Synthesis, cytostatic and anti-HCV activity of 6-(N-substituted aminomethyl)-, 6-(O-substituted hydroxymethyl)- and 6-(S-substituted sulfanylmethyl)purine nucleosides

Available online at www.sciencedirect.com

Bioorganic & Medicinal Chemistry 16 (2008) 2329–2366

Synthesis, cytostatic and anti-HCV activity of 6-(N-substituted

aminomethyl)-, 6-(O-substituted hydroxymethyl)-

and 6-(S-substituted sulfanylmethyl)purine nucleosides

a

a,

a

b

ˇ

*

´

Peter Silhar, Michal Hocek, Radek Pohl, Ivan Votruba, I-hung Shih,

Eric Mabery^band Richard Mackman^b

^aInstitute of Organic Chemistry and Biochemistry, v.v.i., 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 4 September 2007; revised 21 November 2007; accepted 23 November 2007

Available online 19 December 2007

Abstract—An eﬃcient and facile synthesis of a large series of diverse 6-(N-substituted aminomethyl)-, 6-(O-substituted hydroxy-

methyl)- and 6-(S-substituted sulfanylmethyl)purine nucleosides (55 examples of both ribo- and 2⁰-deoxyribonucleosides), aimed

at identifying novel homologues of natural nucleosides, was developed. The key transformation involved nucleophilic substitutions

of Tol-protected 6-(mesyloxymethyl)purine nucleosides by primary or secondary amines, alcoholates or thiolates. While the 2⁰-

deoxyribonucleosides were inactive, the ribonucleosides exerted considerable cytostatic eﬀects and some anti-HCV activity with

low selectivity.

1. Introduction

signiﬁcant cytostatic eﬀect on leukaemia cell lines

(IC₅₀= 10 nM). The hydroxymethyl group is a versatile

intermediate for further functional group manipulation.

Thus, the 6-(hydroxymethyl)purines were transformed

to 6-(ﬂuoromethyl)purines¹⁰via direct deoxyﬂuorina-

tion or via a three-step sequence consisting of mesyla-

tion, Finkelstein reaction and nucleophilic substitution

by AgF. In another study the hydroxymethyl group

was used in the synthesis of 6-(diﬂuoromethyl)purines¹¹

via oxidation and deoxoﬂuorination. Both 6-(ﬂuorom-

ethyl)-¹⁰and 6-(diﬂuoromethyl)purine¹¹ribonucleosides

showed cytostatic eﬀects but weaker than the parent 6-

(hydroxymethyl)purine nucleoside. Continuing the

study of bioactive purine derivatives bearing functional-

ized methyl groups in position 6, we report here on the

synthesis and biological activity of 6-(N-substituted

aminomethyl)-, 6-(O-substituted hydroxymethyl)- and

6-(S-substituted sulfanylmethyl)purines. As the mecha-

nism of action of the parent nucleosides is yet un-

known, we aimed our study at the wide diversity of

substituents rather than on rational design of speciﬁc

derivatives.

Purine nucleosides bearing diverse C-substituents (aryl,

alkenyl, alkynyl or alkyl groups) in position 6 are an

important class of compounds that possess a broad

spectrum of biological eﬀects: for example, cytostatic,¹

antiviral,²and antimicrobial³activity or receptor mod-

ulation.⁴Purines bearing functionalized C-substituents

in position 6 could possess metabolic stability due to

the CAC bond, while the presence of functional groups

could allow the possibility of H-bond formation with

target enzymes or receptors. However, due to a lack

of practical synthetic methodologies, such compounds

are still quite rare and therefore they are the subject

of extensive study in our laboratory. Recently, we have

reported the synthesis of 6-(hydroxymethyl)purines,^5,6

as well as of (purin-6-yl)alanines⁷and phenylalanines⁸

by cross-coupling reactions⁹of 6-halopurines with pro-

tected, functionalized organometallics. 6-(Hydroxy-

methyl)purine ribonucleoside was found⁵to exert a

Keywords: Purines; Nucleosides; Cytostatics; Antivirals.

*

The C-6 aminomethyl group of purines can be consid-

ered to be a homologation of the exocyclic amino

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

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

doi:10.1016/j.bmc.2007.11.067

ˇ

´

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2330

function found in the naturally occurring adenine base.

This functional modiﬁcation is interesting due to in-

creased basicity of the amine and can be useful in struc-

OH

O

N

Dess-Martin

N

ture–activity

relationship

studies.

In

general,

(aminomethyl)purines are known¹²to be quite unstable

and usually isolated as stable N-acyl derivatives.^12b,c

Unsubstituted (aminomethyl)purines have been pre-

pared by catalytic hydrogenation of cyanopurines^12,13

in yields of 60–70%. Two alternative low yielding syn-

theses based on nucleophilic substitution of 6-(chloro-

methyl)purine¹⁴or radical substitution of purines¹⁵

have been reported without detailed experimental proce-

dures and spectral data. Structurally related 6-(1-amino-

ethyl)purines were prepared by reductive amination of

6-acetylpurines.¹⁶Finally, several acyclic nucleotide

analogues derived from 6-(aminomethyl)purine have

been shown to possess antiviral activity.¹³

CH₂Cl₂

r.t., 2h

92-95 %

N

TolO

O

TolO OTol

1

3

1. R¹R²NH.HCl (5eq)

2. NaBH₃CN (1.2eq)

NR¹R²

OH

N

R²

+

R¹

5

N

Me

Bn

H

a

TolO

O

Several poorly characterized 6-(alkyl- or acyloxymeth-

yl)-^14,17and 6-(alkyl- or acylsulfanylmethyl)purines^14,18

have been prepared from 6-(chloromethyl)purines via

low yielding multistep procedures from 6-chloropurines.

However, to our knowledge, no nucleoside derivatives

have ever been reported and there are no data on the

biological activity of any of the above-mentioned

nucleobases.

b

c

Cyclohexyl

Gly-OEt

d

m

TolO OTol

Morpholine

1

5

Scheme 1. Synthesis of 6-(N-substituted aminomethyl)purines 5 by

reductive amination.

entries 1–3), due to reduction of 6-formylpurine. On

the other hand, the Tol-protecting groups of the sugar

moiety were stable to the reaction conditions. In order

to avoid the undesirable reduction a modiﬁed procedure

consisting of stepwise addition of NaBH₃CN (5·

0.25 equiv), change of solvent (ethanol instead of meth-

anol) and increased reaction temperature (55 ꢁC) was at-

tempted. This modiﬁed procedure aﬀorded the desired

products 5 in improved yields (43–70%) whilst decreas-

ing the amount of side-product 1 (0–30%) (Table 1, en-

tries 4–8).

2. Results and discussion

2.1. Chemistry

Our ﬁrst attempt at the synthesis of 6-(N-substituted

aminomethyl)purine nucleosides (both ribo- and 2⁰-

deoxyribo series) was reductive amination¹⁹of protected

6-formylpurines 3 with various primary and secondary

amine hydrochlorides and NaBH₃CN as the reducing

agent. The starting toluoyl (Tol) protected 6-formylpu-

rine nucleosides were prepared¹¹eﬃciently by oxidation

of 6-(hydroxymethyl)purines 1 with Dess–Martin peri-

odinane. In a typical experiment, 5 equiv of amine

hydrochloride were added to the solution of 6-formylp-

urine 3 in methanol at room temperature, and after

30 min, 1.2 equiv of NaBH₃CN reducing agent (Scheme

1). Application of this methodology aﬀorded the corre-

sponding protected (N-substituted aminomethyl)purine

nucleosides 5 in moderate yields of 33–51%. Unfortu-

nately, in all cases, the 6-(hydroxymethyl)purine 1 was

formed as a by-product in yields of 17–45% (Table 1,

Despite this improvement, we were interested in the

development of a practical and eﬃcient methodology

for the synthesis of (N-substituted aminomethyl)purine

nucleosides 5 and 6. Therefore, we tried another ap-

proach comprising nucleophilic substitution of 6-(mesyl-

oxymethyl)purines 7 or 8 with primary or secondary

amines (Scheme 2). In case of the primary amines, there

is a possibility of formation of dimeric side-products, 9

or 10, by double substitution of the amine with 2 equiv

of mesylate (Scheme 2). To avoid this side-reaction, the

Table 1. Synthesis of 5 by reductive amination of 6-formylpurines 3

Entry

Start. compd.

R¹R²NHÆHCl

Conditions

Product (yield %)

By-product 1 (%)

1

2

3

4

5

6

7

8

3

MeNH₂

BnNH₂

CyNH₂

48 h, MeOH

72 h, MeOH

5a (36)

5b (51)

5c (33)

5a (46)

5b (70)

5c (43)

5d (50)

5m (49)

17

20

45

5

72 h, MeOH

MeNH₂

BnNH₂

CyNH₂

16 h, EtOH, SA^a

6 h, EtOH, 55 ꢁC, SA^a

8 h, EtOH, 55 ꢁC, SA^a

0

21

0

Gly-OEt

Morpholine

30

^aSA, stepwise addition of NaBH₃CN (5· 0.25 equiv).

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P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2331

NR¹R²

OH

R

OMs

N

Ms₂O

N

R¹R²NH

N

+

For R²= H:

2. AcCl, Et₃N,

CH₂Cl₂

CH₂Cl_2,Et₃N,

90-96 %

N

R

N

R

5, 6

R

7, 8

1, 2

H₃C

N

TolO

In 1, 5, 7, 9: R =

O

R¹

R²

5, 6

NR¹R²

5, 6

aa

ba

ca

d

CH₃

Bn

Ac

H

l

piperidin-1-yl

N

TolO OTol

N

R

9a, 10a

m

n

o

p

morpholin-1-yl

thiazolidin-1-yl

TolO

In 2, 6, 8, 10: R =

O

cHex

CH₂COOEt

CH₂COOH

CH₃

indolin-1-yl

indol-1-yl

OTol

da

e

H

CH₃

pyrazol-1-yl

q

f

g

iPr

CH₃

iPr

Bn

4-pyrimidone-1-yl

2-pyrimidone-1-yl

r

s

t

h

CH₃

cPr

Ph

Ac

2-pyrrolidinone-1-yl

ia

j

Pro-OMe

Pro-OH

N₃

u

ua

v

CH₂CH₂OH CH₂CH₂OH

NHNHAc

k

H

Scheme 2. Synthesis of 6-(N-substituted aminomethyl)purines 5 and 6 by nucleophilic substitutions.

mesylates 7 or 8 were added dropwise to a solution of

10- to 20-fold excess of primary amines. As expected,

the reactions with both primary and secondary amines

proceeded smoothly to give the desired products 5 or 6

in excellent yields of 74–94 % based on the mesylate

(Table 2, entries 1–19). Only in the reactions with

methylamine, were the corresponding dimeric side-

products 9 and 10 formed in low yields of 5–8% (Ta-

ble 2, entries 1 and 2). While 6-(N,N-disubstituted

aminomethyl)purine nucleosides were stable, the

corresponding mono-substituted 6-(N-alkylaminom-

ethyl)purines 5a–c or 6a–c were not, and after a

few days turned brown to generate a complex mix-

ture of decomposition products (presumably by air

oxidation¹²). In order to isolate and characterize the

6-(N-monoalkylaminomethyl)purines, the secondary

nitrogen was acetylated with AcCl/Et₃N to give stable

acetylamide products 5aa–ca or 6aa–ca. Also in these

nucleophilic substitutions, the Tol-ester protective

groups on the sugar moiety were stable in the pres-

ence of amines and no signiﬁcant deprotection was

observed under the reaction conditions. This method-

ology provides an eﬃcient and convenient access to

the 6-(N-substituted aminomethyl)purine derivatives

in very good yields.

by molecules which contain more than one nucleophilic

centres such as 4- or 2-pyridone, was also studied. We

observed preferential formation of N-substituted pyri-

dones by reaction of their sodium salts (Scheme 3 and

Table 2, entries 28–31), while reaction of pyridones in

the presence of the Hunig’s base furnished slightly high-

¨

er amounts of O-substituted pyridines 13f, 14f and 13g,

14g (Scheme 3 and Table 2, entries 32–35). In contrast,

substitution with 2-pyrrolidinone in the presence of the

Hunig’s base did not proceed. Only the reaction with so-

¨

dium salt of 2-pyrrolidinone was successful to aﬀord N-

substituted products 5t and 6t in good yields (Table 2,

entries 36 and 37).

The acyl protecting groups in 6-(N,N-disubstituted

aminomethyl)purine derivatives 5 and 6 were cleaved

by catalytic amounts of NaOMe in methanol to yield

6-(N,N-disubstituted aminomethyl)purine nucleosides

11 or 12 in good yields (Scheme 4 and Table 3). In con-

trast, the toluoyl protecting groups in 6-(N-acetyl-N-

alkylaminomethyl) derivatives were cleaved by aqueous

ammonia in methanol at 50 ꢁC to prevent deacetylation

of the amino group.

To further employ the mesylate intermediates 7 and 8,

substitutions of the mesylate with various O- and S-

nucleophiles (Scheme 5) were undertaken. Several reac-

tions with either unfunctionalized or functionalized

nucleophiles were performed, and a series of new modi-

ﬁed purine nucleosides was prepared. Poorly nucleo-

philic alcohols were used as solvents in the

substitution reaction with amines without observing

Reaction of 7 with pyrrole did not proceed and the re-

lated indolyl-derivative 5p was only formed in low yield

(15%) by substitution with the sodium salt of indole (Ta-

ble 2, entry 26). Therefore, an alternative approach was

sought for the synthesis of 5p based on the mild oxida-

tion of indoline derivative 5o with DDQ. Substitution

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P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2332

Table 2. Synthesis of 5 and 6 by nucleophilic substitutions of mesylates 7 and 8

Entry

Start. compd.

R¹R²NH

Conditions

Product (yield %)

1

7

8

7

8

7

8

7

8

7

8

7

8

7

8

7

8

7

8

7

8

7

8

7

8

7

8

7

8

7

8

7

MeNH₂

MeCN, 2 h, AcCl^a

MeCN, 4 h, AcCl^a

MeCN, 6 h, AcCl^a

5aa (80) + 9a (8)

6aa (90) + 10a (5)

5ba (87)

2

3

BnNH₂

4

6ba (92)

5ca (82)

5

cHexNH₂

Gly-OEtÆHCl

Me₂NH

6

6ca (74)

5d (82)

i

7

MeCN, Pr₂NEt, 8 h

MeCN, 4 h

8

5e (79)

6e (85)

9

Me₂NH

ⁱPr₂NH

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

MeCN, 55 ꢁC, 36 h

MeCN, 8 h

5f (78)

6f (86)

BnNHMe

PhNHMe

cPrNH₂

5g (81)

5h (62)

MeCN, 8 h

6h (60)

5ia (94)

MeCN, 6 h, AcCl^a

MeCN, 8 h

cPrNH₂

6ia (95)

5j (72)

Diethanolamine

AcNHNH₂

Piperidine

Morpholine

Thiazolidine

Indoline

MeCN, 8 h

i

MeCN, Pr₂NEt, 24 h

6j (78)

5k (65)

MeCN, 8 h

5l (89)

6l (94)

MeCN, 8 h

5m (88)

6m (94)

5n (75)

5o (90)

MeCN, 12 h,

MeCN, NaH, 10 h

MeCN, 70 ꢁC, 72 h

THF, NaH, 6 h

Indole

Pyrazole

5p (15)

5q (73)

4-Pyridone

2-Pyridone

4-Pyridone

2-Pyridone

2-Pyrrolidinone

Pro-OMeÆHCl

NaN₃

5r (88) + 13f (4)

6r (85) + 14f (4)

5s (94)

6s (95)

i

MeCN, Pr₂NEt, 50 ꢁC, 12 h

5r (70) + 13f (8)

6r (78) + 14f (10)

5s (47) + 13g (17)

6s (38) + 14g (22)

5t (51)

i

MeCN, Pr₂NEt, 50 ꢁC, 12 h

i

MeCN, Pr₂NEt, 55 ꢁC, 48 h

i

MeCN, Pr₂NEt, 55 ꢁC, 48 h

THF, NaH, 6 h

i

MeCN, Pr₂NEt, 50 ꢁC, 12 h

DMF, 6 h

6t (72)

5u (96)

5v (95)

^aAcetylation with AcCl/Et₃N after evaporation of solvent and excess of amine.

NR¹R²

N

O

MeONa / MeOH

N

O

N

O

or

N

NH₃/ MeOH

HO

TolO

N

O

N

O

N

50˚C

N

+

H

N

X

TolO

HO

X

R

OMs

N

11

5 X = OTol

X = OH

5r, 6r

13f, 14f

6

12 X = H

X = H

N

Tol = -Methylbenzoyl

p

N

O

N

Scheme 4. Deprotection of toluoyl-protective groups.

R

N

O

7, 8

any O-substitution. The corresponding sodium alcohol-

ates in alcohol, however, reacted with 7 or 8 to give the

desired alkoxymethylpurine nucleosides. In the case of

NaOMe, simultaneous cleavage of the Tol-protecting

groups occurred to directly provide free nucleosides

15a and 16a in moderate yields, whereas sodium pheno-

late gave phenyloxymethyl nucleosides 13b and 14b in

N

+

N

R

N

O

5s, 6s

H

13g, 14g

Scheme 3. Formation of N- and O-substituted pyridones.

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P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2333

Table 3. Cleavage of protective groups

mesylates 7 and 8 smoothly to give the desired S-substi-

tuted 6-(sulfanylmethyl)purine nucleosides in close to

quantitative yields without cleavage of the protecting

groups on the sugar (Table 4, entries 7–21).

Entry Start. compd. Reagent

Product (yield %)

1

5aa

6aa

5ba

6ba

5ca

6ca

5d

5e

NH₃/MeOH

NaOH/H₂O/THF

MeONa

11aa (82)

12aa (92)

11ba (84)

12ba (92)

11ca (84)

12ca (86)

11da (65)

11e (71)

12e (88)

11f (65)

12f (60)

11g (84)

11h (89)

12h (80)

11ia (79)

12ia (82)

11j (90)

12j (78)

11k (80)

11l (65)

12l (81)

11m (69)

12m (85)

11n (67)

11p (93)

11q (83)

11r (70)

12r (97)

11s (72)

12s (97)

11t (61)

12t (78)

2

3

The deprotections of the intermediates 13, 14 and 17, 18

were performed in analogy to the previous derivatives.

Thus, 6-(O-substituted hydroxymethyl)- and 6-(S-

substituted sulfanylmethyl)purine nucleosides 15, 16

and 19, 20 were prepared in good yields by treatment

with sodium methoxide (catalytic amount) or aqueous

ammonia in methanol at ambient temperature (Scheme

5) (Table 4, last column). The thioglycolate methyl es-

ters 17d and 18d were hydrolysed by treatment with

NaOMe followed by aq NaOH to remove all the ester

groups and provide carboxylic acids 19da and 20da.

4

5

6

7

8

9

6e

5f

MeONa

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

6f

MeONa

5g

5h

6h

5ia

6ia

5j

MeONa

NH₃/MeOH

MeONa

2.2. Biological activity

6j

MeONa

5k

5l

NH₃/MeOH

MeONa

All the title 6-(N-substituted aminomethyl)-, 6-(O-

substituted hydroxymethyl)- and 6-(S-substituted sulfa-

nylmethyl)purine nucleosides 11, 12, 15, 16, 19, 20 were

subjected to biological activity screening. The cytostatic

activity in vitro (inhibition of cell growth) was studied

on the following cell cultures: (i) mouse leukaemia

L1210 cells (ATCC CCL 219); (ii) human promyelocytic

leukaemia 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 com-

pounds from this series were evaluated by estimating

the cell count in a haematological analyzer (haemocy-

tometer). In parallel the cell viability was determined

by XTT staining.²⁰Whilst the 2⁰-deoxyribonucleoside

derivatives were all inactive, many ribonucleosides 11,

15 or 19 exerted considerable antiproliferative eﬀects

at low micromolar concentrations (Table 5). The most

susceptible cell line was human HL-60, whilst the

6l

5m

6m

5n

5p

5q

5r

MeONa

NH₃/MeOH

6r

5s

6s

5t

6t

5u

5v

MeONa/NaOH/H₂O 11ua (78)

NH₃/MeOH 11v (30)

excellent yields without cleavage of the protecting

groups. All S-nucleophiles (both sodium thiolates and

thiols in the presence of Hunig’s base) reacted with

¨

OR³

MeONa / MeOH

N

R³ONa

N

R³

N

13-20

a

N

O

N

TolO

HO

(or NH₃/MeOH)

O

CH₃

b

c

Ph

Bn

TolO

X

OH X

15 X = OH

16 X = H

7 or 8

13 X = OTol

14 X = H

d

CH₂COOMe

CH₂COOH

SR³

da

SR³

e

g

h

ia

CH₂CH₂OH

pyridin-2-yl

benzothiazol-2-yl

Ac

N

MeONa / MeOH

N

R³SNa or

N

O

R³SH, iPr₂NEt

HO

N

TolO

O

i

H

OH X

TolO

X

19 X = OH

20 X = H

17 X = OTol

18 X = H

Scheme 5. Synthesis of 13, 14 and 17, 18 by nucleophilic substitutions.

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P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2334

Table 4. Nucleophilic substitutions of mesylates 7 and 8 with O- and S-nucleophiles and deprotection

Entry

Start. compd.

Nucleophile

Conditions

Product (yield %)

Deprotection

Product (yield %)

1

7

8

7

8

MeONa

PhONa

MeOH, 12 h

THF, 6 h

Simultaneous

MeONa

15a (30)

16a (44)

15b (86)

16b (90)

15g (80)

16g (89)

19a (81)

20a (93)

19b (88)

20b (91)

19c (89)

20c (92)

19da (75)

20da (83)

19e (84)

20e (93)

19g (78)

20g (57)

19h (86)

19i (57)

20i (86)

2

3

13b (89)

14b (95)

13g^c

4

THF, 6 h

MeONa

5

NH₃/MeOH

MeONa

6

14g^c

7

8

7

8

7

8

7

8

7

8

7

8

7

8

MeSNa

DME, 4 h

MeCN, 6 h

17a (96)

18a (96)

17b (76)

18b (90)

17c (98)

18c (98)

17d (99)

18d (99)

17e (98)

18e (98)

17g (98)

18g (98)

17h (98)

17ia (95)

18ia (96)

8

MeONa

9

PhSNa

10

11

12

13

14

15

16

17

18

19

20

21

MeONa

i

BnSH

AN, Pr₂NEt, 10 h

i

AN, Pr₂NEt, 10 h

i

AN, Pr₂NEt, 10 h

HSCH₂CO₂Me

HSCH₂CH₂OH

2-MPy^a

MeONa/NaOH/H₂O

MeONa

i

AN, Pr₂NEt, 10 h

i

AN, Pr₂NEt, 10 h

i

AN, Pr₂NEt, 10 h

MeONa

i

AN, Pr₂NEt, 12 h

2-MPy^a

AN, Pr₂NEt, 12 h

i

AN, Pr₂NEt, 12 h

MeONa

i

2-MBT^b

AcSK

AN, 5h

MeONa

^a2-MPy, 2-mercaptopyridine.

^b2-MBT, 2-mercaptobenzothiazole.

^cFor synthesis of 13g and 14g, see Scheme 3.

CCRF-CEM and L1210 cell lines were less sensitive to

most of the compounds. None of the compounds were

active in HeLaS3 cell line. Within the aminomethyl ser-

ies, the dialkylaminomethyl derivatives (i.e., 11e–11h

and 11j–11n) generally exerted cytostatic eﬀects, while

acetylated monoalkylaminomethyl and heteroarylmeth-

yl derivatives were less active. Also 6-(methoxymethyl)-,

6-(methylsulfanyl)- and 6-(benzylsulfanyl)-purine ribonu-

cleosides 15a, 19a and 19c showed considerable cyto-

static activity. 6-(Sulfanylmethyl)purine ribonucleoside

19i, the thia-analogue of the highly cytostatic⁵

6-(hydroxymethyl)purine 15i, exerted only moderate

cytostatic activity in the micromolar range. The most

powerful anti-proliferative compound from the series

was the azidomethyl derivative 11v with IC₅₀values

0.4–1.9 lM. The viability data (XTT) in many cases

indicate signiﬁcantly lower IC₅₀values compared to

the cell count IC₅₀. Taken together, this diﬀerence sug-

gests a signiﬁcant amount of apoptosis in cells upon

exposure to the tested compounds. The cell cycle analy-

sis (Tables 6 and 7) following treatment with selected

compounds (11v, 11h, 11j, 15a, 19c, 19i) indicated an

accumulation of cells in G1 phase and depletion of S

phase for compounds 11v, 11j and 15a. In contrast, com-

pounds 11h and 19i did not aﬀect the S phase to a signif-

icant extent, whilst the cells treated with compound 19c

show S phase arrest. In agreement with the data on inhi-

bition of cell proliferation all compounds with cytostatic

activity induce apoptosis. None of the compounds

showed any signiﬁcant inhibition of adenosine deami-

nase²¹at 12.5 lM concentration.

ity in the HCV replicon. Unfortunately, in most cases

the compounds lacked selectivity. The exceptions of

note were 11p, 11v and 19a, which demonstrated

>10-fold selectivity in the replicon huh-7 cells. Upon

evaluation of these analogues in the MT-4 cell line re-

duced selectivity (<6-fold) was observed, consistent

with the cytostatic eﬀects measured in the other cell

lines. These results suggest that the modiﬁed purine

ribonucleosides interfere with critical cell growth pro-

cesses and most of the activity towards HCV viral

replication is non-speciﬁc.

3. Conclusions

This approach based on nucleophilic substitutions of

6-[(mesyloxy)methyl]purine nucleosides by amines,

alcoholates or thiolates is a suitable methodology

for the generation of diverse aminomethyl, alkyloxym-

ethyl and alkylsulfanylmethyl derivatives of purine

nucleosides as homologues of natural adenosine or

inosine nucleosides. A large number of modiﬁed deriva-

tives can be easily generated from this one common

intermediate in one or two simple steps. Some of the

ribonucleosides prepared exert considerable cytostatic

eﬀects.

4. Experimental

4.1. General

The title modiﬁed nucleosides were also tested up to

100 lM for antiviral activities in HCV genotype 1b

replicon²²(Table 5). With the exception of 12ca and

20i, the 2⁰-deoxyribonucleosides were inactive, but

many of the ribonucleosides displayed antiviral activ-

Starting materials. 6-Formylpurine-9-(2,3,5-tri-O-tolu-

oyl-b-^D-ribofuranosyl)purine and 9-(2-deoxy-3,5-di-O-

toluoyl-b-^D-erythro-pentofuranosyl)-6-formylpurine

were prepared as described in Ref. 11 6-(Methanesulfo-

nyloxymethyl)-9-(2,3,5-tri-O-toluoyl-b-^D-ribofuranosyl)-

ˇ

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2335

Table 5. Biological activities of title nucleosides 11, 15 and 19

a

Compound

Cytostatic activity IC₅₀(lM)

HCV antiviral activity and cytotoxicity

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

b

c,d

L1210

HL60 CCRF-CEM

11aa

11ba

11ca

11da

11e

n.a.

>100

87

>100

18

n.a.

5.1 0.4

17 1.5

4.8 0.3

n.a.

4.0 0.4

13 0.9

n.a.

41

3

11f

11g

5.6 0.3 (2.4 0.2)

4.0 0.32 (3.4 0.35)

n.a.

20.3 1.2

n.a.

9

21

9

21

11h

11ia

11j

n.a.

14.3 0.85

n.a.

6.7 0.42 (3.72 0.36)

>100

15

65

>100

10

14.7 1.2 (4.37 0.33)

6.6 0.4 (11.4 0.2)

6.9 0.4

11k

11l

18.0 1.36 (10.3 1.0)

n.a.

>250

87

12.16 0.8

n.a.

42

11m

11n

13.0 0.7

n.a.

19.6 1.2

3.4 0.21 (1.96 0.1)

186

7

>250

21

7.8 0.4

n.a.

5.2 0.35 (3.12 0.1)

5.7 0.32 (9.1 0.14)

n.a.

11p

11q

7.6

62

>250 (45)

>250 (48)

>100

45

n.a.

11r

11s

n.a.

>100

91

14

11t

11v

n.a.

1.59 0.09

n.a.

1.88 0.11 (0.78 0.02) 0.39 0.03 (0.34 0.04)

13.0 0.9 (1.68 0.06)

n.a.

6

13

>250 (32)

>100

>250

>100 (32)

>100

>100 (>100)

>100

54

15a

15b

6.0 0.35 (1.14 0.03)

n.d.

>100

>250

10

15g

19a

n.a.

12.0 0.81 (14.3 0.7)

13.4 1.04 (5.0 0.16)

16.6 1.1 (10.8 0.65)

15.0 1.1 (3.2 0.23)

> 30

n.a.

19b

19c

n.a.

10.7 0.8 (19.2 0.58)

n.a.

9.2 0.6 (4.65 0.28)

>100

46

n.a.

19da

19e

n.a.

19g

19h

n.a.

44

n.a.

>100

39

20

19i

3.5 0.18(1.2 0.06)

n.a.

12ca^e

20i^e

15i^f

n.a.

>100 (>100)

41

—

n.a.

0.01 0.0011

n.a.

20

—

0.012 0.003 0.012 0.003

0.15 0.0011

0.017 0.004

—

FUdR^g

2⁰CMeA^h

—

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 harbouring con-1 replicon (N = 2).

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

^e2⁰-Deoxyribonucleosides.

^fTaken from Ref. 5a.

^g1-(b-D-2-Deoxy-erythro-pentofuranosyl)-5-ﬂuorouracil.

^h2⁰-Methyl-adenosine.

Table 6. Cell cycle analysis of HL-60 cells: changes relative to control^a

purine and 6-(methanesulfonyloxymethyl)-9-(2-deoxy-

3,5-di-O-toluoyl-b-^D-erythro-pentofuranosyl)purine were

Compound

G1

S

G2/M

prepared as described in Ref. 10 NMR spectra were re-

corded on Bruker Avance 400 MHz spectrometer (¹H at

400, ¹³C at 100.6 MHz), a Bruker Avance (500 MHz for

¹H and 125.8 MHz for ¹³C). Chemical shifts (in ppm, d

scale) were referenced to TMS as internal standard. The

assignment of carbons was based on C,H HSQC and

C,H HMBC experiments. Melting points were deter-

mined on a Koﬂer block and are uncorrected. Optical

rotations were measured at 25 ꢁC on a Autopol IV (Ru-

dolph Research Analytical) polarimeter, [a]_Dvalues are

given in 10^ꢀ1deg cm²g^ꢀ1. Mass spectra were measured

on a ZAB-EQ (VG Analytical) spectrometer using FAB

(ionization by Xe, accelerating voltage 8 kV, glycerol

11h (3 lmol l^ꢀ1

)

1.12

1.57

1.99

0.87

0.63

0.43

1.08

1.30

0.88

11v (1 lmol l^ꢀ1

)

19c (22.5 lmol l^ꢀ1

^aAfter 72 h treatment.

)

Table 7. Cell cycle analysis of HL-60 cells: changes after 72 h

treatment with compound 11v

Concentration (lmol l^ꢀ1

)

G1

S

G2/M

0

34

54

33

24

58

37

59

69

7

10

8

1

2.5

5

8

ˇ

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P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2336

matrix). Cytostatic activity tests were performed as de-

scribed in Ref. 1.

4.6. 6-[(N-Methylamino)methyl]-9-(2,3,5-tri-O-toluoyl-b-

D-ribofuranosyl)purine (5a)

4.2. General procedure for reductive aminations

Prepared by reductive amination in 46% of yield. Yel-

lowish foam which after 1 day turns brown to form

complex mixture of decomposition products. Exact

mass (FAB HR MS) found: 650.2628; calcd for

C₃₆H₃₆N₅O₇: 650.2615. FAB MS m/z (%): 650 (MH⁺,

2); 487 (8); 163 (3); 119 (100). ¹H NMR (500 MHz,

CDCl₃): 2.37 and 2.42 (2· s, 9H, CH₃-Tol); 2.55 (s,

An amine hydrochloride (5 mmol) was added to the

solution of 6-formylpurine 3 (1 mmol) in methanol or

ethanol (20 ml). After 30 min NaBH₃CN was added

either in one portion (90 mg, 1.2 mmol, 85% purity)

or stepwise (5· 20 mg) and the mixture was stirred at

ambient temperature for 24–72 h. In the case of

sterically hindered amines (e.g., benzyl, cyclohexyl

amine) heating of reaction mixture at 55 ꢁC has been

performed. The solvent was then evaporated, the

residue was dissolved in 1 M aq NaH₂PO₄(20 ml)

and extracted with ethyl acetate (4· 25 ml). Collected

organic layers were dried over MgSO₄, the solvent

was evaporated and the oily residue was chromato-

graphed on silica gel (hexanes/ethyl acetate, 1:1–0:1).

Yields of the particular products are summarised in

Table 1.

3H, CH₃N); 4.34 (s, 2H, CH₂N); 4.67 (dd, 1H, J_gem

=

12.3, J_{5 b;4}¼ 4:2, H-5⁰b); 4.82 (td, 1H, J_{4 ;3}¼ 4:7,

0

J_{4 ;5}¼ 4:2, 3.2, H-4⁰); 4.89 (dd, 1H, J_gem= 12.3,

0

J_{5 a;4}¼ 3:2, H-5⁰a); 6.21 (dd, 1H, J_{3 ;2}¼ 5:8, J_{3 ;4}

¼

0

4:7, H-3⁰); 6.38 (t, 1H, J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:4, H-2⁰);

0

6.48 (d, 1H, J_{1 ;2}¼ 5:4, H-1⁰); 7.16, 7.22 and 7.25 (3·

m, 3· 2H, H-m-Tol); 7.81, 7.91 and 7.99 (3· m, 3·

2H, H-o-Tol); 8.21 (s, 1H, H-8); 8.83 (s, 1H, H-2). ¹³C

NMR (125.8 MHz, CDCl₃): 21.70 and 21.73 (CH₃-

Tol); 35.99 (CH₃N); 51.94 (CH₂N); 63.42 (CH₂-5⁰);

71.41 (CH-3⁰); 73.72 (CH-2⁰); 81.04 (CH-4⁰); 86.92

(CH-1⁰); 125.65, 126.04 and 126.59 (C-i-Tol); 129.23,

129.27 and 129.34 (CH-m-Tol); 129.79, 129.88 and

129.89 (CH-o-Tol); 132.81 (C-5); 142.93 (CH-8);

144.24, 144.58 and 144.71 (C-p-Tol); 150.77 (C-4);

152.72 (CH-2); 159.07 (C-6); 165.17, 165.38 and 166.19

(CO). IR (CCl₄): m = 3346, 2795, 1732, 1612, 1594,

0

4.3. General procedure for nucleophilic substitutions of

mesylates 7 and 8 with primary amines

A solution of mesylate 7 or 8 (1 mmol) in dry MeCN or

THF (5 ml) was added dropwise to a solution of nucleo-

phile (10–20 mmol) in dry MeCN or THF (10 ml). After

complete consumption of starting material (monitoring

by TLC) the solvent and excess of amine were evaporated

in vacuo (45 ꢁC, 130 Pa for 2 h). The residue was dis-

solved in CH₂Cl₂(20 ml) and Et₃N (0.3 ml, 2.2 mmol) fol-

lowed by AcCl (0.1 ml, 1.4 mmol) were added. Reaction

was quenched after 8 h with 1 M aq NaH₂PO₄(30 ml)

and the mixture extracted with CHCl₃(4· 30 ml). Col-

lected organic layers were dried over MgSO₄, the solvent

was evaporated and the oily residue was chromato-

graphed on silica gel (hexanes/ethyl acetate, 1:1–0:1).

1498, 1409, 1333, 1266, 1179, 1092, 644 cm^ꢀ1

.

4.7. 6-[(N-Acetyl-N-methylamino)methyl]-9-(2,3,5-tri-O-

toluoyl-b-^D-ribofuranosyl)purine (5aa)

Prepared by nucleophilic substitution of mesylate 7

(500 mg, 0.7 mmol) with MeNH₂/THF (7 ml,

c = 2 mol l^ꢀ1) in MeCN (10 ml) and subsequent acetyla-

tion. Yield: 80% as white foam. Exact mass (FAB HR

MS) found: 692.2731; calcd for C₃₈H₃₈N₅O₈: 692.2720.

