Synthesis of substituted 6-cyclopropylpurine bases and nucleosides by cross-coupling reactions or cyclopropanations

Article abstract of DOI:10.1039/b802833h

Synthesis of novel purine bases and nucleosides bearing unsubstituted or substituted cyclopropyl rings in position 6 is reported. Unsubstituted 6-cyclopropylpurines were efficiently prepared by cross-coupling reactions of 6-chloropurines with cyclopropylzinc chloride. 6-Vinylpurines underwent Cu-mediated cyclopropanations with ethyl diazoacetate to give 6-[(ethoxycarbonyl)cyclopropyl]purines that were further transformed to carboxylic acids, amides and alcohols. 6-Cyclopropylpurine ribonucleoside exerted a significant cytostatic effect while all substituted derivatives were inactive.

Full text of DOI:10.1039/b802833h

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis of substituted 6-cyclopropylpurine bases and nucleosides by
cross-coupling reactions or cyclopropanations†
Martin Kucharˇ, Radek Pohl, Blanka Klepeta´rˇova´, Ivan Votruba and Michal Hocek*
Received 19th February 2008, Accepted 11th April 2008
First published as an Advance Article on the web 2nd May 2008
DOI: 10.1039/b802833h
Synthesis of novel purine bases and nucleosides bearing unsubstituted or substituted cyclopropyl rings
in position 6 is reported. Unsubstituted 6-cyclopropylpurines were efficiently prepared by
cross-coupling reactions of 6-chloropurines with cyclopropylzinc chloride. 6-Vinylpurines underwent
Cu-mediated cyclopropanations with ethyl diazoacetate to give 6-[(ethoxycarbonyl)cyclopropyl]purines
that were further transformed to carboxylic acids, amides and alcohols. 6-Cyclopropylpurine
ribonucleoside exerted a significant cytostatic effect while all substituted derivatives were inactive.
Introduction
Purine bases and nucleosides bearing diverse C-substituents
(aryl, alkenyl, alkynyl or alkyl groups) in position 6 are an
important class of compounds possessing a broad spectrum of
biological effects: e.g. cytostatic,1 antiviral2 and antimicrobial3
activity or receptor modulation.4 6-Methylpurine, as well as its
ribonucleoside, is highly cytotoxic5 and its liberation by purine nu-
cleoside phosphorylases from its non-toxic deoxyribonucleoside
was proposed as a novel principle in the gene therapy of cancer.6
We have been interested in the synthesis of purines bearing func-
tionalized alkyl substituents and reported syntheses and cyto-
static affects of 6-(hydroxymethyl)-,7 6-(fluoromethyl)-8 and 6-(di-
fluoromethyl)purine9 bases and nucleosides and (purin-6-yl)-
alanines10 and -phenylalanines.11 Very recently we have finished
syntheses of a large series of 6-(dialkylamino)methyl-, 6-alko-
xymethyl- and 6-(alkylsulfanylmethyl)purine derivatives,12 as well
Chart 1 Biologically active 6-substituted purine nucleosides.
as homologous 6-(dialkylamino)ethyl-, 6-(dialkylamino)vinyl-, 6-
alkoxyethyl- and 6-[2-(alkylsulfanyl)ethyl]purines13 that also ex-
and substituted 6-cyclopropylpurine bases and nucleosides and
erted significant cytostatic effects and moderate non-selective anti-
HCV activities.
to study their biological activities. The results of our efforts are
presented here.
The cyclopropane ring14 is a privileged pharmacophore present
in a large number of biologically active compounds,15 including
antiviral and antitumor nucleosides.16 Surprisingly, only two
examples of C-linked cyclopropylpurines have been reported.
Free 6-cyclopropylpurine bases were prepared via coupling of
6-chloropurine derivatives with organocuprates followed by de-
protection by Dvorˇa´k et al.17 but no biological activity data were
reported. Several 6-(2-phenylcyclopropyl)purine derivatives were
described by Gundersen et al.18 as inhibitors of 15-lipoxygenase,
and were prepared by cross-coupling of 6-chlorpurines with
phenylcyclopropylzinc halides.
Results and discussion
There are two possible approaches to the construction of 6-
cyclopropylpurines: (i) attachment of the cyclopropyl ring via
cross-coupling or (ii) cyclopropyl ring formation (e.g. by cyclo-
propanation of 6-vinylpurines). We wanted to try both of them
and test their suitability for the synthesis of either unsubstituted
or substituted 6-cyclopropylpurines.
Synthesis of unsubstituted 6-cyclopropylpurine base in a low
yield of 24% has been reported by Dvorˇa´k et al.17 who used a cross-
coupling reaction of 9-(tetrahydropyran-2-yl) (THP) protected 6-
chloropurine with organocuprate derived from cyclopropylmag-
nesium bromide followed by deprotection. We have first tried
classical carbene cyclopropanation19 of 9-benzyl-6-vinylpurine.
Carbene was generated in situ by diethylzinc from diiodomethane
in various solvents under various conditions but all these attempts
led only to complex mixtures of products. Then we studied the
Negishi cross-coupling reactions of 9-benzyl-6-chlorpurines 1a
with cyclopropylzinc chloride (Scheme 1, Table 1). The organozinc
Therefore, as a logical extension of our previous studies
(Chart 1), we have decided to prepare a series of unsubstituted
Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the
Czech Republic, Gilead & IOCB Research Center, Flemingovo nam. 2, CZ-
16610 Prague 6, Czech Republic. E-mail: hocek@uochb.cas.cz; Fax: +420
220183559; Tel: +420 220183324
† Electronic supplementary information (ESI) available: Complete exper-
imental part and characterization data, crystal data in cif format, CCDC
numbers 677191 and 677192. See DOI: 10.1039/b802833h
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Scheme 1 Synthesis of 6-cyclopropylpurines.
Table 1 The Neghishi cross coupling reactions
Scheme 2 Cyclopropanations of 6-vinylpurines with ethyl diazoacetate.
Entry
Starting compound
Product
Yield (%)
benzyl-6-[2-(ethoxycarbonyl)cyclopropyl]purine (4a) and the open
ring byproduct 5a (entries 2,3). On the other hand, in toluene
at ca. 100 ◦C the reaction proceeded relatively smoothly to
give substituted cyclopropylpurine 4a in a good yield of 75%
(entry 4). Then, analogous reactions with ethyl diazoacetate
were performed with THP-protected 6-vinylpurine 3b and silyl-
protected 6-vinylpurine nucleosides 3e,f to give the desired 6-
[2-(ethoxycarbonyl)-cyclopropyl]purines 4b,e,f in moderate but
acceptable yields of 41–60% (entries 5–7). The corresponding
minor (estimated 5–10% by TLC) diazenylacrylates 5, as well as
polymeric by-products, were observed on TLC but not isolated.
In all cases, the reactions proceeded stereoselectively to give trans
relative configuration at the cyclopropyl ring. However, in the
case of nucleosides, there was no asymmetric induction due to the
homochiral sugar part and the products 4e,f were (inseparable)
diastereomeric mixtures (1 : 1). In the case of 10h, the initially
formed 1 : 1 mixture was by repeated column chromatography
enriched to 2 : 1.
1
2
3
4
1a
1b
1c
1d
2a
2b
2c
2d
88
83
99
99
was generated in situ from cyclopropylmagnesium bromide and
zinc chloride at −10 ◦C and reacted with 1a at 40 ◦C in the presence
of Pd(PPh3)4 in THF for 2 h to give 6-cyclopropylpurine 2a in
excellent 88% yield. This procedure was then applied for THP-
protected 6-chloropurine 1b, as well as for 4-methylbenzoyl (Tol)
protected 6-chloropurine nucleosides 1c,d. In all cases, the desired
protected 6-cyclopropylpurine base 2b and nucleosides 2c,d were
obtained in excellent to quantitative yields (83–99%).
In order to have access to diverse substituted 6-
cyclopropylpurines, we have further studied cyclopropanations
of 6-vinylpurines with ethyl diazoacetate (Scheme 2, Table 2).
The reaction of 9-benzyl-6-vinylpurine (3a) with ethyldiazoacetate
20
was tested in the presence of either Rh2(OAc)4 catalyst or Cu
powder21 under various conditions. The rhodium catalyst (entry 1)
rapidly decomposed ethyl diazoacetate and we obtained complex
mixture of products. More promising was the use of Cu powder.
In dioxane, the reaction at 70 ◦C led to mixtures of the desired 9-
Having gained an access to ester intermediates 4a,b,e,f, we
have further studied functional group transformations leading to
amides, carboxylic acids and alcohols. The amidations of the esters
4a,b,e,f were performed with several amines in the presence of
Table 2 Cyclopropanations of 6-vinylpurines with ethyl diazoacetate
Entry
Starting compound
Solvent
Catalyst
Conditions
Results
1
2
3
4
5
6
7
3a
3a
3a
3a
3b
3e
3f
CH2Cl2
Dioxane
Dioxane
Toluene
Toluene
Toluene
Toluene
Rh2(OAc)4
Rt, 1h
Decomposition
4a (trace), 5a (29%),
4a (53%), 5a (9%)
4a (75%), 5a (trace)
4b (41%)
Cu
Cu
Cu
Cu
Cu
Cu
70 ◦C, 8 h
70 ◦C, 2 d
95 ◦C, 6 h
100 ◦C, 2 h
100 ◦C, 2 h
100 ◦C, 2 h
4e (60%)
4f (44%)
2378 | Org. Biomol. Chem., 2008, 6, 2377–2387
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22
Table 4 Deprotections
AlCl3 in dichloromethane (Scheme 3). The reactions proceeded
smoothly at ambient temperature and the desired products 6–8
were isolated in high yields (Table 3). The products of reactions
with benzyl(methyl)amine (entries 2 and 6) were in solution
mixtures of 4 diastereoisomeric amide rotamers (NMR).
Entry
Starting compound
Method
Product
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
2b
4b
6b
10b
2c
A
A
A
A
B
B
C
C
C
C
C
C
C
C
2g
4g
6g
10g
2h
2i
4h
4i
6h
7h
8h
6i
47
85
95
21
65
42
75
80
95
98
97
83
76
44
2d
4e
4f
6e
7e
8e
6f
10e
10f
10h
10i
Hydrolysis of esters 4 to carboxylic acids was performed using
NaOH in a water–THF mixture at ambient temperature. For
purine bases 4a and 4g, the corresponding free carboxylic acids 9a
and 9g were successfully isolated in good yields (entries 9, 10). In
the case of protected nucleosides 4e and 4f, complex inseparable
mixtures of partially deprotected products were observed (entries
11, 12).
Reduction of esters 4a,b,e,f to alcohols was performed using a
large excess of NaBH4 (50 equiv.) in ethanol at 60 ◦C. The reactions
proceeded rather slowly (24 h) to give the corresponding alcohols
10a,b,e,f in moderate to good yields of 46–68% (entries 13–16).
DIBAH (2 equiv.) in dry CH2Cl2 at ambient temperature was used
for reduction of free purine base 4g, which proceeded to give 10g
in 65% yield (entry 17).
The whole series of THP-protected purines (2b, 4b, 6b and 10b)
was deprotected by treatment with acidic cation exchanger Dowex
(H+ form) in ethanol (method A, Table 4) to get the corresponding
free purine bases (2g, 4g, 6g and 10g). The toluoyl-protected
nucleosides 2c and 2d were deprotected by treatment with sodium
methoxide in methanol (method B) to afford free nucleosides 2h
and 2i. The TBS-protected nucleosides (6–8e, 6f, 10e and 10f) were
deprotected by treatment with Et3N·3HF in THF (method C). In
certain cases (entries 1, 4, 6 and 14), the isolated yields were quite
low due to difficult isolation of the polar final products by column
chromatography.
Scheme 3 Transformations of the ester function.
Table 3 Transformations of the ester function
All compounds were fully characterized. Crystal structures
of cyclopropylpurines 2g and 6a were determined by X-ray
crystallography confirming the trans-relative configuration on the
cyclopropane in 6a (Fig. 1).
Starting
compound
Entry
Reagent
Product
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4a
4a
4a
4b
4e
4e
4e
4f
4a
4g
4e
4f
Et2NH, AlCl3
Bn(Me)NH, AlCl3
Morpholine, AlCl3
Et2NH, AlCl3
Et2NH, AlCl3
Bn(Me)NH, AlCl3
Morpholine, AlCl3
Et2NH, AlCl3
NaOH
NaOH
NaOH
NaOH
NaBH4
6a
89
85
82
66
85
65
76
71
81
80
All the title cyclopropylpurine bases and nucleosides 3, 4, 6–10
were evaluated for biological activity. Cytostatic activity in vitro
(inhibition of cell growth) was studied on the following cell cul-
tures: (i) mouse leukaemia L1210 cells (ATCC CCL 219); human
promyelocytic leukemia HL60 cells (ATCC CCL 240); human
cervix carcinoma HeLaS3 cells (ATCC CCL 2.2) and human T
lymphoblastoid CCRF-CEM cell line (ATCC CCL 119). Antiviral
activities were tested in HCV genotype 1b replicon.23 Unsubsti-
tuted 6-cyclopropylpurine ribonucleoside 2h showed significant
7a
8a
6b
6e
7e
8e
6f
9a
9g
Mixture
Mixture
10a
10b
10e
10f
10g
cytostatic effect, IC50(L1210) = 4.89
0.35 lM, IC50(HL60) =
4a
4b
4e
4f
57
57
68
46
65
11.94
0.78 lM and IC50(CEM) = 0.92
0.07 lM (which
NaBH4
NaBH4
NaBH4
DIBAH
is comparable to 6-methylpurine ribonucleoside5) and a non-
selective anti-HCV effect in replicon, EC50 = 3.4 lM, CC50 (huh-
7) > 100 lM. On the other hand, free 6-cyclopropylpurine base 2g
4g
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according to literature procedures: 1a,24 1b,25 1c,8 1d,26 3a,27 3b,28
3e.29
General method for the Negishi cross-coupling
THF (3 ml) was added to flame–vacuum dried zinc chloride
(272 mg, 2 mmol) under argon atmosphere. The mixture was
stirred at −10 ◦C and a cyclopropylmagnesium bromide (4 ml,
0.5 M in THF) was added dropwise. The mixture was stirred
for 40 min and then a solution of a 6-chloropurine 1 (1 mmol)
and Pd(PPh3)4 (70 mg, 0.06 mmol) in THF (3 ml) was added.
