Synthesis, cytostatic, and antiviral activity of novel 6-[2-(dialkylamino)ethyl]-, 6-(2-alkoxyethyl)-, 6-[2-(alkylsulfanyl)ethyl]-, and 6-[2-(dialkylamino)vinyl]purine nucleosides

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Bioorganic & Medicinal Chemistry 16 (2008) 1400–1424

Synthesis, cytostatic, and antiviral activity of novel

6-[2-(dialkylamino)ethyl]-, 6-(2-alkoxyethyl)-,

6-[2-(alkylsulfanyl)ethyl]-, and 6-[2-(dialkylamino)vinyl]purine

nucleosides

a,

a

b

ˇ ^a

*

Martin Kuchar, Michal Hocek, Radek Pohl, Ivan Votruba, I-hung Shih,

Eric Mabery^band Richard Mackman^b

^aInstitute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,

Gilead Sciences & IOCB Research Center, Flemingovo nam. 2, CZ-16610 Prague 6, Czech Republic

^bGilead Sciences, Inc., 333 Lakeside Drive, Foster City, CA 94404, USA

Received 10 August 2007; revised 17 October 2007; accepted 18 October 2007

Available online 23 October 2007

Abstract—An eﬃcient and facile synthesis of a large series of diverse 6-[2-(dialkylamino)vinyl]-, 6-[2-(dialkylamino)ethyl]-, 6-(2-alk-

oxyethyl)-, and 6-[2-(alkylsulfanyl)ethyl]purine nucleosides (35 examples of both ribo- and 2⁰-deoxyribonucleosides) was developed.

The key transformations involved conjugate nucleophilic additions of amines, alcoholates, or thiolates to Tol-protected 6-alkylylp-

urine or 6-vinylpurine nucleosides. 6-[(2-Dialkylamino)vinyl]- and some 6-[(2-dialkylamino)ethyl]purine ribonucleosides exerted sig-

niﬁcant cytostatic eﬀects and some anti-HCV activity with low selectivity.

1. Introduction

coupling reactions¹¹of 6-halopurines with functional-

ized organometallics followed by further functional

group transformations (deoxoﬂuorination, etc.). Then

we turned our interest toward studying the biological

activity of related 6-(2-substituted ethyl)purines that

are not readily accessible via analogous cross-coupling

reactions since the corresponding b-substituted organo-

metallics can easily undergo b-elimination.^12,13There-

fore the methods of our choice were conjugate

additions of nucleophiles to 6-vinyl- and 6-ethynylpu-

rines. Some scattered examples of these reactions were

known,^14,15however, recently we have reported¹⁶a sys-

tematic study of the scope and limitations of this meth-

odology. Diverse amines, thiolates, and alkoxides

readily added¹⁶to protected 6-vinylpurine bases at

ambient temperature without any catalyst to form the

corresponding 6-(2-dialkylaminoethyl)-, 6-(2-alkylsulfa-

nylethyl)-, and 6-(2-alkoxyethyl)purines. An interesting

dichotomy was observed¹⁶for additions to 6-ethynylpu-

rines. While the additions of amines led to enamine

derivatives (one equivalent of the nucleophile reacted),

S- and O-nucleophiles underwent double additions¹⁶to

form the corresponding acetals and thioacetals. Some

of the b-substituted 6-ethyl- and 6-vinylpurine bases

exerted¹⁶moderate cytostatic activities. Taking into

Purine bases and nucleosides bearing diverse C-substitu-

ents (aryl, alkenyl, alkynyl, or alkyl groups) in position 6

are an important class of compounds possessing broad

spectrum of biological eﬀects: for example, cytostatic,¹

antiviral,²and antimicrobial³activity or receptor modu-

lation.⁴Purines bearing functionalized C-substituents

are still quite rare and therefore are a subject of exten-

sive study in our laboratory. We have reported the syn-

thesis and cytostatic activity of 6-(hydroxymethyl)-,⁵

6-(ﬂuoromethyl)-,⁶and 6-(diﬂuoromethyl)purine⁷bases

and nucleosides, as well as the synthesis of (purin-6-

yl)alanines⁸and -phenylalanines.⁹Very recently we have

ﬁnished¹⁰a synthesis of a large series of 6-(mono- and

dialkylaminomethyl)-, 6-(alkoxymethyl)-, and 6-(alkyl-

sulfanylmethyl)purine nucleosides that also exerted sig-

niﬁcant cytostatic eﬀects and moderate non-selective

anti-HCV activities. All these syntheses relied on cross-

Keywords: Purines; Nucleosides; Conjugate additions; Cytostatic

activity.

*

Corresponding author. Tel.: +420 220183324; fax: +420

220183559; e-mail: hocek@uochb.cas.cz

doi:10.1016/j.bmc.2007.10.063

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M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1401

account these promising results and also the known¹⁵

NR'₂

cytostatic eﬀect of 6-(aminoethyl)purine ribonucleoside,

we have decided to prepare large series of purine nucleo-

sides (both in ribo and 2⁰-deoxyribo series) bearing these

functionalized ethyl or vinyl groups in position 6. Here

we report on the synthesis of these compounds using

conjugate additions of nucleophiles and on their cyto-

static and antiviral activities.

N

NHR'₂

N

THF, rt

24 h

N

R

N

R

3, 4

1, 2

NR'₂

=

R =

CH₃

TolO

2. Results and discussion

2.1. Chemistry

a

b

N

e

f

N

O

N

O

CH₃

Me

OTol OTol

1, 3

CH₂CH₃

In order to apply the conjugate additions of nucleo-

philes to 6-vinyl- or 6-ethynylpurine nucleosides, suit-

able protecting groups for the sugar moiety must be

selected. The protecting groups must be reasonably sta-

ble toward nucleophiles (amines and thiolates) under

mild conditions but, on the other hand, be easily remov-

able at the end. Therefore, we have chosen p-toluoyl

(Tol) groups that are more stable toward nucleophilic

cleavage compared to acetyl groups. Starting Tol-pro-

tected 6-ethynylpurine nucleosides 1 and 2 were pre-

CH₂CH₃

TolO

S

N

O

(CH₂)₃CH₃

g

c

N

OTol

2, 4

(CH₂)₃CH₃

N

d

Scheme 2. Additions of amines to 6-ethynylpurine nucleosides.

pared¹⁷

by

cross-coupling

reactions

of the

Table 1. Additions of amines to 6-ethynylpurine nucleosides

corresponding protected 6-chloropurine nucleosides

with (trimethylsilyl)acetylene followed by desilylation

of the intermediate using TBAF in THF/AcOH to pre-

vent deacylation of the sugar (Scheme 1).

Entry Starting

compound

Amine

Product Yield (%)

1

2

1

2

Dimethylamine

Diethylamine

Dibutylamine

Piperidine

3a

3b

3c

3d

3e

78

92

89

68

97

62

73

90

87

79

96

78

95

41

3

Initially we focused on the conjugate additions of

amines. A series of experiments with seven secondary

amines were performed under previously established

conditions at ambient temperature in dry THF without

any catalyst or additive. In all cases the reactions pro-

ceeded very well to provide a series of protected (E)-6-

[2-(dialkylamino)vinyl]purines 3a–3g and 4a–4g in good

to excellent yields (Scheme 2, Table 1). In accordance

with our previous report,¹⁶only E-conﬁguration enam-

ines were formed by addition of secondary amines.

Cleavage of the toluoyl groups was not observed under

these reaction conditions (see Scheme 2).

4

5

Morpholine

6

Benzyl(methyl)amine 3f

7

Thiazolidine

Dimethylamine

Diethylamine

Dibutylamine

Piperidine

3g

4a

4b

4c

4d

4e

8

9

10

11

12

13

14

Morpholine

Benzyl(methyl)amine 4f

Thiazolidine 4g

Furthermore, we have examined the nucleophilic addi-

tion of ethane-1,2-dithiol in the presence of catalytic

amounts (10 mol%) of NaH in dry THF. These reac-

tions proceeded smoothly at ambient temperature in

24 h to give the dithioacetals 5 and 6 in excellent yields

(Scheme 3). Similarly, in these reactions no cleavage of

the toluoyl-protecting groups was observed.

TMS

Cl

TMS

N

Pd(PPh₃)_4,CuI

DMF, Et₃N

N

R

R =

TBAF, AcOH

THF

In additon, we have studied nucleophilic additions

onto toluoylated 6-vinylpurine nucleosides 7 and 8,

easily available by the Stille cross-coupling of the cor-

responding Tol-protected 6-chloropurine nucleosides

with vinyl(tributyl)tin (analogy to Ref. 14d). Conju-

gate addition, by a series of secondary amines, to

protected 6-vinylpurine ribonucleoside 7 and 2⁰-deoxy-

ribonucleoside 8 was performed under analogous

conditions (THF at room temperature) to provide a

series of 6-(2-dialkylaminoethyl)purine nucleosides

9a–9g and 10a–10g in very good yields (Scheme 4

and Table 2).

TolO

O

OTol OTol

N

1

N

1

O

R

70%

OTol

2 73%

2

Scheme 1. Preparation of the starting 6-ethynylpurine nucleosides.

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M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1402

11a–11d in very good yields (Scheme 5 and Table 3)

without cleavage of the protecting groups.

S

HS

SH

N

With some S- or O-nucleophiles the addition proceeded

with simultaneous deprotection of the toluoyl-protect-

ing groups to yield the target free purine nucleosides

in one step (Scheme 6, Table 4). Additions of sodium

methanethiolate were performed in a mixture of MeOH

and water (Entries 1 and 3) to provide the desired 6-[2-

(methylsulfanyl)ethyl]purine nucleosides 12e and 13e,

clearly demonstrating the higher reactivity of the S-

nucleophiles compared to O-nucleophiles. Addition of

sodium methoxide in methanol produced the 6-[2-(meth-

oxy)ethyl]purines 12f and 13f (Entries 2 and 4).

N

NaH, THF

rt, 24 h

N

R

90%

84%

N

R

1, 2

R =

5

6

TolO

O

OTol

2, 6

OTol OTol

1, 5

Scheme 3. Additions of ethane-1,2-dithiol to 6-ethynylpurine

nucleosides.

The whole series of toluoyl-protected nucleosides 3–6,

9–11 was deprotected by treatment with sodium meth-

oxide in methanol to give the corresponding free nucleo-

sides 12–19 generally in good yields (Scheme 7 and

Table 5). In some cases the isolated yields were moderate

due to attrition of material during column chromatogra-

phy isolation (Entries 17 and 25).

NR'₂

N

NHR'₂

N

R

9, 10

7, 8

3. Biological activity

NR'₂

All the title 35 nucleosides 12–19 were subjected to bio-

logical activity screening. The cytostatic activity in vitro

(inhibition of cell growth) was studied on the following

cell cultures: (i) mouse leukemia L1210 cells (ATCC

CCL 219); (ii) human promyelocytic leukemia HL60 cells

(ATCC CCL 240); (iii) human cervix carcinoma HeLaS3

cells (ATCC CCL 2.2); and (iv) human T lymphoblastoid

CCRF-CEM cell line (ATCC CCL 119). The cytostatic

activities of compounds from this series were evaluated

by estimating the cell count in a haematological analyzer.

In parallel the cell viability was determined by XTT

analysis. Whilst the 2⁰-deoxyribonucleoside derivatives

=

R =

CH₃

TolO

a

b

N

e

f

N

O

Me

OTol OTol

7, 9

CH₂CH₃

N

CH₂CH₃

TolO

S

N

O

(CH₂)₃CH₃

g

c

d

N

OTol

8, 10

(CH₂)₃CH₃

N

Scheme 4. Additions of amines to 6-vinylpurine nucleosides.

XR'

Table 2. Additions of amines to 6-vinylpurine nucleosides

N

HXR'

N

Entry Starting

compound

Amine

Product Yield (%)

NaH, THF

N

R

1

2

7

8

Dimethylamine

Diethylamine

Dibutylamine

Piperidine

9a

9b

81

84

80

75

82

78

79

96

88

84

90

11

7

3

9c

9d

R =

TolO

XR'

S

=

4

5

Morpholine

Benzyl(methyl)amine

Thiazolidine

9e

a

b

O

6

9f

9g

7

OTol OTol

8

Dimethylamine

Dibutylamine

Morpholine

10a

10c

10e

S

O

9

7, 11

10

11

OMe

Benzyl(methyl)amine 10f

S

c

d

S

N

S

A study in which various thiolates were added to the

protected 6-vinylpurine ribonucleoside 7 was our next

goal. Addition of thiols in the presence of a catalytic

amount (10 mol%) of NaH proceeded at room tempera-

ture to give the 6-{[(alkyl)sulfanyl]ethyl}purines

N

Scheme 5. Additions of thiolates to 6-vinylpurine nucleosides.

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M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1403

Table 3. Additions of thiolates to 6-vinylpurine nucleosides

Entry

Starting compound

Thiol

Reaction time

Product

Yield (%)

1

2

3

4

7

BnSH

6 days

24 h

11a

11b

11c

11d

56

57

87

Methyl thioglycolate

2-Sulfanylbenzothiazole

2-Sulfanylthiazoline

24 h

13, 15, 17, and 19 were all inactive, many ribonucleosides

exerted considerable antiproliferative eﬀects at low

micromolar concentrations in HL-60, CCRF-CEM and

L1210 leukemia cell lines (Table 6). None of the com-

pounds demonstrated eﬀects in the HeLa S3 cell line.

The most powerful antiproliferative compounds were

the 6-(2-dialkylaminovinyl)purine ribonucleosides 14a–

14g, all of which exerted cytostatic eﬀects at low micro-

molar concentrations. The viability data in all these

examples indicated signiﬁcantly lower IC₅₀values com-

pared to the cell count IC₅₀. Taken together, this diﬀer-

ence suggests a signiﬁcant amount of apoptosis in cells

upon exposure to the tested compounds. On the other

hand, several 6-(2-dialkylaminoethyl)purine ribonucleo-

sides 18b, 18c, 18f, which also exerted antiproliferative

eﬀects at micromolar concentrations, gave higher IC₅₀

values in the cell viability assay. This discrepancy was

conﬁrmed by the cell ﬂow analysis. In agreement with

the data on inhibition of cell proliferation, these com-

pounds do not aﬀect the cell cycle course at concentra-

tions corresponding to the cell count IC₅₀. The

signiﬁcant changes were found at the cell viability IC₅₀

determined by XTT test, which shows the G1 block

apparent as an accumulation of cells in G1 phase and

depletion of S phase (Table 7). All the alkoxyethyl- or

(alkylsulfanylethyl)purine ribonucleosides 12a–12f were

inactive.

The title modiﬁed nucleosides were also tested up to

100 lM for antiviral activities in HCV genotype 1b rep-

licon¹⁸(Table 6). With the exception of 15c, 15d and

19a, 19e, the 2⁰-deoxyribonucleosides were inactive,

but many of the ribonucleosides displayed antiviral

activity in the HCV replicon. Unfortunately, in most

cases the compounds lacked selectivity. High anti-

HCV activities (low micromolar concentrations) of the

aminovinyl nucleosides 14a–14g correspond to their

cytostatic eﬀects. These results suggest that the modiﬁed

purine ribonucleosides interfere with critical cell growth

processes and most of the activity toward HCV viral

replication is non-speciﬁc.

The 6-(2-dialkylaminovinyl)-purine ribonucleosides

14a–14g represent a new promising class of antiprolifer-

ative compounds strongly active against leukemia cell

lines. Apparently the mechanism of action of these com-

pounds is diﬀerent from the series of 6-(substituted

methyl)purine ribonucleosides^5–7,10and therefore any

direct comparison or SAR over the whole class of com-

pounds is not possible. On the other hand, the antiviral

eﬀect is only connected with the cytostatic activity and is

non-speciﬁc. Hence these compounds are not promising

antiviral agents.

SMe

MeSNa

N

MeOH, THF

N

R'

N

12e, 13e

N

OMe

N

R

7, 8

MeONa

MeOH

N

4. Conclusions

N

R'

12f, 13f

N

The approach described, based on nucleophilic

conjugate additions of N-, O-, and S-nucleophiles to 6-

vinyl- and 6-ethynylpurine nucleosides, is a convenient

methodology for the generation of diverse dialkylamino-

vinyl, dialkylaminoethyl, alkyloxyethyl, and alkylsulfa-

nylethyl derivatives of purine nucleosides. A large

number of modiﬁed derivatives can be easily generated

from the common intermediates in one or two simple

steps. Some of the ribonucleosides (in particular

6-(2-dialkylaminovinyl)purine derivatives 14) exert

strong cytostatic eﬀects.

R' =

HO

O

OH OH

OH

13e,f

12e,f

Scheme 6. One-pot addition of nucleophiles to 6-vinylpurines with

simultaneous deprotection.

Table 4. One-pot addition of nucleophiles to 6-vinylpurines with simultaneous deprotection

Entry

Starting compound

Nucleophile

Solvent

Reaction time

Product

Yield (%)

1

2

3

4

7

8

MeSNa

MeONa

MeSNa

MeOH

MeOH, THF

MeOH

1 h

12e

12f

13e

13f

44

35

94

70

24 h

1 h

MeOH, THF

MeOH

24 h

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M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1404

5. Experimental

Bruker Avance 400 (¹H at 400 MHz, ¹³C at 100.6 MHz).

¹H and ¹³C NMR spectra were referenced to the signal

of TMS or to the solvent residual signal. ¹H, ¹³C-HMBC

experiments were performed for complete assignment of

all signals. Starting compounds 2a, 2b¹⁷were prepared

according to literature procedures.

Mass spectra were measured on a ZAB-EQ (VG Analyt-

ical) spectrometer. NMR spectra were recorded on Bru-

ker Avance 500 (¹H at 500 MHz, ¹³C at 125.8 MHz) and

X

5.1. 6-[2-(Trimethylsilyl)ethynyl]-9-(2,3,5-tri-O-toluoyl-

b-^D-ribofuranosyl)purine

R =

TolO

MeONa

MeOH

N

O

Triethylamine (2 ml) and (trimethylsilyl)acetylene

(6.5 ml, 26.5 mmol) were added to an argon purged mix-

ture of 6-chloropurine nucleoside (8.5 g, 13.26 mmol),

CuI (200 mg, 1.05 mmol) and [Pd(PPh₃)₄] (300 mg,

0.26 mmol) in DMF (80 ml) and the mixture was stirred

at 90 ꢁC for 6 h. The resulting mixture was concentrated

under reduced pressure and the residue was puriﬁed by

column chromatography (silica gel, hexane/ethyl ace-

tate) aﬀording the product as yellowish foam (8.58 mg,

N

OTol OTol

R

R'

3, 5, 9, 11

3, 4

14, 15

TolO

O

S

N

OTol

MeONa

MeOH

4, 6, 10

N

R

N

1

R' =

HO

94%). H NMR (400 MHz, CDCl₃): 0.33 (s, 9H, CH₃-

TMS); 2.37 and 2.42 (2· s, 9H, CH₃-Tol); 4.66 (dd,

R'

5, 6

16, 17

1H, J_gem= 12.3, J_{5 b,4}= 4.0, H-5⁰b); 4.82 (td, 1H,

O

0

J_{4 ,3}= 4.4, J_{4 ,5}= 4.0, 3.1, H-4⁰); 4.91 (dd, 1H,

X

0

OH OH

J_gem= 12.3, J_{5 a,4}= 3.1, H-5⁰a); 6.22 (dd, 1H,

0

12, 14, 16, 18

J_{3 ,2}= 5.6, J_{3 ,4}= 4.4, H-3⁰); 6.40 (t, 1H, J_{2 ,3}= 5.6,

0

MeONa

MeOH

N

HO

0

N

J_{2 ,1}= 5.4, H-2⁰); 6.49 (d, 1H, J_{1 ,2}= 5.4, H-1⁰); 7.15

and 7.25 (2· m, 6H, H-m-Tol); 7.80, 7.92, and 7.97

(3· m, 3· 2H, H-o-Tol); 8.28 (s, 1H, H-8); 8.80 (s, 1H,

H-2). ¹³C NMR (100.6 MHz, CDCl₃): ꢀ0.48 (CH₃-

TMS); 21.65 (CH₃-Tol); 63.21 (CH₂-5⁰); 71.33 (CH-3⁰);

73.61 (CH-2⁰); 81.08 (CH-4⁰); 86.91 (CH-1⁰); 98.24

O

N

R

R'

OH

9, 10, 11

12, 18, 19

15, 17, 19

Scheme 7. The cleavage of the toluoyl-protective group.

Table 5. The cleavage of the toluoyl-protective group

Entry

Starting compound

X

Product

Yield (%)

1

2

3a

3b

3c

Me₂N–

Et₂N–

Bu₂N–

14a

14b

14c

14d

14e

14f

14g

15a

15b

15c

15d

15e

15f

15g

16

72

84

66

71

89

90

63

89

81

95

77

76

90

68

84

96

41

63

59

56

76

68

71

79

38

68

76

78

80

68

91

3

4

3d

3e

Piperidine-1-yl

Morpholine-4-yl

Bn(Me)N-

5

6

3f

7

3g

4a

4b

4c

Thiazolidine-1-yl

Me₂N–

Et₂N–

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

Bu₂N–

4d

4e

Piperidine-1-yl

Morpholine-4-yl

Bn(Me)N–

4f

4g

5

Thiazolidine-1-yl

–SCH₂CH₂S–

Me₂N–

6

17

9a

9b

9c

18a

18b

18c

18d

18e

18f

18g

19a

19c

19e

19f

12a

12b

12c

12d

Et₂N–

Bu₂N–

9d

9e

Piperidine-1-yl

Morpholine-4-yl

Bn(Me)N–

9f

9g

10a

10c

10e

10f

11a

11b

11c

11d

Thiazolidine-1-yl

Me₂N–

Bu₂N–

Morpholine-4-yl

Bn(Me)N–

BnS–

MeOCOCH₂S–

Benzothiazole-2-ylsulfanyl

Thiazoline-2-ylsulfanyl

5.2. 6-Ethynyl-9-(2,3,5-tri-O-toluoyl-b-^D-ribofurano-

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M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1405

Table 6. Biological activities of title nucleosides

a

Compound

Cytostatic activity IC₅₀(lM)

HCV antiviral activity and cytotoxicity

EC₅₀(lM) HCV replicon^bCC₅₀(lM) Huh7^c(MT-4)^d

L1210

HL60

CCRF-CEM

12a

12b

n.a.

>100

54

>100

>100 (>100)

12c

12d

n.a.

>100

40

>100

>100 (13)

5

12e

12f

n.a.

14a

14b

2.2 0.12

2.2 0.13

2.0 0.1

1.55 0.09

2.3 0.1

2.1 0.1

4.8 0.25

n.a.

3.3 0.2 (0.62 0.03)

2.3 0.1 (0.81 0.02)

7.2 0.4 (0.84 0.03)

1.25 0.07 (0.8 0.02)

1.0 0.07 (0.67 0.05)

2.5 0.12 (0.83 0.12)

4

8

14c

14d

1

2

2.3 0.1 (0.44 0.026) 2.1 0.15 (0.32 0.01)

4.5 0.2 (0.31 0.01) 2.4 0.16 (0.41 0.04)

3.6 0.2 (0.57 0.021) 2.3 0.11 (0.78 0.07) 0.34

1

26 (6)

23

14e

14f

5

1

14g

9.1 0.5 (1.4 0.08)

n.a.

4.8 0.25 (0.39 0.02)

3

7

15c^e

15d^e

16

n.a.

85

53

>100

7

>100

20

n.a.

18a

18b

n.a.

6.8 0.49 (17.3 0.8)

5.3 0.3 (13.8 0.6)

5.2 0.35

4.4 0.25

n.a.

1.25 0.07 (0.8 0.02) 6.7

6.4 0.44 (4.59 0.14) 5.6

45

37

18c

18d

n.a.

37

6

>250

31

132

18e

n.a.

18f

7.9 0.5

n.a.

11.2 0.75 (17.7 1.5) 5.7 0.36 (5.83 0.23) 11

19a^e

19e^e

FUdR^f

2⁰CMeA^g

n.a.

116

25

>250

>100 (13)

—

0.012 0.003 0.012 0.003

—

0.017 0.004

—

0.23

—

>100

^aConcentration of a compound needed to reduce population growth by 50% in vitro (in parentheses in italics values of XTT test).

^bAntiviral activity in HCV-Con1 replicon (N = 2).

^cMTT measurement of cellular toxicity in Huh-7 cells harboring con-1 replicon (N = 2).

^dCellular toxicity in MT-4 cells (N = 2).

^e2⁰-Deoxyribonucleosides.

^f1-(b-D-2-Deoxy-erythro-pentofuranosyl)-5-ﬂuorouracil.

^g2⁰-Methyl-adenosine.

Table 7. The cell cycle analysis in HL-60 cells (relative changes)^a

syl)purine (1)

Compound

G1_t/G1_c

S_t/S_c

G2/M_t/G2/M_c

18b, 4.5 lM

18b, 18 lM

18c, 3.5 lM

18c, 14 lM

18g, 9 lM

18g, 18 lM

18f, 4.5 lM

18f, 18 lM

0.99

1.38

0.85

1.51

1.13

0.58

1.08

nd

1.08

0.78

1.15

0.68

0.96

0.95

nd

0.80

0.65

0.93

0.64

0.72

0.80

0.94

nd

A solution of TBAFÆ3H₂O (7.5 mmol) in THF (20 ml)

was slowly added to a stirred mixture of 6-[(trimethyl-

silyl)ethynyl]purine nucleoside (475 mg, 1 mmol), acetic

acid (0.55 ml, 9 mmol) in THF (30 ml) at 0 ꢁC. TLC

indicated the disappearance of starting TMS derivative

after 0.5 h. The mixture was diluted with AcOEt

(150 ml) and washed with saturated aqueous sodium

chloride solution (3· 150 ml). The organic phase was

dried over MgSO₄and evaporated in vacuo and the res-

idue was puriﬁed by column chromatography (silica gel,

hexane/ethyl acetate) aﬀording product 1 (3.32 g, 70%)

^ac, control cells; t, cells grown in the presence of tested compound; nd,

not determinable.

1

as yellowish foam. H NMR (400 MHz, CDCl₃): 2.37

and 2.41 (2· s, 9H, CH₃-Tol); 3.72 (s, 1H, HC„C–);

(–C„C-TMS); 105.80 (–C„C-TMS); 125.53, 125.95,

and 126.47 (C-i-Tol); 129.17, 129.22, and 129.29 (CH-

m-Tol); 129.68, 129.81 (CH-o-Tol); 134.83 (C-5);

141.60 (C-6); 144.18, 144.54, and 144.65 (C-p-Tol);

144.02 (CH-8); 151.34 (C-4); 152.70 (CH-2); 165.07,

165.31, and 166.09 (CO). FAB-MS, m/z (rel %) = 703

(10) [M+H]⁺, 487 (42), 325 (8), 279 (10), 215 (6), 119

(100), 91 (10). HRMS Calcd for C₃₉H₃₉N₄O₇Si

[M+H]⁺703.2588. Found: 703.2578. IR (CHCl₃):

3115, 3093, 3063, 3034, 2903, 1727, 1612, 1582, 1528,

1510, 1497, 1409, 1379, 1334, 1326, 1311, 1296, 1280,

1267, 1254, 1180, 1126, 1114, 1093, 1020, 855, 849,

840, 691, 640, 476.

4.67 (dd, 1H, J_gem= 12.3, J_{5 b,4}= 4.0, H-5⁰b); 4.84 (td,

0

1H, J_{4 ,3}= 4.4, J_{4 ,5}= 4.0, 3.1, H-4⁰); 4.92 (dd, 1H,

0

J_gem= 12.3, J_{5 a,4}= 3.1, H-5⁰a); 6.22 (dd, 1H,

J_{3 ,2}= 5.6, J_{3 ,4}= 4.4, H-3⁰); 6.40 (t, 1H, J_{2 ,3}= 5.6,

0

J_{2 ,1}= 5.3, H-2⁰); 6.49 (d, 1H, J_{1 ,2}= 5.3, H-1⁰); 7.16

and 7.25 (2· m, 6H, H-m-Tol); 7.81, 7.92, and 7.97

(3· m, 3· 2H, H-o-Tol); 8.31 (s, 1H, H-8); 8.83 (s, 1H,

H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.62 (CH₃-

Tol); 63.16 (CH₂-5⁰); 71.29 (CH-3⁰); 73.67 (CH-2⁰);

77.73 (–C„CH); 81.07 (CH-4⁰); 86.33 (HC„C–);

86.99 (CH-1⁰); 125.49, 125.90, and 126.42 (C-i-Tol);

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1406

129.16, 129.20, and 129.27 (CH-m-Tol); 129.63, 129.79

(CH-o-Tol); 135.42 (C-5); 140.99 (C-6); 144.20, 144.54,

and 144.67 (C-p-Tol); 144.27 (CH-8); 151.24 (C-4);

152.69 (CH-2); 165.08, 165.28, and 166.06 (CO). FAB-

MS, m/z (rel %) = 653 (34) [M+Na]⁺, 631 (10)

[M+H]⁺, 487 (78), 215 (8), 119 (100), 91 (12). HRMS

Calcd for C₃₆H₃₁N₄O₇[M+H]⁺631.2192. Found:

631.2167. IR (CHCl₃): 3303, 3031, 2119, 1727, 1612,

1583, 1510, 1494, 1455, 1408, 1379, 1334, 1298,

1245, 1180, 1126, 1114, 1093, 1043, 1020, 839, 691,

639, 476.

J_cis= 11.4, J_gem= 1.6, –CH@CHaHb); 6.60 (dd, 1H,

J_{1 ,2}= 8.4, 5.8, H-1⁰); 7.01 (dd, 1H, J_trans= 17.5,

J_gem= 1.6, –CH@CHaHb); 7.20 and 7.28 (2· m, 2·

2H, H-m-Tol); 7.28 (dd, 1H, J_trans= 17.57, J_cis= 11.4,

–CH@CHaHb); 7.88 and 7.97 (2· m, 2· 2H, H-o-Tol);

8.23 (s, 1H, H-8); 8.85 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, CDCl₃): 21.63 and 21.69 (CH₃-Tol);

37.76 (CH₂-2⁰); 63.90 (CH₂-5⁰); 75.06 (CH-3⁰); 83.08

(CH-4⁰); 84.86 (CH-1⁰); 126.34 and 126.57 (C-i-Tol);

126.43 (–CH@CHaHb); 129.21 and 129.24 (CH-m-

Tol); 129.56 and 129.76 (CH-o-Tol); 131.63 (C-5);

131,78 (–CH@CHaHb); 142.56 (CH-8); 144.09 and

144.48 (C-p-Tol); 151.48 (C-4); 152.39 (CH-2); 153.81

(C-6); 165.88 and 166.08 (CO). FAB-MS, m/z (rel

%) = 521 (28) [M+Na]⁺, 499 (10) [M+H]⁺, 305 (16),

293 (42), 279 (12), 185 (8), 173 (18), 147 (18), 119

(100), 81 (64). HRMS Calcd for C₂₈H₂₇N₄O₅[M+H]⁺

499.1981. Found: 499.1964. IR (CHCl₃): 3093, 3066,

3031, 1721, 1635, 1612, 1586, 1572, 1510, 1495, 1422,

1411, 1391, 1382, 1330, 1269, 1248, 1178, 1121, 1103,

1045, 1020, 992, 950, 841, 691, 645, 476.