FAB MS m/z (%): 692 (MH⁺, 2); 649 (0.5); 487 (32);

119 (100). A mixture of cis/trans amides ꢁ1:0.7. ¹H

NMR (400 MHz, CDCl₃): 2.21 and 2.25 (2· s, 2· 3H,

CH₃CO); 2.38 and 2.42 (2· s, 18H, CH₃-Tol); 3.03

and 3.14 (2· s, 2· 3H, CH₃-N); 4.67 and 4.68 (2· dd,

4.4. General procedure for nucleophilic substitutions of

mesylates 7 and 8 with secondary amines

2· 1H, J_gem= 12.1, J_{5 b;4}¼ 4:0, H-5⁰b); 4.82 (m, 2H,

0

A solution of mesylate 7 or 8 (1 mmol) in dry MeCN or

THF (5 ml) was added to a solution of nucleophile (1.5–

4 mmol) in dry MeCN or THF (10 ml). After complete

consumption of starting material (monitoring by TLC)

the reaction was quenched with 1 M aq NaH₂PO₄

(40 ml) and the mixture extracted with ethyl acetate

(4· 30 ml). Collected organic layers were dried over

MgSO₄, the solvent was evaporated and the oily residue

was chromatographed on silica gel (hexanes/ethyl ace-

tate, 1:1–0:1).

H-4⁰); 4.88 and 4.90 (2· dd, 2· 1H, J_gem= 12.1,

J_{5 a;4}¼ 3:0, H-5⁰a); 4.96 and 5.10 (2· s, 2· 2H,

0

CH₂N); 6.20 and 6.21 (2· dd, 2· 1H, J_{3 ;2}¼ 5:7,

J_{3 ;4}¼ 5:0, H-3⁰); 6.37 and 6.39 (2· t, 2· 1H,

0

J_{2 ;3}¼ 5:7, J_{2 ;1}¼ 5:2, H-2⁰); 6.47 and 6.48 (2· d, 2·

0

1H, J_{1 ;2}¼ 5:2, H-1⁰); 7.16, 7.21, 7.23 and 7.26 (4· m,

6· 2H, H-m-Tol); 7.81, 7.90, 7.91 and 8.00 (5· m, 6·

2H, H-o-Tol); 8.18 and 8.22 (2· s, 2· 1H, H-8); 8.81

and 8.82 (2· s, 2· 1H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 20.99, 21.62 and 21.70 (CH₃CO and CH₃-

Tol); 37.31 (CH₃N), 49.03 and 51.74 (CH₂N); 63.36

and 63.52 (CH₂-5⁰); 71.31 and 71.43 (CH-3⁰); 73.61

and 73.64 (CH-2⁰); 81.01 (CH-4⁰); 86.71 and 87.08

(CH-1⁰); 125.58, 125.64, 125.98, 126.02 and 126.59 (C-

i-Tol); 129.21, 129.25, 129.27 and 129.33 (CH-m-Tol);

129.79 and 129.86 (CH-o-Tol); 132.70 (C-5); 142.91

and 143.42 (CH-8); 144.21, 144.49, 144.55, 144.66 and

144.78 (C-p-Tol); 150.53 (C-4); 152.70 and 152.86

(CH-2); 158.81 and 159.54 (C-6); 165.37 and 166.25

(CO-Tol); 173.69 (COCH₃). IR (CCl₄): m = 3038, 1732,

0

4.5. General procedure for nucleophilic substitutions of

mesylates 7 and 8 with O- or S-nucleophiles

A solution of mesylate 7 or 8 (1 mmol) in dry MeCN or

THF (5 ml) was added to a solution of nucleophile (1.5–

3 mmol) in dry MeCN or DME (10 ml). After complete

consumption of starting material (monitoring by TLC)

the reaction mixture was adsorbed on silica gel and

chromatographed on silica (hexanes/ethyl acetate, 2/

1:1/5).

ˇ

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2337

1658, 1612, 1595, 1498, 1408, 1334, 1267, 1179, 1092,

645 cm^ꢀ1

4.10. Bis{N,N-[9-(2-deoxy-3,5-di-O-toluoyl-b-^D-erythro-

pentofuranosyl)purin-6-yl]methyl}methylamine (10a)

.

4.8. Bis{N,N-[9-(2,3,5-tri-O-toluoyl-b-^D-ribofurano-

syl)purin-6-yl]methyl}methylamine 9a

Prepared as by-product in nucleophilic substitution of

mesylate 8 with MeNH₂/THF (see 6aa). Yield: 5% as

white foam. Exact mass (FAB HR MS) found:

1000.3974; calcd for C₅₅H₅₄N₉O₁₀Na: 1000.3994. FAB

MS m/z (%): 1000 (M+H⁺, 2); 119 (100). ¹H NMR

(400 MHz, CDCl₃): 2.39 and 2.45 (2· s, 2· 6H, CH₃-

Tol); 2.47 (s, 3H, CH₃N); 2.84 (ddd, 2H, J_gem= 14.2,

Prepared as by-product in nucleophilic substitution of

mesylate 7 with MeNH₂/THF (see 5aa). Yield: 8% as

white foam. Exact mass (FAB HR MS) found:

1290.4519; calcd for C₇₁H₆₅N₉O₁₄Na: 1290.4549.

FAB MS m/z (%): 1290 (M+Na⁺, 3); 487 (44); 119

(100). ¹H NMR (400 MHz, CDCl₃): 2.36, 2.39 and

2.41 (3· s, 18H, CH₃-Tol); 2.52 (s, 3H, CH₃N); 4.32

and 4.37 (2· d, 4H, J_gem= 14.1, CH₂N); 4.66 (dd,

J_{2 b;1}¼ 5:7, J_{2 b;3}¼ 2:0, H-2⁰b); 3.21 (ddd, 2H,

0

J_gem= 14.2, J_{2 a;1}¼ 8:4, J_{2 a;3}¼ 6:4, H-2⁰a); 4.38 and

4.42 (2· d, 4H, J_gem= 14.2, CH₂N); 4.65–4.69 (m, 4H,

H-5⁰b and H-4⁰); 4.75–4.80 (m, 2H, H-5⁰a); 5.84 (dt,

0

2H, J_gem= 12.3, J_{5 b;4}¼ 4:3, H-5⁰b); 4.81 (td, 2H,

2H, J_{3 ;2}¼ 6:4, 2.0, J_{3 ;4}¼ 2:0, H-3⁰); 6.59 (dd, 2H,

0

J_{4 ;3}¼ 4:9, J_{4 ;5}¼ 4:3, 3.2, H-4⁰); 4.88 (dd, 2H,

J_{1 2}¼ 8:4, 5.7, H-1⁰); 7.21 and 7.29 (2· m, 2· 4H, H-

m-Tol); 7.91 and 7.98 (2· m, 2· 4H, H-o-Tol); 8.18 (s,

2H, H-8); 8.90 (s, 2H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 21.58 and 21.65 (CH₃-Tol); 37.57 (CH₂-2⁰);

42.49 (CH₃N); 57.47 (CH₂N); 63.89 (CH₂-5⁰); 75.02

(CH-3⁰); 82.96 (CH-4⁰); 84.74 (CH-1⁰); 126.32 and

126.58 (C-i-Tol); 129.17 and 129.19 (CH-m-Tol);

129.55 and 129.72 (CH-o-Tol); 133.78 (C-5); 142.44

(CH-8); 144.02 and 144.42 (C-p-Tol); 150.68

(C-4); 152.37 (CH-2); 158.37 (C-6); 165.83 and 166.05

(CO).

0

0 0

J_gem= 12.3, J_{5 a;4}¼ 3:2, H-5⁰a); 6.25 (t, 2H,

0

J_{3 ;2}¼ 5:7, J_{3 ;4}¼ 4:9, H-3⁰); 6.38 (t, 2H, J_{2 ;3}¼ 5:7,

0

J_{2 ;1}¼ 5:2, H-2⁰); 6.48 (d, 2H, J_{1 ;2}¼ 5:2, H-1⁰);

7.14, 7.21 and 7.23 (3· m, 3· 4H, H-m-Tol); 7.81,

7.90 and 7.97 (3· m, 3· 4H, H-o-Tol); 8.14 (s, 2H,

H-8); 8.87 (s, 2H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 21.69 (CH₃-Tol); 42.91 (CH₃N); 57.17

(CH₂N); 63.45 (CH₂-5⁰); 71.36 (CH-3⁰); 73.73 (CH-

2⁰); 80.88 (CH-4⁰); 86.84 (CH-1⁰); 125.68, 126.05 and

126.58 (C-i-Tol); 129.19, 129.23 and 129.29 (CH-m-

Tol); 129.78 and 129.87 (CH-o-Tol); 133.85 (C-5);

142.92 (CH-8); 144.16, 144.50 and 144.60 (C-p-Tol);

150.91 (C-4); 152.68 (CH-2); 158.61 (C-6); 165.18,

165.37 and 166.22 (CO).

0

4.11. 6-[(N-Benzylamino)methyl]-9-(2,3,5-tri-O-toluoyl-b-

D-ribofuranosyl)purine (5b)

Benzylamine hydrochloride (720 mg, 5 mmol) was

added to a solution of 6-formylpurine 3 (635 mg,

1 mmol) in ethanol (20 ml) and stirred at 55 ꢁC. After

30 minutes NaBH₃CN (20 mg, 0.27 mmol, 85% purity)

was added. Stepwise addition of NaBH₃CN (20 mg)

was repeated four times every next hour. After 6 h the

solvent was evaporated, the residue was dissolved in

1 M aq NaH₂PO₄(30 ml) and extracted with ethyl ace-

tate (4· 30 ml). Chromatography on silica gel (hex-

anes/AcOEt, 1:1–0:1) aﬀorded 510 mg (70%) of 5b as

yellowish foam which after 1 day turns brown to form

complex mixture of decomposition products. Exact

mass (FAB HR MS) found: 726.2937; calcd for

C₄₂H₄₀N₅O₇: 726.2928. FAB MS m/z (%): 726 (MH⁺,

4.9. 6-[(N-Acetyl-N-methylamino)methyl]-9-(2-deoxy-

3,5-di-O-toluoyl-b-^D-erythro-pentofuranosyl)purine (6aa)

Prepared by nucleophilic substitution of mesylate 8

(410 mg, 0.7 mmol) with MeNH₂/THF (7 ml,

c = 2 mol l^ꢀ1) in MeCN (10 ml) and subsequent acety-

lation. Yield: 90% as white foam. Exact mass (FAB

HR MS) found: 558.2336; calcd for C₃₀H₃₂N₅O₆:

558.2353. FAB MS m/z (%): 558 (MH⁺, 5); 353 (2);

119 (100). A mixture of cis/trans amides ꢁ1:0.7. ¹H

NMR (400 MHz, CDCl₃): 2.22 and 2.26 (2· s, 6H,

CH₃CO); 2.42 and 2.45 (2· s, 12H, CH₃-Tol); 2.85

(m, 2H, H-2⁰b); 3.03 and 3.14 (2· s, 6H, CH₃-N);

3.20 (m, 2H, H-2⁰a); 4.65–4.70 (m, 4H, H-5⁰b and

H-4⁰); 4.77 (m, 2H, H-5⁰a); 4.96 and 5.10 (2· s, 4H,

CH₂N); 5.83 (m, 2H, H-3⁰); 6.59 (m, 2H, H-1⁰); 7.24

and 7.29 (2· m, 8H, H-m-Tol); 7.91, 7.92 and 7.98

(3· m, 8H, H-o-Tol); 8.20 and 8.25 (2· s, 2H, H-8);

8.85 and 8.87 (2· s, 2H, H-2). ¹³C NMR

(100.6 MHz, CDCl₃): 21.65, 21.69 and 21.74 (CH₃CO

and CH₃-Tol); 34.47 and 37.44 (CH₃N), 37.71 and

37.75 (CH₂-2⁰); 49.12 and 51.69 (CH₂-pur); 63.90

and 63.99 (CH₂-5⁰); 74.96 and 75.07 (CH-3⁰); 83.08

and 83.15 (CH-4⁰); 84.81 and 84.99 (CH-1⁰); 126.32,

126.36, 126.63 and 126.66 (C-i-Tol); 129.28 (CH-m-

Tol); 129.65 and 129.81 (CH-o-Tol); 132.68 (C-5);

142.50 and 143.03 (CH-8); 144.18, 144.22, 144.55

and 144.61 (C-p-Tol); 150.76 and 150.98 (C-4);

152.45 and 152.62 (CH-2); 156.43 and 157.70 (C-6);

165.92 and 166.16 (CO); 171.61 (COCH₃). IR (CCl₄):

m = 3038, 1727, 1660, 1613, 1594, 1401, 1332, 1267,

1

0.5); 487 (4); 119 (100). H NMR (500 MHz, CDCl₃):

2.37, 2.41 and 2.42 (3· s, 3· 3H, CH₃-Tol); 3.88 (s,

2H, CH₂-Ph); 4.34 (s, 2H, CH₂-pur); 4.67 (dd, 1H,

J_gem= 12.2, J_{5 b;4}¼ 4:2, H-5⁰b); 4.82 (td, 1H,

0

J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:2, 3.2, H-4⁰); 4.89 (dd, 1H,

0

J_gem= 12.2, J_{5 a;4}¼ 3:2, H-5⁰a); 6.22 (dd, 1H,

0

J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:7, H-3⁰); 6.38 (t, 1H, J_{2 ;3}¼ 5:8,

0

J_{2 ;1}¼ 5:4, H-2⁰); 6.47 (d, 1H, J_{1 ;2}¼ 5:4, H-1⁰); 7.16

(m, 2H, H-m-Tol); 7.19–7.31 (m, 7H, 2· H-m-Tol + H-

m,p-Ph); 7.34 (m, 2H, H-o-Ph); 7.81, 7.91 and 7.99 (3·

m, 3· 2H, H-o-Tol); 8.18 (s, 1H, H-8); 8.83 (s, 1H, H-

2). ¹³C NMR (125.8 MHz, CDCl₃): 21.69 and 21.73

(CH₃-Tol); 49.33 (CH₂-pur); 53.64 (CH₂-Ph); 63.44

(CH₂-5⁰); 71.42 (CH-3⁰); 73.73 (CH-2⁰); 81.02 (CH-4⁰);

86.88 (CH-1⁰); 125.67, 126.05 and 126.60 (C-i-Tol);

126.98 (CH-p-Ph); 128.31 and 128.34 (CH-o,m-Ph);

129.23, 129.26 and 129.33 (CH-m-Tol); 129.79, 129.88

and 129.89 (CH-o-Tol); 132.75 (C-5); 139.87 (C-i-Ph);

142.68 (CH-8); 144.22, 144.57 and 144.69 (C-p-Tol);

0

1178, 1100, 646 cm^ꢀ1

.

ˇ

´

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2338

150.67 (C-4); 152.72 (CH-2); 160.34 (C-6); 165.17,

165.38 and 166.20 (CO).

(100.6 MHz, CDCl₃): 21.54, 21.69 and 21.75 (CH₃CO

and CH₃-Tol); 37.73 and 37.78 (CH₂-2⁰); 46.98 and

48.46 (CH₂-pur); 49.06 and 53.28 (CH₂Ph); 63.90 and

64.01 (CH₂-5⁰); 74.94 and 75.08 (CH-3⁰); 83.07 and

83.12 (CH-4⁰); 84.80 and 84.95 (CH-1⁰); 126.33,

126.36, 126,63 and 126.66 (C-i-Tol); 126.58 (CH-o-Ph);

127.24 and 127.63 (CH-p-Ph); 128.33 (CH-o-Ph);

128.48 and 128.87 (CH-m-Ph); 129.29 (CH-m-Tol);

129.65 and 129.81 (CH-o-Tol); 132.63 and 132.75 (C-

5); 136.62 and 137.33 (C-i-Ph); 142.39 and 142.86

(CH-8); 144.19, 144.24, 144.55 and 144.61 (C-p-Tol);

150.70 and 150.84 (C-4); 152.43 and 152.54 (CH-2);

156.70 and 157.78 (C-6); 165.92 and 166.13 (CO);

171.64 and 171.82 (COCH₃). IR (CCl₄): m = 3034,

1726, 1658, 1613, 1594, 1407, 1331, 1267, 1178, 1100,

4.12. 6-[(N-Acetyl-N-benzylamino)methyl]-9-(2,3,5-tri-O-

toluoyl-b-^D-ribofuranosyl)purine (5ba)

Prepared by nucleophilic substitution of mesylate 7 with

BnNH₂(15 equiv) and subsequent acetylation. Yield:

87% as white foam. Exact mass (FAB HR MS) found:

768.3041; calcd for C₄₄H₄₂N₅O₈: 768.3033. FAB MS

m/z (%): 790 (M+Na⁺, 10); 768 (MH⁺, 1); 487 (10);

119 (100); 91 (26). A mixture of cis/trans amides ꢁ1:1.

¹H NMR (500 MHz, CDCl₃): 2.26 and 2.31 (2· s, 2·

3H, CH₃CO); 2.377, 2.382, 2.413, 2.417 and 2.424 (5·

s, 18H, CH₃-Tol); 4.66 and 4.67 (2· dd, 2· 1H,

J_gem= 12.3, J_{5 b;4}¼ 4:4, H-5⁰b); 4.72 and 4.73 (2· s,

2· 2H, CH₂Ph); 4.81 and 4.83 (2· td, 2· 1H,

646 cm^ꢀ1

.

0

J_{4 ;3}¼ 4:5, J_{4 ;5}¼ 4:4, 3.2, H-4⁰); 4.88 (dd, 1H,

4.14. 6-[(N-Cyclohexylamino)methyl]-9-(2,3,5-tri-O-tolu-

oyl-b-^D-ribofuranosyl)purine (5c)

0

J_gem= 12.3, J_{5 a;4}¼ 3:2, H-5⁰a); 4.87 (s, 2H, CH₂N);

0

4.90 (dd, 1H, J_gem= 12.3, J_{5 a;4}¼ 3:2, H-5⁰a); 5.05 and

0

5.09 (2· d, 2H, J_gem= 16.9, CH₂N); 6.19 and 6.21 (2·

Cyclohexylamine hydrochloride (680 mg, 5 mmol) was

added to a solution of 6-formylpurine 3 (635 mg,

1 mmol) in ethanol (20 ml) and stirred at 55 ꢁC. Step-

wise addition of NaBH₃CN was accomplished analo-

gously as before (see 5b). Chromatography on silica

gel (hexanes/AcOEt, 1:1–0:1) aﬀorded 310 mg (43%) of

5c and 130 mg (21%) of alcohol 1. Product was unstable

and after few days turns brown and decomposition

products were formed. Exact mass (FAB HR MS)

found: 718.3252; calcd for C₄₁H₄₄N₅O₇: 718.3241.

FAB MS m/z (%): 718 (MH⁺, 7); 487 (6); 119 (100).

¹H NMR (500 MHz, CDCl₃): 1.12–1.30, 1.59, 1.73 and

1.97 (4· m, 10H, CH₂-cyclohex); 2.38 and 2.42 (2· s,

9H, CH₃-Tol); 2.50 (m, 1H, CH-cyclohex); 4.34 and

4.38 (2· d, 2H, J_gem= 15.5, CH₂N); 4.67 (dd, 1H,

dd, 2· 1H, J_{3 ;2}¼ 5:7, J_{3 ;4}¼ 4:5, H-3⁰); 6.36 (t, 1H,

0

J_{2 ;3}¼ 5:7, J_{2 ;1}¼ 5:6, H-2⁰); 6.37 (t, 1H, J_{2 ;3}¼ 5:7,

0

J_{2 ;1}¼ 5:3, H-2⁰); 6.45 (d, 1H, J_{1 ;2}¼ 5:3, H-1⁰); 6.47

0

(d, 1H, J_{1 ;2}¼ 5:6, H-1⁰); 7.15–7.30 (m, 18H, H-o,p-Ph

and H-m-Tol); 7.31–7.36 (m, 4H, H-m-Ph); 7.82, 7.90,

7.91 and 8.00 (4· m, 12H, H-o-Tol); 8.16 and 8.20 (2·

s, 2· 1H, H-8); 8.80 and 8.81 (2· s, 2· 1H, H-2). ¹³C

NMR (125.7 MHz, CDCl₃): 21.51, 21.70, 21.72 and

22.05 (CH₃CO and CH₃-Tol); 46.82 and 48.49

(CH₂N); 49.08 and 53.11 (CH₂Ph); 63.36 and 63.52

(CH₂-5⁰); 71.27 and 71.40 (CH-3⁰); 73.59 and 73.63

(CH-2⁰); 80.94 and 80.98 (CH-4⁰); 86.65 and 87.01

(CH-1⁰); 125.56, 125.61, 125.93, 125.98, 126.53 and

126.56 (C-i-Tol); 126.57 (CH-o-Ph); 127.25 and 127.61

(CH-p-Ph); 128.30 (CH-o-Ph); 128.46 and 128.84 (CH-

m-Ph); 129.20, 129.24, 129.25, 129.26 and 129.32 (CH-

m-Tol); 129.77, 129.84 and 129.87 (CH-o-Tol); 132.61

and 132.67 (C-5); 136.51 and 137.22 (C-i-Ph); 142.82

and 143.26 (CH-8); 144.21, 144.29, 144.55, 144.62,

144.66 and 144.79 (C-p-Tol); 150.89 and 150.94 (C-4);

152.65 and 152.75 (CH-2); 156.77 and 157.85 (C-6);

165.14, 165.18, 165.37, 166.18 and 166.20 (CO-Tol);

171.73 and 171.83 (COCH₃).

0

J_gem= 12.2, J_{5 b;4}¼ 4:2, H-5⁰b); 4.81 (td, 1H,

0

J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:2, 3.2, H-4⁰); 4.89 (dd, 1H,

0

J_gem= 12.2, J_{5 a;4}¼ 3:2, H-5⁰a); 6.21 (dd, 1H,

0

J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:7, H-3⁰); 6.37 (t, 1H, J_{2 ;3}¼ 5:8,

0

J_{2 ;1}¼ 5:4, H-2⁰); 6.48 (d, 1H, J_{1 ;2}¼ 5:4, H-1⁰); 7.16,

7.22 and 7.25 (3· m, 3· 2H, H-m-Tol); 7.81, 7.90 and

7.99 (3· m, 3· 2H, H-o-Tol); 8.18 (s, 1H, H-8); 8.82

(s, 1H, H-2). ¹³C NMR (125.8 MHz, CDCl₃): 21.69

and 21.72 (CH₃-Tol); 24.90, 26.10 and 33.30 (CH₂-

cyclohex); 47.47 (CH₂N); 56.47 (CH-cyclohex); 63.45

(CH₂-5⁰); 71.42 (CH-3⁰); 73.74 (CH-2⁰); 81.01 (CH-4⁰);

86.87 (CH-1⁰); 125.67, 126.05 and 126.61 (C-i-Tol);

129.22, 129.26 and 129.33 (CH-m-Tol); 129.79, 129.88

and 129.89 (CH-o-Tol); 132.69 (C-5); 142.63 (CH-8);

144.21, 144.56 and 144.68 (C-p-Tol); 150.62 (C-4);

152.73 (CH-2); 160.66 (C-6); 165.16, 165.38 and 166.20

(CO). IR (CCl₄): m = 3328, 2929, 2855, 1732, 1613,

0

4.13. 6-[(N-Acetyl-N-benzylamino)methyl]-9-(2-deoxy-

3,5-di-O-toluoyl-b-^D-erythro-pentofuranosyl)purine (6ba)

Prepared by nucleophilic substitution of mesylate 8 with

BnNH₂(15 equiv) and subsequent acetylation. Yield:

92% as white foam. Exact mass (FAB HR MS) found:

634.2657; calcd for C₃₆H₃₆N₅O₆: 634.2666. FAB MS

m/z (%): 634 (MH⁺, 22); 353 (3); 282 (94); 119 (100);

1595, 1497, 1409, 1333, 1266, 1179, 1092, 645 cm^ꢀ1

.

1

91 (73). A mixture of cis/trans amides ꢁ1:1. H NMR

(400 MHz, CDCl₃): 2.27 and 2.33 (2· s, 6H, CH₃CO);

2.40 and 2.45 (2· s, 12H, CH₃-Tol); 2.85 (m, 2H, H-

2⁰b); 3.18 (m, 2H, H-2⁰a); 4.65–4.70 (m, 4H, H-5⁰b and

H-4⁰); 4.74 and 4.76 (2· s, 4H, CH₂Ph); 4.77 (m, 2H,

H-5⁰a); 4.88 and 5.07 (2 ·s, 4H, CH₂N); 5.83 (m, 2H,

H-3⁰); 6.58 (m, 2H, H-1⁰); 7.22–7.30 (m, 14H, H-o,p-

Ph and H-m-Tol); 7.32–7.36 (m, 4H, H-m-Ph); 7.92

and 7.98 (2· m, 8H, H-o-Tol); 8.18 and 8.22 (2· s,

2H, H-8); 8.85 and 8.86 (2· s, 2H, H-2). ¹³C NMR

4.15. 6-[(N-Acetyl-N-cyclohexylamino)methyl]-9-(2,3,5-

tri-O-toluoyl-b-^D-ribofuranosyl)purine (5ca)

A solution of mesylate 7 (575 mg, 0.8 mmol) in MeCN

(5 ml) was dropwise added to a solution of cyclohexyl-

amine (0.9 ml, 8 mmol) in MeCN (10 ml). After comple-

tion of the reaction (monitoring by TLC) the solvent

and excess of amine were evaporated in vacuo (45 ꢁC,

130 Pa for 3 h). The residue was dissolved in CH₂Cl₂

ˇ

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2339

(20 ml) and Et₃N (0.34 ml, 2.4 mmol) followed by AcCl

(0.12 ml, 1.6 mmol) were added. Reaction was quenched

after 8 h with 1 M aq NaH₂PO₄(30 ml) and extracted

with CHCl₃(4· 30 ml). Crude oily product was chro-

matographed on silica gel (hexanes/AcOEt, 1/1:1/5) to

gave 500 mg (82%) of 5ca as white foam. Exact mass

(FAB HR MS) found:760.3366; calcd for C₄₃H₄₆N₅O₈:

760.3346. FAB MS m/z (%): 782 (M+Na⁺, 10); 760

(MH⁺, 2); 487 (16); 273 (3); 119 (100). ¹H NMR

(500 MHz, CDCl₃): 0.8–1.43, 1.53–1.96 (2· m, 2· 10H,

CH₂-cyclohex); 2.14 and 2.27 (2· s, 2· 3H, CH₃CO);

2.37, 2.38, 2.41 and 2.42 (4· s, 18H, CH₃-Tol); 3.69–

3.80 (m, 2· 1H, CH-cyclohex); 4.67 (dd, 1H, J_gem= 12.1,

J_gem= 111.6, CH₂N); 5.03(s, 2H, CH₂N); 5.82 (dt, 1H,

J_{3 ;2}¼ 6:3, 1.9, J_{3 ;4}¼ 2:0, H-3⁰); 5.84 (dt, 1H,

0

J_{3 ;2}¼ 6:4, 2.3, J_{3 ;4}¼ 1:9, H-3⁰); 6.59 (dd, 1H,

0

J_{1 ;2}¼ 8:6, 5.7, H-1⁰); 6.60 (dd, 1H, J_{1 ;2}¼ 8:3, 5.8, H-

1⁰); 7.24, 7.28 and 7.29 (3· m, 8H, H-m-Tol); 7.93 and

7.98 (2· m, 8H, H-o-Tol); 8.18 and 8.24 (2· s, 2· 1H,

H-8); 8.82 and 8.85 (2· s, 2· 1H, H-2). ¹³C NMR

(125.7 MHz, CDCl₃): 21.70, 21.74, 21.80 and 22.77

(CH₃CO and CH₃-Tol); 25.26, 25.50, 25.70, 25.87,

30.61, 31.64 and 31.68 (CH₂-cyclohex); 37.70 and

37.78 (CH₂-2⁰); 42.65 and 44.85 (CH₂N); 53.20 and

58.27 (CH-cyclohex); 63.90 and 64.05 (CH₂-5⁰); 74.93

and 75.11 (CH-3⁰); 83.03 and 83.08 (CH-4⁰); 84.70 and

84.88 (CH-1⁰); 126.30, 126.36, 126.63 and 126.66 (C-i-

Tol); 129.28 and 129.31 (CH-m-Tol); 129.66 and

129.81 (CH-o-Tol); 131.90 and 132.06 (C-5); 141.95

and 142.63 (CH-8); 144.19, 144.24, 144.53 and 144.62

(C-p-Tol); 150.48 and 150.60 (C-4); 152.35 and 152.54

(CH-2); 158.37 and 159.29 (C-6); 165.94, 166.15 and

166.20 (CO-Tol); 170.90 and 171.65 (COCH₃). IR

(CCl₄): m = 2936, 2859, 1721, 1631, 1612, 1593, 1407,

0

J_{5 b;4}¼ 4:2, H-5⁰b); 4.68 (dd, 1H, J_gem= 12.3,

0

J_{5 b;4}¼ 4:2, H-5⁰b); 4.80 (td, 1H, J_{4 ;3}¼ 4:4, J_{4 ;5}¼ 4:2,

0

3.1, H-4⁰); 4.83 (ddd, 1H, J_{4 ;3}¼ 5:0, J_{4 ;5}¼ 4:2, 3.1, H-

0

4⁰); 4.87 (dd, 1H, J_gem= 12.1, J_{5 a;4}¼ 3:1, H-5⁰a); 4.90

0

(dd, 1H, J_gem= 12.3, J_{5 a;4}¼ 3:1, H-5⁰a); 4.97 and 5.04

0

(2· s, 2· 2H, CH₂N); 6.19 (dd, 1H, J_{3 ;2}¼ 5:7,

J_{3 ;4}¼ 4:4, H-3⁰); 6.23 (dd, 1H, J_{3 ;2}¼ 5:7, J_{3 ;4}¼ 5:0,

0

H-3⁰); 6.35 (t, 1H, J_{2 ;3}¼ 5:7, J_{2 ;1}¼ 5:6, H-2⁰); 6.37 (t,

0

1H, J_{2 ;3}¼ 5:7, J_{2 ;1}¼ 5:1, H-2⁰); 6.46 (d, 1H,

1334, 1269, 1179, 1102, 646 cm^ꢀ1

.

0

J_{1 ;2}¼ 5:6, H-1⁰); 6.49 (d, 1H, J_{1 ;2}¼ 5:1, H-1⁰); 7.16,

7.17, 7.20, 7.22, 7.26 and 7.27 (6· m, 6· 2H, H-m-Tol);

7.81, 7.82, 7.89, 7.91, 8.00 and 8.01 (6· m, 6· 2H, H-o-

Tol); 8.16 and 8.21 (2· s, 2· 1H, H-8); 8.79 and 8.80 (2·

s, 2· 1H, H-2). ¹³C NMR (125.8 MHz, CDCl₃): 21.71,

21.81 and 22.77 (CH₃CO and CH₃-Tol); 24.86, 25.25,

25.51, 25.69, 25.87, 30.61, 31.65 and 33.23 (CH₂-cyclo-

hex); 42.65 and 44.84 (CH₂N); 58.27 (CH-cyclohex);

63.34 and 63.63 (CH₂-5⁰); 71.24 and 71.46 (CH-3⁰);

73.64 and 73.74 (CH-2⁰); 80.90 and 81.01 (CH-4⁰); 86.51

and 87.12 (CH-1⁰); 25.58, 125.65, 125.94, 126.02 and

126.58 (C-i-Tol); 129.20, 129.23, 129.26, 129.27, 129.32

and 129.35 (CH-m-Tol); 129.80, 129.86 and 129.89

(CH-o-Tol); 131.88 and 132.05 (C-5); 142.33 and 143.05

(CH-8); 144.20, 144.30, 144.53, 144.63 and 144.81 (C-p-

Tol); 150.70 (C-4); 152.59 and 152.77 (CH-2); 158.49

and 159.44 (C-6); 165.23, 165.38 and 166.23 (CO-Tol);

170.90 and 171.68 (COCH₃). IR (CCl₄): m = 2933, 2857,

1732, 1653, 1613, 1592, 1499, 1409, 1334, 1266, 1179,

0

4.17. 6-[N-(Ethoxycarbonylmethyl)aminomethyl]-9-

(2,3,5-tri-O-toluoyl-b-^D-ribofuranosyl)purine (5d)

A solution of mesylate 7 (575 mg, 0.8 mmol) in MeCN

(10 ml) was added to a solution of glycine ethyl ester

hydrochloride (1.70 g, 12 mmol), ⁱPr₂NEt (0.7 ml,

4 mmol) in MeCN (20 ml). After aqueous work-up

and chromatography on silica gel (hexanes/AcOEt/

MeOH, 10:20:0.3–10:30:1) 475 mg (82%) of 5d was iso-

lated as yellowish foam. Exact mass (FAB HR MS)

found: 722.2822; calcd for C₃₉H₄₀N₅O₉: 722.2826.

FAB MS m/z (%): 722 (MH⁺, 1); 487 (6); 119 (100).

¹H NMR (500 MHz, CDCl₃): 1.26 (t, 3H, J_vic= 7.1,

CH₃CH₂O); 2.38, and 2.43 (2· s, 9H, CH₃-Tol); 3.53

(s, 2H, NCH₂CO); 4.18 (q, 2H, J_vic= 7.1, CH₃CH₂O);

4.38 (s, 2H, pur-CH₂N); 4.66 (dd, 1H, J_gem= 12.4,

J_{5 b;4}¼ 4:1, H-5⁰b); 4.83 (td, 1H, J_{4 ;3}¼ 4:6,

0

J_{4 ;5}¼ 4:1, 3.1, H-4⁰); 4.91 (dd, 1H, J_gem= 12.4,

0

1092, 645 cm^ꢀ1

.

J_{5 a;4}¼ 3:1, H-5⁰a); 6.23 (dd, 1H, J_{3 ;2}¼ 5:8,

0

J_{3 ;4}¼ 4:6, H-3⁰); 6.39 (t, 1H, J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:5,

0

H-2⁰); 6.49 (d, 1H, J_{1 ;2}¼ 5:5, H-1⁰); 7.17, 7.23 and

7.27 (3· m, 3· 2H, H-m-Tol); 7.81, 7.91 and 8.01 (3·

m, 3· 2H, H-o-Tol); 8.20 (s, 1H, H-8); 8.83 (s, 1H, H-

2). ¹³C NMR (125.8 MHz, CDCl₃): 14.19 (CH₃CH₂O);

21.74 and 21.78 (CH₃-Tol); 49.74 (pur-CH₂N); 50.43

(NCH2CO); 60.81 (CH₃CH₂O); 63.38 (CH₂-5⁰); 71.28

(CH-3⁰); 73.54 (CH-2⁰); 80.91 (CH-4⁰); 86.68 (CH-1⁰);

125.44, 125.83 and 126.40 (C-i-Tol); 129.21, 129.26

and 129.34 (CH-m-Tol); 129.73 and 129.82 (CH-o-

Tol); 132.58 (C-5); 142.84 (CH-8); 144.28, 144.62 and

144.72 (C-p-Tol); 150.61 (C-4); 152.71 (CH-2); 159.42

(C-6); 165.15, 165.38 and 166.20 (CO-Tol); 172.00

(CO-Et). IR (CCl₄): m = 3345, 1734, 1612, 1597, 1498,

0

4.16. 6-[(N-Acetyl-N-cyclohexylamino)methyl]-9-(2-

deoxy-3,5-di-O-toluoyl-b-^D-erythro-pentofurano-

syl)purine (6ca)

Prepared by nucleophilic substitution of mesylate 8 with

CyNH₂(15 equiv) and subsequent acetylation. Yield:

92% as white foam. Exact mass (FAB HR MS) found:

626.2969; calcd for C₃₅H₄₀N₅O₆: 626.2979. FAB MS

m/z (%): 626 (MH⁺, 2); 274 (78); 119 (100). A mixture

1

of cis/trans amides ꢁ7:5. H NMR (500 MHz, CDCl₃):

0.80–1.43, 1.53–1.93 (2· m, 20H, CH₂-cyclohex); 2.14

and 2.27 (2· s, 2· 3H, CH₃CO); 2.41, 2.42, 2.44 and

2.45 (4· s, 18H, CH₃-Tol); 2.82 (ddd, J_gem= 14.1,

J_{2 b;1}¼ 5:7, J_{2 b;3}¼ 1:9, H-2⁰b); 2.85 (ddd, J_gem= 14.2,

1409, 1334, 1266, 1194, 1180, 1092, 644 cm^ꢀ1

.

