Synthesis of 2-substituted 6-(hydroxymethyl)purine bases and nucleosides

2-Substituted 6-(Hydroxymethyl)purine Bases

1669

SYNTHESIS OF 2-SUBSTITUTED 6-(HYDROXYMETHYL)PURINE BASES

AND NUCLEOSIDES

1,

Peter ŠILHÁR, Radek POHL, Ivan VOTRUBA and Michal HOCEK *

Centre for New Antivirals and Antineoplastics, Institute of Organic Chemistry and Biochemistry,

Academy of Sciences of the Czech Republic, Flemingovo nám. 2, CZ-166 10 Prague 6,

1

Czech Republic; e-mail: hocek@uochb.cas.cz

Received July 18, 2005

Accepted August 12, 2005

Dedicated to the jubilee 70th volume of Collection of Czechoslovak Chemical Communications and to

the memory of its founders, Professors Jaroslav Heyrovský and Emil Votoček.

A facile an d efficien t m eth odology of th e syn th esis of 6-(h ydroxym eth yl)purin e derivatives

(bases an d n ucleosides) was developed based on Pd-catalyzed cross-couplin g reaction s of

6-h alopurin es or N-protected 2-am in o-6-h alopurin es with (ben zoyloxym eth yl)zin c iodide

followed by deprotection . Regioselective h ydroxym eth ylation s of 2,6-dih alopurin es were

also studied an d used for th e syn th esis of 2-ch loro-6-(h ydroxym eth yl)- or 2,6-bis(h ydroxy-

m eth yl)purin es. Th e 6-(h ydroxym eth yl)purin e ribon ucleoside 5f exerted h igh cytostatic

effect an d m oderate in h ibition of aden osin e deam in ase, wh ile all th e oth er derivatives were

m uch less effective or en tirely in active.

Keyw ord s: Purin es; Nucleosides; Cross-couplin g reaction s; Hydroxym eth ylation ; Palladium ;

Fun ction alized organ ozin c reagen ts; Cytostatic activity; Aden osin e deam in ase.

Purin e bases an d n ucleosides bearin g C-substituen ts in th e position 6 pos-

sess cytostatic¹, an ti-HCV ²or an tim icrobial³activity. Cross-couplin g reac-

tion s of 6-h alopurin es with diverse organ om etallics are a powerful tool⁴for

th e syn th esis of th ese com poun ds but, in m ost cases, were on ly used for an

in troduction of sim ple un fun ction alized carbon substituen ts. On th e oth er

h an d, purin es bearin g C-substituen ts at position 6 con tain in g fun ction al

groups (OH, NH₂, COOH etc.) would provide n ew exploitable m oieties for

in teraction s with com plem en tary n ucleobases, en zym es, or receptors wh ile

still preservin g h igh er stability towards en zym atic degradation due to th e

presen ce of C–C bon d in position 6. However, due to very lim ited syn th etic

accessibility, such com poun ds are scarcely reported in th e literature an d

very little is kn own about th eir biological activity. Th erefore, an exten sion

of th e cross-couplin g m eth odology to fun ction alized C-substituen ts is a

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

doi:10.1135/cccc20051669

1670

Šilhár, Pohl, Votruba, Hocek:

useful an d ch allen gin g goal. Recen tly we h ave developed syn th eses of

(purin -6-yl)glycin es⁵an d -alan in es⁶as exam ples of such derivatives. Th e

h ydroxym eth yl group is on e of th e sim plest an d m ost useful fun ction alized

substituen ts an d its in troduction to purin e m oiety is a subject of th is paper.

6-(Hydroxym eth yl)-9-(β-D-ribofuran osyl)purin e was isolated from

Collybia maculata an d reported to possess an tifun gal, cytotoxic an d an tivi-

ral (vesicular stom atitis virus) activity⁷an d in h ibition of aden osin e

deam in ase⁸. Syn th etic approach es to 6-(h ydroxym eth yl)purin es publish ed

so far were based on th e radical ph otoaddition of m eth an ol to un substi-

tuted purin e in aerobic con dition s^8a,9or recen tly reported reaction of

6-m agn esiated purin e with paraform aldeh yde¹⁰. Un fortun ately, th e ph oto-

addition in aerobic con dition proceeds with low ch em oselectivity an d a

very com plex reaction profile^9b; in argon atm osph ere th e m ain product is

1,6-dih ydro-6-(h ydroxym eth yl)purin e wh ich can be oxidatively con verted

on th e 6-(h ydroxym eth yl)purin e^9b. Th e yield of n ucleoph ilic addition of

6-m agn esiated purin e to form aldeh yde is rath er low because of low reactiv-

ity of purin ylm agn esium reagen t¹⁰. On th e oth er h an d, 6-lith iated purin e is

m uch m ore reactive but it is stable on ly for few m in utes at –130 °C ¹¹. In di-

rect routes from 6-m eth ylpurin e: oxidation to aldeh yde followed by reduc-

tion ¹²or rearran gem en t of its N-oxide with Ac₂O to 6-(acetoxym eth yl)-

purin e¹³gave low yields.

Recen tly, we h ave publish ed a prelim in ary com m un ication ¹⁴on a n ovel

facile an d efficien t syn th esis of 6-(h ydroxym eth yl)purin es by th e Negish i

cross-couplin g reaction s of (acyloxym eth yl)zin c iodides with 9-substituted

6-h alopurin es followed by deprotection . Later on , we h ave also successfully

con verted¹⁵th ese h ydroxym eth yl derivatives to 6-(fluorom eth yl)purin es.

Here we presen t a full accoun t of th e m eth odology of h ydroxym eth ylation

of 6-h alopurin es, n ow also exten ded to 2-am in opurin es an d to regio-

selective h ydroxym eth ylation s of 2,6-dih alopurin es.

RESULTS AND DISCUSSION

In th e prelim in ary com m un ication on th e h ydroxym eth ylation m eth odol-

ogy, th ree (acyloxym eth yl)zin c iodides (acetyl, ben zoyl an d pivaloyl es-

ters)¹⁶were used in th e Pd-catalyzed cross-couplin g reaction s with h alo-

purin es. Th e best results were obtain ed with (ben zoyloxym eth yl)zin c iodide

(1). Its cross-couplin g reaction s gave very good yields (72–96%) an d th e

ben zoyl group was easily an d efficien tly cleaved un der m ild con dition s.

Th erefore, th is reagen t was used in preparative scale in all furth er experi-

m en ts. Th e stock solution of (ben zoyloxym eth yl)zin c iodide (1) in THF was

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2-Substituted 6-(Hydroxymethyl)purine Bases

1671

OBz

OH

X

BzOCH₂ZnI (3 eqiv.)

MeONa

MeOH

N

1

N

Pd(PPh₃)₄

THF, r.t. 6-10h

N

R

R´

R

4a-d

Yield: 72-96%

2a-d, X = Cl

3a,b,d, X = I

5a,b,f,g

In compounds 2-5:

a

Bn

R =

AcO

TolO

O

b

THP

c

d

AcO OAc

OTol

Dowex [H⁺]

MeONa / MeOH

R' =

e

H

HO

O

g

f

HO

Bn = benzyl

HO OH

Bz = benzoyl

Tol = 4-methylbenzoyl

SCHEME 1

Cross-couplin gs of (ben zoyloxym eth yl)zin c iodide with 6-h alopurin es

TABLE I

Cross-couplin g reaction s of 1 with h alopurin es 2 or 3

En try

Startin g com poun d

Tim e, h

Product (Yield, %)

1

2

3

4

5

6

7

2a

3a

2b

3b

2c

2d

3d

8

6

4a (81)

4a (96)

4b (72)

4b (95)

4c (94)

4d (91)

4d (93)

10

6

8

6

TABLE II

Cleavage of protectin g groups in preparation s of 6-(h ydroxym eth yl)purin e bases an d n ucleo-

sides 5

En try

Startin g com poun d

Reagen t

Product (Yield, %)

1

2

3

4

5

4a

4b

4c

4d

5b

MeONa

5a (88)

5b (85)

5f (81)

5g (86)

5e (78)

MeONa

Dowex (H⁺)

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1672

Šilhár, Pohl, Votruba, Hocek:

prepared¹⁴by reaction of activated zin c with th e iodom eth yl ben zoate¹⁷at

5–10 °C un der argon . It was stored in a freezer for several weeks with out de-

com position . Th e cross-couplin g reaction s of 1 with a series of protected

6-h alopurin e bases an d n ucleosides 2 or 3 (Sch em e 1, Table I) gave

6-(ben zoyloxym eth yl)purin es 4, gen erally in very good yields. Th e effect of

leavin g group was n ot crucial: 6-iodopurin es 3 usually gave just sligh tly

better yields th an 6-ch loropurin es 2.

Th e ester groups of in term ediates 4 were efficien tly cleaved with NaOMe

in m eth an ol at room tem perature to give th e correspon din g free 6-(h y-

droxym eth yl)purin e bases an d n ucleosides 5 in good yields (Table II). Th e

THP protective group in position 9 of purin e 5b was cleaved usin g Dowex

50X8 (H⁺form ) in eth an ol¹⁸to give th e correspon din g 9H-purin e 5e.

Havin g an optim ized m eth odology in h an ds, our furth er efforts focused

on preparation of 2-am in o-6-(h ydroxym eth yl)purin es as h om ologs of gua-

n in e base an d n ucleosides. An alogous cross-couplin g reaction s of organ o-

zin c reagen t 1 with un protected 2-am in o-6-h alo-9-protected purin es pro-

ceeded with very low yields (9–20%) even wh en usin g large excess of th e

organ ozin c. Th erefore a suitable protectin g group for th e 2-am in o group

h ad to be foun d. (Dim eth ylam in o)m eth yliden e is often used to protect

both acidic h ydrogen s of a n ucleobase am in o groups¹⁹an d th erefore it was

also our group of ch oice. It was in troduced by th e reaction s of 2-am in o-

6-ch loropurin es 6 with DMF/dim eth ylacetal (3 equivalen ts) in DMF at

50 °C an d th e in term ediates 7 were used with out purification in th e n ext

step after evaporation an d dryin g. Th eir cross-couplin g reaction s with 1

proceeded sm ooth ly at room tem perature to give good con version s to th e

correspon din g 6-(ben zoyloxym eth yl)purin es 8 (Sch em e 2, Table III). How-

ever, durin g work-up an d colum n ch rom atograph y on silica gel, th e

(dim eth ylam in o)m eth yliden e group was partly h ydrolyzed to form form yl

derivatives 9 as by-products. Th erefore, th e in separable m ixtures of in ter-

m ediates 8 an d 9 were directly used in th e deprotection step usin g aqueous

am m on ia in m eth an ol at 55 °C to sim ultan eously cleave all th e O-acyl

groups an d th e (dim eth ylam in o)m eth yliden e/form yl groups affordin g th e

desired 2-am in o-6-(h ydroxym eth yl)purin es 10a, 10f an d 10g in good yields

(Table IV).

For th e syn th esis of th e corespon din g purin e base 10e, differen t protect-

in g groups were used. In th is case, we h ave started from N²,9-bis(THP) pro-

18

tected 2-am in o-6-h alopurin es 11b or 12b ²⁰. In th ese particular cases, th e

reactivity of th e two derivatives differed sign ifican tly. Th e cross-couplin g of

1 with th e ch loro derivative 11b gave th e desired product 13b in low yield,

wh ile th e reaction with th e iodo derivative 12b gave 13b in good yield of

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2-Substituted 6-(Hydroxymethyl)purine Bases

1673

BzO

N

OH

Cl

BzOCH₂ZnI (3 eqiv.)

NH₃(aq)

N

1

N

MeOH

55°C, 24h

R¹R²N

N

H₂N

N

Pd(PPh₃)₄

N

R

R´

THF, r.t. 12h

R

7a,c,d

R¹,R²= Me₂NCH= 8a,c,d

R¹= -CHO, R²= H 9a,c,d

10a,f,g

OMe

N

In compounds 6-10:

AcO

TolO

DMF, 50°C,12h

O

c

R =

a

Bn

d

Cl

AcO OAc

OTol

N

NH₃(aq) / MeOH

N

H₂N

N

HO

R' =

O

R

g

6a,c,d

f

OH

OH OH

SCHEME 2

Cross-couplin gs of (ben zoyloxym eth yl)zin c iodide with protected 2-am in o-6-h alopurin es

TABLE III

Cross-couplin gs of 1 with protected 2-am in o-6-h alopurin es

En try

Startin g com poun d

Product (Yield, %)

Ratio 8:9

1

2

3

4

5

6a

11b

12b

6c

8a + 9a (77)^a

13b (30)

1:2

–

13b (68)

–

8c + 9c (85)^a

8d + 9d (83)^a

8:5

5:2

6d

a

Approx. yield (ratio 8:9 accordin g ¹H NMR).

TABLE IV

Cleavage of protectin g groups in preparation s of 2-am in o-6-(h ydroxym eth yl)purin es

En try

Startin g com poun d

Reagen t

Product (Yield, %)

1

2

3

4

5

8a + 9a

13b

NH₃(aq.)

TsOH

10a (66)

14b (79)

10f (67)

10g (65)

10e (67)

8c + 9c

8d + 9d

14b

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1674

Šilhár, Pohl, Votruba, Hocek:

68%. Th e ben zoyl group was cleaved with am m on ia to give in term ediate

14b an d th e THP protective groups in position 9 an d N²of purin e were

even tually cleaved usin g p-toluen esulfon ic acid (2.5 equivalen ts) in eth an ol

to afford th e free base 10e in 67% yield (Sch em e 3).

