concise and efficient syntheses of preq base, q base, and (ent) … · 2012-09-17 · concise and...

S1

Concise and Efficient Syntheses of preQ1 base, Q base, and (ent)-Q Base

Supporting Information

Hans-Dieter Gerber and Gerhard Klebe*

Institut für Pharmazeutische Chemie, Fachbereich Pharmazie der Philipps-Universität Marburg,

Marbacher Weg 6, 35032 Marburg, Germany

Concise schematic overview (Schemes S1 and S2) and brief discussion

of previously reported procedures for the synthesis of preQ1 and Q

base

S1

NMR-Spectra 1H-NMR (DMSO-d6) 1 S6 1H-NMR (CD3OD) 1 S7 13C-NMR (DMSO-d6) 1 S8 13C-NMR (D2O/CD3OD) 1 S9 1H-NMR (CD3OD) 2 S10 1H-NMR (D2O) 2 S11 13C-NMR (CD3OD) 2 S12 1H-NMR (CD3OD) 3 S13 1H-NMR (D2O) 3 S14 13C-NMR (CD3OD) 3 S15 13C-NMR (D2O/CD3OD) 3 S16 1H-NMR (DMSO-d6) 6 S17 13C-NMR (DMSO-d6) 6 S18 1H-NMR (DMSO-d6) 7 S19 13C-NMR (DMSO-d6) 7 S20 1H-NMR (DMSO-d6) 8 S21 13C-NMR (DMSO-d6) 8 S22 1H-NMR (DMSO-d6) 9 S23 13C-NMR (DMSO-d6) 9 S24 1H-NMR (CDCl3) 10b S25

Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012

S2

1H-NMR (CDCl3) 11a S26 13C-NMR (CDCl3) 11a S27 1H-NMR (CDCl3) 11b S28 13C-NMR (CDCl3) 11b S29 1H-NMR (CDCl3) 12a S30 13C-NMR (CDCl3) 12a S31 1H-NMR (CDCl3) 12b S32 13C-NMR (CDCl3) 12b S33 1H-NMR (CDCl3) 13a S34 13C-NMR (CDCl3) 13a S35 1H-NMR (CDCl3) 13b S36 13C-NMR (CDCl3) 13b S37 1H-NMR (CD3OD) 14a (HCl) S38 13C-NMR (CD3OD) 14a (HCl) S39 1H-NMR (CD3OD) 14a (base) S40 1H-NMR (DMSO-d6) 14b (HCl) S41 1H-NMR (CD3OD) 14b (HCl) S42 13C-NMR (CD3OD) 14b (HCl) S43 1H-NMR (CD3OD) 14b (base) S44 1H-NMR (CDCl3) 15 S45 1H-NMR (CDCl3) 16 S46 1H-NMR (CD3OD) 17 S47 1H-NMR (CD3OD) 17 S48


S3

Overview and brief discussion of the most recently published procedures for preQ1 by Carell et al.: 1

The two most recent procedures suggested to access the modified guanine analogue preQ1 base were

reported by Carell et al. in 2005, both starting from pyrimidine 4 (Scheme S1).1 The first one (Route A),

being a short and seemingly straightforward five-step synthesis, involves intermediate formation of preQ0

base from pyrimidine 4 and 2-chloro-3-oxopropanenitrile, followed by a subsequent hydrogenation step to

yield preQ1 base. However, this approach only yields 6.6 % of the desired nucleobase. The second route

represents a higher-yielding, yet synthetically slightly more elaborate six-step sequence rendering preQ1 base

in 25 % overall yield. After an intermediate phthalimide deprotection step with hydrazine, the resulting

product mixture is reprotected by treatment with (Boc)2O in DMF to enable separation of the product from

the simultaneously formed side-products (mainly Phthalhydrazide) by flash chromatography yielding 31 %

of Boc-protected preQ1 base. Final deprotection gives rise to the desired nucleobase 1.

NH

N

O

NH2NH

NH2

N

O

O OH

NH

N

O

NH2 NH2

NH

N

O

NH2 NH2

O

H

Cl

CN

H

O

OMe Cl CN

preQ1 base, 1

+ +

4 4

Route A Route B

+

6 steps,25 % overall

5 steps,6.6 % overall

Scheme S1: Retrosynthetic approaches of most recent preQ1 syntheses by Carell et al.1

Overview and brief discussion of all hitherto published synthetic approaches for Q base:

The first synthesis was reported by Goto et al.2 in 1983. This rather lengthy and time-consuming route finally

rendered Q base in 19 steps applying a reductive amination with cyclopentenylamin 19 as key step. In 1988,

Akimoto et al.3 published a shorter, apparently more straightforward synthetic approach. The crucial step of

their strategy is based on a regioselective Mannich reaction at the pyrrolo moiety of the previously prepared

octanoyl-protected heterocyclic core 20 to introduce a dibenzylated aminomethyl side chain at position 5 of

the heterocycle. The resulting intermediate 21 finally allows implementation of the required side chain

moiety of queuine by an amine exchange reaction utilizing excessive amounts of the above-mentioned amine

19. Although the regioselectivity of the Mannich reaction (ratio of 5- versus 6-position substitution = 14.2 :

1) is quite high, the obtained product still might contain low amounts of the unwanted 6-substituted isomer.

In addition, the synthesis of the required substrate 19 for the following amine exchange is rather challenging

and, moreover, has to be applied in large excess (five-fold) in order to achieve a reasonable yield. In 2000,

Grubb et al.4 described an alternative route utilizing a different disconnection approach. Herein, the key

reaction is the ring closure via a cyclic condensation to install the pyrrolopyrimidine core of the nucleobase


S4

employing 2,6-diaminopyrimidine-4-one (4) and α-bromoaldehyde intermediate 22, prior to this derived via

cyclopentenol 10 starting from D-(-)-ribose, and the fully protected 3-aminopropanol precursor 23.