0

J_{2 b;1}¼ 5:8, J_{2 b;3}¼ 2:3, H-2⁰b); 3.14 (ddd, J_gem= 14.1,

0

J_{2 a;1}¼ 8:6, J_{2 a;3}¼ 6:3, H-2⁰a); 3.14 (ddd, J_gem= 14.2,

4.18. 6-[(N,N-Dimethylamino)methyl]-9-(2,3,5-tri-O-tol-

uoyl-b-^D-ribofuranosyl)purine (5e)

0

J_{2 a;1}¼ 8:3, J_{2 a;3}¼ 6:4, H-2⁰a); 3.74 (tt, 1H, J_vic= 11.3,

3.5, CH-cyclohex); 4.58 (tt, 1H, J_vic= 12.1, 3.5, CH-

cyclohex); 4.62–4.71 (m, 4H, H-4⁰and H-5⁰b); 4.74–

4.80 (m, 2H, H-5⁰a); 4.95 and 4.98 (2· d, 2H,

0

A solution of mesylate 7 (550 mg, 0.77 mmol) in MeCN

(10 ml) was added to a solution of Me₂NH/THF

ˇ

´

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2340

(1.54 ml, c = 2 mol/l, 3.08 mmol) in MeCN (10 ml).

After aqueous work-up and chromatography on silica

gel (hexanes/AcOEt/MeOH, 10:20:0.3–10:30:1) 405 mg

(79%) of 5e was isolated as white foam. Exact mass

(FAB HR MS) found: 664.2764; calcd for

C₃₇H₃₈N₅O₇: 664.2771. FAB MS m/z (%): 664 (MH⁺,

mass (FAB HR MS) found: 720.3422; calcd for

C₄₁H₄₆N₅O₇: 720.3397. FAB MS m/z (%): 720 (MH⁺,

21); 487 (8); 119 (100). H NMR (400 MHz, CDCl₃):

1

1.08 (d, 12H, J_vic= 6.5, (CH₃)₂CH); 2.38 and 2.42 (2·

s, 9H, CH₃-Tol); 3.21 (h, 2H, J_vic= 6.5, CH(CH₃)₂);

4.17 and 4.21 (2· d, 2H, J_gem= 16.0, CH₂N); 4.67 (dd,

1

1H, J_gem= 12.2, J_{5 b;4}¼ 4:1, H-5⁰b); 4.82 (td, 1H,

0

7); 487 (16); 178 (5); 119 (100). H NMR (400 MHz,

CDCl₃): 2.38 (s, 3H, CH₃-Tol); 2.40 (s, 6H, CH₃N);

2.42 (s, 6H, CH₃-Tol); 4.04 (s, 2H, CH₂N); 4.67 (dd,

J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:1, 3.1, H-4⁰); 4.89 (dd, 1H,

0

J_gem= 12.2, J_{5 a;4}¼ 3:1, H-5⁰a); 6.24 (dd, 1H,

0

1H, J_gem= 12.2, J_{5 b;4}¼ 4:1, H-5⁰b); 4.82 (td, 1H,

J_{3 ;2}¼ 5:7, J_{3 ;4}¼ 4:7, H-3⁰); 6.39 (t, 1H, J_{2 ;3}¼ 5:7,

0

J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:1, 3.1, H-4⁰); 4.90 (dd, 1H,

J_{2 ;1}¼ 5:4, H-2⁰); 6.47 (d, 1H, J_{1 ;2}¼ 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); 8.17 (s, 1H,

H-8); 8.87 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 20.66 and 20.71 ((CH₃)₂CH); 21.70 and

21.73 (CH₃-Tol); 46.34 (CH₂N); 49.88 (CH(CH₃)₂);

63.46 (CH₂-5⁰); 71.34 (CH-3⁰); 73.69 (CH-2⁰); 80.90

(CH-4⁰); 86.83 (CH-1⁰); 125.70, 126.05 and 126.61

(C-i-Tol); 129.22, 129.24 and 129.33 (CH-m-Tol);

129.80 and 129.88 (CH-o-Tol); 132.89 (C-5); 142.29

(CH-8); 144.18, 144.53 and 144.66 (C-p-Tol); 150.50

(C-4); 153.03 (CH-2); 163.34 (C-6); 165.18, 165.38

and 166.23 (CO). IR (CCl₄): m = 2965, 1732, 1613,

1592, 1497, 1409, 1380, 1332, 1266, 1179, 1092,

0

J_gem= 12.2, J_{5 a;4}¼ 3:1, H-5⁰a); 6.23 (dd, 1H,

0

J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:7, H-3⁰); 6.40 (t, 1H, J_{2 ;3}¼ 5:8,

0

J_{2 ;1}¼ 5:4, H-2⁰); 6.48 (d, 1H, J_{1 ;2}¼ 5:4, H-1⁰); 7.16,

7.22 and 7.26 (3· m, 3· 2H, H-m-Tol); 7.81, 7.91 and

8.00 (3· m, 3· 2H, H-o-Tol); 8.21 (s, 1H, H-8); 8.86

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

and 21.73 (CH₃-Tol); 45.87 (CH₃N); 59.84 (CH₂N);

63.39 (CH₂-5⁰); 71.36 (CH-3⁰); 73.64 (CH-2⁰); 80.99

(CH-4⁰); 86.84 (CH-1⁰); 125.64, 126.02 and 126.58 (C-

i-Tol); 129.22, 129.25 and 129.33 (CH-m-Tol); 129.78

and 129.87 (CH-o-Tol); 133.62 (C-5); 143.02 (CH-8);

144.22, 144.57 and 144.69 (C-p-Tol); 150.96 (C-4);

152.81 (CH-2); 158.76 (C-6); 165.17, 165.38 and 166.20

(CO). IR (CCl₄): m = 3039, 1732, 1612, 1594, 1498,

0

644 cm^ꢀ1

.

1409, 1332, 1266, 1179, 1092, 644 cm^ꢀ1

.

4.21. 6-[(N,N-Diisopropylamino)methyl]-9-(2-deoxy-3,5-

di-O-toluoyl-b-^D-erythro-pentofuranosyl)purine (6f)

4.19. 6-[(N,N-Dimethylamino)methyl]-9-(2-deoxy-3,5-di-

O-toluoyl-b-^D-erythro-pentofuranosyl)purine (6e)

Prepared from mesylate 8 by procedure described above

(see 5f). Yield: 86% of white foam. Exact mass (FAB

HR MS) found: 586.3036; calcd for C₃₃H₄₀N₅O₅:

586.3029. FAB MS m/z (%): 586 (MH⁺, 26); 353 (2);

234 (26); 190 (25); 148 (15); 134 (25); 119 (100); 100

(16). ¹H NMR (400 MHz, CDCl₃): 1.09 (d, 12H,

J_vic= 6.6, (CH₃)₂CH); 2.41 and 2.45 (2· s, 9H, CH₃-

Prepared from mesylate 8 by procedure described above

(see 5e). Yield: 85% of white crystals (mp 119–120 ꢁC).

Exact mass (FAB HR MS) found: 530.2382; calcd for

C₂₉H₃₂N₅O₅: 530.2403. FAB MS m/z (%): 530 (MH⁺,

18); 353 (2); 178 (64); 134 (19); 119 (100). H NMR

(400 MHz, CDCl₃): 2.41 and 2.45 (2· s, 2· 3H, CH₃-

Tol); 2.47 (s, 6H, (CH₃)₂N); 2.85 (ddd, 1H, J_gem= 14.3,

1

0

Tol); 2.84 (ddd, 1H, J_gem= 14.2, J_{2 b;1}¼ 5:8,

J_{2 b;1}¼ 5:7, J_{2 b;3}¼ 2:1, H-2⁰b); 3.21 (ddd, 1H,

J_{2 b;3}¼ 2:1, H-2⁰b); 3.21 (ddd, 1H, J_gem= 14.2,

0

J_gem= 14.3, J_{2 a;1}¼ 8:5, J_{2 a;3}¼ 6:4, H-2⁰a); 4.12 (s,

J_{2 a;1}¼ 8:5, J_{2 a;3}¼ 6:3, H-2⁰a); 3.23 (h, 2H, J_vic= 6.6,

CH(CH₃)₂); 4.17 and 4.22 (2· d, 2H, J_gem= 15.9,

CH₂N); 4.63–4.70 (m, 2H, H-5⁰b and H-4⁰); 4.77 (dd,

0

2H, CH₂N); 4.64–4.70 (m, 2H, H-5⁰b and H-4⁰); 4.78

(dd, 1H, J_gem= 13.3, J_{5 a;4}¼ 5:2, H-5⁰a); 5.84 (dt, 1H,

0

J_{3 ;2}¼ 6:4, 2.1, J_{3 ;4}¼ 2:0, H-3⁰); 6.61 (dd, 1H,

1H, J_gem= 11.5, J_{5 a;4}¼ 3:5, H-5⁰a); 5.84 (dt, 1H,

0

J_{1 2}¼ 8:5, 5.7, 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); 8.24 (s,

1H, H-8); 8.91 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 21.68 and 21.74 (CH₃-Tol); 37.74 (CH₂-2⁰);

45.48 ((CH₃)₂N and CH₂N); 63.91 (CH₂-5⁰); 75.03

(CH-3⁰); 83.12 (CH-4⁰); 84.85 (CH-1⁰); 126.34 and

126.63 (C-i-Tol); 129.29 (CH-m-Tol); 129.64 and

129.81 (CH-o-Tol); 133.76 (C-5); 142.85 (CH-8);

144.21 and 144.59 (C-p-Tol); 150.90 (C-4); 152.54

(CH-2); 157.25 (C-6); 165.94 and 166.14 (CO). IR

(CHCl₃): m = 2827, 2779, 1721, 1612, 1597, 1495, 1407,

J_{3 ;2}¼ 6:4, 2.1, J_{3 ;4}¼ 2:2, H-3⁰); 6.60 (dd, 1H,

0

J_{1 2}¼ 8:5, 5.8, H-1⁰); 7.23 and 7.29 (2· m, 2· 2H, H-

m-Tol); 7.92 and 7.98 (2· m, 2· 2H, H-o-Tol); 8.20 (s,

1H, H-8); 8.91 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 20.64 and 20.70 ((CH₃)₂CH); 21.68 and 21.73

(CH₃-Tol); 37.70 (CH₂-2⁰); 46.26 (CH₂N); 49.93

(CH(CH₃)₂); 63.98 (CH₂-5⁰); 75.07 (CH-3⁰); 83.01

(CH-4⁰); 84.76 (CH-1⁰); 126.39 and 126.68 (C-i-Tol);

129.28 (CH-m-Tol); 129.66 and 129.81 (CH-o-Tol);

132.89 (C-5); 141.89 (CH-8); 144.14 and 144.54 (C-p-

Tol); 150.36 (C-4); 152.78 (CH-2); 163.09 (C-6); 165.94

and 166.17 (CO). IR (CCl₄): m = 2965, 1727, 1613,

1592, 1495, 1407, 1383, 1330, 1267, 1179, 1101,

0

1332, 1269, 1179, 1102, 646 cm^ꢀ1

.

4.20. 6-[(N,N-Diisopropylamino)methyl]-9-(2,3,5-tri-O-

toluoyl-b-^D-ribofuranosyl)purine (5f)

646 cm^ꢀ1

.

4.22. 6-[(N-Benzyl-N-methylamino)methyl]-9-(2,3,5-tri-

O-toluoyl-b-^D-ribofuranosyl)purine (5g)

ⁱPr₂NH (0.5 ml, 3.5 mmol) was added to a solution of

mesylate 7 (575 mg, 0.8 mmol) in MeCN (10 ml) and

stirred at 55 ꢁC for 36 h. After aqueous work-up and

chromatography on silica gel (hexanes/AcOEt, 1:1–1:4)

450 mg (78%) of 5f was isolated as white foam. Exact

N-Benzylmethylamine (0.36 ml, 2.8 mmol) was added to

a solution of mesylate 7 (500 mg, 0.7 mmol) in MeCN

(20 ml). After aqueous work-up and chromatography

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P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2341

on silica gel (hexanes/AcOEt, 2:1–1:2) 420 mg (81%) of

4.24. 6-[(N-Methyl-N-phenylamino)methyl]-9-(2-deoxy-

3,5-di-O-toluoyl-b-^D-erythro-pentofuranosyl)purine (6 h)

5g was isolated as white foam. Exact mass (FAB HR

MS) found: 740.3072; calcd for C₄₃H₄₂N₅O₇: 740.3084.

FAB MS m/z (%): 740 (MH⁺, 3); 487 (7); 119 (100); 91

(22). ¹H NMR (400 MHz, CDCl₃): 2.34 (s, 3H,

CH₃N); 2.38, 2.41 and 2.42 (3· s, 3· 3H, CH₃-Tol);

3.71 (s, 2H, CH₂Ph); 4.13 (s, 2H, CH₂pur); 4.67 (dd,

Prepared from mesylate 8 by procedure described above

(see 5h). Yield: 60% of white foam. Exact mass (FAB

HR MS) found: 592.2551; calcd for C₃₄H₃₄N₅O₅:

592.2560. FAB MS m/z (%): 592 (MH⁺, 27); 353 (3);

240 (55); 134 (60); 119 (100). ¹H NMR (400 MHz,

CDCl₃): 2.41 and 2.44 (2· s, 2· 3H, CH₃-Tol); 2.84

1H, J_gem= 12.2, J_{5 b;4}¼ 4:1, H-5⁰b); 4.81 (td, 1H,

0

J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:1, 3.1, H-4⁰); 4.90 (dd, 1H,

0

J_gem= 12.2, J_{5 a;4}¼ 3:1, H-5⁰a); 6.23 (dd, 1H,

(ddd, 1H, J_gem= 14.2, J_{2 b;1}¼ 5:8, J_{2 b;3}¼ 2:6, H-2⁰b);

0

J_{3 ;2}¼ 5:7, J_{3 ;4}¼ 4:7, H-3⁰); 6.39 (t, 1H, J_{2 ;3}¼ 5:7,

3.19 (ddd, 1H, J_gem= 14.2, J_{2 a;1}¼ 8:4, J_{2 a;3}¼ 6:2, H-

2⁰a); 3.25 (s, 3H, CH₃N); 4.63–4.70 (m, 2H, H-5⁰b and

H-4⁰); 4.76 (m, 1H, H-5⁰a); 4.98 (s, 2H, CH₂N); 5.83

0

J_{2 ;1}¼ 5:4, H-2⁰); 6.47 (d, 1H, J_{1 ;2}¼ 5:4, H-1⁰); 7.16

(m, 2H, H-m-Tol); 7.20 (m, 1H, H-p-Ph); 7.22 and

7.23 (2· m, 2· 2H, H-m-Tol); 7.27 (m, 2H, H-m-Ph);

7.37 (m, 2H, H-o-Ph); 7.82, 7.90 and 8.00 (3· m, 3·

2H, H-o-Tol); 8.20 (s, 1H, H-8); 8.87 (s, 1H, H-2). ¹³C

NMR (100.6 MHz, CDCl₃): 21.69 and 21.73 (CH₃-

Tol); 42.80 (CH₃N); 57.70 (CH₂pur); 62.33 (CH₂Ph);

63.41 (CH₂-5⁰); 71.36 (CH-3⁰); 73.67 (CH-2⁰); 80.97

(CH-4⁰); 86.85 (CH-1⁰); 125.65, 126.02 and 126.58 (C-

i-Tol); 126.88 (CH-p-Ph); 127.02 (CH-m-Ph); 129.22,

129.25, 129.27 and 129.33 (CH-m-Tol); 129.79 and

129.87 (CH-o-Tol); 132.72 (C-5); 138.25 (C-i-Ph);

142.84 (CH-8); 144.21, 144.56 and 144.68 (C-p-Tol);

150.86 (C-4); 152.78 (CH-2); 159.26 (C-6); 165.17,

165.38 and 166.21 (CO). IR (CCl₄): m = 2790, 1732,

1612, 1593, 1496, 1454, 1409, 1331, 1266, 1179, 1092,

0

(dt, 1H, J_{3 ;2}¼ 6:2, 2.6, J_{3 ;4}¼ 2:1, H-3⁰); 6.59 (dd,

0

1H, J_{1 2}¼ 8:4, 5.8, H-1⁰); 6.68 (m, 1H, H-p-Ph); 6.89

(m, 2H, H-o-Ph); 7.18 (m, 2H, H-m-Ph); 7.22 and 7.28

(2· m, 2· 2H, H-m-Tol); 7.91 and 7.97 (2· m, 2· 2H,

H-o-Tol); 8.24 (s, 1H, H-8); 8.86 (s, 1H, H-2). ¹³C

NMR (100.6 MHz, CDCl₃): 21.69 and 21.74 (CH₃-

Tol); 37.73 (CH₂-2⁰); 39.95 (CH₃N); 54.14 (CH₂N);

63.97 (CH₂-5⁰); 75.05 (CH-3⁰); 83.08 (CH-4⁰); 84.88

(CH-1⁰); 112.62 (CH-o-Ph); 116.82 (CH-p-Ph); 126.37

and 126.66 (C-i-Tol); 129.05 (CH-m-Ph); 129.28 and

129.30 (CH-m-Tol); 129.66 and 129.82 (CH-o-Tol);

133.01 (C-5); 142.44 (CH-8); 144.17 and 144.56 (C-p-

Tol); 149.32 (C-i-Ph); 150.80 (C-4); 152.56 (CH-2);

159.48 (C-6); 165.94 and 166.17 (CO). IR (CCl₄):

m = 2822, 1727, 1613, 1592, 1507, 1406, 1331, 1267,

0

644 cm^ꢀ1

.

1178, 1100, 645 cm^ꢀ1

.

4.23. 6-[(N-Methyl-N-phenylamino)methyl]-9-(2,3,5-tri-

O-toluoyl-b-^D-ribofuranosyl)purine (5h)

4.25. 6-[(N-Acetyl-N-cyclopropylamino)methyl]-9-(2,3,5-

tri-O-toluoyl-b-^D-ribofuranosyl)purine (5i)

N-Methylaniline (0.35 ml, 3.2 mmol) was added to a

solution of mesylate 7 (575 mg, 0.8 mmol) in MeCN

(20 ml) under Ar atmosphere. After aqueous work-

up and chromatography on silica gel (hexanes/AcOEt,

2:1–1:2) 360 mg (62%) of 5h was isolated as white

foam. Exact mass (FAB HR MS) found: 726.2953;

calcd for C₄₂H₄₀N₅O₇: 726.2928. FAB MS m/z (%):

A solution of mesylate 7 (500 mg, 0.7 mmol) in MeCN

(10 ml) was dropwise added to a solution of cyclopro-

pylamine (0.5 ml, 7.2 mmol) in MeCN (10 ml). After

completion of the reaction (monitoring by TLC) the sol-

vent and excess of amine were evaporated in vacuo

(45 ꢁC, 130 Pa for 2 h). The residue was dissolved in

CH₂Cl₂(20 ml) and Et₃N (0.3 ml, 2.2 mmol) followed

by AcCl (0.1 ml, 1.4 mmol) were added. Reaction was

quenched after 8 h with 1 M aq NaH₂PO₄(30 ml) and

extracted with CHCl₃(4· 30 ml). Crude oily product

was chromatographed on silica gel (hexanes/AcOEt,

1:1–1:5) to give 472 mg (94%) of 5i as white foam. Exact

mass (FAB HR MS) found: 718.2884; calcd for

C₄₀H₄₀N₅O₈: 718.2877. FAB MS m/z (%): 718 (MH⁺,

1

726 (MH⁺, 1); 487 (8); 134 (6); 119 (100). H NMR

(400 MHz, CDCl₃): 2.37 and 2.41 (2· s, 9H, CH₃-

Tol); 3.23 (s, 3H, CH₃N); 4.67 (dd, 1H, J_gem= 12.2,

J_{5 b;4}¼ 4:2, H-5⁰b); 4.81 (td, 1H, J_{4 ;3}¼ 4:6,

0

J_{4 ;5}¼ 4:2, 3.1, H-4⁰); 4.87 (dd, 1H, J_gem= 12.2,

0

J_{5 a;4}¼ 3:1, H-5⁰a); 4.98 (s, 2H, CH₂N); 6.21 (dd,

0

1H, J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:6, H-3⁰); 6.38 (t, 1H,

0

J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:5, H-2⁰); 6.47 (d, 1H, J_{1 ;2}¼ 5:5,

H-1⁰); 6.68 (m, 1H, H-p-Ph); 6.88 (m, 2H, H-o-Ph);

7.16 (m, 2H, H-m-Tol); 7.18 (m, 2H, H-m-Ph); 7.23

and 7.24 (2· m, 2· 2H, H-m-Tol); 7.81, 7.90 and

7.99 (3· m, 3· 2H, H-o-Tol); 8.21 (s, 1H, H-8);

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

21.71 and 21.73 (CH₃-Tol); 39.87 (CH₃N); 54.19

(CH₂N); 63.47 (CH₂-5⁰); 71.36 (CH-3⁰); 73.66 (CH-

2⁰); 80.98 (CH-4⁰); 86.81 (CH-1⁰); 112.64 (CH-o-Ph);

116.85 (CH-p-Ph); 125.64, 126.01 and 126.58 (C-i-

Tol); 129.05 (CH-m-Ph); 129.22, 129.25 and 129.33

(CH-m-Tol); 129.79, 129.87 and 129.89 (CH-o-Tol);

132.98 (C-5); 142.82 (CH-8); 144.21, 144.57 and

144.68 (C-p-Tol); 149.36 (C-i-Ph); 150.96 (C-4);

152.82 (CH-2); 159.64 (C-6); 165.17, 165.38 and

166.22 (CO). IR (CCl₄): m = 2822, 1732, 1612, 1593,

0

1

0.5); 487 (2); 133 (92); 119 (100). H NMR (500 MHz,

CDCl₃): 0.80–0.90 (m, 4H, CH₂-cycloprop); 2.34 (s,

3H, CH₃CO); 2.38, 2.416 and 2.422 (3· s, 3· 3H,

CH₃-Tol); 2.95 (tt, 1H, J_vic= 6.9, 3.6, CH-cycloprop);

4.67 (dd, 1H, J_gem= 12.2, J_{5 b;4}¼ 4:3, H-5⁰b); 4.81 (td,

0

1H, J_{4 ;3}¼ 4:5, J_{4 ;5}¼ 4:3, 3.2, H-4⁰); 4.88 (dd, 1H,

0

J_gem= 12.2, J_{5 a;4}¼ 3:2, H-5⁰a); 5.09 (s, 2H, CH₂N);

0

6.19 (dd, 1H, J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:5, H-3⁰); 6.36 (t, 1H,

0

J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:5, H-2⁰); 6.48 (d, 1H, J_{1 ;2}¼ 5:5,

H-1⁰); 7.16, 7.21 and 7.26 (3· m, 3· 2H, H-m-Tol);

7.81, 7.89 and 8.00 (3· m, 3· 2H, H-o-Tol); 8.17 (s,

1H, H-8); 8.79 (s, 1H, H-2). ¹³C NMR (125.8 MHz,

CDCl₃): 9.37 and 9.41 (CH₂-cycloprop); 21.70 and

21.73 (CH₃-Tol); 22.55 (CH₃CO); 31.55 (CH-cyclo-

prop); 48.49 (CH₂N); 63.55 (CH₂-5⁰); 71.42 (CH-3⁰);

73.63 (CH-2⁰); 80.99 (CH-4⁰); 86.62 (CH-1⁰); 125.63,

0

1507, 1408, 1333, 1266, 1179, 1092, 644 cm^ꢀ1

.

ˇ

´

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2342

126.00 and 126.58 (C-i-Tol); 129.21, 129.24 and 129.34

(CH-m-Tol); 129.79, 129.86 and 129.89 (CH-o-Tol);

132.38 (C-5); 142.63 (CH-8); 144.21, 144.55 and 144.66

(C-p-Tol); 150.85 (C-4); 152.61 (CH-2); 158.57 (C-6);

165.15, 165.38 and 166.22 (CO-Tol); 174.47 (COCH₃).

IR (CCl₄): m = 3010, 1732, 1669, 1613, 1594, 1497,

81.04 (CH-4⁰); 87.28 (CH-1⁰); 125.59, 125.97 and

126.59 (C-i-Tol); 129.23, 129.25 and 129.31 (CH-m-

Tol); 129.80, 129.86 and 129.90 (CH-o-Tol); 132.70 (C-

5); 143.42 (CH-8); 144.21, 144.57 and 144.71 (C-p-

Tol); 150.98 (C-4); 152.53 (CH-2); 161.04 (C-6);

165.16, 165.35 and 166.21 (CO). IR (CCl₄): m = 3382,

1727, 1612, 1593, 1499, 1409, 1335, 1267, 1093,

1409, 1334, 1266, 1179, 1092, 645 cm^ꢀ1

.

646 cm^ꢀ1

.

4.26. 6-[(N-Acetyl-N-cyclopropylamino)methyl]-9-(2-

deoxy-3,5-di-O-toluoyl-b-^D-erythro-pentofurano-

syl)purine (6i)

4.28. 6-{[N,N-Bis(2-hydroxyethyl)amino]methyl}-9-(2-

deoxy-3,5-di-O-toluoyl-b-^D-erythro-pentofurano-

syl)purine (6j)

Prepared from mesylate 8 by procedure described above

(see 5i). Yield: 95% of white foam. Exact mass (FAB HR

MS) found: 584.2529; calcd for C₃₂H₃₄N₅O₆: 584.2509.

FAB MS m/z (%): 584 (MH⁺, 25); 353 (3); 232 (83);

190 (17); 133 (20); 119 (100). ¹H NMR (400 MHz,

CDCl₃): 0.73–0.93 (m, 4H, CH₂-cycloprop); 2.35 (s,

3H, CH₃CO); 2.41 and 2.45 (2· s, 2· 3H, CH₃-Tol);

Prepared from mesylate 8 by procedure described above

(see 5j). Yield: 78% of white foam. Exact mass (FAB HR

MS) found: 590.2598; calcd for C₃₁H₃₆N₅O₇: 590.2615.

FAB MS m/z (%): 590 (MH⁺, 12); 238 (44); 119 (100).

¹H NMR (400 MHz, CDCl₃): 2.41 and 2.45 (2· s, 2·

3H, CH₃-Tol); 2.83 (m, 4H, CH₂N); 2.85 (ddd, 1H,

2.83 (ddd, 1H, J_gem= 14.2, J_{2 b;1}¼ 5:8, J_{2 b;3}¼ 2:1, H-

J_gem= 14.4, J_{2 b;1}¼ 5:8, J_{2 b;3}¼ 2:0, H-2⁰b); 3.21 (ddd,

0

2⁰b); 2.98 (tt, 1H, J_vic= 6.9, 4.1, CH-cycloprop); 3.15

1H, J_gem= 14.4, J_{2 a;1}¼ 8:2, J_{2 a;3}¼ 6:5, H-2⁰a); 3.63

(m, 4H, CH₂O); 4.19 and 4.25 (2· d, 2H, J_gem= 16.0,

CH₂-pur); 4.64–4.70 (m, 2H, H-5⁰b and H-4⁰); 4.76 (m,

0

(ddd, 1H, J_gem= 14.2, J_{2 a;1}¼ 8:5, J_{2 a;3}¼ 6:4, H-2⁰a);

0

4.63–4.70 (m, 2H, H-5⁰b and H-4⁰); 4.76 (m, 1H, H-

5⁰a); 5.09 (s, 2H, CH₂N); 5.82 (dt, 1H, J_{3 ;2}¼ 6:4, 2.1,

1H, H-5⁰a); 5.83 (dt, 1H, J_{3 ;2}¼ 6:5, 2.0, J_{3 ;4}¼ 2:0,

0

J_{3 ;4}¼ 1:9, H-3⁰); 6.59 (dd, 1H, J_{1 ;2}¼ 8:5, 5.8, H-1⁰);

7.24 and 7.29 (2· m, 2· 2H, H-m-Tol); 7.91 and 7.98

(2· m, 2· 2H, H-o-Tol); 8.19 (s, 1H, H-8); 8.82 (s, 1H,

H-2). ¹³C NMR (100.6 MHz, CDCl₃): 9.39 and 9.41

(CH₂-cycloprop); 21.68 and 21.74 (CH₃-Tol); 22.54

(CH₃CO); 31.68 (CH-cycloprop); 37.78 (CH₂-2⁰); 48.61

(CH₂N); 64.02 (CH₂-5⁰); 75.09 (CH-3⁰); 83.06 (CH-4⁰);

84.77 (CH-1⁰); 126.37 and 126.67 (C-i-Tol); 129.29

(CH-m-Tol); 129.66 and 129.82 (CH-o-Tol); 133.36 (C-

5); 142.23 (CH-8); 144.19 and 144.55 (C-p-Tol); 150.64

(C-4); 152.37 (CH-2); 158.46 (C-6); 165.94 and 166.19

(CO-Tol); 174.47 (COCH₃). IR (CCl₄): m = 3010, 1726,

1668, 1613, 1594, 1390, 1333, 1267, 1178, 1101,

H-3⁰); 6.61 (dd, 1H, J_{1 2}¼ 8:2, 5.8, H-1⁰); 7.24 and

7.29 (2· m, 2· 2H, H-m-Tol); 7.91 and 7.98 (2· m, 2·

2H, H-o-Tol); 8.28 (s, 1H, H-8); 8.82 (s, 1H, H-2). ¹³C

NMR (100.6 MHz, CDCl₃): 21.69 and 21.75 (CH₃-

Tol); 37.63 (CH₂-2⁰); 57.39 (CH₂N); 57.75 (CH₂-pur);

59.41 (CH₂O); 63.88 (CH₂-5⁰); 74.96 (CH-3⁰); 83.21

(CH-4⁰); 85.13 (CH-1⁰); 126.33 and 126.63 (C-i-Tol);

129.29 (CH-m-Tol); 129.66 and 129.82 (CH-o-Tol);

132.68 (C-5); 142.94 (CH-8); 144.17 and 144.56 (C-p-

Tol); 150.84 (C-4); 152.29 (CH-2); 160.89 (C-6); 165.90

and 166.15 (CO). IR (CCl₄): m = 3382, 1721, 1612,

0

0 0

1593, 1407, 1334, 1269, 1179, 1102, 647 cm^ꢀ1

.

646 cm^ꢀ1

.

4.29. 6-[(2-Acetylhydrazinyl)methyl]-9-(2,3,5-tri-O-tolu-

oyl-b-^D-ribofuranosyl)purine (5k)

4.27. 6-{[N,N-Bis(2-hydroxyethyl)amino]methyl}-9-

(2,3,5-tri-O-toluoyl-b-^D-ribofuranosyl)purine (5j)

Acetylhydrazide (416 mg, 5.6 mmol) was added to a

solution of mesylate 7 (200 mg, 0.28 mmol) and ⁱPr₂NEt

(0.1 ml, 0.57 mmol) in MeCN (10 ml). After aqueous

work-up and chromatography on silica gel (AcOEt/

MeOH, 1:0–10:1) 125 mg (65%) of 5k was isolated as

white foam. Exact mass (FAB HR MS) found:

693.2686; calcd for C₃₇H₃₇N₆O₈: 693.2673. FAB MS

Diethanolamine (0.22 ml, 2.3 mmol) was added to a

solution of mesylate 7 (400 mg, 0.56 mmol) in MeCN

(10 ml). After aqueous work-up and chromatography

on silica gel (AcOEt/MeOH, 10:0.1–10:2) 290 mg

(72%) of 5j was isolated as white foam. Exact mass

(FAB HR MS) found: 724.2947; calcd for

C₃₉H₄₂N₅O₉: 724.2983. FAB MS m/z (%): 724 (MH⁺,

2); 487 (4); 237 (3); 119 (100). ¹H NMR (500 MHz,

CDCl₃): 2.38 and 2.42 (2· s, 9H, CH₃-Tol); 2.83 (m,

4H, CH₂N); 3.63 (m, 4H, CH₂O); 4.23 and 4.25 (2· d,

2H, J_gem= 16.1, CH₂pur); 4.68 (dd, 1H, J_gem= 12.2,

1

m/z (%): 693 (MH⁺, 2); 487 (14); 119 (100). H NMR

(500 MHz, CDCl₃): 1.94 (s, 3H, CH₃CO); 2.38, 2.417

and 2.422 (3· s, 3· 3H, CH₃-Tol); 4.53 (s, 2H, CH₂N);

4.67 (dd, 1H, J_gem= 12.3, J_{5 b;4}¼ 4:2, H-5⁰b); 4.83 (td,

0

1H, J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:2, 3.2, H-4⁰); 4.90 (dd, 1H,

0

J_gem= 12.3, J_{5 a;4}¼ 3:2, H-5⁰a); 5.37 (bs, 1H, NH);

0

J_{5 b;4}¼ 4:5, H-5⁰b); 4.82 (td, 1H, J_{4 ;3}¼ 4:9,

6.21 (dd, 1H, J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:7, H-3⁰); 6.38 (t, 1H,

0

J_{4 ;5}¼ 4:5, 3.3, H-4⁰); 4.88 (dd, 1H, J_gem= 12.2,

J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:4, H-2⁰); 6.48 (d, 1H, J_{1 ;2}¼ 5:4,

H-1⁰); 7.16, 7.22 and 7.25 (3· m, 3· 2H, H-m-Tol);

7.80, 7.91 and 7.99 (3· m, 3· 2H, H-o-Tol); 8.24 (s,

1H, H-8); 8.26 (bs, 1H, NH-CO); 8.82 (s, 1H, H-2).

¹³C NMR (125.7 MHz, CDCl₃): 21.29 (CH₃CO); 21.71

and 21.74 (CH₃-Tol); 53.91 (CH₂N); 63.38 (CH₂-5⁰);

71.35 (CH-3⁰); 73.69 (CH-2⁰); 81.03 (CH-4⁰); 86.96

(CH-1⁰); 125.55, 125.95 and 126.54 (C-i-Tol); 129.24,

129.28 and 129.33 (CH-m-Tol); 129.77 and 129.87

0

J_{5 a;4}¼ 3:3, H-5⁰a); 6.20 (dd, 1H, J_{3 ;2}¼ 5:8,

0

J_{3 ;4}¼ 4:9, H-3⁰); 6.38 (t, 1H, J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:3,

0

H-2⁰); 6.45 (d, 1H, J_{1 ;2}¼ 5:3, H-1⁰); 7.16, 7.21 and

7.26 (3· m, 3· 2H, H-m-Tol); 7.81, 7.90 and 7.99 (3·

m, 3· 2H, H-o-Tol); 8.27 (s, 1H, H-8); 8.78 (s, 1H, H-

2). ¹³C NMR (125.80 MHz, CDCl₃): 21.71 and 21.73

(CH₃-Tol); 57.39 (CH₂N); 57.60 (CH₂pur); 59.43

(CH₂O); 63.42 (CH₂-5⁰); 71.29 (CH-3⁰); 73.62 (CH-2⁰);

0

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P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2343

(CH-o-Tol); 132.25 (C-5); 143.10 (CH-8); 144.29, 144.63

and 144.77 (C-p-Tol); 151.04 (C-4); 152.55 (CH-2);

159.33 (C-6); 165.19, 165.39 and 166.18 (CO-Tol);

168.98 (CON).

(CCl₄): m = 2937, 1726, 1613, 1594, 1496, 1408, 1329,

1267, 1178, 1101, 646 cm^ꢀ1

.

4.32. 6-[(Morpholin-4-yl)methyl]-9-(2,3,5-tri-O-toluoyl-b-

D-ribofuranosyl)purine (5m)

4.30. 6-[(Piperidin-1-yl)methyl]-9-(2,3,5-tri-O-toluoyl-b-

D-ribofuranosyl)purine (5l)

Morpholine (0.2 ml, 2.24 mmol) was added to a solution

of mesylate 7 (400 mg, 0.56 mmol) in MeCN (10 ml).

After aqueous work-up and chromatography on silica

gel (hexanes/AcOEt, 1:1–0:1) 347 mg (88%) of 5m was

isolated as white foam. Exact mass (FAB HR MS)

found: 706.2850; calcd for C₃₉H₄₀N₅O₈: 706.2877.

FAB MS m/z (%): 706 (MH⁺, 3); 487 (7); 119 (100).

¹H NMR (400 MHz, CDCl₃): 2.38, and 2.42 (2· s, 9H,

CH₃-Tol); 2.62 (bt, 4H, J_vic= 4.5, CH₂N-morph); 3.75

(t, 4H, J_vic= 4.5, CH₂O-morph); 4.08 (s, 2H, CH₂N);

Piperidine (0.32 ml, 3.2 mmol) was added to a solution

of mesylate 7 (575 mg, 0.8 mmol) in MeCN (10 ml).

After aqueous work-up and chromatography on silica

gel (hexanes/AcOEt, 1:1–0:1) 500 mg (89%) of 5l was

isolated as white foam. Exact mass (FAB HR MS)

found: 704.3105; calcd for C₄₀H₄₂N₅O₇: 704.3084.