BzO

OH

X

BzOCH₂ZnI (3 eqiv.)

NH₃(aq)

N

1

N

MeOH

r.t., 16h

Pd(PPh₃)₄

THF, r.t. 12h

N

HN

THP

N

HN

THP

N

HN

N

THP

14b

13b

11b, X = Cl

12b, X = I

OH

N

TsOH

N

EtOH

70°C

H₂N

H

10e

SCHEME 3

Cross-couplin g reaction s of dih alopurin es with on e equivalen t of an

organ om etallic reagen t are regioselective^21,22. In gen eral 2,6- or 6,8-di-

ch loropurin es react²¹preferen tially in position 6, wh ile ch loroiodopurin es

in th e position of iodin e. Th e on ly exception s from th is rule are th e Fe-

catalyzed reaction s²²of 6,8-dich loropurin es with Grign ard reagen ts occur-

rin g in position 8. Th ese regioselective reaction s were exten sively used in

th e syn th esis of di- an d trisubstituted purin e bases an d n ucleosides^21,22. As

n o fun ction alized organ om etallic reagen t h as ever been applied in th ese re-

action s, in vestigation of regioselectivity of cross-couplin g reaction s of

BzOCH₂Zn I (1) with 2,6-dih alopurin es was an oth er aim of our study.

2,6-Bis(h ydroxym eth yl)purin es are h om ologs of xan th in e derivatives an d

2-ch loro-6-(h ydroxym eth yl)purin es are related to an tin eoplastic cladribin e

(2-ch loro-2′-deoxyaden osin e)²³. Th erefore th e syn th esis of th ese two types

of com poun ds by th e regioselective cross-couplin gs is of in terest.

At first we h ave used 2,6-dich loropurin es as substrates for cross-couplin g

reaction s with th e organ ozin c 1. Th e cross-couplin gs were perform ed with

eith er 1.1 or 4 equivalen ts of th e organ ozin c reagen t. 6-(Ben zoyloxy-

m eth yl)-2-ch loropurin es 16 were form ed as m ain products wh en usin g

1.1 equivalen ts of BzOCH₂Zn I in accord with th e previous kn owledge of

h igh er reactivity of ch lorin e in th e position 6 (Sch em e 4, Table V). How-

ever, even wh en usin g 4 equivalen ts of th e organ ozin c reagen t th e yields of

disubstituted products 17 were still very low wh ile com poun ds 16 were

m ajor products (Table V, en tries 2, 4, 6, 8). Also a reaction of purified

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2-Substituted 6-(Hydroxymethyl)purine Bases

1675

6-(ben zoyloxym eth yl)-9-ben zyl-2-ch loropurin e 16a with BzOCH₂Zn I

(3 equivalen ts) proceeded with on ly n egligible yield of com poun d 17a. Th is

sh ows th at th e reactivity of ch lorin e in position 2 is too low for an efficien t

cross-couplin g with reagen t 1.

In order to perform cross-couplin g in th e position 2, we h ave turn ed our

atten tion to 2-iodopurin es as th e iodin e is sign ifican tly better leavin g group

com pared to ch lorin e. Hen ce, we h ave studied cross-couplin g reaction s of 1

with 6-ch loro-2-iodopurin es 18. Th e first experim en ts were perform ed with

3 equivalen ts of th e organ ozin c 1 at am bien t tem perature (con dition s A).

BzO

N

BzO

N

Cl

BzOCH₂ZnI

(1.1 or 4 eqiv.)

N

+

BzO

Pd(PPh₃)₄

THF, r.t., 12h

Cl

N

Cl

N

R

15a,b,d,h

16a,b,d,h

17a,b,d,h

In compounds 15-17:

TolO

BzO

O

a

Bn

R =

h

d

b

THP

OTol

BzO

OBz

SCHEME 4

Cross-couplin gs of (ben zoyloxym eth yl)zin c iodide with 2,6-ch loropurin es

TABLE V

Regioselective cross-couplin gs of 1 with 2,6-ch loropurin es

Startin g

com poun d

BzOCH₂Zn I

equivalen t

En try

Product (Yield, %)

1

2

3

4

5

6

7

8

9

15a

15b

15h

15d

16a

1.1

4

16a (89)

16a (63)

16b (78)

16b (66)

16h (84)

16h (53)

16d (67)

16d (77)

17a (5)

17a (10)

17b (8)

17b (18)

17h (<1)

17h (6)

17d (3)

17d (15)

17a (5)

1.1

4

1.1

4

1.1

4

3

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1676

Šilhár, Pohl, Votruba, Hocek:

B or C

BzO

Cl

N

A

N

+

BzO

N

I

N

R

19a-d

18a-d

17a-d

A

AcO

A BzOCH₂ZnI (3 eqiv.), Pd(PPh₃)₄(5%), THF,r.t., 12h

B 1. BzOCH₂ZnI (4 eqiv.), Pd(PPh₃)₄(5%), THF, 0°C, 12 h

2. Pd(PPh₃)₄(5%), r.t. 12 h

O

a

Bn

R =

c

AcO OAc

C BzOCH₂ZnI (3 eqiv.), Pd(PPh₃)₄(20%), THF,r.t., 12h

TolO

b

THP

O

d

OTol

SCHEME 5

Cross-couplin gs of (ben zoyloxym eth yl)zin c iodide with 6-ch loro-2-iodopurin es (18)

TABLE VI

Cross-couplin gs of (ben zoyloxym eth yl)zin c iodide with 6-ch loro-2-iodopurin es

En try

Startin g com poun d

Con dition s

Product (Yield, %)

1

2

18a

18b

18c

18d

19a

19b

19c

19d

18a

18b

18c

18d

18a

A

B

C

19a (90)

19b (87)

19c (88)

19d (90)

17a (3)

17b (1)

17c (<1)

17d (1)

3

4

5

17a (98)

6

17b (97)

17c (92)

17d (91)

17a (81)

17b (85)

17c (83)

17d (88)

17a (86)

7

8

9

10

11

12

13

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2-Substituted 6-(Hydroxymethyl)purine Bases

1677

Despite th e excess of th e reagen t, th e m ain products were th e 2-(ben zoyl-

oxym eth yl)-6-ch loropurin es 19. Th is was quite un expected sin ce we h ave

kn own th e relatively h igh reactivity of 6-ch loropurin es in th e cross-

couplin gs with 1. On th e oth er h an d, reaction s of purified 2-(ben zoyloxy-

m eth yl)-6-ch loropurin es 19a–19d with 1 (3 equivalen ts) afforded th e

2,6-bis(ben zoyloxym eth yl)purin es 17a–17d in excellen t yields of 91–98%

In compounds 16, 17, 20, 21:

BzO

N

HO

N

Dowex [H⁺]

N

e R' = H

NH₃(aq)

MeOH

R =

a

Bn

b

THP

Cl

N

Cl

N

R

R'

TolO

BzO

AcO

20a,b,f,g

O

16a,b,d,h

O

h

d

c

OTol

BzO

OBz

AcO

R' =

OAc

BzO

HO

N

NH₃(aq) or MeONa

MeOH

MeONa(cat.)

MeOH

N

BzO

HO

N

HO

R

R'

O

g

f

21a,b,f,g

17a-d

OH

SCHEME 6

TABLE VII

Cleavage of protectin g groups in preparation s of 2-ch loro-6-(h ydroxym eth yl)purin es an d

2,6-bis(h ydroxym eth yl)purin es

En try

Startin g com poun d

Reagen t

Product (Yield, %)

1

2

16a

16b

16h

16d

20b

17a

17b

17c

17d

21b

NH₃(aq.)

Dowex (H⁺)

MeONa

20a (87)

20b (90)

20f (84)

20g (87)

20e (84)

21a (88)

21b (89)

21f (80)

21g (90)

21e (74)

3

4

5

6

7

MeONa

8

MeONa

9

MeONa

Dowex (H⁺)

10

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1678

Šilhár, Pohl, Votruba, Hocek:

(Sch em e 5, Table VI). Apparen tly, th e cause m igh t h ave been eith er in low

stability of th e organ ozin c reagen t at room tem perature or deactivation of

catalytic system . To solve th is problem , we h ave perform ed two experi-

m en ts: (i) addition of a secon d portion of Pd(PPh ₃)₄catalyst after 12 h an d

(ii) h igh er loadin g of catalyst (20 m ole %) (Sch em e 5, Table VI, con dition s

B or C). In both cases th e disubstituted products 17 were obtain ed in good

yields (81–88%) in dicatin g th at th e problem was deactivation of catalyst.

Th e deprotection s of th e 2,6-disubstituted purin es were perform ed in

an alogy to th e previous derivatives. Free 2-ch loro-6-(h ydroxym eth yl)purin e

bases 20a, 20b an d n ucleosides 20f, 20g were prepared from in term ediates

16 usin g aqueous am m on ia in m eth an ol at am bien t tem perature (Sch em e 6)

in good yields (Table VII). Nucleobase 20e was prepared from 20b by acidic

cleveage of THP protective group with Dowex 50X8 (H⁺form )¹⁸in eth an ol

in 84% of yield. Th e ester groups of in term ediates 17 were cleaved with

NaOMe in m eth an ol at room tem perature to give free 2,6-bis(h ydroxy-

m eth yl)purin e bases 21a, 21b an d n ucleosides 21f, 21g (Sch em e 6,

Table VII). Th e THP protective group of 21b was cleaved usin g Dowex 50X8

(H⁺form ) in eth an ol to gave 21e in 74% yield.

Biological Activity

All th e title un substituted an d 2-substituted 6-(h ydroxym eth yl)purin e base

an d n ucleosides 5, 10, 20 an d 21 were subjected to biological activity

screen in g. Cytostatic activity in vitro (in h ibition of cell growth ) was stud-

ied on th e followin g cell cultures: (i) m ouse leukem ia L1210 cells (ATCC

CCL 219), h um an prom yelocytic leukem ia HL60 cells (ATCC CCL 240), h u-

m an cervix carcin om a HeLaS3 cells (ATCC CCL 2.2) an d h um an T lym ph o-

blastoid CCRF-CEM cell lin e (ATCC CCL 119). Aden osin e deam in ase (ADA)

in h ibition was studied²⁴on calf in testin al aden osin e am in oh ydrolase. Th e

results are sum m arized in Table VIII. Th e m ost active was th e 6-(h ydroxy-

m eth yl)purin e ribon ucleoside (5f) exertin g a very h igh cytostatic effect an d

also sign ifican t in h ibition of ADA. Th e related 6-(h ydroxym eth yl)purin e

base 5e an d 2-deoxyribon ucleoside 5g were m uch less active. All th e

2-substituted derivatives 10, 20 an d 21 were devoid of an y con siderable

cytostatic effect an d on ly som e of th em sh owed m oderate in h ibition of

ADA.

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2-Substituted 6-(Hydroxymethyl)purine Bases

1679

TABLE VIII

Biological activity of title purin e bases an d n ucleosides^a

IC₅₀, µm ol l^{–1 b}

Com poun d

HL60

CCRF-CEM

ADA

NA

5e

5f

12.0 (±0.96)

~30

0.01 (±0.0011)

0.15 (±0.0011)

1.70 (±0.136)

5g

NA^b

NA

10.0 (±0.90)

10e

10f

10g

20e

20f

20g

21e

21f

21g

NA

45.0 (±2.7)

45.0 (±2.8)

NA

a

b

Values are m ean s of four experim en ts, stan dard deviation is given in paren th eses. NA,

n ot active (in h ibition of cell growth at 10 µM was lower th an 30%).

CONCLUSIONS

A n ovel facile an d efficien t m eth odology for h ydroxym eth ylation of

h alopurin es h as been developed. It con sists in Pd-catalyzed cross-couplin g

reaction s of h alopurin es with (ben zoyloxym eth yl)zin c iodide. Th ese cross-

couplin gs are perform ed at room tem perature an d gen erally give very h igh

yields of th e (ben zoyloxym eth yl)purin e in term ediates th at are easily

deprotected to th e title (h ydroxym eth yl)purin es with am m on ia or sodium

m eth oxide. Th e m eth odology was applied in th e syn th esis of th e corre-

spon din g purin e bases an d n ucleosides. In 2-am in o-6-ch loropurin es, th e

am in o group h as to be protected by (dim eth ylam in o)m eth yliden e group

prior to th e cross-couplin g. Reaction s of 2,6-dih alopurin es proceed with

h igh regioselectivity givin g eith er 6- or 2-substituted purin es. As th e

h ydroxym eth ylpurin es are biologically active an d m ay also serve as in ter-

m ediates in furth er fun ction al group tran sform ation s to oth er n ew types of

purin e derivatives, th is efficien t syn th etic m eth odology is of great im por-

tan ce.

