU

7507.39 Hz

SCANS

32

ACQTM

6.9835 sec

PD 5.0000 sec

PW1

6.35 usec

IRNUC

1HCTEMP

22.4 c

SLVNT

DMSO

EXREF

0.00 ppm

BF 0.12 Hz

RGAIN

44

single_pulse


uchi\デス

クト

ップ

\oxime isostere NMR\LJ\LJ35\LJ35 RGD amidin

e deprotected 1H rt DMSO-1.als

0.982

0.7890.930

1.0661.0001.1341.1271.131

7.180

0.015 1.198 1.1670.5711.290

1.1500.609

2.829 1.2381.993

0.938

1.3051.200

4.083

7.636

9.79.6

9.642

9.2

9.154

9.0

8.959

8.5

8.522

8.38.306

8.18.124

7.9

7.9487.930

7.77.721

7.2

7.247

7.204

7.189 4.70

4.633 4.60

4.55

4.568

4.4

4.418

4.2

4.2344.223

3.942

3.735

3.13.100

3.088

3.02.992

2.8

2.828

2.786

2.602.602

1.9

1.9391.925

1.81.783

1.6

1.4

1.4651.4131.399

0.7

0.7460.732

N HNH

H NO

O

N H

NH

HN

O O

Phe

Asp

Val

Arg

17Gly


S22

PPM

200

175

150

125

100

7550

25

DFILE

LJ35 RGD amidine deprotect

eCOMNT


eDATIM

03-11-2010 13:02:34

OBNUC

13C

EXMOD

single_pulse_dec

OBFRQ

125.77 MHz

OBSET

7.87 KHz

OBFIN

4.21 Hz

POINT

26214

FREQU

31446.06 Hz

SCANS

17914

ACQTM

0.8336 sec

PD 2.0000 sec

PW1

10.50 usec

IRNUC

1HCTEMP

24.2 c

SLVNT

DMSO

EXREF

39.50 ppm

BF 0.12 Hz

RGAIN

60



uchi\デス

クト

ップ

\oxime isostere NMR\LJ\LJ35\LJ35 RGD amidin

e deprotected 13C rt DMSO-1.als

171.653171.262171.196170.671166.837164.767158.367156.755

137.239

129.065128.187126.356

59.855 54.170 51.862 51.661 40.273 40.006 39.929 39.834 39.672 39.500 39.338 39.166 39.004 37.068 37.039 34.206 29.609 28.178 25.269 19.193 17.924

N HNH

H NO

O

N H

NH

HN

O O

Phe

Asp

Val

Arg

17Gly


S23

PPM

1210

86

42

0DFILE

RGD deprotected amide 1H r

tCOMNT

single_pulse

DATIM

01-11-2010 22:35:19

OBNUC

1HEXMOD

single_pulse.ex2

OBFRQ

500.16 MHz

OBSET

2.41 KHz

OBFIN

6.01 Hz

POINT

52428

FREQU

7507.39 Hz

SCANS

8

ACQTM

6.9835 sec

PD 5.0000 sec

PW1

6.35 usec

IRNUC

1HCTEMP

25.0 c

SLVNT

DMSO

EXREF

0.00 ppm

BF 0.12 Hz

RGAIN

44

single_pulse


uchi\デス

クト

ップ

\oxime isostere NMR\LJ\RGD amide

deprotect\RGD deprotected amide 1H rt DMSO-1.als

0.653

0.909

0.887 0.8680.887 0.8190.924

2.024 2.794

1.001 0.959

0.987 0.9180.923

0.8171.713

0.7990.816 0.764

0.735

0.783 0.7550.866

1.655

6.000

12.3

12.262

8.35

8.368

8.086 8.008.005 7.907.883 7.807.786 7.607.579

7.257.242

7.15

7.166

4.6

4.6324.554.554

4.1

4.121

4.029 3.85

3.80

3.821 3.30

3.25

3.273

3.1

3.107

3.094

2.929

2.82.819

2.72.710

2.42.406

2.395

1.8

1.8561.843

1.7

1.734

1.5

1.5111.491

1.41.402

1.388

0.80.753

0.7400.6850.671

N HNH

H NO

O

N H

OHN

O O

Phe

Asp

Val

Arg

16Gly


S24

PPM

200

175

150

125

100

75

50

250

DFILE

RGD deprotected amide 13C

rCOMNT


eDATIM

02-11-2010 08:16:13

OBNUC

13C

EXMOD

single_pulse_dec

OBFRQ

125.77 MHz

OBSET

7.87 KHz

OBFIN

4.21 Hz

POINT

26214

FREQU

31446.06 Hz

SCANS

12288

ACQTM

0.8336 sec

PD 2.0000 sec

PW1

3.50 usec

IRNUC

1HCTEMP

25.5 c

SLVNT

DMSO

EXREF

0.00 ppm

BF 0.12 Hz

RGAIN

60



uchi\デス

クト

ップ

\oxime isostere NMR\LJ\RGD amide

deprotect\RGD deprotected amide 13C rt DMSO-2.als

171.613171.108170.993170.593169.811169.420158.346156.562

137.275

128.987127.985126.125

60.082 53.911 52.022 48.779 43.008 40.185 40.013 39.927 39.851 39.756 39.679 39.594 39.517 39.422 39.260 39.088 38.926 37.142 34.777 29.464 28.186 25.305 19.105 18.123 0.000

N HNH

H NO

O

N H

OHN

O O

Phe

Asp

Val

Arg

16Gly


S25

N HNH

H NO

O

N H

OHN

O O

Phe

Asp

Val

Arg

16Gly


S26

N HNH

H NO

O

N H

NH

HN

O O

Phe

Asp

Val

Arg

17Gly