FAB MS m/z (%): 704 (MH⁺, 8); 487 (7); 119 (100).

¹H NMR (400 MHz, CDCl₃): 1.42 (bm, 2H, CH₂-pip);

1.61 (p, 4H, J_vic= 5.9, CH₂-pip); 2.38 and 2.42 (2· s,

9H, CH₃-Tol); 2.55 (bm, 4H, CH₂N-pip); 4.05 (s, 2H,

4.66 (dd, 1H, J_gem= 12.3, J_{5 b;4}¼ 4:2, H-5⁰b); 4.82 (td,

0

1H, J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:2, 3.1, H-4⁰); 4.90 (dd, 1H,

0

CH₂N); 4.66 (dd, 1H, J_gem= 12.2, J_{5 b;4}¼ 4:1, H-5⁰b);

J_gem= 12.3, J_{5 a;4}¼ 3:1, H-5⁰a); 6.23 (dd, 1H,

0

4.82 (td, 1H, J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:1, 3.1, H-4⁰); 4.90

J_{3 ;2}¼ 5:7, J_{3 ;4}¼ 4:7, H-3⁰); 6.40 (t, 1H, J_{2 ;3}¼ 5:7,

0

(dd, 1H, J_gem= 12.2, J_{5 a;4}¼ 3:1, H-5⁰a); 6.24 (dd, 1H,

J_{2 ;1}¼ 5:4, H-2⁰); 6.47 (d, 1H, J_{1 ;2}¼ 5:4, H-1⁰); 7.16,

7.22 and 7.26 (3· m, 3· 2H, H-m-Tol); 7.81, 7.91 and

8.00 (3· m, 3· 2H, H-o-Tol); 8.21 (s, 1H, H-8); 8.87

(s, 1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.71

and 21.74 (CH₃-Tol); 54.02 (CH₂N-morph); 58.95

(CH₂N); 63.39 (CH₂-5⁰); 66.77 (CH₂O-morph); 71.33

(CH-3⁰); 73.63 (CH-2⁰); 80.97 (CH-4⁰); 86.93 (CH-1⁰);

125.61, 125.99 and 126.57 (C-i-Tol); 129.24, 129.26

and 129.33 (CH-m-Tol); 129.79 and 129.87 (CH-o-

Tol); 133.89 (C-5); 143.15 (CH-8); 144.23, 144.59 and

144.74 (C-p-Tol); 150.96 (C-4); 152.84 (CH-2); 157.89

(C-6); 165.19, 165.38 and 166.19 (CO). IR (CCl₄):

m = 2961, 1732, 1613, 1595, 1498, 1410, 1333, 1266,

0

J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:7, H-3⁰); 6.40 (t, 1H, J_{2 ;3}¼ 5:8,

0

J_{2 ;1}¼ 5:4, H-2⁰); 6.48 (d, 1H, J_{1 ;2}¼ 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); 8.20 (s, 1H, H-8); 8.87

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

and 21.73 (CH₃-Tol); 24.05 and 25.72 (CH₂-pip); 54.97

(CH₂N-pip); 59.27 (CH₂N); 63.40 (CH₂-5⁰); 71.34

(CH-3⁰); 73.66 (CH-2⁰); 80.95 (CH-4⁰); 86.85 (CH-1⁰);

125.65, 126.01 and 126.58 (C-i-Tol); 129.22, 129.25

and 129.33 (CH-m-Tol); 129.79, 129.87 and 129.88

(CH-o-Tol); 133.93 (C-5); 142.91 (CH-8); 144.21,

144.56 and 144.69 (C-p-Tol); 150.84 (C-4); 152.84

(CH-2); 157.85 (C-6); 165.18, 165.38 and 166.21 (CO).

IR (CCl₄): m = 2937, 1732, 1613, 1594, 1498, 1409,

0

1179, 1119, 1092, 644 cm^ꢀ1

.

1331, 1266, 1179, 1092, 644 cm^ꢀ1

.

4.33. 6-[(Morpholin-4-yl)methyl]-9-(2-deoxy-3,5-di-O-

toluoyl-b-^D-erythro-pentofuranosyl)purine (6m)

4.31. 6-[(Piperidin-1-yl)methyl]-9-(2-deoxy-3,5-di-O-tolu-

oyl-b-^D-erythro-pentofuranosyl)purine (6l)

Prepared from mesylate 8 by procedure described above

(see 5m). Yield: 94% of white foam. Exact mass (FAB

HR MS) found: 572.2518; calcd for C₃₁H₃₄N₅O₆:

572.2509. FAB MS m/z (%): 572 (MH⁺, 9); 353 (4);

220 (53); 134 (28); 119 (100). ¹H NMR (500 MHz,

CDCl₃): 2.42 and 2.46 (2· s, 2· 3H, CH₃-Tol); 2.63

(bt, 4H, J_vic= 4.7, CH₂N-morph); 2.86 (ddd, 1H,

Prepared from mesylate 8 by procedure described above

(see 5l). Yield: 94% of white foam. Exact mass (FAB HR

MS) found: 570.2723; calcd for C₃₂H₃₆N₅O₅: 570.2716.

FAB MS m/z (%): 570 (MH⁺, 30); 353 (2); 218 (100);

1

134 (24); 119 (91). H NMR (400 MHz, CDCl₃): 1.43

(bm, 2H, CH₂-pip); 1.62 (p, 4H, J_vic= 5.6, CH₂-pip);

2.41 and 2.45 (2· s, 2· 3H, CH₃-Tol); 2.56 (bm, 4H,

J_gem= 14.1, J_{2 b;1}¼ 5:7, J_{2 b;3}¼ 2:0, H-2⁰b); 3.22 (ddd,

0

1H, J_gem= 14.1, J_{2 a;1}¼ 8:6, J_{2 a;3}¼ 6:4, H-2⁰a); 3.76

(t, 4H, J_vic= 4.7, CH₂O-morph); 4.09 (s, 2H, CH₂N);

4.65–4.70 (m, 2H, H-5⁰b and H-4⁰); 4.80 (dd, 1H,

0

CH₂N-pip); 2.85 (ddd, 1H, J_gem= 14.2, J_{2 b;1}¼ 5:7,

J_{2 b;3}¼ 2:1, H-2⁰b); 3.21 (ddd, 1H, J_gem= 14.2,

0

J_{2 a;1}¼ 8:4, J_{2 a;3}¼ 6:4, H-2⁰a); 4.05 (s, 2H, CH₂N);

J_gem= 13.3, J_{5 b;4}¼ 5:0, H-5⁰a); 5.85 (dt, 1H,

0

4.63–4.70 (m, 2H, H-5⁰b and H-4⁰); 4.78 (m, 1H, H-

J_{3 ;2}¼ 6:4, 2.0, J_{3 ;4}¼ 2:0, H-3⁰); 6.62 (dd, 1H,

0

5⁰a); 5.84 (dt, 1H, J_{3 ;2}¼ 6:4, 2.1, J_{3 ;4}¼ 2:1, H-3⁰);

J_{1 2}¼ 8:6, 5.7, H-1⁰); 7.24 and 7.30 (2· m, 2· 2H, H-

m-Tol); 7.93 and 7.99 (2· m, 2· 2H, H-o-Tol); 8.24 (s,

1H, H-8); 8.91 (s, 1H, H-2). ¹³C NMR (125.8 MHz,

CDCl₃): 21.73 and 21.78 (CH₃-Tol); 37.63 (CH₂-2⁰);

53.97 (CH₂N-morph); 58.88 (CH₂N); 63.91 (CH₂-5⁰);

66.72 (CH₂O-morph); 75.00 (CH-3⁰); 83.03 (CH-4⁰);

84.76 (CH-1⁰); 126.17 and 126.49 (C-i-Tol); 129.29

(CH-m-Tol); 129.60 and 129.78 (CH-o-Tol); 133.79 (C-

5); 142.74 (CH-8); 144.24 and 144.62 (C-p-Tol); 150.70

(C-4); 152.59 (CH-2); 157.61 (C-6); 165.94 and 166.15

(CO). IR (CCl₄): m = 2819, 1721, 1612, 1598, 1497,

0

0 0

6.60 (dd, 1H, J_{1 2}¼ 8:4, 5.7, H-1⁰); 7.23 and 7.29 (2·

m, 2· 2H, H-m-Tol); 7.92 and 7.98 (2· m, 2· 2H, H-

o-Tol); 8.22 (s, 1H, H-8); 8.91 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, CDCl₃): 21.69 and 21.74 (CH₃-Tol);

24.05 and 25.72 (CH₂-pip); 37.73 (CH₂-2⁰); 55.00

(CH₂N-pip); 59.28 (CH₂N); 63.95 (CH₂-5⁰); 75.06

(CH-3⁰); 83.07 (CH-4⁰); 84.81 (CH-1⁰); 126.36 and

126.65 (C-i-Tol); 129.29 (CH-m-Tol); 129.65 and

129.81 (CH-o-Tol); 133.93 (C-5); 142.49 (CH-8);

144.18 and 144.57 (C-p-Tol); 150.68 (C-4); 152.60

(CH-2); 158.59 (C-6); 165.94 and 166.16 (CO). IR

0

1408, 1333, 1269, 1179, 1103, 646 cm^ꢀ1

.

ˇ

´

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2344

4.34. 6-[(Thiazolidin-3-yl)methyl]-9-(2,3,5-tri-O-toluoyl-

b-^D-ribofuranosyl)purine (5n)

126.57 (C-i-Tol); 127.25 (CH-4-indoline); 129.22,

129.26 and 129.33 (CH-m-Tol); 129.79 (C-3a-indoline

and CH-o-Tol); 129.87 and 129.88 (CH-o-Tol);

132.20 (C-5); 143.02 (CH-8); 144.23, 144.58 and

144.70 (C-p-Tol); 151.03 (C-4); 151.94 (C-7a-indoline);

152.84 (CH-2); 158.54 (C-6); 165.18, 165.38 and

166.22 (CO).

Thiazolidine (0.28 ml, 3.6 mmol) was added to a solu-

tion of mesylate 7 (645 mg, 0.9 mmol) in MeCN

(10 ml). After aqueous work-up and chromatography

on silica gel (hexanes/AcOEt, 1:1–1:5) 480 mg (75%)

of 5n was isolated as white foam. Exact mass (FAB

HR MS) found: 708.2508; calcd for C₃₈H₃₈N₅O₇S:

708.2492. FAB MS m/z (%): 708 (MH⁺, 2); 487

(11); 119 (100). ¹H NMR (400 MHz, CDCl₃): 2.38

and 2.42 (2· s, 9H, CH₃-Tol); 3.04 (t, 2H, J_vic= 6.4,

H-5-thiazolidine); 3.21 (t, 2H, J_vic= 6.4, H-4-thiazoli-

dine); 4.12 (s, 2H, H-2-thiazolidine); 4.23 (s, 2H,

4.36. 6-[(Indol-1-yl)methyl]-9-(2,3,5-tri-O-toluoyl-b-^D-

ribofuranosyl)purine (5p)

4.36.1. Method A. Indole (88 mg, 0.75 mmol) was added

to a suspension of NaH (28 mg, 0.7 mmol, 60% purity)

in MeCN (10 ml). After 30 min. solution of mesylate 7

(430 mg, 0.6 mmol) in MeCN (10 ml) was added. After

aqueous work-up and chromatography on silica gel

(hexanes/AcOEt, 1:1–1:5) 66 mg (15%) of 5p was iso-

lated as white foam.

0

CH₂N); 4.66 (dd, 1H, J_gem= 12.3, J_{5 b;4}¼ 4:1, H-

5⁰b); 4.82 (td, 1H, J_{4 ;3}¼ 4:6, J_{4 ;5}¼ 4:1, 3.1, H-4⁰);

0

4.90 (dd, 1H, J_gem= 12.3, J_{5 a;4}¼ 3:1, H-5⁰a); 6.22

0

(dd, 1H, J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:6, H-3⁰); 6.40 (t, 1H,

0

J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:5, H-2⁰); 6.48 (d, 1H, J_{1 ;2}¼ 5:5,

H-1⁰); 7.16, 7.22 and 7.26 (3· m, 3· 2H, H-m-Tol);

7.81, 7.91 and 8.00 (3· m, 3· 2H, H-o-Tol); 8.22 (s,

1H, H-8); 8.87 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 21.70 and 21.73 (CH₃-Tol); 29.63 (CH₂-5-

thia); 53.48 (CH₂-2-thia); 58.38 (CH₂-4-thia); 61.28

(CH₂N); 63.40 (CH₂-5⁰); 71.38 (CH-3⁰); 73.63 (CH-

2⁰); 81.04 (CH-4⁰); 86.88 (CH-1⁰); 125.62, 126.01 and

126.57 (C-i-Tol); 129.23, 129.27 and 129.34 (CH-m-

Tol); 129.79 and 129.87 (CH-o-Tol); 133.46 (C-5);

143.25 (CH-8); 144.24, 144.59 and 144.72 (C-p-Tol);

151.07 (C-4); 152.91 (CH-2); 158.37 (C-6); 165.17,

165.38 and 166.19 (CO). IR (CCl₄): m = 2949, 2875,

1732, 1612, 1597, 1498, 1409, 1334, 1266, 1179,

0

4.36.2. Method B. Oxidation of indoline derivative 5o

with DDQ. 2,3-Dichloro-5,6-dicyano-p-benzoquinone

(100 mg, 0.44 mmol) was added to a solution of 5o

(245 mg, 0.33 mmol) in toluene (20 ml) and stirred for

3 h at ambient temperature. Unfortunately, monitoring

of reaction mixture by TLC is impossible due to the

same R_fof starting compound and product. Reaction

mixture was adsorbed on silica gel and chromato-

graphed (hexanes/AcOEt, 1:1–1:5) to give 182 mg

(74%) of product 5p as white foam.

1092, 644 cm^ꢀ1

.

Exact mass (FAB HR MS) found: 736.2750; calcd for

C₄₃H₃₈N₅O₇: 736.2771. FAB MS m/z (%): 736 (MH⁺,

4); 487 (14); 119 (50). ¹H NMR (400 MHz, CDCl₃):

2.36 and 2.41 (2· s, 9H, CH₃-Tol); 4.65 (dd, 1H,

4.35. 6-[(Indolin-1-yl)methyl]-9-(2,3,5-tri-O-toluoyl-b-^D-

ribofuranosyl)purine (5o)

J_gem= 12.2, J_{5 b;4}¼ 4:1, H-5⁰b); 4.80 (td, 1H, J_{4 ;3}

¼

0

4:5, J_{4 ;5}¼ 4:1, 3.1, H-4⁰); 4.86 (dd, 1H, J_gem= 12.2,

0

Indoline (0.15 ml, 1.26 mmol) was added to a solution

of mesylate 7 (300 mg, 0.42 mmol) in MeCN (15 ml).

After aqueous work-up and chromatography on silica

gel (hexanes/AcOEt, 1:1–1:5) 278 mg (90%) of 5o was

isolated as white foam. Exact mass (FAB HR MS)

found: 738.2951; calcd for C₄₃H₄₀N₅O₇: 738.2928.

FAB MS m/z (%): 738 (MH⁺, 1); 487 (6); 119

(100). ¹H NMR (500 MHz, CDCl₃): 2.38, 2.41 and

2.42 (3· s, 3· 3H, CH₃-Tol); 3.00 (t, 2H, J_vic= 8.4,

H-3-indoline); 3.59 (t, 2H, J_vic= 8.4, H-2-indoline);

J_{5 a;4}¼ 3:1, H-5⁰a); 5.76 (s, 2H, CH₂N); 6.18 (dd, 1H,

0

J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:5, H-3⁰); 6.35 (t, 1H, J_{2 ;3}¼ 5:8,

0

J_{2 ;1}¼ 5:5, H-2⁰); 6.46 (d, 1H, J_{1 ;2}¼ 5:5, H-1⁰); 6.54

(dd, 1H, J_3,2= 3.2, J_3,7= 0.9, H-3-indole); 7.05 (ddd,

1H, J_5,4= 7.9, J_5,6= 7.0, J_5,7= 1.1, H-5-indole); 7.16

(m, 2H, H-m-Tol); 7.15 (ddd, 1H, J_6,7= 7.9, J_6,5= 7.0,

J_6,4= 1.3, H-6-indole); 7.21 and 7.23 (2· m, 2· 2H, H-

m-Tol); 7.43 (d, 1H, J_2,3= 3.2, H-2-indole); 7.56 (dq,

1H, J_7,6= 7.9, J_7,5= 1.1, J_7,3= 0.9, J_7,4= 0.6, H-7-in-

dole); 7.58 (dt, 1H, J_4,5= 7.9, J_4,6= 1.3, J_4,7= 0.6, H-

4-indole); 7.79, 7.89 and 7.97 (3· m, 3· 2H, H-o-Tol);

8.25 (s, 1H, H-8); 8.78 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, CDCl₃): 21.69 and 21.73 (CH₃-Tol);

47.11 (CH₂N); 63.43 (CH₂-5⁰); 71.37 (CH-3⁰); 73.67

(CH-2⁰); 81.08 (CH-4⁰); 86.85 (CH-1⁰); 101.94 (CH-3-in-

dole); 109.88 (CH-7-indole); 119.57 (CH-5-indole);

120.85 (CH-4-indole); 121.71 (CH-6-indole); 125.60,

125.99 and 126.55 (C-i-Tol); 128.59 (C-3a-indole);

128.94 (CH-2-indole); 129.21, 129.25 and 129.33 (CH-

m-Tol); 129.77, 129.86 and 129.88 (CH-o-Tol); 132.74

(C-5); 136.30 (C-7a-indole); 143.49 (CH-8); 144.22,

144.58 and 144.69 (C-p-Tol); 151.35 (C-4); 152.94

(CH-2); 155.98 (C-6); 165.15, 165.36 and 166.18 (CO).

IR (CCl₄): m = 3040, 1732, 1612, 1598, 1498, 1463,

0

4.67 (dd, 1H, J_gem= 12.3, J_{5 b;4}¼ 4:2, H-5⁰b); 4.67

0

(s, 2H, CH₂N); 4.82 (td, 1H, J_{4 ;3}¼ 4:6, J_{4 ;5}¼ 4:2,

3.1, H-4⁰); 4.89 (dd, 1H, J_gem= 12.3, J_{5 a;4}¼ 3:1, H-

0

5⁰a); 6.22 (dd, 1H, J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:6, H-3⁰);

0

6.40 (t, 1H, J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:4, H-2⁰); 6.48 (d,

0

1H, J_{1 ;2}¼ 5:4, H-1⁰); 6.65 (td, 1H, J_5,4= J_5,6= 7.4,

J_5,7= 1.0, H-5-indoline); 6.71 (bd, 1H, J_7,6= 7.8, H-

7-indoline); 7.01–7.08 (m, 2H, H-4,6-indoline); 7.16,

7.22 and 7.25 (3· m, 3· 2H, H-m-Tol); 7.81, 7.90

and 8.00 (3· m, 3· 2H, H-o-Tol); 8.23 (s, 1H, H-

8); 8.86 (s, 1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃):

21.71 and 21.74 (CH₃-Tol); 28.67 (CH₂-3-indoline);

50.61 (CH₂N); 54.46 (CH₂-2-indoline); 63.43 (CH₂-

5⁰); 71.36 (CH-3⁰); 73.65 (CH-2⁰); 80.99 (CH-4⁰);

86.87 (CH-1⁰); 107.47 (CH-7-indoline); 117.98 (CH-5-

indoline); 124.35 (CH-6-indoline); 125.63, 126.00 and

0

1409, 1334, 1266, 1179, 1091, 643 cm^ꢀ1

.

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P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2345

4.37. 6-[(Pyrazol-1-yl)methyl]-9-(2,3,5-tri-O-toluoyl-b-D-

ribofuranosyl)purine (5q)

¹H NMR (500 MHz, CDCl₃): 2.38 and 2.43 (2· s, 9H,

0

CH₃-Tol); 4.67 (dd, 1H, J_gem= 12.3, J_{5 b;4}¼ 4:3, H-

5⁰b); 4.84 (td, 1H, J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:3, 3.1, H-4⁰);

0

4.90 (dd, 1H, J_gem= 12.3, J_{5 a;4}¼ 3:1, H-5⁰a); 5.35 (s,

0

Pyrazole (145 mg, 2.13 mmol) was added to a solution

of mesylate 7 (300 mg, 0.42 mmol) in MeCN (15 ml)

and stirred for 3 days at 75 ꢁC. Reaction mixture was

adsorbed on silica gel and chromatographed (hexanes/

AcOEt, 1:1–1:5) to give 210 mg (73%) of 5q as white

foam. Exact mass (FAB HR MS) found: 687.2535; calcd

for C₃₈H₃₅N₆O₇: 687.2567. FAB MS m/z (%): 687

0

2H, CH₂N); 6.18 (dd, 1H, J_{3 ;2}¼ 5:9, J_{3 ;4}¼ 4:7, H-

3⁰); 6.36 (t, 1H, J_{2 ;3}¼ 5:9, J_{2 ;1}¼ 5:3, H-2⁰); 6.41 (m,

0

2H, H-3,5-py); 6.47 (d, 1H, J_{1 ;2}¼ 5:3, H-1⁰); 7.16,

7.23 and 7.26 (3· m, 3· 2H, H-m-Tol); 7.60 (m, 2H,

H-2,6-py); 7.79, 7.91 and 7.99 (3· m, 3· 2H, H-o-Tol);

8.29 (s, 1H, H-8); 8.81 (s, 1H, H-2). ¹³C NMR

(125.8 MHz, CDCl₃): 21.70, 21.72 and 21.73 (CH₃-

Tol); 56.47 (CH₂N); 63.33 (CH₂-5⁰); 71.30 (CH-3⁰);

73.69 (CH-2⁰); 81.13 (CH-4⁰); 87.23 (CH-1⁰); 118.82

(CH-3,5-py); 125.47, 125.90 and 126.52 (C-i-Tol);

129.27, 129.30 and 129.33 (CH-m-Tol); 129.77 and

129.86 (CH-o-Tol); 132.63 (C-5); 140.68 (CH-2,6-py);

144.34 (C-p-Tol); 144.42 (CH-8); 144.70 and 144.88

(C-p-Tol); 151.65 (C-4); 152.97 (CH-2); 153.15 (C-6);

165.22, 165.38 and 166.15 (CO); 178.93 (C-4-py). IR

(CCl₄): m = 1727, 1640, 1612, 1577, 1499, 1406, 1335,

0

1

(MH⁺, 1); 119 (75). H NMR (400 MHz, CDCl₃): 2.37

and 2.42 (2· s, 9H, CH₃-Tol); 4.66 (dd, 1H, J_gem= 12.2,

J_{5 b;4}¼ 4:1, H-5⁰b); 4.81 (td, 1H, J_{4 ;3}¼ 4:5, J_{4 ;5}¼ 4:1,

0

3.1, H-4⁰); 4.88 (dd, 1H, J_gem= 12.2, J_{5 a;4}¼ 3:1, H-5⁰a);

0

5.82 (s, 2H, CH₂N); 6.19 (dd, 1H, J_{3 ;2}¼ 5:7,

J_{3 ;4}¼ 4:5, H-3⁰); 6.30 (t, 1H, J_4,3= 1.8, J_4,5= 2.1, H-

0

4-pyrazole); 6.37 (t, 1H, J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:6, H-2⁰);

0

6.48 (d, 1H, J_{1 ;2}¼ 5:6, H-1⁰); 7.15, 7.22 and 7.25 (3·

m, 3· 2H, H-m-Tol); 7.54 (dd, 1H, J_3,4= 1.8,

J_3,5= 0.4, H-3-pyrazole); 7.66 (dd, 1H, J_5,4= 2.1,

J_5,3= 0.4, H-5-pyrazole); 7.80, 7.90 and 7.99 (3· m, 3·

2H, H-o-Tol); 8.25 (s, 1H, H-8); 8.83 (s, 1H, H-2). ¹³C

NMR (100.6 MHz, CDCl₃): 21.71 (CH₃-Tol); 52.45

(CH₂N); 63.44 (CH₂-5⁰); 71.40 (CH-3⁰); 73.61 (CH-2⁰);

81.11 (CH-4⁰); 86.82 (CH-1⁰); 106.13 (CH-4-pyrazole);

125.57, 125.97 and 126.53 (C-i-Tol); 129.21, 129.26

and 129.34 (CH-m-Tol); 129.77, 129.85 and 129.87

(CH-o-Tol); 130.45 (CH-5-pyrazole); 132.72 (C-5);

140.07 (CH-3-pyrazole); 143.74 (CH-8); 144.24, 144.59

and 144.70 (C-p-Tol); 151.42 (C-4); 152.97 (CH-2);

155.17 (C-6); 165.13, 165.36 and 166.17 (CO). IR

(CCl₄): m = 3039, 1732, 1612, 1598, 1498, 1409, 1334,

0

1267, 1093, 643 cm^ꢀ1

.

For 13f: white foam. Exact mass (FAB HR MS) found:

714.2581; calcd for C₄₀H₃₆N₅O₈: 714.2564. FAB MS m/z

(%): 714 (MH⁺, 16); 487 (6); 228 (4); 119 (100). ¹H NMR

(500 MHz, CDCl₃): 2.38, 2.41 and 2.42 (3· s, 3· 3H,

0

CH₃-Tol); 4.67 (dd, 1H, J_gem= 12.3, J_{5 b;4}¼ 4:2, H-

5⁰b); 4.83 (td, 1H, J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:2, 3.1, H-4⁰);

0

4.91 (dd, 1H, J_gem= 12.3, J_{5 a;4}¼ 3:1, H-5⁰a); 5.63 (s,

0

2H, CH₂O); 6.22 (dd, 1H, J_{3 ;2}¼ 5:9, J_{3 ;4}¼ 4:7, H-

3⁰); 6.39 (t, 1H, J_{2 ;3}¼ 5:9, J_{2 ;1}¼ 5:3, H-2⁰); 6.48 (d,

0

1H, J_{1 ;2}¼ 5:3, H-1⁰); 6.97 (m, 2H, H-3,5-py); 7.16,

7.23 and 7.25 (3· m, 3· 2H, H-m-Tol); 7.81, 7.91 and

7.99 (3· m, 3· 2H, H-o-Tol); 8.27 (s, 1H, H-8); 8.42

(m, 2H, H-2,6-py); 8.89 (s, 1H, H-2). ¹³C NMR

(125.8 MHz, CDCl₃): 21.71 and 21.74 (CH₃-Tol);

63.33 (CH₂-5⁰); 65.96 (CH₂O); 71.33 (CH-3⁰); 73.73

(CH-2⁰); 81.08 (CH-4⁰); 87.09 (CH-1⁰); 110.62 (CH-3,5-

py); 125.56, 125.96 and 126.55 (C-i-Tol); 129.26,

129.29 and 129.34 (CH-m-Tol); 129.78 and 129.88

(CH-o-Tol); 132.70 (C-5); 143.87 (CH-8); 144.29,

144.65 and 144.80 (C-p-Tol); 151.10 (CH-2,6-py);

151.45 (C-4); 152.91 (CH-2); 154.88 (C-6); 164.50 (C-4-

py); 165.20, 165.38 and 166.17 (CO). IR (CCl₄):

m = 1727, 1612, 1594, 1500, 1410, 1335, 1267, 1093,

0

1266, 1179, 1090, 643 cm^ꢀ1

.

4.38. 6-[(4-Oxopyridin-1(4H)-yl)methyl]-9-(2,3,5-tri-O-

toluoyl-b-^D-ribofuranosyl)purine (5r) and 6-[(Pyridin-4-

yloxy)methyl]-9-(2,3,5-tri-O-toluoyl-b-^D-ribofurano-

syl)purine (13f)

4.38.1. Method A. Dry THF (10 ml) was added to a

mixture of 4-pyridone (43 mg, 0.45 mmol) and NaH

(15 mg, 0.36 mmol, 60% purity) under Ar atmosphere

and stirred for 45 min. Then a solution of mesylate 7

(215 mg, 0.3 mmol) in THF (5 ml) was added to pre-

formed solution of sodium salt of 4-pyridone. After

aqueous work-up (extraction with AcOEt) and chro-

matography on silica gel (hexanes/AcOEt/MeOH,

10:20:0.3–10:60:4) two compounds were isolated. Less

polar was O-substituted pyridine derivative 13f, 8 mg

(4%) and more polar was N-substituted pyridone 5r,

188 mg (88%).

643 cm^ꢀ1

.

4.39. 6-[(4-Oxopyridin-1(4H)-yl)methyl]-9-(2-deoxy-3,5-

di-O-toluoyl-b-^D-erythro-pentofuranosyl)purine (6r) and

6-[(Pyridin-4-yloxy)methyl]-9-(2-deoxy-3,5-di-O-toluoyl-

b-^D-erythro-pentofuranosyl)purine (14f)

i

4.38.2. Method B. Pr₂NEt (0.42 ml, 2.4 mmol) was

Prepared from mesylate 8 by procedures described

above (see 5r and 13f).

added to a solution of mesylate 7 (575 mg, 0.8 mmol)

and 4-pyridone (305 mg, 3.2 mmol) in MeCN (15 ml)

and stirred at 50 ꢁC for 12 h. After aqueous work-up

(extraction with AcOEt) and chromatography two com-

pounds were isolated: 46 mg (8%) of 13f, and 400 mg

(70%) of 5r.

4.39.1. Method A. Compound 6r (85%) as white crystals

(mp 219–220 ꢁC) and 4% of 14f as white foam.

4.39.2. Method B. Compound 6r (78%) and 10% of

14f.

For 5r: White foam. Exact mass (FAB HR MS) found:

714.2577; calcd for C₄₀H₃₆N₅O₈: 714.2564. FAB MS

m/z (%): 714 (MH⁺, 29); 487 (4); 228 (29); 119 (100).

For 6r: Exact mass (FAB HR MS) found: 580.2209;

calcd for C₃₂H₃₀N₅O₆: 580.2196. FAB MS m/z (%):

ˇ

´

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2346

580 (MH⁺, 35); 228 (94); 133 (11); 119 (100); 96 (15). ¹H

pyridone 5s as white foam and 17% of O-substituted

pyridine derivative 13g as white foam.

NMR (500 MHz, CDCl₃): 2.42 and 2.45 (2· s, 9H, CH₃-

0

Tol); 2.87 (ddd, 1H, J_gem= 14.2, J_{2 b;1}¼ 5:9,

J_{2 b;3}¼ 2:2, H-2⁰b); 3.21 (ddd, 1H, J_gem= 14.2,

For 5s: Exact mass (FAB HR MS) found: 714.2571;

calcd for C₄₀H₃₆N₅O₈: 714.2564. FAB MS m/z (%):

736 (M+Na⁺, 18); 487 (8); 228 (4); 119 (100). ¹H

NMR (500 MHz, CDCl₃): 2.38, 2.415 and 2.419 (3· s,

3· 3H, CH₃-Tol); 4.67 (dd, 1H, J_gem= 12.2,

0

J_{2 a;1}¼ 8:2, J_{2 a;3}¼ 6:4, H-2⁰a); 4.65–4.69 (m, 2H, H-

0

5⁰b and H-4⁰); 4.78 (dd, 1H, J_gem= 13.3, J_{5 a;4}¼ 5:2,

0

H-5⁰a); 5.33 (s, 2H, CH₂N); 5.84 (dt, 1H, J_{3 ;2}¼ 6:4,

0

2.2, J_{3 ;4}¼ 2:3, H-3⁰); 6.36 (m, 2H, H-3,5-py); 6.59

0

(dd, 1H, J_{1 2}¼ 8:2, 5.9, H-1⁰); 7.22 and 7.29 (2· m, 2·

2H, H-m-Tol); 7.59 (m, 2H, H-2,6-py); 7.90 and 7.97

(2· m, 2· 2H, H-o-Tol); 8.31 (s, 1H, H-8); 8.87 (s, 1H,

H-2). ¹³C NMR (125.8 MHz, CDCl₃): 21.70 and 21.74

(CH₃-Tol); 37.75 (CH₂-2⁰); 56.44 (CH₂N); 63.84 (CH₂-

5⁰); 74.88 (CH-3⁰); 83.28 (CH-4⁰); 85.20 (CH-1⁰);

118.90 (CH-3,5-py); 126.24 and 126.56 (C-i-Tol);

129.27 and 129.31 (CH-m-Tol); 129.62 and 129.80

(CH-o-Tol); 132.67 (C-5); 140.49 (CH-2,6-py); 144.03

(CH-8); 144.29 and 144.66 (C-p-Tol); 151.47 (C-4);

152.72 (CH-2); 153.08 (C-6); 165.91 and 166.10 (CO);

178.86 (C-4-py). IR (CHCl₃): m = 1721, 1640, 1612,

1602, 1578, 1497, 1406, 1333, 1269, 1179, 1102,

J_{5 b;4}¼ 4:2, H-5⁰b); 4.81 (td, 1H, J_{4 ;3}¼ 4:4,

0

J_{4 ;5}¼ 4:2, 3.2, H-4⁰); 4.87 (dd, 1H, J_gem= 12.2,

0

J_{5 a;4}¼ 3:2, H-5⁰a); 5.61 and 5.65 (2· d, 2H, J_gem= 15.8,

0

CH₂N); 6.18 (dd, 1H, J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:4, H-3⁰); 6.21

0

(td, 1H, J_5,6= 6.8, J_5,4= 6.6, J_5,3= 1.4, H-5-py); 6.37 (t,

1H, J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:7, H-2⁰); 6.49 (d, 1H,

0

J_{1 ;2}¼ 5:7, H-1⁰); 6.60 (ddd, 1H, J_3,4= 9.1, J_3,5= 1.4,

J_3,6= 0.7, H-3-py); 7.15, 7.21 and 7.26 (3· m, 3· 2H,

H-m-Tol); 7.36 (ddd, 1H, J_4,3= 9.1, J_4,5= 6.6,

J_4,6= 2.1, H-4-py); 7.47 (ddd, 1H, J_6,5= 6.8, J_6,4= 2.1,

J_6,3= 0.7, H-6-py); 7.81, 7.90 and 8.00 (3· m, 3· 2H,

H-o-Tol); 8.23 (s, 1H, H-8); 8.79 (s, 1H, H-2). ¹³C

NMR (125.8 MHz, CDCl₃): 21.70 and 21.73 (CH₃-

Tol); 49.54 (CH₂N); 63.53 (CH₂-5⁰); 71.4 (CH-3⁰);

73.59 (CH-2⁰); 81.11 (CH-4⁰); 86.70 (CH-1⁰); 105.97

(CH-5-py); 121.15 (CH-3-py); 125.59, 125.99 and

126.55 (C-i-Tol); 129.20, 129.25 and 129.35 (CH-m-

Tol); 129.78, 129.86 and 129.89 (CH-o-Tol); 132.64 (C-

5); 138.58 (CH-6-py); 139.87 (CH-4-py); 143.37 (CH-

8); 144.23, 144.57 and 144.67 (C-p-Tol); 151.13 (C-4);

152.82 (CH-2); 155.55 (C-6); 162.59 (C-2-py); 165.14,

165.37 and 166.20 (CO). IR (CCl₄): m = 1731, 1668,

1612, 1596, 1541, 1498, 1410, 1336, 1267, 1179, 1093,

0

644 cm^ꢀ1

.

For 14f: Exact mass (FAB HR MS) found: 580.2206;

calcd for C₃₂H₃₀N₅O₆: 580.2196. FAB MS m/z (%):

580 (MH⁺, 30); 353 (2); 228 (29); 134 (13); 119 (100);

96 (18). ¹H NMR (500 MHz, CDCl₃): 2.41 and 2.45

(2· s, 9H, CH₃-Tol); 2.87 (ddd, 1H, J_gem= 14.2,

J_{2 b;1}¼ 5:9, J_{2 b;3}¼ 2:3, H-2⁰b); 3.21 (ddd, 1H,

0

J_gem= 14.2, J_{2 a;1}¼ 8:3, J_{2 a;3}¼ 6:4, H-2⁰a); 4.65–4.70

0

(m, 2H, H-5⁰b and H-4⁰); 4.79 (dd, 1H, J_gem= 13.2,

J_{5 a;4}¼ 5:1, H-5⁰a); 5.61 and 5.64 (2 ·d, 2H, J_gem= 13.3,

644 cm^ꢀ1

.