NH

N

O

NH2 NH2

NH

N

O

NH2NH

NH

OH

OH

NNs

O

Br

H

O O

NH

N

O

NH

NH

Trt

HO

O O

NH2

O O

OHNH OTBS

Ns

NH2 OH

NH

N

O

NH

NH

NBn

H15C7

O

Bn

O O

NH2

N

N

O

NH2N

O

OH

Bn

O O

NH2

NH

N

O

NH2NH

CN

NH

N

O

NH

NHH15C7

O

O O

N3

O O

OH

D-(-)-ribose

1.) silylation2.) reduction

+

Q base 2

+

+

D-(-)-ribose

+ +

5 equiv.

Showalter et al.5

Akimoto et al.3

Goto et al.2

Grubb et al.4

5

6

5

6

regiosel.Mannich

Mitsunobu

Staudinger red.

Mitsunobu

aminedisplacem.

red. amin.

red. amin.

5- vers. 6-subst.

cycl.condens.

19

19

20

21

22

23

24

25

2610

10

4

19

Scheme S2: Retrosynthetic approach and key steps of previously reported syntheses of Q base

In total, this sequence requires 14 steps in a convergent approach applying several protection strategies to

finally yield Q base (2) in an overall yield of 1.6 % from D-(-)-ribose. In 2010, Showalter et al.5 reported a

significantly shorter strategy using the biochemical preQ1 precursor preQ0 base (24), available in two

preceding steps from heterocycle 4,6 as starting material. Reductive amination of the trityl-protected formyl

deazaguanine derivative 25, obtained from preQ0 base 24, with cyclopentenylamine 19, furnishes, after a


S5

final deprotection step, queuine (2) as monohydrochloride in 36 % over four steps from 24.

Cyclopentenylamine 19 is accessible via the corresponding cyclopentenylazide 26 by a modified four-step

protocol of Carell et al.7 in 14.5 % overall yield. However, a necessary requirement of this synthesis is the

implementation of an intermediate silylation step with 24 thus gaining sufficient solubility of the

heterocyclic intermediate for the successive nitrile reduction with DIBAL-H to form the trityl-protected

derivative 25 at lower temperatures.

1. F. Klepper, K. Polborn and T. Carell, Helv. Chim. Acta, 2005, 88, 2610-2616. 2. T. Kondo, T. Ohgi and T. Goto, Chem. Lett., 1983, 12, 419-422. 3. H. Akimoto, E. Imamiya, T. Hitaka, H. Nomura and S. Nishimura, J. Chem. Soc., Perkin Trans. 1, 1988, 1637-

1644. 4. C. J. Barnett and L. M. Grubb, Tetrahedron, 2000, 56, 9221-9225. 5. A. F. Brooks, G. A. Garcia and H. D. H. Showalter, Tetrahedron Lett., 2010, 51, 4163-4165. 6. M. T. Migawa, J. M. Hinkley, G. C. Hoops and L. B. Townsend, Synth. Commun., 1996, 26, 3317-3322. 7. F. Klepper, E.-M. Jahn, V. Hickmann and T. Carell, Angew. Chem. Int. Ed., 2007, 46, 2325-2327.


S6

2-Amino-5-(aminomethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (1, DMSO-d6)

(M

illio

ns)

01

.02

.03

.04

.05

.06

.0

X : parts per Million : 1H

14.0 13.0 12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

11

.58

7

8

.35

7

7

.45

3

7.3

51

7

.24

9

6.8

55

5

.43

5

4

.03

1

4.0

25

4

.02

0

2

.50

8

2.5

04

-0

.00

0

5.5

0

3.9

5

3.0

5

2.0

3

1.9

5

1.0

0

NH

N NH

NH2O

NH2

*2 HCl * H2O


S7

2-Amino-5-(aminomethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (1, CD3OD)

(M

illio

ns)

01

.02

.03

.04

.05

.06

.07

.08

.09

.01

0.0

11

.01

2.0

13

.01

4.0

15

.01

6.0

17

.0


14.0 13.0 12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

6.9

71

4

.88

9

4

.20

9

3

.31

3

3.3

09

3

.30

6

3.3

03

3

.30

0

-0

.00

0

2.0

2

1.0

0

NH

N NH

NH2O

NH2

*2 HCl * H2O


S8

2-Amino-5-(aminomethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (1, DMSO-d6)

(T

ho

usa

nd

s)0

10

0.0

20

0.0

30

0.0

40

0.0

X : parts per Million : 13C

160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0

15

8.6

23

15

2.0

38

14

5.0

40

11

7.0

44

11

1.1

99

98

.44

8

40

.00

5 3

9.8

37

39

.66

9 3

9.5

01

39

.33

3 3

9.1

65

39

.00

5 3

4.7

01

NH

N NH

NH2O

NH2

*2 HCl * H2O


S9

2-Amino-5-(aminomethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride hydrate (1, D2O/CD3OD)

ab

un

dan

ce0

0.0

10

.02

0.0

30

.04

0.0

50

.06

0.0

70

.08

0.0

90

.10

.11

0.1

20

.13

0.1

40

.15

0.1

6


240.0 230.0 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0

16

0.6

08

15

1.9

95

14

2.8

38

11

9.9

94

11

1.6

86

99

.80

1

49

.51

5 4

9.3

43

49

.17

2 4

9.0

00

48

.82

8 4

8.6

57

48

.48

5 3

6.0

37

NH

N NH

NH2O

NH2

*2 HCl * H2O


S10

2-Amino-5({[(1S,4S,5R)-4,5-dihydroxycyclopent-2-en-1-yl]amino}methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride

hydrate (2, CD3OD)

ab

un

dan

ce0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

1.5

1.6


7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

6

.97

3

6

.26

2

6.2

61

6

.24

7

6.2

46

6

.07

2

6.0

70

6

.06

8

6.0

56

6

.05

4

6.0

53

4

.89

1

4

.60

8

4.4

93

4

.42

0

4.3

85

4

.32

2

4.3

09

4

.29

4

4.2

21

4

.21

6

3

.32

0

3.3

16

3

.31

2

3.3

08

3

.30

4

0

.00

0

2.0

61

.83

6.1

82

.06

2.0

6

1.6

06

.30

1.3

7

5.7

21

3.5

11

3.7

45

.72

2.0

3

1.0

2

1.0

1

1.0

1

1.0

1

1.0

0

1.0

0

NH

N NH

NH

O

NH2

OH

OH

(S) (R)