The resulting mixture was stirred for 2 hours at 40 ◦C. After
completion, the reaction mixture was diluted with water (50 ml)
and washed with ethyl acetate (3 × 50 ml). The collected
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, ethyl
acetate/hexane 0–30%) and crystallized from chloroform–heptane
to give the product.
Fig. 1 ORTEP drawings of crystal structures of 2g (a) and 6a (b)
with atom numbering scheme. Thermal ellipsoids are drawn at the 50%
probability level.
was inactive (in contrast to strongly cytotoxic 6-methylpurine5).
This indicates that the mechanism of action of these two very re-
lated compounds (6-methyl and 6-cyclopropylpurine nucleosides)
might be different. All the other compounds including the 2ꢀ-
deoxyribonucleosides and all the compounds with a substituted
cyclopropyl ring were entirely inactive in the above mentioned
assays at 10 lM concentrations.
9-Benzyl-6-cyclopropylpurine (2a)
White solid, yield 88%. 1H NMR (600 MHz, CDCl3): 1.24 and 1.43
(2 × m, 2 × 2H, H-2,3-cycloprop); 2.78 (tt, 1H, Jvic = 8.2, 4.7 Hz,
H-1-cycloprop); 5.43 (s, 2H, CH2Ph); 7.28–7.38 (m, 5H, Ph); 7.98
(s, 1H, H-8); 8.80 (s, 1H, H-2). 13C NMR (151 MHz, CDCl3): 11.54
(CH2-2,3-cycloprop); 12.97 (CH-1-cycloprop); 47.13 (CH2Ph);
127.73 (CH-o-Ph); 128.49 (CH-p-Ph); 129.09 (CH-m-Ph); 132.25
(C-5); 135.29 (C-i-Ph); 143.15 (CH-8); 150.01 (C-4); 152.75 (CH-
2); 164.34 (C-6). FAB-MS, m/z (rel.%) 279 (6) [M + Na]+, 251
(100) [M + H]+, 161 (10), 91 (75). HRMS calcd for C15H15N4 [M +
H]+ 251.1296; found: 251.1287. IR (CHCl3): 3112, 3093, 3069,
3035, 1595, 1580, 1500, 1457, 1412, 1331, 1078, 1030, 806, 700,
651, 619, 542, 456.
Conclusions
In conclusion, two approaches to the construction of 6-
cyclopropylpurines have been studied. Cross-coupling of 6-
chloropurines with cyclopropylzinc chloride was used for
the synthesis of unsubstituted 6-cyclopropylpurines, while
a
Cu-mediated cyclopropanation of 6-vinylpurines with
ethyl diazoacetate was used for the synthesis of 6-[2-
(ethoxycarbonyl)cyclopropyl]purines. Further functional group
transformation of the esters led to amides, carboxylic acids
and alcohols. A series of modified cyclopropylpurine bases and
nucleosides has been prepared and tested for biological activity.
Only unsubstituted 6-cyclopropylpurine ribonucleoside 2h showed
significant cytostatic and anti-HCV effects.
6-Cyclopropyl-9-(2,3,5-tri-O-toluoyl-b-D-ribofuranosyl)purine (2c)
1
White foam, yield 99%. H NMR (500 MHz, CDCl3): 1.22 and
1.41 (2 × m, 2 × 2H, H-2,3-cycloprop); 2.37 and 2.41 (2 × s, 9H,
CH3-Tol); 2.74 (tt, 1H, Jvic = 8.2, 4.7, H-1-cycloprop); 4.67 (dd,
1H, Jgem = 12.2, J5 b,4 = 4.2 Hz, H-5ꢀb); 4.81 (ddd, 1H, J4 ,3 = 4.6,
ꢀ
ꢀ
ꢀ ꢀ
J4 ,5 = 4.2, 3.2 Hz, H-4ꢀ); 4.88 (dd, 1H, Jgem = 12.2, J5 a,4 = 3.2 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
H-5ꢀa); 6.22 (dd, 1H, J3 ,2 = 5.8, J3 ,4 = 4.6 Hz, H-3ꢀ); 6.40 (dd,
ꢀ
ꢀ
ꢀ ꢀ
1H, J2 ,3 = 5.8, J2 ,1 = 5.4 Hz, H-2ꢀ); 6.47 (d, 1H, J1 ,2 = 5.4 Hz,
H-1ꢀ); 7.16, 7.21 and 7.25 (3 × m, 3 × 2H, H-m-Tol); 7.82, 7.90
and 7.99 (3 × m, 3 × 2H, H-o-Tol); 8.15 (s, 1H, H-8); 8.68 (s, 1H,
H-2). 13C NMR (125.7 MHz, CDCl3): 11.62 and 11.66 (CH2-2,3-
cycloprop); 13.00 (CH-1-cycloprop); 21.69 and 21.71 (CH3-Tol);
63.48 (CH2-5ꢀ); 71.41 (CH-3ꢀ); 73.64 (CH-2ꢀ); 80.90 (CH-4ꢀ); 86.69
(CH-1ꢀ); 125.67, 126.02 and 126.57 (C-i-Tol); 129.19, 129.23 and
129.30 (CH-m-Tol); 129.75, 129.85 and 129.86 (CH-o-Tol); 132.96
(C-5); 141.91 (CH-8); 144.15, 144.52 and 144.62 (C-p-Tol); 149.66
(C-4); 152.82 (CH-2); 164.77 (C-6); 165.15, 165.37 and 166.21
(CO). FAB-MS, m/z (rel.%) 647 (50) [M + H]+, 529 (10), 487 (22),
369 (10), 295 (10), 279 (20), 197 (10), 181 (26), 161 (18), 149 (10),
119 (100), 93 (30), 73 (20). HRMS calcd for C37H35N4O7 [M + H]+
647.2505; found: 647.2494. IR (CHCl3): 3117, 3095, 3033, 1727,
1612, 1596, 1580, 1509, 1500, 1412, 1371, 1332, 1311, 1298, 1245,
1193, 1180, 1126, 1114, 1020, 839, 806, 691, 645, 476.
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
Experimental
Melting points were determined on a Kofler block and are uncor-
rected. Mass spectra were measured on aZAB-EQ(VGAnalytical)
spectrometer. IR spectra were measured on a Bruker equinox 55
and FTIR spectrometer Nicolet 6700. NMR spectra were recorded
on Bruker Avance 600 (1H at 600 MHz, 13C at 151 MHz), Bruker
Avance 500 (1H at 500 MHz, 13C at 125.8 MHz) and Bruker Avance
1
400 (1H at 400 MHz, 13C at 100.6 MHz) spectrometers. H and
13C NMR spectra were referenced to the signal of TMS or to the
solvent residual signal [DMSO-d6: 2.50 ppm (1H), 39.70 ppm (13C);
CD3OD: 3.31 ppm (1H); 49.00 ppm (13C)]. H,C-HSQC and H,C-
HMBC experiments were performed for complete assignment of
all signals. Optical rotations were measured at 25 ◦C on an Autopol
IV (Rudolph Research Analytical) polarimeter, [a]D values are
given in 10−1 deg cm2 g−1. Starting compounds were prepared
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6-Cyclopropyl-9-(2-deoxy-3,5-di-O-toluoyl-b-D-erythro-
pentafuranosyl)purine (2d)
3.84 (dd, 1H, Jgem = 17.5, Jvic = 5.0 Hz, CHaHb-pur); 4.21 (q, 2H,
=
Jvic = 7.1 Hz, CH3CH2O); 4.54 (dd, 1H, Jvic = 12.3, 5.0 Hz, CH );
5.47 (s, 2H, CH2Ph); 6.99 (bs, 1H, NH); 7.26–7.40 (m, 5H, Ph);
8.11 (s, 1H, H-8); 8.97 (s, 1H, H-2). 13C NMR (100.6 MHz, CDCl3):
1
White foam, yield 99%. H NMR (500 MHz, CDCl3): 1.23 and
1.41 (2 × m, 2 × 2H, H-2,3-cycloprop); 2.41 and 2.44 (2 × s, 2 ×
=
14.09 (CH3CH2O); 35.63 (CH2-pur); 47.25 (CH2Ph); 60.61 (CH );
3H, CH3-Tol); 2.75 (tt, 1H, Jvic = 8.2, 4.7 Hz, H-1-cycloprop); 2.84
61.89 (CH3CH2O); 127.69 (CH-o-Ph); 128.57 (CH-p-Ph); 129.12
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(ddd, 1H, Jgem = 14.2, J2 b,1 = 5.8, J2 b,3 = 2.2 Hz, H-2 b); 3.19 (ddd,
(CH-m-Ph); 130.05 (C-5); 135.08 (C-i-Ph); 145.06 (CH-8); 148.87
1H, Jgem = 14.2, J2 a,1 = 8.4, J2 a,3 = 6.4 Hz, H-2ꢀa); 4.63–4.70 (m,
ꢀ
ꢀ
ꢀ
ꢀ
=
and 148.94 (C-6 and C–N NH); 152.06 (C-4); 152.44 (CH-2);
2H, H-4ꢀ and H-5ꢀb); 4.76 (m, 1H, Jgem = 11.4, J5 a,4 = 3.5, H-5ꢀa);
ꢀ
ꢀ
172.04 (CO). ESI-MS, m/z (rel.%) 373 (95) [M + Na]+, 351 (30)
[M + H]+, 316 (37), 288 (100). HRMS calcd for C18H18N6O2Na
[M + Na]+ 373.13889; found 373.13812. IR (micr. refl.): 3282,
2980, 2930, 1727, 1599, 1541, 1499, 1455, 1409, 1383, 1366, 1328,
1264, 1212, 1186, 1158, 1097, 1057, 995, 927, 883, 844, 806, 775,
760, 730, 697.
5.83 (ddd, 1H, J3 ,2 = 6.4, 2.2, J3 ,4 = 2.0 Hz, H-3ꢀ); 6.59 (dd, 1H,
ꢀ
ꢀ
ꢀ ꢀ
J1 ,2 = 8.4, 5.8 Hz, H-1ꢀ); 7.22 and 7.28 (2 × m, 2 × 2H, H-m-Tol);
7.90 and 7.97 (2 × m, 2 × 2H, H-o-Tol); 8.17 (s, 1H, H-8); 8.71 (s,
1H, H-2). 13C NMR (125.7 MHz, CDCl3): 11.57 and 11.58 (CH2-
2,3-cycloprop); 12.96 (CH-1-cycloprop); 21.66 and 21.71 (CH3-
Tol); 37.72 (CH2-2ꢀ); 63.98 (CH2-5ꢀ); 75.12 (CH-3ꢀ); 82.99 (CH-4ꢀ);
84.74 (CH-1ꢀ); 126.36 and 126.62 (C-i-Tol); 129.25 and 129.26
(CH-m-Tol); 129.61 and 129.78 (CH-o-Tol); 132.98 (C-5); 141.46
(CH-8); 144.11 and 144.50 (C-p-Tol); 149.45 (C-4); 152.57 (CH-2);
164.61 (C-6); 165.93 and 166.14 (CO). FAB-MS, m/z (rel.%) 535
(5) [M + Na]+, 513 (15) [M + H]+, 161 (80), 119 (100), 91 (15),
81 (65). HRMS calcd for C29H31N4O6 [M + H]+ 513.2137; found:
513.2160. IR (CHCl3): 3126, 3096, 3063, 1721, 1612, 1596, 1582,
1509, 1498, 1411, 1332, 1311, 1250, 1191, 1179, 1121, 1103, 1021,
841, 806, 691, 646, 476.