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1680

Šilhár, Pohl, Votruba, Hocek:

EXPERIMENTAL

Gen eral

Startin g m aterials: 9-ben zyl-6-ch loropurin e²⁵, 9-ben zyl-6-iodopurin e²⁵an d an alogously

9-ben zyl-2,6-dich loropurin e an d 2-am in o-9-ben zyl-6-ch loropurin e, 6-ch loro-9-(tetrah ydro-

pyran -2-yl)purin e²⁶, 6-iodo-9-(tetrah ydropyran -2-yl)purin e²⁶an d an alogously 2,6-dich loro-

9-(tetrah ydropyran -2-yl)purin e, 6-ch loro-2-(tetrah ydropyran -2-yl)am in o-9-(tetrah ydropyran -

2-yl)purin e¹⁸

,

6-iodo-2-(tetrah ydropyran -2-yl)am in o-9-(tetrah ydropyran -2-yl)purin e²⁰

9-(2,3,5-tri-O-acetyl-β-D-ribo-

,

9-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)-6-ch loropurin e²⁷

,

furan osyl)-2-am in o-6-ch loropurin e²⁸, 6-ch loro-9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pen to-

furan osyl)purin e²⁹an d an alogously 6-iodo-9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pen to-

furan osyl)purin e, 2-am in o-6-ch loro-9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pen tofuran osyl)-

purin e³⁰, 9-ben zyl-6-ch loro-2-iodopurin e^21gan d an alogously 6-ch loro-2-iodo-9-(tetrah ydro-

pyran -2-yl)purin e from 6-ch loro-2-(tetrah ydropyran -2-yl)am in o-9-(tetrah ydropyran -2-yl)-

purin e, 9-(2,3,5-tri-O-acetyl-β-D-ribofuran osyl)-6-ch loro-2-iodopurin e³¹an d an alogously

6-ch loro-2-iodo-9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pen tofuran osyl)purin e. All prepara-

tion s of (acyloxym eth yl)zin c iodides¹⁴an d cross-couplin g reaction s were con ducted un der

argon atm osph ere. THF was dried an d distilled from sodium /ben zoph en on e. NMR spectra

were recorded on a Bruker Avan ce 400 MHz spectrom eter (¹H at 400, ¹³C at 100.6 MHz) an d

a Bruker Avan ce (500 MHz for ¹H an d 125.8 MHz for ¹³C). Ch em ical sh ifts (in ppm , δ scale)

were referen ced to TMS as in tern al stan dard, couplin g con stan ts (J) are given in Hz. Th e as-

sign m en t of carbon s was based on C,H-HSQC an d C,H-HMBC experim en ts. Meltin g poin ts

were determ in ed on a Kofler block an d are un corrected. Optical rotation s were m easured at

25 °C on a Autopol IV (Rudolph Research An alytical) polarim eter, [α]_Dvalues are given in

10^–1deg cm ²g^–1. IR spectra were recorded on Nicolet 750 FT-IR an d waven um bers are given

in cm ^–1. Mass spectra were m easured on a ZAB-EQ (VG An alytical) spectrom eter usin g FAB

(ion ization by Xe, acceleratin g voltage 8 kV, glycerol m atrix). Cytostatic activity tests were

perform ed as described in ref.^1aADA in h ibition assay was perform ed by stan dard tech-

n ique²⁴

.

6-Ch loro-9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pen tofuran osyl)-2-iodopurin e (18d )

Yield 69%, wh ite solid, m .p. 162–163 °C. Prepared an alogously as 9-(2,3,5-tri-O-acetyl-

β-D-ribofuran osyl)-6-ch loro-2-iodopurin e³¹(18c) from 2-am in o-6-ch loro-9-(2-deoxy-

3,5-di-O-toluoyl-β-D-erythro-pen tofuran osyl)purin e (6d ). Exact m ass (FAB HR MS) calculated

for C₂₆H₂₃ClIN₄O₅: 633.0402, foun d: 633.0373. FAB MS, m/z (%): 633 (MH⁺, 2); 353 (8); 281

(6); 153 (5); 119 (73). ¹H NMR (400 MHz, CDCl₃): 2.41 an d 2.45 (2 × s, 2 × 3 H, CH₃-Tol);

2.91–3.03 (m , 2 H, H-2′); 4.65 (dd, 1 H, J_gem= 11.5, J_5′b,4′= 4.1, H-5′b); 4.68 (ddd, 1 H, J_4′,5′

4.1, 3.1, J_4′,3′= 2.3, H-4′); 4.80 (dd, 1 H, J_gem= 11.5, J_5′a,4′= 3.1, H-5′a); 5.80 (ddd, 1 H, J_3′,2′

=

5.3, 3.6, J_3′,4′= 2.3, H-3′); 6.54 (dd, 1 H, J_1′2′= 7.8, 6.4, H-1′); 7.21 an d 7.30 (2 × m , 2 × 2 H,

H-m-Tol); 7.82 an d 7.98 (2 × m , 2 × 2 H, H-o-Tol); 8.21 (s, 1 H, H-8). ¹³C NMR (100.6 MHz,

CDCl₃): 21.68 an d 21.76 (CH₃-Tol); 38.58 (CH₂-2′); 63.76 (CH₂-5′); 74.99 (CH-3′); 83.69

(CH-4′); 85.39 (CH-1′); 116.66 (C-2); 126.20 an d 126.29 (C-i-Tol); 129.33 (CH-m-Tol); 129.47

an d 129.85 (CH-o-Tol); 132.07 (C-5); 143.03 (CH-8); 144.41 an d 144.69 (C-p-Tol); 150.66

(C-6); 151.68 (C-4); 165.93 an d 165.98 (CO-Tol).

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2-Substituted 6-(Hydroxymethyl)purine Bases

1681

Preparation of (Ben zoyloxym eth yl)zin c Iodide (1)

A solution of iodom eth yl ben zoate (2.882 g, 11 m m ol) in THF (5 m l) was added at 10–15 °C

to th e suspen sion of zin c dust (1.44 g, 22 m m ol) in THF (4 m l), wh ich was preactivated with

dibrom oeth an e (20 µl) an d trim eth ylsilyl ch loride (20 µl). After 1 h , a GC an alysis of a h y-

drolyzed aliquot sh owed a virtually com plete con version of startin g iodom eth yl ben zoate

an d a yield ca. 85–90% of m eth yl ben zoate (ben zyl acetate was used as an in tern al stan -

dard). Th us th e con cen tration of (ben zoyloxym eth yl)zin c iodide (1) was ca. 0.9 m ol l^–1

.

Gen eral Procedure of Cross-Couplin gs of 1 with 6-Halopurin es 2 an d 3

A solution of (ben zoyloxym eth yl)zin c iodide 1 (3.4 m l, 3 m m ol) in THF was added at room

tem perature to a solution of 6-h alopurin e 2 or 3 (1 m m ol), Pd(PPh ₃)₄(57 m g, 0.05 m m ol) in

THF (10 m l) un der Ar an d stirred at room tem perature for 6–12 h . Th e reaction was

quen ch ed with 1 M NaH₂PO₄(50 m l) an d extracted with CHCl₃(4 × 30 m l). Th e collected

organ ic ph ases were dried over MgSO₄, filtered an d th e solven t was evaporated. Crude oily

products were purified by ch rom atograph y on silica gel (h exan es/eth yl acetate).

6-(Benzoyloxymethyl)-9-benzylpurine (4a). Yield 96% from 3a, wh ite crystals, m .p. 106–108 °C.

For C₂₀H₁₆N₄O₂(344.4) calculated: 69.76% C, 4.68% H, 16.27% N; foun d: 69.38% C, 4.63% H,

16.08 N. FAB MS, m/z (%): 345 (M⁺, 65), 224 (12), 149 (6), 105 (76), 91 (100). ¹H NMR

(500 MHz, CDCl₃): 5.45 (s, 2 H, N-CH₂); 5.88 (s, 2 H, O-CH₂); 7.30–7.47 (m , 5 H, Bn ); 7.44

(m , 2 H, H-m-Bz); 7.56 (m , 1 H, H-p-Bz); 8.04 (s, 1 H, H-8); 8.15 (m , 2 H, H-o-Bz); 8.99 (s,

1 H, H-2). ¹³C NMR (125.8 MHz, CDCl₃): 47.39 (N-CH₂); 63.03 (O-CH₂); 127.97 (CH-M-Bn );

128.35 (CH-m-Bz); 128.70 (CH-p-Bn ); 129.20 (CH-o-Bn ); 129.89 (C-i-Bz); 130.02 (CH-o-Bz);

131.77 (C-5); 133.08 (CH-p-Bz); 134.95 (C-i-Bn ); 144.60 (CH-8); 151.79 (C-4); 152.63 (CH-2);

155.36 (C-6); 166.40 (CO). IR (CCl₄): 3070, 3036, 2939, 1731, 1593, 1500, 1452, 1407, 1332,

1270, 1114.

6-(Benzoyloxymethyl)-9-(tetrahydropyran-2-yl)purine (4b). Yield 95% from 3b, yellowish oil.

FAB MS, m/z (%): 339 (M⁺, 15), 255 (89), 149 (17), 105 (100), 85 (53). ¹H NMR (500 MHz,

CDCl₃): 1.64–1.86 an d 2.02–2.20 (m , 6 H, CH₂-THP); 3.80 (dt, 1 H, J = 11.7 an d 2.6,

bCH₂-O-THP); 4.18 (ddt, 1 H, J = 11.7, 4.5 an d 1.5, aCH₂-O-THP); 5.82 (dd, 1 H, J = 10.3 an d

2.6, CH-O-THP); 5.86 (d, 1 H, J = 14.1, O-CH₂b); 5.90 (d, 1 H, J = 14.1, O-CH₂a); 7.44 (m ,

2 H, H-m-Ph ); 7.56 (m , 1 H, H-p-Ph ); 8.14 (m , 2 H, H-o-Ph ); 8.31 (s, 1 H, H-8); 8.97 (s, 1 H,

H-2). ¹³C NMR (125.8 MHz, CDCl₃): 22.72, 24.86 an d 31.84 (CH₂-THP); 62.97 (O-CH₂);

68.84 (CH₂-O-THP); 82.13 (CH-O-THP); 128.34 (CH-m-Ph ); 129.86 (C-i-Ph ); 130.01

(CH-o-Ph ); 131.91 (C-5); 133.07 (CH-p-Ph ); 142.71 (CH-8); 150.92 (C-4); 152.44 (CH-2);

155.31 (C-6); 166.36 (CO). IR (CHCl₃): 2952, 2862, 1725, 1601, 1586, 1496, 1452, 1409,

1375, 1334, 1273, 1251, 1114, 1087.

6-(Benzoyloxymethyl)-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (4c). Yield 94% from 2c,

yellowish oil. ESI MS, m/z (%): 535 (M + Na⁺, 100), 513 (M + H⁺, 17), 444 (10), 259 (6).

¹H NMR (400 MHz, CDCl₃): 2.09, 2.12 an d 2.16 (3 × s, 3 × 3 H, CH₃CO); 4.38 (m , 1 H,

H-5′b); 4.42–4.50 (m , 2 H, H-5′a an d H-4′); 5.67 (dd, 1 H, J_3′2′= 5.7, J_3′4′= 4.5, H-3′); 5.87 (s,

2 H, O-CH₂); 5.98 (t, 1 H, J_2′3′= 5.7, J_2′1′= 5.4, H-2′); 6.26 (d, 1 H, J_1′2′= 5.4, H-1′); 7.45 (m ,

2 H, H-m-Ph ); 7.58 (m , 1 H, H-p-Ph ); 8.15 (m , 2 H, H-o-Ph ); 8.26 (s, 1 H, H-8); 8.98 (s, 1 H,

H-2). ¹³C NMR (100.6 MHz, CDCl₃): 20.37, 20.52 an d 20.74 (CH₃); 62.92 (O-CH₂); 62.99

(CH₂-5′); 70.59 (CH-3′); 72.99 (CH-2′); 80.44 (CH-4′); 86.35 (CH-1′); 128.38 (CH-m-Ph );

129.68 (C-i-Ph ); 130.00 (CH-o-Ph ); 132.43 (C-5); 133.17 (CH-p-Ph ); 143.16 (CH-8); 151.21

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1682

Šilhár, Pohl, Votruba, Hocek:

(C-4); 152.68 (CH-2); 155.92 (C-6); 166.36 (CO-Bz); 169.27, 169.49 an d 170.22 (CO-Ac).

IR (CHCl₃): 3030, 1751, 1727, 1599, 1499, 1452, 1374, 1336, 1272, 1227, 1206, 1113.

6-(Benzoyloxymethyl)-9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pentofuranosyl)purine (4d ). Yield

93% from 3d, wh ite crystals, m .p. 118–120 °C. For C₃₄H₃₀N₄O₇(606.6) calculated: 67.32% C,

4.98% H, 9.24% N; foun d: 66.93% C, 4.90% H, 8.94% N. FAB MS, m/z (%): 607 (M⁺, 7), 255

(59), 119 (100), 105 (45), 91 (28). ¹H NMR (400 MHz, CDCl₃): 2.40 an d 2.44 (2 × s, 2 × 3 H,

CH₃-Tol); 2.86 (ddd, 1 H, J_gem= 14.2, J_2′b1′= 5.8, J_2′b3′= 2.2, H-2′b); 3.19 (ddd, 1 H, J_gem

14.2, J_2′a1′= 8.4, J_2′a3′= 6.4, H-2′a); 4.64–4.70 (m , 2 H, H-5′b an d H-4′); 4.77 (dd, 1 H, J_gem

=

13.4, J_5′a4′= 5.4, H-5′a); 5.83 (dt, 1 H, J_3′2′a= 6.4, J_3′4′= 2.2, J_3′2′b= 2.1, H-3′); 5.85 (s, 2 H,

O-CH₂); 6.61 (dd, 1 H, J_1′2′a= 8.4, J_1′2′b= 5.8, H-1′); 7.21 an d 7.29 (2 × m , 2 × 2 H, H-m-Tol);

7.45 (m , 2 H, H-m-Ph ); 7.57 (m , 1 H, H-p-Ph ); 7.90 an d 7.98 (2 × m , 2 × 2 H, H-o-Tol); 8.14

(m , 2 H, H-o-Ph ); 8.27 (s, 1 H, H-8); 8.90 (s, 1 H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.67

an d 21.74 (CH₃-Tol); 37.80 (CH₂-2′); 62.88 (O-CH₂); 63.92 (CH₂-5′); 75.04 (CH-3′); 83.16

(CH-4′); 84.94 (CH-1′); 126.33 an d 126.60 (C-i-Tol); 128.36 (CH-m-Bz); 129.28 an d 129.29

(CH-m-Tol); 129.62 (CH-o-Tol); 129.70 (C-i-Bz); 129.81 (CH-o-Tol); 130.00 (CH-o-Bz); 132.45

(C-5); 133.14 (CH-p-Bz); 143.09 (CH-8); 144.20 an d 144.57 (C-p-Tol); 151.11 (C-4); 152.46

(CH-2); 155.58 (C-6); 165.93, 166.15 an d 166.35 (CO). IR (CHCl₃): 1723, 1612, 1601, 1496,

1440, 1270, 1179, 1103, 1021.