0

5.3. 6-Vinyl-9-(2,3,5-tri-O-toluoyl-b-^D-ribofurano-

syl)purine (7)

Tributyl(vinyl)tin (2 ml) was added to an argon purged

mixture of 6-chloropurine nucleoside (3.2 g, 5 mmol),

[PdCl₂(PPh₃)₂] (200 mg, 0.26 mmol) in DMF (80 ml)

and the mixture was stirred at 90 ꢁC for 6 h. The result-

ing mixture was concentrated under reduced pressure

and the residue was puriﬁed by column chromatography

(silica gel, hexane/ethyl acetate) aﬀording product 7 as

yellowish foam (2.33 g, 74%). ¹H NMR (400 MHz,

CDCl₃): 2.37 and 2.41 (2· s, 9H, CH₃-Tol); 4.67 (dd,

1H, J_gem= 12.2, J_{5 b,4}= 4.1, H-5 b); 4.82 (td, 1H,

6. General method of nucleophilic addition to amines

0

J_{4 ,3}= 4.4, J_{4 ,5}= 4.1, 3.2, H-4⁰); 4.90 (dd, 1H,

An amine (15 mmol) was added to a solution of ethy-

nylpurines (1.5 mmol) or vinylpurines in dry THF at

room temperature. The mixture was stirred at room

temperature for one day. The resulting mixture was con-

centrated under reduced pressure and the residue was

puriﬁed by column chromatography (silica gel, hexane/

ethyl acetate).

0

J_gem= 12.1, J_{5 a,4}= 3.2, H-5⁰a); 5.95 (dd, 1H,

J_cis= 10.9, J_gem= 1.5, –CH@CHaHb); 6.24 (dd, 1H,

0

J_{3 ,2}= 5.6, J_{3 ,4}= 4.4, H-3⁰); 6.42 (t, 1H, J_{2 ,3}= 5.6,

0

J_{2 ,1}= 5.3, H-2⁰); 6.47 (d, 1H, J_{1 ,2}= 5.3, H-1⁰); 7.01

(dd, 1H, J_trans= 17.6, J_gem= 1.5, –CH@CHaHb); 7.15

and 7.23 (2· m, 6H, H-m-Tol); 7.25 (dd, 1H,

J_trans= 17.6, J_cis= 10.9, –CH@CHaHb); 7.82, 7.90,

and 7.98 (3· m, 3· 2H, H-o-Tol); 8.23 (s, 1H, H-8);

8.83 (s, 1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃):

21.65 and 21.68 (CH₃-Tol); 63.34 (CH₂-5⁰); 71.36

(CH-3⁰); 73.67 (CH-2⁰); 80.94 (CH-4⁰); 86.82

(CH-1⁰); 125.63, 125.99, and 126.53 (C-i-Tol); 126.57

(–CH@CHaHb); 129.16, 129.20, and 129.26 (CH-m-

Tol); 129.71, 129.82 (CH-o-Tol); 131.60 (C-5), 131.78

(–CH@CHaHb); 142.99 (CH-8); 144.13, 144.50, and

144.61 (C-p-Tol); 151.66 (C-4); 152.64 (CH-2); 153.98

(C-6); 165.12, 165.33, and 166.14 (CO). FAB-MS, m/z

(rel %) = 655 (20) [M+Na]⁺, 487 (30), 215 (5), 142 (5),

119 (100), 91 (10). HRMS Calcd for C₃₆H₃₃N₄O₇

[M+H]⁺633.2349. Found: 633.2336. IR (CHCl₃):

3112, 3096, 3063, 3033, 1727, 1635, 1612, 1587, 1574,

1510, 1497, 1423, 1410, 1393, 1379, 1331, 1310, 1298,

1282, 1267, 1249, 1180, 1126, 1114, 1093, 1020, 991,

952, 839, 691, 644, 477.

0

6.1. 6-[(E)-2-(Dimethylamino)vinyl]-9-(2,3,5-tri-O-toluo-

yl-b-^D-ribofuranosyl)purine (3a)

1

Yield 78%, yellow foam. H NMR (400 MHz, CDCl₃):

2.37 and 2.41 (2· s, 9H, CH₃-Tol); 3.04 (br s, 6H,

CH₃–N); 4.67 (dd, 1H, J_gem= 12.1, J_{5 b,4}= 4.1, H-

0

5⁰b); 4.78 (td, 1H, J_{4 ,3}= 4.4, J_{4 ,5}= 4.1, 3.2, H-4⁰);

0

4.86 (dd, 1H, J_gem= 12.1, J_{5 a,4}= 3.2, H-5⁰a); 5.65 (d,

0

1H, J_trans= 12.9, @CH-pur); 6.21 (dd, 1H, J_{3 ,2}= 5.7,

J_{3 ,4}= 4.4, H-3⁰); 6.35 (t, 1H, J_{2 ,3}= 5.7, J_{2 ,1}= 5.6,

0

H-2⁰); 6.47 (d, 1H, J_{1 ,2}= 5.6, H-1⁰); 7.15, 7.20, and

7.25 (3· m, 3· 2H, H-m-Tol); 7.83 and 7.89 (2· m, 2·

2H, H-o-Tol); 7.99 (s, 1H, H-8); 8.01 (m, 2H, H-o-

Tol); 8.25 (br d, 1H, J_trans= 12.9, @CH–N); 8.50 (s,

1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.69 and

21.71 (CH₃-Tol); 63.71 (CH₂-5⁰); 71.51 (CH-3⁰); 73.73

(CH-2⁰); 80.81 (CH-4⁰); 86.15 (CH-1⁰); 90.42 (@CH-

pur); 125.81, 126.12, and 126.66 (C-i-Tol); 128.05 (C-

5); 129.16, 129.20, and 129.33 (CH-m-Tol); 129.79,

129.87, and 129.91 (CH-o-Tol); 139.25 (CH-8); 144.07,

144.43, and 144.49 (C-p-Tol); 149.68 (C-4); 149.80

(@CH–N); 152.82 (CH-2); 157.74 (C-6); 165.16,

165.40, and 166.26 (CO); CH₃N not observed due to

very broad signal. FAB-MS, m/z (rel %) = 676 (30)

[M+H]⁺, 397 (30), 215 (10), 147 (8), 119 (100), 91 (20).

HRMS Calcd for C₃₈H₃₈N₅O₇[M+H]⁺676.2771.

Found: 676.2783. IR (CHCl₃): 3032, 2811, 1727, 1633,

1612, 1586, 1574, 1559, 1510, 1503, 1436, 1417, 1392,

1326, 1311, 1297, 1249, 1180, 1127, 1114, 1099, 1039,

1020, 998, 975, 839, 691, 476.

0

5.4. 6-Vinyl-9-(2-deoxy-3,5-di-O-toluoyl-b-^D-erythro-

pentafuranosyl)purine (8)

This compound was prepared from corresponding 6-

chlorpurine nucleoside according to the procedure for

the preparation of compound 7 in 70% yield as yellowish

foam. ¹H NMR (400 MHz, CDCl₃): 2.39 and 2.43 (2· s,

2· 3H, CH₃-Tol); 2.84 (ddd, 1H, J_gem= 14.2,

J_{2 b,1}= 5.8, J_{2 b,3}= 2.1, H-2⁰b); 3.19 (ddd, 1H,

0

J_gem= 14.2, J_{2 a,1}= 8.4, J_{2 a,3}= 6.4, H-2⁰a); 4.65 (m,

0

2H, H-4⁰, H-5⁰b); 4.78 (m, 1H, H-5⁰a); 5.84 (dt, 1H,

J_{3 ,2}= 6.4, 2.1, J_{3 ,4}= 2.0, H-3⁰); 5.95 (dd, 1H,

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1407

6.2. 6-[(E)-2-(Diethylamino)vinyl]-9-(2,3,5-tri-O-toluoyl-

b-^D-ribofuranosyl)purine (3b)

1612, 1582, 1570, 1559, 1510, 1502, 1430, 1409, 1368,

1326, 1311, 1297, 1246, 1180, 1126, 1114, 1094, 1020,

839, 813, 691, 646, 476.

Yield 92%, yellowish foam. ¹H NMR (400 MHz,

CDCl₃): 1.24 (t, 6H, J_vic= 7.2, CH₃CH₂N); 2.37 and

2.41 (2· s, 9H, CH₃-Tol); 3.35 (q, 4H, J_vic= 7.2,

6.4. 6-[(E)-2-(Piperidine-1-yl)vinyl]-9-(2,3,5-tri-O-tolu-

oyl-b-^D-ribofuranosyl)purine (3d)

0

CH₃CH₂N); 4.67 (dd, 1H, J_gem= 12.1, J_{5 b,4}= 4.1, H-

1

Yield 68%, orange foam. H NMR (400 MHz, CDCl₃):

5⁰b); 4.78 (td, 1H, J_{4 ,3}= 4.3, J_{4 ,5}= 4.1, 3.2, H-4⁰);

0

4.85 (dd, 1H, J_gem= 12.1, J_{5 a,4}= 3.2, H-5⁰a); 5.70 (d,

1.60–1.70 (m, 6H, CH₂-pip); 2.37 and 2.41 (2· s, 9H,

CH₃-Tol); 3.38 (m, 4H, CH₂N-pip); 4.67 (dd, 1H,

0

1H, J_trans= 13.1, @CH-pur); 6.20 (dd, 1H, J_{3 ,2}= 5.7,

J_{3 ,4}= 4.3, H-3⁰); 6.34 (t, 1H, J_{2 ,3}= J_{2 ,1}= 5.7, H-2⁰);

J_gem= 12.1, J_{5 b,4}= 4.1, H-5⁰b); 4.78 (td, 1H,

0

0 0

6.47 (d, 1H, J_{1 ,2}= 5.7, H-1⁰); 7.15, 7.20, and 7.25 (3·

m, 3· 2H, H-m-Tol); 7.82 and 7.89 (2· m, 2· 2H, H-

o-Tol); 7.98 (s, 1H, H-8); 8.01 (m, 2H, H-o-Tol); 8.26

(br d, 1H, J_trans= 13.1, @CH–N); 8.49 (s, 1H, H-2).

¹³C NMR (100.6 MHz, CDCl₃): 13.44 (CH₃CH₂N);

21.69 and 21.71 (CH₃-Tol); 49.43 (CH₃CH₂N); 63.74

(CH₂-5⁰); 71.54 (CH-3⁰); 73.74 (CH-2⁰); 80.83 (CH-4⁰);

86.03 (CH-1⁰); 89.60 (@CH-pur); 125.82, 126.13, and

126.66 (C-i-Tol); 127.86 (C-5); 129.15, 129.20, and

129.33 (CH-m-Tol); 129.79, 129.88, and 129.91 (CH-o-

Tol); 139.03 (CH-8); 144.06, 144.42, and 144.47 (C-p-

Tol); 147.82 (@CH–N); 149.60 (C-4); 152.85 (CH-2);

158.03 (C-6); 165.15, 165.40, and 166.26 (CO). FAB-

MS, m/z (rel %) = 704.3 (30) [M+H]⁺, 487 (4), 218

(22), 119 (100), 91 (14). HRMS Calcd for C₄₀H₄₂N₅O₇

[M+H]⁺704.3084. Found: 704.3073. IR (CHCl₃):

2876, 1727, 1623, 1612, 1584, 1571, 1557, 1510, 1502,

1431, 1409, 1381, 1360, 1326, 1311, 1295, 1281, 1267,

1244, 1180, 1125, 1114, 1094, 1020, 1001, 975, 839,

814, 691, 646, 476.

J_{4 ,3}= 4.4, J_{4 ,5}= 4.1, 3.1, H-4⁰); 4.86 (dd, 1H,

0

J_gem= 12.1, J_{5 a,4}= 3.1, H-5⁰a); 5.78 (d, 1H,

0

J_trans= 13.1, @CH-pur); 6.20 (dd, 1H, J_{3 ,2}= 5.7,

J_{3 ,4}= 4.4, H-3⁰); 6.33 (t, 1H, J_{2 ,3}= J_{2 ,1}= 5.7, H-2⁰);

0

6.47 (d, 1H, J_{1 ,2}= 5.7, H-1⁰); 7.15, 7.20, and 7.25 (3·

m, 3· 2H, H-m-Tol); 7.82 and 7.89 (2· m, 2· 2H, H-

o-Tol); 7.99 (s, 1H, H-8); 8.00 (m, 2H, H-o-Tol); 8.24

(br d, 1H, J_trans= 13.1, @CH–N); 8.48 (s, 1H, H-2).

¹³C NMR (100.6 MHz, CDCl₃): 21.68 and 21.71

(CH₃-Tol); 24.21 and 25.60 (CH₂-pip); 50.57 (CH₂N-

pip); 63.71 (CH₂-5⁰); 71.51 (CH-3⁰); 73.74 (CH-2⁰);

80.81 (CH-4⁰); 86.11 (CH-1⁰); 89.66 (@CH-pur);

125.81, 126.12, and 126.66 (C-i-Tol); 128.04 (C-5);

129.15, 129.19, and 129.32 (CH-m-Tol); 129.78, 129.87,

and 129.91 (CH-o-Tol); 139.13 (CH-8); 144.06, 144.42,

and 144.48 (C-p-Tol); 148.73 (@CH–N); 149.60 (C-4);

152.82 (CH-2); 158.09 (C-6); 165.15, 165.39, and

166.26 (CO). FAB-MS, m/z (rel %) = 716 (16)

[M+H]⁺, 230 (16), 215 (10), 119 (100), 91 (14). HRMS

Calcd for C₄₁H₄₂N₅O₇[M+H]⁺716.3084. Found:

716.3060. IR (CHCl₃): 2945, 2861, 1727, 1624, 1612,

1584, 1571, 1559, 1500, 1446, 1440, 1407, 1344, 1335,

1326, 1295, 1247, 1180, 1162, 1115, 1043, 1026, 1020,

988, 975, 840, 814, 691, 646, 476.

0

6.3. 6-[(E)-2-(Dibutylamino)vinyl]-9-(2,3,5-tri-O-toluoyl-

b-^D-ribofuranosyl)purine (3c)

1

Yield 89%, orange foam. H NMR (500 MHz, CDCl₃):

0.94 (t, 6H, J_vic= 7.3, CH₃CH₂CH₂CH₂N); 1.35 and

1.62 (2· m, 8H, CH₃CH₂CH₂CH₂N); 2.37 and 2.41

(2· s, 9H, CH₃-Tol); 3.27 (t, 4H, J_vic= 7.6,

CH₃CH₂CH₂CH₂N); 4.67 (dd, 1H, J_gem= 12.2,

6.5. 6-[(E)-2-(Morpholine-4-yl)vinyl]-9-(2,3,5-tri-O-tolu-

oyl-b-^D-ribofuranosyl)purine (3e)

1

Yield 97%, yellow foam. H NMR (400 MHz, CDCl₃):

J_{5 b,4}= 4.1, H-5⁰b); 4.78 (td, 1H, J_{4 ,3}= 4.3,

2.37 and 2.41 (2· s, 9H, CH₃-Tol); 3.40 (m, 4H,

CH₂N-morph); 3.76 (m, 4H, CH₂O-morph); 4.67 (dd,

0

J_{4 ,5}= 4.1, 3.2, H-4⁰); 4.85 (dd, 1H, J_gem= 12.2,

0

J_{5 a,4}= 3.2, H-5⁰a); 5.67 (d, 1H, J_trans= 13.1, @CH-

1H, J_gem= 12.2, J_{5 b,4}= 4.2, H-5⁰b); 4.79 (td, 1H,

0 0

0

pur); 6.20 (dd, 1H, J_{3 ,2}= 5.7, J_{3 ,4}= 4.3, H-3⁰); 6.34

J_{4 ,3}= 4.5, J_{4 ,5}= 4.2, 3.2, H-4⁰); 4.87 (dd, 1H,

0 0 0 0

0

(t, 1H, J_{2 ,1}= 5.8; J_{2 ,3}= 5.7, H-2⁰); 6.48 (d, 1H,

J_gem= 12.2, J_{5 a,4}= 3.2, H-5⁰a); 5.86 (d, 1H,

0

0 0

J_{1 ,2}= 5.8, H-1⁰); 7.15, 7.20, and 7.26 (3· m, 3· 2H,

H-m-Tol); 7.82 and 7.89 (2· m, 2· 2H, H-o-Tol); 7.99

(s, 1H, H-8); 8.01 (m, 2H, H-o-Tol); 8.29 (br d, 1H,

J_trans= 13.1, @CH–N); 8.49 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, CDCl₃): 13.83 (CH₃CH₂CH₂CH₂N);

20.12 (CH₃CH₂CH₂CH₂N); 21.68 and 21.71 (CH₃-

Tol); 28.70 and 31.11 (CH₃CH₂CH₂CH₂N); 47.81 and

56.11 (CH₃CH₂CH₂CH₂N); 63.75 (CH₂-5⁰); 71.53

(CH-3⁰); 73.71 (CH-2⁰); 80.81 (CH-4⁰); 85.97 (CH-1⁰);

89.69 (@CH-pur); 125.80, 126.12, and 126.65 (C-i-Tol);

127.81 (C-5); 129.14, 129.19, and 129.32 (CH-m-Tol);

129.79, 129.87, and 129.90 (CH-o-Tol); 138.96 (CH-8);

144.05, 144.42, and 144.46 (C-p-Tol); 148.99 (@CH–

N); 149.58 (C-4); 152.87 (CH-2); 158.09 (C-6); 165.14,

165.40, and 166.26 (CO). FAB-MS, m/z (rel %) = 760

(8) [M+H]⁺, 274 (10), 215 (8), 119 (100), 91 (12). HRMS

Calcd for C₄₄H₅₀N₅O₇[M+H]⁺760.3710. Found:

760.3738. IR (CHCl₃): 2962, 2933, 2875, 1727, 1622,

J_trans= 13.2, @CH-pur); 6.20 (dd, 1H, J_{3 ,2}= 5.7,

0

J_{3 ,4}= 4.5, H-3⁰); 6.34 (t, 1H, J_{2 ,3}= 5.7, J_{2 ,1}= 5.6,

0

H-2⁰); 6.46 (d, 1H, J_{1 ,2}= 5.6, H-1⁰); 7.16, 7.20, and

7.25 (3· m, 3· 2H, H-m-Tol); 7.82, 7.89, and 8.00 (3·

m, 3· 2H, H-o-Tol); 8.02 (s, 1H, H-8); 8.22 (br d, 1H,

J_trans= 13.2, @CH–N); 8.53 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, CDCl₃): 21.69 and 21.71 (CH₃-Tol);

49.19 (CH₂N-morph); 63.66 (CH₂-5⁰); 66.31 (CH₂O-

morph); 71.47 (CH-3⁰); 73.74 (CH-2⁰); 80.81 (CH-4⁰);

86.33 (CH-1⁰); 91.70 (@CH-pur); 125.78, 126.09, and

126.65 (C-i-Tol); 128.51 (C-5); 129.17, 129.21, and

129.31 (CH-m-Tol); 129.78, 129.87, and 129.89 (CH-o-

Tol); 139.80 (CH-8); 144.07, 144.45, and 144.53 (C-p-

Tol); 148.40 (@CH–N); 149.87 (C-4); 152.78 (CH-2);

157.42 (C-6); 165.16, 165.39, and 166.24 (CO). FAB-

MS, m/z (rel %) = 718 (14) [M+H]⁺, 487 (4), 232 (14),

215 (20), 119 (100), 91 (15). HRMS Calcd for

C₄₀H₄₀N₅O₈[M+H]⁺718.2876. Found: 718.2866. IR

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1408

(CHCl₃): 2974, 2925, 2904, 2863, 1727, 1626, 1612, 1587,

1573, 1564, 1510, 1498, 1455, 1443, 1431, 1409, 1388,

1375, 1363, 1327, 1311, 1296, 1245, 1180, 1114, 1094,

1020, 993, 972, 839, 691, 476.

144.10 (C-p-Tol); 144.46 (@CH–N); 144.48 and 144.55

(C-p-Tol); 149.96 (C-4); 152.78 (CH-2); 157.07 (C-6);

165.17, 165.39, and 166.25 (CO). FAB-MS, m/z (rel

%) = 720 (18) [M+H]⁺, 487 (12), 215 (12), 181 (17),

119 (100), 105 (7), 91 (20), 75 (12), 61(10), 57 (22).

HRMS Calcd for C₃₉H₃₉N₅O₇S [M+H]⁺720.2491.

Found: 720.2474. IR (CHCl₃): 3020, 2981, 2869, 1727,

1624, 1612, 1588, 1573, 1564, 1510, 1497, 1438, 1421,

1390, 1368, 1332, 1327, 1311, 1297, 1244, 1180, 1127,

1114, 1094, 1020, 997, 974, 839, 817, 691, 646, 477.

6.6. 6-[(E)-2-(Benzyl(methyl)amino)vinyl]-9-(2,3,5-tri-O-

toluoyl-b-^D-ribofuranosyl)purine (3f)

1

Yield 62%, orange foam. H NMR (500 MHz, CDCl₃):

2.37, 2.40, and 2.41 (3· s, 3· 3H, CH₃-Tol); 2.91 (br s,

3H, CH₃N); 4.50 (s, 2H, CH₂Ph); 4.67 (dd, 1H,

J_gem= 12.2, J_{5 b,4}= 4.1, H-5⁰b); 4.79 (td, 1H,

6.8. 6-[(E)-2-(Dimethylamino)vinyl]-9-(2-deoxy-3,5-di-O-

toluoyl-b-^D-erythro-pentafuranosyl)purine (4a)

0

J_{4 ,3}= 4.4, J_{4 ,5}= 4.1, 3.2, H-4⁰); 4.86 (dd, 1H,

0

J_gem= 12.2, J_{5 a,4}= 3.2, H-5⁰a); 5.79 (d, 1H,

0

1

Yield 90%, orange foam. H NMR (500 MHz, CDCl₃):

0

J_trans= 13.1, @CH-pur); 6.21 (dd, 1H, J_{3 ,2}= 5.8,

J_{3 ,4}= 4.4, H-3⁰); 6.35 (t, 1H, J_{2 ,3}= 5.8, J_{2 ,1}= 5.7,

2.40 and 2.44 (2· s, 2· 3H, CH₃-Tol); 2.83 (ddd, 1H,

0

H-2⁰); 6.48 (d, 1H, J_{1 ,2}= 5.7, H-1⁰); 7.16 and 7.20 (2·

m, 2· 2H, H-m-Tol); 7.24 (m, 4H, H-o-Ph and H-m-

Tol); 7.29 (m, 1H, H-p-Ph); 7.34 (m, 2H, H-m-Ph);

7.83, 7.89, and 8.00 (3· m, 3· 2H, H-o-Tol); 8.00 (s,

1H, H-8); 8.50 (br d, 1H, J_trans= 13.1, @CH–N); 8.53

(s, 1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.69

and 21.71 (CH₃-Tol); 35.18 (CH₃N); 61.40 (CH₂Ph);

63.70 (CH₂-5⁰); 71.51 (CH-3⁰); 73.73 (CH-2⁰); 80.82

(CH-4⁰); 86.15 (CH-1⁰); 90.93 (@CH-pur); 125.78,

126.10, and 126.64 (C-i-Tol); 127.33 (CH-o-Ph); 127.78

(CH-p-Ph); 128.24 (C-5); 128.79 (CH-m-Ph); 129.16,

129.20, and 129.32 (CH-m-Tol); 129.78, 129.87, and

129.90 (CH-o-Tol); 136.42 (C-i-Ph); 139.42 (CH-8);

144.08, 144.44, and 144.50 (C-p-Tol); 149.71 (@CH–

N); 149.76 (C-4); 152.83 (CH-2); 157.76 (C-6); 165.15,

165.40, and 166.26 (CO). FAB-MS, m/z (rel %) = 752

(40) [M+H]⁺, 616 (8), 589 (6), 487 (4), 294 (10), 266

(28), 251 (8), 215 (6), 119 (100), 91 (32). HRMS Calcd

for C₄₄H₄₂N₅O₇[M+H]⁺752.3084. Found: 752.3117.

IR (CHCl₃): 3090, 3065, 3033, 2807, 1727, 1625, 1612,

1584, 1571, 1561, 1510, 1505, 1497, 1450, 1413, 1399,

1326, 1311, 1296, 1248, 1180, 1127, 1093, 1020, 839,

815, 691, 646, 476.

J_gem= 14.2, J_{2 b,1}= 5.7, J_{2 b,3}= 2.0, H-2⁰b); 3.07 (br s,

0

6H, CH₃N); 3.09 (ddd, 1H, J_gem= 14.2, J_{2 a,1}= 8.6,

0

J_{2 a,3}= 6.3, H-2⁰a); 4.63 (td, 1H, J_{4 ,5}= 4.2, 4.0,

0

J_{4 ,3}= 2.2, H-4⁰); 4.67 (dd, 1H, J_gem= 12.0,

0

J_{5 b,4}= 4.2, H-5⁰b); 4.74 (dd, 1H, J_gem= 12.0,

0

J_{5 a,4}= 4.0, H-5⁰a); 5.69 (d, 1H, J_trans= 12.9, @CH-

0

pur); 5.80 (dt, 1H, J_{3 ,2}= 6.3, 2.0, J_{3 ,4}= 2.2, H-3⁰);

0

6.57 (dd, 1H, J_{1 ,2}= 8.6, 5.7, H-1⁰); 7.23 and 7.28 (2·

m, 2· 2H, H-m-Tol); 7.92 and 7.97 (2· m, 2· 2H, H-

o-Tol); 8.02 (s, 1H, H-8); 8.33 (br d, 1H, J_trans= 12.9,

@CH–N); 8.51 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 21.67 and 21.73 (CH₃-Tol); 37.96 (CH₂-2⁰);

43.90 (CH₃N); 64.13 (CH₂-5⁰); 75.22 (CH-3⁰); 82.86

(CH-4⁰); 84.40 (CH-1⁰); 90.06 (@CH-pur); 126.43 and

126.71 (C-i-Tol); 127.92 (C-5); 129.26 and 129.28 (CH-

m-Tol); 129.64 and 129.82 (CH-o-Tol); 138.90 (CH-8);

144.08 and 144.46 (C-p-Tol); 149.28 (C-4); 150.19

(@CH–N); 152.19 (CH-2); 157.30 (C-6); 165.97 and

166.20 (CO). FAB-MS, m/z (rel %) = 542 (60)

[M+H]⁺, 190 (100), 174 (8), 147 (14), 119 (70), 91 (20),

81 (48), 58 (8). HRMS Calcd for C₃₀H₃₃N₅O₅[M+H]⁺

542.2403. Found: 542.2404. IR (CHCl₃): 2811, 1720,

1612, 1587, 1572, 1558, 1509, 1503, 1436, 1417, 1413,

1391, 1326, 1311, 1249, 1179, 1120, 1103, 1048, 1021,

841, 814, 691, 647, 475.

0

6.7. 6-[(E)-2-(Thiazolidine-1-yl)vinyl]-9-(2,3,5-tri-O-toluo-

yl-b-^D-ribofuranosyl)purine (3g)

6.9. 6-[(E)-2-(Diethylamino)vinyl]-9-(2-deoxy-3,5-di-O-

toluoyl-b-^D-erythro-pentafuranosyl)purine (4b)

1

Yield 73%, yellow foam. H NMR (500 MHz, CDCl₃):

2.37 and 2.41 (2· s, 9H, CH₃-Tol); 3.09 (t, 2H, J_vic= 6.2,

H-5-thiazolidine); 3.74 (t, 2H, J_vic= 6.2, H-4-thiazoli-

dine); 4.18 (s, 2H, H-2-thiazolidine); 4.67 (dd, 1H,

1

Yield 87%, orange foam. H NMR (500 MHz, CDCl₃):

1.25 (t, 6H, J_vic= 7.2, CH₃CH₂N); 2.40 and 2.44 (2· s,

2· 3H, CH₃-Tol); 2.82 (ddd, 1H, J_gem= 14.2,

J_gem= 12.2, J_{5 b,4}= 4.2, H-5⁰b); 4.79 (td, 1H,

0

J_{4 ,3}= 4.5, J_{4 ,5}= 4.2, 3.2, H-4⁰); 4.86 (dd, 1H,

J_{2 b,1}= 5.7, J_{2 b,3}= 1.9, H-2⁰b); 3.08 (ddd, 1H,

0 0 0 0

0

J_gem= 12.2, J_{5 a,4}= 3.2, H-5⁰a); 5.76 (d, 1H,

J_gem= 14.2, J_{2 a,1}= 8.7, J_{2 a,3}= 6.3, H-2⁰a); 3.37 (q,

0

0 0

4H, J_vic= 7.2, CH₃CH₂N); 4.62 (td, 1H, J_{4 ,5}= 4.2,

J_trans= 13.2, @CH-pur); 6.22 (dd, 1H, J_{3 ,2}= 5.8,

J_{3 ,4}= 4.5, H-3⁰); 6.36 (t, 1H, J_{2 ,3}= 5.8, J_{2 ,1}= 5.5,

4.0, J_{4 ,3}= 2.2, H-4⁰); 4.67 (dd, 1H, J_gem= 12.0,

0

0 0

H-2⁰); 6.46 (d, 1H, J_{1 ,2}= 5.5, H-1⁰); 7.16, 7.20, and

7.25 (3· m, 3· 2H, H-m-Tol); 7.82, 7.89, and 8.00 (3·

m, 3· 2H, H-o-Tol); 8.03 (s, 1H, H-8); 8.41 (br d, 1H,

J_trans= 13.2, @CH–N); 8.54 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, CDCl₃): 21.70 and 21.72 (CH₃-Tol);

30.33 (CH₂-5-thiazolidine); 52.80 (CH₂-4-thiazolidine);

55.41 (CH₂-2-thiazolidine); 63.65 (CH₂-5⁰); 71.47 (CH-

3⁰); 73.74 (CH-2⁰); 80.82 (CH-4⁰); 86.35 (CH-1⁰); 93.74

(@CH-pur); 125.76, 126.08, and 126.63 (C-i-Tol);

128.55 (C-5); 129.18, 129.21, and 129.32 (CH-m-Tol);

129.78, 129.87, and 129.90 (CH-o-Tol); 139.94 (CH-8);

J_{5 b,4}= 4.2, H-5⁰b); 4.74 (dd, 1H, J_gem= 12.0,

0

J_{5 a,4}= 4.0, H-5⁰a); 5.72 (d, 1H, J_trans= 13.1, @CH-

0

pur); 5.79 (dt, 1H, J_{3 ,2}= 6.3, 1.9, J_{3 ,4}= 2.2, H-3⁰);

0

6.57 (dd, 1H, J_{1 ,2}= 8.7, 5.7, H-1⁰); 7.23 and 7.28 (2·

m, 2· 2H, H-m-Tol); 7.92 and 7.97 (2· m, 2· 2H, H-

o-Tol); 8.00 (s, 1H, H-8); 8.27 (br d, 1H, J_trans= 13.1,

@CH–N); 8.50 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 11.83 and 14.30 (CH₃CH₂N); 21.67 and 21.72

(CH₃-Tol); 37.97 (CH₂-2⁰); 42.06 and 50.20

(CH₃CH₂N); 64.16 (CH₂-5⁰); 75.26 (CH-3⁰); 82.82

(CH-4⁰); 84.32 (CH-1⁰); 89.35 (@CH-pur); 126.44 and

0

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M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1409

126.72 (C-i-Tol); 127.85 (C-5); 129.25 and 129.27 (CH-

m-Tol); 129.64 and 129.81 (CH-o-Tol); 138.61 (CH-8);

144.05 and 144.44 (C-p-Tol); 147.79 (@CH–N); 149.29

(C-4); 152.55 (CH-2); 157.90 (C-6); 165.97 and 166.21

(CO). FAB-MS, m/z (rel %) = 592 (6), 570 (40)

[M+H]⁺, 244 (6), 218 (100), 202 (6), 188 (25), 174 (6),

161 (8), 147 (14), 135 (7), 119 (97), 91 (25), 81(64).