0

CH₂O); 5.84 (dt, 1H, J_{3 ;2}¼ 6:4, 2.3, J_{3 ;4}¼ 2:2, H-3⁰);

0

6.61 (dd, 1H, J_{1 2}¼ 8:3, 5.9, H-1⁰); 6.98 (m, 2H, H-

3,5-py); 7.22 and 7.29 (2· m, 2· 2H, H-m-Tol); 7.90

and 7.98 (2· m, 2· 2H, H-o-Tol); 8.30 (s, 1H, H-8);

8.42 (m, 2H, H-2,6-py); 8.94 (s, 1H, H-2). ¹³C NMR

(125.8 MHz, CDCl₃): 21.69 and 21.75 (CH₃-Tol);

37.80 (CH₂-2⁰); 63.87 (CH₂-5⁰); 65.98 (CH₂O); 74.97

(CH-3⁰); 83.22 (CH-4⁰); 85.03 (CH-1⁰); 110.60 (CH-3,5-

py); 126.29 and 126.58 (C-i-Tol); 129.28 and 129.31

(CH-m-Tol); 129.63 and 129.81 (CH-o-Tol); 132.71 (C-

5); 143.48 (CH-8); 144.25 and 144.63 (C-p-Tol); 151.14

(CH-2,6-py); 151.27 (C-4); 152.66 (CH-2); 154.71 (C-

6); 164.45 (C-4-py); 165.93 and 166.12 (CO). IR

(CHCl₃): m = 1721, 1612, 1594, 1574, 1500, 1408, 1333,

For 13g: Exact mass (FAB HR MS) found: 714.2545;

calcd for C₄₀H₃₆N₅O₈: 714.2564. FAB MS m/z (%):

736 (M+Na⁺, 4); 714 (MH⁺, 1); 487 (9); 228 (2); 119

(100). ¹H NMR (500 MHz, CDCl₃): 2.38, 2.41 and

2.42 (3· s, 3· 3H, CH₃-Tol); 4.67 (dd, 1H, J_gem= 12.3,

0

J_{5 b;4}¼ 4:1, H-5⁰b); 4.82 (td, 1H, J_{4 ;3}¼ 4:6,

0

J_{4 ;5}¼ 4:1, 3.1, H-4⁰); 4.89 (dd, 1H, J_gem= 12.3,

0

J_{5 a;4}¼ 3:1, H-5⁰a); 5.89 and 5.92 (2· d, 2H, J_gem= 14.9,

0

CH₂O); 6.22 (dd, 1H, J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:6, H-3⁰); 6.39

0

(t, 1H, J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:4, H-2⁰); 6.49 (d, 1H,

0

J_{1 ;2}¼ 5:4, H-1⁰); 6.86 (ddd, 1H, J_5,4= 7.1, J_5,6= 5.1,

J_5,3= 1.0, H-5-py); 6.93 (dt, 1H, J_3,4= 8.4, J_3,5= 1.0,

J_3,6= 0.9, H-3-py); 7.16, 7.22 and 7.25 (3· m, 3· 2H,

H-m-Tol); 7.59 (ddd, 1H, J_4,3= 8.4, J_4,5= 7.1,

J_4,6= 2.0, H-4-py); 7.82, 7.90 and 7.99 (3· m, 3· 2H,

H-o-Tol); 8.09 (ddd, 1H, J_6,5= 5.1, J_6,4= 2.0,

J_6,3= 0.9, H-6-py); 8.23 (s, 1H, H-8); 8.87 (s, 1H, H-

2). ¹³C NMR (125.8 MHz, CDCl₃): 21.70 and 21.74

(CH₃-Tol); 63.39 (CH₂-5⁰); 63.70 (CH₂O); 71.36 (CH-

3⁰); 73.69 (CH-2⁰); 81.01 (CH-4⁰); 86.84 (CH-1⁰);

111.31 (CH-3-py); 117.21 (CH-5-py); 125.63, 126.00

and 126.55 (C-i-Tol); 129.22, 129.26 and 129.34 (CH-

m-Tol); 129.77, 129.87 and 129.88 (CH-o-Tol); 132.50

(C-5); 138.65 (CH-4-py); 143.19 (CH-8); 144.23, 144.57

and 144.69 (C-p-Tol); 146.73 (CH-6-py); 151.12 (C-4);

152.81 (CH-2); 157.41 (C-6); 162.97 (C-2-py); 165.17,

165.38 and 166.21 (CO). IR (CCl₄): m = 1732, 1612,

1598, 1572, 1498, 1474, 1433, 1334, 1266, 1179, 1092,

0

1269, 1179, 1102, 645 cm^ꢀ1

.

4.40. 6-[(2-Oxopyridin-1(2H)-yl)methyl]-9-(2,3,5-tri-O-

toluoyl-b-^D-ribofuranosyl)purine (5s) and 6-[(Pyridin-2-

yloxy)methyl]-9-(2,3,5-tri-O-toluoyl-b-^D-ribofurano-

syl)purine (13g)

4.40.1. Method A. Analogously as in synthesis of the 4-

pyridone derivatives 5r and 13f. Only N-substituted

pyridone 5s was isolated in the yield of 94% as white

foam.

4.40.2. Method B. Analogously as in synthesis of the 4-

pyridone derivatives 5r and 13f. But slightly higher tem-

perature was used (55 ꢁC) and prolongation of reaction

time was necessary (48 h). Yields: 47% of N-substituted

644 cm^ꢀ1

.

ˇ

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2347

4.41. 6-[(2-Oxopyridin-1(2H)-yl)methyl]-9-(2-deoxy-3,5-

di-O-toluoyl-b-^D-erythro-pentofuranosyl)purine (6s) and

6-[(Pyridin-2-yloxy)methyl]-9-(2-deoxy-3,5-di-O-toluoyl-

b-^D-erythro-pentofuranosyl)purine (14g)

(CH-3⁰); 83.12 (CH-4⁰); 84.88 (CH-1⁰); 111.32 (CH-3-

py); 117.22 (CH-5-py); 126.36 and 126.63 (C-i-Tol);

129.28 and 129.29 (CH-m-Tol); 129.64 and 129.82

(CH-o-Tol); 132.51 (C-5); 138.67 (CH-4-py); 142.78

(CH-8); 144.19 and 144.57 (C-p-Tol); 146.71 (CH-6-

py); 150.95 (C-4); 152.56 (CH-2); 157.25 (C-6); 163.01

(C-2-py); 165.94 and 166.15 (CO). IR (CHCl₃):

m = 1721, 1612, 1599, 1573, 1496, 1474, 1434, 1408,

Prepared from mesylate 8 by procedures described

above (see 5s and 13g).

4.41.1. Method A. Only N-substituted pyridone 6s was

isolated in the yield of 95% as white crystals (mp 164–

165 ꢁC).

1334, 1269, 1179, 1102, 645 cm^ꢀ1

.

4.42. 6-[(2-Oxopyrrolidin-1-yl)methyl]-9-(2,3,5-tri-O-tol-

uoyl-b-^D-ribofuranosyl)purine (5t)

4.41.2. Method B. Compound 6s (38%) and 22% of 14g

as white foam.

2-Pyrrolidinone (90 ll, 1.2 mmol) was added to a sus-

pension of NaH (39 mg, 0.96 mmol, 60% purity) in dry

THF (10 ml) under Ar atmosphere and stirred for

45 min. Then a solution of mesylate 7 (575 mg,

0.8 mmol) in THF (5 ml) was added to the preformed

solution of sodium salt of 2-pyrrolidinone. Reaction

was quenched with 1 M aq NaH₂PO₄(40 ml) and the

mixture extracted with AcOEt (4· 30 ml). Collected or-

ganic layers were dried with MgSO₄, the solvent was

evaporated and the residue chromatographed on silica

gel (hexanes/AcOEt, 1:1–1:5) to give 285 mg (51%) of

5t as white foam. Exact mass (FAB HR MS) found:

704.2735; calcd for C₃₉H₃₈N₅O₈: 704.2720. FAB MS

m/z (%): 726 (M+Na⁺, 7); 487 (6); 134 (7); 119 (100).

¹H NMR (500 MHz, CDCl₃): 2.08 (m, 2H, H-4-pyrr);

2.38, 2.42 and 2.43 (3· s, 3· 3H, CH₃-Tol); 2.50 (t,

2H, J_vic= 8.1, H-3-pyrr); 3.47 (t, 2H, J_vic= 7.1, H-5-

For 6s: Exact mass (FAB HR MS) found: 580.2203;

calcd for C₃₂H₃₀N₅O₆: 580.2196. FAB MS m/z (%):

602 (M+Na⁺, 44); 580 (MH⁺, 8); 353 (4); 228 (84); 134

1

(11); 119 (100); 96 (8). H NMR (500 MHz, CDCl₃):

2.41 and 2.44 (2· s, 9H, CH₃-Tol); 2.83 (ddd, 1H,

J_gem= 14.2, J_{2 b;1}¼ 5:8, J_{2 b;3}¼ 2:1, H-2⁰b); 3.17 (ddd,

0

1H, J_gem= 14.2, J_{2 a;1}¼ 8:5, J_{2 a;3}¼ 6:3, H-2⁰a); 4.63–

4.70 (m, 2H, H-5⁰b and H-4⁰); 4.76 (m, 1H, H-5⁰a);

5.60 and 5.66 (2· d, 2H, J_gem= 15.8, CH₂N); 5.82 (dt,

0

1H, J_{3 ;2}¼ 6:3, 2.1, J_{3 ;4}¼ 2:0, H-3⁰); 6.23 (td, 1H,

0

J_5,4= J_5,6= 6.7, J_5,3= 1.4, H-5-py); 6.59 (dd, 1H,

J_{1 ;2}¼ 8:5, 5.8, H-1⁰); 6.60 (ddd, 1H, J_3,4= 9.2,

J_3,5= 1.4, J_3,6= 0.7, H-3-py); 7.23 and 7.28 (2· m, 2·

2H, H-m-Tol); 7.38 (ddd, 1H, J_4,3= 9.2, J_4,5= 6.7,

J_4,6= 2.0, H-4-py); 7.49 (ddd, 1H, J_6,5= 6.7, J_6,4= 2.0,

J_6,3= 0.7, H-6-py); 7.92 and 7.97 (2· m, 2· 2H, H-o-

Tol); 8.25 (s, 1H, H-8); 8.83 (s, 1H, H-2). ¹³C NMR

(125.8 MHz, CDCl₃): 21.69 and 21.74 (CH₃-Tol);

37.74 (CH₂-2⁰); 49.74 (CH₂N); 63.98 (CH₂-5⁰); 75.07

(CH-3⁰); 83.14 (CH-4⁰); 84.91 (CH-1⁰); 105.97 (CH-5-

py); 121.14 (CH-3-py); 126.33 and 126.62 (C-i-Tol);

129.29 and 129.30 (CH-m-Tol); 129.65 and 129.81

(CH-o-Tol); 132.64 (C-5); 138.67 (CH-6-py); 139.93

(CH-4-py); 143.01 (CH-8); 144.21 and 144.57 (C-p-

Tol); 150.91 (C-4); 152.56 (CH-2); 155.39 (C-6); 162.61

(C-2-py); 165.93 and 166.17 (CO). IR (CHCl₃):

m = 1721, 1659, 1612, 1594, 1543, 1496, 1408, 1336,

0

pyrr); 4.67 (dd, 1H, J_gem= 12.3, J_{5 b;4}¼ 4:3, H-5⁰b);

0

4.82 (td, 1H, J_{4 ;3}¼ 4:6, J_{4 ;5}¼ 4:3, 3.2, H-4⁰); 4.89

0

(dd, 1H, J_gem= 12.3, J_{5 a;4}¼ 3:2, H-5⁰a); 4.99 (s, 2H,

0

CH₂N); 6.20 (dd, 1H, J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:6, H-3⁰);

0

6.38 (t, 1H, J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:5, H-2⁰); 6.47 (d, 1H,

0

J_{1 ;2}¼ 5:5, H-1⁰); 7.16, 7.22 and 7.26 (3· m, 3· 2H,

H-m-Tol); 7.81, 7.90 and 8.00 (3· m, 3· 2H, H-o-Tol);

8.21 (s, 1H, H-8); 8.81 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, CDCl₃): 17.91 (CH₂-4-pyrr); 21.69 and

21.72 (CH₃-Tol); 30.52 (CH₂-3-pyrr); 44.08 (CH₂N);

47.71 (CH₂-5-pyrr); 63.43 (CH₂-5⁰); 71.35 (CH-3⁰);

73.58 (CH-2⁰); 80.98 (CH-4⁰); 86.81 (CH-1⁰); 125.58,

125.96 and 126.54 (C-i-Tol); 129.21, 129.24 and 129.32

(CH-m-Tol); 129.77, 129.84 and 129.86 (CH-o-Tol);

132.75 (C-5); 143.22 (CH-8); 144.24, 144.58 and 144.70

(C-p-Tol); 151.05 (C-4); 152.70 (CH-2); 156.76 (C-6);

165.15, 165.37 and 166.19 (CO); 175.88 (C-2-pyrr). IR

(CCl₄): m = 1700, 1612, 1595, 1493, 1334, 1267, 1179,

0

1269, 1179, 1102, 645 cm^ꢀ1

.

For 14g: Exact mass (FAB HR MS) found: 580.2209;

calcd for C₃₂H₃₀N₅O₆: 580.2196. FAB MS m/z (%):

602 (M+Na⁺, 10); 580 (MH⁺, 1); 228 (19); 119 (38); 95

1

(20). H NMR (400 MHz, CDCl₃): 2.40 and 2.45 (2·

s,

9

0

H, CH₃-Tol); 2.85 (ddd, 1H, J_gem= 14.1,

0

1093, 645 cm^ꢀ1

.

J_{2 b;1}¼ 5:8, J_{2 b;3}¼ 2:2, H-2⁰b); 3.20 (ddd, 1H,

0

J_gem= 14.1, J_{2 a;1}¼ 8:4, J_{2 a;3}¼ 6:4, H-2⁰a); 4.64–4.70

4.43. 6-[(2-Oxopyrrolidin-1-yl)methyl]-9-(2-deoxy-3,5-di-

O-toluoyl-b-^D-erythro-pentofuranosyl)purine (6t)

0

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

(dt, 1H, J_{3 ;2}¼ 6:4, 2.2, J_{3 ;4}¼ 2:0, H-3⁰); 5.89 and

0

5.93 (2 · d, 2H, J_gem= 15.3, CH₂O); 6.61 (dd, 1H,

Prepared from mesylate 8 by procedure described

above (see 5t). Yield: 72% of 6t as white foam. Exact

mass (FAB HR MS) found: 570.2354; calcd for

C₃₁H₃₂N₅O₆: 570.2353. FAB MS m/z (%): 592

(M+Na⁺, 33); 570 (MH⁺, 8); 353 (3); 218 (80); 134

(10); 119 (100). ¹H NMR (500 MHz, CDCl₃): 2.09

(m, 2H, H-4-pyrr); 2.42 and 2.45 (2· s, 2· 3H, CH₃-

Tol); 2.51 (t, 2H, J_vic= 7.8, H-3-pyrr); 2.84 (ddd,

J_{1 ;2}¼ 8:4, 5.8, H-1⁰); 6.87 (ddd, 1H, J_5,4= 7.1,

J_5,6= 5.1, J_5,3= 1.0, H-5-py); 6.94 (dt, 1H, J_3,4= 8.4,

J_3,5= 1.0, J_3,6= 0.9, H-3-py); 7.22 and 7.29 (2· m, 2·

2H, H-m-Tol); 7.60 (ddd, 1H, J_4,3= 8.4, J_4,5= 7.1,

J_4,6= 2.0, H-4-py); 7.90 and 7.98 (2· m, 2· 2H, H-o-

Tol); 8.09 (ddd, 1H, J_6,5= 5.1, J_6,4= 2.0, J_6,3= 0.9, H-

6-py); 8.25 (s, 1H, H-8); 8.91 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, CDCl₃): 21.68 and 21.74 (CH₃-Tol);

37.80 (CH₂-2⁰); 63.72 (CH₂O); 63.93 (CH₂-5⁰); 75.06

0

1H, J_gem= 14.2, J_{2 b;1}¼ 5:8, J_{2 b;3}¼ 2:1, H-2⁰b); 3.18

0

(ddd, 1H, J_gem= 14.2, J_{2 a;1}¼ 8:4, J_{2 a;3}¼ 6:4, H-

ˇ

´

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2348

2⁰a); 3.50 (t, 2H, J_vic= 6.9, H-5-pyrr); 4.63–4.69 (m,

graphed (hexanes/AcOEt, 1:1–1:4) to give 314 mg

(95%) of product 5v as oil. Exact mass (FAB HR

MS) found: 662.2383; calcd for C₃₅H₃₂N₇O₇:

662.2363. FAB MS m/z (%): 662 (MH⁺, 0.5); 487

(3); 119 (100). ¹H NMR (400 MHz, CDCl₃): 2.38

and 2.42 (2· s, 9H, CH₃-Tol); 4.67 (dd, 1H,

0

2H, H-5⁰b and H-4⁰); 4.77 (m, 1H, H-5⁰a); 5.00 (s,

0

2H, CH₂N); 5.83 (dt, 1H, J_{3 ;2}¼ 6:4, 2.1, J_{3 ;4}¼ 2:1,

H-3⁰); 6.59 (dd, 1H, J_{1 2}¼ 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); 8.85 (s, 1H, H-

2). ¹³C NMR (100.6 MHz, CDCl₃): 19.97 (CH₂-4-

pyrr); 21.68 and 21.73 (CH₃-Tol); 30.55 (CH₂-3-pyrr);

37.72 (CH₂-2⁰); 44.11 (CH₂N); 47.82 (CH₂-5-pyrr);

63.95 (CH₂-5⁰); 75.03 (CH-3⁰); 83.10 (CH-4⁰); 84.85

(CH-1⁰); 126.34 and 126.63 (C-i-Tol); 129.29 (CH-m-

Tol); 129.64 and 129.81 (CH-o-Tol); 132.75 (C-5);

142.78 (CH-8); 144.22 and 144.57 (C-p-Tol); 150.87

(C-4); 152.47 (CH-2); 156.67 (C-6); 165.94 and

166.16 (CO); 175.91 (C-2-pyrr). IR (CCl₄): m = 1699,

1613, 1595, 1493, 1439, 1423, 1408, 1332, 1268, 1178,

0

b;4⁰

J_gem= 12.2, J₅

¼ 4:1, H-5⁰b); 4.83 (m, 1H, H-4⁰);

4.84 (s, 2H, CH₂N₃); 4.91 (dd, 1H, J_gem= 12.2,

0

J_{5 a;4}¼ 3:1, H-5⁰a); 6.21 (dd, 1H, J_{3 ;2}¼ 5:7,

0

J_{3 ;4}¼ 4:7, H-3⁰); 6.39 (t, 1H, J_{2 ;3}¼ 5:7, J_{2 ;1}¼ 5:4,

0

H-2⁰); 6.48 (d, 1H, J_{1 ;2}¼ 5:4, H-1⁰); 7.16, 7.23 and

7.26 (3· m, 3· 2H, H-m-Tol); 7.81, 7.91 and 7.99

(3· m, 3· 2H, H-o-Tol); 8.25 (s, 1H, H-8); 8.87 (s,

1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.71 and

21.75 (CH₃-Tol); 50.55 (CH₂N); 63.33 (CH₂-5⁰);

71.35 (CH-3⁰); 73.70 (CH-2⁰); 81.09 (CH-4⁰); 87.00

(CH-1⁰); 125.56, 125.97 and 126.52 (C-i-Tol); 129.23,

129.27 and 129.34 (CH-m-Tol); 129.75 and 129.87

(CH-o-Tol); 132.54 (C-5); 143.61 (CH-8); 144.28,

144.62 and 144.75 (C-p-Tol); 151.26 (C-4); 152.82

(CH-2); 155.50 (C-6); 165.16, 165.37 and 166.16

(CO). IR (CCl₄): m = 2102, 1732, 1612, 1599, 1498,

0

1101, 646 cm^ꢀ1

.

4.44. 6-[(2-Methoxycarbonylpyrrolidin-1-yl)methyl]-9-

(2,3,5-tri-O-toluoyl-b-^D-ribofuranosyl)purine (5u)

Mixture of mesylate 7 (205 mg, 0.29 mmol), L-proline

methyl ester hydrochloride (93 mg, 0.56 mmol) and ⁱPr_2-

NEt (0.1 ml, 0.56 mmol) in MeCN (15 ml) was stirred at

50 ꢁC for 12 h. Reaction mixture was adsorbed on silica

gel and chromatographed (hexanes/AcOEt, 1:1–0:1) to

give 205 mg (96%) of product 5u as oil. Exact mass

(FAB HR MS) found: 748.3003; calcd for

C₄₁H₄₂N₅O₉: 748.2983. FAB MS m/z (%): 770

(M+Na⁺, 100); 748 (MH⁺, 8); 487 (7); 119 (85). ¹H

NMR (400 MHz, CDCl₃): 1.76–1.83 (m, 1H, H-4b-

Pro); 1.88–2.03 (m, 2H, H-3b-Pro and H-4a-Pro);

2.12–2.17 (m, 1H, H-3a-Pro); 2.38 and 2.42 (2· s, 9H,

CH₃-Tol); 2.68 (m, 1H, H-5b-Pro); 3.22 (m, 1H, H-5a-

Pro); 3.58 (m, 1H, H-2-Pro); 3.65 (s, 3H, CH₃O); 4.29

and 4.46 (2· d, 2H, J_gem= 14.0, CH₂-pur); 4.67 (dd,

1409, 1334, 1266, 1179, 1091, 643 cm^ꢀ1

.

4.46. 6-(Phenyloxymethyl)-9-(2,3,5-tri-O-toluoyl-b-^D-

ribofuranosyl)purine (13b)

Phenol (85 mg, 0.9 mmol) was added to a suspension

of NaH (30 mg, 0.75 mmol, 60% purity) in dry THF

(10 ml) under Ar atmosphere and stirred for 30 min.

Then a solution of mesylate 7 (430 mg, 0.6 mmol) in

THF (5 ml) was added to the preformed solution of

sodium phenoxide. Reaction was quenched with 1 M

aq NaH₂PO₄(40 ml) and the mixture extracted with

CHCl₃(4· 40 ml). Collected organic layers were dried

with MgSO₄, the solvent was evaporated and the res-

idue chromatographed on silica gel (hexanes/AcOEt,

2:1–1:2) to give 380 mg (89%) of 13b as oil. Exact

mass (FAB HR MS) found: 713.2583; calcd for

C₄₁H₃₇N₄O₈: 713.2611. FAB MS m/z (%): 713

(MH⁺, 3); 487 (8); 119 (100). ¹H NMR (400 MHz,

CDCl₃): 2.38, 2.41 and 2.42 (3· s, 9H, CH₃-Tol);

1H, J_gem= 12.2, J_{5 b;4}¼ 4:1, H-5⁰b); 4.81 (td, 1H,

0

J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:1, 3.1, H-4⁰); 4.90 (dd, 1H,

0

J_gem= 12.2, J_{5 a;4}¼ 3:1, H-5⁰a); 6.22 (dd, 1H,

0

J_{3 ;2}¼ 5:7, J_{3 ;4}¼ 4:7, H-3⁰); 6.39 (t, 1H, J_{2 ;3}¼ 5:7,

0

J_{2 ;1}¼ 5:5, H-2⁰); 6.48 (d, 1H, J_{1 ;2}¼ 5:5, H-1⁰); 7.16,

7.22 and 7.26 (3· m, 3· 2H, H-m-Tol); 7.81, 7.90 and

8.00 (3· m, 3· 2H, H-o-Tol); 8.19 (s, 1H, H-8); 8.84

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

and 21.72 (CH₃-Tol); 23.16 (CH₂-4-Pro); 29.31 (CH₂-

3-Pro); 53.58 (CH₂-pur and CH₂-5-Pro); 59.12

(CH₃O); 63.44 (CH₂-5⁰); 64.87 (CH-2-Pro); 71.38 (CH-

3⁰); 73.60 (CH-2⁰); 80.97 (CH-4⁰); 86.81 (CH-1⁰);

125.62, 126.00 and 126.58 (C-i-Tol); 129.20, 129.24

and 129.32 (CH-m-Tol); 129.78, 129.85 (CH-o-Tol);

133.44 (C-5); 142.98 (CH-8); 144.19, 144.55 and 144.67

(C-p-Tol); 150.91 (C-4); 152.71 (CH-2); 156.01 (C-6);

165.13, 165.36 and 166.18 (CO-Tol); 170.62 (COOMe).

IR (CCl₄): m = 1733, 1612, 1594, 1435, 1409, 1333,

0

4.67 (dd, 1H, J_gem= 12.2, J_{5 b;4}¼ 4:1, H-5⁰b); 4.82

0

(td, 1H, J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:1, 3.1, H-4⁰); 4.90 (dd,

0

1H, J_gem= 12.2, J_{5 a;4}¼ 3:1, H-5⁰a); 5.59 (s, 2H,

0

CH₂O); 6.22 (dd, 1H, J_{3 ;2}¼ 5:7, J_{3 ;4}¼ 4:7, H-3⁰);

0

6.39 (t, 1H, J_{2 ;3}¼ 5:7, J_{2 ;1}¼ 5:4, H-2⁰); 6.49 (d,

0

1H, J_{1 ;2}¼ 5:4, H-1⁰); 6.95 (m, 1H, H-p-Ph); 7.06

(m, 1H, H-o-Ph); 7.16 (m, 2H, H-m-Tol); 7.22 and

7.25 (m, 2H, H-m-Tol); 7.27 (m, 1H, H-m-Ph); 7.81,

7.91 and 7.99 (3· m, 3· 2H, H-o-Tol); 8.25 (s, 1H,

H-8); 8.90 (s, 1H, H-2). ¹³C NMR (100.6 MHz,

CDCl₃): 21.71 and 21.74 (CH₃-Tol); 63.36 (CH₂-5⁰);

66.37 (CH₂N); 71.37 (CH-3⁰); 73.72 (CH-2⁰); 81.08

(CH-4⁰); 86.94 (CH-1⁰); 114.95 (CH-o-Ph); 121.32

(CH-p-Ph); 125.61, 126.00 and 126.55 (C-i-Tol);

129.23, 129.27 and 129.34 (CH-m-Tol); 129.45 (H-m-

Ph); 129.77, 129.87 and 129.88 (CH-o-Tol); 132.65

(C-5); 143.50 (CH-8); 144.25, 144.59 and 144.72 (C-

p-Tol); 151.31 (C-4); 152.93 (CH-2); 156.43 (C-6);

158.44 (C-i-Ph); 165.17, 165.37 and 166.18 (CO). IR

(CCl₄): m = 1732, 1612, 1600, 1589, 1495, 1409, 1334,

0

1266, 1179, 1092, 645 cm^ꢀ1

.

4.45. 6-(Azidomethyl)-9-(2,3,5-tri-O-toluoyl-b-^D-ribofur-

anosyl)purine (5v)

Sodium azide (50 mg, 0.77 mmol) was added to a solu-

tion of mesylate 7 (360 mg, 0.5 mmol) in DMF (10 ml)

and stirred at ambient temperature for 6 h. Reaction

mixture was adsorbed on silica gel and chromato-

1266, 1179, 1092, 643 cm^ꢀ1

.

ˇ

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2349

4.47. 6-(Phenyloxymethyl)-9-(2-deoxy-3,5-di-O-toluoyl-

b-^D-erythro-pentofuranosyl)purine (14b)

C₂₈H₂₉N₄O₅S: 533.1859. FAB MS m/z (%): 533 (MH⁺,

11); 181 (62); 119 (100). H NMR (500 MHz, CDCl₃):

2.17 (s, 3H, CH₃S); 2.41 and 2.45 (2· s, 6H, CH₃-Tol);

1

0

Prepared analogously as 13b. Yield: 95% as oil. Exact

mass (FAB HR MS) found: 579.2245; calcd for

C₃₃H₃₁N₄O₆: 579.2244. FAB MS m/z (%): 579 (MH⁺,

2.85 (ddd, 1H, J_gem= 14.2, J_{2 b;1}¼ 5:8, J_{2 b;3}¼ 2:1, H-

2⁰b); 3.20 (ddd, 1H, J_gem= 14.2, J_{2 a;1}¼ 8:4,

0 0

J_{2 a;3}¼ 6:4, H-2⁰a); 4.13 (s, 2H, CH₂S); 4.66–4.69 (m,

0

1

12); 227 (60); 119 (100). H NMR (500 MHz, CDCl₃):

2.40 and 2.45 (2· s, 6H, CH₃-Tol); 2.86 (ddd, 1H,

2H, H-5⁰b and H-4⁰); 4.78 (dd, 1H, J_gem= 13.3,

J_{5 a;4}¼ 5:3, H-5⁰a); 5.84 (dt, 1H, J_{3 ;2}¼ 6:4, 2.1,

0

J_gem= 14.2, J_{2 b;1}¼ 5:8, J_{2 b;3}¼ 2:0, H-2⁰b); 3.20 (ddd,

J_{3 ;4}¼ 2:1, H-3⁰); 6.60 (dd, 1H, J_{1 2}¼ 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); 8.230 (s, 1H, H-8); 8.85 (s,

1H, H-2). ¹³C NMR (125.8 MHz, CDCl₃): 15.96

(CH₃S); 21.69 and 21.75 (CH₃-Tol); 34.52 (CH₂S);

37.79 (CH₂-2⁰); 63.94 (CH₂-5⁰); 75.05 (CH-3⁰); 83.12

(CH-4⁰); 84.89 (CH-1⁰); 126.34 and 126.62 (C-i-Tol);

129.29 (CH-m-Tol); 129.63 and 129.81 (CH-o-Tol);

132.78 (C-5); 142.56 (CH-8); 144.19 and 144.57 (C-p-

Tol); 150.83 (C-4); 152.50 (CH-2); 159.13 (C-6); 165.93

and 166.14 (CO). IR (CCl₄): m = 1727, 1613, 1594,

0

0 0

1H, J_gem= 14.2, J_{2 a;1}¼ 8:2, J_{2 a;3}¼ 6:4, H-2⁰a); 4.65–

0

4.69 (m, 2H, H-5⁰b and H-4⁰); 4.79 (dd, 1H, J_gem= 13.3,

J_{5 a;4}¼ 5:1, H-5⁰a); 5.59 (s, 2H, CH₂O); 5.84 (dt, 1H,

0

J_{3 ;2}¼ 6:4, 2.0, J_{3 ;4}¼ 2:2, H-3⁰); 6.61 (dd, 1H,

0

J_{1 2}¼ 8:2, 5.8, H-1⁰); 6.96 (m, 1H, H-p-Ph); 7.08 (m,

1H, H-o-Ph); 7.22 (m, 2H, H-m-Tol); 7.27 (m, 1H, H-m-

Ph); 7.29 (m, 2H, H-m-Tol); 7.90 and 7.98 (2· m, 2·

2H, H-o-Tol); 8.28 (s, 1H, H-8); 8.95 (s, 1H, H-2). ¹³C

NMR (125.8 MHz, CDCl₃): 21.69 and 21.75 (CH₃-Tol);

37.83 (CH₂-2⁰); 63.90 (CH₂-5⁰); 66.39 (CH₂O); 75.04

(CH-3⁰); 83.19 (CH-4⁰); 84.97 (CH-1⁰); 114.94 (CH-o-

Ph); 121.32 (CH-p-Ph); 126.35 and 126.62 (C-i-Tol);

129.29 and 129.30 (CH-m-Tol); 129.45 (H-m-Ph);

129.63 and 129.82 (CH-o-Tol); 132.69 (C-5); 143.11

(CH-8); 144.21 and 144.59 (C-p-Tol); 151.14 (C-4);

152.68 (CH-2); 156.25 (C-6); 158.44 (C-i-Ph); 165.93

and 166.13 (CO). IR (CCl₄): m = 1727, 1613, 1600, 1588,

0

1494, 1438, 1407, 1331, 1267, 1178, 1100, 645 cm^ꢀ1

.

4.50. 6-(Phenylsulfanylmethyl)-9-(2,3,5-tri-O-toluoyl-b-

D-ribofuranosyl)purine (17b)

PhSNa (150 mg, 1.02 mmol, 90% purity) was added to a

solution of mesylate 7 (500 mg, 0.70 mmol) in dry

MeCN (15 ml) and stirred for 4 h. Reaction mixture

was adsorbed on silica gel and chromatographed (hex-

anes/AcOEt, 2:1–1:2) to give 390 mg (76%) of 17 b as

oil. Exact mass (FAB HR MS) found: 729.2392; calcd

for C₄₁H₃₇N₄O₇S: 729.2383. FAB MS m/z (%): 729

(MH⁺, 3); 487 (18); 119 (100). ¹H NMR (500 MHz,

CDCl₃): 2.38 and 2.42 (2· s, 9H, CH₃-Tol); 4.58 and

4.61 (2· d, 2H, J_gem= 13.5, CH₂S); 4.66 (dd, 1H,

1495, 1408, 1331, 1267, 1178, 1100, 645 cm^ꢀ1

.

4.48. 6-(Methylsulfanylmethyl)-9-(2,3,5-tri-O-toluoyl-b-

D-ribofuranosyl)purine (17a)

MeSNa (36 mg, 0.46 mmol, 90% purity) was added to a

solution of mesylate 7 (300 mg, 0.42 mmol) in dry 1,2-

dimethoxyethane (15 ml) and stirred for 2 h. Reaction

mixture was adsorbed on silica gel and chromatographed

(hexanes/AcOEt, 1:1–1:4) to give 270 mg (96%) of 17a as

oil. Exact mass (FAB HR MS) found: 667.2233; calcd for

C₃₆H₃₅N₄O₇S: 667.2226. FAB MS m/z (%): 667 (MH⁺, 6);

487 (12); 119 (100). ¹H NMR (400 MHz, CDCl₃): 2.15 (s,

3H, CH₃S); 2.38 and 2.42 (2· s, 9H, CH₃-Tol); 4.12 (s, 2H,

J_gem= 12.3, J_{5 b;4}¼ 4:2, H-5⁰b); 4.81 (ddd, 1H,

0

J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:2, 3.1, H-4⁰); 4.89 (dd, 1H,

0

J_gem= 12.3, J_{5 a;4}¼ 3:1, H-5⁰a); 6.21 (dd, 1H,

0

J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:7, H-3⁰); 6.36 (t, 1H, J_{2 ;3}¼ 5:8,

0

J_{2 ;1}¼ 5:5, H-2⁰); 6.46 (d, 1H, J_{1 ;2}¼ 5:5, H-1⁰); 7.13

(m, 1H, H-p-Ph); 7.16 (m, 2H, H-m-Tol); 7.20 (m, 2H,

H-m-Ph); 7.22 and 7.25 (2· m, 2· 2H, H-m-Tol); 7.39

(m, 2H, H-o-Ph); 7.81, 7.90 and 7.99 (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 21.74 (CH₃-Tol);

35.40 (CH₂S); 63.39 (CH₂-5⁰); 71.35 (CH-3⁰); 73.67

(CH-2⁰); 81.02 (CH-4⁰); 86.85 (CH-1⁰); 125.60, 125.98

and 126.54 (C-i-Tol); 126.65 (CH-p-Ph); 128.83 (CH-

m-Ph); 129.23, 129.26 and 129.35 (CH-m-Tol); 129.77,

129.86 and 129.88 (CH-o-Tol); 130.13 (CH-o-Ph);

132.94 (C-5); 135.09 (C-i-Ph); 143.02 (CH-8); 144.25,

144.59 and 144.71 (C-p-Tol); 150.96 (C-4); 152.76

(CH-2); 158.16 (C-6); 165.15, 165.38 and 166.19 (CO).

IR (CCl₄): m = 3064, 1732, 1612, 1595, 1497, 1409,

0

CH₂S); 4.67 (dd, 1H, J_gem= 12.2, J_{5 b;4}¼ 4:1, H-5⁰b);

0

4.82 (td, 1H, J_{4 ;3}¼ 4:5, J_{4 ;5}¼ 4:1, 3.0, H-4⁰); 4.90 (dd,

0

1H, J_gem= 12.2, J_{5 a;4}¼ 3:0, H-5⁰a); 6.23 (t, 1H,

0

J_{3 ;2}¼ 5:5, J_{3 ;4}¼ 4:5, H-3⁰); 6.40 (t, 1H, J_{2 ;3}¼ 5:5,

0

J_{2 ;1}¼ 5:5, H-2⁰); 6.48 (d, 1H, J_{1 ;2}¼ 5:5, H-1⁰); 7.16,

7.22 and 7.25 (3· m, 3· 2H, H-m-Tol); 7.81, 7.90 and

8.00 (3· m, 3· 2H, H-o-Tol); 8.21 (s, 1H, H-8); 8.81 (s,

1H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 15.91

(CH₃S); 21.73 (CH₃-Tol); 34.50 (CH₂S); 63.41 (CH₂-5⁰);

71.37 (CH-3⁰); 73.69 (CH-2⁰); 81.02 (CH-4⁰); 86.95 (CH-

1⁰); 125.62, 126.00 and 126.56 (C-i-Tol); 129.23, 129.36

and 129.44 (CH-m-Tol); 129.81, 129.91 and 129.94 (CH-

o-Tol); 132.80 (C-5); 142.91 (CH-8); 144.23, 144.58 and

144.70 (C-p-Tol); 151.01 (C-4); 152.60 (CH-2); 159.27

(C-6); 165.17, 165.38 and 166.19 (CO). IR (CCl₄):

m = 1733, 1612, 1594, 1497, 1408, 1333, 1266, 1179,

0

1333, 1266, 1179, 1092, 644 cm^ꢀ1

.