Gen eral Procedure for Deacylation Reaction s

A 1 M m eth an olic MeONa (50–100 µl, 0.05–0.1 m m ol) was added to a solution of protected

purin es or n ucleosides 4a–4d (0.2–0.5 m m ol) in m eth an ol (10–20 m l) an d th e m ixture was

stirred at am bien t tem perature. After com plete deprotection th e solven t was evaporated an d

th e residue was ch rom atograph ed.

9-Benzyl-6-(hydroxymethyl)purine (5a). Yield 88% (ch rom atograph y on silica gel, eth yl

acetate/m eth an ol 95:5). Th e product was crystallized from eth yl acetate/h eptan e (m .p.

110–112 °C). For C₁₃H₁₂N₄O (240.3) calculated: 64.99% C, 5.03% H, 23.32% N; foun d:

64.65% C, 5.08% H, 22.96% N. FAB MS, m/z (%): 241 (M⁺, 100), 224 (6), 149 (9), 91 (83).

¹H NMR (500 MHz, CDCl₃): 5.22 (s, 2 H, O-CH₂); 5.47 (s, 2 H, N-CH₂); 7.29–7.40 (m , 5 H,

Ph ); 8.03 (s, 1 H, H-8); 8.98 (s, 1 H, H-2). ¹³C NMR (125.8 MHz, CDCl₃): 47.43 (N-CH₂);

61.37 (O-CH₂); 127.89, 128.74 an d 129.22 (CH-ph en yl); 130.47 (C-5); 134.95 (C-i-ph en yl);

144.11 (CH-8); 151.05 (C-4); 152.18 (CH-2); 159.17 (C-6). IR (CHCl₃): 3457, 1601, 1585,

1500, 1407, 1335, 1228, 1069.

6-(Hydroxymethyl)-9-(tetrahydropyran-2-yl)purine (5b). Yield 85% (ch rom atograph y on silica

gel, eth yl acetate/m eth an ol 98:2). Product was crystallized from eth yl acetate/h exan es (m .p.

75–78 °C). For C₁₁H₁₄N₄O₂(234.3) calculated: 56.40% C, 6.02% H, 23.92% N; foun d:

56.15% C, 5.98% H, 23.55% N. FAB MS, m/z (%): 235 (M⁺, 35), 151 (100), 135 (17), 85 (22).

¹H NMR (400 MHz, CDCl₃): 1.65–1.89 an d 2.03–2.20 (m , 6 H, CH₂-THP); 3.80 (dt, 1 H, J =

11.7 an d 2.7, bCH₂-O-THP); 4.20 (ddt, 1 H, J = 11.7, 4.0 an d 1.9, aCH₂-O-THP); 5.22 (s, 2 H,

O-CH₂); 5.83 (dd, 1 H, J = 10.2 an d 2.6, CH-O-THP); 8.29 (s, 1 H, H-8); 8.95 (s, 1 H, H-2).

¹³C NMR (100.6 MHz, CDCl₃): 22.73, 24.83 an d 31.87 (CH₂-THP); 61.30 (O-CH₂); 68.89

(CH₂-O-THP); 82.12 (CH-O-THP); 130.57 (C-5); 142.18 (CH-8); 150.12 (C-4); 151.96 (CH-2);

159.07 (C-6). IR (CHCl₃): 3450, 2952, 2863, 1602, 1585, 1497, 1410, 1336, 1087, 1046.

6-(Hydroxymethyl)-9-(β-D-ribofuranosyl)purine (5f). Yield 81% (ch rom atograph y on silica gel,

eth yl acetate/m eth an ol 95:5–80:20), wh ite h ygroscopic solid (m .p. 65–69 °C) wh ich was

lyoph ilized from water as m on oh ydrate, [α ]²_D⁰–12.4 (c 0.49, MeOH); lit.³²: [α ]²_D⁰–9.7 (c 3.0,

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2-Substituted 6-(Hydroxymethyl)purine Bases

1683

MeOH). For C₁₁H₁₄N₄O₅·H₂O (300.3) calculated: 44.00% C, 5.37% H, 18.66% N; foun d:

44.40% C, 5.29% H, 18.37% N. FAB MS, m/z (%): 283 (MH⁺, 7), 281 (19), 207 (11), 151 (43),

133 (18), 121 (11), 115 (11), 73 (100). ¹H NMR (400 MHz, MeOD): 3.77 (dd, 1 H, J_gem

=

12.3, J_5′b4′= 3.3, H-5′b); 3.89 (dd, 1 H, J_gem= 12.3, J_5′a4′= 3.0, H-5′a); 4.16 (q, 1 H, J_4′3′= 3.6,

J_4′5′b= 3.3, J_4′5′a= 3.0, H-4′); 4.36 (dd, 1 H, J_3′2′= 5.1, J_3′4′= 3.6, H-3′); 4.74 (t, 1 H, J_2′1′= 5.6,

J_2′3′= 5.1, H-2′); 5.09 (s, 2 H, O-CH₂); 6.14 (d, 1 H, J_1′2′= 5.6, H-1′); 8.74 (s, 1 H, H-8); 8.89

(s, 1 H, H-2). ¹³C NMR (100.6 MHz, MeOD): 61.51 (O-CH₂); 62.99 (CH₂-5′); 72.18 (CH-3′);

75.76 (CH-2′); 87.62 (CH-4′); 90.71 (CH-1′); 132.82 (C-5); 146.32 (CH-8); 152.10 (C-4);

153.05 (CH-2); 161.07 (C-6). IR (KBr): 3413, 1602, 1500, 1406, 1336, 1122, 1083, 1054.

9-(2-Deoxy-β-D-erythro-pentofuranosyl)-6-(hydroxymethyl)purine (5g). Yield 86% (ch rom atog-

raph y on silica gel, eth yl acetate/m eth an ol 95:5–80:20), wh ite h ygroscopic solid (m .p. 69–

71 °C) wh ich was lyoph ilized from water as a m on oh ydrate, [α ]²_D⁰+6.1 (c 0.7, MeOH). For

C

₁₁H₁₄N₄O₄·H₂O (284.3) calculated: 46.48% C, 5.67% H, 19.71% N; foun d: 46.25% C,

5.63% H, 19.35% N. FAB MS, m/z (%): 267 (MH⁺, 54), 151 (100), 131 (11), 115 (41), 73 (49).

¹H NMR (400 MHz, MeOD): 2.48 (ddd, 1 H, J_gem= 13.5, J_2′b1′= 6.3, J_2′b3′= 3.4, H-2′b); 2.85

(ddd, 1 H, J_gem= 13.5, J_2′a1′= 7.3, J_2′a3′= 6.0, H-2′a); 3.75 (dd, 1 H, J_gem= 12.1, J_5′b4′= 4.0,

H-5′a); 3.83 (dd, 1 H, J_gem= 12.1, J_5′a4′= 3.5, H-5′a); 4.06 (q, 1 H, J_4′5′b= 4.0, J_4′5′a= 3.5,

J_4′3′= 3.4, H-4′); 4.60 (dt, 1 H, J_3′2′a= 6.0, J_3′4′= 3.4, J_3′2′b= 3.4, H-3′); 5.08 (s, 2 H, O-CH₂);

6.57 (dd, 1 H, J_1′2′a= 7.3, J_1′2′b= 6.3, H-1′); 8.71 (s, 1 H, H-8); 8.88 (s, 1 H, H-2). ¹³C NMR

(100.6 MHz, MeOD): 41.38 (CH₂-2′); 61.49 (O-CH₂); 63.27 (CH₂-5′); 72.67 (CH-3′); 86.58

(CH-1′); 89.68 (CH-4′); 132.71 (C-5); 146.11 (CH-8); 151.93 (C-4); 153.00 (CH-2); 160.87

(C-6). IR (KBr): 3401, 3108, 1596, 1584, 1497, 1448, 1396, 1339, 1094, 1050.

6-(Hydroxym eth yl)-9H-purin e (5e)

Yield 78% (85 m g). Prepared from 5b (170 m g, 0.73 m m ol), with Dowex 50X8 (H⁺) (ca. 100 m g)

in eth an ol (20 m l, 96%). Reaction m ixture was stirred at 70–75 °C for 2 h , filtered, wash ed

resin with eth an olic am m on ia an d evaporated to dryn ess. Crude product was ch rom atog-

raph ed (ch loroform /m eth an ol 99:1–90:10) to afford a wh ite solid th at was crystallized from

eth an ol/h eptan e (m .p. > 300 °C). For C₆H₆N₄O (150.1) calculated: 48.00% C, 4.03% H,

37.32% N; foun d: 47.61% C, 3.97% H, 36.97% N. FAB MS, m/z (%): 151 (MH⁺, 21), 133 (6),

110 (23), 91 (100). ¹H NMR (400 MHz, DMSO-d₆): 4.88 (s, 2 H, O-CH₂); 8.55 (s, 1 H, H-8);

8.83 (s, 1 H, H-2). ¹³C NMR (100.6 MHz, DMSO-d₆): 62.15 (O-CH₂); 124.98 (C-5); 146.51

(CH-8); 151.61 (CH-2); 156.54 (C-6); 157.85 (C-4). IR (KBr): 3421, 3174, 1616, 1568, 1479,

1404, 1370, 1335, 1242, 1089.

Gen eral Procedure for Cross-Couplin gs of Organ ozin c 1 with 2-Am in o-6-ch loropurin es 6

Dim eth ylform am ide dim eth ylacetal (0.4 m l,

3 m m ol) was added to th e solution of

2-am in o-6-ch loropurin e 6 (1 m m ol) in dry DMF (10 m l) an d stirred at 50 °C for 12–16 h .

Volatiles were evaporated in vacuo (130 Pa, 50 °C) an d crude product 7 was used in th e n ext

step. Th us, th e solution of (ben zoyloxym eth yl)zin c iodide (3.4 m l, 3 m m ol) in THF was

added at room tem perature to a solution of 7 (1 m m ol), Pd(PPh ₃)₄(57 m g, 0.05 m m ol) in

THF (10 m l) un der Ar an d stirred at room tem perature for 12 h . Th e reaction was quen ch ed

with 1 M NaH₂PO₄(50 m l) an d extracted with CHCl₃(4 × 30 m l). Collected organ ic ph ases

were dried over MgSO₄, filtered an d th e solven t was evaporated. Th e crude oily product was

purified by ch rom atograph y on silica gel (h exan es/eth yl acetate 2:1–1:2). Th e desired prod-

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1684

Šilhár, Pohl, Votruba, Hocek:

ucts 8a, 8c or 8d were con tam in ated with correspon din g form ylam in o derivatives 9a, 9c or

9d . For yields an d ratios (8/9), see Table III.

6-(Benzoyloxymethyl)-9-benzyl-2-{[(dimethylamino)methylidene]amino}purine (8a). Exact m ass

(FAB HR MS) calculated for C₂₃H₂₃N₆O₂: 415.1882; foun d: 415.1896. FAB MS, m/z (%): 415

(MH⁺, 88), 324 (4), 309 (9), 219 (5), 176 (7), 105 (91), 91 (100). ¹H NMR (400 MHz, CDCl₃):

2.99 an d 3.15 (2 × s, 2 × 3 H, (CH₃)₂N); 5.40 (s, 2 H, CH₂-N-9); 5.80 (s, 2 H, CH₂-O-6);

7.25–7.40 (m , 5 H, H-Bn ); 7.45 (m , 2 H, H-m-Bz); 7.56 (m , 1 H, H-p-Bz); 7.77 (s, 1 H, H-8);

8.15 (m , 2 H, H-o-Bz); 8.65 (s, 1 H, HC=N). ¹³C NMR (125.8 MHz, CDCl₃): 35.17 an d 41.00

((CH₃)₂N); 62.88 (CH₂-5′); 46.67 (CH₂-N-9); 63.55 (CH₂-O-6); 127.66 (C-5); 127.89

(CH-o-Bn ); 128.32 (CH-m-Bn ); 129.00 (CH-p-Bn ); 129.44 (CH-m-Bz); 129.97 (CH-o-Bz);

130.17 (C-i-Bz); 132.95 (CH-p-Bz); 135.55 (CH-i-Bn ); 142.89 (CH-8); 153.80 (C-4); 155.18

(C-6); 158.79 (HC=N); 162.62 (C-2); 166.48 (CO-Bz). IR (CHCl₃): 3068, 3030, 2457, 1725,

1708, 1630, 1601, 1516, 1488, 1456, 1406, 1363, 1274, 1114, 1029, 712, 646.