ꢀ
ꢀ
6-[2-(Ethoxycarbonyl)cyclopropyl]-9-(2,3,5-tri-O-tert-
butyldimethylsilyl-b-D-ribofuranosyl)purine (4e)
1
Yellow oil, yield 60%. Diastereomeric mixture 1 : 1. H NMR
(600 MHz, CDCl3): −0.25, −0.23, −0.041, −0.036, 0.096, 0.100,
0.104, 0.106, 0.139, 0.143, 0.148 and 0.153 (12 × s, 12 × 3H,
CH3Si); 0.79, 0.80, 0.93, 0.94, 0.960 and 0.963 (6 × s, 6 ×
9H, (CH3)3C); 1.275 and 1.277 (2 × t, 2 × 3H, Jvic = 7.1 Hz,
CH3CH2O); 1.811 and 1.813 (2 × ddd, 2 × 1H, Jvic = 8.9, 5.8,
Jgem = 3.37 Hz, H-3b-cycloprop); 1.86 and 1.87 (2 × ddd, 2 × 1H,
Jvic = 8.6, 6.0, Jgem = 3.7 Hz, H-3a-cycloprop); 2.59 and 2.60 (2 ×
ddd, 2 × 1H, Jvic = 8.6, 5.8, 3.9 Hz, H-2-cycloprop); 3.34 and 3.35
(2 × ddd, 2 × 1H, Jvic = 8.9, 6.0, 3.9 Hz, H-1-cycloprop); 3.79 and
General method for cyclopropanation of 6-vinylpurines
A mixture of a vinylpurine 3 (0.5 mmol) and copper powder
(10 mg, 0.15 mmol) in dry toluene (5 ml) was heated to 95 ◦C under
stirring. Then ethyldiazoacetate (0.3 ml, 2.5 mmol) was added at
once. The mixture was further stirred at 95 ◦C for 6 h. The solids
were removed by filtration, the filtrate was evaporated and purified
by column chromatography (silica gel, ethyl acetate/hexane 0–
30%).
3.80 (2 × dd, 2 × 1H, Jgem = 11.4, J5 b,4 = 2.7 Hz, H-5ꢀb); 4.02
ꢀ
ꢀ
and 4.03 (2 × dd, 2 × 1H, Jgem = 11.4, J5 a,4 = 3.9 Hz, H-5ꢀa); 4.14
ꢀ
ꢀ
(ddd, 2H, J4 ,5 = 3.9, 2.7, J4 ,3 = 3.7 Hz, H-4ꢀ); 4.17 and 4.18 (2 ×
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
ꢀ
q, 2 × 2H, Jvic = 7.1 Hz, CH3CH2O); 4.32 (dd, 2H, J3 ,2 = 4.4,
J3 ,4 = 3.7 Hz, H-3ꢀ); 4.64 and 4.67 (2 × dd, 2 × 1H, J2 ,1 = 5.1,
ꢀ
ꢀ
ꢀ ꢀ
J2 ,3 = 4.4 Hz, H-2ꢀ); 6.10 and 6.11 (2 × d, 2 × 1H, J1 ,2 = 5.1 Hz,
H-1ꢀ); 8.40 and 8.41 (2 × s, 2 × 1H, H-8); 8.75 (s, 2H, H-2). 13C
NMR (151 MHz, CDCl3): −5.37, −5.04, −4.99, −4.75, −4.73,
−4.69 and −4.42 (CH3Si); 14.20 (CH3CH2O); 17.82, 17.83, 18.07,
18.16, 18.53 and 18.54 ((CH3)3C and CH2-3-cycloprop); 22.54
and 22.56 (CH-1-cycloprop); 25.21 and 25.26 (CH-2-cycloprop);
25.63, 25.64, 25.82 and 26.08 ((CH3)3C); 60.85 (CH3CH2O); 62.41
and 62.46 (CH2-5ꢀ); 71.81 and 71.90 (CH-3ꢀ); 75.86 and 75.88
(CH-2ꢀ); 85.40 and 85.50 (CH-4ꢀ); 88.21 and 88.22 (CH-1ꢀ); 132.94
(C-5); 142.88 and 142.93 (CH-8); 150.27 (C-4); 152.33 (CH-2);
159.94 and 159.95 (C-6); 172.43 (CO). FAB-MS, m/z (rel.%) 729
(10) [M + Na]+, 707 (14) [M + H]+, 231 (10), 177 (25), 154 (32),
137 (25), 109 (10), 89 (7), 73 (100), 59 (11). HRMS calcd for
C34H63N4O6Si3 [M + H]+ 707.4055; found: 707.4045. IR (CHCl3):
3118, 3066, 1723, 1596, 1581, 1499, 1472, 1463, 1408, 1390, 1363,
1327, 1258, 1186, 1168, 1110, 1084, 1070, 939, 839, 813, 647.
ꢀ
ꢀ
ꢀ ꢀ
9-Benzyl-6-[2-(ethoxycarbonyl)cyclopropyl]purine (4a)
Light yellow crystals, yield 75%, mp 83–89 ◦C. 1H NMR
(400 MHz, CDCl3): 1.27 (t, 3H, Jvic = 7.2 Hz, CH3CH2O); 1.82
(ddd, 1H, Jvic = 8.9, 5.8, Jgem = 3.7 Hz, 3b-cycloprop); 1.90
(ddd, 1H, Jvic = 8.6, 5.9, Jgem = 3.7 Hz, 3a-cycloprop); 2.60
(ddd, 1H, Jvic = 8.6, 5.8, 3.9 Hz, 2-cycloprop); 3.34 (dddd, 1H,
Jvic = 8.9, 5.9, 3.9, JCH,2 = 0.3 Hz, 1-cycloprop); 4.17 (m, 2H,
CH3CH2O); 5.44 (s, 2H, CH2Ph); 7.29 (m, 2H, H-o-Ph); 7.31–
7.38 (m, 3H, H-m,p-Ph); 8.01 (s, 1H, H-8); 8.81 (s, 1H, H-2).
13C NMR (100.6 MHz, CDCl3): 14.19 (CH3CH2O); 17.95 (CH2-
3-cycloprop); 22.62 (CH2-1-cycloprop); 25.31 (CH2-2-cycloprop);
47.22 (CH2Ph); 60.85 (CH3CH2O); 127.74 (CH-o-Ph); 128.57
(CH-p-Ph); 129.12 (CH-m-Ph); 132.28 (C-5); 135.12 (C-i-Ph);
143.77 (CH-8); 150.54 (C-4); 152.60 (CH-2); 160.09 (C-6); 172.37
(CO). FAB-MS, m/z (rel.%) 323 (62) [M + H]+, 249 (8), 159 (10),
91 (100), 63 (6). HRMS calcd for C18H19N4O2 [M + H]+ 323.1508;
found: 323.1520. IR (CHCl3): 3112, 3092, 3069, 3032, 1723, 1596,
1583, 1502, 1477, 1456, 1410, 1403, 1386, 1367, 1327, 1185, 1105,
1090, 1079, 1030, 699, 651, 642, 619, 542, 455.
General method for amidation of esters
A suspension of dry AlCl3 (267 mg, 2 mmol) in dichloromethane
(4 ml) was cooled to 0 ◦C followed by addition of an amine
(5 mmol). The reaction mixture was stirred for 10 min at 0 ◦C
until AlCl3 was dissolved. Then a solution of ester 4a (or 4b, 4e,
4f) (1 mmol) in dichloromethane (2 ml) was added in one go. The
resulting mixture was stirred for 1 h at ambient temperature. After
completion, the reaction mixture was diluted with water (50 ml),
9-Benzyl-6-[3-diazenyl-3-(ethoxycarbonyl)prop-2-enyl]purine (5a)
Yellow solid. 1H NMR (400 MHz, CDCl3): 1.29 (t, 3H, Jvic = 7.1,
CH3CH2O); 3.58 (dd, 1H, Jgem = 17.5, Jvic = 12.3 Hz, CHaHb-pur);
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and then washed with ethyl acetate (3 × 50 ml). The collected
organic layers were washed with brine, dried over anhydrous
MgSO4, filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel, ethyl
acetate/hexane 0–30%) and crystallized from chloroform–heptane
to give the product.
756 (35) [M + Na]+, 734 (60) [M + H]+, 718 (12), 676 (12), 416 (12),
147 (10), 89 (6), 73 (100), 59 (12). HRMS calcd for C36H68N5O5Si3
[M + H]+ 734.4528; found: 734.4536. IR (CHCl3): 3118, 3064,
2898, 1629, 1595, 1580, 1497, 1485, 1471, 1463, 1410, 1382, 1363,
1327, 1258, 1083, 1072, 939, 839, 681, 647.
General method for ester reduction
9-Benzyl-6-[2-(diethylcarbamoyl)cyclopropyl]purine (6a)
A mixture of ester 4a (or 4b, 4e, 4f) (1 mmol) and NaBH4
(1.89 g, 50 mmol) in dry ethanol (50 ml) was heated to 60 ◦C
under argon atmosphere for 1 day. After completion, the reaction
mixture was diluted with aqueous saturated solution of NH4Cl
(200 ml), and then washed with ethyl acetate (3 × 50 ml).
The collected organic layers were washed with brine, dried over
anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, ethyl acetate/hexane 0–30%) and crystallized from
chloroform–heptane.
◦
1
White crystals, mp 94–97 C, yield 89%. H NMR (600 MHz,
CDCl3): 1.12 and 1.18 (2 × t, 2 × 3H, Jvic = 7.1 Hz, CH3CH2N);
1.74 (ddd, 1H, Jvic = 8.5, 5.6, Jgem = 3.2 Hz, H-3b-cycloprop); 1.90
(ddd, 1H, Jvic = 8.9, 5.8, Jgem = 3.2 Hz, H-3a-cycloprop); 2.80 (ddd,
1H, Jvic = 8.5, 5.8, 4.0 Hz, H-2-cycloprop); 3.31 (ddd, 1H, Jvic
=
8.9, 5.6, 4.0 Hz, H-1-cycloprop); 3.35–3.50 (m, 4H, CH3CH2N);
5.43 (s, 2H, CH2Ph); 7.29–7.38 (m, 5H, Ph); 8.01 (s, 1H, H-8);
8.82 (s, 1H, H-2). 13C NMR (151 MHz, CDCl3): 13.18 and 14.83
(CH3CH2N); 18.23 (CH2-3-cycloprop); 22.12 (CH-1-cycloprop);
23.84 (CH-2-cycloprop); 40.91 and 42.15 (CH3CH2N); 47.18
(CH2Ph); 127.77 (CH-o-Ph); 128.52 (CH-p-Ph); 129.08 (CH-m-
Ph); 132.36 (C-5); 135.16 (C-i-Ph); 143.62 (CH-8); 150.41 (C-4);
152.55 (CH-2); 161.34 (C-6); 169.92 (CO). FAB-MS, m/z (rel.%) =
350 (94) [M + H]+ (cation), 277 (40), 249 (15), 159 (10), 91 (100),
74 (5). HRMS calcd for C20H24N5O [M + H]+ 350.1980; found:
350.1978. Anal. calcd for C20H23N5O: C 68.74, H 6.63, N 20.04.
Found: C 68.42, H 6.47, N 19.82%. IR (CHCl3): 3112, 3092, 3069,
3035, 1630, 1603, 1595, 1579, 1500, 1456, 1423, 1410, 1382, 1329,
1079, 1030, 808, 701, 642, 619, 454.
9-Benzyl-6-[2-(hydroxymethyl)cyclopropyl]purine (10a)
Chromatography methanol/chloroform 0–10%, white crystals,
mp 103–104 ◦C, yield 57%. 1H NMR (600 MHz, DMSO-d6): 1.18
(ddd, 1H, Jvic = 8.5, 6.2, Jgem = 3.5 Hz, H-3b-cycloprop); 1.40
(ddd, 1H, Jvic = 8.4, 4.8, Jgem = 3.5 Hz, H-3a-cycloprop); 1.92
(m, 1H, H-2-cycloprop); 2.59 (ddd, 1H, Jvic = 8.5, 4.8, 4.2 Hz,
H-1-cycloprop); 3.44 and 3.58 (2 × dt, 2H, Jgem = 11.3, Jvic
=
5.6 Hz, CH2O); 4.74 (t, 1H, Jvic = 5.6, OH); 5.48 (2H, CH2Ph);
7.26–7.35 (m, 5H, Ph); 8.63 (s, 1H, H-8); 8.69 (s, 1H, H-2). 13C
NMR (151 MHz, DMSO-d6): 15.56 (CH2-3-cycloprop); 18.21
(CH-1-cycloprop); 27.44 (CH-2-cycloprop); 46.56 (CH2Ph); 62.81
(CH2O); 127.74 (CH-o-Ph); 128.08 (CH-p-Ph); 128.96 (CH-m-Ph);
131.67 (C-5); 136.89 (C-i-Ph); 145.41 (CH-8); 149.96 (C-4); 152.24
(CH-2); 162.44 (C-6). FAB-MS, m/z (rel.%) = 281 (100) [M + H]+
(cation), 263 (10), 220 (5), 91 (100). HRMS calcd for C16H17N4O
[M + H]+ 281.1402; found: 281.1406. IR (KBr): 3424, 3228, 1600,
1581, 1510, 1497, 1454, 1410, 1329, 1217, 1080, 1030, 1002, 812,
732, 697, 618, 466.