4.51. 6-(Phenylsulfanylmethyl)-9-(2-deoxy-3,5-di-O-tolu-

oyl-b-^D-erythro-pentofuranosyl)purine (18b)

1092, 644 cm^ꢀ1

.

4.49. 6-(Methylsulfanylmethyl)-9-(2-deoxy-3,5-di-O-tolu-

oyl-b-^D-erythro-pentofuranosyl)purine (18a)

Prepared analogously as 17b. Yield: 90% as oil. Exact

mass (FAB HR MS) found: 595.2004; calcd for

C₃₃H₃₁N₄O₅S: 595.2015. FAB MS m/z (%): 595 (MH⁺,

13); 243 (64); 119 (95). H NMR (400 MHz, CDCl₃):

2.41 and 2.45 (2· s, 6H, CH₃-Tol); 2.84 (ddd, 1H,

1

Prepared analogously as 17a. Yield: 96% as oil. Exact

mass (FAB HR MS) found: 533.1870; calcd for

ˇ

´

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2350

1

1); 257 (12); 119 (100). H NMR (400 MHz, CDCl₃):

2.40 and 2.45 (2· s, 6H, CH₃-Tol); 2.85 (ddd, 1H,

J_gem= 14.2, J_{2 b;1}¼ 5:8, J_{2 b;3}¼ 2:0, H-2⁰b); 3.18 (ddd,

0

1H, J_gem= 14.2, J_{2 a;1}¼ 8:3, J_{2 a;3}¼ 6:4, H-2⁰a); 4.59

and 4.63 (2· d, 2H, J_gem= 13.6, CH₂S); 4.65–4.69 (m,

2H, H-5⁰b and H-4⁰); 4.77 (dd, 1H, J_gem= 13.4,

0

J_gem= 14.2, J_{2 b;1}¼ 5:8, J_{2 b;3}¼ 2:1, H-2⁰b); 3.18 (ddd,

0

1H, J_gem= 14.2, J_{2 a;1}¼ 8:3, J_{2 a;3}¼ 6:4, H-2⁰a); 3.83

(s, 2H, CH₂Ph); 4.08 (s, 2H, CH₂-pur); 4.66–4.70 (m,

2H, H-5⁰b and H-4⁰); 4.79 (dd, 1H, J_gem= 13.6,

0

J_{5 a;4}¼ 5:4, H-5⁰a); 5.83 (dt, 1H, J_{3 ;2}¼ 6:3, 2.1,

0

J_{3 ;4}¼ 2:1, H-3⁰); 6.58 (dd, 1H, J_{1 2}¼ 8:3, 5.8, H-1⁰);

7.15 ( m, 1H, H-p-Ph); 7.22 (m, 2H, H-m-Ph); 7.22

and 7.29 (2· m, 2· 2H, H-m-Tol); 7.42 (m, 2H, H-o-

Ph); 7.90 and 7.98 (2· m, 2· 2H, H-o-Tol); 8.21 (s,

1H, H-8); 8.84 (s, 1H, H-2). ¹³C NMR (125.8 MHz,

CDCl₃): 21.70 and 21.75 (CH₃-Tol); 35.32 (CH₂S);

37.78 (CH₂-2⁰); 63.92 (CH₂-5⁰); 75.04 (CH-3⁰); 83.13

(CH-4⁰); 84.91 (CH-1⁰); 126.33 and 126.61 (C-i-Tol);

126.57 (CH-p-Ph); 128.84 (CH-m-Ph); 129.29 (CH-m-

Tol); 129.63 and 129.81 (CH-o-Tol); 129.92 (CH-o-Ph);

132.92 (C-5); 135.30 (C-i-Ph); 142.63 (CH-8); 144.21

and 144.58 (C-p-Tol); 150.79 (C-4); 152.51 (CH-2);

158.01 (C-6); 165.93 and 166.14 (CO). IR (CCl₄):

m = 3064, 1727, 1613, 1594, 1585, 1494, 1440, 1407,

0

0 0

J_{5 a;4}¼ 5:5, H-5⁰a); 5.84 (dt, 1H, J_{3 ;2}¼ 6:4, 2.1,

0

J_{3 ;4}¼ 2:1, H-3⁰); 6.59 (dd, 1H, J_{1 2}¼ 8:3, 5.8, H-1⁰);

7.20 (m, 1H, H-p-Ph); 7.22 and 7.29 (2· m, 2· 2H, H-

m-Tol); 7.25 (m, 2H, H-m-Ph); 7.38 (m, 2H, H-o-Ph);

7.91 and 7.98 (2· m, 2· 2H, H-o-Tol); 8.22 (s, 1H, H-

8); 8.86 (s, 1H, H-2). ¹³C NMR (125.8 MHz, CDCl₃):

21.68 and 21.75 (CH₃-Tol); 31.92 (CH₂-pur); 36.47

(CH₂-Ph); 37.83 (CH₂-2⁰); 63.95 (CH₂-5⁰); 75.06 (CH-

3⁰); 83.12 (CH-4⁰); 84.88 (CH-1⁰); 126.37 and 126.64

(C-i-Tol); 126.99 (CH-p-Ph); 128.33 (CH-m-Ph); 129.13

(CH-o-Ph); 129.30 (CH-m-Tol); 129.64 and 129.82

(CH-o-Tol); 132.70 (C-5); 137.88 (C-i-Ph); 142.40 (CH-

8); 144.20 and 144.57 (C-p-Tol); 150.77 (C-4); 152.46

(CH-2); 159.37 (C-6); 165.93 and 166.15 (CO). IR

(CCl₄): m = 3033, 1727, 1613, 1593, 1495, 1454, 1407,

0

0 0

1331, 1267, 1178, 1100, 645 cm^ꢀ1

.

4.52. 6-(Benzylsulfanylmethyl)-9-(2,3,5-tri-O-toluoyl-b-^D-

ribofuranosyl)purine (17c)

1331, 1267, 1178, 1101, 645 cm^ꢀ1

.

4.54. 6-[(Methoxycarbonylmethyl)sulfanylmethyl]-9-

(2,3,5-tri-O-toluoyl-b-^D-ribofuranosyl)purine (17d)

Benzyl mercaptan (50 ll, 0.42 mmol) was added to a

solution of mesylate 7 (200 mg, 0.28 mmol) and ⁱPr₂EtN

(50 ll, 0.29 mmol) in dry MeCN (10 ml) and stirred for

8 h. Reaction mixture was adsorbed on silica gel and

chromatographed (hexanes/AcOEt, 2:1–1:2) to give

203 mg (98%) of 17c as oil. Exact mass (FAB HR MS)

found: 743.2565; calcd for C₄₂H₃₉N₄O₇S: 743.2539.

FAB MS m/z (%): 743 (MH⁺, 3); 487 (6); 257 (3); 119

(100). ¹H NMR (500 MHz, CDCl₃): 2.38, 2.41 and

2.42 (3· s, 3· 3H, CH₃-Tol); 3.81 (s, 2H, CH₂Ph); 4.08

(s, 2H, CH₂-pur); 4.67 (dd, 1H, J_gem= 12.3,

Methyl thioglycolate (0.19 ml, 2.13 mmol) was added to

a solution of mesylate 7 (500 mg, 0.70 mmol) and

ⁱPr₂EtN (0.19 ml, 1.09 mmol) in dry MeCN (15 ml)

and stirred for 8 h. Reaction mixture was adsorbed on

silica gel and chromatographed (hexanes/AcOEt, 2:1–

1:2) to give 502 mg (99%) of 17d as oil. Exact mass

(FAB HR MS) found: 725.2266; calcd for

C₃₈H₃₇N₄O₉S: 725.2281. FAB MS m/z (%): 725 (MH⁺,

1

4); 487 (10); 119 (100). H NMR (500 MHz, CDCl₃):

2.38 and 2.42 (2· s, 9H, CH₃-Tol); 3.42 (s, 2H,

SCH₂CO); 3.69 (s, 3H, CH₃O); 4.29 (s, 2H, CH₂-pur);

J_{5 b;4}¼ 4:2, H-5⁰b); 4.83 (td, 1H, J_{4 ;3}¼ 4:7,

0

J_{4 ;5}¼ 4:2, 3.1, H-4⁰); 4.90 (dd, 1H, J_gem= 12.3,

0

J_{5 a;4}¼ 3:1, H-5⁰a); 6.22 (dd, 1H, J_{3 ;2}¼ 5:8,

4.67 (dd, 1H, J_gem= 12.3, J_{5 b;4}¼ 4:2, H-5⁰b); 4.82 (td,

0

J_{3 ;4}¼ 4:7, H-3⁰); 6.38 (t, 1H, J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:4,

1H, J_{4 ;3}¼ 4:6, J_{4 ;5}¼ 4:2, 3.2, H-4⁰); 4.90 (dd, 1H,

0

H-2⁰); 6.47 (d, 1H, J_{1 ;2}¼ 5:4, H-1⁰); 7.17 (m, 2H, H-

m-Tol); 7.18 (m, 1H, H-p-Ph); 7.22 (m, 2H, H-m-Tol);

7.24 (m, 2H, H-m-Ph); 7.25 (m, 2H, H-m-Tol); 7.36

(m, 2H, H-o-Ph); 7.83, 7.91 and 8.00 (3· m, 3· 2H, H-

o-Tol); 8.20 (s, 1H, H-8); 8.81 (s, 1H, H-2). ¹³C NMR

(125.7 MHz, CDCl₃): 21.70 and 21.73 (CH₃-Tol);

31.92 (CH₂-pur); 36.43 (CH₂-Ph); 63.42 (CH₂-5⁰);

71.36 (CH-3⁰); 73.69 (CH-2⁰); 80.99 (CH-4⁰); 86.85

(CH-1⁰); 125.62, 125.99 and 126.55 (C-i-Tol); 126.97

(CH-p-Ph); 128.30 (CH-m-Ph); 129.11 (CH-o-Ph);

129.22, 129.25 and 129.33 (CH-m-Tol); 129.77, 129.86

and 129.88 (CH-o-Tol); 132.69 (C-5); 137.83 (C-i-Ph);

142.82 (CH-8); 144.24, 144.57 and 144.70 (C-p-Tol);

150.93 (C-4); 152.68 (CH-2); 159.47 (C-6); 165.16,

165.37 and 166.19 (CO). IR (CCl₄): m = 3034, 1733,

1612, 1593, 1495, 1454, 1409, 1333, 1266, 1179, 1092,

J_gem= 12.3, J_{5 a;4}¼ 3:2, H-5⁰a); 6.21 (dd, 1H,

0

J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:6, H-3⁰); 6.39 (t, 1H, J_{2 ;3}¼ 5:8,

0

J_{2 ;1}¼ 5:5, H-2⁰); 6.48 (d, 1H, J_{1 ;2}¼ 5:5, H-1⁰); 7.17,

7.22 and 7.26 (3· m, 3· 2H, H-m-Tol); 7.81, 7.91 and

8.00 (3· m, 3· 2H, H-o-Tol); 8.21 (s, 1H, H-8); 8.80

(s, 1H, H-2). ¹³C NMR (125.7 MHz, CDCl₃): 21.71

and 21.74 (CH₃-Tol); 32.65 (CH₂-pur); 33.43

(SCH₂CO); 52.43 (CH₃O); 63.43 (CH₂-5⁰); 71.37 (CH-

3⁰); 73.63 (CH-2⁰); 81.04 (CH-4⁰); 86.88 (CH-1⁰);

125.60, 125.998 and 126.55 (C-i-Tol); 129.23, 129.26

and 129.34 (CH-m-Tol); 129.78, 129.86 and 129.88

(CH-o-Tol); 132.73 (C-5); 143.11 (CH-8); 144.25,

144.59 and 144.72 (C-p-Tol); 151.06 (C-4); 152.73

(CH-2); 158.59 (C-6); 165.16, 165.38 and 166.19 (CO-

Tol); 170.51 (COOMe). IR (CCl₄): m = 3038, 1733,

1612, 1595, 1497, 1454, 1409, 1333, 1266, 1179, 1092,

0

643 cm^ꢀ1

.

644 cm^ꢀ1

.

4.53. 6-(Benzylsulfanylmethyl)-9-(2-deoxy-3,5-di-O-tolu-

oyl-b-^D-erythro-pentofuranosyl)purine (18c)

4.55. 6-[(Methoxycarbonylmethyl)sulfanylmethyl]-9-(2-

deoxy-3,5-di- O-toluoyl-b-^D-erythro-pentofurano-

syl)purine (18d)

Prepared analogously as 17c. Yield: 98% as oil. Exact

mass (FAB HR MS) found: 609.2148; calcd for

C₃₄H₃₃N₄O₅S: 609.2172. FAB MS m/z (%): 609 (MH⁺,

Prepared analogously as 17d. Yield: 99% as oil. Exact

mass (FAB HR MS) found: 591.1926; calcd for

ˇ

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2351

C₃₀H₃₁N₄O₇S: 591.1913. FAB MS m/z (%): 591 (MH⁺,

8); 239 (40); 119 (100). H NMR (400 MHz, CDCl₃):

2.41 and 2.45 (2· s, 6H, CH₃-Tol); 2.85 (ddd, 1H,

2.41 and 2.45 (2· s, 6H, CH₃-Tol); 2.82 (m, 2H,

1

0

CH₂S); 2.87 (ddd, 1H, J_gem= 14.2, J_{2 b;1}¼ 5:8,

J_{2 b;3}¼ 2:0, H-2⁰b); 3.18 (ddd, 1H, J_gem= 14.2,

0 0

J_gem= 14.2, J_{2 b;1}¼ 5:8, J_{2 b;3}¼ 2:1, H-2⁰b); 3.20 (ddd,

J_{2 a;1}¼ 8:1, J_{2 a;3}¼ 6:5, H-2⁰a); 3.91 (m, 2H, CH₂O);

0

1H, J_gem= 14.2, J_{2 a;1}¼ 8:4, J_{2 a;3}¼ 6:4, H-2⁰a); 3.44

(s, 2H, SCH₂CO); 3.72 (s, 3H, CH₃O); 4.30 (s, 2H,

CH₂-pur); 4.65–4.69 (m, 2H, H-5⁰b and H-4⁰); 4.78

4.29 (s, 2H, CH₂-pur); 4.65–4.69 (m, 2H, H-5⁰b and H-

0

4⁰); 4.78 (dd, 1H, J_gem= 13.2, J_{5 a;4}¼ 5:1, H-5⁰a); 5.83

0

(dt, 1H, J_{3 ;2}¼ 6:5, 2.0, J_{3 ;4}¼ 2:2, H-3⁰); 6.59 (dd,

0

(dd, 1H, J_gem= 13.3, J_{5 a;4}¼ 5:3, H-5⁰a); 5.84 (dt, 1H,

1H, J_{1 2}¼ 8:1, 5.8, H-1⁰); 7.22 and 7.29 (2· m, 2· 2H,

H-m-Tol); 7.90 and 7.98 (2· m, 2· 2H, H-o-Tol); 8.25

(s, 1H, H-8); 8.85 (s, 1H, H-2). ¹³C NMR (125.8 MHz,

CDCl₃): 21.68 and 21.74 (CH₃-Tol); 32.03 (CH₂S);

36.08 (CH₂O); 37.84 (CH₂-2⁰); 62.19 (CH₂-pur); 63.90

(CH₂-5⁰); 75.01 (CH-3⁰); 83.23 (CH-4⁰); 85.09 (CH-1⁰);

126.31 and 126.58 (C-i-Tol); 129.21 and 129.39 (CH-m-

Tol); 129.66 and 126.79 (CH-o-Tol); 132.53 (C-5);

142.85 (CH-8); 144.24 and 144.60 (C-p-Tol); 150.82 (C-

4); 152.63 (CH-2); 159.47 (C-6); 165.93 and 166.13

(CO). IR (CHCl₃): m = 3293, 1721, 1612, 1597, 1496,

0

0 0

J_{3 ;2}¼ 6:2, 2.0, J_{3 ;4}¼ 2:0, H-3⁰); 6.59 (dd, 1H,

0

J_{1 2}¼ 8:3, 5.8, H-1⁰); 7.22 and 7.29 (2· m, 2· 2H, H-

m-Tol); 7.90 and 7.98 (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): 21.68 and 21.74 (CH₃-Tol); 32.67 (CH₂-pur);

33.51 (SCH₂CO); 37.78 (CH₂-2⁰); 52.44 (CH₃O); 63.94

(CH₂-5⁰); 75.05 (CH-3⁰); 83.14 (CH-4⁰); 84.94 (CH-1⁰);

126.35 and 126.63 (C-i-Tol); 129.29 (CH-m-Tol);

129.63 and 129.81 (CH-o-Tol); 132.72 (C-5); 142.69

(CH-8); 144.20 and 144.57 (C-p-Tol); 150.89 (C-4);

152.49 (CH-2); 158.46 (C-6); 165.92 and 166.13 (CO-

Tol); 170.49 (COOMe). IR (CCl₄): m = 3037, 1728,

1613, 1595, 1494, 1436, 1407, 1332, 1267, 1178, 1101,

0

1407, 1333, 1269, 1179, 1102, 646 cm^ꢀ1

.

4.58. 6-[(Pyridin-2-yl)sulfanylmethyl]-9-(2,3,5-tri-O-tolu-

oyl-b-^D-ribofuranosyl)purine (17g)

645 cm^ꢀ1

.

4.56. 6-[(2-Hydroxyethyl)sulfanylmethyl]-9-(2,3,5-tri-O-

toluoyl-b-^D-ribofuranosyl)purine (17e)

2-Mercaptopyridine (310 mg, 2.79 mmol) was added to

a solution of mesylate 7 (500 mg, 0.70 mmol) and

ⁱPr₂EtN (0.37 ml, 2.1 mmol) in dry MeCN (15 ml) and

stirred for 8 h. Reaction mixture was adsorbed on silica

gel and chromatographed (CHCl₃/MeOH, 99:1–98:2) to

give 500 mg (98%) of 17g as oil. Exact mass (FAB HR

MS) found: 730.2326; calcd for C₄₀H₃₆N₅O₇S:

730.2335. FAB MS m/z (%): 730 (MH⁺, 8); 487 (17);

2-Mercaptoethanol (0.15 ml, 2.14 mmol) was added to a

solution of mesylate 7 (500 mg, 0.70 mmol) and ⁱPr₂EtN

(0.19 ml, 1.09 mmol) in dry MeCN (15 ml) and stirred

for 8 h. Reaction mixture was adsorbed on silica gel

and chromatographed (hexanes/AcOEt, 1:1–0:1) to give

478 mg (98%) of 17e as oil. Exact mass (FAB HR MS)

found: 697.2308; calcd for C₃₇H₃₇N₄O₈S: 697.2332.

FAB MS m/z (%): 697 (MH⁺, 4); 487 (12); 119 (100).

¹H NMR (400 MHz, CDCl₃): 2.38 and 2.42 (2· s, 9H,

CH₃-Tol); 2.81 (m, 2H, CH₂S); 3.90 (m, 2H, CH₂O);

4.28 (s, 2H, CH₂-pur); 4.67 (dd, 1H, J_gem= 12.2,

1

119 (100). H NMR (400 MHz, CDCl₃): 2.38 and 2.42

(2· s, 9H, CH₃-Tol); 4.66 (dd, 1H, J_gem= 12.2,

J_{5 b;4}¼ 4:1, H-5⁰b); 4.81 (td, 1H, J_{4 ;3}¼ 4:6,

0

J_{4 ;5}¼ 4:1, 3.1, H-4⁰); 4.89 (dd, 1H, J_gem= 12.2,

0

J_{5 a;4}¼ 3:1, H-5⁰a); 4.95 and 4.99 (2· d, 2H, J_gem= 14.3,

0

CH₂S); 6.21 (dd, 1H, J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:6, H-3⁰); 6.39

0

J_{5 b;4}¼ 4:1, H-5⁰b); 4.83 (td, 1H, J_{4 ;3}¼ 4:6,

(t, 1H, J_{2 ;3}¼ 5:8, J_{2 ;1}¼ 5:5, H-2⁰); 6.48 (d, 1H,

0

J_{4 ;5}¼ 4:1, 3.1, H-4⁰); 4.90 (dd, 1H, J_gem= 12.2,

J_{1 ;2}¼ 5:5, H-1⁰); 6.96 (ddd, 1H, J_5,4= 7.4, J_5,6= 4.9,

J_5,3= 1.1, H-5-py); 7.16, 7.21 and 7.25 (3· m, 3· 2H,

H-m-Tol); 7.27 (dt, 1H, J_3,4= 8.1, J_3,5= 1.1, J_3,6= 1.0,

H-3-py); 7.46 (ddd, 1H, J_4,3= 8.1, J_4,5= 7.4, J_4,6= 1.9,

H-4-py); 7.81, 7.90 and 7.99 (3· m, 3· 2H, H-o-Tol);

8.22 (s, 1H, H-8); 8.40 (ddd, 1H, J_6,5= 4.9, J_6,4= 1.9,

J_6,3= 1.0, H-6-py); 8.81 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, CDCl₃): 21.70 and 21.73 (CH₃-Tol);

31.15 (CH₂S); 63.41 (CH₂-5⁰); 71.38 (CH-3⁰); 73.67

(CH-2⁰); 81.02 (CH-4⁰); 86.84 (CH-1⁰); 119.68 (CH-5-

py); 121.97 (CH-3-py); 125.63, 126.01 and 126.55 (C-i-

Tol); 129.21, 129.25 and 129.34 (CH-m-Tol); 129.77,

129.86 and 129.88 (CH-o-Tol); 133.11 (C-5); 135.99

(CH-4-py); 142.95 (CH-8); 144.22, 144.56 and 144.68

(C-p-Tol); 149.45 (CH-6-py); 150.84 (C-4); 152.86

(CH-2); 157.54 (C-2-py); 158.49 (C-6); 165.15, 165.37

and 166.20 (CO). IR (CCl₄): m = 1732, 1612, 1593,

1580, 1496, 1453, 1415, 1334, 1266, 1179, 1092,

0

J_{5 a;4}¼ 3:1, H-5⁰a); 6.20 (dd, 1H, J_{3 ;2}¼ 5:7,

0

J_{3 ;4}¼ 4:6, H-3⁰); 6.37 (t, 1H, J_{2 ;3}¼ 5:7, J_{2 ;1}¼ 5:4,

0

H-2⁰); 6.48 (d, 1H, J_{1 ;2}¼ 5:4, H-1⁰); 7.16, 7.23 and

7.26 (3· m, 3· 2H, H-m-Tol); 7.81, 7.91 and 7.99 (3·

m, 3· 2H, H-o-Tol); 8.23 (s, 1H, H-8); 8.81 (s, 1H, H-

2). ¹³C NMR (100.6 MHz, CDCl₃): 21.71 and 21.74

(CH₃-Tol); 31.99 (CH₂S); 35.98 (CH₂O); 62.11 (CH₂-

pur); 63.39 (CH₂-5⁰); 71.37 (CH-3⁰); 73.72 (CH-2⁰);

81.10 (CH-4⁰); 86.98 (CH-1⁰); 125.58, 125.98 and

126.54 (C-i-Tol); 129.24, 129.27 and 129.35 (CH-m-

Tol); 129.77, 129.87 and 129.88 (CH-o-Tol); 132.57 (C-

5); 143.20 (CH-8); 144.28, 144.61 and 144.75 (C-p-

Tol); 151.03 (C-4); 152.75 (CH-2); 159.57 (C-6);

165.19, 165.37 and 166.18 (CO). IR (CHCl₃): m = 3300,

1727, 1612, 1596, 1498, 1409, 1335, 1267, 1180, 1093,

0

644 cm^ꢀ1

.

4.57. 6-[(2-Hydroxyethyl)sulfanylmethyl]-9-(2-deoxy-3,5-

di-O-toluoyl-b-^D-erythro-pentofuranosyl)purine (18e)

644 cm^ꢀ1

.

4.59. 6-[(Pyridin-2-yl)sulfanylmethyl]-9-(2-deoxy-3,5-di-

O-toluoyl-b-^D-erythro-pentofuranosyl)purine (18 g)

Prepared analogously as 17e. Yield: 98% as oil. Exact

mass (FAB HR MS) found: 563.1993; calcd for

C₂₉H₃₁N₄O₆S: 563.1964. FAB MS m/z (%): 563 (MH⁺,

Prepared analogously as 17g. Yield: 98% as oil. Exact

mass (FAB HR MS) found: 596.1989; calcd for

1

14); 211 (65); 119 (100). H NMR (500 MHz, CDCl₃):

ˇ

´

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2352

C₃₂H₃₀N₅O₅S: 596.1968. FAB MS m/z (%): 596 (MH⁺,

5); 244 (50); 119 (100). H NMR (400 MHz, CDCl₃):

2.41 and 2.45 (2· s, 6H, CH₃-Tol); 2.85 (ddd, 1H,

and 144.72 (C-p-Tol); 151.00 (C-4); 152.82 (CH-2);

153.08 (C-3a-benzothiazole); 156.37 (C-6); 165.17,

165.37 and 166.19 (C-2-benzothiazole and CO). IR

(CCl₄): m = 1732, 1612, 1595, 1496, 1463, 1457, 1429,

1

J_gem= 14.2, J_{2 b;1}¼ 5:8, J_{2 b;3}¼ 2:0, H-2⁰b); 3.19 (ddd,

0

1H, J_gem= 14.2, J_{2 a;1}¼ 8:4, J_{2 a;3}¼ 6:4, H-2⁰a); 4.65–

1409, 1334, 1266, 1179, 1092, 643 cm^ꢀ1

.

0

4.69 (m, 2H, H-5⁰b and H-4⁰); 4.77 (dd, 1H, J_gem= 13.4,

J_{5 a;4}¼ 5:4, H-5⁰a); 4.95 and 5.00 (2· d, 2H, J_gem= 14.2,

4.61. 6-(Acetylsulfanylmethyl)-9-(2,3,5-tri-O-toluoyl-b-^D-

ribofuranosyl)purine (17ia)

0

CH₂S); 5.83 (dt, 1H, J_{3 ;2}¼ 6:4, 2.0, J_{3 ;4}¼ 2:0, H-3⁰);

0

6.59 (dd, 1H, J_{1 2}¼ 8:4, 5.8, H-1⁰); 6.97 (ddd, 1H,

J_5,4= 7.3, J_5,6= 4.9, J_5,3= 1.0, H-5-py); 7.22 and 7.29

(2· m, 2· 2H, H-m-Tol); 7.27 (ddd, 1H, J_3,4= 8.1,

J_3,5= 1.0, J_3,6= 1.0, H-3-py); 7.47 (ddd, 1H, J_4,3= 8.1,

J_4,5= 7.4, J_4,6= 1.9, H-4-py); 7.90 and 7.97 (2· m, 2·

2H, H-o-Tol); 8.25 (s, 1H, H-8); 8.42 (ddd, 1H,

J_6,5= 4.9, J_6,4= 1.9, J_6,3= 1.0, H-6-py);8.86 (s, 1H, H-

2). ¹³C NMR (100.6 MHz, CDCl₃): 21.69 and 21.74

(CH₃-Tol); 31.15 (CH₂S); 37.79 (CH₂-2⁰); 63.94 (CH₂-

5⁰); 75.07 (CH-3⁰); 83.13 (CH-4⁰); 84.91 (CH-1⁰);

119.67 (CH-5-py); 121.07 (CH-3-py); 126.36 and

126.63 (C-i-Tol); 129.29 (CH-m-Tol); 129.63 and

129.81 (CH-o-Tol); 133.10 (C-5); 135.99 (CH-4-py);

142.55 (CH-8); 144.18 and 144.55 (C-p-Tol); 149.44

(CH-6-py); 150.67 (C-4); 152.61 (CH-2); 157.77 (C-2-

py); 158.33 (C-6); 165.93 and 166.14 (CO). IR (CCl₄):

m = 3049, 1727, 1613, 1593, 1579, 1562, 1494, 1453,

0

Potassium thioacetate (96 mg, 0.84 mmol) was added to

a solution of mesylate 7 (410 mg, 0.57 mmol) in dry

MeCN (15 ml) and stirred for 6 h. Reaction mixture

was adsorbed on silica gel and chromatographed (hex-

anes/AcOEt, 2:1–1:2) to give 375 mg (95%) of 17ia as

foam. Exact mass (FAB HR MS) found: 695.2200; calcd

for C₃₇H₃₅N₄O₈S: 695.2176. FAB MS m/z (%): 695

(MH⁺, 4); 487 (9); 119 (100). ¹H NMR (400 MHz,

CDCl₃): 2.377 (s, 3H, CH₃-Tol); 2.382 (s, 3H, CH₃CO);

2.42 (s, 6H, CH₃-Tol); 4.65 (s, 2H, CH₂S); 4.66 (dd, 1H,

J_gem= 12.2, J_{5 b;4}¼ 4:1, H-5⁰b); 4.81 (ddd, 1H,

0

J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:1, 3.1, H-4⁰); 4.89 (dd, 1H, J_gem

=

0

12.2, J_{5 a;4}¼ 3:1, H-5⁰a); 6.21 (dd, 1H, J_{3 ;2}¼ 5:7,

0

J_{3 ;4}¼ 4:7, H-3⁰); 6.39 (t, 1H, J_{2 ;3}¼ 5:7, J_{2 ;1}¼ 5:5,

0

H-2⁰); 6.47 (d, 1H, J_{1 ;2}¼ 5:5, H-1⁰); 7.16, 7.22 and

7.26 (3· m, 3· 2H, H-m-Tol); 7.81, 7.90 and 7.99 (3·

m, 3· 2H, H-o-Tol); 8.23 (s, 1H, H-8); 8.81 (s, 1H, H-

2). ¹³C NMR (100.6 MHz, CDCl₃): 21.70 and 21.73

(CH₃-Tol); 30.15 (CH₃CO); 30.22 (CH₂S); 63.41 (CH₂-

5⁰); 71.38 (CH-3⁰); 73.62 (CH-2⁰); 81.06 (CH-4⁰); 86.88

(CH-1⁰); 125.62, 126.01 and 126.56 (C-i-Tol); 129.26,

129.26 and 129.34 (CH-m-Tol); 129.78, 129.86 and

129.88 (CH-o-Tol); 133.02 (C-5); 143.23 (CH-8);

144.23, 144.58 and 144.70 (C-p-Tol); 150.93 (C-4);

152.84 (CH-2); 157.31 (C-6); 165.15, 165.37 and 166.19

(CO-Tol); 193.89 (S-CO). IR (CCl₄): m = 1732, 1702,

1612, 1594, 1497, 1454, 1409, 1334, 1266, 1179, 1093,

0

1447, 1418, 1332, 1267, 1178, 1101, 645 cm^ꢀ1

.

4.60. 6-[(Benzothiazol-2-yl)sulfanylmethyl]-9-(2,3,5-tri-

O-toluoyl-b-^D-ribofuranosyl)purine (17h)

2-Mercaptobenzothiazole (350 mg, 2.09 mmol) was

added to a solution of mesylate 7 (500 mg, 0.70 mmol)

and ⁱPr₂EtN (0.19 ml, 1.09 mmol) in dry MeCN

(15 ml) and stirred for 8 h. Reaction mixture was ad-

sorbed on silica gel and chromatographed (hexanes/

AcOEt, 2:1–1:2) to give 540 mg (98%) of 17h as foam.

Exact mass (FAB HR MS) found: 786.2096; calcd for

C₄₂H₃₆N₅O₇S₂: 786.2056. FAB MS m/z (%): 786

(MH⁺, 1); 487 (10); 119 (100). ¹H NMR (500 MHz,

CDCl₃): 2.37, 2.41 and 2.42 (3· s, 3· 3H, CH₃-Tol);

643, 623 cm^ꢀ1

.

4.62. 6-(Acetylsulfanylmethyl)-9-(2-deoxy-3,5-di-O-tolu-

oyl-b-^D-erythro-pentofuranosyl)purine (18ia)

4.66 (dd, 1H, J_gem= 12.3, J_{5 b;4}¼ 4:1, H-5⁰b); 4.82

0

(td, 1H, J_{4 ;3}¼ 4:7, J_{4 ;5}¼ 4:1, 3.1, H-4⁰); 4.90 (dd,

Prepared analogously as 17ia. Yield: 96% as foam. Ex-

act mass (FAB HR MS) found: 561.1784; calcd for

C₂₉H₂₉N₄O₆S: 561.1808. FAB MS m/z (%): 561 (MH⁺,

0

1H, J_gem= 12.3, J_{5 a;4}¼ 3:1, H-5⁰a); 5.12 and 5.16

0

(2· d, 2H, J_gem= 14.3, CH₂S); 6.21 (dd, 1H,

1

J_{3 ;2}¼ 5:8, J_{3 ;4}¼ 4:7, H-3⁰); 6.39 (t, 1H, J_{2 ;3}¼ 5:8,

6); 209 (27); 167 (14); 119 (100). H NMR (500 MHz,

CDCl₃): 2.39 (s, 3H, CH₃CO); 2.41 and 2.45 (2· s, 2·

0

J_{2 ;1}¼ 5:4, H-2⁰); 6.48 (d, 1H, J_{1 ;2}¼ 5:4, H-1⁰);

7.16, 7.22 and 7.24 (3· m, 3· 2H, H-m-Tol); 7.28

(ddd, 1H, J_6,7= 8.0, J_6,5= 7.3, J_6,4= 1.2, H-6-benzo-

thiazole); 7.38 (ddd, 1H, J_5,4= 8.2, J_5,6= 7.3,

J_5,7= 1.3, H-5-benzothiazole); 7.73 (ddd, 1H,

J_7,6= 8.0, J_7,5= 1.3, J_7,4= 0.6, H-7-benzothiazole);

7.81 (m, 2H, H-o-Tol); 7.85 (ddd, 1H, J_4,5= 8.2,

J_4,6= 1.2, J_4,7= 0.6, H-4-benzothiazole); 7.91 and

7.98 (2· m, 2· 2H, H-o-Tol); 8.25 (s, 1H, H-8); 8.83

(s, 1H, H-2). ¹³C NMR (125.7 MHz, CDCl₃): 21.70

and 21.74 (CH₃-Tol); 34.35 (CH₂S); 63.35 (CH₂-5⁰);

71.35 (CH-3⁰); 73.69 (CH-2⁰); 81.07 (CH-4⁰); 86.95

(CH-1⁰); 120.95 (CH-7-benzothiazole); 121.78 (CH-4-

benzothiazole); 124.30 (CH-6-benzothiazole); 125.59,

125.98 and 126.52 (CH-5-benzothiazole and C-i-Tol);

129.23, 129.26 and 129.34 (CH-m-Tol); 129.75,

129.86 and 129.88 (CH-o-Tol); 133.04 (C-5); 135.55

(C-7a-benzothiazole); 143.32 (CH-8); 144.27, 144.60

0

3H, CH₃-Tol); 2.85 (ddd, 1H, J_gem= 14.2, J_{2 b;1}¼ 5:8,

J_{2 b;3}¼ 2:1, H-2⁰b); 3.20 (ddd, 1H, J_gem= 14.2,

0

J_{2 a;1}¼ 8:4, J_{2 a;3}¼ 6:4, H-2⁰a); 4.64–4.69 (m, 2H, H-

0

5⁰b and H-4⁰); 4.66 (s, 2H, CH₂S); 4.77 (m, 1H, H-

5⁰a); 5.83 (dt, 1H, J_{3 ;2}¼ 6:4, 2.1, J_{3 ;4}¼ 2:1, H-3⁰);

0

6.58 (dd, 1H, J_{1 2}¼ 8:4, 5.8, H-1⁰); 7.23 and 7.29 (2·

m, 2· 2H, H-m-Tol); 7.90 and 7.97 (2· m, 2· 2H, H-

o-Tol); 8.25 (s, 1H, H-8); 8.85 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, CDCl₃): 21.69 and 21.74 (CH₃-Tol);

30.16 (CH₃CO); 30.22 (CH₂S); 37.75 (CH₂-2⁰); 63.92

(CH₂-5⁰); 75.05 (CH-3⁰); 83.15 (CH-4⁰); 84.95 (CH-1⁰);

126.35 and 126.62 (C-i-Tol); 129.29 (CH-m-Tol);

129.63 and 129.81 (CH-o-Tol); 133.03 (C-5); 142.85

(CH-8); 144.20 and 144.57 (C-p-Tol); 150.73 (C-4);

152.59 (CH-2); 157.13 (C-6); 165.93 and 166.14 (CO);

193.89 (S-CO). IR (CCl₄): m = 1727, 1703, 1613, 1594,

0

1494, 1454, 1407, 1332, 1266, 1178, 1100, 645, 623 cm^ꢀ1

.