9-(2,3,5-Tri-O-acetyl-β-D-ribofuranosyl)-6-(benzoyloxymethyl)-2-{[(dimethylamino)methylidene]-

amino}purine (8c). Exact m ass (FAB HR MS) calculated for C₂₇H₃₁N₆O₉: 583.2153, foun d:

583.2166. FAB MS, m/z (%): 583 (MH⁺, 100), 478 (7), 325 (37), 259 (9), 219 (16), 105 (47).

¹H NMR (500 MHz, CDCl₃): 2.07, 2.08 an d 2.14 (3 × s, 3 × 3 H, CH₃-Ac); 3.08 an d 3.17 (2 ×

s, 2 × 3 H, (CH₃)₂N); 4.31 (m , 1 H, H-5′b); 4.34–4.43 (m , 2 H, H-4′ an d H-5′a); 5.68 (t, 1 H,

J_3′,2′= 5.2, J_3′,4′= 5.2, H-3′); 5.75 (s, 2 H, CH₂-O-6); 5.97 (t, 1 H, J_2′,3′= 5.2, J_2′,1′= 5.1, H-2′);

6.29 (d, 1 H, J_1′,2′= 5.1, H-1′); 7.45 (m , 2 H, H-m-Bz); 7.57 (m , 1 H, H-p-Bz); 8.00 (s, 1 H,

H-8); 8.15 (m , 2 H, H-o-Bz); 8.69 (s, 1 H, HC=N). ¹³C NMR (125.8 MHz, CDCl₃): 20.44, 20.53

an d 20.67 (CH₃-Ac); 35.43 an d 41.03 ((CH₃)₂N); 62.88 (CH₂-5′); 63.67 (CH₂-O-6); 70.36

(CH-3′); 72.85 (CH-2′); 79.59 (CH-4′); 85.31 (CH-1′); 128.34 (CH-m-Bz an d C-5); 130.00

(CH-o-Bz); 130.05 (C-i-Bz); 133.01 (CH-p-Bz); 141.04 (CH-8); 153.30 (C-4); 156.09 (C-6);

158.90 (HC=N); 162.88 (C-2); 166.41 (CO-Bz); 169.41, 169.61 an d 170.34 (CO-Ac).

IR (CHCl₃): 2817, 1750, 1725, 1631, 1594, 1508, 1491, 1452, 1370, 1273, 1114, 1028, 712,

639.

6-(Benzoyloxymethyl)-2-{[(dimethylamino)methylidene]amino}-9-(2-deoxy-3,5-di-O-toluoyl-

β-D-erythro-pentofuranosyl)purine (8d ). Exact m ass (FAB HR MS) calculated for C₃₇H₃₇N₆O₇:

677.2724, foun d: 677.2726. FAB MS, m/z (%): 677 (MH⁺, 34), 572 (3), 353 (5), 325 (50), 219

(19), 119 (100), 105 (45). ¹H NMR (400 MHz, CDCl₃): 2.40 an d 2.44 (2 × s, 2 × 3 H,

CH₃-Tol); 2.85 (m , 2 H, H-2′); 3.00 an d 3.15 (2 × s, 2 × 3 H, (CH₃)₂N); 4.58 (td, 1 H, J_4′,5′

4.0, 3.8, J_4′,3′= 2.5, H-4′); 4.65 (dd, 1 H, J_gem= 12.0, J_5′b,4′= 4.0, H-5′b); 4.72 (dd, 1 H, J_gem

=

12.0, J_5′a,4′= 3.8, H-5′a); 5.74 an d 5.78 (2 × d, 2 H, J_gem= 14.0, CH₂-O-6); 5.80 (m , 1 H,

H-3′); 6.71 (dd, 1 H, J_1′,2′= 8.1, 6.3, H-1′); 7.22 an d 7.29 (2 × m , 2 × 2 H, H-m-Tol); 7.45 (m ,

2 H, H-m-Bz); 7.57 (m , 1 H, H-p-Bz); 7.89 an d 7.96 (2 × m , 2 × 2 H, H-o-Tol); 8.04 (s, 1 H,

H-8); 8.16 (m , 2 H, H-o-Bz); 8.67 (s, 1 H, HC=N). ¹³C NMR (100.6 MHz, CDCl₃): 21.67 an d

21.74 (CH₃-Tol); 35.18 (CH₃N); 38.49 (CH₂-2′); 40.98 (CH₃N); 63.56 (CH₂-O-6); 64.13

(CH₂-5′); 75.00 (CH-3′); 82.67 (CH-4′); 83.71 (CH-1′); 126.38 an d 126.60 (C-i-Tol); 128.18

(C-5); 128.32 (CH-m-Bz); 129.26 an d 129.36 (CH-m-Tol); 129.56 an d 129.85 (CH-o-Tol);

129.99 (CH-o-Bz); 130.14 (C-i-Bz); 132.95 (CH-p-Bz); 140.51 (CH-8); 144.21 an d 144.47

(C-p-Tol); 153.19 (C-4); 155.49 (C-6); 158.80 (HC=N); 162.62 (C-2); 165.99 an d 166.19

(CO-Tol); 166.43 (CO-Bz). IR (CHCl₃): 2817, 1721, 1630, 1592, 1503, 1492, 1452, 1368,

1270, 1178, 1109, 712, 638.

6-(Benzoyloxymethyl)-9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pentofuranosyl)-2-(formylamino)-

purine (9d ). Exact m ass (FAB HR MS) calculated for C₃₅H₃₂N₅O₈: 650.2251, foun d: 650.2266.

FAB MS, m/z (%): 650 (MH⁺, 6), 622 (1), 353 (2), 298 (16), 119 (100), 105 (42). ¹H NMR (400 MHz,

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2-Substituted 6-(Hydroxymethyl)purine Bases

1685

CDCl₃): 2.39 an d 2.45 (2 × s, 2 × 3 H, CH₃-Tol); 2.81 (ddd, 1 H, J_gem= 14.2, J_2′b,1′= 6.0,

J_2′b,3′= 2.6, H-2′b); 3.10 (ddd, 1 H, J_gem= 14.2, J_2′a,1′= 7.9, J_2′a,3′= 6.3, H-2′a); 4.63–4.69 (m ,

3 H, H-4′ an d H-5′b); 4.78 (dd, 1 H, J_gem= 13.4, J_5′a,4′= 5.6, H-5′a); 5.77 (s, 2 H, CH₂-O-6);

5.82 (dt, 1 H, J_3′,2′= 6.3, 2.6, J_3′,4′= 2.6, H-3′); 6.48 (dd, 1 H, J_1′2′= 7.9, 6.0, H-1′); 7.20 an d

7.29 (2 × m , 2 × 2 H, H-m-Tol); 7.46 (m , 2 H, H-m-Bz); 7.59 (m , 1 H, H-p-Bz); 7.86 an d 7.97

(2 × m , 2 × 2 H, H-o-Tol); 8.12 (s, 1 H, H-8); 8.13 (m , 2 H, H-o-Bz); 8.27 (d, 1 H, J = 10.6,

NH); 9.47 (d, 1 H, J = 10.6, HCO). ¹³C NMR (100.6 MHz, CDCl₃): 21.67 an d 21.75 (CH₃-Tol);

37.62 (CH₂-2′); 62.44 (CH₂-O-6); 63.69 (CH₂-5′); 74.76 (CH-3′); 82.93 (CH-4′); 84.71 (CH-1′);

126.29 an d 126.48 (C-i-Tol); 128.48 (CH-m-Bz); 129.30 an d 129.33 (CH-m-Tol); 129.55 (C-5);

129.59 (CH-o-Tol); 129.82 (CH-o-Bz); 129.91 (CH-o-Tol an d C-i-Bz); 133.30 (CH-p-Bz); 142.32

(CH-8); 144.33 an d 144.64 (C-p-Tol); 151.92 (C-4); 152.23 (C-2); 157.05 (C-6); 162.84

(HCO); 165.91 an d 166.17 (CO-Tol); 166.30 (CO-Bz). IR (CHCl₃): 3406, 3028, 1719, 1603,

1513, 1489, 1452, 1381, 1270, 1178, 1103, 712, 643.

6-(Benzoyloxymethyl)-2-(tetrahydropyran-2-yl)amino-9-(tetrahydropyran-2-yl)purine (13b). Yield

68%, yellowish oil, m ixture of diastereom ers (1:1). Exact m ass (FAB HR MS) calculated for

C

₂₃H₂₈N₅O₄: 438.2141, foun d: 438.2130. FAB MS, m/z (%): 438 (MH⁺, 83; 354 (100), 270

(37), 248 (8), 164 (19), 105 (72), 85 (40). ¹H NMR (400 MHz, DMSO-d₆): 1.40–2.14 (m , 12 H,

CH₂-THP); 3.42 (bm , 1 H, bCH₂-O-THP-NH); 3.74 an d 3.75 (ddd, 1 H, J = 11.5, 11.4, 7.5,

bCH₂-O-THP-N); 3.92 (bm , 1 H, aCH₂-O-THP-NH); 4.14 (ddt, 1 H, J = 11.4, 4.3, 1.9, 1.9,

aCH₂-O-THP-N); 5.27 an d 5.32 (bdt, 1 H, J = 9.8, 9.6, 2.4, CH-O-THP-NH); 5.61 (dd, 1 H, J =

10.0, 2.5, CH-O-THP-N); 5.64 (bd, 1 H, J = 9.8, NH); 5.67 an d 5.69 (d, 1 H, J = 14.1,

bCH₂-O); 5.74 (d, 1 H, J = 14.1, aCH₂-O); 7.45 (m , 2 H, m-H-Ph ); 7.56 (m , 1 H, p-H-Ph ); 7.96

(s, 1 H, H-8); 8.15 (m , 2 H, o-H-Ph ). ¹³C NMR (100.6 MHz, DMSO-d₆): 22.76 an d 22.83,

22.89 an d 22.95, 24.90 an d 24.92, 25.21, 31.33 an d 31.49, 31.73 (CH₂-THP); 62.91

(CH₂-O-Bz); 66.41 an d 66.44, 68.57 (CH₂-O-THP); 80.12 an d 80.23, 81.18 an d 81.61

(CH-O-THP); 126.25 an d 126.29 (C-5); 128.28 (m-CH-Ph ); 129.99 (o-CH-Ph ); 130.10 an d

130.13 (i-C-Ph ); 132.92 (p-CH-Ph ); 139.63 an d 139.76 (CH-8); 152.61 an d 152.76 (C-4);

155.82 an d 155.91 (C-6); 157.77 an d 157.83 (C-2); 166.30 (C=O). IR (CHCl₃): 3440, 2948,

2856, 1724, 1610, 1597, 1528, 1470, 1406, 1353, 1276, 1176, 1031, 712, 643.

Gen eral Procedure for Cleavage of Protectin g Groups from Mixtures 8 an d 9

Aqueous am m on ia (25% solution , 10 m l) was added to a solution of protected purin es or

n ucleosides 8 an d 9 (1 m m ol) in m eth an ol (60 m l) an d th e m ixture was stirred at 55 °C for

24 h . After com plete deprotection th e volatiles were evaporated an d th e residue was

ch rom atograph ed.

2-Amino-9-benzyl-6-(hydroxymethyl)purine (10a). Yield 66%, yellowish solid, m .p. 154–156 °C.

For C₁₃H₁₃N₅O (255.3) calculated: 61.17% C, 5.13% H, 27.43% N; foun d: 59.82% C, 5.23% H,

27.15% N. Exact m ass (FAB HR MS) calculated for C₁₃H₁₄N₅O: 256.1198, foun d: 256.1210.

FAB MS, m/z (%): 256 (M⁺, 100), 239 (7), 164 (7), 91 (70). ¹H NMR (500 MHz, DMSO-d₆):

4.69 (d, 2 H, J_CH2,OH= 5.9, CH₂-O); 5.08 (t, 1 H, J_OH,CH2= 5.9, OH-CH₂); 5.29 (s, 2 H,

CH₂-N); 6.49 (bs, 2 H, NH₂); 7.24 (m , 2 H, H-o-Ph ); 7.28 (m , 1 H, H-p-Ph ); 7.34 (m , 2 H,

H-m-Ph ); 8.12 (s, 1 H, H-8). ¹³C NMR (125.8 MHz, DMSO-d₆): 45.76 (CH₂-N); 60.27 (CH₂-O);

124.22 (C-5); 127.26 (CH-o-Ph ); 127.79 (CH-p-Ph ); 128.85 (CH-m-Ph ); 137.30 (C-i-Ph );

141.99 (CH-8); 153.22 (C-4); 160.37 an d 160.50 (C-2 + C-6). IR (KBr): 3395, 3310, 3191,

1637, 1605, 1593, 1520, 1474, 1401, 1375, 1036, 712, 646.