6-[2-(Diethylcarbamoyl)cyclopropyl]-9-(2,3,5-tri-O-tert-
butyldimethylsilyl-b-D-ribofuranosyl)purine (6e)
1
White foam, yield 85%. Diastereomeric mixture 1 : 1. H NMR
(600 MHz, CDCl3): −0.27, −0.24, −0.046, −0.039, 0.100, 0.103,
0.108, 0.112, 0.138, 0.142, 0.145 and 0.151 (12 × s, 12 × 3H,
CH3Si); 0.78, 0.79, 0.937, 0.939, 0.958 and 0.963 (6 × s, 6 × 9H,
(CH3)3C); 1.130, 1.131, 1.150 and 1.152 (4 × t, 4 × 3H, Jvic
=
7.2 Hz, CH3CH2N); 1.738 and 1.740 (2 × ddd, 2 × 1H, Jvic = 8.4,
5.6, Jgem = 3.3 Hz, H-3b-cycloprop); 1.90 and 1.91 (2 × ddd, 2 ×
1H, Jvic = 8.1, 5.7, Jgem = 3.3, H-3a-cycloprop); 2.77 and 2.79 (2 ×
ddd, 2 × 1H, Jvic = 8.4, 5.7, 4.0 Hz, H-2-cycloprop); 3.286 and
3.290 (2 × ddd, 2 × 1H, Jvic = 8.1, 5.6, 4.0 Hz, H-1-cycloprop);
6-[2-(Hydroxymethyl)cyclopropyl]-9-(2,3,5-tri-O-tert-
butyldimethylsilyl-b-D-ribofuranosyl)purine (10e)
1
White foam, yield 68%. Diastereomeric mixture 1 : 1. H NMR
ꢀ
ꢀ
3.37–3.50 (m, 8H, CH3CH2N); 3.80 (dd, 2H, Jgem= 11.4, J5 b,4
=
=
(600 MHz, CDCl3): −0.23, −0.21, −0.04, −0.03, 0.100, 0.101,
0.106, 0.109, 0.14 and 0.15 (10 × s, 36H, CH3Si); 0.79, 0.80, 0.94
and 0.96 (4 × s, 54H, (CH3)3C); 1.21 and 1.67 (2 × m, 2 × 2H, H-
3-cycloprop); 2.13 (m, 2H, H-2-cycloprop); 2.74 (dt, 2H, Jvic = 8.8,
4.6 Hz, H-1-cycloprop); 3.65 (dd, 1H, Jgem = 11.5, Jvic = 7.1 Hz,
2.7, H-5ꢀb); 4.02 and 4.03 (2 × dd, 2 × 1H, Jgem = 11.4, J5 a,4
ꢀ
ꢀ
4.0 Hz, H-5ꢀa); 4.13–4.16 (m, 2H, H-4ꢀ); 4.32 and 4.34 (2 × dd,
2 × 1H, J3 ,2 = 4.3, J3 ,4 = 3.6 Hz, H-3ꢀ); 4.64 and 4.67 (2 ×
ꢀ
ꢀ
ꢀ ꢀ
dd, 2 × 1H, J2 ,1 = 5.3, J2 ,3 = 4.3, H-2ꢀ); 6.10 and 6.11 (2 × d,
ꢀ
ꢀ
ꢀ ꢀ
2 × 1H, J1 ,2 = 5.3, H-1ꢀ); 8.38 and 8.41 (2 × s, 2 × 1H, H-8);
8.76 (s, 2H, H-2). 13C NMR (151 MHz, CDCl3): −5.40, −5.13,
−5.09, −4.75, −4.73, −4.71, −4.69, −4.45 and −4.44 (CH3Si);
13.22 and 14.80 (CH3CH2N); 17.80 ((CH3)3C); 18.02 (CH2-3-
cycloprop); 18.05 ((CH3)3C); 18.11 (CH2-3-cycloprop); 18.50 and
18.51 ((CH3)3C); 22.19 and 22.25 (CH-1-cycloprop); 23.92 and
24.01 (CH-2-cycloprop); 25.61, 25.81, 26.05 and 26.06 ((CH3)3C);
40.97 and 42.18 (CH3CH2N); 62.45 and 62.47 (CH2-5ꢀ); 71.85 and
71.91 (CH-3ꢀ); 75.77 and 75.96 (CH-2ꢀ); 85.48 and 85.53 (CH-4ꢀ);
88.10 and 88.14 (CH-1ꢀ); 132.946 and 132.254 (C-5); 142.69 and
142.80 (CH-8); 150.18 (C-4); 152.30 and 152.31 (CH-2); 161.18
and 161.22 (C-6); 169.99 and 170.00 (CO). FAB-MS, m/z (rel.%)
CHaHbO); 3.79 and 3.80 (2 × dd, 2 × 1H, Jgem= 11.3, J5 b,4
=
ꢀ
ꢀ
ꢀ
ꢀ
2.6 Hz, H-5ꢀb); 3.81 (dd, 1H, Jgem = 11.5, Jvic = 6.0 Hz, CHaHbO);
ꢀ
ꢀ
4.03 and 4.04 (2 × dd, 2 × 1H, Jgem = 11.3, J5 a,4 = 3.9 Hz, H-
5ꢀa); 4.14 (ddd, 2H, J4 ,5 = 3.9, 2.6, J4 ,3 = 3.7 Hz, H-4ꢀ); 4.32
ꢀ
ꢀ
ꢀ ꢀ
and 4.33 (2 × dd, 2 × 1H, J3 ,2 = 4.5, J3 ,4 = 3.7 Hz, H-3ꢀ); 4.66
ꢀ
ꢀ
ꢀ ꢀ
and 4.67 (2 × dd, 2 × 1H, J2 ,1 = 5.0, J2 ,3 = 4.5 Hz, H-2ꢀ); 6.09
ꢀ
ꢀ
ꢀ ꢀ
and 6.10 (2 × d, 2 × 1H, J1 ,2 = 5.0 Hz, H-1ꢀ); 8.39 (s, 2H, H-8);
8.73 (s, 2H, H-2). 13C NMR (151 MHz, CDCl3): −5.38, −5.37,
−5.04, −5.00, −4.75, −4.71, −4.43 and −4.41 (CH3Si); 15.37 and
15.43 (CH2-3-cycloprop); 17.82, 17.83 and 18.06 ((CH3)3C); 18.52
(CH-1-cycloprop); 25.63, 25.64, 25.82 and 26.07 ((CH3)3C); 27.48
and 27.54 (CH-2-cycloprop); 62.35 and 62.45 (CH2-5ꢀ); 65.58 and
ꢀ
ꢀ
2382 | Org. Biomol. Chem., 2008, 6, 2377–2387
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©

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65.60 (CH2O); 71.74 and 71.86 (CH-3ꢀ); 75.74 and 75.93 (CH-2ꢀ);
85.30 and 85.43 (CH-4ꢀ); 88.20 and 88.32 (CH-1ꢀ); 132.68 and
132.73 (C-5); 142.41 and 142.47 (CH-8); 149.76 and 149.78 (C-4);
152.42 and 152.45 (CH-2); 162.55 (C-6). FAB-MS, m/z (rel.%) =
665 (10) [M + H]+ (cation), 147 (10), 115 (8), 89 (10), 73 (100), 59
(12). HRMS calcd for C32H61N4O5Si3 [M + H]+ 665.3949; found:
665.3948. IR (CHCl3): 3613, 3354, 3119, 3065, 1596, 1580, 1499,
1473, 1463, 1409, 1390, 1363, 1331, 1258, 1115, 1083, 1073, 1049,
939, 839, 813, 648.
6); 175.99 (CO). FAB-MS, m/z (rel.%) 295 (92) [M + H]+, 224
(6), 91 (100). HRMS calcd for C16H15N4O2 [M + H]+ 295.1195;
found: 295.1193. IR (KBr): 3111, 3070, 3032, 2571, 2508, 1708,
1700, 1596, 1584, 1508, 1498, 1456, 1409, 1338, 1316, 1212, 1078,
1023, 804, 729, 696, 653, 639, 619, 454.
6-[2-(Carboxy)cyclopropyl]-9H-purine (9g)
White solid, yield 80%. 1H NMR (600 MHz, DMSO-d6 + DCl):
1.74 (ddd, 1H, Jvic = 8.9, 5.9, Jgem = 3.8 Hz, H-3b-cycloprop);
1.90 (ddd, 1H, Jvic = 8.7, 5.9, Jgem = 3.8 Hz, H-3a-cycloprop); 2.51
(ddd, 1H, Jvic = 8.7, 5.9, 3.9 Hz, H-2-cycloprop); 3.18 (ddd, 1H,
Jvic = 8.9, 5.9, 3.9 Hz, H-1-cycloprop); 8.93 (s, 1H, H-2); 9.06 (s,
1H, H-8). 13C NMR (151 MHz, DMSO-d6 + DCl): 18.25 (CH2-
3-cycloprop); 22.05 (CH-1-cycloprop); 25.66 (CH-2-cycloprop);
127.33 (C-5); 146.34 (CH-8); 151.05 (CH-2); 152.59 (C-4); 156.19
(C-6); 172.93 (CO). FAB-MS, m/z (rel.%) = 231 (30), 227 (14) [M +
Na]+ (cation), 205 (30) [M + H]+ (cation), 177 (60), 154 (100), 137
(90), 109 (30), 105 (7), 92 (18), 79 (15), 61 (12). HRMS calcd for
C9H9N4O2 [M + H]+ 205.0725; found: 205.0729. IR (KBr): 3114,
3078, 2570, 2484, 1708, 1600, 1490, 1432, 1404, 1383, 1261, 807,
648, 641.
6-[2-(Hydroxymethyl)cyclopropyl]-9H-purine (10g)
Dichloromethane (5 ml) was added to dry ester 4g (190 mg,
0.8 mmol) under argon atmosphere. The mixture was stirred at
0
◦C and DIBAH (2 ml, 1 M in hexane) was added dropwise.
The mixture was stirred for 1 h at ambient temperature. After
completion, the reaction mixture was quenched with ethanol
(50 ml) and then MnO2 (200 mg) was added. The mixture
was sonicated at ambient temperature for 1 h, filtered and the
solvent was evaporated. The residue was purified by column
chromatography (silica gel, methanol/chloroform 5–15%) and
crystallized from chloroform–heptane to give 10g (100 mg, 65%)
◦
1
as white crystals, mp 238–242 C. H NMR (500 MHz, DMSO-
d6 + DCl): 1.53 (ddd, 1H, Jvic = 8.5, 6.8, Jgem = 4.2 Hz, H-3b-
cycloprop); 1.88 (ddd, 1H, Jvic = 9.0, 5.2, Jgem = 4.2 Hz, H-3a-
cycloprop); 2.34 (m, 1H, H-2-cycloprop); 2.71 (ddd, 1H, Jvic = 8.5,
5.2, 4.2 Hz, H-1-cycloprop); 3.46 (dd, 1H, Jgem = 11.6, Jvic = 6.1 Hz,
CHaHbO); 3.60 (dd, 1H, Jgem = 11.6, Jvic = 5.0 Hz, CHaHbO); 9.01
(s, 1H, H-2); 9.11 (s, 1H, H-8). 13C NMR (125.7 MHz, DMSO-d6 +
DCl): 18.12 (CH2-3-cycloprop); 18.52 (CH-1-cycloprop); 30.81
(CH-2-cycloprop); 62.17 (CH2O); 127.21 (C-5); 147.83 (CH-2);
147.91 (CH-8); 152.82 (C-4); 158.68 (C-6). FAB-MS, m/z (rel.%) =
239 (60), 231 (12), 191 (10) [M + H]+ (cation), 177 (18), 160 (22),
154 (42), 149 (12), 137 (42), 102 (100). HRMS calcd for C9H11N4O
[M + H]+ 191.0932; found: 191.0939. IR (KBr): 3435, 2850, 1632,
1604, 1476, 1398, 1324, 1037, 808, 644.
General method for the cleavage of the THP protective group
A THP-protected compound (1 mmol) was dissolved in ethanol
(10 ml) and Dowex 50 (H+ form, 100 mg) was added. The mixture
was heated at 70 ◦C and stirred for 6 h. After completion, the
Dowex was filtered and the filtrate was concentrated under reduced
pressure. The residue was purified by column chromatography
(silica gel, methanol/chloroform 5–15%) and crystallized from
MeOH–chloroform–heptane to give the product.
6-Cyclopropyl-9H-purine (2g)
◦
1
White crystals, mp 186–191 C, yield 47%. H NMR (600 MHz,
DMSO-d6 + DCl): 1.52 and 1.70 (2 × m, 2 × 2H, H-2,3-
cycloprop); 2.83 (tt, 1H, Jvic = 8.2, 4.8 Hz, H-1-cycloprop); 9.03
(s, 1H, H-2); 9.14 (s, 1H, H-8). 13C NMR (151 MHz, DMSO-d6 +
DCl): 13.62 (CH-1-cycloprop); 14.13 (CH2-2,3-cycloprop); 126.99
(C-5); 147.50 (CH-8); 148.18 (CH-2); 152.53 (C-4); 159.38 (C-6).
FAB-MS, m/z (rel.%) = 161 (100) [M + H]+ (cation), 147 (10), 109
(8). HRMS calcd for C8H9N4 [M + H]+ 161.0827; found: 161.0832.
Anal. calcd for C8H8N4: C 59.99, H 5.03, N 34.98. Found: C 59.65,
H 4.76, N 34.68%. IR (KBr): 3097, 3064, 1597, 1489, 1415, 1325,
1193, 807, 646.