ˇ

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2353

4.63. General procedure for cleavage of toluoyl protective

groups

2). ¹³C NMR (100.6 MHz, DMSO-d₆): 21.64 and 21.75

(CH₃CO); 33.99 and 37.47 (CH₃-N); 39.39(CH₂-2⁰);

48.73 and 51.25 (CH₂-pur); 61.71 and 61.74 (CH₂-5⁰);

70.80 and 70.83 (CH-3⁰); 83.87 and 83.96 (CH-1⁰);

88.17 and 88.20 (CH-4⁰); 131.90 and 132.14 (C-5);

144.60 and 145.06 (CH-8); 150.54 and 150.79 (C-4);

151.81 and 152.07 (CH-2); 156.41 and 157.61 (C-6);

170.59 and 170.67 (CO). IR (KBr): m = 3409, 1631,

4.63.1. Method A. A 1-M methanolic MeONa (100 ll,

0.1 mmol) was added to a solution of protected purine

nucleosides 5, 6, 13, 14, 17, 18 (0.5 mmol) in methanol

(30 ml) and the mixture was stirred at ambient tempera-

ture. After complete deprotection the product was ad-

sorbed on silica gel and chromatographed (ethyl

acetate/methanol, 1:0–7:3).

1596, 1495, 1401, 1333, 1211, 1094, 1057, 646 cm^ꢀ1

.

4.66. 6-[(N-Acetyl-N-benzyl)aminomethyl]-9-(b-^D-ribo-

furanosyl)purine (11ba)

4.63.2. Method B. An aqueous ammonia (1 ml) was

added to a solution of protected purine nucleoside 5

or 6 (0.5 mmol) in methanol (30 ml) and the mixture

was stirred at 50 ꢁC in sealed ﬂask. After complete

deprotection the reaction mixture was adsorbed on silica

gel and chromatographed (ethyl acetate/methanol, 1:0–

7:3).

Prepared from 5ba (430 mg) by deprotection method B

to give 195 mg (84%) of 11ba as white foam.

20

D

½aꢂ ꢀ 28:8 (c = 2.59, MeOH). Anal. calcd for

C₂₀H₂₃N₅O₅ÆH₂O: C, 55.68; H, 5.84; N, 16.23; found:

C, 55.46; H, 5.66; N, 15.85. Exact mass (FAB HR

MS) found: 414.1766; calcd for C₂₀H₂₄N₅O₅: 414.1777.

FAB MS m/z (%): 414 (MH⁺, 42); 282 (100); 240 (11);

191 (15); 149 (21); 134 (36); 91 (85). A mixture of cis/

4.64. 6-[(N-Acetyl-N-methyl)aminomethyl]-9-(b-^D-ribo-

furanosyl)purine (11aa)

1

trans amides ꢁ1:0.6. H NMR (400 MHz, DMSO-d₆):

Prepared from 5aa (360 mg) by deprotection method B

to give 145 mg (82%) of 11aa as white foam.

2.12 and 2.24 (2· s, 6H, CH₃CO); 3.54–3.61 (m, 2H,

H-5⁰b); 3.66–3.73 (m, 2H, H-5⁰a); 3.96–4.00 (m, 2H,

H-4⁰); 4.17–4.21 (m, 2H, H-3⁰); 4.55 and 4.78 (2· s,

4H, CH₂Ph); 4.61–4.66 (m, 2H, H-2⁰); 4.91 and 4.94

(2· s, 4H, CH₂-pur); 5.09–5.13 (m, 2H, OH-5⁰); 5.24

20

D

MS) found: 338.1453; calcd for C₁₄H₂₀N₅O₅: 338.1464.

½aꢂ ꢀ 43:1 (c = 3.16, H₂O). Exact mass (FAB HR

FAB MS m/z (%): 338 (MH⁺, 18); 206 (100); 164 (10);

1

0

134 (12). A mixture of cis/trans amides ꢁ1:1. H NMR

(d, 1H, J_OH;3¼ 5:0, OH-3⁰); 5.26 (d, 1H, J_OH;3¼ 5:0,

0

(400 MHz, DMSO-d₆): 2.08 and 2.10 (2· s, 6H,

CH₃CO); 2.87 and 3.15 (2· s, 6H, CH₃-N); 3.57 (m,

2H, H-5⁰b); 3.69 (m, 2H, H-5⁰a); 3.98 (m, 2H, H-4⁰);

4.19 (m, 2H, H-3⁰); 4.64 (m, 2H, H-2⁰); 4.96 and 5.02

(2· s, 4H, CH₂-pur); 5.10 (m, 2H, OH-5⁰); 5.24 and

OH-3⁰); 5.54 (d, 1H, J_OH;2¼ 6:0, OH-2⁰); 5.55 (d, 1H,

J_OH;2¼ 6:0, OH-2⁰); 6.03 (d, 1H, J_{1 ;2}¼ 5:7, H-1⁰);

0

6.04 (d, 1H, J_{1 ;2}¼ 5:6, H-1⁰); 7.21–7.24, 7.26–7.31

and 7.36–7.39 (3· m, 10H, H-o,m,p-Ph); 8.79 and 8.84

(2· s, 2H, H-8); 8.86 and 8.92 (2· s, 1H, H-2). ¹³C

NMR (100.6 MHz, DMSO-d₆): 21.52 and 21.95

(CH₃CO); 46.89 and 48.43 (CH₂-pur); 48.52 and 52.89

(CH₂Ph); 61.39 and 61.47 (CH₂-5⁰); 70.43 and 70.53

(CH-3⁰); 73.83 and 73.89 (CH-2⁰); 85.86 and 85.89

(CH-4⁰); 87.77 and 87.85 (CH-1⁰); 126.99 (CH-o-Ph);

127.15 and 127.46 (CH-p-Ph); 127.87 (CH-o-Ph);

128.44 and 128.86 (CH-m-Ph); 131.95 and 134.26 (C-

5); 137.75 and 137.85 (C-i-Ph); 144.66 and 145.10

(CH-8); 150.82 and 151.04 (C-4); 151.88 and 152.14

(CH-2); 156.37 and 157.57 (C-6); 170.77 and 170.96

(COCH₃). IR (KBr): m = 3379, 1656, 1631, 1596, 1496,

0

5.25 (2· d, 2H, J_OH;3¼ 5:0, OH-3⁰); 5.54 (d, 2H,

0

J_OH;2¼ 5:9, OH-2⁰); 6.03 and 6.05(2· d, 2H,

0

J_{1 ;2}¼ 6:0, H-1⁰); 8.79, 8.85 and 8.92 (3· s, 4H, H-8

and H-2). ¹³C NMR (100.6 MHz, DMSO-d₆): 21.64

and 21.75 (CH₃CO); 34.00 and 37.50 (CH₃-N); 48.78 and

51.26 (CH₂-pur); 61.42 and 61.47 (CH₂-5⁰); 70.48 and

70.53 (CH-3⁰); 73.83 and 73.85 (CH-2⁰); 85.92 (CH-4⁰);

87.77 and 87.84 (CH-1⁰); 131.89 and 132.13 (C-5);

144.68 and 145.13 (CH-8); 150.83 and 151.08

(C-4); 151.89 and 152.16 (CH-2); 156.55 and 157.74

(C-6); 170.61 and 170.68 (CO). IR (KBr): m = 3421,

1628, 1598, 1496, 1404, 1334, 1210, 1126, 1085, 1055,

0

1418, 1333, 1209, 1086, 1056, 646 cm^ꢀ1

.

645 cm^ꢀ1

.

4.67. 6-[(N-Acetyl-N-benzyl)aminomethyl]-9-(2-deoxy-b-

D-erythro-pentofuranosyl)purine (12ba)

4.65. 6-[(N-Acetyl-N-methyl)aminomethyl]-9-(2-deoxy-b-

D-erythro-pentofuranosyl)purine (12aa)

Prepared from 6ba (330 mg) by deprotection method B

20

D

Prepared from 6aa (360 mg) by deprotection method B

to give 190 mg (92%) of 12aa as lyophilized solid.

½aꢂ ꢀ 17:0 (c = 2.93, H₂O). Exact mass (FAB HR

to give 190 mg (92%) of 12ba as white foam. ½aꢂ ꢀ 9:1

(c = 2.37, MeOH). Anal. calcd for C₂₀H₂₃N₅O₄ÆH₂O:

C, 57.82; H, 6.07; N, 16.86; found: C, 57.89; H, 5.69;

N, 16.45. Exact mass (FAB HR MS) found: 398.1832;

calcd for C₂₀H₂₄N₅O₄: 398.1828. FAB MS m/z (%):

398 (MH⁺, 18); 282 (100); 240 (9); 191 (8); 148 (9); 134

(21); 91 (50). A mixture of cis/trans amides ꢁ1 : 0.6.

¹H NMR (400 MHz, DMSO-d₆): 2.11 and 2.24 (2· s,

6H, CH₃CO); 2.32–2.38 (m, 2H, H-2⁰b); 2.74–2.82 (m,

2H, H-2⁰a); 3.50–3.56 (m, 2H, H-5⁰b); 3.60–3.66 (m,

2H, H-5⁰a); 3.88–3.91 (m, 2H, H-4⁰); 4.43–4.47 (m,

2H, H-3⁰); 4.55 and 4.77 (2· s, 4H, CH₂Ph); 4.91 and

4.93 (2· s, 4H, CH₂-pur); 4.98–5.01 (m, 2H, OH-5⁰);

20

D

MS) found: 322.1525; calcd for C₁₄H₂₀N₅O₄: 322.1515.

FAB MS m/z (%): 322 (MH⁺, 27); 206 (100); 164 (12);

1

134 (16). A mixture of cis/trans amides ꢁ1:1. H NMR

(400 MHz, DMSO-d₆): 2.07 and 2.10 (2· s, 6H,

CH₃CO); 2.35 (m, 2H, H-2⁰b); 2.79 (m, 2H, H-2⁰a);

2.86 and 3.14 (2· s, 6H, CH₃-N); 3.52 (m, 2H, H-5⁰b);

3.62 (m, 2H, H-5⁰a); 3.89 (m, 2H, H-4⁰); 4.45 (m, 2H,

H-3⁰); 4.95 and 5.00 (2· s, 4H, CH₂-pur); 4.98 (m, 2H,

OH-5⁰); 5.36 (m, 2H, OH-3⁰); 6.48 (m, 2H, H-1⁰); 8.75

and 8.81 (2· s, 2H, H-8); 8.84 and 8.91 (2· s, 2H, H-

ˇ

´

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2354

5.36 (m, 2H, OH-3⁰); 6.47 (m, 2H, H-1⁰); 7.20–7.23,

7.25–7.30 and 7.35–7.39 (3· m, 10H, H-o,m,p-Ph); 8.75

and 8.80 (2· s, 2H, H-8); 8.85 and 8.90 (2· s, 1H, H-

2). ¹³C NMR (100.6 MHz, DMSO-d₆): 21.51 and 21.95

(CH₃CO); 39.44 (CH₂-2⁰); 46.83 and 48.43 (CH₂-pur);

48.53 and 52.86 (CH₂Ph); 61.71 and 61.75 (CH₂-5⁰);

70.79 and 70.84 (CH-3⁰); 83.88 and 83.96 (CH-1⁰);

88.17 and 88.19 (CH-4⁰); 126.97 (CH-o-Ph); 127.12

and 127.44 (CH-p-Ph); 127.85 (CH-o-Ph); 128.41 and

128.84 (CH-m-Ph); 131.96 and 132.27 (C-5); 137.73

and 137.84 (C-i-Ph); 144.57 and 145.04 (CH-8); 150.52

and 150.73 (C-4); 151.80 and 152.03 (CH-2); 156.24

and 157.42 (C-6); 170.74 and 170.95 (COCH₃). IR (KBr):

m = 3413, 1653, 1635, 1596, 1496, 1419, 1333, 1210, 1095,

MS) found: 390.2125; calcd for C₁₉H₂₈N₅O₄: 390.2141.

FAB MS m/z (%): 390 (MH⁺, 9); 274 (100); 231 (14);

192 (12); 149 (22); 134 (30). A mixture of cis/trans

amides ꢁ1:1. ¹H NMR (400 MHz, DMSO-d₆): 1.17–

1.71 and 1.84–1.86 (2· m, 20H, CH₂-cyclohex); 2.05

and 2.11 (2· s, 6H, CH₃); 2.35 (m, 2H, H-2⁰b); 2.80

(m, 2H, H-2⁰a); 3.52 (m, 2H, H-5⁰b); 3.62 (m, 2H, H-

5⁰a); 3.76 (m, 1H, CH-cyclohex); 3.89 (m, 2H, H-4⁰);

4.32 (m, 1H, CH-cyclohex); 4.45 (m, 2H, H-3⁰); 4.86

and 4.98 (2· s, 4H, CH₂N); 4.99 (m, 2H, OH-5⁰); 5.36

(m, 2H, OH-3⁰); 6.47 (m, 2H, H-1⁰); 8.72 (s, 1H, H-8);

8.78 (s, 1H, H-2); 8.80 (s, 1H, H-8); 8.89 (s, 1H, H-2).

¹³C NMR (100.6 MHz, DMSO-d₆): 21.76 and 22.77

(CH₃); 24.98, 25.19, 25.50, 25.60, 30.19 and 31.24

(CH₂-cyclohex); 39.34 and 39.36 (CH₂-2⁰); 42.40 and

44.60 (CH₂N); 52.88 and 57.35 (CH-cyclohex); 61.74

and 61.79 (CH₂-5⁰); 70.84 and 70.88 (CH-3⁰); 83.83

and 83.95 (CH-1⁰); 88.15 and 88.20 (CH-4⁰); 131.48 and

131.51 (C-5); 144.10 and 144.85 (CH-8); 150.26 and

150.54 (C-4); 151.56 and 151.91 (CH-2); 158.06

and 159.06 (C-6); 169.57 and 170.61 (CO). IR (KBr):

m = 3421, 2932, 2857, 1624, 1595, 1496, 1452, 1420,

1057, 645 cm^ꢀ1

.

4.68. 6-[(N-Acetyl-N-cyclohexyl)aminomethyl]-9-(b-^D-

ribofuranosyl)purine (11ca)

Prepared from 5ca (300 mg) by deprotection method B

to give 135 mg (84%) of 11ca as white crystals (mp 75–

20

D

77 ꢁC, crystallization from EtOH/heptane). ½aꢂ ꢀ 31:7

(c = 2.48, H₂O). Anal. calcd for C₁₉H₂₇N₅O₅ÆH₂O: C,

53.89; H, 6.90; N, 16.54; found: C, 53.87; H, 7.06; N,

16.09. Exact mass (FAB HR MS) found: 406.2084; calcd

for C₁₉H₂₈N₅O₅: 406.2090. FAB MS m/z (%): 406

(MH⁺, 9); 274 (100); 232 (21); 148 (28); 134 (37). A mix-

ture of cis/trans amides ꢁ1:1. ¹H NMR (500 MHz,

DMSO-d₆): 1.15–1.73 and 1.82–1.88 (2· m, 20H, CH₂-

cyclohex); 2.06 and 2.12 (2· s, 2· 3H, CH₃); 3.56 and

1333, 1212, 1096, 1058, 647 cm^ꢀ1

.

4.70. 6-[N-(Hydroxycarbonylmethyl)aminomethyl]-9-(b-

D-ribofuranosyl)purine (11da)

An aq NaOH (3.5 ml, c = 0.5 mol/l) was added to a solu-

tion of protected nucleoside 5d (330 mg, 0.46 mmol) in

methanol (10 ml) and stirred at rt for 1 h. Next, the sol-

vent was evaporated and the residue was puriﬁed by

HPLC on C18 column with H₂O/MeOH as mobile

0

3.57 (2· ddd, 2· 1H, J_gem= 12.0, J_{5 b;OH}¼ 5:7,

J_{5 b;4}¼ 4:1, H-5⁰b); 3.68 and 3.69 (2· ddd, 2· 1H,

0

J_gem= 12.0, J_{5 a;OH}¼ 5:7, J_{5 a;4}¼ 4:1, H-5⁰a); 3.77 (m,

phase to give 85 mg (55%) of 11da as lyophilized solid.

0

20

D

1H, CH-cyclohex); 3.97 and 3.98 (2· q, 2· 1H,

½aꢂ ꢀ 18:5 (c = 2.19, H₂O). Anal. calcd for

J_{4 ;5}¼ 4:1, J_{4 ;3}¼ 3:8, H-4⁰); 4.18 and 4.19 (2· q, 2·

C₁₃H₁₇N₅O₆Æ2H₂O C, 41.60; H, 5.64; N, 18.66; found:

C, 42.02; H, 5.42; N, 18.38. Exact mass (FAB HR

MS) found: 340.1263; calcd for C₁₃H₁₈N₅O₆: 340.1257.

FAB MS m/z (%): 340 (MH⁺, 12); 208 (10); 149 (8).

¹H NMR (500 MHz, DMSO-d₆): 3.39 (s, 2H,

0

1H, J_{3 ;2}¼ 4:9, J_{3 ;OH}¼ 4:0, J_{3 ;4}¼ 3:8, H-3⁰); 4.32 (m,

0

1H, CH-cyclohex); 4.65 and 4.66 (2· q, 2· 1H,

J_{2 ;OH}¼ 6:0, J_{2 ;1}¼ 5:8, J_{2 ;3}¼ 4:7, H-2⁰); 4.87 and

5.00 (2· s, 2· 2H, CH₂N); 5.10 and 5.11 (2· t, 2· 1H,

0

J_OH;5¼ 5:7, OH-5⁰); 5.25 and 5.28 (2· d, 2· 1H,

NCH₂CO); 3.58 (dd, 1H, J_gem= 12.0, J_{5 b;4}¼ 4:1, H-

0

J_OH;3¼ 4:0, OH-3⁰); 5.56 (d, 2H, J_OH;2¼ 6:0, OH-2⁰);

5⁰b); 3.69 (dd, 1H, J_gem= 12.0, J_{5 a;4}¼ 4:1, H-5⁰a);

0

6.02 and 6.04 (2· d, 2· 1H, J_{1 ;2}¼ 5:8, H-1⁰); 8.75 (s,

1H, H-8); 8.79 (s, 1H, H-2); 8.84 (s, 1H, H-8); 8.90 (s,

1H, H-2). ¹³C NMR (125.8 MHz, DMSO-d₆): 21.78

and 22.78 (CH₃); 24.99, 25.20, 25.51, 25.61, 30.20 and

31.24 (CH₂-cyclohex); 42.45 and 44.62 (CH₂N); 52.87

and 57.36 (CH-cyclohex); 61.47 and 61.53 (CH₂-5⁰);

70.52 and 70.60 (CH-3⁰); 73.75 and 73.79 (CH-2⁰);

85.93 and 85.97 (CH-4⁰); 87.72 and 87.78 (CH-1⁰);

131.49 and 131.54 (C-5); 144.23 and 144.97 (CH-8);

150.58 and 150.86 (C-4); 151.65 and 152.04 (CH-2);

158.22 and 159.22 (C-6); 169.61 and 170.65 (CO). IR

(KBr): m = 3409, 2931, 2857, 1623, 1596, 1497, 1416,

3.98 (q, 1H, J_{4 ;5}¼ 4:1, J_{4 ;3}¼ 3:6, H-4⁰); 4.19 (dd,

0

1H, J_{3 ;2}¼ 5:0, J_{3 ;4}¼ 3:6, H-3⁰); 4.36 (s, 2H,

0

NCH₂pur); 4.63 (t, 1H, J_{2 ;1}¼ 5:7, J_{2 ;3}¼ 5:0, H-2⁰);

0

6.04 (d, 1H, J_{1 ;2}¼ 5:7, H-1⁰); 8.84 (s, 1H, H-8); 8.93

(s, 1H, H-2). ¹³C NMR (125.8 MHz, DMSO-d₆): 48.32

(NCH₂pur); 50.14 (NCH₂CO); 61.43 (CH₂-5⁰); 70.48

(CH-3⁰); 73.90 (CH-2⁰); 85.92 (CH-4⁰); 87.83 (CH-1⁰);

131.94 (C-5); 144.94 (CH-8); 150.81 (C-4); 151.91 (CH-

2); 156.88 (C-6); 171.25 (CO). IR (KBr): m = 3409,

1631, 1607, 1585, 1498, 1404, 1337, 1211, 1123, 1083,

0

1055, 644 cm^ꢀ1

.

1334, 1211, 1124, 1084, 1055, 647 cm^ꢀ1

.

4.71. 6-[(N,N-Dimethylamino)methyl]-9-(b-^D-ribofurano-

syl)purine (11e)

4.69. 6-[(N-Acetyl-N-cyclohexyl)aminomethyl]-9-(2-

deoxy-b-^D-erythro-pentofuranosyl)purine (12ca)

Prepared from 5e (380 mg) by deprotection method A to

give 125 mg (71%) of 11e as white solid (mp 175–

20

D

Prepared from 6ca (260 mg) by deprotection method B

to give 140 mg (86%) of 12ca as white foam.

177 ꢁC). ½aꢂ ꢀ 35:9 (c = 1.81, H₂O). Anal. calcd for

C₁₃H₁₉N₅O₄ÆH₂O: C, 47.70; H, 6.47; N, 21.39; found:

C, 48.03; H, 6.66; N, 20.95. Exact mass (FAB HR

MS) found: 310.1523; calcd for C₁₃H₂₀N₅O₄: 310.1515.

FAB MS m/z (%): 310 (MH⁺, 45); 266 (7); 178 (100);

20

D

½aꢂ ꢀ 16:3 (c = 2.50, MeOH). Anal. calcd for

C₁₉H₂₇N₅O₄ÆH₂O: C, 56.01; H, 7.17; N, 17.19; found:

C, 56.38; H, 7.51; N, 16.78. Exact mass (FAB HR

ˇ

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2355

1

134 (38). H NMR (400 MHz, DMSO-d₆): 2.24 (s, 6H,

(CO). IR (KBr): m = 3354, 2962, 1597, 1499, 1405,

1335, 1212, 1119, 1086, 1055, 645 cm^ꢀ1

0

(CH₃)₂N); 3.56 (dd, 1H, J_gem= 12.1, J_{5 b;4}¼ 3:7, H-

.

5⁰b); 3.67 (dd, 1H, J_gem= 12.1, J_{5 a;4}¼ 4:0, H-5⁰a);

0

3.89 (s, 2H, CH₂N); 3.98 (q, 1H, J_{4 ;5}¼ 4:0, 3.7,

4.74. 6-[N,N-(Diisopropylamino)methyl]-9-(2-deoxy-b-^D-

erythro-pentofuranosyl)purine (12f)

J_{4 ;3}¼ 3:6, H-4⁰); 4.20 (dd, 1H, J_{3 ;2}¼ 4:8, J_{3 ;4}¼ 3:6,

0

H-3⁰); 4.64 (t, 1H, J_{2 ;1}¼ 5:8, J_{2 ;3}¼ 4:8, H-2⁰); 5.20

0

(b, 1H, OH-5⁰); 5.35 (b, 1H, OH-3⁰); 5.65 (b, 1H, OH-

Prepared from 6f (400 mg) by deprotection method A to

20

D

2⁰); 6.03 (d, 1H, J_{1 ;2}¼ 5:8, H-1⁰); 8.81 (s, 1H, H-8);

8.88 (s, 1H, H-2). ¹³C NMR (100.6 MHz, DMSO-d₆):

45.48 ((CH₃)₂N); 59.05 (CH₂N); 61.46 (CH₂-5⁰); 70.54

(CH-3⁰); 73.82 (CH-2⁰); 85.91 (CH-4⁰); 87.72 (CH-1⁰);

133.53 (C-5); 144.81 (CH-8); 151.06 (C-4); 151.77 (CH-

2); 157.53 (C-6). IR (KBr): m = 3409, 2830, 2783, 1599,

give 145 mg (60%) of 12f as white foam. ½aꢂ ꢀ 15:9

0

(c = 2.08, H₂O). Exact mass (FAB HR MS) found:

350.2185; calcd for C₁₇H₂₈N₅O₃: 350.2192. FAB MS m/z

(%): 350 (MH⁺, 53); 234 (47); 190 (41); 148 (23); 134

1

(100); 114 (97); 100 (23). H NMR (400 MHz, DMSO-

d₆): 1.02 (d, 12H, J_vic= 6.6, (CH₃)₂CH); 2.34 (ddd, 1H,

1499, 1404, 1334, 1210, 1124, 1085, 1055, 645 cm^ꢀ1

.

J_gem= 13.3, J_{2 b;1}¼ 6:3, J_{2 b;3}¼ 3:3, H-2⁰b); 2.79 (ddd,

0

1H, J_gem= 13.3, J_{2 a;1}¼ 7:3, J_{2 a;3}¼ 5:9, H-2⁰a); 3.13 (p,

0

4.72. 6-[(N,N-Dimethylamino)methyl]-9-(2-deoxy-b-^D-

erythro-pentofuranosyl)purine (12e)

2H, J_vic= 6.6, CH(CH₃)₂); 3.52 and 3.62 (2· dd, 2H,

J_gem= 11.8, J_{5 ;4}¼ 4:6, H-5⁰); 3.89 (td, 1H, J_{4 ;5}¼ 4:6,

0

J_{4 ;3}¼ 3:0, H-4⁰); 4.03 (s, 2H, CH₂N); 4.44 (ddd, 1H,

0

J_{3 ;2}¼ 5:9, 3.3, J_{3 ;4}¼ 3:0, H-3⁰); 6.46 (t, 1H, J_{1 ;2}¼ 7:3,

6.3, H-1⁰); 8.72 (s, 1H, H-8); 8.84 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, DMSO-d₆): 20.91 ((CH₃)₂CH); 39.32

(CH₂-2⁰); 45.46 (CH₂N); 48.46 (CH(CH₃)₂); 61.80 (CH₂-

5⁰); 70.90 (CH-3⁰); 83.80 (CH-1⁰); 88.14 (CH-4⁰); 132.85

(C-5); 144.24 (CH-8); 150.52 (C-4); 151.79 (CH-2);

161.63 (C-6). IR (KBr): m = 3401, 2965, 1595, 1497, 1400,

0

Prepared from 6e (390 mg) by deprotection method B to

20

D

give 190 mg (88%) of 12e as white foam. ½aꢂ ꢀ 19:6

(c = 2.86, H₂O). Anal. calcd for C₁₃H₁₉N₅O₃Æ1/2H₂O:

C, 51.65; H, 6.67; N, 23.16; found: C, 52.04; H, 6.69;

N, 23.00. Exact mass (FAB HR MS) found: 294.1563;

calcd for C₁₃H₂₀N₅O₃: 294.1566. FAB MS m/z (%):

1

294 (MH⁺, 60); 250 (9); 178 (100); 134 (56). H NMR

(400 MHz, DMSO-d₆): 2.24 (s, 6H, (CH₃)₂N); 2.35

(ddd, 1H, J_gem= 13.3, J_{2 b;1}¼ 6:3, J_{2 b;3}¼ 3:5, H-2⁰b);

1333, 1211, 1096, 1058, 647 cm^ꢀ1

.

0

2.79 (ddd, 1H, J_gem= 13.3, J_{2 a;1}¼ 7:2, J_{2 a;3}¼ 6:0, H-

4.75. 6-[(N-Benzyl-N-methylamino)methyl]-9-(b-^D-ribo-

furanosyl)purine (11g)

2⁰a); 3.52 and 3.62 (2· dt, 2H, J_gem= 11.7,

J_{5 ;OH}¼ 5:5, J_{5 ;4}¼ 4:6, H-5⁰); 3.88 (s, 2H, CH₂N);

0

3.89 (td, 1H, J_{4 ;5}¼ 4:6, J_{4 ;3}¼ 3:0, H-4⁰); 4.45 (ddt,

Prepared from 5g (390 mg) by deprotection method A to

give 170 mg (84%) of 11g as yellowish hygroscopic solid.

0

1H, J_{3 ;2}¼ 6:0, 3.5, J_{3 ;OH}¼ 4:1, J_{3 ;4}¼ 3:0, H-3⁰);

0

20

D

4.99 (t, 1H, J_OH;5¼ 5:5, OH-5⁰); 5.36 (d, 1H,

½aꢂ ꢀ 36:6 (c = 2.27, MeOH). Anal. calcd for

0

J_OH;3¼ 4:1, OH-3⁰); 6.47 (t, 1H, J_{1 ;2}¼ 7:2, 6.3, H-1⁰);

8.75 (s, 1H, H-8); 8.88 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, DMSO-d₆): 39.38 (CH₂-2⁰); 45.45

((CH₃)₂N); 59.01(CH₂-pur); 61.75 (CH₂-5⁰); 70.84

(CH-3⁰); 83.86 (CH-1⁰); 88.16 (CH-4⁰); 133.43 (C-5);

144.65 (CH-8); 150.74 (C-4); 151.66 (CH-2); 157.39 (C-

6). IR (KBr): m = 3421, 2828, 2780, 1598, 1497, 1401,

C₁₉H₂₃N₅O₄ÆH₂O: C, 56.57; H, 6.25; N, 17.36; found:

C, 56.55; H, 6.31; N, 17.05. Exact mass (FAB HR

MS) found: 386.1836; calcd for C₁₉H₂₄N₅O₄: 386.1828.

FAB MS m/z (%): 386 (MH⁺, 4); 254 (23); 162 (16);

147 (8); 134 (34); 91 (100). ¹H NMR (500 MHz,

DMSO-d₆): 2.17 (s, 3H, CH₃N); 3.58 (ddd, 1H,

0

J_gem= 12.1, J_{5 b;OH}¼ 6:1, J_{5 b;4}¼ 4:1, H-5⁰b); 3.67 (s,

0

1333, 1211, 1096, 1058, 646 cm^ꢀ1

.

2H, CH₂Ph); 3.69 (ddd, 1H, J_gem= 12.1, J_{5 a;OH}¼ 5:0,

0

J_{5 a;4}¼ 4:3, H-5⁰a); 3.98 (q, 1H, J_{4 ;5}¼ 4:3, 4.1

0

J_{4 ;3}¼ 3:1, H-4⁰); 4.05 (s, 2H, CH₂pur); 4.19 (q, 1H,

0

4.73. 6-[N,N-(Diisopropylamino)methyl]-9-(b-^D-ribofur-

anosyl)purine (11f)

J_{3 ;OH}¼ 4:9, J_{3 ;2}¼ 4:9, J_{3 ;4}¼ 3:1, H-3⁰); 4.65 (q, 1H,

0

J_{2 ;OH}¼ 6:0, J_{2 ;1}¼ 5:8, J_{2 ;3}¼ 4:9, H-2⁰); 5.12 (t, 1H,

0

J_OH;5¼ 6:1, 5.0, OH-5⁰); 5.25 (d, 1H, J_OH;3¼ 4:9,

0

Prepared from 5f (400 mg) by deprotection method A to

20

D

OH-3⁰); 5.54 (d, 1H, J_OH;2¼ 6:0, OH-2⁰); 6.04 (d, 1H,

0

give 132 mg (65%) of 11f as foam. ½aꢂ ꢀ 42:2 (c = 1.67,

J_{1 ;2}¼ 5:8, H-1⁰); 7.23 (m, 1H, H-p-Ph); 7.31 (m, 2H,

H-m-Ph); 7.37 (m, 2H, H-o-Ph); 8.80 (s, 1H, H-8); 8.92

(s, 1H, H-2). ¹³C NMR (125.8 MHz, DMSO-d₆): 42.08

(CH₃N); 57.13 (CH₂pur); 61.35 (CH₂Ph); 61.50 (CH₂-

5⁰); 70.55 (CH-3⁰); 73.81 (CH-2⁰); 85.92 (CH-4⁰); 87.75

(CH-1⁰); 127.08 (CH-p-Ph); 128.29 (CH-m-Ph); 128.96

(CH-o-Ph); 133.53 (C-5); 139.04 (C-i-Ph); 144.81 (CH-

8); 151.07 (C-4); 151.85 (CH-2); 157.85 (C-6). IR

(KBr): m = 3401, 2795, 1598, 1497, 1454, 1405, 1334,

0

H₂O). Exact mass (FAB HR MS) found: 366.2132; calcd

for C₁₇H₂₈N₅O₄: 366.2141. FAB MS m/z (%): 366

(MH⁺, 100); 276 (12); 234 (100); 190 (42); 148 (29);

134 (49). ¹H NMR (400 MHz, DMSO-d₆): 1.02 (d,

12H, J_vic= 6.6, (CH₃)₂CH); 3.14 (p, 2H, J_vic= 6.6,

0

CH(CH₃)₂); 3.57 (dd, 1H, J_gem= 12.0, J_{5 b;4}¼ 4:1, H-

5⁰b); 3.68 (dd, 1H, J_gem= 12.0, J_{5 a;4}¼ 4:1, H-5⁰a);

0

3.97 (q, 1H, J_{4 ;5}¼ 4:1, J_{4 ;3}¼ 3:4, H-4⁰); 4.05 (s, 2H,

0

CH₂N); 4.18 (dd, 1H, J_{3 ;2}¼ 5:0, J_{3 ;4}¼ 3:4, H-3⁰);

0

4.66 (dd, 1H, J_{2 ;1}¼ 5:9, J_{2 ;3}¼ 5:0, H-2⁰); 6.02 (d,

1210, 1080, 1055, 646 cm^ꢀ1

.