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1686

Šilhár, Pohl, Votruba, Hocek:

2-Amino-6-(hydroxymethyl)-9-(β-D-ribofuranosyl)purine (10f). Yield 67%, yellowish solid,

m .p. 204–205 °C, [α ]²_D⁰–38.3 (c 0.36, MeOH). For C₁₁H₁₅N₅O₅(297.3) calculated: 44.44% C,

5.09% H, 23.56% N; foun d: 44.09% C, 5.14% H, 23.15% N. Exact m ass (FAB HR MS) calcu-

lated for C₁₁H₁₆N₅O₅: 298.1151, foun d: 298.1163. FAB MS, m/z (%): 298 (MH⁺, 38), 166

(50), 149 (11), 131 (14), 115 (89). ¹H NMR (400 MHz, DMSO-d₆): 3.54 (ddd, 1 H, J_gem= 12.0,

J_5′b,OH= 5.8, J_5′b,4′= 4.2, H-5′b); 3.64 (ddd, 1 H, J_gem= 12.0, J_5′a,OH= 5.1, J_5′a,4′= 4.3, H-5′a);

3.90 (q, 1 H, J_4′,5′= 4.3, 4.2, J_4′,3′= 3.1, H-4′); 4.12 (bq, 1 H, J_3′,OH= 4.5, J_3′,2′= 3.8, J_3′,4′

=

3.1, H-3′); 4.50 (bq, 1 H, J_2′,1′= 6.0, J_2′,OH= 5.0, J_2′,3′= 3.8, H-2′); 4.68 (d, 2 H, J_CH2,OH= 6.0,

CH₂-O); 5.06 (t, 1 H, J_OH,5′= 5.8, 5.1, OH-5′); 5.11 (t, 1 H, J_OH,CH2= 6.0, OH-CH₂); 5.17 (bd,

1 H, J_OH,3′= 4.5, OH-3′); 5.44 (t, 1 H, J_OH,2′= 5.0, OH-2′); 5.83 (d, 1 H, J_1′,2′= 6.0, H-1′); 6.51

(bs, 2 H, NH₂); 8.26 (s, 1 H, H-8). ¹³C NMR (100.6 MHz, DMSO-d₆): 61.28 (CH₂-O); 61.59

(CH₂-5′); 70.59 (CH-3′); 73.62 (CH-2′); 85.48 (CH-4′); 86.58 (CH-1′); 124.53 (C-5); 140.12

(CH-8); 153.27 (C-4); 160.32 (C-2); 160.59 (C-6). IR (KBr): 3344, 3221, 1609, 1516, 1474,

1405, 1318, 1224, 1084, 1053, 637.

2-Amino-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-(hydroxymethyl)purine (10g). Yield 65%,

yellowish solid, m .p. 158–160 °C, [α ]²_D⁰+2.2 (c 0.27, MeOH). For C₁₁H₁₅N₅O₄·H₂O (299.3)

calculated: 44.14% C, 5.73% H, 23.40% N; foun d: 44.08% C, 5.41% H, 23.07% N. Exact

m ass (FAB HR MS) calculated for C₁₁H₁₆N₅O₄: 282.1202, foun d: 282.1209. FAB MS, m/z (%):

282 (MH⁺, 8), 166 (8), 149 (4), 115 (5). ¹H NMR (500 MHz, DMSO-d₆): 2.23 (ddd, 1 H, J_gem

=

13.2, J_2′b,1′= 6.1, J_2′b,3′= 3.2, H-2′b); 2.62 (ddd, 1 H, J_gem= 13.2, J_2′a,1′= 7.8, J_2′a,3′= 5.8,

H-2′a); 3.51 (ddd, 1 H, J_gem= 11.7, J_5′b,OH= 5.5, J_5′b,4′= 4.6, H-5′b); 3.58 (dt, 1 H, J_gem= 11.7,

J_5′a,OH= 5.5, J_5′a,4′= 4.8, H-5′a); 3.83 (td, 1 H, J_4′,5′= 4.8, 4.6, J_4′,3′= 2.8, H-4′); 4.37 (dq, 1 H,

J_3′,2′= 5.8, 3.2, J_3′,OH= 4.0, J_3′,4′= 2.8, H-3′); 4.67 (d, 2 H, J_CH2,OH= 5.9, CH₂-O); 4.96 (t, 1 H,

J_OH,5′= 5.5, OH-5′); 5.08 (t, 1 H, J_OH,CH2= 5.9, OH-CH₂); 5.28 (d, 1 H, J_OH,3′= 4.0, OH-3′);

6.26 (dd, 1 H, J_1′,2′= 7.8, 6.1, H-1′); 6.49 (bs, 2 H, NH₂); 8.23 (s, 1 H, H-8). ¹³C NMR

(125.8 MHz, DMSO-d₆): 39.42 (CH₂-2′); 60.26 (CH₂-O); 61.87 (CH₂-5′); 70.92 (CH-3′); 82.80

(CH-1′); 87.79 (CH-4′); 124.54 (C-5); 139.90 (CH-8); 152.87 (C-4); 160.26 (C-2); 160.49 (C-6).

IR (KBr): 3430, 3320, 3205, 3121, 1605, 1517, 1477, 1388, 1223, 1089, 1054, 639.

6-(Hydroxymethyl)-2-(tetrahydropyran-2-yl)amino-9-(tetrahydropyran-2-yl)purine (14b ). Yield

79%, wh ite foam , diastereom eric m ixture (1:1). Exact m ass (FAB HR MS) calculated for

C

₁₆H₂₄N₅O₃: 334.1879, foun d: 334.1893. FAB MS, m/z (%): 334 (MH⁺, 61), 250 (100), 166

(46), 148 (16), 85 (63). ¹H NMR (400 MHz, DMSO-d₆): 1.35–2.01 an d 2.22–2.37 (2 × m , 12 H,

CH₂-THP); 3.46, 3.64, 3.82 an d 4.01 (4 × m , 4 × 1 H, CH₂-O-THP); 4.71 an d 4.72 (2 × d, 2 H,

J_vic= 5.9, CH₂-O); 5.12 (t, 1 H, J_vic= 5.9, OH); 5.28 an d 5.54 (2 × m , 2 × 1 H, CH-O-THP);

7.64 (bd, 1 H, J_vic= 9.3, NH); 8.281 an d 8.285 (2 × s, 1 H, H-8). ¹³C NMR (100.6 MHz,

DMSO-d₆): 22.70, 22.72, 22.84, 22.86, 24.71, 25.24, 29.91, 30.02 an d 30.65 (CH₂-THP);

60.33 (CH₂-O); 65.71, 67.80 an d 67.85 (CH₂-O-THP); 80.12, 80.76 an d 80.79 (CH-O-THP);

125.04 (C-5); 140.49 (CH-8); 152.40 an d 152.44 (C-4); 158.13 an d 158.15 (C-2); 160.39 an d

160.42 (C-6). IR (CHCl₃): 3440, 2948, 2856, 1607, 1526, 1497, 1407, 1078, 1059, 1033, 644.

2-Am in o-6-(h ydroxym eth yl)-9H-purin e (10e)

Yield 67%, yellowish solid, m .p. > 360 °C. Prepared from 14b by acidic cleveage of THP pro-

tectin g groups with p-toluen esulfon ic acid (2.5 equivalen ts) in eth an ol at 70 °C. Reaction

was quen ch ed by addition of aqueous am m on ia an d volatiles were evaporated. Th e residue

was dissolved in water an d aplied on Dowex 50WX8 (H⁺) colum n . After desaltin g, th e

product was eluted with gradien t of aqueous am m on ia (0.1–1%) an d recrystallized from

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2-Substituted 6-(Hydroxymethyl)purine Bases

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EtOH/eth yl acetate. Exact m ass (FAB HR MS) calculated for C₆H₈N₅O: 166.0729, foun d:

166.0733. FAB MS, m/z (%): 166 (MH⁺, 13), 149 (4), 109 (9), 91 (49). ¹H NMR (500 MHz,

DMSO-d₆+ CF₃COOD): 4.98 (s, 2 H, CH₂-O); 8.66 (s, 1 H, H-8). ¹³C NMR (125.8 MHz,

DMSO-d₆+ CF₃COOD): 57.97 (CH₂-O); 120.26 (C-5); 146.71 (CH-8); 154.44 (C-6); 155.31

(C-2); 157.03 (C-4). IR (KBr): 3401, 3317, 3203, 1624, 1596, 1509, 1471, 1381, 1086, 629.

Gen eral Procedure for Cross-Couplin gs of Organ ozin c 1 with 2,6-Dich loropurin es 15

A solution of organ ozin c 1 (0.6 or 2.22 m l; 0.55 or 2 m m ol) in THF was added at room tem -

perature to a solution of a 2,6-dichloropurine 15 (0.5 m m ol), Pd(PPh₃)₄(29 m g, 0.025 m m ol) in

THF (3 m l) an d stirred at room tem perature for 12 h . Th e reaction was quen ch ed with

1

M NaH₂PO₄(40 m l) an d extracted with CHCl₃(3 × 30 m l). Th e collected organ ic ph ases

were dried over MgSO₄, filtered an d th e solven t was evaporated. Crude oily products were

purified by ch rom atograph y on silica gel (h exan es/eth yl acetate 3:1–1:1). Yields are given in

Table V.

6-(Benzoyloxymethyl)-9-benzyl-2-chloropurine (16a ). W h ite solid, m .p. 143–144 °C. For

C

₂₀H₁₅ClN₄O₂(378.8) calculated: 63.41% C, 3.99% H, 9.36% Cl, 14.79% N; foun d:

63.27% C, 3.90% H, 9.25% Cl, 14.55% N. FAB MS, m/z (%): 379 (M⁺, 26), 345 (3), 105 (83),

91 (100). ¹H NMR (400 MHz, CDCl₃): 5.40 (s, 2 H, CH₂-N); 5.80 (s, 2 H, CH₂-O-6); 7.28–7.49

(m , 7 H, Bn an d H-m-Bz); 7.58 (m , 2 H, H-p-Bz); 7.98 (s, 1 H, H-8); 8.14 (m , 2 H, H-o-Bz).

¹³C NMR (100.6 MHz, CDCl₃): 47.53 (CH₂-N); 63.04 (CH₂-O); 128.13 (CH-m-Bn ); 128.38

(CH-m-Bz); 128.90 (CH-p-Bn ); 129.28 (CH-o-Bn ); 129.64 (C-i-Bn ); 130.01 (CH-o-Bz); 130.93

(C-5); 133.19 (CH-p-Bz); 134.33 (C-i-Bn ); 145.31 (CH-8); 153.58 (C-4); 154.20 (C-2); 157.59

(C-6); 166.33 (CO). IR (CHCl₃): 3035, 2943, 1726, 1592, 1502, 1452, 1356, 1317, 1272, 1115,

1029, 712, 646.

2,6-Bis(benzoyloxymethyl)-9-benzylpurine (17a ). W h ite solid, m .p. 116–117 °C. For

C

₂₈H₂₂N₄O₄(478.5) calculated: 70.28% C, 4.63% H, 11.71% N; foun d: 70.00% C, 4.63% H,

11.46% N. FAB MS, m/z (%): 479 (M⁺, 27), 374 (3), 105 (100), 91 (74). ¹H NMR (400 MHz,

CDCl₃): 5.34 (s, 2 H, CH₂-N); 5.66 (s, 2 H, CH₂-O-2); 5.84 (s, 2 H, CH₂-O-6); 7.23–7.32

(m , 5 H, Bn ); 7.37–7.47 (m , 4 H, H-m-Bz); 7.51–7.61 (m , 2 H, H-p-Bz); 8.02 (s, 1 H, H-8);

8.06–8.16 (m , 2 H, H-o-Bz). ¹³C NMR (100.6 MHz, CDCl₃): 47.47 (CH₂-N); 63.13 (CH₂-O-6);

66.65 (CH₂-O-2); 128.22 (CH-m-Bn ); 128.31 an d 128.34 (CH-m-Bz); 128.61 (CH-p-Bn );

129.06 (CH-o-Bn ); 129.84 an d 129.93 (CH-o-Bz); 130.15 (C-i-Bn ); 130.69 (C-5); 132.99

(CH-p-Bz); 134.86 (C-i-Bn ); 144.64 (CH-8); 152.24 (C-4); 155.35 (C-6); 159.02 (C-2); 166.37

(CO). IR (CHCl₃): 3033, 2949, 1725, 1596, 1505, 1452, 1403, 1367, 1316, 1273, 1118, 1028,

712, 647.

6-(Benzoyloxymethyl)-2-chloro-9-(tetrahydropyran-2-yl)purine (16b). Wh ite solid, m .p. 92–93 °C.

For C₁₈H₁₇ClN₄O₃(372.8) calculated: 57.99% C, 4.60% H, 9.51% Cl, 15.03% N; foun d:

58.01% C, 4.54% H, 9.46% Cl, 14.77% N. FAB MS, m/z (%): 373 (M⁺, 9), 289 (57), 183 (5),

105 (100), 85 (93). ¹H NMR (400 MHz, CDCl₃): 1.62–1.87 an d 1.90–2.19 (m , 6 H, CH₂-THP);

3.78 (td, 1 H, J = 11.6 an d 2.8, bCH₂-O-THP); 4.17 (ddt, 1 H, J = 11.6, 4.3 an d 1.9,

aCH₂-O-THP); 5.77 (d, 1 H, J = 14.3, bCH₂-O-6); 5.79 (dd, 1 H, J = 11.0 an d 2.5, CH-O-THP);

5.79 (d, 1 H, J = 14.3, aCH₂-O-6); 7.46 (m , 2 H, H-m-Ph ); 7.68 (m , 1 H, H-p-Ph ); 8.14 (m ,

2 H, H-o-Ph ); 8.27 (s, 1 H, H-8). ¹³C NMR (125.8 MHz, CDCl₃): 22.60, 24.77 an d 32.05

(CH₂-THP); 62.98 (CH₂-O-6); 68.90 (CH₂-O-THP); 81.95 (CH-O-THP); 128.37 (CH-m-Ph );

129.63 (C-i-Ph ); 130.02 (CH-o-Ph ); 131.08 (C-5); 133.18 (CH-p-Ph ); 143.39 (CH-8); 152.63

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1688

Šilhár, Pohl, Votruba, Hocek:

(C-4); 153.99 (C-2); 157.45 (C-6); 166.30 (CO). IR (CHCl₃): 3031, 2952, 2866, 1726, 1594,

1452, 1368, 1316, 1272, 1115, 1089, 1028, 712, 642.

2,6-Bis(benzoyloxymethyl)-9-(tetrahydropyran-2-yl)purine (17b). Wh ite solid, m .p. 89–91 °C.