General method for ester hydrolysis
A mixture of ester 4a (or 4g) (1 mmol) and NaOH (240 mg,
6 mmol) in 50% aqueous THF (15 ml) was stirred at ambient
temperature for 1 h. After completion, the reaction mixture was
neutralized with 10% aqueous H2SO4. Solid salts were filtered
off and the filtrate was concentrated under reduced pressure.
The residue was purified by column chromatography (silica gel,
methanol/chloroform 5–15%) and crystallized from chloroform–
heptane.
6-[2-(Ethoxycarbonyl)cyclopropyl]-9H-purine (4g)
9-Benzyl-6-[2-(carboxy)cyclopropyl]purine (9a)
White crystals, 85%, mp 190–191 ◦C. 1H NMR (600 MHz, DMSO-
White solid, yield 81%. 1H NMR (500 MHz, CD3OD): 1.74 (ddd,
1H, Jvic = 8.9, 5.7, Jgem = 3.6Hz, H-3b-cycloprop); 1.86 (ddd, 1H,
Jvic = 8.5, 5.9, Jgem = 3.6 Hz, H-3a-cycloprop); 2.48 (ddd, 1H,
Jvic = 8.5, 5.7, 3.9 Hz, H-2-cycloprop); 3.24 (ddd, 1H, Jvic = 8.9,
5.9, 3.9 Hz, H-1-cycloprop); 5.50 (s, 2H, CH2Ph); 7.25–7.37 (m,
5H, H-o,m,p-Ph); 8.46 (s, 1H, H-8); 8.74 (s, 1H, H-2). 13C NMR
(125.7 MHz, CD3OD): 18.34 (CH2-3-cycloprop); 22.25 (CH-1-
cycloprop); 26.11 (CH-2-cycloprop); 48.17 (CH2Ph); 128.90 (CH-
o-Ph); 129.36 (CH-p-Ph); 130.00 (CH-m-Ph); 133.01 (C-5); 137.27
(C-i-Ph); 146.86 (CH-8); 151.75 (C-4); 153.52 (CH-2); 160.94 (C-
d6 + DCl): 1.19 (t, 3H, Jvic = 7.2, CH3CH2O); 1.74 (ddd, 1H, Jvic =
9.0, 5.8, Jgem = 3.9 Hz, H-3b-cycloprop); 1.88 (ddd, 1H, Jvic = 8.6,
6.0, Jgem = 3.9 Hz, H-3a-cycloprop); 2.53 (ddd, 1H, Jvic = 8.6,
5.8, 3.9 Hz, H-2-cycloprop); 3.19 (ddd, 1H, Jvic = 9.0, 6.0, 3.9 Hz,
H-1-cycloprop); 4.12 (q, 2H, Jvic = 7.2 Hz, CH3CH2O); 8.88 (s,
1H, H-2); 8.95 (s, 1H, H-8). 13C NMR (151 MHz, DMSO-d6 +
DCl): 14.34 (CH3CH2O); 18.02 (CH2-3-cycloprop); 22.28 (CH-
1-cycloprop); 25.06 (CH-2-cycloprop); 61.09 (CH3CH2O); 127.83
(C-5); 146.01 (CH-8); 151.45 (CH-2); 152.76 (C-4); 155.94 (C-
6); 171.66 (CO). FAB-MS, m/z (rel.%) = 233 (100) [M + H]+
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2377–2387 | 2383
©

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ꢀ
ꢀ
ꢀ
(cation), 187 (8), 159 (10), 134 (8), 102 (25), 93 (10). HRMS calcd
for C11H13N4O2 [M + H]+ 233.1038; found: 233.1039. IR (KBr):
3200, 3111, 3072, 2400, 1720, 1600, 1566, 1490, 1475, 1402, 1383,
1338, 1222, 1187, 1180, 1106, 1090, 810, 650.
7.3, J2 a,3 = 5.9 Hz, H-2ꢀa); 3.52 (ddd, 1H, Jgem = 11.7, J5 b,OH
=
=
=
=
5.9, J5 b,4 = 4.5 Hz, H-5ꢀb); 3.62 (ddd, 1H, Jgem = 11.7, J5 a,OH
ꢀ
ꢀ
ꢀ
5.3, J5 a,4 = 4.8 Hz, H-5ꢀb); 3.88 (ddd, 1H, J4 ,5 = 4.8, 4.5, J4 ,3
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
3.0 Hz, H-4ꢀ); 4.44 (m, 1H, J3 ,2 = 5.9, 3.4, J3 ,OH = 4.1, J3 ,4
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
3.0 Hz, H-3ꢀ); 5.03 (dd, 1H, JOH,5 = 5.9, 5.3 Hz, OH-5ꢀ); 5.37 (d,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
1H, JOH,3 = 4.1 Hz, OH-3 ); 6.44 (dd, 1H, J1 ,2 = 7.3, 6.2 Hz, H-1 );
8.69 (s, 2H, H-2,8). 13C NMR (125.7 MHz, DMSO-d6): 11.20 and
11.23 (CH2-2,3-cycloprop); 12.92 (CH-1-cycloprop); 39.48 (CH2-
2ꢀ); 61.80 (CH2-5ꢀ); 70.88 (CH-3ꢀ); 83.92 (CH-1ꢀ); 88.16 (CH-4ꢀ);
132.39 (C-5); 143.90 (CH-8); 149.51 (C-4); 152.07 (CH-2); 163.04
(C-6). FAB-MS, m/z (rel.%) = 277 (15) [M + H]+ (cation), 161
(100), 133 (76). HRMS calcd for C13H17N4O3 [M + H]+ 277.1300;
found: 277.1295. Anal. calcd for C13H16N4O3: C 56.51, H 5.84, N
20.28. Found: C 56.13, H 5.69, N 20.08%. IR (KBr): 3420, 3357,
3183, 3113, 3079, 1632, 1595, 1582, 1499, 1421, 1405, 1338, 1324,
1206, 1100, 1067, 1059, 811, 805, 642. [a]D −13.6 (c 0.45, MeOH).
6-[2-(Diethylcarbamoyl)cyclopropyl]-9H-purine (6g)
White hygroscopic solid, yield 66%. 1H NMR (500 MHz, DMSO-
d6+DCl): 1.01 and 1.09 (2 × t, 2 × 3H, Jvic = 7.1 Hz, CH3CH2N);
1.77 (ddd, 1H, Jvic = 8.8, 6.1, Jgem = 3.5 Hz, H-3b-cycloprop); 1.95
(ddd, 1H, Jvic = 8.6, 5.7, Jgem = 3.5 Hz, H-3a-cycloprop); 3.08–3.16
(m, 2H, H-1,2-cycloprop); 3.30 and 3.44 (2 × q, 2 × 2H, Jvic
=
7.1 Hz, CH3CH2N); 9.04 (s, 1H, H-2); 9.20 (s, 1H, H-8). 13C NMR
(125.7 MHz, DMSO-d6 + DCl): 13.46 and 15.17 (CH3CH2N);
19.13 (CH2-3-cycloprop); 21.37 (CH-1-cycloprop); 24.84 (CH-2-
cycloprop); 40.83 and 42.07 (CH3CH2N); 127.23 (C-5); 147.51
(CH-8); 149.28 (CH-2); 152.68 (C-4); 156.36 (C-6); 168.51 (CO).
FAB-MS, m/z (rel.%) = 260 (100) [M + H]+ (cation), 187 (14),
159 (12), 134 (10), 73 (5). HRMS calcd for C13H18N5O [M + H]+
260.1511; found: 260.1514. IR (CHCl3): 3440, 1620, 1598, 1565,
1487, 1436, 1404, 1382, 1375, 1327, 811, 643
General method for the cleavage of the TBS protective group
A TBS-protected compound (1.0 mmol) was dissolved in a
solution of NEt3·3HF (1 ml, 6 mmol) in THF (3 ml). The mixture
was stirred at ambient temperature for 1 day, evaporated and
the residue was purified by silica gel column chromatography
(methanol/chloroform 5–15%).
General method for the cleavage of the Tol protective group
A Tol-protected compound (1.0 mmol) was dissolved in a solution
of MeONa (0.3 mmol) in methanol (40 ml). The mixture was
stirred at ambient temperature for 16 h, evaporated and the
residue was purified by a silica gel column chromatography
(methanol/chloroform 5–15%) and crystallized from MeOH–
chloroform–heptane.
6-[2-(Ethoxycarbonyl)cyclopropyl]-9-(b-D-ribofuranosyl)purine
(4h)
1
White foam, yield 75%. Diastereomeric mixture 1 : 1. H NMR
(600 MHz, DMSO-d6): 1.202 and 1.204 (2 × t, 2 × 3H, Jvic
=
7.1 Hz, CH3CH2O); 1.703 and 1.705 (2 × ddd, 2 × 1H, Jvic
=
6-Cyclopropyl-9-(b-D-ribofuranosyl)purine (2h)
9.0, 5.6, Jgem = 3.7 Hz, H-3b-cycloprop); 1.81 and 1.83 (2 × ddd,
2 × 1H, Jvic = 8.6, 6.0, Jgem = 3.7 Hz, H-3a-cycloprop); 2.43 and
2.45 (2 × ddd, 2 × 1H, Jvic = 8.6, 5.6, 4.0 Hz, H-2-cycloprop);
3.100 and 3.102 (2 × ddd, 2 × 1H, Jvic = 9.0, 6.0, 4.0 Hz, H-1-
ꢀ
◦
1
White crystals, yield 65%, mp 158–160 C. H NMR (600 MHz,
DMSO-d6): 1.22 and 1.27 (2 × m, 2 × 2H, H-2,3-cycloprop);
2.69 (tt, 1H, Jvic = 8.0, 4.8 Hz, H-1-cycloprop); 3.57 (ddd, 1H,
Jgem = 12.0, J5 b,OH = 6.2, J5 b,4 = 4.0 Hz, H-5ꢀb); 3.69 (ddd, 1H,
cycloprop); 3.569 and 3.570 (2 × ddd, 2 × 1H, Jgem = 12.0, J5 b,OH
=
ꢀ
ꢀ
ꢀ
6.1, J5 b,4 = 4.0 Hz, H-5ꢀb); 3.688 and 3.691 (2 × ddd, 2 × 1H,
ꢀ
ꢀ
Jgem = 12.0, J5 a,OH = 5.1, J5 a,4 = 4.0 Hz, H-5ꢀa); 3.97 (td, 1H,
ꢀ
ꢀ
ꢀ
Jgem = 12.0, J5 a,OH = 5.0, J5 a,4 = 4.0 Hz, H-5ꢀa); 3.97 (td, 2H,
ꢀ
ꢀ
ꢀ
J4 ,5 = 4.0, J4 ,3 = 3.6 Hz, H-4ꢀ); 4.18 (td, 1H, J3 ,2 = J3 ,OH
=
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
J4 ,5 = 4.0, J4 ,3 = 3.7 Hz, H-4ꢀ); 4.128 and 4.129 (2 × q, 2 ×
ꢀ
ꢀ
ꢀ ꢀ
4.9, J3 ,4 = 3.6 Hz, H-3ꢀ); 4.62 (ddd, 1H, J2 ,OH = 6.0, J2 ,1 = 5.8,
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
J2 ,3 = 4.9 Hz, H-2ꢀ); 5.16 (dd, 1H, JOH,5 = 6.2, 5.1 Hz, OH-
2H, Jvic = 7.1 Hz, CH3CH2O); 4.177 and 4.185 (2 × td, 2 × 1H,
ꢀ
ꢀ
ꢀ
J3 ,2 = J3 ,OH = 5.0, J3 ,4 = 3.7 Hz, H-3ꢀ); 4.59 and 4.60 (2 × ddd,
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
5ꢀ); 5.25 (d, 1H, JOH,3 = 4.9 Hz, OH-3ꢀ); 5.53 (dd, 1H, JOH,2
=
ꢀ
ꢀ
2 × 1H, J2 ,OH = 5.9, J2 ,1 = 5.6, J2 ,3 = 5.0 Hz, H-2ꢀ); 5.131 and
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
6.0 Hz, OH-2ꢀ); 6.00 (d, 1H, J1 ,2 = 5.8 Hz, H-1ꢀ); 8.71 (s, 1H, H-
2); 8.74 (s, 1H, H-8). 13C NMR (151 MHz, DMSO-d6): 11.34 and
11.37 (CH2-2,3-cycloprop); 12.98 (CH-1-cycloprop); 61.55 (CH2-
5ꢀ); 70.57 (CH-3ꢀ); 73.86 (CH-2ꢀ); 85.91 (CH-4ꢀ); 87.84 (CH-1ꢀ);
132.45 (C-5); 144.10 (CH-8); 149.82 (C-4); 152.20 (CH-2); 163.22
(C-6). ESI-MS, m/z (rel.%) 315 (100) [M + Na]+, 293 (60) [M +
H]+. HRMS calcd for C13H17N4O4 [M + H]+ 293.12498; found
293.12438. Anal. calcd for C13H16N4O4: C 53.42, H 5.52, N 19.17.
Found: C 53.16, H 5.41, N 18.89%. IR (KBr): 3408, 3169, 3117,
3106, 3070, 1501, 1420, 1405, 1341, 1330, 1222, 1210, 811, 804,
649, 640. [a]D −56.4 (c 0.35, MeOH).