HRMS Calcd for C₃₂H₃₆N₅O₅[M+H]⁺570.2716.

Found: 570.2724. IR (CHCl₃): 2979, 1720, 1623, 1613,

1584, 1570, 1558, 1499, 1431, 1403, 1326, 1311, 1243,

1179, 1120, 1103, 1048, 1020, 840, 814, 691, 647, 474.

1H, J_trans= 13.1, @CH–N); 8.51 (s, 1H, H-2). ¹³C

NMR (100.6 MHz, CDCl₃): 21.67 and 21.72 (CH₃-

Tol); 24.19 and 25.56 (CH₂-pip); 37.92 (CH₂-2⁰); 64.14

(CH₂-5⁰); 75.24 (CH-3⁰); 82.81 (CH-4⁰); 84.32 (CH-1⁰);

89.52 (@CH-pur); 126.44 and 126.72 (C-i-Tol); 128.04

(C-5); 129.24 and 129.27 (CH-m-Tol); 129.64 and

129.81 (CH-o-Tol); 138.68 (CH-8); 144.04 and 144.43

(C-p-Tol); 148.62 (@CH–N); 149.32 (C-4); 152.58 (CH-

2); 158.02 (C-6); 165.96 and 166.20 (CO); CH₂N-pip

not observed due to very broad signal. FAB-MS, m/z

(rel %) = 604 (8), 582 (35) [M+H]⁺, 230 (85), 216 (8),

160 (8), 147 (18), 134 (8), 119 (100), 96 (12), 91 (30),

81 (64). HRMS Calcd for C₃₃H₃₆N₅O₅[M+H]⁺

582.2716. Found: 5822734. IR (CHCl₃): 2945, 2860,

1720, 1624, 1613, 1584, 1569, 1510, 1497, 1446, 1440,

1403, 1362, 1345, 1326, 1311, 1246, 1179, 1163, 1120,

1104, 1021, 841, 691, 475.

6.10. 6-[(E)-2-(Dibutylamino)vinyl]-9-(2-deoxy-3,5-di-O-

toluoyl-b-^D-erythro-pentafuranosyl)purine (4c)

1

Yield 79%, yellow foam. H NMR (500 MHz, CDCl₃):

0.95 (t, 6H, J_vic= 7.3, CH₃CH₂CH₂CH₂N); 1.36 and

1.63 (2· m, 8H, CH₃CH₂CH₂CH₂N); 2.40 and 2.44

(2· s, 2· 3H, CH₃-Tol); 2.82 (ddd, 1H, J_gem= 14.2,

6.12. 6-[(E)-2-(Morpholine-4-yl)vinyl]-9-(2-deoxy-3,5-di-

O-toluoyl-b-^D-erythro-pentafuranosyl)purine (4e)

J_{2 b,1}= 5.7, J_{2 b,3}= 1.9, H-2⁰b); 3.08 (ddd, 1H,

0

J_gem= 14.2, J_{2 a,1}= 8.7, J_{2 a,3}= 6.3, H-2⁰a); 3.28 (br t,

4H, J_vic= 7.6, CH₃CH₂CH₂CH₂N); 4.62 (td, 1H,

0

Yield 78%, yellowish foam. ¹H NMR (500 MHz,

J_{4 ,5}= 4.3, 4.1, J_{4 ,3}= 2.2, H-4⁰); 4.67 (dd, 1H,

CDCl₃): 2.40 and 2.44 (2· s, 2· 3H, CH₃-Tol); 2.83

0

J_gem= 12.0, J_{5 b,4}= 4.3, H-5⁰b); 4.73 (dd, 1H,

(ddd, 1H, J_gem= 14.2, J_{2 b,1}= 5.7, J_{2 b,3}= 2.0, H-2⁰b);

0 0 0 0

0

J_gem= 12.0, J_{5 a,4}= 4.1, H-5⁰a); 5.69 (d, 1H,

3.11 (ddd, 1H, J_gem= 14.2, J_{2 a,1}= 8.6, J_{2 a,3}= 6.3, H-

0

J_trans= 13.0, @CH-pur); 5.79 (dt, 1H, J_{3 ,2}= 6.3, 1.9,

2⁰a); 3.40 (m, 4H, CH₂N-morph); 3.77 (m, 4H, CH₂O-

0

J_{3 , 4}= 2.2, H-3⁰); 6.57 (dd, 1H, J_{1 ,2}= 8.7, 5.7, H-1⁰);

7.23 and 7.28 (2· m, 2· 2H, H-m-Tol); 7.92 and 7.97

(2· m, 2· 2H, H-o-Tol); 8.00 (s, 1H, H-8); 8.30 (br d,

1H, J_trans= 13.1, @CH–N); 8.50 (s, 1H, H-2). ¹³C

NMR (100.6 MHz, CDCl₃): 13.83 (CH₃CH₂CH₂

CH₂N); 20.06 (CH₃CH₂CH₂CH₂N); 21.67 and 21.72

(CH₃-Tol); 28.49 and 31.41 (CH₃CH₂CH₂CH₂N);

37.97 (CH₂-2⁰); 47.71 and 55.91 (CH₃CH₂CH₂CH₂N);

64.18 (CH₂-5⁰); 75.27 (CH-3⁰); 82.81 (CH-4⁰); 84.34

(CH-1⁰); 89.31 (@CH-pur); 126.47 and 126.75 (C-i-

Tol); 127.84 (C-5); 129.26 (CH-m-Tol); 129.66 and

129.82 (CH-o-Tol); 138.58 (CH-8); 144.04 and 144.43

(C-p-Tol); 148.95 (@CH–N); 149.29 (C-4); 152.58 (CH-

2); 157.99 (C-6); 165.97 and 166.21 (CO). FAB-MS, m/

z (rel %) = 626 (8) [M+H]⁺, 274 (44), 244 (7), 188 (8),

174 (8), 147 (8), 134 (7), 119 (100), 98 (10), 91 (21), 81

(36), 69 (12), 57 (16). HRMS Calcd for C₃₆H₄₃N₅O₅

[M+H]⁺626.3342. Found: 626.3324. IR (CHCl₃):

3095, 3034, 1720, 1622, 1614, 1582, 1568, 1561, 1510,

1499, 1429, 1370, 1325, 1297, 1269, 1249, 1179, 1120,

1103, 1049, 1021, 841, 813, 691, 475.

0

morph); 4.63 (td, 1H, J_{4 ,5}= 4.3, 4.0, J_{4 , 3}= 2.2, H-

0

4⁰); 4.67 (dd, 1H, J_gem= 11.9, J_{5 b,4}= 4.3, H-5⁰b); 4.75

0

(dd, 1H, J_gem= 11.9, J_{5 a,4}= 4.0, H-5⁰a); 5.80 (dt, 1H,

0

J_{3 ,2}= 6.3, 2.0, J_{3 ,4}= 2.2, H-3⁰); 5.86 (d, 1H,

0

J_trans= 13.3, @CH-pur); 6.57 (dd, 1H, J_{1 ,2}= 8.6, 5.7,

H-1⁰); 7.23 and 7.28 (2· m, 2· 2H, H-m-Tol); 7.92 and

7.97 (2· m, 2· 2H, H-o-Tol); 8.03 (s, 1H, H-8); 8.17

(d, 1H, J_trans= 13.3, @CH–N); 8.55 (s, 1H, H-2). ¹³C

NMR (100.6 MHz, CDCl₃): 21.68 and 21.73 (CH₃-

Tol); 37.91 (CH₂-2⁰); 48.80 (CH₂N-morph); 64.12

(CH₂-5⁰); 66.32 (CH₂O-morph); 75.21 (CH-3⁰); 82.88

(CH-4⁰); 84.47 (CH-1⁰); 91.59 (@CH-pur); 126.44 and

126.73 (C-i-Tol); 128.53 (C-5); 129.27 (CH-m-Tol);

129.66 and 129.82 (CH-o-Tol); 139.37 (CH-8); 144.08

and 144.48 (C-p-Tol); 148.36 (@CH–N); 149.64 (C-4);

152.51 (CH-2); 157.31 (C-6); 165.97 and 166.20 (CO).

FAB-MS, m/z (rel %) = 584 (17) [M+H]⁺, 232 (50),

215 (8), 181 (8), 160 (10), 147 (15), 131 (18), 119 (100),

105 (15), 91 (35), 81 (45), 57(23). HRMS Calcd for

C₃₂H₃₄N₅O₆[M+H]⁺584.2509. Found: 584.2496. IR

(CHCl₃): 3036, 2974, 2925, 2903, 2863, 1720, 1626,

1578, 1572, 1561, 1496, 1455, 1443, 1430, 1401, 1389,

1376, 1362, 1349, 1310, 1297, 1249, 1179, 1169, 1104,

1079, 1027, 1021, 927, 867, 841, 817, 647.

6.11. 6-[(E)-2-(Piperidine-1-yl)vinyl]-9-(2-deoxy-3,5-di-O-

toluoyl-b-^D-erythro-pentafuranosyl)purine (4d)

1

Yield 96%, orange foam. H NMR (500 MHz, CDCl₃):

6.13. 6-[(E)-2-(Benzyl(methyl)amino)vinyl]-9-(2-deoxy-

3,5-di-O-toluoyl-b-^D-erythro-pentafuranosyl)purine (4f)

1.60–1.70 (m, 6H, CH₂-pip); 2.40 and 2.44 (2· s, 2· 3H,

CH₃-Tol); 2.82 (ddd, 1H, J_gem= 14.2, J_{2 b,1}= 5.7,

0

1

Yield 95%, yellow foam. H NMR (500 MHz, CDCl₃):

J_{2 b,3}= 2.0, H-2⁰b); 3.09 (ddd, 1H, J_gem= 14.2,

0

J_{2 a,1}= 8.7, J_{2 a,3}= 6.3, H-2⁰a); 3.38 (m, 4H, CH₂N-

2.40 and 2.44 (2· s, 2· 3H, CH₃-Tol); 2.82 (ddd, 1H,

0

pip); 4.62 (td, 1H, J_{4 ,5}= 4.2, 4.1, J_{4 ,3}= 2.2, H-4⁰);

4.67 (dd, 1H, J_gem= 12.0, J_{5 b,4}= 4.2, H-5⁰b); 4.74

0

(dd, 1H, J_gem= 12.0, J_{5 a,4}= 4.1, H-5 a); 5.79 (d, 1H,

J_gem= 14.2, J_{2 b,1}= 5.8, J_{2 b,3}= 2.0, H-2⁰b); 2.92 (br s,

0 0 0 0

0

3H, CH₃N); 3.11 (ddd, 1H, J_gem= 14.2, J_{2 a,1}= 8.6,

0 0

0

J_{2 a,3}= 6.3, H-2⁰a); 4.51 (s, 2H, CH₂Ph); 4.63 (td, 1H,

0

J_trans= 13.1, @CH-pur); 5.80 (dt, 1H, J_{3 ,2}= 6.3, 2.0,

J_{4 ,5}= 4.3,4.0, J_{4 ,3}= 2.2, H-4⁰); 4.68 (dd, 1H,

0 0 0 0

0

J_{3 ,4}= 2.2, H-3⁰); 6.57 (dd, 1H, J_{1 ,2}= 8.7, 5.7, H-1⁰);

7.23 and 7.28 (2· m, 2· 2H, H-m-Tol); 7.92 and 7.97

(2· m, 2· 2H, H-o-Tol); 8.00 (s, 1H, H-8); 8.19 (br d,

J_gem= 12.0, J_{5 b,4}= 4.3, H-5⁰b); 4.75 (dd, 1H,

0

J_gem= 12.0, J_{5 a,4}= 4.0, H-5⁰a); 5.78–5.83 (m, 2H, H-

0

3⁰and @CH-pur); 6.58 (dd, 1H, J_{1 ,2}= 8.6, 5.8, H-1⁰);

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1410

0

7.23 (m, 2H, H-m-Tol); 7.25 (m, 2H, H-o-Ph); 7.28 (m,

2H, H-m-Tol); 7.29 (m, 1H, H-p-Ph); 7.35 (m, 2H, H-

m-Ph); 7.92 and 7.97 (2· m, 2· 2H, H-o-Tol); 8.02 (s,

1H, H-8); 8.49 (br d, 1H, J_trans= 13.0, @CH–N); 8.54

(s, 1H, H-2). ¹³C NMR (125.7 MHz, CDCl₃): 21.68

and 21.73 (CH₃-Tol); 35.22 (CH₃N); 37.92 (CH₂-2⁰);

61.52 (CH₂Ph); 64.14 (CH₂-5⁰); 75.25 (CH-3⁰); 82.84

(CH-4⁰); 84.37 (CH-1⁰); 90.88 (@CH-pur); 126.43 and

126.71 (C-i-Tol); 127.33 (CH-o-Ph); 127.80 (CH-p-Ph);

128.27 (C-5); 128.79 (CH-m-Ph); 129.26 and 129.28

(CH-m-Tol); 129.65 and 129.82 (CH-o-Tol); 136.61

(C-i-Ph); 138.99 (CH-8); 144.07 and 144.46 (C-p-Tol);

149.51 (C-4); 149.55 (@CH–N); 152.60 (CH-2); 157.68

(C-6); 165.97 and 166.20 (CO). FAB-MS: m/z (rel

%) = 640 (10), 618 (30) [M+H]⁺, 397 (30), 215 (10),

147 (8), 119 (100), 91 (20). HRMS Calcd for

C₃₈H₃₈N₅O₇[M+H]⁺618.2716. Found: 618.2734. IR

(CHCl₃): 3089, 3066, 3032, 2800, 1720, 1613, 1584,

1569, 1560, 1511, 1497, 1411, 1398, 1375, 1326, 1297,

1248, 1179, 1120, 1103, 1047, 1029, 841, 815, 692, 647,

475.

1H, J_gem= 12.2, J_{5 b,4}= 4.2, H-5⁰b); 4.81 (ddd, 1H,

J_{4 ,3}= 4.7, J_{4 ,5}= 4.2, 3.3, H-4⁰); 4.88 (dd, 1H,

0

J_gem= 12.2, J_{5 a,4}= 3.3, H-5⁰a); 6.23 (dd, 1H,

0

J_{3 ,2}= 5.7, J_{3 ,4}= 4.7, H-3⁰); 6.39 (dd, 1H, J_{2 ,3}= 5.7,

0

J_{2 ,1}= 5.4, H-2⁰); 6.47 (d, 1H, J_{1 ,2}= 5.4, H-1⁰); 7.16,

7.21, and 7.25 (3· m, 3· 2H, H-m-Tol); 7.82, 7.90, and

8.00 (3· m, 3· 2H, H- o-Tol); 8.18 (s, 1H, H-8); 8.80

(s, 1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.70

and 21.73 (CH₃-Tol); 31.04 (CH₂-pur); 45.24 (CH₃N);

57.57 (CH₂N); 63.50 (CH₂-5⁰); 71.40 (CH-3⁰); 73.65

(CH-2⁰); 80.94 (CH-4⁰); 86.79 (CH-1⁰); 125.67, 126.03,

and 126.60 (C-i-Tol); 129.21, 129.24, and 129.31 (CH-

m-Tol); 129.79, 129.86, and 129.88 (CH-o-Tol); 133.60

(C-5); 142.41 (CH-8); 144.18, 144.54, and 144.66 (C-p-

Tol); 150.45 (C-4); 152.70 (CH-2); 161.57 (C-6);

165.17, 165.38, and 166.21 (CO). FAB-MS, m/z (rel

%) = 678 (10) [M+H]⁺, 486 (10), 215 (20), 142 (8), 119

(100), 91 (25). HRMS Calcd for C₃₈H₄₀N₅O₇[M+H]⁺

678.2927. Found: 678.2920. IR (CHCl₃): 3117, 3095,

3064, 3037, 2826, 2783, 1725, 1612, 1597, 1584, 1510,

1498, 1409, 1378, 1334, 1311, 1297, 1180, 1126, 1114,

1094, 1020, 840, 691, 645, 476.

0

6.14. 6-[(E)-2-(Thiazolidine-1-yl)vinyl]-9-(2-deoxy-3,5-di-

O-toluoyl-b-^D-erythro-pentafuranosyl)purine (4g)

6.16. 6-[2-(Diethylamino)ethyl]-9-(2,3,5-tri-O-toluoyl-b-

D-ribofuranosyl)purine (9b)

1

Yield 41%, yellow foam. H NMR (400 MHz, CDCl₃):

2.40 and 2.44 (2· s, 9H, CH₃-Tol); 2.88 (ddd, 1H,

Yield 84%, yellowish foam. ¹H NMR (400 MHz,

CDCl₃): 1.09 (br t, 6H, J_vic= 7.4, CH₃CH₂); 2.38 and

2.42 (2· s, 9H, CH₃-Tol); 2.67 (br m, 4H, CH₂CH₃);

3.10 (br m, 2H, CH₂N); 3.34 (br m, 2H, CH₂-pur);

0

J_gem= 14.1, J_{2 b,1}= 5.7, J_{2 b,3}= 2.0, H-2 b); 3.10 (t,

2H, J_vic= 6.2, H-5-thiazolidine); 3.12 (ddd, 1H,

J_gem= 14.1, J_{2 a,1}= 8.5, J_{2 a,3}= 6.2, H-2⁰a); 3.76 (t,

2H, J_vic= 6.2, H-4-thiazolidine); 4.49 (s, 2H, H-2-thia-

0

4.67 (dd, 1H, J_gem= 12.2, J_{5 b,4}= 4.2, H-5⁰b); 4.81

0

(ddd, 1H, J_{4 ,3}= 4.8, J_{4 ,5}= 4.2, 3.1, H-4⁰); 4.88 (dd,

0

zolidine); 4.64 (ddd, 1H, J_{4 ,5}= 4.2, 3.8, J_{4 ,3}= 2.3, H-

0

4⁰); 4.67 (dd, 1H, J_gem= 11.8, J_{5 b,4}= 4.2, H-5⁰b); 4.75

1H, J_gem= 12.2, J_{5 a,4}= 3.1, H-5⁰a); 6.23 (dd, 1H,

0 0

0

(dd, 1H, J_gem= 11.8, J_{5 a,4}= 3.8, H-5⁰a); 5.78 (d, 1H,

J_{3 ,2}= 5.9, J_{3 ,4}= 4.8, H-3⁰); 6.39 (dd, 1H, J_{2 ,3}= 5.9,

0

J_trans= 13.1, @CH-pur); 5.81 (ddd, 1H, J_{3 ,2}= 6.2, 2.0,

J_{2 ,1}= 5.3, H-2⁰); 6.46 (d, 1H, J_{1 ,2}= 5.3, H-1⁰); 7.16,

7.21, and 7.25 (3· m, 3· 2H, H-m-Tol); 7.82, 7.90, and

8.00 (3· m, 3· 2H, H-o-Tol); 8.17 (s, 1H, H-8); 8.79

(s, 1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 11.94

(CH₃CH₂); 21.70 and 21.73 (CH₃-Tol); 29.66 (CH₂-

pur); 46.88 (CH₂CH₃); 50.71 (CH₂N); 63.46 (CH₂-5⁰);

71.37 (CH-3⁰); 73.66 (CH-2⁰); 80.91 (CH-4⁰); 86.84

(CH-1⁰); 125.68, 126.03, and 126.60 (C-i-Tol); 129.22,

129.25, and 129.31 (CH-m-Tol); 129.79 and 129.87

(CH-o-Tol); 133.55 (C-5); 142.38 (CH-8); 144.19,

144.55, and 144.67 (C-p-Tol); 150.38 (C-4); 152.68

(CH-2); 161.88 (C-6); 165.17, 165.38, and 166.22 (CO).

FAB-MS, m/z (rel %) = 706 (7) [M+H]⁺, 147 (10), 119

(30), 109 (5), 93 (8) 86 (100), 69 (8). HRMS Calcd for

C₄₀H₄₄N₅O₇[M+H]: 706.3240. Found: 706.3249. IR

(CHCl₃): 3117, 3095, 3065, 3038, 1727, 1612, 1597,

1589, 1510, 1498, 1409, 1379, 1334, 1311, 1297, 1248,

1180, 1126, 1114, 1093, 1045, 1020, 840, 691, 476.

J_{3 ,4}= 2.3, H-3⁰); 6.57 (dd, 1H, J_{1 ,2}= 8.5, 5.7, H-1⁰);

7.23 and 7.28 (2· m, 2· 2H, H-m-Tol); 7.92 and 7.97

(2· m, 2· 2H, H-o-Tol); 8.05 (s, 1H, H-8); 8.44 (d,

1H, J_trans= 13.1, @CH–N); 8.56 (s, 1H, H-2). ¹³C

NMR (100.6 MHz, CDCl₃): 21.68 and 21.73 (CH₃-

Tol); 30.33 (CH₂-5-thiazolidine); 37.94 (CH₂-2⁰); 51.53

(CH₂-2-thiazolidine); 52.70 (CH₂-4-thiazolidine); 64.10

(CH₂-5⁰); 75.19 (CH-3⁰); 82.93 (CH-4⁰); 84.54 (CH-1⁰);

93.30 (@CH-pur); 126.42 and 126.70 (C-i-Tol); 128.43

(C-5); 129.27 (CH-m-Tol); 129.64 and 129.81 (CH-o-

Tol); 139.59 (CH-8); 144.10 and 144.48 (C-p-Tol);

145.01 (@CH–N); 149.58 (C-4); 152.13 (CH-2);

157.62 (C-6); 165.96 and 166.18 (CO). FAB-MS, m/z

(rel %) = 586 (12) [M+H]⁺, 234 (36), 174 (10), 147

(10), 137 (10), 119 (100), 91 (24), 81 (73). HRMS

Calcd for C₃₈H₃₈N₅O₇[M+H]⁺676.2771. Found:

676.2783. IR (CHCl₃): 3126, 3094, 3032, 1720, 1613,

1510, 1588, 1572, 1561, 1496, 1419, 1389, 1326, 1269,

1251, 1179, 1121, 1103, 1020, 997, 841, 817, 691,

817, 647.

0

6.17. 6-[2-(Dibutylamino)ethyl-9-(2,3,5-tri-O-toluoyl-b-^D-

ribofuranosyl)purine (9c)

1

Yield 80%, yellow foam. H NMR (400 MHz, CDCl₃):

6.15. 6-[2-(Dimethylamino)ethyl]-9-(2,3,5-tri-O-toluoyl-b-

D-ribofuranosyl)purine (9a)

0.88 (t, 6H, J_vic= 7.3, CH₃CH₂CH₂CH₂); 1.26 (m, 4H,

CH₃CH₂CH₂CH₂); 1.43 (m, 4H, CH₃CH₂CH₂CH₂);

2.38 and 2.42 (2· s, 9H, CH₃-Tol); 2.51 (m, 4H,

CH₃CH₂CH₂CH₂); 3.05 (m, 2H, CH₂N); 3.31 (m, 2H,

Yield 81%, yellowish foam. ¹H NMR (400 MHz,

CDCl₃): 2.33 (s, 6H, CH₃N); 2.38 and 2.42 (2· s, 9H,

CH₃-Tol); 2.92 (t, 2H, J_vic= 7.5, CH₂N); 3.34 and 3.38

(2· dt, 2H, J_gem= 13.9, J_vic= 7.5, CH₂-pur); 4.67 (dd,

0

CH₂-pur); 4.67 (dd, 1H, J_gem= 12.1, J_{5 b,4}= 4.1, H-

0

5⁰b); 4.81 (ddd, 1H, J_{4 ,3}= 4.7, J_{4 ,5}= 4.1, 3.1, H-4⁰);

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1411

4.88 (dd, 1H, J_gem= 12.1, J_{5 a,4}= 3.1, H-5⁰a); 6.23 (dd,

1H, J_gem= 12.2, J_{5 a,4}= 3.1, H-5⁰a); 6.23 (dd, 1H,

0

1H, J_{3 ,2}= 5.8, J_{3 ,4}= 4.7, H-3⁰); 6.39 (dd, 1H,

J_{3 ,2}= 5.7, J_{3 ,4}= 4.8, H-3 ); 6.40 (dd, 1H, J_{2 ,3}= 5.7,

0

J_{2 ,3}= 5.8, J_{2 ,1}= 5.5, H-2⁰); 6.47 (d, 1H, J_{1 ,2}= 5.5,

H-1⁰); 7.16, 7.21, and 7.25 (3· m, 3· 2H, H-m-Tol);

7.82, 7.90, and 8.00 (3· m, 3· 2H, H-o-Tol); 8.17 (s,

1H, H-8); 8.79 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

J_{2 ,1}= 5.3, H-2⁰); 6.46 (d, 1H, J_{1 ,2}= 5.3, H-1⁰); 7.16,

7.22, and 7.25 (3· m, 3· 2H, H-m-Tol); 7.82, 7.90, and

7.99 (3· m, 3· 2H, H-o-Tol); 8.17 (s, 1H, H-8); 8.79

(s, 1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.69

and 21.72 (CH₃-Tol); 30.38 (CH₂-pur); 53.36 (CH₂N-

morph); 55.82 (CH₂N); 63.44 (CH₂-5⁰); 66.93 (CH₂O-

morph); 71.35 (CH-3⁰); 73.66 (CH-2⁰); 80.89 (CH-4⁰);

86.93 (CH-1⁰); 125.65, 126.00, and 126.58 (C-i-Tol);

129.22, 129.25, and 129.30 (CH-m-Tol); 129.78 and

129.86 (CH-o-Tol); 133.57 (C-5); 142.46 (CH-8);

144.19, 144.56, and 144.70 (C-p-Tol); 150.38 (C-4);

152.64 (CH-2); 161.43 (C-6); 165.18, 165.37, and

166.19 (CO). FAB-MS, m/z (rel %) = 720 (10)

[M+H]⁺, 706 (60), 487 (10), 274 (20), 230 (8), 215 (32)

177 (12), 163 (14), 119 (100), 100 (28), 86 (98)91. HRMS

Calcd for C₄₀H₄₂N₅O₈[M+H]: 720.3033. Found:

720.3049. IR (CHCl₃): 3117, 3095, 3065, 3033, 2970,

2925, 2899, 2863, 1727, 1612, 1598, 1586, 1510, 1498,

1409, 1375, 1335, 1311, 1297, 1246, 1180, 1126, 1071,

868, 645.

0

CDCl₃):

14.06

(CH₃CH₂CH₂CH₂);

20.65

(CH₃CH₂CH₂CH₂); 21.69 and 21.72 (CH₃-Tol); 29.47

(CH₃CH₂CH₂CH₂); 30.04 (CH₂-pur); 52.17 (CH₂N);

53.59 (CH₃CH₂CH₂CH₂); 63.48 (CH₂-5⁰); 71.38 (CH-

3⁰); 73.64 (CH-2⁰); 80.91 (CH-4⁰); 86.78 (CH-1⁰);

125.68, 126.03, and 126.60 (C-i-Tol); 129.21, 129.24,

and 129.31 (CH-m-Tol); 129.78 and 129.86 (CH-o-

Tol); 133.56 (C-5); 142.25 (CH-8); 144.17, 144.53, and

144.65 (C-p-Tol); 150.32 (C-4); 152.64 (CH-2); 162.36

(C-6); 165.16, 165.38, and 166.21 (CO). FAB-MS, m/z

(rel %) = 762 (15) [M+H]⁺, 215 (6), 197 (4), 180 (6),

142 (100), 119 (84), 100 (10), 91 (15), 73 (14), 57 (22).

HRMS Calcd for C₄₄H₅₂N₅O₇[M+H]⁺762.3866.

Found: 762.3877. IR (CHCl₃): 3117, 3095, 3065, 3035,

1727, 1612, 1597, 1585, 1510, 1498, 1409, 1334, 1311,

1297, 1246, 1180, 1126, 1093, 1044, 1020, 840, 691,

645, 476.