For C₂₆H₂₄N₄O₅(472.5) calculated: 66.09% C, 5.12% H, 11.86% N; foun d: 65.85% C, 5.03% H,

11.63% N. FAB MS, m/z (%): 473 (M⁺, 14), 389 (36), 283 (2), 105 (100), 85 (41). ¹H NMR

(400 MHz, CDCl₃): 1.55–1.75 an d 1.93–2.15 (m , 6 H, CH₂-THP); 3.68 (td, 1 H, J = 11.6 an d

2.9, bCH₂-O-THP); 4.12 (ddt, 1 H, J = 11.6, 3.9 an d 2.2, aCH₂-O-THP); 5.63 (s, 2 H,

CH₂-O-2); 5.70 (dd, 1 H, J = 9.8 an d 3.0, CH-O-THP); 5.82 an d 5.86 (2 × d, 2 × 1 H, J = 14.2,

CH₂-O-6); 7.41 (m , 4 H, H-m-Ph ); 7.55 (m , 2 H, H-p-Ph ); 8.09 (m , 4 H, H-o-Ph ); 8.26 (s, 1 H,

H-8). ¹³C NMR (125.8 MHz, CDCl₃): 22.56, 24.77 an d 31.56 (CH₂-THP); 63.10 (CH₂-O-6);

66.78 (CH₂-O-2); 68.65 (CH₂-O-THP); 82.18 (CH-O-THP); 128.29 (CH-m-Ph ); 129.82 an d

129.92 (CH-o-Ph ); 130.19 (C-i-Ph ); 130.89 (C-5); 132.92 an d 132.97 (CH-p-Ph ); 142.94

(CH-8); 151.39 (C-4); 155.32 (C-6); 158.79 (C-2); 166.32 an d 166.42 (CO). IR (CHCl₃): 3030,

2951, 2865, 1725, 1596, 1499, 1452, 1399, 1316, 1273, 1116, 1088, 1028, 712, 645.

6-(Benzoyloxymethyl)-2-chloro-9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)purine (16h ). Wh ite

solid, m .p. 63–65 °C. For C₃₉H₂₉ClN₄O₉(733.1) calculated: 63.89% C, 3.99% H, 4.84% Cl,

7.64% N; foun d: 63.51% C, 4.09% H, 4.85% Cl, 7.27% N. FAB MS, m/z (%): 733 (M⁺, 1), 445

(4), 289 (1), 105 (38). ¹H NMR (400 MHz, CDCl₃): 4.73 (dd, 1 H, J_gem= 12.0, J_5′b4′= 4.1,

H-5′b); 4.85 (q, 1 H, J_4′5′b= 4.1, J_4′3′= 4.0, J_4′5′a= 3.3, H-4′); 4.90 (dd, 1 H, J_gem= 10.6, J_5′a4′

3.3, H-5′a); 5.77 (s, 2 H, CH₂); 6.14 (dd, 1 H, J_3′2′= 5.8, J_3′4′= 4.0, H-3′); 6.17 (t, 1 H, J_2′3′

=

5.8, J_2′1′= 5.2, H-2′); 6.52 (d, 1 H, J_1′2′= 5.2, H-1′); 7.35–7.48 (m , 8 H, m-H-Bz); 7.53–7.63

(m , 4 H, p-H-Bz); 7.95, 8.02, 8.07 an d 8.12 (4 × m , 4 × 2 H, o-H-Bz); 8.22 (s, 1 H, H-8).

¹³C NMR (100.6 MHz, CDCl₃): 62.93 (CH₂); 63.62 (CH₂-5′); 71.51 (CH-3′); 74.24 (CH-2′);

81.28 (CH-4′); 86.47 (CH-1′); 126.16 (C-i-Bz); 128.38, 128.57, 128.59 an d 128.70 (CH-m-Bz);

129.13 an d 129.55 (C-i-Bz); 129.65, 129.86, 129.92 an d 130.03 (CH-o-Bz); 131.58 (C-5);

133.21, 133.54, 133.83 an d 133.92 (CH-p-Bz); 143.47 (CH-8); 153.11 (C-4); 154.44 (C-2);

158.10 (C-6); 165.12, 165.30, 166.08 an d 166.26 (CO). IR (CCl₄): 3073, 3065, 2954, 1734,

1603, 1587, 1494, 1452, 1398, 1316, 1267, 1114, 1094, 1026, 710, 639.

2,6-Bis(benzoyloxymethyl)-9-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)purine (17h ). Wh ite foam .

Exact m ass (FAB HR MS) calculated for C₄₇H₃₇N₄O₁₁: 833.2459, foun d: 833.2425. FAB MS,

m/z (%): 833 (M⁺, 8), 713 (5), 445 (9), 389 (4), 180 (15), 105 (100). ¹H NMR (200 MHz,

CDCl₃): 4.59–4.80 (m , 3 H, H-4′ an d 2 × H-5′); 5.60 an d 5.68 (2 × d, 2 × 1 H, J = 14.0,

CH₂-O-2); 5.83 (s, 2 H, CH₂-O-6); 6.06 (t, 1 H, J = 5.4, H-3′); 6.32 (dd, 1 H, J_2′3′= 5.6, J_2′1′

=

4.4, H-2′); 6.40 (d, 1 H, J_1′2′= 4.4, H-1′); 7.30–7.60 (m , 15 H, m-H-Bz an d p-H-Bz); 7.86–8.11

(m , 10 H, o-H-Bz); 8.20 (s, 1 H, H-8). ¹³C NMR (125.8 MHz, CDCl₃): 63.05 (CH₂O-6); 63.81

(CH₂-5′); 66.47 (CH₂O-2); 71.64 (CH-3′); 74.14 (CH-2′); 80.70 (CH-4′); 87.51 (CH-1′); 128.28,

128.32, 128.44, 128.50 an d 128.53 (CH-m-Bz); 129.28 (C-i-Bz); 129.66, 129.81, 129.82,

129.86 an d 129.96 (CH-o-Bz); 131.54 (C-5); 132.91, 133.02, 133.38, 133.60, an d 133.79

(CH-p-Bz); 143.77 (CH-8); 151.63 (C-4); 156.07 (C-6); 159.47 (C-2); 165.03, 165.09, 166.02,

166.17 an d 166.32 (C=O).

2,6-Bis(benzoyloxymethyl)-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (17c). Wh ite foam .

Exact m ass (FAB HR MS) calculated for C₃₂H₃₁N₄O₁₁: 647.1989, foun d: 647.1989. FAB MS,

m/z (%): 647 (MH⁺, 8), 389 (10), 259 (9), 105 (100). ¹H NMR (400 MHz, CDCl₃): 2.03, 2.06

an d 2.08 (3 × s, 3 × 3 H, CH₃-Ac); 4.28 (dd, 1 H, J_gem= 12.2, J_5′b,4′= 5.0, H-5′b); 4.32 (dd,

1 H, J_gem= 12.2, J_5′a,4′= 3.8, H-5′a); 4.40 (td, 1 H, J_4′,5′= 5.0, 3.8, J_4′,3′= 4.8, H-4′); 5.52 (t,

1 H, J_3′,2′= 5.4, J_3′,4′= 4.8, H-3′); 5.62 an d 5.66 (2 × d, 2 H, J_gem= 14.3, CH₂O-2); 5.84 (s,

2 H, CH₂O-6); 5.93 (t, 1 H, J_2′,3′= 5.4, J_2′,1′= 5.2, H-2′); 6.17 (d, 1 H, J_1′,2′= 5.2, H-1′);

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2-Substituted 6-(Hydroxymethyl)purine Bases

1689

7.38–7.46 (m , 4 H, H-m-Bz); 7.53–7.59 (m , 2 H, H-p-Bz); 8.07–8.13 (m , 4 H, H-o-Bz); 8.18 (s,

1 H, H-8). ¹³C NMR (100.6 MHz, CDCl₃): 20.29, 20.43 an d 20.69 (CH₃); 63.06 (CH₂O-6);

63.13 (CH₂-5′); 66.50 (CH₂O-2); 70.62 (CH-3′); 72.99 (CH-2′); 80.30 (CH-4′); 86.62 (CH-1′);

128.33 (CH-m-Bz); 129.73 (C-i-Bz); 129.93 (CH-o-Bz); 131.47 (C-5); 132.99 an d 133.06

(CH-p-Bz); 143.36 (CH-8); 151.62 (C-4); 156.09 (C-6); 159.36 (C-2); 166.15 an d 166.33

(CO-Bz); 169.24, 169.35 an d 170.20 (CO-Ac). IR (CCl₄): 3072, 3065, 1756, 1732, 1594, 1501,

1452, 1370, 1316, 1270, 1223, 1116, 1071, 642.

6-(Benzoyloxymethyl)-2-chloro-9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pentofuranosyl)purine

(16d ). Wh ite solid, m .p. 136–137 °C. For C₃₄H₂₉ClN₄O₇(641.1) calculated: 63.70% C,

4.56% H, 5.53% Cl, 8.74% N; foun d: 63.58% C, 4.61% H, 5.59% Cl, 8.53% N. Exact m ass

(FAB HR MS) calculated for C₃₄H₃₀ClN₄O₇: 641.1803, foun d: 641.1793. FAB MS, m/z (%):

641 (MH⁺, 4), 521 (3), 353 (4), 289 (12), 119 (85), 105 (20). ¹H NMR (500 MHz, CDCl₃): 2.39

an d 2.45 (2 × s, 2 × 3 H, CH₃-Tol); 2.90 (ddd, 1 H, J_gem= 14.3, J_2′b,1′= 6.2, J_2′b,3′= 2.6,

H-2′b); 2.95 (ddd, 1 H, J_gem= 14.3, J_2′a,1′= 8.1, J_2′a,3′= 5.9, H-2′a); 4.64–4.70 (m , 3 H, H-4′

an d H-5′b); 4.75 (m , 1 H, H-5′a); 5.77 (s, 2 H, CH₂-O-6); 5.78 (dt, 1 H, J_3′,2′= 5.9, 2.6 J_3′,4′

=

2.4, H-3′); 6.59 (dd, 1 H, J_1′2′= 8.1, 6.2, H-1′); 7.20 an d 7.29 (2 × m , 2 × 2 H, H-m-Tol); 7.45

(m , 2 H, H-m-Bz); 7.58 (m , 1 H, H-p-Bz); 7.86 an d 7.98 (2 × m , 2 × 2 H, H-o-Tol); 8.13 (m ,

2 H, H-o-Bz); 8.24 (s, 1 H, H-8). ¹³C NMR (125.8 MHz, CDCl₃): 21.68 an d 21.76 (CH₃-Tol);

38.47 (CH₂-2′); 62.92 (CH₂-O-6); 63.92 (CH₂-5′); 74.94 (CH-3′); 83.37 (CH-4′); 84.75 (CH-1′);

126.22 an d 126.46 (C-i-Tol); 128.39 (CH-m-Bz); 129.32 an d 129.33 (CH-m-Tol); 129.56

(CH-o-Tol); 129.64 (C-i-Bz); 129.85 (CH-o-Tol); 130.02 (CH-o-Bz); 131.53 (C-5); 133.22

(CH-p-Bz); 143.33 (CH-8); 144.31 an d 144.65 (C-p-Tol); 152.84 (C-4); 154.13 (C-2); 157.79

(C-6); 165.93 an d 166.07 (CO-Tol); 166.29 (CO-Bz). IR (CCl₄): 3038, 1730, 1613, 1590, 1495,

1452, 1317, 1267, 1211, 1178, 1099, 1021, 709, 638.

2,6-Bis(benzoyloxymethyl)-9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pentofuranosyl)purine (17d ).

W h ite solid, m .p. 92–93 °C. For C₄₂H₃₆N₄O₉(740.8) calculated: 68.10% C, 4.90% H,

7.56% N; foun d: 67.92% C, 4.89% H, 7.44% N. Exact m ass (FAB HR MS) calculated for

C

₄₂H₃₇N₄O₉: 741.2561, foun d: 741.2533. FAB MS, m/z (%): 741 (MH⁺, 20), 621 (11), 435

(16), 389 (30), 269 (17), 119 (100), 105 (66). ¹H NMR (400 MHz, CDCl₃): 2.39 an d 2.45 (2 ×

s, 2 × 3 H, CH₃-Tol); 2.72 (ddd, 1 H, J_gem= 14.3, J_2′b,1′= 6.0, J_2′b,3′= 2.2, H-2′b); 3.17 (ddd,

1 H, J_gem= 14.3, J_2′a,1′= 8.1, J_2′a,3′= 6.4, H-2′a); 4.55–4.65 (m , 3 H, H-4′ an d H-5′); 5.59 (dt,

1 H, J_3′,2′= 6.4, 2.2, J_3′,4′= 2.2, H-3′); 5.61 an d 5.66 (2 × d, 2 H, J_gem= 14.3, CH₂-O-2); 5.82

(s, 2 H, CH₂-O-6); 6.49 (dd, 1 H, J_1′2′= 8.1, 6.0, H-1′); 7.19 an d 7.27 (2 × m , 2 × 2 H,

H-m-Tol); 7.35 an d 7.40 (2 × m , 2 × 2 H, H-m-Bz); 7.47 an d 7.55 (2 × m , 2 × 1 H, H-p-Bz);

7.83 an d 7.92 (2 × m , 2 × 2 H, H-o-Tol); 8.06–8.12 (m , 4 H, H-o-Bz); 8.21 (s, 1 H, H-8).

