concise and efficient syntheses of preq base, q base, and (ent) … · 2012-09-17 · concise and...
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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
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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
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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
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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
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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.
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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
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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
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
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
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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
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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
X : parts per Million : 13C
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
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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
X : parts per Million : 1H
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
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S11
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, D2O)
ab
un
da
nce
01
.02
.0
X : parts per Million : 1H
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
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S12
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)
(T
ho
usa
nd
s)0
10
0.0
20
0.0
30
0.0
40
0.0
X : parts per Million : 13C
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
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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
X : parts per Million : 1H
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
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S14
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, D2O)
ab
un
dan
ce0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
X : parts per Million : 1H
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
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S15
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
0.1
0.2
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
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
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S16
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, D2O/CD3OD)
ab
un
dan
ce0
0.0
20
.04
0.0
60
.08
0.1
0.1
20
.14
0.1
60
.18
X : parts per Million : 13C
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
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 1H
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 13C
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 1H
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 13C
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 1H
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 13C
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
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
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
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 13C
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
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 1H
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 1H
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 13C
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
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
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 13C
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 1H
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
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 -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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 1H
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
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
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
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
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 13C
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 1H
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 13C
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 1H
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
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
S39
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)
(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
X : parts per Million : 13C
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
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
S40
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 (14a, CD3OD)
abu
nd
an
ce0
0.1
0.2
0.3
0.4
0.5
0.6
X : parts per Million : 1H
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 1H
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
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
S42
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, DMSO-d6)
abu
nd
an
ce0
1.0
2.0
3.0
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
.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
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
S43
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)
abu
nd
an
ce0
0.1
0.2
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
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
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
S44
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 (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
X : parts per Million : 1H
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 1H
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 1H
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)
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
X : parts per Million : 1H
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
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012
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
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
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
Electronic Supplementary Material (ESI) for Organic & Biomolecular ChemistryThis journal is © The Royal Society of Chemistry 2012