(S)

*2 HCl * H2O


S11


hydrate (2, D2O)

ab

un

da

nce

01

.02

.0


7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

6

.98

4

6

.25

1

6.2

48

6

.24

6

6.2

40

6

.23

5

6.2

30

6

.22

4

6.0

67

6

.06

3

6.0

51

6

.04

7

4

.79

0

4.6

54

4

.64

8

4.6

43

4

.63

9

4.6

34

4

.48

4

4.4

50

4

.40

2

4.3

70

4

.35

7

4.3

43

4

.26

7

4.2

63

4

.25

8

4.2

53

4

.24

9

2.0

66

.41

1.8

36

.30

1.6

0

1.6

05

.72

13

.74

5.7

23

.09

1.0

1

1.0

1

1.0

1

1.0

0

1.0

0

NH

N NH

NH

O

NH2

OH

OH

(S) (R)

(S)

*2 HCl * H2O


S12


hydrate (2, CD3OD)

(T

ho

usa

nd

s)0

10

0.0

20

0.0

30

0.0

40

0.0


170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0

16

0.9

63

15

3.3

63

14

5.8

16

13

9.7

27

12

9.8

14

12

0.6

50

11

0.5

93

10

0.3

22

75

.23

2 7

4.3

85

68

.54

8

49

.51

7 4

9.3

49

49

.18

1 4

9.0

06

48

.83

8 4

8.6

70

48

.49

4 4

3.0

16

NH

N NH

NH

O

NH2

OH

OH

(S) (R)

(S)

*2 HCl * H2O


S13

2-Amino-5({[(1R,4R,5S)-4,5-dihydroxycyclopent-2-en-1-yl]amino}methyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one dihydrochloride

hydrate (3, CD3OD)

ab

un

dan

ce0

1.0

2.0

3.0

4.0

5.0

6.0

7.0


7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

6

.97

9

6

.25

8

6.2

44

6

.24

3

6.2

38

6

.06

4

6.0

62

6

.06

0

6.0

48

6

.04

6

6.0

44

4

.89

5

4

.59

7

4.4

99

4

.42

1

4.3

87

4

.30

9

4.2

96

4

.28

1

4.2

14

4

.21

0

3

.31

6

3.3

12

3

.30

8

3.3

04

3

.30

0

-0

.00

0

6.1

82

.06

1.6

06

.41

1.6

0

6.1

81

3.9

71

3.7

45

.72

1.0

1

1.0

01

.00

1.0

0

1.0

0

1.0

0

0.9

9

0.9

9

NH

N NH

NH

O

NH2

OH

OH

(R) (S)

(R)

*2 HCl *H2O


S14


hydrate (3, D2O)

ab

un

dan

ce0

1.0

2.0

3.0

4.0

5.0

6.0

7.0


7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

6

.98

2

6

.24

6

6.2

31

6

.22

9

6.2

25

6

.06

8

6.0

66

6

.06

4

6.0

52

6

.05

1

6.0

49

4

.79

0

4.6

39

4

.63

8

4.4

89

4

.45

4

4.4

09

4

.37

3

4.3

70

4

.35

6

4.3

43

4

.26

8

4.2

64

4

.25

4

4.2

50

3

.30

7

2.0

62

.52

2.0

66

.30

1.8

32

.52

1.8

3

1.3

76

.18

1.3

7

5.7

2

13

.97

14

.20

5.5

05

.50

1.6

05

.50

1.6

02

.00

1.0

1

1.0

1

1.0

1

1.0

0

1.0

0

0.9

5

NH

N NH

NH

O

NH2

OH

OH

(R) (S)

(R)

*2 HCl *H2O


S15


hydrate (3, CD3OD)

ab

un

dan

ce0

0.1

0.2


160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0

16

1.2

09

15

3.6

07

14

4.4

88

13

9.7

86

12

9.8

18

12

0.2

80

11

0.5

70

10

0.2

69

79

.51

3 7

9.2

56

78

.99

8 7

5.4

59

74

.36

2 6

8.4

49

49

.63

0 4

9.5

15

49

.45

8 4

9.3

43

49

.28

6 4

9.1

72

49

.00

0 4

8.8

38

48

.66

6 4

8.4

94

43

.16

3

-0

.01

8

NH

N NH

NH

O

NH2

OH

OH

(R) (S)

(R)

*2 HCl *H2O


S16


hydrate (3, D2O/CD3OD)

ab

un

dan

ce0

0.0

20

.04

0.0

60

.08

0.1

0.1

20

.14

0.1

60

.18


240.0 230.0 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0

16

1.1

52

15

2.5

58

14

5.4

52

13

8.7

75

12

9.8

28

12

0.9

48

10

9.5

78

99

.75

3

74

.51

5 7

3.9

14

67

.63

8

49

.51

5 4

9.3

43

49

.17

2 4

9.0

00

48

.82

8 4

8.6

57

48

.47

5 4

2.5

90

NH

N NH

NH

O

NH2

OH

OH

(R) (S)