0

1H, J_{1 ;2}¼ 5:9, H-1⁰); 8.76 (s, 1H, H-8); 8.85 (s, 1H,

H-2). ¹³C NMR (100.6 MHz, DMSO-d₆): 20.89 and

20.90 ((CH₃)₂CH); 45.48 (CH₂N); 48.51 (CH(CH₃)₂);

61.54 (CH₂-5⁰); 70.59 (CH-3⁰); 73.69 (CH-2⁰); 85.92

(CH-4⁰); 87.65 (CH-1⁰); 132.85 (C-5); 144.37 (CH-8);

150.83 (C-4); 151.87 (CH-2); 161.73 (C-6); 172.21

0

4.76. 6-[(N-Methyl-N-phenylamino)methyl]-9-(b-^D-ribo-

furanosyl)purine (11h)

Prepared from 5h (350 mg) by deprotection method A to

20

D

give 160 mg (89%) of 11h as white foam. ½aꢂ ꢀ 50:3

ˇ

´

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2356

(c = 3.60, CHCl₃). Exact mass (FAB HR MS) found:

372.1678; calcd for C₁₈H₂₂N₅O₄: 372.1672. FAB MS

m, 4H, CH₂-cycloprop); 2.20 (s, 3H, CH₃CO); 2.99 (tt,

1H, J_vic= 7.0, 3.9, CH-cycloprop); 3.57 (ddd, 1H,

1

m/z (%): 372 (MH⁺, 19); 240 (23); 134 (36). H NMR

(400 MHz, DMSO-d₆): 3.22 (s, 3H, CH₃N); 3.56 (ddd,

J_gem= 12.0, J_{5 b;OH}¼ 5:9, J_{5 b;4}¼ 4:1, H-5⁰b); 3.68

0

(ddd, 1H, J_gem= 12.0, J_{5 a;OH}¼ 5:3, J_{5 a;4}¼ 4:0, H-5⁰a);

0

1H, J_gem= 12.0, J_{5 b;OH}¼ 6:0, J_{5 b;4}¼ 4:1, H-5⁰b); 3.68

3.97 (q, 1H, J_{4 ;5}¼ 4:1, 4.0, J_{4 ;3}¼ 3:5, H-4⁰); 4.18 (q,

0

(ddd, 1H, J_gem= 12.0, J_{5 a;OH}¼ 5:2, J_{5 a;4}¼ 4:2, H-

1H, J_{3 ;OH}¼ 4:7, J_{3 ;2}¼ 4:2, J_{3 ;4}¼ 3:7, H-3⁰); 4.64 (q,

0

5⁰a); 3.97 (q, 1H, J_{4 ;5}¼ 4:2, 4.1, J_{4 ;3}¼ 3:6, H-4⁰);

1H, J_{2 ;1}¼ 5:8, J_{2 ;OH}¼ 5:7, J_{2 ;3}¼ 4:2, H-2⁰); 4.91 (2·

0

4.18 (q, 1H, J_{3 ;OH}¼ 4:9, J_{3 ;2}¼ 4:7, J_{3 ;4}¼ 3:6, H-3⁰);

d, 2H, J_gem= 17.6, CH₂N); 5.11 (t, 1H, J_OH;5¼ 5:9, 5.3,

0

4.65 (q, 1H, J_{2 ;OH}¼ 6:0, J_{2 ;1}¼ 5:8, J_{2 ;3}¼ 4:7, H-2⁰);

OH-5⁰); 5.25 (d, 1H, J_OH;3¼ 4:7, OH-3⁰); 5.55 (d, 1H,

0

4.99 (s, 2H, CH₂N); 5.10 (t, 1H, J_OH;5¼ 6:0, 5.2, OH-

J_OH;2¼ 5:7, OH-2⁰); 6.03 (d, 1H, J_{1 ;2}¼ 5:8, H-1⁰); 8.79

(s, 1H, H-8); 8.83 (s, 1H, H-2). ¹³C NMR (125.8 MHz,

DMSO-d₆): 9.18 (CH₂-cycloprop); 22.55 (CH₃CO);

31.67 (CH-cycloprop); 48.29 (CH₂N); 61.50 (CH₂-5⁰);

70.56 (CH-3⁰); 73.82 (CH-2⁰); 85.93 (CH-4⁰); 87.77 (CH-

1⁰); 131.73 (C-5); 144.63 (CH-8); 150.81 (C-4); 151.90

(CH-2); 158.19 (C-6); 173.12 (CO). IR (KBr): m = 3400,

3012, 1635, 1596, 1498, 1420, 1403, 1335, 1211, 1121,

0

5⁰); 5.25 (d, 1H, J_OH;3¼ 4:9, OH-3⁰); 5.54 (d, 1H,

0

J_OH;2¼ 6:0, OH-2⁰); 6.02 (d, 1H, J_{1 ;2}¼ 5:8, H-1⁰);

6.55 (m, 1H, H-p-Ph); 6.76 (m, 2H, H-o-Ph); 7.08 (m,

2H, H-m-Ph); 8.83 (s, 1H, H-8); 8.85 (s, 1H, H-2). ¹³C

NMR (100.6 MHz, DMSO-d₆): 39.85 (CH₃N); 53.08

(CH₂N); 61.47 (CH₂-5⁰); 70.53 (CH-3⁰); 73.75 (CH-2⁰);

85.93 (CH-4⁰); 87.77 (CH-1⁰); 111.95 (CH-o-Ph);

115.98 (CH-p-Ph); 129.03 (CH-m-Ph); 132.44 (C-5);

144.86 (CH-8); 149.09 (C-i-Ph); 150.96 (C-4); 152.00

(CH-2); 158.91 (C-6). IR (CHCl₃): m = 3305, 2825,

0

1083, 1055, 647 cm^ꢀ1

.

4.79. 6-[(N-Acetyl-N-cyclopropylamino)methyl]-9-(2-

deoxy-b-^D-erythro-pentofuranosyl)purine (12i)

1596, 1507, 1418, 1335, 1116, 1083, 1048, 645 cm^ꢀ1

.

4.77. 6-[(N-Methyl-N-phenylamino)methyl]-9-(2-deoxy-b-

D-erythro-pentofuranosyl)purine (12h)

Prepared from 6i (460 mg) by deprotection method B to

give 225 mg (82%) of 12i as white hygroscopic solid (mp

20

D

129–131 ꢁC). ½aꢂ ꢀ 7:6 (c = 2.10, H₂O). Anal. calcd for

Prepared from 6 h (230 mg) by deprotection method A

to give 110 mg (80%) of 12h, as white foam.

C₁₆H₂₁N₅O₄: C, 55.32; H, 6.09; N, 20.16; found: C,

54.95; H, 6.17; N, 20.09. Exact mass (FAB HR MS)

found: 370.1494; calcd for C₁₆H₂₁N₅O₄+Na: 370.1491.

FAB MS m/z (%): 370 (M+Na⁺, 28); 348 (MH⁺, 6);

254 (17); 232 (31); 209 (12); 133 (88). ¹H NMR

(400 MHz, DMSO-d₆): 0.78 and 0.88 (2· m, 2· 2H,

CH₂-cycloprop); 2.20 (s, 3H, CH₃CO); 2.34 (ddd, 1H,

20

D

½aꢂ þ 11:7 (c = 2.58, MeOH). Anal. calcd for

C₁₈H₂₀N₅O₃ÆH₂O: C, 57.90; H, 6.21; N, 18.76; found:

C, 57.86; H, 5.85; N, 18.39. Exact mass (FAB HR

MS) found: 378.1559; calcd for C₁₈H₂₁N₅O₃Na:

378.1542. FAB MS m/z (%): 378 (M+Na⁺, 8); 240

1

J_gem= 13.3, J_{2 b;1}¼ 6:3, J_{2 b;3}¼ 3:5, H-2⁰b); 2.79 (ddd,

0

(41); 224 (17); 160 (23); 147 (35); 134 (81); 77 (51). H

NMR (400 MHz, DMSO-d₆): 2.34 (ddd, 1H,

1H, J_gem= 13.3, J_{2 a;1}¼ 7:3, J_{2 a;3}¼ 5:9, H-2⁰a); 2.98

0

J_gem= 13.3, J_{2 b;1}¼ 6:3, J_{2 b;3}¼ 3:5, H-2⁰b); 2.79 (ddd,

(tt, 1H, J_vic= 7.0, 3.9, CH-cycloprop); 3.52 and 3.62

0

1H, J_gem= 13.3, J_{2 a;1}¼ 7:1, J_{2 a;3}¼ 6:0, H-2⁰a); 3.21

(2· dt, 2H, J_gem= 12.0, J_{5 ;OH}¼ 5:4, J_{5 ;4}¼ 4:6, H-5⁰);

0

3.89 (td, 1H, J_{4 ;5}¼ 4:6, J_{4 ;3}¼ 3:0, H-4⁰); 4.45 (ddt,

0

(s, 3H, CH₃N); 3.52 and 3.62 (2· dt, 2H, J_gem= 11.7,

J_{5 ;OH}¼ 5:7, J_{5 ;4}¼ 4:6, H-5⁰); 3.88 (td, 1H, J_{4 ;5}¼ 4:6,

1H, J_{3 ;2}¼ 5:9, 3.5, J_{3 ;OH}¼ 4:1, J_{3 ;4}¼ 3:0, H-3⁰);

0

J_{4 ;3}¼ 3:0, H-4⁰); 4.44 (ddt, 1H, J_{3 ;2}¼ 6:0, 3.5,

4.92 (s, 2H, CH₂N); 5.00 (t, 1H, J_OH;5¼ 5:4, OH-5⁰);

0

J_{3 ;OH}¼ 4:2, J_{3 ;4}¼ 3:0, H-3⁰); 4.98 (s, 2H, CH₂N);

5.36 (d, 1H, J_OH;3¼ 4:1, OH-3⁰); 6.47 (dd, 1H,

0

4.98 (t, 1H, J_OH;5¼ 5:7, OH-5⁰); 5.35 (d, 1H,

J_{1 ;2}¼ 7:3, 6.3, H-1⁰); 8.70 (s, 1H, H-8); 8.82 (s, 1H,

H-2). ¹³C NMR (100.6 MHz, DMSO-d₆): 9.15 (CH₂-

cycloprop); 22.53 (CH₃CO); 31.63 (CH-cycloprop);

39.36 (CH₂-2⁰); 48.24 (CH₂N); 61.74 (CH₂-5⁰); 70.83

(CH-3⁰); 83.86 (CH-1⁰); 88.17 (CH-4⁰); 131.72 (C-5);

144.52 (CH-8); 150.49 (C-4); 151.79 (CH-2); 158.04 (C-

6); 173.06 (CO). IR (KBr): m = 3392, 3269, 1626, 1594,

0

J_OH;3¼ 4:2, OH-3⁰); 6.46 (t, 1H, J_{1 ;2}¼ 7:1, 6.3, H-1⁰);

6.55 (m, 1H, H-p-Ph); 6.76 (m, 2H, H-o-Ph); 7.08 (m,

2H, H-m-Ph); 8.79 (s, 1H, H-8); 8.84 (s, 1H, H-2). ¹³C

NMR (100.6 MHz, DMSO-d₆): 39.32 (CH₂-2⁰); 39.84

(CH₃-N); 53.08 (CH₂-pur); 61.74 (CH₂-5⁰); 70.83 (CH-

3⁰); 83.90 (CH-1⁰); 88.17 (CH-4⁰); 111.94 (CH-o-Ph);

115.95 (CH-p-Ph); 129.01 (CH-m-Ph); 132.43 (C-5);

144.75 (CH-8); 149.08 (C-i-Ph); 150.66 (C-4); 151.90

(CH-2); 158.76 (C-6). IR (KBr): m = 3408, 3066, 2820,

0

1500, 1422, 1404, 1332, 1210, 1097, 1060, 645 cm^ꢀ1

.

4.80. 6-[N,N-Bis(2-hydroxyethyl)aminomethyl]-9-(b-^D-

ribofuranosyl)purine (11j)

1598, 1507, 1419, 1334, 1210, 1096, 1056, 750, 645 cm^ꢀ1

.

4.78. 6-[(N-Acetyl-N-cyclopropylamino)methyl]-9-(b-^D-

ribofuranosyl)purine (11i)

Prepared from 5j (260 mg) by deprotection method A to

give 120 mg (90%) of 11j as yellow hygroscopic oil.

Product was puriﬁed by extraction of aqueous solution

with Et₂O (removing of methyl toluate) and by chroma-

tography on reverse phase (C-18, mobile phase—H₂O/

MeOH). Exact mass (FAB HR MS) found: 370.1742;

calcd for C₁₅H₂₄N₅O₆: 370.1727. FAB MS m/z (%):

392 (M+Na⁺, 58); 370 (MH⁺, 17); 238 (13); 134 (11);

115 (100). ¹H NMR (400 MHz, DMSO-d₆): 2.69 (m,

4H, CH₂N); 3.47 (m, 4H, CH₂O); 3.57 (dd, 1H,

Prepared from 5i (450 mg) by deprotection method B to

give 180 mg (79%) of 11i as white hygroscopic solid (mp

20

D

ꢁ50 ꢁC). ½aꢂ ꢀ 26:8 (c = 3.53, H₂O). Anal. calcd for

C₁₆H₂₁N₅O₅Æ1/2H₂O: C, 51.61; H, 6.08; N, 18.81; found:

C, 51.84; H, 6.09; N, 18.38. Exact mass (FAB HR MS)

found: 364.1631; calcd for C₁₆H₂₂N₅O₅: 364.1621. FAB

MS m/z (%): 364 (MH⁺, 31); 232 (100); 190 (52); 134

(37). ¹H NMR (500 MHz, DMSO-d₆): 0.79 and 0.89 (2·

J_gem= 12.0, J_{5 b;4}¼ 4:0, H-5⁰b); 3.68 (ddd, 1H,

0

ˇ

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

´

2357

J_gem= 12.0, J_{5 a;4}¼ 4:1, H-5⁰a); 3.97 (q, 1H, J_{4 ;5}¼ 4:1,

(CO). IR (KBr): m = 3392, 3292, 1654, 1600, 1585,

0

4.0, J_{4 ;3}¼ 3:7, H-4⁰); 4.16 (s, 2H, CH₂-pur); 4.19 (dd,

1498, 1405, 1335, 1211, 1122, 1085, 1055, 645 cm^ꢀ1

.

0

1H, J_{3 ;2}¼ 4:8, J_{3 ;4}¼ 3:7, H-3⁰); 4.61 (dd, 1H,

0

J_{2 ;1}¼ 5:7, J_{2 ;3}¼ 4:8, H-2⁰); 6.03 (d, 1H, J_{1 ;2}¼ 5:7,

H-1⁰); 8.84 (s, 1H, H-8); 8.87 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, DMSO-d₆): 55.19 (CH₂-pur); 56.97

(CH₂N); 59.15 (CH₂O); 61.48 (CH₂-5⁰); 70.45 (CH-3⁰);

73.97 (CH-2⁰); 85.97 (CH-4⁰); 87.85 (CH-1⁰); 132.88

(C-5); 144.67 (CH-8); 150.92 (C-4); 151.78 (CH-2);

159.41 (C-6). IR (KBr): m = 3428, 1601, 1585, 1499,

4.83. 6-[(Piperidin-1-yl)methyl]-9-(b-^D-ribofurano-

syl)purine (11l)

0

Prepared from 5l (600 mg) by deprotection method A to

give 195 mg (65%) of 11l as white hygroscopic solid (mp

20

D

(FAB HR MS) found: 350.1818; calcd for C₁₆H₂₄N₅O₄:

80–82 ꢁC). ½aꢂ ꢀ 32:5 (c = 1.26, H₂O). Exact mass

1406, 1334, 1212, 1082, 1048, 646 cm^ꢀ1

.

350.1828. FAB MS m/z (%): 350 (MH⁺, 22); 218 (28);

134 (8). H NMR (500 MHz, DMSO-d₆): 1.33 (m, 2H,

1

4.81. 6-[N,N-Bis(2-hydroxyethyl)aminomethyl]-9-(2-

deoxy-b-^D-erythro-pentofuranosyl)purine (12j)

CH₂-pip); 1.45 (p, 4H, J_vic= 5.8, CH₂-pip); 2.47 (bm,

4H, CH₂N-pip); 3.57 (ddd, 1H, J_gem= 12.0,

J_{5 b;OH}¼ 5:7, J_{5 b;4}¼ 4:0, H-5⁰b); 3.68 (ddd, 1H,

0

J_gem= 12.0, J_{5 a;OH}¼ 5:3, J_{5 a;4}¼ 4:2, H-5⁰a); 3.92 (s,

0

Prepared from 6j (300 mg) by deprotection method A to

give 140 mg (78%) of 12j as white hygroscopic oil. Puri-

ﬁcation of product was accomplished analogously as

0

2H, CH₂N); 3.98 (q, 1H, J_{4 ;5}¼ 4:2, 4.0, J_{4 ;3}¼ 3:3, H-

4⁰); 4.19 (q, 1H, J_{3 ;2}¼ 4:9, J_{3 ;OH}¼ 4:6, J_{3 ;4}¼ 3:3, H-

0

20

3⁰); 4.65 (q, 1H, J_{2 ;OH}¼ J_{2 ;1}¼ 5:8, J_{2 ;3}¼ 4:9, H-2⁰);

0

above (see 11j). ½aꢂ ꢀ 17:3 (c = 2.13, H₂O). Anal. calcd

D

5.13 (t, 1H, J_OH;5¼ 5:7, 5.3, OH-5⁰); 5.27 (d, 1H,

0

for C₁₅H₂₃N₅O₅Æ1/2H₂O: C, 49.72; H, 6.68; N, 19.33;

found: C, 49.86; H, 6.62; N, 18.91. Exact mass (FAB

HR MS) found: 354.1769; calcd for C₁₅H₂₄N₅O₅:

354.1777. FAB MS m/z (%): 354 (MH⁺, 60); 238 (43);

J_OH;3¼ 4:6, OH-3⁰); 5.57 (d, 1H, J_OH;2¼ 5:8, OH-2⁰);

0

6.03 (d, 1H, J_{1 ;2}¼ 5:8, H-1⁰); 8.79 (s, 1H, H-8); 8.88 (s,

1H, H-2). ¹³C NMR (125.8 MHz, DMSO-d₆): 23.90 and

25.74 (CH₂-pip); 54.32 (CH₂N-pip); 58.83 (CH₂N);

61.47 (CH₂-5⁰); 70.55 (CH-3⁰); 73.78 (CH-2⁰); 85.92

(CH-4⁰); 87.70 (CH-1⁰); 133.56 (C-5); 144.80 (CH-8);

151.02 (C-4); 151.77 (CH-2); 157.40 (C-6). IR (KBr):

m = 3402, 2936, 2856, 1598, 1499, 1407, 1334, 1210,

0

1

174 (100); 134 (23). H NMR (400 MHz, DMSO-d₆):

0

2.35 (ddd, 1H, J_gem= 13.3, J_{2 b;1}¼ 6:3, J_{2 b;3}¼ 3:4, H-

2⁰b); 2.69 (m, 4H, CH₂N); 2.79 (ddd, 1H, J_gem= 13.3,

J_{2 a;1}¼ 7:2, J_{2 a;3}¼ 6:0, H-2⁰a); 3.46 (m, 4H, CH₂O);

0

3.53 and 3.62 (2· dd, 2H, J_gem= 11.7, J_{5 ;4}¼ 4:5, H-

5⁰); 3.89 (td, 1H, J_{4 ;5}¼ 4:5, J_{4 ;3}¼ 3:0, H-4⁰); 4.15 (s,

1102, 1056, 646 cm^ꢀ1

.

0

2H, CH₂-pur); 4.45 (ddd, 1H, J_{3 ;2}¼ 6:0, 3.4,

J_{3 ;4}¼ 3:0, H-3⁰); 6.48 (t, 1H, J_{1 ;2}¼ 7:2, 6.3, H-1⁰);

8.79 (s, 1H, H-8); 8.86 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, DMSO-d₆): 39.40 (CH₂-2⁰); 55.19 (CH₂-

pur); 56.98 (CH₂N); 59.20 (CH₂O); 61.74 (CH₂-5⁰);

70.83 (CH-3⁰); 83.88 (CH-1⁰); 88.20 (CH-4⁰); 132.88

(C-5); 144.57 (CH-8); 150.61 (C-4); 151.68 (CH-2);

159.34 (C-6). IR (KBr): m = 3392, 1597, 1585, 1497,

4.84. 6-[(Piperidin-1-yl)methyl]-9-(2-deoxy-b-^D-erythro-

pentofuranosyl)purine (12l)

0

Prepared from 6l (480 mg) by deprotection method A to

give 228 mg (81%) of 12l as white hygroscopic solid (mp

20

D

ꢁ60 ꢁC). ½aꢂ ꢀ 16:6 (c = 2.47, H₂O). Anal. calcd for

C₁₆H₂₃N₅O₃ÆH₂O: C, 54.69; H, 7.17; N, 19.93; found:

C, 54.44; H, 7.08; N, 19.45. Exact mass (FAB HR

MS) found: 334.1888; calcd for C₁₆H₂₄N₅O₃: 334.1879.

FAB MS m/z (%): 334 (MH⁺, 97); 218 (100); 134 (45).

¹H NMR (400 MHz, DMSO-d₆): 1.32 (m, 2H, CH₂-

pip); 1.45 (p, 4H, J_vic= 5.7, CH₂-pip); 2.34 (ddd, 1H,

1402, 1334, 1212, 1093, 1057, 646 cm^ꢀ1

.

4.82. 6-[(2-Acetylhydrazinyl)methyl]-9-(b-^D- ribofurano-

syl)purine (11k)

J_gem= 13.3, J_{2 b;1}¼ 6:3, J_{2 b;3}¼ 3:5, H-2⁰b); 2.46 (bt,

0

Prepared from 5k (200 mg) by deprotection method B to

give 79 mg (80%) of 11k as white lyophilized solid. Exact

mass (FAB HR MS) found: 339.1416; calcd for

C₁₃H₁₉N₆O₅: 339.1417. FAB MS m/z (%): 339 (MH⁺,

4H, J_vic= 5.7, CH₂N-pip); 2.79 (ddd, 1H, J_gem= 13.3,

0

J_{2 a;1}¼ 7:4, J_{2 a;3}¼ 5:9, H-2⁰a); 3.52 and 3.62 (2· ddd,

0

2H, J_gem= 11.8, J_{5 ;4}¼ 4:6, H-5⁰); 3.89 (td, 1H,

0

1

J_{4 ;5}¼ 4:6, J_{4 ;3}¼ 3:0, H-4⁰); 3.90 (s, 2H, CH₂N); 4.45

0

95); 207 (23); 148 (54); 134 (20). H NMR (400 MHz,

DMSO-d₆): 1.74 (s, 3H, CH₃); 3.57 (ddd, 1H,

(dt, 1H, J_{3 ;2}¼ 5:9, 3.5, J_{3 ;4}¼ 3:0, H-3⁰); 5.00 (bs,

0

J_gem= 12.0, J_{5 b;OH}¼ 6:0, J_{5 b;4}¼ 4:2, H-5⁰b); 3.69

1H, OH-5⁰); 5.38 (bs, 1H, OH-3⁰); 6.47 (t, 1H,

0

(ddd, 1H, J_gem= 12.0, J_{5 a;OH}¼ 5:3, J_{5 a;4}¼ 4:1, H-

J_{1 ;2}¼ 7:4, 6.3, H-1⁰); 8.74 (s, 1H, H-8); 8.87 (s, 1H,

H-2). ¹³C NMR (100.6 MHz, DMSO-d₆): 23.92 and

25.75 (CH₂-pip); 39.37 (CH₂-2⁰); 54.33 (CH₂N-pip);

58.84 (CH₂N); 61.76 (CH₂-5⁰); 70.86 (CH-3⁰); 83.87

(CH-1⁰); 88.17 (CH-4⁰); 133.58 (C-5); 144.69 (CH-8);

150.72 (C-4); 151.68 (CH-2); 157.35 (C-6). IR (KBr):

m = 3413, 2935, 2855, 1598, 1497, 1403, 1332, 1210,

0

5⁰a); 3.98 (q, 1H, J_{4 ;5}¼ 4:2, 4.1, J_{4 ;3}¼ 3:6, H-4⁰);

0

4.19 (td, 1H, J_{3 ;OH}¼ 4:9, J_{3 ;2}¼ 4:9, J_{3 ;4}¼ 3:6, H-3⁰);

0

4.30 (d, 2H, J_CH; NH = 5.8, CH₂NH); 4.64 (q, 1H,

2

J_{2 ;OH}¼ 5:8, J_{2 ;1}¼ 5:7, J_{2 ;3}¼ 4:9, H-2⁰); 5.12 (t, 1H,

0

J_OH;5¼ 6:0, 5.3, OH-5⁰); 5.26 (d, 1H, J_OH;3¼ 4:9,

0

OH-3⁰); 5.54 (d, 1H, J_OH;2¼ 5:8, OH-2⁰); 5.60 (dt, 1H,

0

J

_NH,CH2= 5.8, J_NH,NH= 6.4, NH-CH₂); 6.04 (d, 1H,

1100, 1057, 646 cm^ꢀ1

.

J_{1 ;2}¼ 5:7, H-1⁰); 8.81 (s, 1H, H-8); 8.90 (s, 1H, H-2);

9.40 (d, 1H, J_NH,NH= 6.4, NH-Ac). ¹³C NMR

(100.6 MHz, DMSO-d₆): 20.84 (CH₃); 52.00 (CH₂NH);

61.46 (CH₂-5⁰); 70.49 (CH-3⁰); 73.83 (CH-2⁰); 85.89

(CH-4⁰); 87.77 (CH-1⁰); 132.59 (C-5); 144.79 (CH-8);

150.90 (C-4); 151.89 (CH-2); 157.44 (C-6); 168.36

0

4.85. 6-[(Morpholin-4-yl)methyl]-9-(b-^D-ribofurano-

syl)purine (11m)

Prepared from 5m (340 mg) by deprotection method A

to give 116 mg (69%) of 11m as yellowish hygroscopic

ˇ

´

P. Silhar et al. / Bioorg. Med. Chem. 16 (2008) 2329–2366

2358

20

solid (mp ꢁ60 ꢁC). ½aꢂ ꢀ 34:3 (c = 2.07, H₂O). Exact

0

4-thiazolidine); 3.57 (dd, 1H, J_gem= 12.0, J_{5 b;4}¼ 3:8,

D

mass (FAB HR MS) found: 352.1617; calcd for

H-5⁰b); 3.69 (dd, 1H, J_gem= 12.0, J_{5 a;4}¼ 4:2, H-5⁰a);

0

C₁₅H₂₂N₅O₅: 352.1621. FAB MS m/z (%): 352 (MH⁺,

100); 220 (98); 134 (33). H NMR (400 MHz, DMSO-

3.95 (s, 2H, H-2-thiazolidine); 3.98 (q, 1H, J_{4 ;5}¼ 4:2,

0

1

3.8, J_{4 ;3}¼ 3:7, H-4⁰); 4.17 (s, 2H, CH₂N); 4.19 (dd,

0

1H, J_{3 ;2}¼ 5:0, J_{3 ;4}¼ 3:7, H-3⁰); 4.64 (t, 1H,

0

d₆): 2.52 (m, 4H, CH₂N-morph); 3.54 (m, 4H, CH₂O-

morph); 3.57 (ddd, 1H, J_gem= 12.0, J_{5 b;OH}¼ 6:0,

J_{2 ;1}¼ 5:7, J_{2 ;3}¼ 5:0, H-2⁰); 5.10 (bs, 1H, OH-5⁰);

0

J_{5 b;4}¼ 4:0, H-5⁰b); 3.69 (ddd, 1H, J_gem= 12.0,

5.25 (bs, 1H, OH-3⁰); 5.54 (bs, 1H, OH-2⁰); 6.04 (d,

0

J_{5 a;OH}¼ 5:2, J_{5 a;4}¼ 4:9, H-5⁰a); 3.96 (s, 2H, CH₂N);

1H, J_{1 ;2}¼ 5:7, H-1⁰); 8.82 (s, 1H, H-8); 8.91 (s, 1H,

H-2). ¹³C NMR (100.6 MHz, DMSO-d₆): 29.19 (CH₂-

5-thiazolidine); 52.74 (CH₂-2-thiazolidine); 58.15 (CH₂-

4-thiazolidine); 61.08 (CH₂N); 61.44 (CH₂-5⁰); 70.48

(CH-3⁰); 73.83 (CH-2⁰); 85.89 (CH-4⁰); 87.81 (CH-1⁰);

133.12 (C-5); 144.98 (CH-8); 151.16 (C-4); 151.96 (CH-

2); 157.61 (C-6). IR (KBr): m = 3425, 1600, 1499, 1405,

0

3.98 (q, 1H, J_{4 ;5}¼ 4:2, 4.0, J_{4 ;3}¼ 3:5, H-4⁰); 4.19 (td,

0

1H, J_{3 ;OH}¼ 5:0, J_{3 ;2}¼ 4:9, J_{3 ;4}¼ 3:5, H-3⁰); 4.65 (q,

0

1H, J_{2 ;OH}¼ 6:0, J_{2 ;1}¼ 5:8, J_{2 ;3}¼ 4:9, H-2⁰); 5.11 (t,

0

1H, J_OH;5¼ 6:0, 5.2, OH-5⁰); 5.25 (d, 1H, J_OH;3¼ 5:0,

0

OH-3⁰); 5.54 (d, 1H, J_OH;2¼ 6:0, OH-2⁰); 6.03 (d, 1H,

0

J_{1 ;2}¼ 5:8, H-1⁰); 8.80 (s, 1H, H-8); 8.90 (s, 1H, H-2).

¹³C NMR (100.6 MHz, DMSO-d₆): 53.89 (CH₂N-

morph); 58.69 (CH₂N); 61.75 (CH₂-5⁰); 66.63 (CH₂O-

morph); 70.81 (CH-3⁰); 74.08 (CH-2⁰); 86.19 (CH-4⁰);

88.03 (CH-1⁰); 133.81 (C-5); 145.19 (CH-8); 151.38 (C-

4); 152.09 (CH-2); 157.10 (C-6). IR (KBr): m = 3360,

2825, 1599, 1499, 1455, 1407, 1335, 1210, 1114, 1057,

0

1335, 1210, 1120, 1083, 1051, 645 cm^ꢀ1

.

4.88. 6-[(Indol-1-yl)methyl]-9-(b-^D-ribofuranosyl)purine

(11p)

Prepared from 5p (175 mg) by deprotection method A to

20

D

865, 647 cm^ꢀ1

.

give 85 mg (93%) of 11p as yellowish foam. ½aꢂ ꢀ 32:7

(c = 1.99, MeOH). Exact mass (FAB HR MS) found:

382.1532; calcd for C₁₉H₂₀N₅O₄: 382.1515. FAB MS

m/z (%): 382 (MH⁺, 52); 250 (100); 134 (14); 117 (38).

¹H NMR (400 MHz, DMSO-d₆): 3.57 (ddd, 1H,

4.86. 6-[(Morpholin-4-yl)methyl]-9-(2-deoxy-b-^D-erythro-

pentofuranosyl)purine (12m)

J_gem= 12.0, J_{5 b;OH}¼ 6:0, J_{5 b;4}¼ 4:1, H-5⁰b); 3.68

0

Prepared from 6m (550 mg) by deprotection method A

to give 275 mg (85%) of 12m as yellowish hygroscopic

0

(ddd, 1H, J_gem= 12.0, J_{5 a;OH}¼ 5:2, J_{5 a;4}¼ 4:2, H-

20

D

5⁰a); 3.97 (q, 1H, J_{4 ;5}¼ 4:2, 4.1, J_{4 ;3}¼ 3:5, H-4⁰);

0

0 0 0

solid (mp 128–130 ꢁC). ½aꢂ ꢀ 18:4 (c = 1.81, H₂O).

4.19 (td, 1H, J_{3 ;OH}¼ 5:0, J_{3 ;2}¼ 4:8, J_{3 ;4}¼ 3:5, H-3⁰);

0

Anal. calcd for C₁₅H₂₁N₅O₄ÆH₂O: C, 50.98; H, 6.56;

N, 19.82; found: C, 50.82; H, 6.28; N, 19.56. Exact mass

(FAB HR MS) found: 336.1680; calcd for C₁₅H₂₂N₅O₄:

336.1672. FAB MS m/z (%): 336 (MH⁺, 19); 220 (100);

4.64 (q, 1H, J_{2 ;OH}¼ 6:0, J_{2 ;1}¼ 5:7, J_{2 ;3}¼ 4:8, H-2⁰);

0

5.09 (t, 1H, J_OH;5¼ 6:0, 5.2, OH-5⁰); 5.24 (d, 1H,

0

J_OH;3¼ 5:0, OH-3⁰); 5.53 (d, 1H, J_OH;2¼ 6:0, OH-2⁰);

0

1

5.86 (s, 2H, CH₂N); 6.03 (d, 1H, J_{1 ;2}¼ 5:7, H-1⁰);

6.46 (dd, 1H, J_3,2= 3.2, J_3,7= 0.8, H-3-indole); 6.98

(ddd, 1H, J_5,4= 7.9, J_5,6= 7.0, J_5,7= 1.1, H-5-indole);

7.06 (ddd, 1H, J_6,7= 8.2, J_6,5= 7.0, J_6,4= 1.2, H-6-in-

dole); 7.49 (dq, 1H, J_7,6= 8.2, J_7,5= 1.1, J_7,3= 0.8,

J_7,4= 0.8, H-7-indole); 7.52 (dt, 1H, J_4,5= 7.9,

J_4,6= 1.2, J_4,7= 0.8, H-4-indole); 7.54 (d, 1H,

J_2,3= 3.2, H-2-indole); 8.83 (s, 1H, H-8); 8.91 (s, 1H,

H-2). ¹³C NMR (100.6 MHz, DMSO-d₆): 46.58 (CH₂-

pur); 61.41 (CH₂-5⁰); 70.48 (CH-3⁰); 73.79 (CH-2⁰);

85.94 (CH-4⁰); 87.89 (CH-1⁰); 101.16 (CH-3-indole);

110.10 (CH-7-indole); 119.29 (CH-5-indole); 120.52

(CH-4-indole); 121.31 (CH-6-indole); 128.36 (C-3a-in-

dole); 129.98 (CH-2-indole); 132.09 (C-5); 136.19 (C-

7a-indole); 145.47 (CH-8); 151.30 (C-4); 152.17 (CH-

2); 155.65 (C-6). IR (KBr): m = 3422, 1600, 1498, 1463,

0

134 (52). H NMR (400 MHz, DMSO-d₆): 2.35 (ddd,

1H, J_gem= 13.4, J_{2 b;1}¼ 6:3, J_{2 b;3}¼ 3:5, H-2⁰b); 2.51

0

(m, 4H, CH₂N-morph); 2.79 (ddd, 1H, J_gem= 13.4,

J_{2 a;1}¼ 7:3, J_{2 a;3}¼ 5:9, H-2⁰a); 3.52 (ddd, 1H,

0

J_gem= 11.8, J_{5 b;OH}¼ 5:8, J_{5 b;4}¼ 4:6, H-5⁰b); 3.54 (m,

0

4H, CH₂O-morph); 3.62 (ddd, 1H, J_gem= 11.8,

0

J_{5 a;OH}¼ 5:5, J_{5 a;4}¼ 4:6, H-5⁰a); 3.89 (td, 1H,

0

J_{4 ;5}¼ 4:6, J_{4 ;3}¼ 3:0, H-4⁰); 3.95 (s, 2H, CH₂N); 4.45

0

(m, 1H, J_{3 ;2}¼ 5:9, 3.5, J_{3 ;OH}¼ 4:2, J_{3 ;4}¼ 3:0, H-3⁰);

0

5.00 (t, 1H, J_OH;5¼ 5:8, 5.5, OH-5⁰); 5.36 (d, 1H,

0

J_OH;3¼ 4:2, OH-3⁰); 6.47 (t, 1H, J_{1 ;2}¼ 7:3, 6.3, H-1⁰);

8.76 (s, 1H, H-8); 8.88 (s, 1H, H-2). ¹³C NMR

(100.6 MHz, DMSO-d₆): 39.36 (CH₂-2⁰); 53.60 (CH₂N-

morph); 58.40 (CH₂N); 61.73 (CH₂-5⁰); 66.34 (CH₂O-

morph); 70.83 (CH-3⁰); 83.87 (CH-1⁰); 88.17 (CH-4⁰);

133.53 (C-5); 144.82 (CH-8); 150.79 (C-4); 151.72 (CH-

2); 156.69 (C-6). IR (KBr): m = 3402, 2819, 1599, 1498,

0

1400, 1335, 1208, 1120, 1082, 1053, 744, 645 cm^ꢀ1

.

1455, 1403, 1334, 1210, 1112, 1056, 863, 645 cm^ꢀ1

.

4.89. 6-[(Pyrazol-1-yl)methyl]-9-(b-^D-ribofurano-

syl)purine (11q)

4.87. 6-[(Thiazolidin-3-yl)methyl]-9-(b-^D-ribofurano-

syl)purine (11n)

Prepared from 5q (205 mg) by deprotection method A to

give 82 mg (83%) of 11q as white solid (mp 76–78 ꢁC).

Prepared from 5n (450 mg) by deprotection method A to

give 148 mg (67%) of 11n as lyophilized solid.

20

D

½aꢂ ꢀ 40:2 (c = 2.93, MeOH). Anal. calcd for

20

D

½aꢂ ꢀ 38:1 (c = 2.73, H₂O). Anal. calcd for

C₁₄H₁₆N₆O₄ÆH₂O: C, 48.00; H, 5.18; N, 23.99; found:

C, 48.06; H, 4.97; N, 23.56. Exact mass (FAB HR

MS) found: 333.1305; calcd for C₁₄H₁₇N₆O₄: 333.1311.

FAB MS m/z (%): 333 (MH⁺, 59); 201 (44); 133 (13).

¹H NMR (400 MHz, DMSO-d₆): 3.57 (ddd, 1H,

C₁₄H₁₉N₅O₄SÆH₂O: C, 45.27; H, 5.70; N, 18.86; found:

C, 45.12; H, 5.43; N, 18.42. Exact mass (FAB HR

MS) found: 354.1234; calcd for C₁₄H₂₀N₅O₄S:

354.1236. FAB MS m/z (%): 354 (MH⁺, 22); 222 (17);

1

0

134 (13). H NMR (400 MHz, DMSO-d₆): 2.94 (t, 2H,

J_vic= 6.4, H-5-thiazolidine); 3.11 (t, 2H, J_vic= 6.4, H-

J_gem= 11.8, J_{5 b;OH}¼ 5:8, J_{5 b;4}¼ 4:2, H-5⁰b); 3.69

0

(ddd, 1H, J_gem= 11.8, J_{5 a;OH}¼ 5:1, J_{5 a;4}¼ 4:2, H-

Article Doi

Synthesis, cytostatic and anti-HCV activity of 6-(N-substituted aminomethyl)-, 6-(O-substituted hydroxymethyl)- and 6-(S-substituted sulfanylmethyl)purine nucleosides

DOI: 10.1016/j.bmc.2007.11.067

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Article abstract of DOI:10.1016/j.bmc.2007.11.067

Full text of DOI:10.1016/j.bmc.2007.11.067

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