6.20. 6-[2-(Benzyl(methyl)amino)ethyl]-9-(2,3,5-tri-O-tol-

uoyl-b-^D-ribofuranosyl)purine (9f)

6.18. 6-[2-(Piperidine-1-yl)ethyl]-9-(2,3,5-tri-O-toluoyl-b-

D-ribofuranosyl)purine (9d)

1

Yield 78%, white foam. H NMR (500 MHz, CDCl₃):

1

Yield 75%, yellow foam. H NMR (500 MHz, CDCl₃):

2.29 (s, 3H, CH₃N); 2.38, 2.41, and 2.42 (3· s, 3· 3H,

CH₃-Tol); 3.02 (t, 2H, J_vic= 7.5, CH₂N); 3.39 and 3.42

(2· dt, 2H, J_gem= 13.5, J_vic= 7.5, CH₂-pur); 3.58 (s,

1.44 and 1.61 (2· br m, 6H, CH₂-pip); 2.38 and 2.42

(2· s, 9H, CH₃-Tol); 2.56 (br m, 4H, J_vic= 6.2, CH₂N-

pip); 2.96 (br m, 2H, CH₂–N); 3.41 (br m, 2H, CH₂-

0

2H, CH₂Ph); 4.67 (dd, 1H, J_gem= 12.3, J_{5 b,4}= 4.2,

pur); 4.67 (dd, 1H, J_gem= 12.2, J_{5 b,4}= 4.2, H-5⁰b);

H-5⁰b); 4.82 (ddd, 1H, J_{4 ,3}= 4.7, J_{4 ,5}= 4.2, 3.1, H-4⁰);

0

4.81 (td, 1H, J_{4 ,3}= 4.7, J_{4 ,5}= 4.2, 3.2, H-4⁰); 4.88

4.89 (dd, 1H, J_gem= 12.3, J_{5 a,4}= 3.1, H-5⁰a); 6.24 (dd,

0 0

0

(dd, 1H, J_gem= 12.2, J_{5 a,4}= 3.2, H-5⁰a); 6.23 (dd, 1H,

J_{3 ,2}= 5.8, J_{3 ,4}= 4.7, H-3⁰); 6.39 (t, 1H, J_{2 ,3}= 5.8,

1H, J_{3 ,2}= 5.8, J_{3 ,4}= 4.7, H-3⁰); 6.40 (dd, 1H,

0

J_{2 ,3}= 5.8, J_{2 ,1}= 5.4, H-2⁰); 6.47 (d, 1H, J_{1 ,2}= 5.4,

H-1⁰); 7.14-7.26 (m, 11H, H-m-Tol, H-o,m,p-Ph); 7.82,

7.91, and 8.00 (3· m, 3· 2H, H-o-Tol); 8.14 (s, 1H, H-

8); 8.78 (s, 1H, H-2). ¹³C NMR (125.7 MHz, CDCl₃):

21.70 and 21.73 (CH₃-Tol); 31.02 (CH₂-pur); 41.86

(CH₃N); 55.59 (CH₂N); 61.80 (CH₂Ph); 63.48 (CH₂-

5⁰); 71.38 (CH-3⁰); 73.64 (CH-2⁰); 80.90 (CH-4⁰); 86.78

(CH-1⁰); 125.65, 126.01, and 126.57 (C-i-Tol); 126.80

(CH-p-Ph); 128.05 (CH-o-Ph); 128.93 (CH-m-Ph);

129.21, 129.24, and 129.31 (CH-m-Tol); 129.78, 129.86,

and 129.88 (CH-o-Tol); 133.57 (C-5); 138.89 (C-i-Ph);

142.30 (CH-8); 144.18, 144.55, and 144.67 (C-p-Tol);

150.34 (C-4); 152.61 (CH-2); 161.90 (C-6); 165.17,

165.38, and 166.21 (CO). FAB-MS, m/z (rel %) = 754

(40) [M+H]⁺, 266 (12), 215 (24), 181 (18), 119 (100),

91 (60), HRMS Calcd for C₄₄H₄₄N₅O₇[M+H]⁺

754.3240. Found: 754.3227. IR (CHCl₃): 3117, 3063,

3034, 2981, 2807, 1727, 1612, 1598, 1585, 1510, 1499,

1409, 1378, 1311, 1297, 1247, 1180, 1126, 1114, 1093,

1020, 840, 691, 645.

0

J_{2 ,1}= 5.4, H-2⁰); 6.46 (d, 1H, J_{1 ,2}= 5.4, H-1⁰); 7.16,

7.21, and 7.25 (3· m, 3· 2H, H-m-Tol); 7.81, 7.90, and

7.99 (3· m, 3· 2H, H-o-Tol); 8.17 (s, 1H, H-8); 8.78

(s, 1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.70

and 21.72 (CH₃-Tol); 24.22 and 25.82 (CH₂-pip); 30.20

(CH₂-pur); 54.09 (CH₂N-pip); 57.12 (CH₂N); 63.44

(CH₂-5⁰); 71.37 (CH-3⁰); 73.65 (CH-2⁰); 80.92 (CH-4⁰);

86.85 (CH-1⁰); 125.67, 126.03, and 126.59 (C-i-Tol);

129.21, 129.24, and 129.31 (CH-m-Tol); 129.78, 129.86,

and 129.88 (CH-o-Tol); 133.49 (C-5); 142.39 (CH-8);

144.19, 144.55, and 144.67 (C-p-Tol); 150.38 (C-4);

152.66 (CH-2); 161.70 (C-6); 165.17, 165.38, and

166.21 (CO). FAB-MS, m/z (rel %) = 718 (18)

[M+H]⁺, 215 (4) 119 (62), 98 (100). HRMS Calcd for

C₄₁H₄₄N₅O₇[M+H]⁺718.3240. Found: 718.3223. IR

(CHCl₃): 2940, 2858, 2807, 1727, 1612, 1597, 1585,

1510, 1498, 1409, 1335, 1298, 1280, 1268, 1247, 1180,

1156, 1094, 1021, 840, 691, 645, 476.

0

6.19. 6-[2-(Morpholine-4-yl)ethyl]-9-(2,3,5-tri-O-toluoyl-

b-^D-ribofuranosyl)purine (9e)

6.21. 6-[2-(Thiazolidine-1-yl)ethyl]-9-(2,3,5-tri-O-toluoyl-

b-^D-ribofuranosyl)purine (9g)

Yield 82%, yellowish foam. ¹H NMR (400 MHz,

CDCl₃): 2.38 and 2.42 (2· s, 9H, CH₃-Tol); 2.58 (m,

4H, CH₂N-morph); 2.97 (t, 2H, J_vic= 7.6, CH₂N);

3.39 (m, 2H, CH₂-pur); 3.69 (m, 4H, CH₂O-morph);

1

Yield 79%, white foam. H NMR (500 MHz, CDCl₃):

2.38 and 2.42 (2· s, 9H, CH₃-Tol); 2.89 (t, 2H, J_vic= 6.2,

H-5-thiazolidine); 3.01 (t, 2H, J_vic= 7.2, CH₂N); 3.10 (t,

2H, J_vic= 6.2, H-4-thiazolidine); 3.36 and 3.39 (2· dt,

2H, J_gem= 14.1, J_vic= 7.2, CH₂-pur); 4.12 (s, 2H, H-2-

4.67 (dd, 1H, J_gem= 12.2, J_{5 b,4}= 4.2, H-5⁰b); 4.82

0

(ddd, 1H, J_{4 ,3}= 4.8, J_{4 ,5}= 4.2, 3.1, H-4⁰); 4.89 (dd,

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1412

0

0 0

CH₂N); 3.20 (ddd, 1H, J_gem= 14.2, J_{2 a,1}= 8.4,

thiazolidine); 4.67 (dd, 1H, J_gem= 12.2, J_{5 b,4}= 4.2, H-

0

5⁰b); 4.82 (ddd, 1H, J_{4 ,3}= 4.8, J_{4 ,5}= 4.2, 3.2, H-4⁰);

J_{2 a,3}= 6.4, H-2⁰a); 3.32 (t, 2H, J_vic= 7.6, CH₂-pur);

0

4.89 (dd, 1H, J_gem= 12.2, J_{5 a,4}= 3.2, H-5⁰a); 6.23 (dd,

4.67 (m, 2H, H-4⁰, H-5⁰b); 4.78 (m, 1H, H-5⁰a); 5.83

0

1H, J_{3 ,2}= 5.8, J_{3 ,4}= 4.8, H-3⁰); 6.39 (dd, 1H,

(dt, 1H, J_{3 ,2}= 6.4, 2.1, H-3⁰); 6.59 (dd, 1H,

0

0 0

J_{2 ,3}= 5.8, J_{2 ,1}= 5.4, H-2⁰); 6.47 (d, 1H, J_{1 ,2}= 5.4,

H-1⁰); 7.16, 7.22, and 7.25 (3· m, 3· 2H, H-m-Tol);

7.82, 7.90, and 8.00 (3· m, 3· 2H, H-o-Tol); 8.18 (s,

1H, H-8); 8.80 (s, 1H, H-2). ¹³C NMR (125.7 MHz,

CDCl₃): 21.71 and 21.73 (CH₃-Tol); 29.55 (CH₂-5-

thiazolidine); 32.85 (CH₂-pur); 50.98 (CH₂N); 57.99

(CH₂-4-thiazolidine); 60.50 (CH₂-2-thiazolidine); 63.46

(CH₂-5⁰); 71.35 (CH-3⁰); 73.66 (CH-2⁰); 80.91 (CH-4⁰);

86.86 (CH-1⁰); 125.63, 125.99, and 126.57 (C-i-Tol);

129.22, 129.25, and 129.31 (CH-m-Tol); 129.78, 129.85,

and 129.87 (CH-o-Tol); 133.68 (C-5); 142.54 (CH-8);

144.20, 144.56, and 144.69 (C-p-Tol); 150.46 (C-4);

152.66 (CH-2); 160.96 (C-6); 165.18, 165.37, and

166.20 (CO). FAB-MS, m/z (rel %) = 722 (38)

[M+H]⁺, 487 (42), 215 (10), 119 (100), 102 (20). HRMS

Calcd for C₃₉H₄₀N₅O₇S [M+H]⁺722.2648. Found:

722.2660. IR (CHCl₃): 3020, 2981, 2869, 1727, 1624,

1612, 1588, 1573, 1564, 1510, 1497, 1438, 1421, 1390,

1332, 1327, 1280, 1268, 1244, 1180, 1127, 1114, 1094,

1020,997, 974, 839, 691, 477.

J_{1 ,2}= 8.4, 5.8, H-1⁰); 7.20 and 7.28 (2· m, 2· 2H, H-

m-Tol); 7.88 and 7.97 (2· m, 2· 2H, H-o-Tol); 8.18 (s,

1H, H-8); 8.82 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

0

CDCl₃):

14.06

(CH₃CH₂CH₂CH₂N);

20.63

(CH₃CH₂CH₂CH₂N); 21.66 and 21.72 (CH₃-Tol);

29.47 (CH₃CH₂CH₂CH₂N); 30.06 (CH₂-pur); 37.68

(CH₂-2⁰); 52.18 (CH₂–N); 53.59 (CH₃CH₂CH₂CH₂N);

63.97 (CH₂-5⁰); 75.08 (CH-3⁰); 82.99 (CH-4⁰); 84.78

(CH-1⁰); 126.37 and 126.65 (C-i-Tol); 129.23 and

129.26 (CH-m-Tol); 129.62 and 129.78 (CH-o-Tol);

133.56 (C-5); 141.81 (CH-8); 144.10 and 144.50 (C-p-

Tol); 150.12 (C-4); 152.36 (CH-2); 162.23 (C-6); 165.90

and 166.13 (CO). FAB-MS, m/z (rel %) = 628 (6)

[M+H]⁺, 274 (8), 232 (12), 142 (100), 119 (44), 98 (24),

81 (22), 70 (7), 87 (26). HRMS Calcd for C₃₆H₄₆N₅O₅

[M+H]⁺628.3498. Found: 628.3482. IR (CHCl₃):

3095, 3063, 3033, 2814, 1612, 1597, 1582, 1510, 1496,

1420, 1408, 1378, 1333, 1311, 1269, 1248, 1179, 1120,

1103, 1020, 841, 691, 646, 476.

6.24. 6-[2-(Morpholine-4-yl)ethyl]-9-(2-deoxy-3,5-di-O-

toluoyl-b-^D-erythro-pentafuranosyl)purine (10e)

6.22. 6-[2-(Dimethylamino)ethyl]-9-(2-deoxy-3,5-di-O-

toluoyl-b-^D-erythro-pentafuranosyl)purine (10a)

1

Yield 84%, white foam. H NMR (400 MHz, CDCl₃):

1

Yield 96%, white foam. H NMR (400 MHz, CDCl₃):

2.41 and 2.45 (2· s, 2· 3H, CH₃-Tol); 2.57 (m, 4H,

J_vic= 4.5, CH₂N-morph); 2.84 (ddd, 1H, J_gem= 14.1,

2.33 (s, 6H, CH₃N); 2.41 and 2.45 (2· s, 2· 3H, CH₃-

Tol); 2.84 (ddd, 1H, J_gem= 14.2, J_{2 b,1}= 5.8,

J_{2 b,1}= 5.8, J_{2 b,3}= 2.1, H-2⁰b); 2. 96 (t, 2H, J_vic= 7.7,

0

J_{2 b,3}= 2.0, H-2⁰b); 2.93 (t, 2H, J_vic= 7.3, CH₂N);

0

0 0

CH₂N); 3.22 (ddd, 1H, J_gem= 14.2, J_{2 a,1}= 8.4,

0

3.19 (ddd, 1H, J_gem= 14.2, J_{2 a,1}= 8.4, J_{2 a,3}= 6.4, H-

2⁰a); 3.38 (t, 2H, J_vic= 7.3, CH₂-pur); 4.65 (m, 2H, H-

4⁰, H-5⁰b); 4.78 (m, 1H, H-5⁰a); 5.83 (dt, 1H,

J_{2 a,3}= 6.4, H-2⁰a); 3.39 (t, 2H, J_vic= 7.7, CH₂-pur);

3.69 (t, 4H, J_vic= 4,5, CH₂O-morph); 4.65 (m, 2H, H-

4⁰, H-5⁰b); 4.78 (m, 1H, H-5⁰a); 5.83 (dt, 1H,

J_{3 ,2}= 6.4, 2.1, J_{3 ,4}= 2.0, H-3⁰); 6.60 (dd, 1H,

0

J_{1 ,2}= 8.4, 5.8, H-1⁰); 7.22 and 7.28 (2· m, 2· 2H, H-

m-Tol); 7.91 and 7.98 (2· m, 2· 2H, H-o-Tol); 8.20 (s,

1H, H-8); 8.84 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 21.67 and 21.73 (CH₃-Tol); 31.01 (CH₂-pur);

37.70 (CH₂-2⁰); 45.30 (CH₃N); 57.63 (CH₂–N); 63.99

(CH₂-5⁰); 75.10 (CH-3⁰); 83.04 (CH-4⁰); 84.84 (CH-1⁰);

126.38 and 126.66 (C-i-Tol); 129.25 and 129.27 (CH-

m-Tol); 129.64 and 129.80 (CH-o-Tol); 133.62 (C-5);

141.96 (CH-8); 144.12 and 144.52 (C-p-Tol); 150.25

(C-4); 152.45 (CH-2); 161.49 (C-6); 165.92 and 166.14

(CO). FAB-MS, m/z (rel %) = 544 (20) [M+H]⁺, 190

(20), 147 (10), 119 (35), 91 (14), 81 (20), 58 (100). HRMS

Calcd for C₃₀H₃₄N₅O₅[M+H]⁺544.2559. Found:

544.2541. IR (CHCl₃): 3095, 3064, 3033, 2825, 2782,

1721, 1612, 1597, 1583, 1509, 1497, 1444, 1420, 1408,

1377 1333, 1311, 1246, 1179, 1121, 1102, 1020, 948,

841, 691, 646, 476.

J_{1 ,2}= 8.4, 5.8, H-1⁰); 7.22 and 7.28 (2· m, 2· 2H, H-

m-Tol); 7.91 and 7.98 (2· m, 2· 2H, H-o-Tol); 8.20 (s,

1H, H-8); 8.82 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 21.66 (CH₃-Tol); 30.35 (CH₂-pur); 37.66

(CH₂-2⁰); 53.36 (CH₂N-morph); 56.82 (CH₂–N); 63.94

(CH₂-5⁰); 66.92 (CH₂O-morph); 75.04 (CH-3⁰); 83.02

(CH-4⁰); 84.81 (CH-1⁰); 126.34 and 126.63 (C-i-Tol);

129.24 and 129.26 (CH-m-Tol); 129.62 and 129.80

(CH-o-Tol); 133.55 (C-5); 142.00 (CH-8); 144.12 and

144.52 (C-p-Tol); 150.20 (C-4); 152.37 (CH-2); 161.27

(C-6); 165.90 and 166.11 (CO). FAB-MS, m/z (rel

%) = 586 (24) [M+H]⁺, 315 (12), 232 (14), 171 (10),

147 (14), 119 (100), 98 (36), 91 (32), 81 (42). HRMS

Calcd for C₃₂H₃₆N₅O₆[M+H]⁺586.2665. Found:

586.2680. IR (CHCl₃): 3095, 3031, 3010, 2968, 2821,

1721, 1612, 1509, 1456, 1446, 1397, 1376, 1318, 1311,

1295, 1269, 1250, 1179, 1115, 1103, 1071, 1036, 1020,

1008, 840, 691, 475.

0

6.23. 6-[2-(Dibutylamino)ethyl]-9-(2-deoxy-3,5-di-O-toluo-

yl-b-^D-erythro-pentafuranosyl)purine (10c)

6.25. 6-[2-(Benzyl(methyl)amino)ethyl]-9-(2-deoxy-3,5-di-

O-toluoyl-b-^D-erythro-pentafuranosyl)purine (10f)

Yield 88%, yellowish foam. ¹H NMR (400 MHz,

CDCl₃): 0.88 (t, 6H, J_vic= 7.3, CH₃CH₂CH₂CH₂N);

1.26 and 1.43 (2· m, 8H, CH₃CH₂CH₂CH₂N); 2.40

and 2.44 (2· s, 2· 3H, CH₃-Tol); 2.51 (t, 4H, J_vic= 7.6,

CH₃CH₂CH₂CH₂N); 2.84 (ddd, 1H, J_gem= 14.1,

Yield 90%, yellowish foam. ¹H NMR (500 MHz,

CDCl₃): 2. 30 (s, 3H, CH₃N); 2.40 and 2.44 (2· s, 2·

3H, CH₃-Tol); 2.84 (ddd, 1H, J_gem= 14.2, J_{2 b,1}= 5.8,

0

J_{2 b,3}= 2.0, H-2⁰b); 3.03 (t, 2H, J_vic= 7.5 CH₂–N);

0

J_{2 b,1}= 5.8, J_{2 b,3}= 2.1, H-2⁰b); 3.05 (t, 2H, J_vic= 7.6,

0

0 0 0 0

3.21 (ddd, 1H, J_gem= 14.2, J_{2 a,1}= 8.4, J_{2 a,3}= 6.4, H-

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1413

2⁰a); 3.40 and 3.44 (2· dt, 2H, J_gem= 13.5, J_vic= 7.5,

1334, 1311, 1267, 1200, 1180, 1126, 1114, 1093, 1041,

1020, 839, 644, 620.

CH₂-pur); 3.58 (s, 2H, CH₂Ph); 4.67 (m, 2H, H-4⁰, H-

5⁰b); 4.78 (m, 1H, H-5⁰a); 5.84 (dt, 1H, J_{3 ,2}= 6.4, 2.0,

0

J_{3 ,4}= 2.2, H-3⁰); 6.60 (dd, 1H, J_{1 ,2}= 8.4, 5.8, H-1⁰);

7.21 and 7.29 (2· m, 9H, H-m-Tol, H-Ph); 7.92 and

7.97 (2· m, 2· 2H, H-o-Tol); 8.17 (s, 1H, H-8); 8.82

(s, 1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.67

and 21.73 (CH₃-Tol); 31.01 (CH₂-pur); 35.97 (CH₃N);

37.70 (CH₂-2⁰); 55.60 (CH₂–N); 61.79 (CH₂Ph); 63.98

(CH₂-5⁰); 75.09 (CH-3⁰); 83.01 (CH-4⁰); 84.77 (CH-1⁰);

126.37 and 126.65 (C-i-Tol); 126.78 (CH-o-Ph); 128.03

(CH-p-Ph); 128.90 (CH-m-Ph); 129.24 and 129.26

(CH-m-Tol); 129.62 and 129.79 (CH-o-Tol); 133.58 (C-

5); 138.92 (C-i-Ph); 141.85 (CH-8); 144.12 and 144.52

(C-p-Tol); 150.16 (C-4); 152.35 (CH-2); 161.77 (C-6);

165.91 and 166.13 (CO). FAB-MS, m/z (rel %) = 620

(47) [M+H]⁺, 266 (7), 176 (8), 147 (16), 134 (100), 119

(64), 91 (75), 81 (36). HRMS Calcd for C₃₆H₃₈N₅O₅

[M+H]⁺620.2872. Found: 620.2860. IR (CHCl₃):

3087, 3065, 3031, 2796, 1721, 1612, 1597, 1583, 1509,

1495, 1454, 1438, 1420, 1408, 1378, 1333, 1250, 1179,

1121, 1075, 1027, 1020, 841, 700, 692, 646, 476.

6.28. 6-[(1,3-Dithiolan-2-yl)methyl]-9-(2-deoxy-3,5-di-O-

toluoyl-b-^D-erythro-pentafuranosyl)purine (6)

0

1

Yield 84%, white foam. H NMR (400 MHz, CDCl₃):

2.41 and 2.45 (2· s, 2· 3H, CH₃-Tol); 2.85 (ddd, 1H,

J_gem= 14.2, J_{2 b,1}= 5.8, J_{2 b,3}= 2.1, H-2⁰b); 3.19 (ddd,

0

1H, J_gem= 14.2, J_{2 a,1}= 8.4, J_{2 a,3}= 6.3, H-2⁰a); 3.26

and 3.35 (2· m, 2· 2H, CH₂–S); 3.70 and 3.74 (2· dd,

2H, J_gem= 14.7, J_vic= 7.5, CH₂-pur); 4.63-4.70 (m,

2H, H-4⁰and H-5⁰b); 4.77 (m, 1H, H-5⁰a); 5.33 (t, 1H,

0

J_vic= 7.5, S–CH–S); 5.84 (dt, 1H, J_{3 ,2}= 6.3, 2.1,

J_{3 ,4}= 2.1, H-3⁰); 6.60 (dd, 1H, J_{1 ,2}= 8.4, 5.8, H-1⁰);

7.23 and 7.29 (2· m, 2· 2H, H-m-Tol); 7.91 and 7.98

(2· m, 2· 2H, H-o-Tol); 8.22 (s, 1H, H-8); 8.87 (s, 1H,

H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.69 and 21.74

(CH₃-Tol); 37.80 (CH₂-2⁰); 38.65 (CH₂–S); 43.24 (CH₂-

pur); 50.82 (S–CH–S); 63.96 (CH₂-5⁰); 75.07 (CH-3⁰);

83.11 (CH-4⁰); 84.85 (CH-1⁰); 126.37 and 126.64 (C-i-

Tol); 129.29 (CH-m-Tol); 129.64 and 129.82 (CH-o-

Tol); 133.36 (C-5); 142.41 (CH-8); 144.18 and 144.56

(C-p-Tol); 150.58 (C-4); 152.42 (CH-2); 159.12 (C-6);

165.94 and 166.15 (CO). FAB-MS, m/z (rel %) = 613

(8), 591 (20) [M+H]⁺, 3239 (45), 179 (12), 154 (7), 134

(10), 119 (100), 105 (36), 91 (22), 81 (87). HRMS Calcd

for C₃₀H₃₁N₄O₅S₂[M+H]⁺591.1735. Found: 591.1724.

IR (CHCl₃): 3126, 3095, 3064, 3034, 2995, 1721, 1612,

1597, 1585, 1509, 1495, 1420, 1407, 1379, 1333, 1269,

1246, 1179, 1120, 1102, 1020, 997, 841, 691, 841, 691,

646.

0

6.26. General method of nucleophilic addition to thiols,

method A

Ethynylpurines 7 or 8 (1.5 mmol) or vinylpurines 1 or 2

(1.5 mmol) were stirred in dry THF at room tempera-

ture with thiol (4.5 mmol) in the presence of catalytic

amount of NaH. The resulting mixture was concen-

trated under reduced pressure and the residue was puri-

ﬁed by column chromatography (silica gel, hexane/ethyl

acetate).

6.29. 6-[2-(Benzylsulfanyl)ethyl]-9-(2,3,5-tri-O-toluoyl-b-

D-ribofuranosyl)purine (11a)

6.27. 6-[(1,3-Dithiolan-2-yl)methyl]-9-(2,3,5-tri-O-toluo-

yl-b-^D-ribofuranosyl)purine (5)

1

Yield 56%, white foam. H NMR (400 MHz, CDCl₃):

1

Yield 90%, white foam. H NMR (400 MHz, CDCl₃):

2.38 and 2.42 (2· s, 9H, CH₃-Tol); 3.20-3.39 (m, 4H,

CH₂–S); 3.69 and 3.73 (2· dd, 2H, J_gem= 14.7,

J_vic= 7.5, CH₂-pur); 4.67 (dd, 1H, J_gem= 12.2,

2.38, 2.41, and 2.42 (3· s, 3· 3H, CH₃-Tol); 3.00 (t,

2H, J_vic= 7.7, CH₂–S); 3.44 and 3.48 (2· dt, 2H,

J_gem= 14.1, J_vic= 7.7, CH₂-pur); 3.77 (s, 2H, CH₂Ph);

4.67 (dd, 1H, J_gem= 12.1, J_{5 b,4}= 4.1, H-5⁰b); 4.82

0

J_{5 b,4}= 4.1, H-5⁰b); 4.81 (td, 1H, J_{4 ,3}= 4.6,

(ddd, 1H, J_{4 ,3}= 4.8, J_{4 ,5}= 4.1, 3.1, H-4⁰); 4.89 (dd,

0

J_{4 ,5}= 4.1, 3.1, H-4⁰); 4.89 (dd, 1H, J_gem= 12.2,

1H, J_gem= 12.1, J_{5 a,4}= 3.1, H-5⁰a); 6.22 (dd, 1H,

0

J_{5 a,4}= 3.1, H-5⁰a); 5.31 (t, 1H, J_vic= 7.5, S–CH–S);

J_{3 ,2}= 5.8, J_{3 ,4}= 4.8, H-3 ); 6.39 (dd, 1H, J_{2 ,3}= 5.8,

0

6.22 (dd, 1H, J_{3 ,2}= 5.8, J_{3 ,4}= 4.6, H-3⁰); 6.38 (t, 1H,

J_{2 ,1}= 5.4, H-2⁰); 6.47 (d, 1H, J_{1 ,2}= 5.4, H-1⁰); 7.14–

7.34 (m, 11H, H-m-Tol, H-o,m,p-Ph); 7.82, 7.90, and

8.00 (3· m, 3· 2H, H-o-Tol); 8.18 (s, 1H, H-8); 8.79

(s, 1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.70

and 21.73 (CH₃-Tol); 29.15 (CH₂S); 32.85 (CH₂-pur);

36.12 (CH₂Ph); 63.47 (CH₂-5⁰); 71.39 (CH-3⁰); 73.69

(CH-2⁰); 80.96 (CH-4⁰); 86.84 (CH-1⁰); 125.66, 126.02,

and 126.59 (C-i-Tol); 126.90 (CH-p-Ph); 128.45 (CH-o-

Ph); 128.89 (CH-m-Ph); 129.22, 129.25, and 129.33

(CH-m-Tol); 129.78, 129.87, and 129.88 (CH-o-Tol);

133.47 (C-5); 138.18 (C-i-Ph); 142.54 (CH-8); 144.21,

144.56, and 144.68 (C-p-Tol); 150.54 (C-4); 152.68

(CH-2); 160.84 (C-6); 165.18, 165.38, and 166.20 (CO).

FAB-MS, m/z (rel %) = 779 (40), 757 (48) [M+H]⁺,

665 (14), 487 (12), 215 (12), 119 (100), 91 (20). HRMS

Calcd for C₄₃H₄₁N₄O₇S [M+H]⁺757.2695. Found:

757.2715. IR (CHCl₃): 3087, 3065, 3033, 1727, 1612,

1597, 1585, 1578, 1510, 1496, 1409, 1379, 1334, 1311,

0

J_{2 ,3}= 5.8, J_{2 ,1}= 5.4, H-2⁰); 6.48 (d, 1H, J_{1 ,2}= 5.4,

H-1⁰); 7.16, 7.21, and 7.26 (3· m, 3· 2H, H-m-Tol);

7.82, 7.90, and 7.99 (3· m, 3· 2H, H-o-Tol); 8.20 (s,

1H, H-8); 8.83 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 21.70 and 21.73 (CH₃-Tol); 38.65 (CH₂–S);

43.25 (CH₂-pur); 50.76 (S–CH–S); 63.46 (CH₂-5⁰);

71.39 (CH-3⁰); 73.70 (CH-2⁰); 81.00 (CH-4⁰); 86.80

(CH-1⁰); 125.66, 126.02, and 126.58 (C-i-Tol); 129.22,

129.25, and 129.34 (CH-m-Tol); 129.78, 129.87, and

129.89 (CH-o-Tol); 133.36 (C-5); 142.82 (CH-8);

144.21, 144.56, and 144.67 (C-p-Tol); 150.76 (C-4);

152.68 (CH-2); 159.27 (C-6); 165.17, 165.38, and

166.20 (CO). FAB-MS, m/z (rel %) = 725 (52)

[M+H]⁺, 487 (12), 215 (14), 119 (100), 105 (10), 91

(20). HRMS Calcd for C₃₈H₃₇N₄O₇S₂[M+H]⁺

725.2155. Found: 725.2130. IR (CHCl₃): 3036, 2996,

2928, 1727, 1612, 1597, 1510, 1498, 1455, 1409, 1379,

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1414

1298, 1281, 1267, 1247, 1180, 1126, 1114, 1093, 1020,

840, 702, 691, 645.

C₄₃H₃₈N₅O₇S₂[M+H]⁺800.2212. Found: 800.2189. IR

(CHCl₃): 3118, 3065, 3034, 2993, 1727, 1612, 1599,

1585, 1498, 1462, 1428, 1409, 1334, 1310, 1297, 1281,

1267, 1180, 1127, 1114, 1093, 1020, 996, 840, 691, 644, 477.