(R)

*2 HCl *H2O


S17

(R,S)-2-(2-Hydroxy-3-nitropropyl)-1 H-isoindole-1,3(2H)-dione (6, DMSO-d6)

ab

un

dan

ce0

1.0

2.0

3.0

4.0


9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

7

.90

4

7.8

96

7

.88

8

7.8

83

7

.88

1

7.8

74

7

.86

3

7.8

52

7

.84

6

7.8

43

7

.83

9

7.8

30

7

.82

3

5

.77

6

5.7

69

5

.76

3

4

.90

5

4.8

87

4

.87

4

4.8

61

4

.84

1

4.4

88

4

.47

6

4.4

51

4

.42

7

3

.70

3

3.6

86

3

.62

8

3.6

15

3

.30

6

2

.51

1

2.5

06

2

.50

2

2.4

98

2

.49

3

0

.00

0

5.2

7

10

.07

7.1

01

3.9

77

.10

5.2

71

3.9

75

.27

4.0

0

2.0

0

2.0

0

0.9

8

0.9

8

N

O

O OH NO2

(R,S)


S18

(R,S)-2-(2-Hydroxy-3-nitropropyl)-1 H-isoindole-1,3(2H)-dione (6, DMSO-d6)

ab

un

dan

ce0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2


240.0230.0 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 -10.0

16

7.9

45

13

4.2

62

13

3.9

84

13

1.7

80

13

1.4

55

12

3.2

14

12

2.9

55

79

.20

1

65

.67

0 6

5.4

59

40

.78

4 4

0.1

23

39

.92

2 3

9.7

11

39

.50

0 3

9.2

89

39

.07

8 3

8.8

77

N

O

O OH NO2

(R,S)


S19

2-[(2E)-3-nitroprop-2-en-1-yl]-1H-isoindole-1,3(2H)-dione (7, DMSO-d6)

ab

un

da

nce

01

.02

.03

.04

.05

.0


9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

7

.90

5

7.8

90

7

.88

3

7.8

61

7

.85

4

7.8

47

7

.83

9

7

.59

7

7.3

92

7

.38

0

7.3

68

7

.35

9

7.3

53

7

.34

7

7.3

34

4

.49

3

4.4

91

4

.48

8

4.4

84

4

.48

1

4.4

78

4

.47

6

3

.30

2

2

.51

1

2.5

06

2

.50

2

2.4

97

2

.49

3

0

.00

0

1.8

31

3.5

11

.83

5.0

41

3.5

15

.04

2.0

64

.92

1.8

3

4.0

3

2.0

0

0.9

7

0.8

7

N

O

O NO2

(E)


S20

2-[(2E)-3-nitroprop-2-en-1-yl]-1H-isoindole-1,3(2H)-dione (7, DMSO-d6)

(M

illio

ns)

01

.02

.03

.0


240.0 230.0 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0

16

7.3

29

14

0.5

76

13

7.9

43

13

4.2

42

13

1.8

77

12

3.0

25

39

.99

6 3

9.8

28

39

.66

8 3

9.5

00

39

.33

2 3

9.1

64

38

.99

6 3

8.8

59

35

.26

5

N

O

O NO2

(E)


S21

(R,S)-2-[2-(2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-3-nitropropyl]-1 H-isoindole-1,3(2H)-dione hydrate (8, DMSO-d6)

(M

illio

ns)

01

.02

.03

.04

.05

.06

.07

.08

.09

.01

0.0

11

.01

2.0

13

.01

4.0

15

.01

6.0


10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

9

.84

1

7

.85

7

7.8

50

7

.84

5

7.8

40

7

.83

2

7.8

24

7

.81

9

7.8

14

7

.80

7

6

.04

6

5

.78

7

5

.21

4

5.2

08

5

.18

9

4.9

26

4

.91

5

4.9

00

4

.88

9

3

.96

8

3.9

55

3

.94

1

3.7

67

3

.75

7

3.7

29

3

.31

1

2

.50

5

2.5

02

2

.49

8

-0

.00

0

9.1

61

2.6

09

.16

5.7

31

3.1

75

.50

7.1

01

3.7

57

.10

5.0

41

3.7

55

.04

4.0

2

1.9

9

1.9

2

1.0

0

0.9

7

0.9

6

0.9

6

0.9

4

0.8

4

NH

NNH2

O

NH2

NO2

N

O

O* H2O

(R,S)


S22

(R,S)-2-[2-(2,4-Diamino-6-oxo-1,6-dihydropyrimidin-5-yl)-3-nitropropyl]-1 H-isoindole-1,3(2H)-dione hydrate (8, DMSO-d6)

(M

illio

ns)

00

.10

.20

.30

.40

.50

.60

.70

.80

.91

.01

.11

.21

.31

.41

.51

.61

.71

.81

.92

.02

.1


180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0

16

8.0

46

16

2.6

05

16

2.3

08

15

3.7

16

13

4.2

12

13

1.7

09

12

2.9

26

83

.23

1

75

.76

1

39

.99

6 3

9.8

28

39

.66

0 3

9.5

00

39

.33

2 3

9.1

64

38

.99

6 3

8.0

65

34

.78

4

NH

NNH2

O

NH2

NO2

N

O

O* H2O

(R,S)