ꢀ
ꢀ
5.134 (2 × dd, 2 × 1H, JOH,5 = 6.1, 5.0 Hz, OH-5ꢀ); 5.26 (d, 2H,
ꢀ
JOH,3 = 5.0 Hz, OH-3ꢀ); 5.537 and 5.539 (2 × d, 2 × 1H, JOH,2
=
ꢀ
ꢀ
5.9 Hz, OH-2ꢀ); 6.015 and 6.016 (2 × d, 2 × 1H, J1 ,2 = 5.6 Hz,
H-1ꢀ); 8.78 (s, 2H, H-2); 8.809 and 8.811 (2 × s, 2 × 1H, H-8).
13C NMR (151 MHz, DMSO-d6): 14.30 (CH3CH2O); 17.42 (CH2-
3-cycloprop); 22.35 (CH-1-cycloprop); 24.48 and 24.56 (CH-2-
cycloprop); 60.94 (CH3CH2O); 61.42 and 61.44 (CH2-5ꢀ); 70.45
and 70.47 (CH-3ꢀ); 73.94 (CH-2ꢀ); 85.87 and 85.89 (CH-4ꢀ); 87.91
and 87.92 (CH-1ꢀ); 132.47 (C-5); 144.85 (CH-8); 150.36 (C-4);
152.22 (CH-2); 158.55 and 158.56 (C-6); 171.88 and 171.90 (CO).
FAB-MS, m/z (rel.%) = 387 (25) [M + Na]+ (cation), 365 (25)
[M + H]+ (cation), 331 (7), 309 (15), 231 (30), 207 (10), 177 (70),
154 (100), 137 (85), 109 (27), 92 (17), 79 (14), 61 (14). HRMS calcd
for C16H21N4O6 [M + H]+ 365.1461; found: 365.1459. IR (KBr):
3423, 3255, 3111, 3070, 1725, 1699, 1632, 1599, 1583, 1499, 1406,
1386, 1366, 1328, 1213, 1182, 1093, 1055, 1043, 1025, 805, 645.
[a]D −40.7 (c 0.24, MeOH).
ꢀ
ꢀ
6-Cyclopropyl-9-(2-deoxy-b-D-erythro-pentafuranosyl)purine (2i)
◦
1
White crystals, mp 124–126 C, yield 42%. H NMR (500 MHz,
DMSO-d6): 1.17–1.29 (m, 4H, H-2,3-cycloprop); 2.32 (ddd, 1H,
Jgem = 13.3, J2 b,1 = 6.2, J2 b,3 = 3.4 Hz, H-2ꢀb); 2.67 (tt, 1H, Jvic
=
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
7.9, 4.7 Hz, H-1-cycloprop); 2.77 (ddd, 1H, Jgem = 13.3, J2 a,1
=
2384 | Org. Biomol. Chem., 2008, 6, 2377–2387
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©

View Article Online
6-[2-(Ethoxycarbonyl)cyclopropyl]-9-(2-deoxy-b-D-erythro-
pentafuranosyl)purine (4i)
159 (23), 134 (8), 102 (35), 74 (12). HRMS calcd for C18H26N5O5
[M + H]+ 392.1933; found: 392.1940. IR (KBr): 3401, 3112, 3070,
1632, 1617, 1598, 1580, 1491, 1406, 1382, 1331, 1218, 807, 646.
[a]D −42.1 (c 0.25, MeOH).
White foam, 80%. Diastereomeric mixture 1 : 1. 1H NMR
(500 MHz, DMSO-d6): 1.196 and 1.198 (2 × t, 2 × 3H, Jvic
=
7.1 Hz, CH3CH2O); 1.687 and 1.690 (2 × ddd, 2 × 1H, Jvic = 9.1,
5.6, Jgem = 3.7 Hz, H-3b-cycloprop); 1.80 and 1.81 (2 × ddd, 2 ×
1H, Jvic = 8.6, 6.2, Jgem = 3.7 Hz, H-3a-cycloprop); 2.34 (ddd, 2H,
6-[2-(Benzyl(methyl)carbamoyl)cyclopropyl]-9-(b-D-
ribofuranosyl)purine (7h)
Jgem = 13.3, J2 b,1 = 6.3, J2 b,3 = 3.5 Hz, H-2ꢀb); 2.41 and 2.43 (2 ×
ddd, 2 × 1H, Jvic = 8.6, 5.6, 3.9 Hz, H-2-cycloprop); 2.760 and
ꢀ
ꢀ
ꢀ
ꢀ
White foam, yield 97%, mp 84–88 ◦C. Diastereomeric mixture of
amide rotamers 1 : 1 : 1 : 1. 1H NMR (500 MHz, DMSO-d6): 1.65–
1.71 and 1.74–1.79 (2 × m, 8H, H-3-cycloprop); 2.68, 2.70, 2.82
and 2.83 (4 × ddd, 4 × 1H, Jvic = 8.1, 5.9, 3.9 Hz, H-2-cycloprop);
2.92 and 2.93 (2 × s, 2 × 3H, CH3N); 2.94 and 2.96 (2 × ddd, 2 ×
1H, Jvic = 8.5, 5.4, 3.9 Hz, H-1-cycloprop); 3.02 and 3.03 (2 × s,
2 × 3H, CH3N); 3.096 and 3.099 (2 × ddd, 2 × 1H, Jvic = 8.5,
5.4, 3.9 Hz, H-1-cycloprop); 3.55–3.60 (m, 4H, H-5ꢀb); 3.66–3.73
(m, 4H, H-5ꢀa); 3.96–4.00 (m, 4H, H-4ꢀ); 4.17–4.21 (m, 4H, H-3ꢀ);
4.522 and 4.525 (2 × d, 2H, Jgem = 14.7 Hz, CHaHbPh); 4.582
and 4.585 (2 × d, 2H, Jgem = 14.7 Hz, CHaHbPh); 4.60–4.66 (m,
6H, H-2ꢀ and CHaHbPh); 4.74 (d, 2H, Jgem = 14.7 Hz, CHaHbPh);
5.13–5.18 (m, 4H, OH-5ꢀ); 5.270, 5.274 and 5.286 (3 × d, 4H,
ꢀ
ꢀ
ꢀ
ꢀ
2.764 (2 × ddd, 2 × 1H, Jgem = 13.3, J2 a,1 = 7.2, J2 a,3 = 5.8 Hz,
H-2ꢀa); 3.084 and 3.086 (2 × ddd, 2 × 1H, Jvic = 9.1, 6.2, 3.9 Hz, H-
ꢀ
1-cycloprop); 3.52 and 3.62 (2 × ddd, 2 × 2H, Jgem = 12.0, J5 ,OH
=
5.6, J5 ,4 = 4.5 Hz, H-5ꢀ); 3.89 (td, 2H, J4 ,5 = 4.5, J4 ,3 = 3.1 Hz,
H-4ꢀ); 4.120 and 4.122 (2 × q, 2 × 2H, Jvic = 7.1 Hz, CH3CH2O);
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
4.44 (m, 2H, J3 ,2 = 5.8, 3.5, J3 ,OH = 4.2, J3 ,4 = 3.1 Hz, H-3ꢀ);
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
5.010 and 5.013 (2 × t, 2 × 1H, JOH,5 = 5.6 Hz, OH-5ꢀ); 5.37 (dd,
ꢀ
2H, JOH,3 = 4.2 Hz, OH-3ꢀ); 6.45 (dd, 2H, J1 ,2 = 7.2, 6.3 Hz, H-
1ꢀ); 8.76 (s, 4H, H-2,8). 13C NMR (125.7 MHz, DMSO-d6): 14.26
(CH3CH2O); 17.35 and 17.41 (CH2-3-cycloprop); 22.33 (CH-1-
cycloprop); 24.43 and 24.49 (CH-2-cycloprop); 39.53 (CH2-2ꢀ);
60.88 (CH3CH2O); 61.72 (CH2-5ꢀ); 70.80 (CH-3ꢀ); 84.00 and 84.02
(CH-1ꢀ); 88.20 (CH-4ꢀ); 132.44 (C-5); 144.70 (CH-8); 150.05 (C-4);
152.08 (CH-2); 158.41 (C-6); 171.86 and 171.87 (CO). FAB-MS,
m/z (rel.%) = 349 (25) [M + H]+ (cation), 259 (6), 233 (100), 187
(15), 159 (24), 147 (7), 134 (7), 117 (10), 73 (10). HRMS calcd for
C16H21N4O5 [M + H]+ 349.1511; found: 349.1521. IR (micr. refl.):
3313, 2979, 2929, 2876, 1727, 1600, 1500, 1456, 1408, 1386, 1366,
1330, 1265, 1213, 1186, 1159, 1095, 1056, 994, 929, 884, 867, 843,
806, 760. [a]D −9.2 (c 0.12, MeOH).
ꢀ
ꢀ ꢀ
JOH,3 = 5.0 Hz, OH-3ꢀ); 5.538, 5.541, 5.542 and 5.553 (4 × d, 4 ×
ꢀ
1H, JOH,2 = 6.0 Hz, OH-2ꢀ); 6.01 and 6.02 (2 × d, 4H, J1 ,2
=
ꢀ
ꢀ ꢀ
5.7 Hz, H-1ꢀ); 7.04–7.16, 7.20–7.28 and 7.30–7.35 (3 × m, 20H,
H-o,m,p-Ph); 8.680 and 8.683 (2 × s, 2 × 1H, H-2); 8.769 and
8.772 (2 × s, 2 × 1H, H-8); 8.78 (s, 2H, H-2); 8.80 (s, 2H, H-8).
13C NMR (125.7 MHz, DMSO-d6): 16.9, 17.03 and 17.42 (CH2-3-
cycloprop); 21.83, 21.86, 22.29 and 22.32 (CH-1-cycloprop); 23.48,
23.52, 23.91 and 24.01 (CH-2-cycloprop); 34.75, 34.79 and 35.04
(CH3N); 50.59 and 52.89 (CH2Ph); 61.47 (CH2-5ꢀ); 70.51 (CH-3ꢀ);
73.89 and 73.90 (CH-2ꢀ); 85.89 (CH-4ꢀ); 87.84 (CH-1ꢀ); 126.46 and
126.49 (CH-o-Ph); 127.09, 127.11 and 127.27 (CH-p-Ph); 127.70
(CH-o-Ph); 128.57, 128.60 and 128.69 (CH-m-Ph); 132.49 (C-5);
137.75, 137.76 and 137.84 (C-i-Ph); 144.41 and 144.56 (CH-8);
150.07, 150.09 and 150.21 (C-4); 151.95 and 152.16 (CH-2); 159.61
and 159.87 (C-6); 170.44 and 170.58 (CO). FAB-MS, m/z (rel.%) =
440 (15) [M + H]+ (cation), 308 (10), 217 (15), 201 (40), 185 (50),
93 (100), 91 (66), 73 (24), 57 (25). HRMS calcd for C22H26N5O5
[M + H]+ 440.1933; found: 440.1940. IR (KBr): 3401, 3401, 3109,
3067, 3030, 1623, 1598, 1582, 1496, 1410, 1333, 1216, 1120, 1082,
1055, 1030, 808, 748, 699, 645. [a]D −37.3 (c 0.49, MeOH).