6.30. 6-(2-{[(Methoxycarbonyl)methyl]sulfanyl}ethyl)-9-

(2,3,5-tri-O-toluoyl-b-^D-ribofuranosyl)purine (11b)

6.32. 6-[2-(Thiazoline-2-ylsulfanyl)ethyl]-9-(2,3,5-tri-O-

toluoyl-b-^D-ribofuranosyl)purine (11d)

Yield 57%, yellowish foam. ¹H NMR (400 MHz,

CDCl₃): 2.38 and 2.42 (2· s, 9H, CH₃-Tol); 3.23 (t,

2H, J_vic= 7.4, CH₂–S); 3.32 (s, 2H, CH₂CO); 3.49 and

3.52 (2· dt, 2H, J_gem= 14.6, J_vic= 7.4, CH₂-pur); 3.73

1

Yield 87%, white foam. H NMR (400 MHz, CDCl₃):

2.38 and 2.42 (2· s, 9H, CH₃-Tol); 3.20 (m, 2H, H-5-thi-

azole); 3.60 (t, 2H, J_vic= 7.2, CH₂-pur); 4.08 (m, 2H, H-

4-thiazole); 4.34 (t, 2H, J_vic= 7.2, CH₂–S); 4.67 (dd, 1H,

0

(s, 3H, CH₃O); 4.67 (dd, 1H, J_gem= 12.3, J_{5 b,4}= 4.3,

H-5⁰b); 4.82 (ddd, 1H, J_{4 ,3}= 4.7, J_{4 ,5}= 4.3, ₀3.1, H-

0

4⁰); 4.89 (dd, 1H, J_gem= 12.3, J_{5 a,4}= 3.1, H-5 a); 6.22

(dd, 1H, J_{3 ,2}= 5.7, J_{3 ,4}= 4.7, H-3 ); 6.39 (dd, 1H,

J_gem= 12.1, J_{5 b,4}= 4.3, H-5⁰b); 4.82 (ddd, 1H,

0

J_{4 ,3}= 4.7, J_{4 ,5}= 4.3, 3.2, H-4⁰); 4.90 (dd, 1H,

0

J_{2 ,3}= 5.7, J_{2 ,1}= 5.3, H-2⁰); 6.47 (d, 1H, J_{1 ,2}= 5.3,

H-1⁰); 7.16, 7.22, and 7.26 (3· m, 3· 2H, H-m-Tol);

7.82, 7.90, and 8.00 (3· m, 3· 2H, H-o-Tol); 8.18 (s,

1H, H-8); 8.80 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 21.69 (CH₃-Tol); 30.28 (CH₂S); 32.47 (CH₂-

pur); 33.26 (CH₂CO); 52.38 (CH₃O); 63.46 (CH₂-5⁰);

71.38 (CH-3⁰); 73.68 (CH-2⁰); 80.97 (CH-4⁰); 86.85

(CH-1⁰); 125.65, 126.01, and 126.58 (C-i-Tol); 129.22,

129.25, and 129.32 (CH-m-Tol); 129.78, 129.86, and

129.88 (CH-o-Tol); 133.50 (C-5); 142.65 (CH-8);

144.21, 144.56, and 144.69 (C-p-Tol); 150.57 (C-4);

152.69 (CH-2); 160.38 (C-6); 165.17, 165.37, and

166.20 (CO-Tol); 170.77 (COOMe). FAB-MS, m/z (rel

%) = 762 (12), 739 (45) [M+H]⁺, 487 (12), 215 (10),

119 (100), 91 (14). HRMS Calcd for C₃₉H₃₉N₄O₉S

[M+H]⁺739.2437. Found: 739.2421. IR (CHCl₃):

3117, 3094, 3031, 2955, 1729, 1612, 1597, 1585, 1510,

1498, 1438, 1409, 1379, 1334, 1311, 1297, 1280, 1267,

1180, 1127, 1114, 1093, 1042, 839, 691, 644.

J_gem= 12.1, J_{5 a,4}= 3.2, H-5⁰a); 6.21 (dd, 1H,

0

J_{3 ,2}= 5.6, J_{3 ,4}= 4.7, H-3⁰); 6.38 (dd, 1H, J_{2 ,3}= 5.6,

0

J_{2 ,1}= 5.4, H-2⁰); 6.47 (d, 1H, J_{1 ,2}= 5.4, H-1⁰); 7.16,

7.22, and 7.26 (3· m, 3· 3H, H-m-Tol); 7.80, 7.91, and

7.99 (3· m, 3· 2H, H-o-Tol); 8.20 (s, 1H, H-8); 8.80

(s, 1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.70

and 21.71 (CH₃-Tol); 27.45 (CH₂-5-thiazole); 30.19

(CH₂-pur); 47.09 (CH₂S); 57.19 (CH₂-4-thiazole); 63.43

(CH₂-5⁰); 71.38 (CH-3⁰); 73.68 (CH-2⁰); 80.99 (CH-4⁰);

86.94 (CH-1⁰); 125.61, 125.99, and 126.57 (C-i-Tol);

129.23, 129.26, and 129.33 (CH-m-Tol); 129.78 and

129.87 (CH-o-Tol); 133.61 (C-5); 142.88 (CH-8);

144.25, 144.60, and 144.72 (C-p-Tol); 150.57 (C-4);

152.66 (CH-2); 159.15 (C-6); 165.19, 165.39, and

166.19 (CO); 196.88 (C-2-thiazole). FAB-MS, m/z (rel

%) = 774 (48), 752 (8) [M+H]⁺, 720 (10), 487 (10), 215

(12), 147 (12), 119 (100), 91 (12). HRMS Calcd for

C₃₉H₃₈N₅O₇S₂[M+H]⁺752.2212. Found: 752.2233. IR

(CHCl₃): 3117, 3095, 3034, 2989, 1727, 1612, 1598,

1585, 1509, 1499, 1488, 1455, 1420, 1410, 1375, 1367,

1334, 1297, 1281, 1267, 1248, 1180, 1126, 1114, 1093,

1020, 840, 691, 645, 476.

0

6.31. 6-[2-(Benzothiazole-2-ylsulfanyl)ethyl]-9-(2,3,5-tri-

O-toluoyl-b-^D-ribofuranosyl)purine (11c)

1

Yield 87%, white foam. H NMR (400 MHz, CDCl₃):

6.33. General method of nucleophilic addition of thiols,

method B

2.38 and 2.42 (2· s, 9H, CH₃-Tol); 3.70 (m, 2H, CH₂-

pur); 4.67 (dd, 1H, J_gem= 12.3, J_{5 b,4}= 4.3, H-5 b);

0

4.82 (ddd, 1H, J_{4 ,3}= 4.7, J_{4 ,5}= 4.3, 3.1, H-4⁰); 4.89

A solution of 6-vinylpurines 7, 8 (1.5 mmol) in THF

(10 ml) was added to a mixture of sodium thiolate

(15 mmol) in methanol (10 ml). The mixture was stirred

at room temperature for one day. The resulting mixture

was neutralized by HCl (2 M in MeOH). Inorganic salt

was ﬁltered and ﬁltrate was concentrated under reduced

pressure. The residue was puriﬁed by column chroma-

tography (silica gel, chloroform/methanol) and crystal-

lized from chloroform/heptane.

0

(dd, 1H, J_gem= 12.3, J_{5 a,4}= 3.1, H-5⁰a); 4.97 (m, 2H,

0

CH₂–S); 6.20 (dd, 1H, J_{3 ,2}= 5.6, J_{3 ,4}= 4.7, H-3⁰);

0

6.34 (dd, 1H, J_{2 ,3}= 5.6, J_{2 ,1}= 5.3, H-2⁰); 6.45 (d,

0

1H, J_{1 ,2}= 5.3, H-1⁰); 7.14–7.31 (m, 9H, H-4,5,6-benzo-

thiazole and H-m-Tol); 7.41 (ddd, 1H, J_7,6= 7.7,

J_7,5= 1.1, J_7,4= 0.7, H-7-benzothiazole); 7.82, 7.91,

and 8.00 (3· m, 3· 2H, H-o-Tol); 8.18 (s, 1H, H-8);

8.83 (s, 1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃):

21.73 and 21.75 (CH₃-Tol); 30.13 (CH₂-pur); 44.25

(CH₂S); 63.42 (CH₂-5⁰); 71.36 (CH-3⁰); 73.71 (CH-2⁰);

81.00 (CH-4⁰); 86.94 (CH-1⁰); 112.32 (CH-4-benzothia-

zole); 121.24 (CH-7-benzothiazole); 124.62 (CH-6-

benzothiazole); 125.66, 126.02, 126.04, and 126.60

(C-7a-benzothiazole and C-i-Tol); 126.87 (CH-5-benzo-

thiazole); 129.27, 129.29, and 129.35 (CH-m-Tol);

129.81, 129.89, and 129.91 (CH-o-Tol); 133.83 (C-5);

141.33 (C-7a-benzothiazole); 142.95 (CH-8); 144.29,

144.61, and 144.76 (C-p-Tol); 150.57 (C-4); 152.77

(CH-2); 158.46 (C-6); 165.18, 165.40, and 166.22 (CO);

189.17 (C-2-benzothiazole). FAB-MS, m/z (rel

%) = 822 (24), 800 (8) [M+H]⁺, 633 (10), 487 (10), 215

(12), 147 (14), 119 (100), 91 (14). HRMS Calcd for

0

6.34. 6-[2-(Methylsulfanyl)ethyl]-9-(b-^D-ribofurano-

syl)purine (12e)

Yield 44%, white hygroscopic crystals. ¹H NMR

(400 MHz, DMSO-d₆): 2.09 (s, 3H, CH₃); 3.03 (t, 2H,

J_vic= 7.3, CH₂–S); 3.39 (t, 2H, J_vic= 7.3, CH₂-pur);

0

3.57 (ddd, 1H, J_gem= 11.9, J_{5 b,OH}= 6.0, J_{5 b,4}= 4.1,

0

H-5⁰b); 3.69 (ddd, 1H, J_gem= 11.9, J_{5 a,OH}= 5.2,

J_{5 a,4}= 3.9, H-5⁰a); 3.97 (q, 1H, J_{4 ,5}= 3.9, 4.1,

0

J_{4 ,3}= 3.7, H-4⁰); 4.18 (q, 1H, J_{3 ,2}= 5.2, J_{3 ,OH}= 4.9,

0

J_{3 ,4}= 3.6, H-3⁰); 4.65 (q, 1H, J_{2 ,OH}= 6.1, J_{2 ,1}= 5.8,

0

J_{2 ,3}= 5.2, H-2⁰); 5.12 (t, 1H, J_OH,5= 6.0, 5.2, OH-5⁰);

0

5.24 (d, 1H, J_OH,3= 4.9, OH-3⁰); 5.53 (d, 1H,

0

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M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1415

J_OH,2= 6.1, OH-2⁰); 6.02 (d, 1H, J_{1 ,2}= 5.8, H-1⁰); 8.78

(s, 1H, H-2); 8.86 (s, 1H, H-8). ¹³C NMR (100.6 MHz,

DMSO-d₆): 14.41 (CH₃); 31.04 (CH₂-pur); 31.90

(CH₂–S); 61.24 (CH₂-5⁰); 70.30 (CH-3⁰); 73.50 (CH-2⁰);

85.67 (CH-4⁰); 87.50 (CH-1⁰); 132.78 (C-5); 144.23

(CH-8); 150.28 (C-4); 151.71 (CH-2); 159.69 (C-6).

FAB-MS, m/z (rel %) = 327 (6) [M+H]⁺, 250 (6), 231

(7), 209 (10), 195 (50). 179 (15), 161 (20), 147 (76), 134

(22), 120 (20), 109 (10), 73 (20), 61 (40), 52 (100). HRMS

Calcd for C₁₃H₁₉N₄O₄S [M+H]⁺327.1127. Found:

327.1143. IR (KBr): 3496, 3401, 3204, 1604, 1587,

1499, 1438, 1420, 1405, 1381, 1338, 1216, 1123, 1096,

1063, 967, 955, 696, 639. Anal. Calcd for C₁₃H₁₈N₄O_4-

SÆ0.25H₂O: C, 47.19; H, 5.64; N, 16.93; S, 9.69. Found:

C, 47.59; H, 5.49; N, 16.56; S, 9.72. [a]_Dꢀ43.3 (c 0.30,

MeOH).

1H, J_{2 ,OH}= 6.1, J_{2 ,1}= 5.8, J_{2 ,3}= 5.2, H-2⁰); 5.12 (t,

0

1H, J_OH,5= 6.0, 5.2, OH-5⁰); 5.24 (d, 1H, J_OH,3= 4.9,

OH-3⁰); 5.53 (d, 1H, J_OH,2= 6.1, OH-2⁰); 6.02 (d, 1H,

0

J_{1 ,2}= 5.8, H-1⁰); 8.77 (s, 1H, H-2); 8.84 (s, 1H,

H-8). ¹³C NMR (100.6 MHz, DMSO-d₆): 32.71

(CH₂-pur); 57.67 (CH₃–O); 61.25(CH₂-5⁰); 69.66

(CH₂–O); 70.30 (CH-3⁰); 73.50 (CH-2⁰); 85.65 (CH-4⁰);

87.51 (CH-1⁰); 132.99 (C-5); 144.15 (CH-8); 150.21

(C-4); 151.65 (CH-2); 159.12 (C-6). FAB-MS, m/z (rel

%) = 311 (16) [M+H]⁺, 221 (6), 189 (10). 179 (100),

161 (16), 147 (72), 135 (20), 120 (14), 109 (10), 94 (7),

73 (14), 57 (16). HRMS Calcd for C₁₃H₁₉N₄O₅

[M+H]⁺311.1355. Found: 311.1368. IR (KBr): 3401,

3284, 3111, 2831, 1603, 1584, 1498, 1409, 1394, 1333,

1213, 1117, 1096, 1082, 1062, 646. Anal. Calcd for

C₁₃H₁₈N₄O₅Æ0.25H₂O: C, 49.60; H, 5.92; N, 17.80.

Found: C, 49.82; H, 5.71; N, 17.39. [a]_Dꢀ48.0 (c 0.27,

MeOH).

0

6.35. 6-[2-(Methylsulfanyl)ethyl]-9-(2-deoxy-b-^D-erythro-

pentafuranosyl)purine (13e)

6.37. 6-(2-Methoxyethyl)-9-(2-deoxy-b-^D-erythro-penta-

furanosyl)purine (13f)

Yield 94%, white hygroscopic foam. ¹H NMR

(400 MHz, DMSO-d₆): 2.09 (s, 3H, CH₃); 2.34 (ddd,

1H, J_gem= 13.3, J_{2 b,1}= 6.3, J_{2 b,3}= 3.4, H-2⁰b); 2.81

Yield 70%, white crystals. ¹H NMR (400 MHz, DMSO-

0

(ddd, 1H, J_gem= 13.3, J_{2 a,1}= 7.2, J_{2 a,3}= 6.0, H-2⁰a);

3.02 (t, 2H, J_vic= 7,3) 3.38 (t, 2H, J_vic= 7,3); 3.52 (dt,

0

d₆): 2.45 (ddd, 1H, J_gem= 13.3, J_{2 b,1}= 6.3, J_{2 b,3}= 3.4,

0

H-2⁰b); 2.80 (ddd, 1H, J_gem= 13.3, J_{2 a,1}= 7.3,

0

1H, J_gem= 11.6, J_{5 b,OH}= 5.6, J_{5 b,4}= 4.7, H-5⁰b); 3.63

J_{2 a,3}= 5.9, H-2⁰a); 3.21 (3H, CH₃–O); 3.32 (t, 2H,

0

(dt, 1H, J_gem= 11.6, J_{5 a,OH}= 5.6, J_{5 a,4}= 4.7, H-5⁰a);

J_vic= 6.6); 3.53 (ddd, 1H, J_gem= 11.7, J_{5 b,OH}= 5.7,

0 0

0

3.88 (td, 1H, J_{4 ,5}= 4.7, J_{4 ,3}= 3.0, H-4⁰); 4.45 (m,

J_{5 b,4}= 4.7, H-5⁰b); 3.62 (ddd, 1H, J_gem= 11.7,

0

1H, J_{3 ,2}= 6.0, 3.4, J_{3 ,OH}= 4.2, J_{3 ,4}= 3.0, H-3⁰); 5.00

J_{5 a,OH}= 5.5, J_{5 a,4}= 4.9, H-5⁰a); 3.88 (t, 2H,₀J_vic= 6.6);

0

(t, 1H, J_OH,5= 6.3, OH-5⁰); 5.36 (d, 1H, J_OH,3= 4.2,

0

0 0 0 0

3.88 (td, 1H, J_{4 ,5}= 4.7, 4.9, J_{4 ,3}= 2.7, H-4 ); 4.45 (m,

OH-3⁰); 6.47 (dd, 1H, J_{1 ,2}= 7.2, 6.3, H-1⁰); 8.74 (s,

1H, H-2); 8.84 (s, 1H, H-2); ¹³C NMR (100.6 MHz,

DMSO-d₆): 14.41 (CH₃); 31.04 (CH₂-pur); 31.91

(CH₂S); 39.10 (C-2⁰); 61.51 (CH₂-5⁰); 70.61 (CH-3⁰);

83.64 (CH-1⁰); 87.91 (CH-4⁰); 132.77 (C-5); 143.12

(CH-8); 149.98 (C-4); 151.63 (CH-2); 159.56 (C-6).

FAB-MS, m/z (rel %) = 311 (24) [M+H]⁺, 295 (8), 274

(14), 257 (18), 249 (8), 215 (6), 202 (8), 195 (24), 149

(14), 115 (8), 57 (28). HRMS Calcd for C₁₃H₁₉N₄O₃S

[M+H]⁺311.1177. Found: 311.1190. IR (KBr): 3612,

3294, 3116, 3076, 1598, 1585, 1438, 1499, 1419, 1400,

1335, 1322, 1105, 1094, 1059, 959, 816, 709, 703, 645.

Anal. Calcd for C₁₃H₁₈N₄O₃SÆ0.25 H₂O: C, 49.59; H,

5.92; N, 17.76; S, 10.18. Found: C, 49.79; H, 5.72; N,

17.63; S, 10.04. [a]_Dꢀ8.7 (c 0.31, MeOH).

1H, J_{3 ,2}= 5.9, 3.4, J_{3 ,OH}= 4.2, J_{3 ,4}= 2.7, H-3⁰); 5.00

0

(t, 1H, J_OH,5= 5.7, 5.5, OH-5⁰); 5.36 (d, 1H,

0

J_OH,3= 4.2, OH-3⁰); 6.46 (dd, 1H, J_{1 ,2}= 7.3, 6.3, H-

1⁰); 8.73 (s, 1H, H-2); 8.83 (s, 1H, H-2); ¹³C NMR

(100.6 MHz, DMSO-d₆): 32.71 (CH₂-pur); 39.11 (C-

2⁰); 57.67 (CH₃–O); 61.52 (CH₂-5⁰); 69.70 (CH₂–O);

70.62 (CH-3⁰); 83.65 (CH-1⁰); 87.91 (CH-4⁰); 133.00

(C-5); 144.05 (CH-8); 149.92 (C-4); 151.57 (CH-2);

158.99 (C-6). FAB-MS, m/z (rel %) = 295 (100)

[M+H]⁺, 179 (65), 147 (15), 93 (7), 72 (6). HRMS Calcd

for C₁₃H₁₉N₄O₄[M+H]⁺295.1406. Found: 295.1411.

IR (KBr): 3325, 3194, 3116, 2833, 1598, 1581, 1500,

1446, 1382, 1340, 1329, 1207, 1116, 1106, 1065, 653.

Anal. Calcd for C₁₃H₁₈N₄O₄: C, 53.05; H, 6.16; N,

19.04. Found: C, 52.76; H, 5.95; N, 18.66. [a]_Dꢀ10.1

(c 0.37, MeOH).

0

6.36. 6-(2-Methoxyethyl)-9-(b-^D-ribofuranosyl)purine

(12f)

6.38. General method of cleavage toluoyl-protective group

A mixture of sodium methanolate (0.5 mmol) in metha-

nol (20 ml) was added to a solution of 6-vinylpurine 7

(1.5 mmol) in THF (10 ml). The mixture was stirred at

room temperature for one day. The resulting mixture

was concentrated under reduced pressure. The residue

was puriﬁed by column chromatography (silica gel,

chloroform/methanol) to obtained 164 mg (35%) as

The toluoyl-protected compound (1.0 mmol) was dis-

solved in a solution of MeONa (0.3 mmol) in methanol

(40 ml). The mixture was stirred at ambient temperature

for 16 h. The mixture was evaporated and puriﬁed by a

silica gel column chromatography (chloroform, methanol).

6.39. 6-[(E)-2-(Dimethylamino)vinyl]-9-(b-^D-ribofurano-

syl)purine (14a)

1

white foam product. H NMR (400 MHz, DMSO-d₆):

3.21 (s, 3H, CH₃–O); 3.34 (t, 2H, J_vic= 6.6, CH₂-pur);

3.57 (ddd, 1H, J_gem= 11.9, J_{5 b,OH}= 6.0, J_{5 b,4}= 4.1,

0

Yield 72%, yellow hygroscopic crystals. ¹H NMR

(500 MHz, DMSO-d₆): 3.01 (br s, 6H, CH₃N); 3.56

0

H-5⁰b); 3.69 (ddd, 1H, J_gem= 11.9, J_{5 a,OH}= 5.2,

J_{5 a,4}= 3.9, H-5⁰a); 3.89 (t, 2H, J_vic= 6.6, CH₂–O);

(dd, 1H, J_gem= 12.1, J_{5 b,4}= 2.6, H-5⁰b); 3.68 (dd, 1H,

0 0

0

3.97 (q, 1H, J_{4 ,5}= 3.9, 4.1, J_{4 ,3}= 3.7, H-4⁰); 4.18 (q,

J_gem= 12.1, J_{5 a,4}= 3.7, H-5⁰a); 3.97 (q, 1H,

0 0

0

1H, J_{3 ,2}= 5.2, J_{3 ,OH}= 4.9, J_{3 ,4}= 3.6, H-3⁰); 4.65 (q,

J_{4 ,5}= 3.7, 2.6, J_{4 ,3}= 3.1, H-4⁰); 4.16 (dd, 1H,

0 0 0 0

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1416

J_{3 ,2}= 5.0, J_{3 ,4}= 3.1, H-3⁰); 4.62 (dd, 1H, J_{2 ,1}= 6.1,

J_{2 ,3}= 4.2, H-2⁰); 5.21 (br d, 1H, J_OH,3= 4.2, OH-3⁰);

0

J_{2 ,3}= 5.0, H-2⁰); 5.23, 5.39, and 5.50 (3· br s, 3· br s,

5.38 (bdd, 1H, J_OH,5= 6.3, 3.3, OH-5⁰); 5.46 (br d,

1H, J_OH,2= 5.6, OH-2⁰); 5.54 (br d, 1H, J_trans= 12.7,

0

OH-2⁰, 3⁰, 5⁰); 5.51 (d, 1H, J_trans= 12.9, @CH-pur);

0

5.91 (d, 1H, J_{1 ,2}= 6.1, H-1⁰); 8.29 (br d, 1H,

J_trans= 12.9, @CH–N); 8.37 (s, 1H, H-2); 8.45 (s, 1H,

H-8). ¹³C NMR (125.7 MHz, DMSO-d₆): 39.96 and

44.41 (CH₃N); 61.81 (CH₂-5⁰); 70.81 (CH-3⁰); 73.61

(CH-2⁰); 86.03 (CH-4⁰); 87.97 (CH-1⁰); 89.71 (@CH-

pur); 127.55 (C-5); 141.53 (CH-8); 149.25 (C-4); 150.14

(@CH–N); 151.80 (CH-2); 157.11 (C-6). FAB-MS, m/z

(rel %) = 322 (40) [M+H]⁺, 232 (7), 215 (20), 190

(100), 165 (7), 147 (15), 115 (14), 105 (18), 57 (30).

HRMS Calcd for C₁₄H₂₀N₅O₄[M+H]⁺322.1515.

Found: 322.1523. IR (KBr): 3205, 3113, 2809, 1634,

1586, 1571, 1560, 1500, 1436, 1414, 1392, 1218, 1103,

1080, 1060, 811, 646. Anal. Calcd for C₁₄H₁₉N₅O₄Æ0.5-

H₂O: C, 50.90; H, 6.10; N, 21.20. Found: C, 51.23; H,

5.96; N, 21.07. [a]_Dꢀ62.6 (c 0.32, MeOH).

@CH-pur); 5.90 (d, 1H, J_{1 ,2}= 6.0, H-1⁰); 8.31 (br d,

1H, J_trans= 12.7, @CH–N); 8.35 (s, 1H, H-2); 8.43 (s,

1H, H-8). ¹³C NMR (125.7 MHz, DMSO-d₆): 13.91

(CH₃CH₂CH₂CH₂); 19.75 (CH₃CH₂CH₂CH₂); 28.36

and 31.31 (CH₃CH₂CH₂CH₂); 47.42 and 55.45

(CH₃CH₂CH₂CH₂); 61.79 (CH₂-5⁰); 70.77 (CH-3⁰);

73.65 (CH-2⁰); 85.99 (CH-4⁰); 87.99 (CH-1⁰); 89.07

(@CH-pur); 127.42 (C-5); 141.42 (CH-8); 148.97

(@CH–N); 149.14 (C-4); 151.78 (CH-2); 157.29 (C-6).

FAB-MS, m/z (rel %) = 406 (75) [M+H]⁺, 316 (12),

302 (8), 274 (100), 244 (7), 230 (12), 216 (12), 188 (10),

174 (12), 160 (8), 147 (15), 135 (15), 57 (13). HRMS

Calcd for C₂₀H₃₂N₅O₄[M+H]⁺406.2454. Found:

406.2459. IR (KBr): 3508, 3211, 1626, 1583, 1574,

1565, 1497, 1466, 1458, 1446, 1428, 1405, 1368, 1332,

1215, 1101, 1077, 1060, 816, 645. Anal. Calcd for

C₂₀H₃₁N₅O₄Æ1.25H₂O: C, 56.12; H, 7.89; N, 16.36.

Found: C, 56.24; H, 7.68; N, 16.38. [a]_Dꢀ52.4 (c 0.32,

MeOH).

0

6.40. 6-[(E)-2-(Diethylamino)vinyl]-9-(b-^D-ribofurano-

syl)purine (14b)

Yield 84%, yellowish hygroscopic crystals. ¹H NMR

(500 MHz, DMSO-d₆): 1.18 (t, 6H, J_vic= 7.1,

CH₃CH₂N); 4.36 (q, 4H, J_vic= 7.1, CH₃CH₂N); 3.56

6.42. 6-[(E)-2-(Piperidine-1-yl)vinyl]-9-(b-^D-ribofurano-

syl)purine (14d)

0

(ddd, 1H, J_gem= 12.1, J_{5 b,OH}= 7.1, J_{5 b,4}= 3.7, H-

0

5⁰b); 3.68 (dt, 1H, J_gem= 12.1, J_{5 a,OH}= 4.5,

Yield 71%, yellowish hygroscopic crystals. ¹H NMR

(500 MHz, DMSO-d₆): 1.54–1.65 (m, 6H, CH₂-pip);

3.36 (m, 4H, CH₂N-pip); 3.56 (ddd, 1H, J_gem= 12.1,

J_{5 a,4}= 3.8, H-5⁰a); 3.96 (q, 1H, J_{4 ,5}= 3.8, 3.7,

0

J_{4 ,3}= 3.2, H-4⁰); 4.15 (td, 1H, J_{3 ,2}= 4.9, J_{3 ,OH}= 4.7,

0

J_{3 ,4}= 3.2, H-3⁰); 4.61 (td, 1H, J_{2 ,OH}= 6.2, J_{2 ,1}= 6.1,

J_{5 b,OH}= 7.0, J_{5 b,4}= 3.7, H-5⁰b); 3.68 (dt, 1H,

0

J_{2 ,3}= 4.9, H-2⁰); 5.17 (d, 1H, J_OH,3= 4.7, OH-3⁰);

J_gem= 12.1, J_{5 a,OH}= 4.6, J_{5 a,4}= 3.6, H-5⁰a); 3.96 (q,

0

5.35 (dd, 1H, J_OH,5= 7.1, 4.5, OH-5⁰); 5.43 (d, 1H,

0

1H, J_{4 ,5}= 3.7, 3.6, J_{4 ,3}= 3.2, H-4 ); 4.15 (td, 1H,

0

J_OH,2= 6.2, OH-2⁰); 5.56 (d, 1H, J_trans= 13.1, @CH-

J_{3 ,2}= 4.9, J_{3 ,OH}= 4.7, J_{3 ,4}= 3.2, H-3⁰); 4.62 (td, 1H,

0

pur); 5.90 (d, 1H, J_{1 ,2}= 6.1, H-1⁰); 8.30 (br d, 1H,

J_trans= 13.1, @CH–N); 8.36 (s, 1H, H-2); 8.43 (s, 1H,

H-8). ¹³C NMR (125.7 MHz, DMSO-d₆): 12.13 and

14.71 (CH₃CH₂N); 41.67 and 49.57 (CH₃CH₂N); 61.76

(CH₂-5⁰); 70.74 (CH-3⁰); 73.59 (CH-2⁰); 85.94 (CH-4⁰);

87.94 (CH-1⁰); 89.12 (@CH-pur); 127.41 (C-5); 141.34

(CH-8); 147.97 (@CH–N); 149.14 (C-4); 151.73 (CH-

2); 157.27 (C-6). FAB-MS, m/z (rel %) = 350 (90)

[M+H]⁺, 260 (12), 260 (12), 246 (8), 218 (100), 188

(15), 174 (7), 161 (8), 147 (15), 135 (10), 120 (6), 84

(7), 57 (7). HRMS Calcd for C₁₆H₂₄N₅O₄[M+H]⁺

350.1828. Found: 350.1831. IR (KBr): 3520, 3391,

3180, 3123, 1326, 1588, 1565, 1500, 1471, 1431, 1403,

1382, 1333, 1220, 813, 639, 646. Anal. Calcd for

C₁₆H₂₃N₅O₄Æ0.75H₂O: C, 52.96; H, 6.80; N, 19.30.

Found: C, 52.63; H, 6.52; N, 19.04. [a]_Dꢀ62.5 (c 0.26,

MeOH).

J_{2 ,OH}= 6.2, J_{2 ,1}= 6.1, J_{2 ,3}= 4.9, H-2⁰); 5.19 (d, 1H,

0

J_OH,3= 4.7, OH-3⁰); 5.37 (dd, 1H, J_OH,5= 7.0, 4.6,

0

OH-5⁰); 5.46 (d, 1H, J_OH,2= 6.2, OH-2⁰); 5.66 (d, 1H,

0

J_trans= 13.1, @CH-pur); 5.91 (d, 1H, J_{1 ,2}= 6.1, H-1⁰);

8.23 (br d, 1H, J_trans= 13.1, @CH–N); 8.37 (s, 1H, H-

2); 8.44 (s, 1H, H-8). ¹³C NMR (125.7 MHz, DMSO-

d₆): 23.87 and 25.51 (CH₂-pip); 47.80 (CH₂N-pip);

61.81 (CH₂-5⁰); 70.80 (CH-3⁰); 73.58 (CH-2⁰); 86.02

(CH-4⁰); 87.96 (CH-1⁰); 89.32 (@CH-pur); 127.63 (C-

5); 141.52 (CH-8); 148.95 (@CH–N); 149.21 (C-4);

151.76 (CH-2); 157.37 (C-6). FAB-MS, m/z (rel

%) = 362 (97) [M+H]⁺, 307 (6), 272 (8), 258 (7), 230

(47), 215 (22), 201 (12), 185 (35), 181 (9), 147 (12), 123

(7), 105 (7), 75 (27), 61 (14), 57 (38). HRMS Calcd for

C₁₇H₂₄N₅O₄[M+H]⁺362.1828. Found: 362.1823. IR

(KBr): 3325, 3180, 3113, 3045, 2932, 2854, 2700, 1628,

1601, 1588, 1571, 1501, 1442, 1426, 1403, 1365, 1327,

1238, 1201, 990, 982, 970, 852, 810, 642. Anal. Calcd

for C₁₇H₂₃N₅O₄Æ0.5H₂O: C, 55.12; H, 6.53; N, 18.91.