S23

2-({[(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]amino}carbonyl)benzoic acid dihydrate (9, DMSO-d6)

ab

un

dan

ce0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

1.5


14.0 13.0 12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

12

.83

2

10

.83

7

10

.33

4

8

.82

8

8.8

21

8

.81

4

8.8

01

7

.71

3

7.7

10

7

.49

9

7.4

96

7

.47

3

7.4

69

6

.62

1

6.6

19

6

.61

7

6

.07

1

4

.48

1

4.4

75

4

.46

8

3

.31

3

2

.51

0

2.5

06

2

.50

1

2.4

97

2

.49

3

0

.00

0

5.5

0

0.9

27

.56

1.3

7

5.2

7

3.0

5

2.0

1

1.9

9

1.0

2

1.0

0

1.0

0

1.0

0

0.9

9

0.8

2

NH

N NH

NH

O

NH2

O

OOH *2 H2O


S24

2-({[(2-Amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-yl)methyl]amino}carbonyl)benzoic acid dihydrate (9, DMSO-d6)

(M

illio

ns)

00

.10

.20

.30

.40

.50

.60

.70

.80

.91

.01

.11

.21

.31

.41

.51

.61

.71

.81

.92

.02

.1


180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0

16

8.2

98

16

7.8

32

15

9.7

90

15

2.2

58

15

1.5

87

13

8.1

95

13

1.4

11

13

1.0

14

12

9.2

67

12

9.0

69

12

7.5

35

11

5.2

80

11

3.9

07

98

.46

2

40

.00

4 3

9.8

36

39

.66

8 3

9.5

00

39

.33

2 3

9.1

72

39

.00

4 3

5.8

91

NH

N NH

NH

O

NH2

O

OOH *2 H2O


S25

(3'aR,4'R,6'aS)-4',6'a-dihydro-3'aH-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxole]-4'-ol (10b, CDCl3)

abu

nd

ance

01

.02

.03

.0


8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

7

.26

8

5

.90

5

5.8

94

5

.89

1

5.8

88

5

.87

9

5.8

77

5

.87

6

5.8

62

5

.86

1

5

.02

4

5.0

14

5

.01

2

5.0

10

4

.75

1

4.7

38

4

.73

1

4.7

24

4

.56

4

4.5

50

4

.54

7

4.5

39

4

.52

5

2

.80

2

2.7

90

2

.77

8

1

.64

5

1.6

21

1

.59

8

1.5

82

1

.41

4

1.4

00

1

.38

6

-0

.00

0

5.5

0

5.5

05

.50

9.8

5

8.5

6

2.0

3

1.9

2

1.0

0

0.9

8

0.9

6

0.9

6

OH

O O

(S)(R)

(R)


S26

(3aS,4S,6aS)-2,2-dimethyl-2H,3aH,4H,6aH-cyclopenta[d][1,3]dioxol-4-yl 4-nitrobenzoate (11a, CDCl3)

ab

un

dan

ce0

1.0

2.0

3.0

4.0

5.0

6.0


9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

8

.30

4

8.2

98

8

.28

6

8.2

81

8

.27

6

8.2

18

8

.21

3

8.2

08

8

.19

5

8.1

91

7

.26

6

6

.24

2

6.2

27

6

.04

2

6.0

37

6

.02

7

6.0

22

5

.87

5

5.8

73

5

.36

4

5.3

61

5

.34

9

5.3

47

4

.76

9

4.7

61

4

.75

4

1

.58

9

1.4

69

1

.38

8

0

.07

2

0.0

00

2.0

62

.06

8.9

32

.06

2.0

61

.83

2.0

68

.93

1.8

32

.29

5.7

2

5.9

50

.69

0.9

25

.72

0.9

2

5.7

2

3.0

43

.01

2.0

01

.99

1.0

0

1.0

0

1.0

0

1.0

0

0.9

7

O

O O

OO2N

(S) (S)

(S)


S27

(3aS,4S,6aS)-2,2-dimethyl-2H,3aH,4H,6aH-cyclopenta[d][1,3]dioxol-4-yl 4-nitrobenzoate (11a, CDCl3)

ab

un

dan

ce0

0.1

0.2

0.3

0.4


240.0230.0 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 -10.0

16

4.0

96

15

0.5

75

13

8.3

19

13

5.1

28

13

0.7

97

13

0.7

49

12

3.4

95

11

2.4

75

84

.67

6 8

3.9

38

83

.15

2 7

7.3

26

77

.00

0 7

6.6

84

27

.21

8 2

5.6

37

-0

.07

3

O

O O

OO2N

(S) (S)

(S)


S28

(3a'S,4'S,6a'S)-4',6a'-dihydro-3a'H-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-4'-yl 4-nitro-benzoate (11b, CDCl3)

ab

un

dan

ce0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

1.5

1.6

1.7

1.8


14.0 13.0 12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

8

.30

1

8.2

96

8

.28

4

8.2

79

8

.21

4

8.2

09

8

.20

4

8.1

92

8

.18

6

7

.26

5

6

.23

2

6.0

32

6

.02

6

5.8

82

5

.87

9

5

.34

6

5.3

44

4

.77

9

4.7

71

4

.76

4

1

.67

4

1.6

59

1

.63

1

1.6

14

1

.57

8

1.5

68

1

.40

9

1.3

96

0

.00

0

2.0

61

.83

8.9

32

.06

2.0

62

.06

8.9

32

.06

5.7

25

.95

0.9

25

.72

0.9

2

5.7

2

8.6

72

.07

1.9

81

.98

1.0

2

1.0

0

0.9

9

0.9

9

0.9

7

O

O

O

O

O2N

(S)

(S)

(S)


S29

(3a'S,4'S,6a'S)-4',6a'-dihydro-3a'H-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxol]-4'-yl 4-nitro-benzoate (11b, CDCl3)

ab

un

dan

ce0

0.1

0.2

0.3

0.4

0.5


240.0230.0 220.0 210.0 200.0 190.0 180.0 170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 -10.0

16

4.1

25

15

0.5

94

13

8.5

68

13

5.2

24

13

0.7

87

12

3.5

43

11

3.2

51

84

.86

7 8

3.5

83

82

.69

2 7

7.3

16

77

.00

0 7

6.6

84

37

.03

1 3

5.2

10

24

.99

5 2

3.9

41

23

.68

2

0

.99

1

O

O

O

O

O2N

(S)