6-[2-(Diethylcarbamoyl)cyclopropyl]9-(b-D-ribofuranosyl)purine
(6h)
1
White foam, yield 95%. Diastereomeric mixture 1 : 1. H NMR
(600 MHz, DMSO-d6): 1.019, 1.020, 1.060 and 1.062 (4 × t, 4 ×
3H, Jvic = 7.1 Hz, CH3CH2N); 1.626 and 1.628 (2 × ddd, 2 ×
1H, Jvic = 8.8, 5.7, Jgem = 3.1 Hz, H-3b-cycloprop); 1.68 and 1.69
(2 × ddd, 2 × 1H, Jvic = 8.6, 5.9, Jgem = 3.1 Hz, H-3a-cycloprop);
2.692 and 2.694 (2 × ddd, 2 × 1H, Jvic = 8.6, 5.7, 4.0 Hz, H-2-
cycloprop); 3.01 (ddd, 2H, Jvic = 8.8, 5.9, 4.0 Hz, H-1-cycloprop);
3.25–3.50 (m, 8H, CH3CH2N); 3.568 and 3.570 (2 × ddd, 2 ×
1H, Jgem = 12.1, J5 b,OH = 6.1, J5 b,4 = 4.0 Hz, H-5ꢀb); 3.684 and
ꢀ
ꢀ
ꢀ
6-[2-(Morpholine-4-carbonyl)cyclopropyl]-9-(b-D-
ribofuranosyl)purine (8h)
ꢀ
ꢀ
ꢀ
3.685 (2 × ddd, 2 × 1H, Jgem = 12.1, J5 a,OH = 5.1, J5 a,4 = 4.0 Hz,
H-5ꢀa); 3.973 and 3.974 (2 × td, 2 × 1H, J4 ,5 = 4.0, J4 ,3 = 3.7 Hz,
ꢀ
ꢀ
ꢀ ꢀ
H-4ꢀ); 4.18 (ddd, 2H, J3 ,2 = 5.1, J3 ,OH = 5.0, J3 ,4 = 3.7 Hz, H-
White foam, yield 98%. Diastereomeric mixture 1 : 1. H NMR
1
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
3ꢀ); 4.614 and 4.615 (2 × ddd, 2 × 1H, J2 ,OH = 6.0, J2 ,1 = 5.7,
(600 MHz, DMSO-d6): 1.63 and 1.64 (2 × ddd, 2 × 1H, Jvic
=
ꢀ
ꢀ ꢀ
J2 ,3 = 5.1 Hz, H-2ꢀ); 5.15 and 5.16 (2 × dd, 2 × 1H, JOH,5 = 6.1,
8.6, 5.6, Jgem = 3.1 Hz, H-3b-cycloprop); 1.73 and 1.74 (2 × ddd,
2 × 1H, Jvic = 8.7, 5.5, Jgem = 3.1 Hz, H-3a-cycloprop); 2.762 and
2.770 (2 × ddd, 2 × 1H, Jvic = 8.7, 5.6, 4.0 Hz, H-2-cycloprop);
3.049 and 3.051 (2 × ddd, 2 × 1H, Jvic = 8.6, 5.5, 4.0 Hz, H-1-
cycloprop); 3.44–3.65 (m, 18H, H-5ꢀb and H-morph); 3.69 (ddd,
ꢀ
ꢀ
ꢀ
5.1 Hz, OH-5ꢀ); 5.270 and 5.274 (2 × d, 2 × 1H, JOH,3 = 5.0 Hz,
ꢀ
OH-3ꢀ); 5.54 and 5.55 (2 × d, 2 × 1H, JOH,2 = 6.0 Hz, OH-2ꢀ);
ꢀ
6.010 and 6.011 (2 × d, 2 × 1H, J1 ,2 = 5.7 Hz, H-1ꢀ); 8.780 (s, 2H,
H-2); 8.784 (s, 2H, H-8). 13C NMR (151 MHz, DMSO-d6): 13.45,
15.07 and 15.08 (CH3CH2N); 17.44 (CH2-3-cycloprop); 21.82 and
21.87 (CH-1-cycloprop); 23.51 and 23.53 (CH-2-cycloprop); 40.69
and 41.98 (CH3CH2N); 61.53 and 61.56 (CH2-5ꢀ); 70.57 and 70.60
(CH-3ꢀ); 73.93 and 73.95 (CH-2ꢀ); 85.96 and 85.99 (CH-4ꢀ); 87.88
(CH-1ꢀ); 132.54 (C-5); 144.65 and 144.68 (CH-8); 150.25 (C-4);
152.28 (CH-2); 160.05 and 160.06 (C-6); 169.31 (CO). FAB-MS,
m/z (rel.%) = 392 (30) [M + H]+ (cation), 260 (100), 187 (25),
ꢀ
ꢀ
2H, Jgem = 12.0, J5 a,OH = 5.2, J5 a,4 = 4.0 Hz, H-5ꢀa); 3.97 (td, 2H,
ꢀ
ꢀ
ꢀ
J4 ,5 = 4.0, J4 ,3 = 3.6, H-4ꢀ); 4.18 (td, 2H, J3 ,2 = J3 ,OH = 4.9,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
J3 ,4 = 3.6 Hz, H-3ꢀ); 4.61 and 4.62 (2 × ddd, 2 × 1H, J2 ,OH = 5.8,
ꢀ
ꢀ
ꢀ
J2 ,1 = 5.7, J2 ,3 = 4.9 Hz, H-2ꢀ); 5.143 and 5.145 (2 × dd, 2 × 1H,
ꢀ
ꢀ
ꢀ ꢀ
JOH,5 = 6.0, 5.2 Hz, OH-5ꢀ); 5.26 and 5.27 (2 × d, 2 × 1H, JOH,3
=
ꢀ
ꢀ
4.9 Hz, OH-3ꢀ); 5.54 (d, 2H, JOH,2 = 5.8 Hz, OH-2ꢀ); 6.01 (d, 2H,
ꢀ
ꢀ
J1 ,2 = 5.7 Hz, H-1 ); 8.77 (s, 2H, H-2); 8.79 (s, 2H, H-8). 13C NMR
ꢀ
ꢀ
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The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 2377–2387 | 2385
©

View Article Online
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
(151 MHz, DMSO-d6): 17.18 and 17.21 (CH2-3-cycloprop); 21.72
and 21.75 (CH-1-cycloprop); 23.05 and 23.09 (CH-2-cycloprop);
42.38 and 45.72 (CH2N-morph); 61.49 and 61.52 (CH2-5ꢀ); 66.21
and 66.42 (CH2O-morph); 70.53 and 70.56 (CH-3ꢀ); 73.90 and
73.93 (CH-2ꢀ); 85.92 and 85.95 (CH-4ꢀ); 87.84 and 87.86 (CH-1ꢀ);
132.55 and 132.56 (C-5); 144.62 and 144.65 (CH-8); 150.24 (C-4);
152.20 (CH-2); 159.84 (C-6); 169.09 (CO). FAB-MS, m/z (rel.%) =
406 (8) [M + H]+ (cation), 390 (7), 274 (20), 201 (7), 185 (18), 110
(8), 102 (100), 93 (32), 75 (8), 57 (7). HRMS calcd for C18H24N5O6
[M + H]+ 406.1726; found: 406.1723. IR (KBr): 3421, 3255, 1632,
1598, 1582, 1498, 1423, 1332, 1216, 1115, 1093, 1057, 1042, 1026,
929, 860, 806, 645. [a]D −18.8 (c 0.42, MeOH).
4.0, J4 ,3 = 3.6 Hz, H-4ꢀ); 4.18 (ddd, 2H, J3 ,OH = 4.9, J3 ,2 = 4.7,
J3 ,4 = 3.6 Hz, H-3ꢀ); 4.60 and 4.61 (2 × ddd, 2 × 1H, J2 ,OH = 6.0,
ꢀ
ꢀ
ꢀ
J2 ,1 = 5.7, J2 ,3 = 4.7 Hz, H-2ꢀ); 4.75 (t, 2H, J = 5.7 Hz, OH); 5.16
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(t, 2H, JOH,5 = 5.7 Hz, OH-5 ); 5.24 (d, 2H, JOH,3 = 4.9 Hz, OH-3 );
5.519 and 5.523 (2 × d, 2 × 1H, JOH,2 = 6.0 Hz, OH-2ꢀ); 5.997 and
ꢀ
5.999 (2 × d, 2 × 1H, J1 ,2 = 5.7 Hz, H-1ꢀ); 8.70 (s, 2H, H-2); 8.726
and 8.729 (2 × s, 2 × 1H, H-8). 13C NMR (125.7 MHz, DMSO-
d6): 15.61 and 15.64 (CH2-3-cycloprop); 18.24 (CH-1-cycloprop);
27.53 and 27.61 (CH-2-cycloprop); 61.52 and 61.54 (CH2-5ꢀ); 62.75
and 62.77 (CH2O); 70.55 and 70.57 (CH-3ꢀ); 73.85 and 73.91 (CH-
2ꢀ); 85.88 and 85.91 (CH-4ꢀ); 87.82 and 87.87 (CH-1ꢀ); 132.27 and
132.29 (C-5); 143.98 and 144.02 (CH-8); 149.80 (C-4); 152.13 (CH-
2); 162.79 and 162.80 (C-6). FAB-MS, m/z (rel.%) = 323 (10) [M +
H]+ (cation), 239 (60), 219 (40), 203 (14), 191 (40), 173 (20), 149
(68), 128 (18), 102 (100), 57 (32). HRMS calcd for C14H19N4O5
[M + H]+ 323.1357; found: 323.1355. IR (KBr): 3421, 3260, 3113,
1632, 1600, 1581, 1497, 1420, 1399, 1333, 1215, 1128, 1095, 1060,
1027, 809, 643. [a]D −35.2 (c 0.20, MeOH).
ꢀ
ꢀ
6-[2-(Diethylcarbamoyl)cyclopropyl]-9-(2-deoxy-b-D-erythro-
pentafuranosyl)purine (6i)
1
White foam, yield 83%. Diastereomeric mixture 1 : 1. H NMR
(500 MHz, DMSO-d6): 1.02 and 1.06 (2 × t, 2 × 6H, Jvic = 7.1 Hz,
CH3CH2N); 1.617 and 1.619 (2 × ddd, 2 × 1H, Jvic = 8.7, 5.6,
Jgem = 2.9 Hz, H-3b-cycloprop); 1.67 and 1.68 (2 × ddd, 2 × 1H,
Jvic = 8.5, 5.7, Jgem = 2.9 Hz, H-3a-cycloprop); 2.330 and 2.333
6-[2-(Hydroxymethyl)cyclopropyl]-9-(2-deoxy-b-D-erythro-
pentafuranosyl)purine (10i)
(2 × ddd, 2 × 1H, Jgem = 13.3, J2 b,1 = 6.4, J2 b,3 = 3.5 Hz, H-2ꢀb);
2.68 and 2.69 (2 × ddd, 2 × 1H, Jvic = 8.5, 5.6, 3.9 Hz, H-2-
ꢀ
ꢀ
ꢀ
ꢀ
1
White foam, yield 44%. Diastereomeric mixture 1 : 1. H NMR
(500 MHz, DMSO-d6): 1.17 and 1.40 (2 × m, 2 × 2H, H-3-
ꢀ
ꢀ
cycloprop); 2.768 and 2.770 (2 × ddd, 2 × 1H, Jgem = 13.3, J2 a,1
=
cycloprop); 1.92 (m, 2H, H-2-cycloprop); 2.32 (ddd, 2H, Jgem
=
ꢀ
ꢀ
ꢀ
7.1, J2 a,3 = 5.9 Hz, H-2 a); 3.00 (ddd, 2H, Jvic = 8.7, 5.7, 3.9 Hz, H-
1-cycloprop); 3.25–3.50 (m, 8H, CH3CH2N); 3.516 and 3.523 (2 ×
13.3, J2 b,1 = 6.2, J2 b,3 = 3.4 Hz, H-2ꢀb); 2.59 (dt, 2H, Jvic = 8.6,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
4.5 Hz, H-1-cycloprop); 2.76 (ddd, 2H, Jgem = 13.3, J2 a,1 = 7.2,
ddd, 2 × 1H, Jgem= 12.0, J5 b,OH = 6.7, J5 b,4 = 4.6 Hz, H-5ꢀb); 3.61
ꢀ
ꢀ
ꢀ
J2 a,3 = 5.8 Hz, H-2ꢀa); 3.45 (dd, 2H, Jgem = 11.4, Jvic = 6.5 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
and 3.62 (2 × ddd, 2 × 1H, Jgem = 12.0, J5 a,OH = 5.2, J5 a,4 = 4.6 Hz,
CHaHbO); 3.52 (dd, 2H, Jgem = 11.8, J5 b,4 = 4.5 Hz, H-5ꢀb); 3.58
ꢀ
ꢀ
H-5ꢀa); 3.88 (td, 2H, J4 ,5 = 4.6, J4 ,3 = 2.8 Hz, H-4ꢀ); 4.44 (m, 2H,
ꢀ
ꢀ
ꢀ ꢀ
(dd, 2H, Jgem = 11.4, Jvic = 5.4 Hz, CHaHbO); 3.62 (dd, 2H, Jgem
=
=
J3 ,2 = 5.9, 3.5, J3 ,OH = 4.1, J3 ,4 = 2.8 Hz, H-3ꢀ); 5.02 and 5.03
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
11.8, J5 a,4 = 4.5 Hz, H-5ꢀb); 3.88 (td, 2H, J4 ,5 = 4.5, J4 ,3
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
ꢀ
ꢀ
(2 × dd, 2 × 1H, JOH,5 = 6.1, 5.2 Hz, OH-5 ); 5.38 (dd, 2H, JOH,3
=
3.0 Hz, H-4ꢀ); 4.44 (ddd, 2H, J3 ,2 = 5.8, 3.4, J3 ,4 = 3.0 Hz, H-3ꢀ);
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
4.1 Hz, OH-3ꢀ); 6.45 (dd, 2H, J1 ,2 = 7.1, 6.4 Hz, H-1 ); 8.75 (s, 2H,
H-8); 8.77 (s, 2H, H-2). 13C NMR (125.7 MHz, DMSO-d6): 13.37
and 15.00 (CH3CH2N); 17.31 (CH2-3-cycloprop); 21.74 and 21.79
(CH-1-cycloprop); 23.40 (CH-2-cycloprop); 39.46 (CH2-2ꢀ); 40.60
and 41.89 (CH3CH2N); 61.76 and 61.77 (CH2-5ꢀ); 70.85 and 70.86
(CH-3ꢀ); 83.95 (CH-1ꢀ); 88.19 (CH-4ꢀ); 132.48 (C-5); 144.46 and
144.48 (CH-8); 149.90 (C-4); 152.11 (CH-2); 159.85 and 159.86
(C-6); 169.24 (CO). FAB-MS, m/z (rel.%) = 398 (60) [M + Na]+
(cation), 376 (7) [M + H]+ (cation), 308 (10), 282 (45), 260 (100),
217 (15), 187 (30), 177 (10), 159 (40), 137 (10), 117 (7), 109 (10), 100
(7), 79 (7), 72 (14), 61 (6). HRMS calcd for C18H26N5O4 [M + H]+
376.1984; found: 376.1992. Anal. calcd for C18H25N5O4·0.5H2O:
C 56.24, H 6.82, N 18.22. Found: C 56.16, H 6.79, N 19.97%. IR
(KBr): 3428, 3111, 3073, 1631, 1621, 1597, 1581, 1490, 1424, 1424,
1405, 1381, 1362, 1329, 1217, 1097, 1058, 807, 646. [a]D −5.1 (c
0.21, MeOH).