Found: C, 54.99; H, 6.45; N, 18.54. [a]_Dꢀ31.4 (c 0.50,

MeOH).

0

6.41. 6-[(E)-2-(Dibutylamino)vinyl]-9-(b-^D-ribofurano-

syl)purine (14c)

Yield 66%, yellowish hygroscopic crystals. ¹H NMR

(500 MHz, DMSO-d₆): 0.92 (t, 6H, J_vic= 7.3,

CH₃CH₂CH₂CH₂); 1.32 and 1.57 (2· m, 2· 4H,

CH₃CH₂CH₂CH₂); 3.29 (br m, 4H, CH₃CH₂CH₂CH₂);

6.43. 6-[(E)-2-(Morpholine-4-yl)vinyl]-9-(b-^D-ribofurano-

syl)purine (14e)

Yield 89%, yellowish hygroscopic crystals. ¹H NMR

(500 MHz, DMSO-d₆): 3.39 (m, 4H, CH₂N-morph);

0

3.55 (ddd, 1H, J_gem= 12.1, J_{5 b,OH}= 6.3, J_{5 b,4}= 3.6,

0

H-5⁰b); 3.68 (ddd, 1H, J_gem= 12.1, J_{5 a,4}= 3.6,

0

J_{5 a,OH}= 3.3, H-5⁰b); 3.97 (q, 1H, J_{4 ,5}= J_{4 ,3}= 3.6,

3.56 (ddd, 1H, J_gem= 12.1, J_{5 b,OH}= 6.9, J_{5 b,4}= 3.8,

0

H-4⁰); 4.15 (btd, 1H, J_{3 ,2}= J_{3 ,OH}= 4.2, J_{3 ,4}= 3.6,

H-5⁰b); 3.67 (m, 4H, CH₂O-morph); 3.68 (dt, 1H,

J_gem= 12.1, J_{5 a,OH}= 4.7, J_{5 a,4}= 3.6, H-5⁰a); 3.97 (q,

0 0 0

0

H-3⁰); 4.61 (bddd, 1H, J_{2 ,1}= 6.0, J_{2 ,OH}= 5.6,

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1417

1H, J_{4 ,5}= 3.8, 3.6, J_{4 ,3}= 3.2, H-4⁰); 4.15 (td, 1H,

0

0 0 0 0

H-4-thiazolidine); 3.97 (q, 1H, J_{4 ,5}= 3.9, J_{4 ,3}= 3.0, H-

J_{3 ,2}= 5.0, J_{3 ,OH}= 4.7, J_{3 ,4}= 3.2, H-3⁰); 4.62 (td, 1H,

4⁰); 4.16 (td, 1H, J_{3 ,2}= J_{3 ,OH}= 4.7, J_{3 ,4}= 3.0, H-3⁰);

4.55 (s, 2H, H-2-thiazolidine); 4.62 (td, 1H,

0

J_{2 ,OH}= 6.2, J_{2 ,1}= 6.1, J_{2 ,3}= 5.0, H-2⁰); 5.20 (d, 1H,

0

J_OH,3= 4.7, OH-3⁰); 5.32 (dd, 1H, J_OH,5= 6.9, 4.7,

J_{2 ,OH}= 6.2, J_{2 ,1}= 6.0, J_{2 ,3}= 4.7, H-2⁰); 5.19 (d, 1H,

0

OH-5⁰); 5.46 (d, 1H, J_OH,2= 6.2, OH-2⁰); 5.74 (d, 1H,

J_OH,3= 4.7, OH-3⁰); 5.28 (br t, 1H, J_OH,5= 6.3, 4.9,

OH-5⁰); 5.47 (d, 1H, J_OH,2= 6.2, OH-2⁰); 5.67 (d, 1H,

0

J_trans= 13.2, @CH-pur); 5.92 (d, 1H, J_{1 ,2}= 6.1, H-1⁰);

8.22 (br d, 1H, J_trans= 13.2, @CH–N); 8.43 (s, 1H, H-

2); 8.49 (s, 1H, H-8). ¹³C NMR (125.7 MHz, DMSO-

d₆): 48.16 (CH₂N-morph); 61.76 (CH₂-5⁰); 65.92

(CH₂O-morph); 70.75 (CH-3⁰); 73.60 (CH-2⁰); 85.99

(CH-4⁰); 87.91 (CH-1⁰); 90.66 (@CH-pur); 127.91 (C-

5); 141.89 (CH-8); 148.92 (@CH–N); 149.47 (C-4);

151.77 (CH-2); 156.90 (C-6). FAB-MS, m/z (rel

%) = 364 (30) [M+H]⁺(cation), 232 (100), 215 (8), 201

(5), 181 (8), 174 (7), 159 (7), 147 (20), 135 (7), 120 (7),

105 (9), 98 (47), 57 (50). HRMS Calcd for

C₁₆H₂₂N₅O₅[M+H]⁺364.1620. Found: 364.1612. IR

(KBr): 3185, 3120, 3045, 1627, 1574, 1560, 1500, 1449,

1427, 1404, 1390, 1375, 1360, 1332, 1230, 1114, 1099,

1060, 1023, 989, 965, 862, 811, 644. Anal. Calcd for

C₁₆H₂₁N₅O₅Æ0.25H₂O: C, 50.99; H, 6.02; N, 18.58.

Found: C, 51.16; H, 5.88; N, 18.49. [a]_Dꢀ45.0 (c 0.30,

MeOH).

0

J_trans= 13.2, @CH-pur); 5.94 (d, 1H, J_{1 ,2}= 6.0, H-1⁰);

8.45 (s, 1H, H-2); 8.47 (br d, 1H, J_trans= 13.2, @CH–

N); 8.52 (s, 1H, H-8). ¹³C NMR (125.7 MHz, DMSO-

d₆): 29.96 (CH₂-5-thiazolidine); 51.95 (CH₂-4-thiazoli-

dine); 52.36 (CH₂-2-thiazolidine); 61.68 (CH₂-5⁰); 70.67

(CH-3⁰); 73.62 (CH-2⁰); 85.93 (CH-4⁰); 87.88 (CH-1⁰);

92.72 (@CH-pur); 127.92 (C-5); 142.03 (CH-8); 145.24

(@CH–N); 149.57 (C-4); 151.69 (CH-2); 156.38 (C-6).

FAB-MS, m/z (rel %) = 366 (20) [M+H]⁺, 307 (7), 279

(5), 234 (12), 215 (24), 197 (12), 181 (14), 149 (10), 119

(20), 61 (18), 57 (51). HRMS Calcd for C₁₅H₂₀N₅O₄S

[M+H]⁺366.1236. Found: 366.1229. IR (KBr): 3399,

3270, 3120, 1624, 1588, 1572, 1496, 1417, 1390, 1331,

1218, 1124, 1101, 1083, 1058, 978, 814, 644. Anal. Calcd

for C₁₅H₁₉N₅O₄SÆ2H₂O: C, 44.88; H, 5.77; N, 17.45.

Found: C, 44.74; H, 5.39; N, 17.10. [a]_Dꢀ53.7 (c 0.30,

MeOH).

0

6.44. 6-[(E)-2-(Benzyl(methyl)amino)vinyl]-9-(b-^D-ribo-

furanosyl)purine (14f)

6.46. 6-[(E)-2-(Dimethylamino)vinyl]-9-(2-deoxy-b-^D-ery-

thro-pentafuranosyl)purine (15a)

Yield 90%, white hygroscopic crystals. ¹H NMR

(500 MHz, DMSO-d₆): 2.91 (br s, 3H, CH₃–N); 3.56

Yield 89%, yellow hygroscopic foam. ¹H NMR

(500 MHz, DMSO-d₆): 2.27 (ddd, 1H, J_gem= 13.2,

(dd, 1H, J_gem= 12.1, J_{5 b,4}= 3.8, H-5⁰b); 3.68 (dd, 1H,

J_{2 b,1}= 6.2, J_{2 b,3}= 3.0, H-2⁰b); 2.74 (ddd, 1H,

0

J_gem= 12.1, J_{5 a,4}= 3.7, H-5⁰a); 3.96 (q, 1H,

J_gem= 13.2, J_{2 a,1}= 7.8, J_{2 a,3}= 5.8, H-2⁰a); 3.01 (br s,

6H, CH₃N); 3.52 and 3.63 (2· dd, 2H, J_gem= 11.9,

0

J_{4 ,5}= 3.8, 3.7, J_{4 ,3}= 3.2, H-4⁰); 4.15 (dd, 1H,

0

J_{3 ,2}= 5.0, J_{3 ,4}= 3.2, H-3 ); 4.58 (s, 2H, CH₂Ph); 4.62

0

J_{5 ,4}= 4.3, H-5⁰); 3.88 (td, 1H, J_{4 ,5}= 4.3, J_{4 ,3}= 2.6,

0 0 0 0 0 0

0

(dd, 1H, J_{2 ,1}= 6.0, J_{2 ,3}= 5.0, H-2⁰); 5.20–5.50 (br s,

H-4⁰); 4.42 (ddd, 1H, J_{3 ,2}= 5.8, 3.0, J_{3 ,4}= 2.6, H-3⁰);

0

3H, OH-2⁰, 3⁰, 5⁰); 5.61 (d, 1H, J_trans= 13.0, @CH-

5.21 (br s, 1H, OH-5⁰); 5.32 (br s, 1H, OH-3⁰); 5.49 (d,

pur); 5.91 (d, 1H, J_{1 ,2}= 6.0, H-1⁰); 7.29 (m, 2H, H-o-

Ph); 7.30 (m, 1H, H-p-Ph); 7.38 (m, 2H, H-m-Ph); 8.41

(s, 1H, H-2); 8.46 (s, 1H, H-2); 8.51 (br d, 1H,

J_trans= 13.0, @CH–N). ¹³C NMR (125.7 MHz,

DMSO-d₆): 35.15 (CH₃N); 60.29 (CH₂Ph); 61.76

(CH₂-5⁰); 70.74 (CH-3⁰); 73.63 (CH-2⁰); 85.97 (CH-4⁰);

87.93 (CH-1⁰); 90.37 (@CH-pur); 127.50 (CH-o-Ph);

127.68 (CH-p-Ph); 127.75 (C-5); 128.89 (CH-m-Ph);

137.62 (C-i-Ph); 141.70 (CH-8); 149.38 (C-4); 149.67

(@CH–N); 151.80 (CH-2); 157.01 (C-6). FAB-MS, m/z

(rel %) = 398 (60) [M+H]⁺, 308 (8), 266 (32), 215 (25),

201 (12), 147 (7), 122 (7), 57 (33). HRMS Calcd for

C₂₀H₂₄N₅O₄[M+H]⁺398.1828. Found: 398.1832. IR

(KBr): 3195, 3118, 1627, 1589, 1583, 1567, 1505, 1496,

1413, 1397, 1328, 1219, 1103, 1083, 1067, 1028, 1003,

821, 810, 737, 698, 646. Anal. Calcd for

C₂₀H₂₃N₅O₄Æ1.25H₂O: C, 57.20; H, 6.12; N, 16.68.

Found: C, 57.55; H, 5.84; N, 16.44. [a]_Dꢀ63.3 (c 0.23,

MeOH).

1H, J_trans= 13.0, @CH-pur); 6.37 (dd, 1H, J_{1 ,2}= 7.8,

6.2, H-1⁰); 8.28 (br d, 1H, J_trans= 13.0, @CH–N); 8.37

(s, 1H, H-2); 8.43 (s, 1H, H-8). ¹³C NMR (125.7 MHz,

DMSO-d₆): 37.34 (CH₃N); 39.53 (CH₂-2⁰); 44.60

(CH₃N); 62.05 (CH₂-5⁰); 71.13 (CH-3⁰); 83.99 (CH-1⁰);

88.17 (CH-4⁰); 89.79 (@CH-pur); 127.50 (C-5); 141.20

(CH-8); 149.06 (C-4); 150.04 (@CH–N); 151.79 (CH-

2); 157.01 (C-6). FAB-MS, m/z (rel %) = 306 (50)

[M+H]⁺, 215 (14), 190 (100), 147 (17), 123 (8), 104

(10), 93 (75), 75 (14), 57 (27). HRMS Calcd for

C₁₄H₂₀N₅O₃[M+H]⁺306.1566. Found: 306.1554. IR

(KBr): 3217, 3106, 2807, 1632, 1581, 1570, 1561, 1497,

1435, 1407, 1394, 1328, 1218, 1099, 1056, 812, 647. Anal.

Calcd for C₁₄H₁₉N₅O₃Æ0.75H₂O: C, 52.74; H, 6.48; N,

21.96. Found: C, 53.17; H, 8.82; N, 21.59. [a]_Dꢀ21.9

(c 0.31, MeOH).

0

6.47. 6-[(E)-2-(Diethylamino)vinyl]-9-(2-deoxy-b-^D-ery-

thro-pentafuranosyl)purine (15b)

6.45. 6-[(E)-2-(Thiazolidine-1-yl)vinyl]-9-(b-^D-ribofurano-

syl)purine (14g)

Yield 81%, yellow hygroscopic foam. ¹H NMR

(500 MHz, DMSO-d₆): 1.17 (t, 6H, J_vic= 7.1, CH₃CH₂);

0

2.27 (ddd, 1H, J_gem= 13.2, J_{2 b,1}= 6.2, J_{2 b,3}= 3.0,

0

Yield 63%, yellowish hygroscopic crystals. ¹H NMR

(500 MHz, DMSO-d₆): 3.11 (t, 2H, J_vic= 6.3, H-5-thia-

H-2⁰b); 2.73 (ddd, 1H, J_gem= 13.2, J_{2 a,1}= 7.8,

0

J_{2 a,3}= 5.8, H-2⁰a); 3.35 (q, 4H, J_vic= 7.1, CH₃CH₂);

0 0

0

zolidine); 3.56 (ddd, 1H, J_gem= 12.1, J_{5 b,OH}= 6.3,

0

3.48 (ddd, 1H, J_gem= 11.7, J_{5 b,OH}= 6.4, J_{5 b,4}= 4.3,

0

J_{5 b,4}= 3.9, H-5⁰b); 3.68 (dt, 1H, J_gem= 12.1,

H-5⁰b); 3.62 (dt, 1H, J_gem= 11.7, J_{5 a,OH}= 4.9,

0

J_{5 a,OH}= 4.9, J_{5 a,4}= 3.9, H-5⁰a); 3.71 (t, 2H, J_vic= 6.3,

J_{5 a,4}= 4.3, H-5⁰a); 3.88 (td, 1H, J_{4 ,5}= 4.3,

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1418

J_{4 ,3}= 2.6, H-4⁰); 4.41 (m, 1H, J_{3 ,2}= 5.8, 3.0,

J_{2 a,3}= 5.8, H-2⁰a); 3.36 (m, 4H, CH₂N-pip); 3.52

0 0

0 0 0

(ddd, 1H, J_gem= 11.7, J_{5 b,OH}= 5.8, J_{5 b,4}= 4.3, H-

0

J_{3 ,OH}= 4.0, J_{3 ,4}= 2.6, H-3⁰); 5.21 (dd, 1H,

0

J_OH,5= 6.4, 4.9, OH-5⁰); 5.32 (d, 1H, J_OH,3= 4.0,

OH-3⁰); 5.55 (d, 1H, J_trans= 13.1, @CH-pur); 6.36 (dd,

5⁰b); 3.62 (dt, 1H, J_gem= 11.7, J_{5 a,4}= 4.3, J_{5 a,OH}= 4.2,

0

H-5⁰a); 3.88 (td, 1H, J_{4 ,5}= 4.3, J_{4 ,3}= 2.6, H-4⁰); 4.41

0

1H, J_{1 ,2}= 7.8, 6.2, H-1⁰); 8.29 (br d, 1H, J_trans= 13.1,

@CH–N); 8.35 (s, 1H, H-2); 8.41 (s, 1H, H-8). ¹³C

NMR (125.7 MHz, DMSO-d₆): 11.60 and 14.75

(CH₃CH₂); 39.56 (CH₂-2⁰); 41.91 and 49.81 (CH₃CH₂);

62.06 (CH₂-5⁰); 71.13 (CH-3⁰); 83.98 (CH-1⁰); 88.17

(CH-4⁰); 89.07 (@CH-pur); 127.38 (C-5); 141.10 (CH-

8); 147.92 (@CH–N); 149.00 (C-4); 151.79 (CH-2);

157.22 (C-6). FAB-MS, m/z (rel %) = 334 (65)

[M+H]⁺, 244 (14), 218 (100), 188 (15), 161 (10), 147

(17), 135 (13), 84 (11), 56 (6). HRMS Calcd for

C₁₆H₂₄N₅O₃[M+H]⁺334.1879. Found: 334.1888. IR

(KBr): 3409, 3259, 1625, 1584, 1568, 1501, 1401, 1329,

(m, 1H, J_{3 ,2}= 5.8, 3.0, J_{3 ,OH}= 4.0, J_{3 ,4}= 2.6, H-3⁰);

0

5.20 (br t, 1H, J_OH,5= 5.8, 4.2, OH-5⁰); 5.32 (d, 1H,

0

J_OH,3= 4.0, OH-3⁰); 5.65 (d, 1H, J_trans= 13.1, @CH-

0

pur); 6.37 (dd, 1H, J_{1 ,2}= 7.8, 6.2, H-1⁰); 8.22 (br d,

1H, J_trans= 13.1, @CH–N); 8.37 (s, 1H, H-2); 8.42 (s,

1H, H-8). ¹³C NMR (125.7 MHz, DMSO-d₆): 23.88

and 25.57 (CH₂-pip); 39.53 (CH₂-2⁰); 62.06 (CH₂-5⁰);

71.13 (CH-3⁰); 83.98 (CH-1⁰); 88.17 (CH-4⁰); 89.40

(@CH-pur); 127.57 (C-5); 141.21 (CH-8); 148.92

(@CH–N); 149.05 (C-4); 151.77 (CH-2); 157.27 (C-6);

CH₂N-pip not observed. FAB-MS, m/z (rel %) = 327

(6) [M+H]⁺, 346 (68), 256 (15), 230 (100), 159 (6), 147

(18), 120 (6), 96 (8), 84 (6), 57 (7). HRMS Calcd for

C₁₇H₂₄N₅O₃[M+H]⁺346.1879. Found: 346.1876. IR

(KBr): 3401, 3255, 2935, 2855, 1625, 1583, 1566, 1500,

1463, 1445, 1431, 1400, 1362, 1343, 1327, 1200, 1162,

1117, 1099, 1058, 1024, 1003, 855, 647. Anal. Calcd

for C₁₇H₂₃N₅O₃Æ0.75H₂O: C, 56.89; H, 6.88; N, 19.50.

Found: C, 56.60; H, 6.50; N, 19.10. [a]_Dꢀ21.5 (c 0.15,

MeOH).

0

1219,

1099,

1058,

647.

Anal.

Calcd

for

C₁₆H₂₃N₅O₃Æ0.75H₂O: C, 55.40; H, 7.12; N, 20.19.

Found: C, 55.79; H, 6.96; N, 19.80. [a]_Dꢀ17.7 (c 0.12,

MeOH).

6.48. 6-[(E)-2-(Dibutylamino)vinyl]-9-(2-deoxy-b-^D-ery-

thro-pentafuranosyl)purine (15c)

Yield 85%, white hygroscopic crystals. ¹H NMR

(500 MHz, DMSO-d₆): 0.92 (t, 6H, J_vic= 7.3,

CH₃CH₂CH₂CH₂); 1.32 and 1.56 (2· m, 2· 4H,

CH₃CH₂CH₂CH₂); 2.27 (ddd, 1H, J_gem= 13.2,

6.50. 6-[(E)-2-(Morpholine-4-yl)vinyl]-9-(2-deoxy-b-^D-

erythro-pentafuranosyl)purine (15e)

J_{2 b,1}= 6.1, J_{2 b,3}= 3.1, H-2⁰b); 2.72 (ddd, 1H,

Yield 76%, yellowish hygroscopic crystals. ¹H NMR

(500 MHz, DMSO-d₆): 2.28 (ddd, 1H, J_gem= 13.2,

0

J_gem= 13.2, J_{2 a,1}= 7.7, J_{2 a,3}= 5.8, H-2⁰a); 3.28 (br

m, 4H, CH₃CH₂CH₂CH₂); 3.52 (ddd, 1H, J_gem= 11.7,

0

J_{2 b,1}= 6.1, J_{2 b,3}= 3.1, H-2⁰b); 2.75 (ddd, 1H,

0

J_{5 b,OH}= 6.5, J_{5 b,4}= 4.2, H-5⁰b); 3.62 ₀(ddd, 1H,

J_gem= 13.2, J_{2 a,1}= 7.7, J_{2 a,3}= 5.8, H-2⁰a); 3.37 (m,

4H, CH₂N-morph); 3.48 and 3.63 (2· bdd, 2H,

0

J_gem= 11.7, J_{5 a,OH}= 5.0, J_{5 a,4}= 4.2, H-5 b); 3.88 (td,

0

1H, J_{4 ,5}= 4.2, J_{4 ,3}= 2.7, H-4⁰); 4.41 (m, 1H,

J_gem= 11.7, J_{5 ,4}= 2.7, H-5⁰); 3.66 (m, 4H, CH₂O-

0 0

0

J_{3 ,2}= 5.8, 3.1, J_{3 ,OH}= 4.1, J_{3 ,4}= 2.7, H-3⁰); 5.21

morph); 3.89 (td, 1H, J_{4 ,5}= 4.3, J_{4 ,3}= 2.7, H-4⁰); 4.42

0

(dd, 1H, J_OH,5= 6.5, 5.0, OH-5⁰); 5.32 (d, 1H,

(br m, 1H, J_{3 ,2}= 5.8, 3.1, J_{3 ,4}= 2.7, H-3⁰); 5.17 (br s,

0

J_OH,3= 4.1, OH-3⁰); 5.52 (br d, 1H, J_trans= 13.3,

1H, OH-5⁰); 5.35 (br s, 1H, OH-3⁰); 5.72 (d, 1H,

0

@CH-pur); 6.36 (dd, 1H, J_{1 ,2}= 7.7, 6.1, H-1⁰); 8.30

(br d, 1H, J_trans= 13.3, @CH–N); 8.35 (s, 1H, H-2);

8.42 (s, 1H, H-8). ¹³C NMR (125.7 MHz, DMSO-d₆):

13.90 (CH₃CH₂CH₂CH₂); 19.49 (CH₃CH₂CH₂CH₂);

27.71 (CH₃CH₂CH₂CH₂); 39.57 (CH₂-2⁰); 47.32 and

55.39 (CH₃CH₂CH₂CH₂); 62.04 (CH₂-5⁰); 71.11 (CH-

3⁰); 83.96 (CH-1⁰); 88.16 (CH-4⁰); 89.17 (@CH-pur);

127.36 (C-5); 141.10 (CH-8); 148.86 (@CH–N); 149.98

(C-4); 151.79 (CH-2); 157.19 (C-6). FAB-MS, m/z (rel

%) = 390 (74) [M+H]⁺, 300 (16), 274 (100), 244 (6),

230 (6), 216 (6), 216 (8), 200 (4), 188 (6), 174 (12), 160

(10), 147 (14), 135 (12), 57 (14). HRMS Calcd for

C₂₀H₃₂N₅O₃[M+H]⁺390.2505. Found: 390.2512. IR

(KBr): 3612, 3199, 1622, 1581, 1562, 1504, 1431, 1418,

1331, 1106, 1085, 1060, 815, 646. Anal. Calcd for

C₂₀H₃₁N₅O₃Æ0.75H₂O: C, 59.61; H, 8.13; N, 17.38.

Found: C, 59.95; H, 8.10; N, 17.00. [a]_Dꢀ11.3 (c 0.29,

MeOH).

J_trans= 13.2, @CH-pur); 6.38 (t, 1H, J_{1 ,2}= 7.7, 6.1,

H-1⁰); 8.21 (d, 1H, J_trans= 13.2, @CH–N); 8.42 (s, 1H,

H-2); 8.47 (s, 1H, H-8). ¹³C NMR (125.7 MHz,

DMSO-d₆): 39.53 (CH₂-2⁰); 48.54 (CH₂N-morph);

62.03 (CH₂-5⁰); 65.93 (CH₂O-morph); 71.11 (CH-3⁰);

83.98 (CH-1⁰); 88.18 (CH-4⁰); 90.80 (@CH-pur); 127.89

(C-5); 141.61 (CH-8); 148.87 (@CH–N); 149.31 (C-4);

151.80 (CH-2); 156.82 (C-6). FAB-MS, m/z (rel

%) = 348 (100) [M+H]⁺, 258 (15), 232 (90), 215 (22),

201 (15), 181 (14) 147 (20), 122 (8), 61 (14), 57 (50).

HRMS Calcd for C₁₆H₂₂N₅O₄[M+H]⁺348.1671.

Found: 348.1675. IR (KBr): 3420, 3211, 3105, 1595,

1578, 1560, 1495, 1445, 1425, 1401, 1359, 1328, 1226,

1172, 1023, 866, 813, 647. Anal. Calcd for

C₁₆H₂₁N₅O₄Æ0.5H₂O: C, 53.92; H, 6.22; N, 19.65. Found:

C, 53.60; H, 6.05; N, 19.37. [a]_Dꢀ24.8 (c 0.27, MeOH).

0

6.51. 6-[(E)-2-(Benzyl(methyl)amino)vinyl]-9-(2-deoxy-b-

D-erythro-pentafuranosyl)purine (15f)

6.49. 6-[(E)-2-(Piperidine-1-yl)vinyl]-9-(2-deoxy-b-^D-ery-

thro-pentafuranosyl)purine (15d)

Yield 90%, yellowish hygroscopic foam. ¹H NMR

(500 MHz, DMSO-d₆): 2.28 (ddd, 1H, J_gem= 13.2,

Yield 77%, yellow hygroscopic foam. ¹H NMR

(500 MHz, DMSO-d₆): 1.52–1.66 (m, 6H, CH₂-pip);

J_{2 b,1}= 6.2, J_{2 b,3}= 3.1, H-2⁰b); 2.74 (ddd, 1H,

0

J_gem= 13.2, J_{2 a,1}= 7.8, J_{2 a,3}= 5.8, H-2⁰a); 2.91 (br s,

0

2.27 (ddd, 1H, J_gem= 13.2, J_{2 b,1}= 6.2, J_{2 b,3}= 3.0,

0

3H, CH₃N); 3.52 (ddd, 1H, J_gem= 11.9, J_{5 b,OH}= 6.4,

0 0

H-2⁰b); 2.74 (ddd, 1H, J_gem= 13.2, J_{2 a,1}= 7.8,

J_{5 b,4}= 4.3, H-5⁰b); 3.63 (dt, 1H, J_gem= 11.7,

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1419

J_{5 a,OH}= 4.9, J_{5 a,4}= 4.3, ₀H-5⁰a); 3.88 (td, 1H,

(ddd, 1H, J_gem= 12.0, J_{5 b,OH}= 6.0, J_{5 b,4}= 4.1, H-

5⁰b); 3.63 (d, 2H, J_vic= 7.6, CH₂-pur); 3.69 (ddd, 1H,

0

J_{4 ,5}= 4.3, J_{4 ,3}= 2.7, H-4 ); 4.42 (m, 1H, J_{3 ,2}= 5.8,

0

3.1, J_{3 ,OH}= 4.1, J_{3 ,4}= 2.7, H-3⁰); 4.56 (s, 2H, CH₂Ph);

J_gem= 12.0, J_{5 a,OH}= 5.3, J_{5 a,4}= 4.2, H-5⁰a); 3.98 (q,

1H, J_{4 ,5}= 4.2, 4.1, J_{4 ,3}= 3.6, H-4⁰); 4.19 (td, 1H,

0

5.18 (br t, 1H, J_OH,5= 6.4, 4.9, OH-5⁰); 5.33 (d, 1H,

0

J_OH,3= 4.1, OH-3⁰); 5.60 (d, 1H, J_trans= 13.0, @CH-

0

J_{3 ,2}= J_{3 ,OH}= 4.9, J_{3 ,4}= 3.6, H-3 ); 4.66 (td, 1H,

0

pur); 6.38 (dd, 1H, J_{1 ,2}= 7.8, 6.2, H-1⁰); 7.28 (m, 2H,

H-o-Ph); 7.30 (m, 1H, H-p-Ph); 7.38 (m, 2H, H-m-Ph);

8.40 (s, 1H, H-2); 8.44 (s, 1H, H-2); 8.50 (br d, 1H,

J_trans= 13.0, @CH–N). ¹³C NMR (125.7 MHz,

DMSO-d₆): 35.44 (CH₃N); 39.53 (CH₂-2⁰); 60.40

(CH₂Ph); 62.03 (CH₂-5⁰); 71.11 (CH-3⁰); 83.96

(CH-1⁰); 88.16 (CH-4⁰); 90.44 (@CH-pur); 126.97

(CH-o-Ph); 127.50 (CH-p-Ph); 127.71 (C-5); 128.89

(CH-m-Ph); 137.61 (C-i-Ph); 141.41 (CH-8); 149.21

(C-4); 149.64 (@CH–N); 151.82 (CH-2); 156.93 (C-6).

FAB-MS, m/z (rel %) = 327 (6) [M+H]⁺, 282 (85), 306

(35), 266 (75), 174 (17), 160 (7), 147 (10), 134 (14), 120

(10), 91 (100), 73 (8), 57 (7). HRMS Calcd for

C₂₀H₂₄N₅O₃[M+H]⁺382.1879. Found: 382.1881. IR

(KBr): 3178, 3062, 3028, 2904, 2798, 1590, 1573, 1560,

1495, 1451, 1408, 1399, 1328, 1219, 1179, 1098, 1083,

1070, 1055, 1048, 1028, 737, 697, 648. Anal. Calcd for

C₂₀H₂₃N₅O₃Æ1.35H₂O: C, 59.20; H, 6.38; N, 17.26.