(S)

(S)


S30

(3aR,4S,6aS)-2,2-dimethyl-2H,3aH,4H,6aH-cyclopenta[d][1,3]dioxol-4-ol (12a, CDCl3)

ab

un

da

nce

01

.02

.03

.04

.05

.06

.0


8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

7

.26

6

6

.04

2

6.0

41

6

.02

8

6.0

26

5

.92

4

5.9

22

5

.91

9

5.9

10

5

.90

4

5

.30

1

5.2

99

5

.28

7

5.2

85

4

.80

7

4.8

01

4

.79

5

4.5

34

4

.52

7

4.5

20

1

.94

9

1.9

42

1

.93

4

1

.64

5

1

.40

4

1.3

53

0

.00

0

5.7

25

.72

0.6

95

.61

0.9

2

4.8

1

5.5

0

5.9

5

3.0

93

.09

1.0

0

0.9

9

0.9

9

0.9

90

.99

0.9

7

OH

O O

(R) (S)

(S)


S31

(3aR,4S,6aS)-2,2-dimethyl-2H,3aH,4H,6aH-cyclopenta[d][1,3]dioxol-4-ol (12a, CDCl3)

ab

un

dan

ce0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0


160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 -10.0

13

5.0

61

13

4.6

49

11

1.5

84

85

.75

8 8

4.1

58

80

.55

5 7

7.3

16

77

.00

0 7

6.6

74

27

.14

2 2

5.5

61

-0

.14

0

OH

O O

(R) (S)

(S)


S32

(3'aR,4'S,6'aS)-4',6'a-dihydro-3'aH-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxole]-4'-ol (12b, CDCl3)

ab

un

dan

ce0

1.0

2.0

3.0


8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

7

.26

5

6

.05

1

6.0

37

5

.91

0

5.9

08

5

.90

7

5.9

05

5

.89

6

5.8

90

5

.29

4

5.2

92

5

.28

0

5.2

78

4

.81

6

4.8

15

4

.80

2

4.5

23

4

.51

7

4.5

10

1

.90

6

1.8

98

1

.89

0

1

.59

1

1.5

84

1

.38

9

1.3

79

-0

.00

0

5.7

20

.92

2.2

90

.92

5.7

20

.92

2.2

90

.92

0.9

25

.61

0.6

9

0.6

95

.95

0.6

9

5.2

7

6.1

8

9.0

0

2.0

0

1.0

2

1.0

1

1.0

0

1.0

01

.00

1.0

0

OH

O O

(S)

(S)

(R)


S33

(3'aR,4'S,6'aS)-4',6'a-dihydro-3'aH-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxole]-4'-ol (12b, CDCl3)

ab

un

dan

ce0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9


160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0

13

5.6

37

13

4.5

93

11

2.4

28

85

.50

1 8

3.8

15

81

.11

3 7

7.3

18

77

.00

2 7

6.6

85

37

.00

4 3

5.0

97

25

.01

6 2

3.9

62

23

.67

4

OH

O O

(S)

(S)

(R)


S34

(3aS,4R,6aS)-4-bromo-2,2-dimethyl-2H,3aH,4H,6aH-cyclopenta[d][1,3]dioxole (13a, CDCl3)

(M

illio

ns)

01

.02

.03

.04

.05

.06

.07

.08

.09

.01

0.0

11

.01

2.0

13

.01

4.0

15

.0


14.0 13.0 12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

7.2

64

5

.99

6

5.9

70

5

.96

8

5.9

67

5

.34

2

5.3

38

5

.33

6

5.3

34

5

.33

1

5.3

28

5

.32

5

4.9

73

4

.96

2

4.8

48

1

.59

6

1.4

19

1

.38

7

1.3

54

1

.32

3

1.2

60

0

.07

0

0.0

06

-0

.00

0 -

0.0

07

2.2

95

.50

2.5

25

.50

0.9

21

.37

1.3

71

.15

5.2

7

3.1

53

.12

1.9

7

0.9

8

0.9

7

0.9

5

0.2

8

Br

O O

(S)

(R)

(S)


S35

(3aS,4R,6aS)-4-bromo-2,2-dimethyl-2H,3aH,4H,6aH-cyclopenta[d][1,3]dioxole (13a, CDCl3)

(M

illio

ns)

01

.02

.0


170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0

13

5.1

07

13

4.1

77

11

2.1

62

8

5.9

97

8

4.1

04

7

7.2

52

7

7.0

00

7

6.7

41

5

4.5

05

2

7.4

46

2

6.2

56

0

.97

6

Filename = C:\Dokumente und Einstellu X_Acq_Duration = 1.0420224[s] X_Pulse = 4.6[us]

Br

O O

(S)

(R)

(S)


S36

(3aS,4R,6aS)-4-bromo-4,6a-dihydro-3aH-spiro[cyclohexane-1,2-cyclopenta[d][1,3]dioxole (13b, CDCl3)

ab

un

dan

ce0

1.0

2.0

3.0

4.0

5.0

6.0

7.0


8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

7

.26

6

5

.98

6

5.9

85

5

.98

2

5.9

81

5

.98

0

5.9

78

5

.97

4

5.9

71

5

.33

4

5.3

32

5

.32

0

5.3

19

4

.96

4

4.9

57

4

.95

0

4.8

62

4

.85

7

4.8

55

4

.85

3

1

.59

6

1.5

80

1

.57

3

1.5

65

1

.38

1

1.3

75

0

.00

0

5.5

0

5.5

01

.60

8.3

0

2.2

0

1.9

9

1.0

0

0.9

9

0.9

5

Br

O O

(S)(S)