ꢀ
ꢀ
6.44 (dd, 2H, J1 ,2 = 7.2, 6.2 Hz, H-1ꢀ); 8.683 and 8.685 (2 × s,
2 × 1H, H-8); 8.691 (s, 2H, H-2). 13C NMR (125.7 MHz, DMSO-
d6): 15.54 and 15.57 (CH2-3-cycloprop); 18.21 (CH-1-cycloprop);
27.46 and 27.53 (CH-2-cycloprop); 39.47 (CH2-2ꢀ); 61.80 (CH2-5ꢀ);
62.75 (CH2O); 70.87 and 70.89 (CH-3ꢀ); 83.92 and 83.94 (CH-1ꢀ);
88.16 (CH-4ꢀ); 132.23 and 132.24 (C-5); 143.85 (CH-8); 149.53
(C-4); 152.01 (CH-2); 162.64 (C-6). ESI-MS, m/z (rel.%) 329 (30)
[M + Na]+, 307 (35) [M + H]+, 238 (37), 190 (92). HRMS calcd for
C14H18N4O4Na [M + Na]+ 329.1226; found 329.1222. IR (CHCl3):
3436, 1632, 1598, 1434, 1399, 1334, 1217, 1098, 1079, 1059, 1037,
641. [a]D −5.6 (c 0.54, MeOH).
ꢀ
ꢀ
X-Ray diffraction
X-Ray crystallographic analysis† of single crystals of 6a (colour-
less, 0.01 × 0.01 × 0.59 mm) and 2g (colourless, 0.07 × 0.37 ×
0.44 mm) was performed with an Xcalibur X-ray diffractometer
˚
6-[2-(Hydroxymethyl)cyclopropyl]-9-(b-D-ribofuranosyl)purine
(10h)
with CuKa (k = 1.54180 A), data collected at 150 K. Both structures
were solved by direct methods with SIR9230 and refined by full-
matrix least-squares on F with CRYSTALS.31 The hydrogen atoms
were all located in a difference map, but those attached to carbon
atoms were repositioned geometrically and then refined with riding
constraints, while all other atoms were refined anisotropically in
both cases.
White foam, yield 76%. Diastereomeric mixture 2 : 1 (after
repeated column chromatography). 1H NMR (500 MHz, DMSO-
d6): 1.20 and 1.41 (2 × m, 2 × 2H, H-3-cycloprop); 1.93 (m, 2H,
H-2-cycloprop); 2.60 (dt, 2H, Jvic = 8.2, 4.5 Hz, H-1-cycloprop);
3.45 (dt, 2H, Jgem = 11.3, Jvic = JHb,OH = 5.7 Hz, CHaHbO); 3.55
ꢀ
ꢀ
ꢀ
ꢀ
(ddd, 2H, Jgem = 11.8, J5 b,OH = 5.7, J5 b,4 = 4.0 Hz, H-5 b); 3.59 (dt,
Crystal data 2g. C8H8N4, monoclinic, space group C2/m, a =
◦
˚
˚
˚
2H, Jgem = 11.3, Jvic = JHa,OH = 5.7 Hz, CHaHbO); 3.69 (dt, 2H,
13.6246(3) A, b = 20.3049(5) A, c = 9.4369(2) A, b = 99.789(2) ,
ꢀ
3
˚
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
Jgem = 11.8, J5 a,OH = 5.7, J5 a,4 = 4.0 Hz, H-5 a); 3.97 (td, 2H, J4 ,5
=
V = 743.25(3) A , Z = 4, M = 160.18, 11 926 reflections measured,
2386 | Org. Biomol. Chem., 2008, 6, 2377–2387
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©

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ˇ
820 independent reflections. Final R = 0.0409, wR = 0.0577,
GoF = 0.9440 for 723 reflections with I > 2r(I) and 75 parameters.
10 P. Capek, R. Pohl, I. Votruba and M. Hocek, J. Org. Chem., 2004, 69,
7985–7988.
ˇ
11 P. Capek, R. Pohl and M. Hocek, J. Org. Chem., 2005, 70, 8001–8008.
ˇ
Crystal data 6a. C20H23N5O1, orthorhombic, space group
12 P. Silha´r, M. Hocek, R. Pohl, I. Votruba, I.-h. Shih, E. Mabery and R.
˚
˚
˚
Mackman, Bioorg. Med. Chem., 2008, 16, 2337–2374.
13 M. Kucharˇ, M. Hocek, R. Pohl, I. Votruba, I.-h. Shih, E. Mabery and
R. Mackman, Bioorg. Med. Chem., 2008, 16, 1400–1424.
14 (a) Review: H.-W. Liu and C. T. Walsh, The chemistry of the cyclopropyl
group, 1987, 959–1025; (b) review: G. Maas, Chem. Soc. Rev., 2004, 33,
183–190.
Pna21, a = 22.2791(2) A, b = 7.0143(1) A, c = 7.8922(2) A, V =
3
˚
1796.64(2) A , Z = 4, M = 349.44, 26 954 reflections measured,
3604 independent reflections. Final R = 0.0296, wR = 0.0328,
GoF = 1.0836 for 2807 reflections with I > 2r(I) and 237
parameters.
15 Review: J. Salau¨n and M. S. Baird, Curr. Med. Chem., 1995, 2, 511–542.
16 (a) Y. L. Qiu, M. B. Ksebati, R. G. Ptak, B. Y. Fan, J. M. Breitenbach,
J. S. Lin, Y. C. Cheng, E. R. Kern, J. C. Drach and J. Zemlicka,
J. Med. Chem., 1998, 41, 10–23; (b) M. Valeria´nova´, B. Otova´, V. B´ıla´, J.
Hanzalova´, I. Votruba, A. Holy´, T. Eckschlager, O. Krejcˇ´ı and J. Trka,
Anticancer Res., 2003, 23, 4933–4939; (c) M. L. Compton, J. J. Toole
and L. R. Paborsky, Biochem. Pharmacol., 1999, 58, 709–714; (d) S. M.
Daluge, S. S. Good, M. B. Faletto, W. H. Miller, M. H. StClair, L. R.
Boone, M. Tisdale, N. R. Parry, J. E. Reardon, R. E. Dornsife, D. R.
Averett and T. A. Krenitsky, Antimicrob. Agents Chemother., 1997, 41,
1082–1093; (e) C. C. Lin, C. Fang, S. Benetton, G. F. Xu and U. T. Yeh,
Antimicrob. Agents Chemother., 2006, 50, 2926–2931.
17 (a) H. Dvorˇa´kova´, D. Dvorˇa´k and A. Holy´, Tetrahedron Lett., 1996,
37, 1285–1288; (b) H. Dvorˇa´kova´, D. Dvorˇa´k and A. Holy´, Collect.
Czech. Chem. Commun., 1998, 63, 2065–2074.
18 A. Bra˚the, L.-L. Gundersen, K. E. Malterud and F. Rise, Arch. Pharm.,
2005, 338, 159–166.
19 (a) J. Furukawa, N. Kawabata and J. Nishimura, Tetrahedron, 1968, 24,
53–58; (b) P. W. Collins, A. F. Gasiecki, W. E. Perkins, G. W. Gullikson,
P. H. Jones and R. F. Bauer, J. Med. Chem., 1989, 32, 1001–1006.
20 P. Mu¨ller and F. Lacrampe, Helv. Chim. Acta, 2004, 87, 2848–2858.
21 (a) P. H. Mazzocchi and H. J. Tamburin, J. Org. Chem., 1973, 38, 2221–
2225; (b) A. Menzek, N. Sarac¸og˘lu, M. Krawiec, W. H. Watson and M.
Balcı, J. Org. Chem., 1995, 60, 829–832.
22 P. Mu¨ller, F. Bernardinelli and P. Nury, Tetrahedron: Asymmetry, 2002,
13, 551–558.
23 L. J. Stuyver, T. Whitaker, T. R. McBrayer, B. I. Hernandez-Santiago,
S. Lostia, P. M. Tharnish, M. Ramesh, C. K. Chu, R. Jordan, J. X.
Shi, S. Rachakonda, K. A. Watanabe, M. J. Otto and R. F. Schinazi,
Antimicrob. Agents Chemother., 2003, 47, 244–254.
24 T. C. McKenzie and J. W. Epstein, J. Org. Chem., 1982, 47, 4881–4884.
25 R. K. Robins, E. F. Godefroi, E. C. Taylor, L. R. Lewis and A. Jackson,
J. Am. Chem. Soc., 1961, 83, 2574–2579.
26 Z. Kazimierczuk, H. B. Cottam, G. R. Revankar and R. K. Robins,
J. Am. Chem. Soc., 1984, 106, 6379–6382.
27 L.-L. Gundersen, A. K. Bakkestuen, A. J. Aasen, H. Øveras and F.
Rise, Tetrahedron, 1994, 50, 9743–9756.
28 A. Brathe, L.-L. Gundersen, F. Rise, A. B. Eriksen, A. V. Vollsnes and
L. Wang, Tetrahedron, 1999, 55, 211–228.
29 A. T. Øveras, A. K. Bakkestuen, L.-L. Gundersen and F. Rise, Acta
Chem. Scand., 1997, 51, 1116–1124.
30 A. Altomare, G. Cascarano, G. Giacovazzo, A. Guagliardi, M. C.
Burla, G. Polidori and M. Camalli, J. Appl. Crystallogr., 1994, 27,
435–435.
31 P. W. Betteridge, J. R. Carruthers, R. I. Cooper, K. Prout and D. J.
Watkin, J. Appl. Crystallogr., 2003, 36, 1487–1487.
Acknowledgements
This work is a part of the research project Z4 055 0506. It
was supported by the “Centre for New Antivirals and Antineo-
plastics” (1M0508), by the Programme for Targeted Research
(1QS400550501) and by Gilead Sciences, Inc. (Foster City, CA,
USA). Antiviral activity was studied by E. Mabery and Drs I. Shih
and R. Mackman (Gilead). The contribution of these scientists is
gratefully acknowledged.
Notes and references
1 (a) M. Hocek, A. Holy´, I. Votruba and H. Dvorˇa´kova´, J. Med. Chem.,
2000, 43, 1817–1825; (b) M. Hocek, A. Holy´, I. Votruba and H.
Dvorˇa´kova´, Collect. Czech. Chem. Commun., 2001, 66, 483–499.
2 M. Hocek, P. Nausˇ, R. Pohl, I. Votruba, P. A. Furman, P. M. Tharnish
and M. J. Otto, J. Med. Chem., 2005, 48, 5869–5873.
3 (a) A. K. Bakkesteun, L.-L. Gundersen, G. Langli, F. Liu and
J. M. J. Nolsøe, Bioorg. Med. Chem. Lett., 2000, 10, 1207–1210; (b) G.
Andersen, L.-L. Gundersen, J. Nissen-Meyer, F. Rise and B. Spilsberg,
Bioorg. Med. Chem. Lett., 2002, 12, 567–569; (c) L.-L. Gundersen, J.
Nissen-Meyer and D. Spilsberg, J. Med. Chem., 2002, 45, 1383–1386;
(d) A. K. Bakkestuen, L.-L. Gundersen and B. T. Utenova, J. Med.
Chem., 2005, 48, 2710–2723; (e) M. Brændvang and L.-L. Gundersen,
Bioorg. Med. Chem., 2005, 13, 6360–6373; (f) M. Brændvang and L.-L.
Gundersen, Bioorg. Med. Chem., 2007, 15, 7144–7165.
4 (a) A. J. Cocuzza, D. R. Chidester, S. Culp, L. Fitzgerald and P. Gilligan,
Bioorg. Med. Chem. Lett., 1999, 9, 1063–1066; (b) L. C. W. Chang, R. F.
Spanjersberg, J. K. von Frijtag, Drabbe Kunzel, T. Mulder-Krieger, J.
Brussee and A. P. Ijzerman, J. Med. Chem., 2006, 49, 2861–2867.
5 J. A. Montgomery and K. Hewson, J. Med. Chem., 1968, 11, 48–52.
6 W. B. Parker, S. A. King, P. W. Allan, L. L. Bennett, Jr., J. A. Secrist
III, J. A. Montgomery, K. S. Gilbert, W. R. Waud, A. H. Wells, G. Y.
Gillespie and E. J. Sorscher, Hum. Gene Ther., 1997, 8, 1637–1644.
ˇ
7 (a) P. Silha´r, R. Pohl, I. Votruba and M. Hocek, Org. Lett., 2004, 6,
ˇ
3225–3228; (b) P. Silha´r, R. Pohl, I. Votruba and M. Hocek, Collect.
Czech. Chem. Commun., 2005, 70, 1669–1695.
ˇ
8 P. Silha´r, R. Pohl, I. Votruba and M. Hocek, Org. Biomol. Chem., 2005,
3, 3001–3007.
ˇ
9 P. Silha´r, R. Pohl, I. Votruba and M. Hocek, Synthesis, 2006, 1848–
1852.
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