Found: C, 59.58; H, 6.03; N, 16.87. [a]_Dꢀ20.2 (c 0.37,

MeOH).

J_{2 ,OH}= 6.1, J_{2 ,1}= 5.8, J_{2 ,3}= 4.9, H-2⁰); 5.10 (dd,

0

1H, J_OH,5= 6.0, 5.3, OH-5⁰); 5.23 (d, 1H, J_OH,3= 4.9,

0

OH-3⁰); 5.32 (t, 1H, J_vic= 7.6, S–CH–S); 5.53 (d, 1H,

J_OH,2= 6.1, OH-2⁰); 6.03 (d, 1H, J_{1 ,2}= 5.8, H-1⁰);

8.79 (s, 1H, H-8); 8.87 (s, 1H, H-2). ¹³C NMR

(125.7 MHz, DMSO-d₆): 38.18 (CH₂–S); 42.62 (CH₂-

pur); 50.37 (S–CH–S); 61.47 (CH₂-5⁰); 70.54 (CH-3⁰);

73.77 (CH-2⁰); 85.94 (CH-4⁰); 87.76 (CH-1⁰); 132.76

(C-5); 144.69 (CH-8); 150.71 (C-4); 151.90 (CH-2);

158.44 (C-6). FAB-MS, m/z (rel %) = 371 (20)

[M+H]⁺, 239 (35), 215 (15), 205 (10), 197 (16), 181

(16), 149 (15), 133 (10), 115 (14), 105 (54), 61 (55), 57

(100). HRMS Calcd for C₁₄H₁₉N₄O₄S₂[M+H]⁺

371.0847. Found: 371.0861. IR (KBr): 3429, 3113,

1607, 1597, 1584, 1503, 1457, 1424, 1405, 1412, 1331,

1213, 1121, 1094, 1056, 649. Anal. Calcd for

C₁₄H₁₈N₄O₄S₂Æ0.5H₂O: C, 44.32; H, 5.05; N, 14.77; S,

16.90. Found: C, 44.60; H, 4.70; N, 14.61; S, 16.62.

[a]_Dꢀ47.7 (c 0.35, MeOH).

0

6.54. 6-[(1,3-Dithiolan-2-yl)methyl]-9-(2-deoxy-b-^D-ery-

thro-pentafuranosyl)purine (17)

6.52. 6-[(E)-2-(Thiazolidine-1-yl)vinyl]-9-(2-deoxy-b-^D-

erythro-pentafuranosyl)purine (15g)

Yield 96%, yellowish hygroscopic foam. ¹H NMR

(400 MHz, DMSO-d₆): 2.35 (ddd, 1H, J_gem= 13.3,

Yield 81%, yellow hygroscopic crystals. ¹H NMR

(500 MHz, DMSO-d₆): 2.29 (ddd, 1H, J_gem= 13.3,

J_{2 b,1}= 6.3, J_{2 b,3}= 3.5, H-2⁰b); 2.79 (ddd, 1H,

0

J_{2 b,1}= 6.2, J_{2 b,3}= 3.2, H-2⁰b); 2.75 (ddd, 1H,

J_gem= 13.3, J_{2 a,1}= 7.2, J_{2 a,3}= 6.0, H-2⁰a); 3.23 and

3.31 (2· m, 2· 2H, CH₂–S); 3.53 (ddd, 1H, J_gem= 11.6,

0

J_gem= 13.3, J_{2 a,1}= 7.7, J_{2 a,3}= 5.8, H-2⁰a); 3.11 (t,

2H, J_vic= 6.3, H-5-thiazolidine); 3.52 and 3.62 (2· bddd,

0

J_{5 b,OH}= 5.6, J_{5 b,4}= 4.8, H-5⁰b); 3.63 (dt, 1H,

0

2H, J_gem= 11.7, J_{5 ,OH}= 5.2, J_{5 ,4}= 4.4, H-5⁰); 3.70 (t,

2H, J_vic= 6.3, H-4-thiazolidine); 3.88 (td, 1H,

J_gem= 11.6, J_{5 a,OH}= 5.6, J_{5 a,4}= 4.8, H-5⁰a); 3.62 (d,

0

0 0

2H, J_vic= 7.5, CH₂-pur); 3.90 (td, 1H, J_{4 ,5}= 4.8,

0

J_{4 ,5}= 4.4, J_{4 ,3}= 2.7, H-4 ); 4.42 (m, 1H, J_{3 ,2}= 5.8,

0

J_{4 ,3}= 3.0, H-4⁰); 4.45 (m, 1H, J_{3 ,2}= 6.0, 3.5,

3.2, J_{3 ,OH}= 3.9, J_{3 ,4}= 2.7, H-3⁰); 4.55 (s, 2H, H-2-thi-

J_{3 ,OH}= 4.2, J_{3 ,4}= 3.0, H-3⁰); 5.00 (t, 1H, J_OH,5= 5.6,

OH-5⁰); 5.32 (t, 1H, J_vic= 7.6, S–CH–S); 5.37 (d, 1H,

0

azolidine); 5.13 (br t, 1H, J_OH,5= 5.2, OH-5⁰); 5.32 (d,

0

1H, J_OH,3= 3.9, OH-3⁰); 5.65 (br d, 1H, J_trans= 13.1,

J_OH,3= 4.2, OH-3⁰); 6.47 (t, 1H, J_{1 ,2}= 7.2, 6.3, H-1⁰);

8.75 (s, 1H, H-2); 8.86 (s, 1H, H-2); ¹³C NMR

(100.6 MHz, DMSO-d₆): 37.93 (CH₂–S); 39.10 (C-2⁰);

42.37 (CH₂-pur); 50.11 (S–CH–S); 61.48 (CH₂-5⁰);

70.58 (CH-3⁰); 83.64 (CH-1⁰); 87.92 (CH-4⁰); 132.49

(C-5); 144.34 (CH-8); 150.15 (C-4); 151.56 (CH-2);

158.07 (C-6). FAB-MS, m/z (rel %) = 355 (100)

[M+H]⁺, 279 (10), 239 (90), 217 (12), 179 (30), 149

(20), 147 (16), 134 (20), 117 (16), 73 (50), 61 (22), 57

(45). HRMS Calcd for C₁₄H₁₉N₄O₃S₂[M+H]⁺

355.0898. Found: 355.0903. IR (KBr): 3428, 3275,

1637, 1598, 1581, 1497, 1420, 1400, 1334, 1211, 1094,

1056, 645. Anal. Calcd for C₁₄H₁₈N₄O₃S₂Æ0.5H₂O: C,

46.27; H, 5.27; N, 15.42. Found: C, 46.65; H, 5.46; N,

15.11. [a]_Dꢀ14.9 (c 0.28, MeOH).

0

@CH-pur); 6.39 (dd, 1H, J_{1 ,2}= 7.7, 6.2, H-1⁰); 8.45

(s, 1H, H-2); 8.47 (br d, 1H, J_trans= 13.1, @CH–N);

8.50 (s, 1H, H-8). ¹³C NMR (125.7 MHz, DMSO-d₆):

30.00 (CH₂-5-thiazolidine); 39.50 (CH₂-2⁰); 51.75

(CH₂-2-thiazolidine); 52.21 (CH₂-4-thiazolidine); 61.96

(CH₂-5⁰); 71.04 (CH-3⁰); 83.95 (CH-1⁰); 88.16 (CH-4⁰);

92.66 (@CH-pur); 127.86 (C-5); 141.84 (CH-8); 145.32

(@CH–N); 149.36 (C-4); 151.62 (CH-2); 156.20 (C-6).

FAB-MS, m/z (rel %) = 350 (60) [M+H]⁺, 260 (10),

234 (100), 204 (8), 188 (7). 174 (22), 149 (12), 147 (27),

135 (7), 119 (26), 93 (14), 73 (16), 57 (12). HRMS Calcd

for C₁₅H₂₀N₄O₃S [M+H]⁺350.1286. Found: 350.1292.

IR (KBr): 3408, 3214, 1625, 1595, 1560, 1493, 1406,

1398, 1327, 1219, 1099, 1054, 646. Anal. Calcd for

C₁₅H₁₉N₅O₃SÆ0.75H₂O: C, 49.64; H, 5.69; N, 19.3; S,

8.83. Found: C, 50.05; H, 5.67; N, 18.97, S, 8.95. [a]_D

ꢀ16.6 (c 0.28, MeOH).

0

6.55. 6-[2-(Dimethylamino)ethyl]-9-(b-^D-ribofurano-

syl)purine (18a)

6.53. 6-[(1,3-Dithiolan-2-yl)methyl]-9-(b-^D-ribofurano-

syl)purine (16)

Yield 41%, white hygroscopic crystals. ¹H NMR

(400 MHz, DMSO-d₆): 2.16 (s, 6H, CH₃); 2.79 (t, 2H,

J_vic= 7.3, CH₂–N); 3.23 (t, 2H, J_vic= 7.3, CH₂-pur);

Yield 84%, white hygroscopic crystals. ¹H NMR

(500 MHz, DMSO-d₆): 3.20–3.35 (m, 4H, CH₂–S); 3.58

3.57 (ddd, 1H, J_gem= 11.9, J_{5 b,OH}= 6.0, J_{5 b,4}= 4.1,

0

H-5⁰b); 3.68 (ddd, 1H, J_gem= 11.9, J_{5 a,OH}= 5.2,

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1420

J_{5 a,4}= 3.9, H-5⁰a); 3.97 (q, 1H, J_{4 ,5}= 3.9, 4.1,

53.01 (CH₃CH₂CH₂CH₂); 61.51 (CH₂-5⁰); 70.53 (CH-

3⁰); 73.83 (CH-2⁰); 85.87 (CH-4⁰); 87.78 (CH-1⁰);

133.08 (C-5); 144.20 (CH-8); 150.35 (C-4); 151.88 (CH-

2); 161.14 (C-6). FAB-MS, m/z (rel %) = 408 (20)

[M+H]⁺, 274 (6), 232 (7), 147 (10), 142 (100), 98 (10),

84 (5), 57 (12). HRMS Calcd for C₂₀H₃₄N₅O₄[M+H]⁺

408.2610. Found: 408.2630. IR (KBr): 3419, 3265,

3115, 3067, 2871, 1630, 1600, 1581, 1499, 1465, 1459,

1418, 1405, 1377, 1334, 1212, 1121, 1085, 1057, 811,

647. Anal. Calcd for C₂₀H₃₃N₅O₄Æ0.5H₂O: C, 57.67; H,

8.23; N, 16.81. Found: C, 57.23; H, 7.85; N, 16.99.

[a]_Dꢀ40.6 (c 0.17, MeOH).

0

J_{4 ,3}= 2.9, H-4⁰); 4.18 (q, 1H, J_{3 ,2}= 5.2, J_{3 ,OH}= 4.9,

0

J_{3 ,4}= 2.9, H-3⁰); 4.65 (q, 1H, J_{2 ,OH}= 6.1, J_{2 ,1}= 5.9,

0

J_{2 ,3}= 5.2, H-2⁰); 5.12 (t, 1H, J_OH,5= 6.0, 5.2, OH-5⁰);

0

5.24 (d, 1H, J_OH,3= 4.9, OH-3⁰); 5.53 (d, 1H,

0

J_OH,2= 6.1 OH-2⁰); 6.02 (d, 1H, J_{1 ,2}= 5.9 H-1⁰); 8.75

(s, 1H, H-2); 8.82 (s, 1H, H-8). ¹³C NMR (100.6 MHz,

DMSO-d₆): 30.59 (CH₂-pur); 44.80 (CH₃); 57.30

(CH₂–N); 61.26 (CH₂-5⁰); 70.31 (CH-3⁰); 73.45 (CH-

2⁰); 85.66 (CH-4⁰); 87.50 (CH-1⁰); 132.85 (C-5); 144.03

(CH-8); 150.13 (C-4); 151.64 (CH-2); 160.55 (C-6).

FAB-MS, m/z (rel %) = 324 (90) [M+H]⁺, 279 (5), 220

(5), 190 (15), 147 (14), 93 (12), 73 (6), 58 (100). HRMS

Calcd for C₁₄H₂₂N₅O₄[M+H]⁺324.1671. Found:

324.1678. IR (KBr): 3535, 3400, 3218, 3115, 2831,

2781, 1605, 1585, 1499, 1463, 1405, 1339, 1218, 1099,

1063, 1039, 804, 642. Anal. Calcd for C₁₄H₂₁N₅O₄Æ1-

H₂O: C, 49.26; H, 6.79; N, 20.52. Found: C, 49.10; H,

6.70; N, 20.17. [a]_Dꢀ44.8 (c 0.38, MeOH).

0

6.58. 6-[2-(Piperidine-1-yl)ethyl]-9-(b-^D-ribofurano-

syl)purine (18d)

Yield 56%, white hygroscopic foam. ¹H NMR

(400 MHz, DMSO-d₆): 1.35 (m, 2H, CH₂-4-pip); 1.45

(m, 4H, CH₂-3-pip); 2.43 (m, 4H, CH₂N-pip); 2.82 (t,

2H, J_vic= 7.5, CH₂N); 3.25 (t, 2H, J_vic= 7.5, CH₂-

0

pur); 3.59 (ddd, 1H, J_gem= 12.0, J_{5 b,OH}= 6.8,

0 0

6.56. 6-[2-(Diethylamino)ethyl]-9-(b-^D-ribofurano-

syl)purine (18b)

J_{5 b,4}= 4.1, H-5⁰b); 3.68 (ddd, H, J_gem= 12.0,

J_{5 a,OH}= 4.4, J_{5 a,4}= 3.9, H-5⁰a); 3.98 (q, 1H,

0

Yield 63%, white hygroscopic foam. ¹H NMR

(400 MHz, DMSO-d₆): 0.93 (t, 6H, J_vic= 7.1, CH₂CH₃);

2.53 (q, 4H, J_vic= 7.1, CH₂CH₃); 2.97 (t, 2H, J_vic= 7.4,

CH₂–N); 3.20 (t, 2H, J_vic= 7.4, CH₂-pur); 3.57 (br m,

1H, H-5⁰b); 3.68 (br m, 1H, H-5⁰a); 3.98 (q, 1H,

J_{4 ,5}= 3.9, 4.1, J_{4 ,3}= 3.7, H-4⁰); 4.15 (q, 1H,

0

J_{3 ,2}= 5.3, J_{3 ,OH}= 4.8, J_{3 ,4}= 3.7, H-3⁰); 4.65 (q, 1H,

0

J_{2 ,OH}= 6.0, J_{2 ,1}= 5.8, J_{2 ,3}= 5.3, H-2⁰); 5.13 (t, 1H,

0

J_OH,5= 6.8, 4.4, OH-5⁰); 5.26 (d, 1H, J_OH,3= 4.8,

0

OH-3⁰); 5.54 (d, 1H, J_OH,2= 6.0, OH-2⁰); 6.03 (d, 1H,

0

J_{4 ,3}= 3.7, H-4⁰); 4.19 (br m, 1H, H-3⁰); 4.65 (br m,

J_{1 ,2}= 5.8, H-1⁰); 8.76 (s, 1H, H-2); 8.82 (s, 1H, H-8).

¹³C NMR (100.6 MHz, DMSO-d₆): 23.85 (CH₂-4-pip);

25.34 (CH₂-3-pip); 29.99 (CH₂-pur); 53.55 (CH₂N-pip);

56.73 (CH₂N); 61.25 (CH₂-5⁰); 70.30 (CH-3⁰); 73.51

(CH-2⁰); 85.65 (CH-4⁰); 87.49 (CH-1⁰); 132.73 (C-5);

144.04 (CH-8); 150.15 (C-4); 151.65 (CH-2); 160.45 (C-

6). FAB-MS, m/z (rel %) = 364 (35) [M+H]⁺, 147 (5),

98 (100). HRMS Calcd for C₁₇H₂₆N₅O₄[M+H]⁺

364.1984. Found: 364.1981. IR (KBr): 3370, 2934,

2855, 2770, 1598, 1580, 1498, 1469, 1454, 1444, 1417,

1405, 1354, 1334, 1212, 1118, 1087, 1057, 647. Anal.

Calcd for C₁₇H₂₅N₅O₄Æ0.9H₂O: C, 53.79; H, 7.12; N,

18.45. Found: C, 54.12; H, 7.01; N, 18.10. [a]_Dꢀ34.3

(c 0.43, MeOH).

0

1H, J_{1 ,2}= 5.8, H-2⁰); 5.12 (br m, OH-5⁰); 5.23 (br m,

0

OH-3⁰); 5.53 (br d, OH-2⁰); 6.02 (d, 1H, J_{1 ,2}= 5.8, H-

1⁰); 8.76 (s, 1H, H-2); 8.82 (s, 1H, H-8). ¹³C NMR

(100.6 MHz, DMSO-d₆): 11.68 (CH₃); 29.50 (CH₂-

pur); 46.09 (CH₂CH₃); 50.31 (CH₂–N); 61.25 (CH₂-5⁰);

70.29 (CH-3⁰); 73.50 (CH-2⁰); 85.65 (CH-4⁰); 87.48

(CH-1⁰); 132.79 (C-5); 144.00 (CH-8); 150.12 (C-4);

151.64 (CH-2); 160.69 (C-6). FAB-MS, m/z (rel

%) = 352 (100) [M+H]⁺, 279 (4), 249 (4), 217 (4), 201

(12), 149 (14), 135 (10), 91 (41), 86 (33), 73 (10), 57

(11). HRMS Calcd for C₁₆H₂₆N₅O₄[M+H]⁺352.1984.

Found: 352.1990. IR (KBr): 3392, 3270, 3110, 3067,

2971, 2876, 1635, 1599, 1583, 1498, 1458, 1418, 1405,

1388, 1334, 1211, 1122, 1086, 1058, 813, 647. Anal.

Calcd for C₁₆H₂₅N₅O₄Æ0.8H₂O: C, 52.53; H, 7.33; N,

19.14. Found: C, 52.83; H, 7.19; N, 18.75. [a]_Dꢀ29.4

(c 0.17, MeOH).

0

6.59. 6-[2-(Morpholine-4-yl)ethyl]-9-(b-^D-ribofurano-

syl)purine (18e)

Yield 76%, white hygroscopic foam. ¹H NMR

(400 MHz, DMSO-d₆): 2.44 (m, 4H, J_vic= 4,6, CH₂N-

morph); 2.83 (t, 2H, J_vic= 7.5, CH₂–N); 3.26 (t, 2H,

J_vic= 7.5, CH₂-pur); 3.51 (t, 4H, J_vic= 4,6, CH₂O-

6.57. 6-[2-(Dibutylamino)ethyl]-9-(b-^D-ribofurano-

syl)purine (18c)

Yield 59%, white hygroscopic foam. ¹H NMR

(500 MHz, DMSO-d₆): 0.82 (t, 6H, J_vic= 7.3,

CH₃CH₂CH₂CH₂); 1.18 and 1.32 (2· m, 2· 4H,

CH₃CH₂CH₂CH₂); 2.42 (m, 4H, CH₃CH₂CH₂CH₂);

2.94 (m, 2H, CH₂N); 3.19 (m, 2H, CH₂-pur); 3.57 and

morph); 3.58 (ddd, 1H, J_gem= 11.8, J_{5 b,OH}= 5.9,

0

J_{5 b,4}= 4.2, H-5⁰b); 3.69 (ddd, 1H, J_gem= 11.8,

0

J_{5 a,OH}= 5.2, J_{5 a,4}= 3.7, H-5⁰a); 3.97 (q, 1H,

0

J_{4 ,5}= 3.9, 4.2, J_{4 ,3}= 3.7, H-4⁰); 4.18 (q, 1H,

0

J_{3 ,2}= 5.2, J_{3 ,OH}= 4.8, J_{3 ,4}= 3.7, H-3⁰); 4.65 (q, 1H,

0

3.69 (2· dd, 2H, J_gem= 12.1, J_{5 ,4}= 4.2, H-5⁰); 3.97

J_{2 ,OH}= 5.8, J_{2 ,1}= 5.8, J_{2 ,3}= 5.2, H-2⁰); 5.12 (t, 1H,

0

J_OH,5= 5.9, 5.2, OH-5⁰); 5.25 (d, 1H, J_OH,3= 4.8,

0

(td, 1H, J_{4 ,5}= 4.2, J_{4 ,3}= 3.6, H-4 ); 4.18 (dd, 1H,

0

J_{3 ,2}= 5.0, J_{3 ,4}= 3.6, H-3⁰); 4.62 (dd, 1H, J_{2 ,1}= 5.7,

OH-3⁰); 5.53 (d, 1H, J_OH,2= 5.8 OH-2⁰); 6.02 (d, 1H,

0

J_{2 ,3}= 5.0, H-2⁰); 5.00–5.70 (br m, 3H, OH-2⁰,3⁰,5⁰);

J_{1 ,2}= 5.8 H-1⁰); 8.76 (s, 1H, H-2); 8.83 (s, 1H, H-8).

¹³C NMR (100.6 MHz, DMSO-d₆): 29.62 (CH₂-pur);

52.73 (CH₂N-morph); 56.21 (CH₂–N); 61.04 (CH₂-5⁰);

65.82 (CH₂O-morph); 70.08 (CH-3⁰); 73.29 (CH-2⁰);

85.44 (CH-4⁰); 87.28 (CH-1⁰); 132.56 (C-5); 143.85

0

6.01 (d, 1H, J_{1 ,2}= 5.7, H-1⁰); 8.75 (s, 1H, H-2); 8.81

(s, 1H, H-8). ¹³C NMR (125.7 MHz, DMSO-d₆): 14.11

(CH₃CH₂CH₂CH₂); 20.14 (CH₃CH₂CH₂CH₂); 29.10

(CH₃CH₂CH₂CH₂); 29.97 (CH₂-pur); 51.87 (CH₂N);

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1421

(CH-8); 149.95 (C-4); 151.45 (CH-2); 160.05 (C-6).

FAB-MS, m/z (rel %) = 366 (60) [M+H]⁺, 270 (6), 234

(7), 147 (12), 135 (7) 100 (100), 98 (18), 91 (18), 73

(10), 57 (15). HRMS Calcd for C₁₆H₂₄N₅O₅[M+H]⁺

366.1777. Found: 366.1772. IR (KBr): 3400, 3265,

3113, 3068, 2820, 1599, 1582, 1499, 1459, 1447, 1417,

1403, 1373, 1358, 1335, 1296, 1211, 1116, 1070, 1036,

1006, 914, 867, 818, 647, 613. Anal. Calcd for

C₁₆H₂₃N₅O₅Æ2.25H₂O: C, 47.34; H, 6.83; N, 17.25.

Found: C, 47.72; H, 6.39; N, 16.84. [a]_Dꢀ33.7 (c 0.44,

MeOH).

87.49 (CH-1⁰); 132.91 (C-5); 144.14 (CH-8); 150.19 (C-

4); 151.65 (CH-2); 160.01 (C-6). FAB-MS, m/z (rel

%) = 368 (47) [M+H]⁺, 236 (17), 176 (8), 147 (26), 135

(14), 102 (100), 73 (10). HRMS Calcd for C₁₅H₂₂N₅O₄S

[M+H]⁺368.1392. Found: 368.1398. IR (KBr): 3307,

3118, 3068, 1599, 1584, 1497, 1417, 1406, 1335, 1212,

1121, 1085, 1057, 816, 646. Anal. Calcd for

C₁₅H₂₁N₅O₄SÆ0.6H₂O: C, 47.03; H, 5.92; N, 18.52.

Found: C, 48.01; H, 6.05; N, 18.13. [a]_Dꢀ39.0 (c 0.19,

MeOH).

6.62. 6-[2-(Diethylamino)ethyl]-9-(2-deoxy-b-^D-erythro-

pentafuranosyl)purine (19a)

6.60. 6-[2-(Benzyl(methyl)amino)ethyl]-9-(b-^D-ribofur-

anosyl)purine (18f)

Yield 79%, white hygroscopic foam. ¹H NMR

(400 MHz, DMSO-d₆): 2.16 (s, 3H, CH₃); 2.33 (ddd,

Yield 68%, white hygroscopic foam. ¹H NMR

(400 MHz, DMSO-d₆): 2.19 (s, 3H, CH₃); 2.90 (t, 2H,

J_vic= 6.8, CH₂–N); 3.30 (t, 2H, J_vic= 7.2, CH₂-pur);

3.52 (s, CH₂-Ph); 3.59 (ddd, 1H, J_gem= 11.9,

0

1H, J_gem= 13.2, J_{2 b,1}= 6.1, J_{2 b,3}= 3.2, H-2 b); 2.78

(t, 2H, J_vic= 7.1, CH₂–N); 2.84 (ddd, 1H, J_gem= 13.2,

J_{2 a,1}= 7.3, J_{2 a,3}= 6.0, H-2⁰a); 3.21 (t, 2H, J_vic= 7.1,

0

J_{5 b,OH}= 6.8, J_{5 b,4}= 4.1, H-5⁰b); 3.68 (ddd, H,

CH₂-pur); 3.52 (dt, 1H, J_gem= 11.4, J_{5 b,OH}= 5.0,

0 0

0

J_gem= 11.9, J_{5 a,OH}= 4.4, J_{5 a,4}= 3.9, H-5⁰a); 3.99 (br

J_{5 b,4}= 4.5, H-5⁰b); 3.63 (dt, 1H, J_gem= 11.4,

0

m, 1H, H-4⁰); 4.20 (br m, 1H, J_{3 ,2}= 4.3, H-3⁰); 4.65

J_{5 a,OH}= 5.0, J_{5 a,4}= 4.5, H-5⁰a); 3.89 (td, 1H,

0 0 0

0

(br m, 1H, J_{2 ,3}= 4.3, H-2⁰); 5.14 (br m, 1H, OH-5⁰);

J_{4 ,5}= 4.5, J_{4 ,3}= 3.0, H-4⁰); 4.42 (m, 1H, J_{3 ,2}= 6.0,

0

5.26 (br m, 1H, OH-3⁰); 5.54 (br d, 1H, J_OH,2= 4.6,

3.2, J_{3 ,OH}= 4.0, J_{3 ,4}= 3.0, H-3⁰); 5.01 (br t, 1H,

J_OH,5= 5.0, 5.0, OH-5⁰); 5.36 (d, 1H, J_OH,3= 4.0,

0

OH-2⁰); 6.03 (br d, 1H, J_{1 ,2}= 5.1, H-1⁰); 7.12 (m, 2H,

H-o-Ph); 7.20 (m, 1H, H-p-Ph); 7.23 (m, 2H, H-m-Ph);

8.74 (s, 1H, H-2); 8.81 (s, 1H, H-2); ¹³C NMR

(100.6 MHz, DMSO-d₆): 30.34 (CH₂-pur); 41.53

(CH₃); 54.92 (CH₂–N); 60.87 (CH₂Ph); 61.27 (CH₂-5⁰);

70.31 (CH-3⁰); 73.55 (CH-2⁰); 85.65 (CH-4⁰); 87.51

(CH-1⁰); 126.69 (CH-p-Ph); 127.93 (CH-m-Ph); 128.44

(CH-o-Ph); 132.84 (C-5); 138.68 (C-i-Ph); 143.99 (CH-

8); 150.13 (C-4); 151.61 (CH-2); 160.51 (C-6). FAB-

MS, m/z (rel %) = 400 (10) [M+H]⁺, 176 (6), 147 (14),

134 (76), 120 (9), 91 (100). HRMS Calcd for

C₂₀H₂₆N₅O₄[M+H]⁺400.1984. Found: 400.1978. IR

(KBr): 3369, 3113, 3090, 3066, 3030, 2795, 1599, 1584,

1497, 1454, 1417, 1406, 1335, 1213, 1123, 1083, 1050,

1027, 809, 742, 700, 647. Anal. Calcd for

C₂₀H₂₅N₅O₄Æ0.5H₂O: C, 58.81; H, 6.42; N, 17.15.

Found: C, 58.78; H, 6.36; N, 16.87. [a]_Dꢀ38.0 (c 0.39,

MeOH).

0

OH-3⁰); 6.46 (dd, 1H, J_{1 ,2}= 7.3, 6.1, H-1⁰); 8.72 (s,

1H, H-2); 8.81 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

DMSO-d₆): 30.55 (CH₂-pur); 39.08 (C-2⁰); 44.78

(CH₃N); 57.28 (CH₂-2⁰); 61.54 (CH₂-5⁰); 70.63 (CH-

3⁰); 83.63 (CH-1⁰); 87.90 (CH-4⁰); 132.84 (C-5); 143.92

(CH-8); 149.84 (C-4); 151.57 (CH-2); 160.39 (C-6).

FAB-MS, m/z (rel %) = 308 (10) [M+H]⁺, 274 (15),

257 (16), 249 (34), 215 (7), 202 (8), 195 (10), 149 (12),

102 (8), 57 (26). HRMS Calcd for C₁₄H₂₂N₅O₃

[M+H]⁺308.1722. Found: 308.1715. IR (KBr): 3429,

3270, 3110, 3065, 2825, 2781, 1627, 1600, 1580, 1497,

1419, 1400, 1334, 1212, 1040, 806, 645. Anal. Calcd

for C₁₄H₂₁N₅O₃Æ0.25H₂O: C, 53.92; H, 6.95; N, 22.46.

Found: C, 54.27; H, 6.82; N, 22.05. [a]_Dꢀ6.0 (c 0.15,

MeOH).