(R)


S37

(3aS,4R,6aS)-4-bromo-4,6a-dihydro-3aH-spiro[cyclohexane-1,2-cyclopenta[d][1,3]dioxole (13b, CDCl3)

ab

un

dan

ce0

0.1

0.2

0.3

0.4


150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0 -10.0

13

5.3

01

13

4.0

84

11

2.8

49

85

.53

8 8

3.6

60

77

.31

6 7

7.0

00

76

.68

4

54

.75

9

37

.15

6 3

5.6

80

24

.91

9 2

3.9

32

23

.68

3

-0

.04

4

Br

O O

(S)(S)

(R)


S38

2-Amino-5({[(3a’R,4’S,6a’S)-2,2-dimethyl-4,6a’-dihydro-3a’H-cyclopenta[d][1,3]dioxol-4-yl]amino}methyl)-3,7-dihydro-4H-pyrrolo[2,3-

d]pyrimidin-4-one hydrochloride (14a, CD3OD)

abu

nd

an

ce0

1.0

2.0

3.0


8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

6

.87

8

6

.31

0

6.3

00

6

.29

6

6.0

03

6

.00

1

5.9

91

5

.98

9

5

.34

9

5.3

42

5

.33

4

4

.91

9

4.9

12

4

.90

4

4.8

83

4

.41

1

4.3

94

4

.37

7

4.3

42

4

.31

4

4.3

10

3

.48

3

3.3

10

3

.30

6

3.3

02

3

.29

8

3.1

29

1

.37

4

1.3

61

-0

.00

0

1.3

75

.72

1.3

7

5.7

2

5.7

2

5.7

2

13

.74

13

.05

6.0

8

2.9

9

1.0

0

1.0

0

0.9

9

0.9

8

1.1

0

NH

N NH

NH

O

NH2

O

O

(S) (R)

(S)

* HCl


S39


d]pyrimidin-4-one hydrochloride (14a, CD3OD)

(T

ho

usa

nd

s)0

10

0.0

20

0.0

30

0.0

40

0.0

50

0.0

60

0.0

70

0.0


170.0 160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0

16

2.6

51

15

4.5

17

15

3.9

67

14

1.0

18

12

8.7

10

11

9.4

31

11

3.5

94

10

9.6

33

99

.75

2

85

.61

2

81

.50

7

69

.16

0

49

.51

1 4

9.3

43

49

.16

8 4

9.0

00

48

.83

2 4

8.6

57

48

.48

9 4

3.3

69

27

.44

3 2

5.7

34

NH

N NH

NH

O

NH2

O

O

(S) (R)

(S)

* HCl


S40


d]pyrimidin-4-one (14a, CD3OD)

abu

nd

an

ce0

0.1

0.2

0.3

0.4

0.5

0.6


8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

7

.90

1

6

.59

0

5

.89

2

5.8

88

5

.88

5

5.8

63

5

.86

1

5.8

57

5

.25

2

5.2

45

5

.23

8

4

.88

6

4

.58

2

4.5

75

4

.56

8

3

.93

1

3.8

98

3

.89

6

3.7

66

3

.75

5

3.7

33

3

.34

5

3.3

15

3

.31

1

3.3

07

3

.30

2

3.2

98

1

.33

4

1.3

16

0

.00

0

1.3

75

.72

1.3

75

.72

5.7

2

5.7

2

5.7

2

0.6

91

3.2

80

.69

13

.28

6.1

2

2.0

9

1.0

8

1.0

8

1.0

0

1.0

0

1.0

0

0.9

8

NH

N NH

NH

O

NH2

O

O

(S) (R)

(S)


S41

5-({[(3'aR, 4'S,6'aS)-4',6'a-dihydro-3'aH-spiro[cyclohexane-1,2'-cyclopenta[d][1,3]dioxole]-4'-yl]amino}methyl)-2-amino-3H,4H,7H-

pyrrolo[2,3-d]pyrimidin-4-one hydrochloride (14b, CD3OD)

ab

un

da

nce

-0.1

00

.10

.20

.30

.40

.50

.60

.70

.80

.91

.01

.11

.21

.31

.4


7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

6

.88

3

6

.31

5

6.3

08

6

.30

1

5.9

95

5

.98

9

5.9

83

5

.34

1

5.3

34

5

.32

8

4

.89

3

4

.41

6

4.3

99

4

.38

2

4.3

49

4

.33

2

4.3

28

4

.31

5

3

.30

6

1

.60

5

1.5

82

1

.39

9

0

.00

0

5.7

2

4.8

1

5.0

4

13

.74

13

.51

8.0

7

3.0

0

2.0

0

1.0

1

1.0

0

1.0

0

1.0

0

NH

N NH

NH

O

NH2

O

O

(S) (R)

(S)

* HCl


S42


pyrrolo[2,3-d]pyrimidin-4-one hydrochloride (14b, DMSO-d6)

abu

nd

an

ce0

1.0

2.0

3.0


14.0 13.0 12.0 11.0 10.0 9.0 8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

11

.27

5

10

.79

4

9

.38

2

6

.83

7

6.3

51

6

.29

7

6.2

90

6

.28

4

5.9

82

5

.97

6

5.9

70

5

.27

5

5.2

62

4

.84

4

4.8

37

4

.83

0

4

.24

2

3

.47

9

3.3

23

2

.50

5

1

.52

9

1.5

02

1

.34

0

0

.00

0

5.5

0

4.8

1

5.0

4

5.7

2

10

.16

7.9

3

3.0

8

3.0

0

1.8

3

2.0

2

1.8

2

1.0

2

1.0

1

1.0

1

1.0

0

0.9

9

0.9

2

1.0

0

NH

N NH

NH

O

NH2

O

O

(S) (R)