0

6.63. 6-[2-(Dibutylamino)ethyl]-9-(2-deoxy-b-^D-erythro-

pentafuranosyl)purine (19c)

6.61. 6-[2-(Thiazolidine-1-yl)ethyl]-9-(b-^D-ribofurano-

syl)purine (18g)

Yield 38%, yellowish hygroscopic foam. ¹H NMR

(400 MHz, CDCl₃): 0.89 (t, 6H, J_vic= 7.3,

CH₃CH₂CH₂CH₂N); 1.26 and 1.45 (2· m, 8H,

CH₃CH₂CH₂CH₂N); 2.38 (ddd, 1H, J_gem= 13.3,

Yield 71%, white hygroscopic foam. ¹H NMR

(400 MHz, DMSO-d₆): 2.77 (t, 2H, J_vic= 6.3, H-5-thia-

zolidine); 2.88 (t, 2H, J_vic= 7.2, CH₂–S); 3.00 (t, 2H,

J_vic= 6.3, H-5-thiazolidine); 3.28 (t, 2H, J_vic= 7.2,

J_{2 b,1}= 5.6, J_{2 b,3}= 1.3, H-2⁰b); 2.53 (t, 4H, J_vic= 7.5,

CH₃CH₂CH₂CH₂N); 3.06 (t, 2H, J_vic= 7.6, CH₂N);

0

CH₂-pur); 3.57 (ddd, 1H, J_gem= 11.9, J_{5 b,OH}= 6.0,

0

3.06 (ddd, 1H, J_gem= 13.3, J_{2 a,1}= 9.0, H-2⁰a); 3.35 (t,

2H, J_vic= 7.6, CH₂-pur); 3.82 (dt, 1H, J_gem= 12.5 H-

5⁰b); 3.62 (dt, 1H, J_gem= 12.5, H-5⁰a); 4.23 (br s, 1H,

H-4⁰); 4.81 (br d, 1H, H-3⁰); 6.43 (dd, 1H, H-1⁰); 8.18

(s, 1H, H-8); 8.84 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

J_{5 b,4}= 4.1, H-5⁰b); 3.69 (ddd, 1H, J_gem= 11.9,

0

J_{5 a,OH}= 5.2, J_{5 a,4}= 3.9, H-5⁰a); 3.97 (q, 1H,

0

J_{4 ,5}= 3.9, 4.1, J_{4 ,3}= 3.6, H-4⁰); 4.18 (q, 1H,

0

J_{3 ,2}= 5.2, J_{3 ,OH}= 4.9, J_{3 ,4}= 3.6, H-3⁰); 4.65 (q, 1H,

0

J_{2 ,OH}= 6.1, J_{2 ,1}= 5.8, J_{2 ,3}= 5.2, H-2⁰); 5.12 (t, 1H,

CDCl₃):

14.04

(CH₃CH₂CH₂CH₂N);

20.65

0

J_OH,5= 6.0, 5.2, OH-5⁰); 5.24 (d, 1H, J_OH,3= 4.9,

(CH₃CH₂CH₂CH₂N); 29.10 (CH₃CH₂CH₂CH₂N);

30.15 (CH₂-pur); 40.75 (CH₂-2⁰); 52.13 (CH₂–N); 53.49

(CH₃CH₂CH₂CH₂N); 63.17 (CH₂-5⁰); 72.74 (CH-3⁰);

87.40 (CH-1⁰); 89.42 (CH-4⁰); 134.60 (C-5); 143.43

(CH-8); 149.37 (C-4); 151.50 (CH-2); 162.93 (C-6).

FAB-MS, m/z (rel %) = 392 (30) [M+H]⁺, 300 (3), 274

(8), 232 (10), 218 (3), 173 (3), 147 (12), 142 (100), 98

0

OH-3⁰); 5.53 (d, 1H, J_OH,2= 6.1 OH-2⁰); 6.02 (d, 1H,

0

J_{1 ,2}= 5.8 H-1⁰); 8.77 (s, 1H, H-2); 8.84 (s, 1H, H-8).

¹³C NMR (100.6 MHz, DMSO-d₆): 28.74 (CH₂-5-thia-

zolidine); 32.06 (CH₂-pur); 50.25 (CH₂-4-thiazolidine);

57.25 (CH₂–N); 60.02 (CH₂-2-thiazolidine); 61.26

(CH₂-5⁰); 70.30 (CH-3⁰); 73.48 (CH-2⁰); 85.66 (CH-4⁰);

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1422

(12), 84 (6), 57 (10). HRMS Calcd for C₂₀H₃₄N₅O₃

[M+H]⁺392.2661. Found: 392.2675. IR (KBr): 3429,

3267, 3120, 3065, 2871, 1626, 1599, 1581, 1498, 1459,

1418, 1401, 1378, 1334, 1212, 1096, 1059, 809, 646. Anal.

Calcd for C₂₀H₃₃N₅O₃Æ0.75H₂O: C, 59.31; H, 8.59; N,

17.29. Found: C, 59.59; H, 8.36; N, 17.18. [a]_Dꢀ1.3 (c

0.24, MeOH).

m/z (rel %) = 384 (100) [M+H]⁺(cation), 294 (5), 268

(6), 249 (15), 241 (5), 201 (6), 147 (9), 134 (68), 122

(10), 91 (52), 73 (8), 57 (10). HRMS Calcd for

C₂₀H₂₆N₅O₃[M+H]⁺384.2036. Found: 384.2041. IR

(KBr): 3422, 3265, 3115, 3088, 3064, 3028, 2793, 1636,

1599, 1581, 1496, 1454, 1418, 1401, 1334, 1212, 1028,

809, 738, 700, 646. Anal. Calcd for C₂₀H₂₅N₅O₃Æ0.65-

H₂O: C, 60.79; H, 6.71; N, 17.72. Found: C, 61.18; H,

6.80; N, 17.40. [a]_Dꢀ8.2 (c 0.31, MeOH).

6.64. 6-[2-(Morpholine-4-yl)ethyl]-9-(2-deoxy-b-^D-ery-

thro-pentafuranosyl)purine (19e)

6.66. 6-[2-(Benzylsulfanyl)ethyl]-9-(b-^D-ribofurano-

syl)purine (12a)

Yield 68%, white hygroscopic foam. ¹H NMR

(400 MHz, DMSO-d₆): 2.33 (ddd, 1H, J_gem= 13.3,

J_{2 b,1}= 6.2, J_{2 b,3}= 3.4, H-2⁰b); 2.43 (m, 4H, J_vic= 4.7,

Yield 78%, white hygroscopic crystals. ¹H NMR

(400 MHz, DMSO-d₆): 2.95 (t, 2H, J_vic= 7.3, CH₂–S);

3.38 (t, 2H, J_vic= 7.3, CH₂-pur); 3.59 (ddd, 1H,

0

CH₂N-morph); 2.77 (ddd, 1H, J_gem= 13.3, J_{2 a,1}= 7.4,

0

J_{2 a,3}= 6.0, H-2⁰a); 2.82 (t, 2H, J_vic= 7.2, CH₂–N);

3.21 (t, 2H, J_vic= 7.1, CH₂-pur); 3.51 (t, 4H, J_vic= 4.7,

0

J_gem= 11.9, J_{5 b,OH}= 6.8, J_{5 b,4}= 4.1, H-5⁰b); 3.68

0

(ddd, H, J_gem= 11.9, J_{5 a,OH}= 4.4, J_{5 a,4}= 3.9, H-5⁰a);

0

CH₂N-morph); 3.52 (dt, 1H, J_gem= 11.7, J_{5 b,OH}= 5.0,

0

J_{5 b,4}= 4.5, H-5⁰b); 3.62 (dt, 1H, J_gem= 11.7,

0

0 0

3.79 (s, 2H, CH₂S); 3.97 (q, 1H, J_{4 ,5}= 3.9, 4.1,

J_{5 a,OH}= 5.0, J_{5 a,4}= 4.5, H-5⁰a); 3.88 (td, 1H,

J_{4 ,3}= 3.7, H-4⁰); 4.15 (q, 1H, J_{3 ,2}= 5.24,

0 0 0 0

0

J_{4 ,5}= 4.5, J_{4 ,3}= 3.0, H-4⁰); 4.45 (m, 1H, J_{3 ,2}= 6.0,

J_{3 ,OH}= 4.9, J_{3 ,4}= 3.7, H-3⁰); 4.65 (q, 1H,

0

3.4, J_{3 ,OH}= 4.2, J_{3 ,4}= 3.0, H-3⁰); 5.0 (t, 1H,

J_{2 ,OH}= 6.1, J_{2 ,1}= 5.8, J_{2 ,3}= 5.24, H-2⁰); 5.12 (t, 1H,

0

J_OH,5= 5.0, OH-5⁰); 5.37 (d, 1H, J_OH,3= 4.2, OH-3 );

J_OH,5= 6.8, 4.4, OH-5⁰); 5.26 (d, 1H, J_OH,3= 4.9,

OH-3⁰); 5.54 (d, 1H, J_OH,2= 6.0, OH-2⁰); 6.03 (d, 1H,

0

6.46 (dd, 1H, J_{1 ,2}= 7.4, 6.2, H-1⁰); 8.72 (s, 1H, H-2);

8.81 (s, 1H, H-2); ¹³C NMR (100.6 MHz, DMSO-d₆):

29.822 (CH₂-pur); 39.12 (C-2⁰); 52.94 (CH₂N-morph);

56.43 (CH₂-2⁰); 61.52 (CH₂-5⁰); 66.03 (CH₂O-morph);

70.62 (CH-3⁰); 83.63 (CH-1⁰); 87.90 (CH-4⁰); 132.77

(C-5); 143.97 (CH-8); 149.87 (C-4); 151.59 (CH-2);

160.13 (C-6). FAB-MS, m/z (rel %) = 350 (66)

[M+H]⁺, 249 (4), 234 (14), 147 (12), 100 (100), 73 (7),

57 (8). HRMS Calcd for C₁₆H₂₄N₅O₄[M+H]⁺

350.1828. Found: 350.1814. IR (KBr): 3613, 3295,

3120, 3072, 2968, 2897, 2817, 2774, 2738, 2694, 1599,

1585, 1499, 1459, 1447, 1419, 1399, 1373, 1336, 1295,

1115, 1095, 1070, 1060, 1036, 1007, 915, 868, 646, 613.

Anal. Calcd for C₁₆H₂₃N₅O₄Æ0.4H₂O: C, 53.89; H,

6.73; N, 19.64. Found: C, 54.28; H, 6.89; N, 19.29.

[a]_Dꢀ12.5 (c 0.27, MeOH).

0

J_{1 ,2}= 5.8, H-1⁰);7.22 (m, 1H, H-p-Ph); 7.29 (m, 2H,

H-m-Ph); 7.31 (m, 2H, H-o-Ph); 8.79 (s, 1H, H-2); 8.85

(s, 1H, H-8). ¹³C NMR (100.6 MHz, DMSO-d₆); 28.47

(CH₂–S); 32.08 (CH₂-pur); 34.74 (CH₂-Ph); 61.24

(CH₂-5⁰); 70.29 (CH-3⁰); 73.51 (CH-2⁰); 85.66 (CH-4⁰);

87.52 (CH-1⁰) 126.89 (CH-p-Ph); 128.44 (CH-m-Ph);

128.90 (CH-o-Ph); 132.92 (C-5); 138.20 (C-i-Ph);

141.71 (CH-8); 150.10 (C-4); 152.40 (CH-2); 160.43 (C-

6). FAB-MS, m/z (rel %) = 403 (36) [M+H]⁺, 313 (8),

271 (96), 179 (24), 147 (40), 134 (8), 121 (7), 91 (100),

73 (12), 57 (12). HRMS Calcd for C₁₉H₂₃N₄O₄S

[M+H]⁺403.1440. Found: 403.1433. IR (KBr): 3391,

3270, 3112, 3088, 3066, 3028, 1599, 1582, 1495, 1453,

1416, 1405, 1334, 1211, 1113, 1082, 1054, 1027, 1003,

815, 745, 703, 645, 546, 471. Anal. Calcd for

C₁₉H₂₂N₄O₄S: C, 56.70; H, 5.51; N, 13.92; S, 7.97.

Found: C, 56.41; H, 5.63; N, 13.69; S, 7.89. [a]_Dꢀ41.2

(c 0.34, MeOH).

0

6.65. 6-[2-(Benzyl(methyl)amino)ethyl]-9-(2-deoxy-b-^D-

erythro-pentafuranosyl)purine (19f)

Yield 76%, white hygroscopic foam. ¹H NMR

(400 MHz, DMSO-d₆): 2.18 (s, 3H, CH₃); 2.35 (ddd,

6.67. 6-(2-{[(Methoxycarbonyl)methyl]sulfanyl}ethyl)-9-

(b-^D-ribofuranosyl)purine (12b)

1H, J_gem= 13.0, J_{2 b,1}= 6.0, J_{2 b,3}= 2.4, H-2⁰b); 2.81

0

(ddd, 1H, J_gem= 13.0, J_{2 a,1}= 7.1, J_{2 a,3}= 6.0, H-2⁰a);

2.88 (t, 2H, J_vic= 7.2, CH₂–N); 3.28 (t, 2H, J_vic= 7.2,

CH₂-pur); 3.50 (s, CH₂-Ph); 3.52 (dt, 1H, J_gem= 11.7,

Yield 80%, white hygroscopic foam. ¹H NMR

(600 MHz, DMSO-d₆): 3.16 (t, 2H, J_vic= 7.1, CH₂S);

3.41 (t, 2H, J_vic= 7.1, CH₂-pur); 3.42 (s, 2H, CH₂CO);

0

J_{5 b,OH}= 5.0, J_{5 b,4}= 4.5, H-5⁰b); 3.63 (dt, 1H,

3.57 (ddd, 1H, J_gem= 12.0, J_{5 b,OH}= 6.1, J_{5 b,4}= 4.0,

0

J_gem= 11.7, J_{5 a,OH}= 5.0, J_{5 a,4}= 4.5, H-5⁰a); 3.90 (td,

H-5⁰b); 3.64 (s, 3H, CH₃O); 3.68 (ddd, 1H, J_gem= 12.0,

0

1H, J_{4 ,5}= 4.5, J_{4 ,3}= 3.0, H-4⁰); 4.45 (m, 1H,

J_{5 a,OH}= 5.1, J_{5 a,4}= 4.1, H-5⁰a); 3.97 (ddd, 1H,

0 0 0

0

J_{3 ,2}= 6.0, 2.4, J_{3 ,OH}= 4.1, J_{3 ,4}= 3.0, H-3⁰); 5.02 (t,

J_{4 ,5}= 4.1, 4.0, J_{4 ,3}= 3.6, H-4⁰); 4.1₀8 (ddd, 1H,

0

1H, J_OH,5= 5.0, OH-5⁰); 5.37 (d, 1H, J_OH,3= 4.1,

0

0 0 0 0 0

J_{3 ,2}= 5.0, J_{3 ,OH}= 4.9, J_{3 ,4}= 3.6, H-3 ); 4.65 (ddd,

OH-3⁰); 6.47 (dd, 1H, J_{1 ,2}= 7.1, 6.0, H-1⁰); 7.12 (m,

2H, H-o-Ph); 7.20 (m, 1H, H-p-Ph); 7.25 (m, 2H, H-m-

Ph); 8.70 (s, 1H, H-2); 8.79 (s, 1H, H-2); ¹³C NMR

(100.6 MHz, DMSO-d₆); 31.35 (CH₂-pur); 39.14 (C-

2⁰); 41.54 (CH₃); 54.94 (CH₂–N); 60.88 (CH₂Ph); 61.55

(CH₂-5⁰); 70.64 (CH-3⁰); 83.62 (CH-1⁰); 87.89 (CH-4⁰);

126.65 (CH-o-Ph); 127.90 (CH-p-Ph); 128.45 (CH-m-

Ph); 132.82 (C-5); 138.76 (C-i-Ph); 143.85 (CH-8);

149.83 (C-4); 151.52 (CH-2); 160.40 (C-6). FAB-MS,

1H, J_{2 ,OH}= 6.1, J_{2 ,1}= 5.8, J_{2 ,3}= 5.0, H-2⁰); 5.13

0

(dd, 1H, J_OH,5= 6.1, 5.1, OH-5⁰); 5.26 (d, 1H,

0

J_OH,3= 4.9, OH-3⁰); 5.55 (d, 1H, J_OH,2= 6.1, OH-2⁰);

0

6.02 (d, 1H, J_{1 ,2}= 5.8, H-1⁰); 8.79 (s, 1H, H-8); 8.86

(s, 1H, H-2). ¹³C NMR (151 MHz, DMSO-d₆): 29.68

(CH₂S); 32.05 (CH₂-pur); 32.64 (CH₂CO); 52.29

(CH₃O); 61.53 (CH₂-5⁰); 70.58 (CH-3⁰); 73.79 (CH-2⁰);

85.96 (CH-4⁰); 87.78 (CH-1⁰); 133.06 (C-5); 144.61

(CH-8); 150.60 (C-4); 152.04 (CH-2); 159.62 (C-6);

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1423

170.78 (CO). FAB-MS, m/z (rel %) = 385 (100) [M+H]⁺,

295 (7), 279 (7), 253 (70), 217 (7), 180 (18), 147 (36), 134

(8), 121 (7), 91 (100), 73 (38), 61 (22), 57 (44). HRMS

Calcd for C₁₅H₂₁N₄O₆S [M+H]⁺385.1181. Found:

385.1168 IR (KBr): 3615, 3306, 3115, 3073, 1734,

1599, 1586, 1500, 1438, 1418, 1335, 1286, 645. Anal.

Calcd for C₁₅H₂₀N₄O₆SÆ0.75 H₂O: C, 45.28; H, 5.45;

N, 14.08; S, 8.06. Found: C, 45.57; H, 5.18; N, 13.71;

S, 8.27. [a]_Dꢀ24.8 (c 0.10, MeOH).

6.02 (d, 1H, J_{1 ,2}= 5.6, H-1⁰); 8.81 (s, 1H, H-8); 8.86

(s, 1H, H-2). ¹³C NMR (151 MHz, DMSO-d₆): 27.24

(CH₂-5-thiazole); 29.57 (CH₂-pur); 46.85 (CH₂S); 57.00

(CH₂-4-thiazole); 61.44 (CH₂-5⁰); 70.47 (CH-3⁰); 73.89

(CH-2⁰); 85.86 (CH-4⁰); 87.83 (CH-1⁰); 133.07 (C-5);

144.64 (CH-8); 150.56 (C-4); 152.00 (CH-2); 158.38 (C-

6); 195.36 (C-2-thiazole). FAB-MS, m/z (rel %) = 398

(12) [M+H]⁺, 147 (20), 126 (10), 91 (100), 73 (40), 61

(20), 57 (50). HRMS Calcd for C₁₅H₂₀N₅O₄S₂[M+H]⁺

398.0956. Found: 398.0961. IR (KBr): 3413, 3270,

1600, 1583, 1494, 1455, 1420, 1405, 1364, 1334, 1292,

1212, 1120, 1081, 1053, 646. Anal. Calcd for

C₁₅H₁₉N₅O₄S₂Æ0.5H₂O: C, 44.32; H, 4.96; N, 17.23; S,

15.77. Found: C, 44.62; H, 4.77; N, 16.94; S, 15.40.

[a]_Dꢀ40.1 (c 0.31, MeOH).

0

6.68. 6-[2-(Benzothiazole-2-ylsulfanyl)ethyl]-9-(b-^D-ribo-

furanosyl)purine (12c)

Yield 68%, white hygroscopic crystals. ¹H NMR

(600 MHz, DMSO-d₆): 3.55 (m, 2H, CH₂-pur); 3.57

0

(ddd, 1H, J_gem= 12.1, J_{5 b,OH}= 5.9, J_{5 b,4}= 3.9, H-

0

5⁰b); 3.69 (ddd, 1H, J_gem= 12.1, J_{5 a,OH}= 5.3,

J_{5 a,4}= 4.2, H-5⁰a); 3.97 (ddd, 1H, J_{4 ,5}= 4.2, 3.9,

7. Biological assays

0

J_{4 ,3}= 3.6, H-4⁰); 4.17 (ddd, 1H, J_{3 ,OH}= 5.1,

0

J_{3 ,2}= 4.8, J_{3 ,4}= 3.6, H-3⁰); 4.57 (ddd, 1H,

7.1. Cytostatic activity assays

0

J_{2 ,OH}= 6.0, J_{2 ,1}= 5.5, J_{2 ,3}= 4.8, H-2 ); 4.95 (m, 2H,

0

CH₂S); 5.13 (dd, 1H, J_OH,5= 5.9, 5.3, OH-5⁰); 5.26 (d,

Inhibition of the cell growth was estimated in mouse

lymphocytic leukemia L1210 cells (ATCC CCL 219),

CCRF-CEM T lymphoblastoid cells (human acute lym-

phoblastic leukemia, ATCC CCL 119), human promye-

locytic leukemia HL-60 cells (ATCC CCL 240) and

human cervix carcinoma HeLa S3 cells (ATCC CCL

2.2). L1210 cells, CCRF-CEM cells and HL-60 cells

were cultivated in RPMI 1640 medium supplemented

with calf foetal serum using 24-well tissue culture plates.

The endpoint of the cell growth was 72 h following the

drug addition. Cells were then counted in Celtac MEK

5208 (NIHON KOHDEN) haematological analyzer.

HeLa S3 cells were seeded to 24-well dishes in RPMI

1640 HEPES modiﬁcation with foetal calf serum. 48 h

following the drug addition the cultivation was stopped

and the cell growth was evaluated after methylene blue

addition. The cell viability was quantiﬁed using XTT

[2]¹⁹standard spectrophotometric assay (Roche Molec-

ular Biochemicals). The inhibitory potency of the com-

pounds tested was expressed as IC₅₀values. The cell

cycle analysis by ﬂow cytometry (BD FACSAria) was

performed by using ethanol-ﬁxed cells stained with pro-

pidium iodide in buﬀer containing RNase A.

0

1H, J_OH,3= 5.1, OH-3 ); 5.54 (d, 1H, J_OH,2= 6.0,

OH-2⁰); 6.01 (d, 1H, J_{1 ,2}= 5.5, H-1⁰); 7.36 (ddd, 1H,

J_6,7= 7.9, J_6,5= 7.3, J_6,4= 1.0, H-6-benzothiazole);

7.46 (ddd, 1H, J_5,4= 8.3, J_5,6= 7.3, J_5,7= 1.3, H-5-ben-

zothiazole); 7.53 (ddd, 1H, J_4,5= 8.3, J_4,6= 1.0,

J_4,7= 0.5, H-4-benzothiazole); 7.78 (ddd, 1H,

J_7,6= 7.9, J_7,5= 1.3, J_7,4= 0.5, H-7-benzothiazole);

8.79 (s, 1H, H-8); 8.86 (s, 1H, H-2). ¹³C NMR

(151 MHz, DMSO-d₆): 29.87 (CH₂-pur); 44.22 (CH₂S);

61.39 (CH₂-5⁰); 70.41 (CH-3⁰); 73.96 (CH-2⁰); 85.79

(CH-4⁰); 87.86 (CH-1⁰); 113.19 (CH-4-benzothiazole);

122.19 (CH-7-benzothiazole); 125.13 (CH-6-benzothia-

zole); 126.85 (C-7a-benzothiazole); 127.41 (CH-5-benzo-

thiazole); 133.28 (C-5); 141.24 (C-3a-benzothiazole);

144.73 (CH-8); 150.53 (C-4); 152.03 (CH-2); 157.62 (C-

6); 188.38 (C-2-benzothiazole). FAB-MS, m/z (rel

%) = 446 (20) [M+H]⁺, 424 (16), 279 (16), 181 (24),

147 (40), 126 (12), 91 (100), 73 (48), 61 (16), 57 (50).

HRMS Calcd for C₁₉H₂₀N₅O₄S₂[M+H]⁺446.0956.

Found: 446.0950. IR (KBr): 3413, 3270, 3112, 3068,

1630, 1600, 1585, 1498, 1461, 1420, 1405, 1374, 1333,

1316, 1261, 1205, 1165, 1144, 1134, 1121, 1082, 1058,

1025, 818, 750, 720, 709, 673, 644. Anal. Calcd for

C₁₉H₁₉N₅O₄S₂Æ0.75H₂O: C, 49.72; H, 4.50; N, 15.26;

S, 13.97. Found: C, 50.08; H, 4.26; N, 14.90; S, 13.75.

[a]_Dꢀ32.5 (c 0.25, MeOH).

0

7.2. EC₅₀determination in HCV replicon cells²⁰

Con-1/lucneo replicon cells were seeded in 96-well plates

at a density of 8 · 10³cells per well in 100 ll of culture

medium, excluding Geneticin. Compound was serially

diluted in 100% DMSO and then added to the cells at

a 1:200 dilution, achieving a ﬁnal concentration of

0.5% DMSO and a total volume of 200 ll. Plates were

incubated at 37 ꢁC for 3 days, after which culture med-

ium was removed and cells were lysed in lysis buﬀer pro-

vided by Promega’s luciferase assay system. Following

the manufacturer’s instruction, 100 ll of luciferase sub-

strate was added to the lysed cells and the luciferase

activity was measured in a TopCount luminometer.

EC₅₀was calculated by non-linear regression. Parallel

plates treated with the same drug dilutions were assayed

for cytotoxicity using the Promega CellTiter-Glo cell

viability assay.

6.69. 6-[2-(Thiazoline-2-ylsulfanyl)ethyl]-9-(b-^D-ribofur-

anosyl)purine (12d)

Yield 91%, white hygroscopic crystals. ¹H NMR

(600 MHz, DMSO-d₆): 3.30 (m, 2H, H-5-thiazole);

3.47 (m, 2H, CH₂-pur); 3.57 (ddd, 1H, J_gem= 12.1,

J_{5 b,OH}= 6.0, J_{5 b,4}= 3.9, H-5⁰b); 3.69 (ddd, 1H,

0

J_gem= 12.1, J_{5 a,OH}= 5.3, J_{5 a,4}= 4.2, H-5⁰a); 3.97

0

(ddd, 1H, J_{4 ,5}= 4.2, 3.9, J_{4 ,3}= 3.6, H-4⁰); 4.185

0

(ddd, 1H, J_{3 ,OH}= 5.0, J_{3 ,2}= 4.8, J_{3 ,4}= 3.6, H-3⁰);

4.19 (m, 2H, H-4-thiazole); 4.23 (m, 2H, CH₂S); 4.61

0

(ddd, 1H, J_{2 ,OH}= 6.1, J_{2 ,1}= 5.6, J_{2 ,3}= 4.8, H-2⁰);

0

5.13 (dd, 1H, J_OH,5= 6.0, 5.3, OH-5⁰); 5.26 (d, 1H,

0

J_OH,3= 5.0, OH-3⁰); 5.54 (d, 1H, J_OH,2= 6.1, OH-2⁰);

0

ˇ

M. Kuchar et al. / Bioorg. Med. Chem. 16 (2008) 1400–1424

1424

see, J.; IJzerman, A. P. J. Med. Chem. 2006, 49, 2861–

2867.

7.3. CC₅₀determination in HCV replicon cells

ˇ

5. (a) Silhar, P.; Pohl, R.; Votruba, I.; Hocek, M. Org. Lett.

´

Replicon cells were seeded in 96-well plates at a density

of 8 · 10³cells per well in 100 ll of culture medium,

excluding Geneticin. Compound was serially diluted in

100% DMSO and then added to the cells at a 1:200 dilu-

tion, achieving a ﬁnal concentration of 0.5% DMSO and

a total volume of 200 ll. Plates were incubated at 37 ꢁC

for 3 days after which 100 ll of CellTiter Glo reagent

was added to each well and luminescence was read in

a TopCount luminometer.

ˇ

´

2004, 6, 3225–3228; (b) Silhar, P.; Pohl, R.; Votruba, I.;

Hocek, M. Collect. Czech. Chem. Commun. 2005, 70,

1669–1695.

ˇ

´

6. Silhar, P.; Pohl, R.; Votruba, I.; Hocek, M. Org. Biomol.

Chem. 2005, 3, 3001–3007.

ˇ

7. Silhar, P.; Pohl, R.; Votruba, I.; Hocek, M. Synthesis

´

2006, 1848–1852.

ˇ

8. Capek, P.; Pohl, R.; Hocek, M. J. Org. Chem. 2004, 69,

7985–7988.

ˇ

9. Capek, P.; Pohl, R.; Hocek, M. J. Org. Chem. 2005, 70,

8001–8008.

7.4. CC₅₀determination in MT4 cells

ˇ

´

10. Silhar, P.; Hocek, M.; Pohl, R.; Votruba, I.; Shih, I.;

Mabery, E.; Mackman, R. Bioorg. Med. Chem., submitted

for publication.

Cells were seeded in 384-well plates at 2 · 10³cells/well

in 20 ll of culture medium. Compounds were serially di-

luted in culture medium and added to each well for a ﬁ-

nal volume of 40 ll. Plates were incubated for 5 days,

after which cell survival was determined by addition of

40 ll of CellTiter Glo reagent followed by luminescence

read-out.

11. (a) Hocek, M. Eur. J. Org. Chem. 2003, 245–254; (b)

Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev.

2003, 103, 1875–1916.

12. Yus, M.; Foueblo, F. In Handbook of Functionalized

Organometallics, Applications in Synthesis; Knochel, P.,

Ed.; Wiley-VCH: Weinheim, Germany, 2005; pp 18–22.

13. An alternative approach to this class of compounds was

based on the cross-coupling with the Reformatsky reagent:

ˇ

´

Hasnık, Z.; Silhar, P.; Hocek, M. Tetrahedron Lett. 2007,

48, 5589–5592.

´

Acknowledgments

14. (a) Nagatsugi, F.; Kawasaki, T.; Usui, D.; Maeda, M.;

Sasaki, S. J. Am. Chem. Soc. 1999, 121, 6753–6754; (b)

Kawasaki, T.; Nagatsugi, F.; Ali, M. M.; Maeda, M.;

Sugiyama, K.; Hori, K.; Sasaki, S. J. Org. Chem. 2005, 70,

14–23; (c) Ali, M. M.; Oishi, M.; Nagatsugi, F.; Mori, K.;

Nagasaki, Y.; Kataoka, K.; Sasaki, S. Angew. Chem. Int.

Ed. 2006, 45, 3136–3140; (d) Øveras, A. T.; Bakkestuen,

A. K.; Gundersen, L.-L.; Rise, F. Acta Chem. Scand. 1997,

51, 1116–1124; (e) Liu, F.; Dalhus, B.; Gundersen, L.-L.;

Rise, F. Acta Chem. Scand. 1999, 53, 269–279.

This work is a part of the research project Z4 055 0506.

It was supported by the ‘Centre for New Antivirals and

Antineoplastics’ (1M0508), by the Programme for Tar-

geted Research (1QS400550501), and by Gilead Sci-

ences, Inc.

References and notes

ˇ´

1. (a) Hocek, M.; Holy´, A.; Votruba, I.; Dvorakova, H. J.

Med. Chem. 2000, 43, 1817–1825; (b) Hocek, M.; Holy´,

´

15. Wang, J.-F.; Zhang, L.-R.; Yang, Z.-J.; Zhang, L.-H.

Bioorg. Med. Chem. 2004, 12, 1425–1429.

ˇ

ˇ´

A.; Votruba, I.; Dvorakova, H. Collect. Czech. Chem.

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Article Doi

Synthesis, cytostatic, and antiviral activity of novel 6-[2-(dialkylamino)ethyl]-, 6-(2-alkoxyethyl)-, 6-[2-(alkylsulfanyl)ethyl]-, and 6-[2-(dialkylamino)vinyl]purine nucleosides

DOI: 10.1016/j.bmc.2007.10.063

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