(S)

* HCl


S43


pyrrolo[2,3-d]pyrimidin-4-one hydrochloride (14b, CD3OD)

abu

nd

an

ce0

0.1

0.2


160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0

16

2.5

06

15

4.4

09

15

3.8

05

13

9.4

12

13

0.5

58

11

8.7

61

11

3.7

88

11

1.9

19

99

.89

3

85

.31

8

81

.97

4

69

.39

2

49

.64

2 4

9.4

22

49

.21

1 4

9.0

00

48

.78

9 4

8.5

69

48

.35

8 4

3.6

53

38

.09

5 3

6.0

25

26

.14

5 2

5.0

24

24

.78

5

NH

N NH

NH

O

NH2

O

O

(S) (R)

(S)

* HCl


S44


pyrrolo[2,3-d]pyrimidin-4-one (14b, CD3OD)

abu

nd

an

ce0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1


7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

6

.64

7

5

.92

7

5.9

17

5

.91

3

5.9

09

5

.84

8

5.8

42

5

.82

7

5.2

41

5

.23

9

5.2

26

5

.22

5

4

.93

1

4.8

88

4

.84

4

4

.55

6

4.5

48

4

.54

1

3

.90

3

3.9

01

3

.79

2

3.7

70

3

.76

6

3.7

59

3

.34

4

3.3

14

3

.31

0

3.3

06

3

.30

1

3.2

97

1

.57

1

1.5

59

1

.55

2

1

.38

1

0

.00

0

1.6

05

.72

5.7

2

0.6

95

.72

0.6

9

5.7

2

0.6

91

3.2

80

.69

13

.05

8.5

7

2.0

3

2.0

0

1.0

1

1.0

0

1.0

0

0.9

90

.99

0.9

9

NH

N NH

NH

O

NH2

O

O

(S) (R)

(S)


S45

(3aS,4R,6aR)-2,2-dimethyl-2H,3aH,4H,6aH-cyclopenta[d][1,3]dioxol-4-ol (15, CDCl3)

abu

nd

an

ce0

1.0

2.0

3.0

4.0

5.0

6.0

7.0

8.0

9.0


8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

7

.26

6

6

.04

2

6.0

28

5

.92

4

5.9

22

5

.91

9

5.9

10

5

.90

7

5.9

04

5

.30

1

5.2

99

5

.28

7

5.2

85

4

.80

8

4.7

94

4

.53

4

4.5

20

1

.94

4

1.9

29

1

.40

3

1.3

53

0

.00

0

3.1

93

.17

1.0

0

1.0

0

1.0

0

1.0

0

0.9

90

.98

OH

O O

(S)

(R)

(R)


S46

(3aR,4S,6aR)-4-bromo-2,2-dimethyl-2H,3aH,4H,6aH-cyclopenta[d][1,3]dioxole (16, CDCl3)

(M

illio

ns)

01

0.0

20

.0


8.0 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

7

.26

4

6

.00

2

6.0

01

5

.99

8

5.9

96

5

.97

1

5.9

69

5

.96

7

5.9

59

5

.33

9

5.3

28

5

.30

2

5.0

04

4

.99

3

4.9

74

4

.96

3

4.9

44

4

.93

3

4.8

79

4

.84

9

4.8

18

1

.38

8

1.3

55

0

.07

0 -

0.0

00

15

.12

5.5

01

5.0

15

.27

15

.12

5.2

7

2.0

0

1.0

1

1.0

10

.98

Br

O O

(S)

(R) (R)


S47

2-Amino-5({[(3a’S,4’R,6a’R)-2,2-dimethyl-4,6a’-dihydro-3a’H-cyclopenta[d][1,3]dioxol-4-yl]amino}methyl)-3,7-dihydro-4H-pyrrolo[2,3-

d]pyrimidin-4-one hydrochloride (17, CD3OD)

(M

illio

ns)

01

.02

.03

.04

.05

.06

.07

.08

.0


7.0 6.0 5.0 4.0 3.0 2.0 1.0 0

6

.88

6

6

.31

1

6.3

08

6

.29

9

6.2

96

6

.00

9

6.0

07

6

.00

4

5.9

98

5

.35

4

5.3

52

5

.34

2

5.3

40

4

.92

4

4.9

12

4

.86

4

4

.41

1

4.3

83

4

.34

6

4.3

19

3

.31

5

3.3

11

3

.30

8

3.3

05

3

.30

1

1

.37

5

1.3

62

0

.00

1

6.0

5

3.0

0

1.1

9

1.0

1

1.0

0

0.9

9

0.9

7

NH

N NH

NH

O

NH2

O

O

(R) (S)

(R)

* HCl


S48

2-Amino-5({[(3a’S,4’R,6a’R)-2,2-dimethyl-4,6a’-dihydro-3a’H-cyclopenta[d][1,3]dioxol-4-yl]amino}methyl)-3,7-dihydro-4H-pyrrolo[2,3-

d]pyrimidin-4-one hydrochloride (17, CD3OD)

ab

un

da

nce

00

.10

.20

.30

.4


160.0 150.0 140.0 130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0 20.0 10.0 0

16

2.6

30

15

4.5

23

15

3.9

50

14

1.0

26

12

8.6

83

11

9.3

83

11

3.5

55

10

9.5

97

99

.71

5

85

.58

9

81

.45

9

69

.09

7

49

.50

6 4

9.3

34

49

.17

2 4

9.0

00

48

.82

8 4

8.6

57

48

.48

5 4

3.2

96

27

.42

4 2

5.6

88

-0

.03

7

NH

N NH

NH

O

NH2

O

O

(R) (S)

(R)

* HCl


concise and efficient syntheses of preq base, q base, and (ent) … · 2012-09-17 · concise and...

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