¹³C NMR (100.6 MHz, CDCl₃): 21.66 an d 21.74 (CH₃-Tol); 37.37 (CH₂-2′); 63.04 (CH₂-O-6);

63.98 (CH₂-5′); 66.55 (CH₂-O-2); 75.07 (CH-3′); 83.13 (CH-4′); 85.26 (CH-1′); 126.40 an d

126.59 (C-i-Tol); 128.32 an d 128.36 (CH-m-Bz); 129.22 an d 129.26 (CH-o-Bz); 129.60, 129.79

an d 129.93 (CH-Tol); 131.51 (C-5); 133.02 (CH-p-Bz); 143.41 (CH-8); 144.12 an d 144.47

(C-p-Tol); 151.51 (C-4); 155.73 (C-6); 159.00 (C-2); 165.74 an d 166.05 (CO-Tol); 166.30

(CO-Bz). IR (CHCl₃): 1723, 1612, 1596, 1501, 1452, 1316, 1272, 1178, 1105, 1021, 713, 644.

2-(Benzoyloxymethyl)-9-benzyl-6-chloropurine (19a ). W h ite solid, m .p. 91–92 °C. For

C

₂₀H₁₅ClN₄O₂(378.8) calculated: 63.41% C, 3.99% H, 9.36% Cl, 14.79% N; foun d:

63.32% C, 3.98% H, 9.21% Cl, 14.62% N. FAB MS, m/z (%): 379 (MH⁺, 17), 345 (1), 273 (2),

105 (78), 91 (100). ¹H NMR (400 MHz, CDCl₃): 5.33 (s, 2 H, CH₂-N); 5.64 (s, 2 H, CH₂-O);

7.22–7.34 (m , 5 H, Bn ); 7.49 (m , 2 H, H-m-Bz); 7.61 (m , 1 H, H-p-Bz); 8.07 (s, 1 H, H-8); 8.17

(m , 2 H, H-o-Bz). ¹³C NMR (100.6 MHz, CDCl₃): 48.01 (CH₂-N); 66.10 (CH₂-O); 128.21

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Šilhár, Pohl, Votruba, Hocek:

(CH-o-Bn ); 128.43 (CH-m-Bz); 128.80 (CH-p-Bn ); 129.14 (CH-m-Bn ); 129.91 (CH-o-Bz);

129.95 (C-i-Bn ); 130.41 (C-5); 133.20 (CH-p-Bz); 134.41 (C-i-Bn ); 144.91 (CH-8); 151.17

(C-6); 152.23 (C-4); 159.32 (C-2); 166.27 (CO). IR (CCl₄): 3070, 3036, 1732, 1596, 1562,

1500, 1452, 1401, 1316, 1270, 1116, 1030, 649.

2-(Benzoyloxymethyl)-6-chloro-9-(tetrahydropyran-2-yl)purine (19b ). W h ite solid, m .p.

106–107 °C. For C₁₈H₁₇ClN₄O₃(372.8) calculated: 57.99% C, 4.60% H, 9.51% Cl, 15.03% N;

foun d: 57.87% C, 4.66% H, 9.41% Cl, 14.94% N. Exact m ass (FAB HR MS) calculated for

C

₁₈H₁₈ClN₄O₃: 373.1067, foun d: 373.1060. FAB MS, m/z (%): 373 (MH⁺, 36), 339 (52), 289

(87), 255 (75), 149 (12), 105 (100), 85 (76). ¹H NMR (500 MHz, CDCl₃): 1.57–1.70 an d

1.92–2.12 (m , 6 H, CH₂-THP); 3.66 (td, 1 H, J = 11.6 an d 3.3, bCH₂-O-THP); 4.11 (ddt, 1 H,

J = 11.6, 4.3 an d 2.0, aCH₂-O-THP); 5.61 (s, 2 H, CH₂-O); 5.65 (dd, 1 H, J = 10.2 an d 2.6,

CH-O-THP); 7.48 (m , 2 H, H-m-Ph ); 7.60 (m , 1 H, H-p-Ph ); 8.16 (m , 2 H, H-o-Ph ); 8.29 (s,

1 H, H-8). ¹³C NMR (125.8 MHz, CDCl₃): 22.42, 24.67 an d 31.52 (CH₂-THP); 66.27 (CH₂-O);

68.68 (CH₂-O-THP); 82.69 (CH-O-THP); 128.38 (CH-m-Ph ); 129.89 (CH-o-Ph ); 129.99

(C-i-Ph ); 131.61 (C-5); 133.14 (CH-p-Ph ); 143.30 (CH-8); 151.13 (C-6); 151.34 (C-4); 159.05

(C-2); 166.34 (C=O). IR (CCl₄): 3073, 2949, 2858, 1732, 1596, 1562, 1494, 1452, 1401, 1316,

1269, 1211, 1115, 647.

2-(Benzoyloxymethyl)-6-chloro-9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)purine (19c). Wh ite foam .

Exact m ass (FAB HR MS) calculated for C₂₄H₂₄ClN₄O₉: 547.1232, foun d: 547.1220. FAB MS,

m/z (%): 547 (MH⁺, 19), 289 (8), 259 (18), 105 (100). ¹H NMR (400 MHz, CDCl₃): 2.02, 2.07

an d 2.08 (3 × s, 3 × 3 H, CH₃-Ac); 4.27 (dd, 1 H, J_gem= 12.2, J_5′b,4′= 4.9, H-5′b); 4.30 (dd,

1 H, J_gem= 12.2, J_5′a,4′= 3.8, H-5′a); 4.40 (td, 1 H, J_4′,3′= 4.9, J_4′,5′= 4.9, 3.8, H-4′); 5.45 (t,

1 H, J_3′,2′= 5.7, J_3′,4′= 4.9, H-3′); 5.61 an d 5.65 (2 × d, 2 H, J_gem= 14.5, CH₂-O); 5.86 (t, 1 H,

J_2′,3′= 5.7, J_2′,1′= 4.9, H-2′); 6.13 (d, 1 H, J_1′,2′= 4.9, H-1′); 7.48 (m , 2 H, H-m-Bz); 7.60 (m ,

1 H, H-p-Bz); 8.17 (m , 2 H, H-o-Bz); 8.26 (s, 1 H, H-8). ¹³C NMR (100.6 MHz, CDCl₃): 20.23,

20.39 an d 20.68 (CH₃); 63.01 (CH₂-5′); 65.99 (CH₂-O); 70.48 (CH-3′); 73.14 (CH-2′); 80.38

(CH-4′); 87.09 (CH-1′); 128.42 (CH-m-Bz); 129.71 (C-i-Bz); 130.02 (CH-o-Bz); 131.26 (C-5);

133.20 (CH-p-Bz); 143.67 (CH-8); 151.52 (C-4); 151.75 (C-6); 159.73 (C-2); 166.05 (CO-Bz);

169.21, 169.30 an d 170.15 (CO-Ac). IR (CCl₄): 3065, 1756, 1733, 1596, 1564, 1497, 1452,

1403, 1270, 1224, 1117, 641.

2-(Benzoyloxymethyl)-6-chloro-9-(2-deoxy-3,5-di-O-toluoyl-β-D-erythro-pentofuranosyl)purine

(19d ). Wh ite foam . Exact m ass (FAB HR MS) calculated for C₃₄H₃₀ClN₄O₇: 641.1803, foun d:

641.1818. FAB MS, m/z (%): 641 (MH⁺, 7), 607 (9), 353 (7), 289 (18), 255 (13), 119 (81), 105

(42). ¹H NMR (400 MHz, CDCl₃): 2.39 an d 2.45 (2 × s, 2 × 3 H, CH₃-Tol); 2.72 (ddd, 1 H,

J_gem= 14.4, J_2′b,1′= 6.1, J_2′b,3′= 2.3, H-2′b); 3.12 (ddd, 1 H, J_gem= 14.4, J_2′a,1′= 7.9, J_2′a,3′

=

6.4, H-2′a); 4.55 (dd, 1 H, J_gem= 10.9, J_5′b,4′= 4.5, H-5′b); 4.58 (ddd, 1 H, J_4′,5′= 4.5, 3.3,

J_4′,3′= 2.2, H-4′); 4.65 (dd, 1 H, J_gem= 10.9, J_5′a,4′= 3.3, H-5′a); 5.57 (dt, 1 H, J_3′,2′= 6.4, 2.3

J_3′,4′= 2.2, H-3′); 5.60 an d 5.64 (2 × d, 2 H, J_gem= 14.5, CH₂-O); 6.44 (dd, 1 H, J_1′2′= 7.9, 6.1,

H-1′); 7.19 an d 7.27 (2 × m , 2 × 2 H, H-m-Tol); 7.40 (m , 2 H, H-m-Bz); 7.49 (m , 1 H, H-p-Bz);

7.80 an d 7.90 (2 × m , 2 × 2 H, H-o-Tol); 8.15 (m , 2 H, H-o-Bz); 8.25 (s, 1 H, H-8). ¹³C NMR

(100.6 MHz, CDCl₃): 21.66 an d 21.74 (CH₃-Tol); 37.57 (CH₂-2′); 63.80 (CH₂-5′); 66.03

(CH₂-O); 75.00 (CH-3′); 83.45 (CH-4′); 85.74 (CH-1′); 126.31 an d 126.40 (C-i-Tol); 128.44

(CH-m-Bz); 129.23 an d 129.26 (CH-m-Tol); 129.51 (CH-o-Bz); 129.77 an d 129.85 (CH-o-Tol);

131.16 (C-5); 133.22 (CH-p-Bz); 143.72 (CH-8); 144.23 an d 144.53 (C-p-Tol); 151.34 (C-4);

151.42 (C-6); 159.24 (C-2); 165.71 an d 165.97 (CO-Tol); 166.22 (CO-Bz). IR (CCl₄): 3037,

1729, 1613, 1595, 1562, 1494, 1452, 1404, 1268, 1215, 1100, 646.

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2-Substituted 6-(Hydroxymethyl)purine Bases

1691

Gen eral Procedure for Deacylation Reaction s of 16

Aqueous am m on ia (25% solution , 1 m l) was added to a solution of protected purin es or n u-

cleosides 15 (0.5 m m ol) in m eth an ol (20 m l) an d th e m ixture was stirred at am bien t tem per-

ature. After com plete deprotection , th e solven t was evaporated an d th e residue was ch rom a-

tograph ed.

9-Benzyl-2-chloro-6-(hydroxymethyl)purine (20a). Yield 87%, wh ite solid, m .p. 127–128 °C.

For C₁₃H₁₁ClN₄O (274.7) calculated: 56.84% C, 4.04% H, 12.91% Cl, 20.40% N; foun d:

56.47% C, 3.90% H, 13.13% Cl, 20.35% N. Exact m ass (FAB HR MS) calculated for

C

₁₃H₁₂ClN₄O: 275.0700, foun d: 275.0708. FAB MS, m/z (%): 275 (MH⁺, 45), 183 (5), 91

(100). ¹H NMR (400 MHz, DMSO-d₆): 4.86 (d, 2 H, J_vic= 6.2, CH₂-O); 5.48 (s, 2 H, CH₂-N);

5.61 (t, 1 H, J_vic= 6.2, OH); 7.28–7.39 (m , 5 H, Ph ); 8.73 (s, 1 H, H-8). ¹³C NMR (100.6 MHz,

DMSO-d₆): 46.78 (CH₂-N); 59.78 (CH₂-O); 127.60 (CH-o-Ph ); 128.20 (CH-p-Ph ); 129.01

(CH-m-Ph ); 130.54 (C-5); 136.26 (C-i-Ph ); 147.30 (CH-8); 152.86 (C-4); 153.03 (C-2); 162.41

(C-6). IR (CHCl₃): 3491, 3070, 1597, 1501, 1456, 1412, 1364, 1319, 1240, 1070, 647.

2-Chloro-6-(hydroxymethyl)-9-(tetrahydropyran-2-yl)purine (20b). Yield 90%, wh ite solid, m .p.

54–55 °C. Exact m ass (FAB HR MS) calculated for C₁₁H₁₄ClN₄O₂: 269.0805, foun d: 269.0797.

FAB MS, m/z (%): 269 (MH⁺, 12), 185 (91), 151 (7), 85 (100). ¹H NMR (500 MHz, DMSO-d₆):

1.55–1.66, 1.76, 1.94–2.03 an d 2.28 (4 × m , 6 H, CH₂-THP); 3.73 an d 4.02 (2 × m , 2 H,

CH₂-O-THP); 4.87 (d, 2 H, J_vic= 6.3, CH₂-O); 5.62 (t, 1 H, J_vic= 6.3, OH); 5.73 (dd, 1 H, J =

10.9, 2.3, CH-O-THP); 8.82 (s, 1 H, H-8). ¹³C NMR (125.8 MHz, DMSO-d₆): 22.36, 24.62 an d

29.88 (CH₂-THP); 59.79 (CH₂-O); 67.92 (CH₂-O-THP); 81.40 (CH-O-THP); 130.60 (C-5);

145.26 (CH-8); 152.46 (C-4); 152.92 (C-2); 162.63 (C-6). IR (CHCl₃): 3481, 1598, 1498, 1455,

1442, 1412, 1385, 1331, 1088, 645.

2-Chloro-6-(hydroxymethyl)-9-(β-D-ribofuranosyl)purine (20f). Yield 84% of wh ite h ygroscopic

solid (m .p. 129–131 °C), wh ich was crystallized from 2-propan ol/h eptan e, [α ]²_D⁰–45.9 (c 0.25,

MeOH). Exact m ass (FAB HR MS) calculated for C₁₁H₁₄ClN₄O₅: 317.0653, foun d: 317.0639.

FAB MS, m/z (%): 317 (MH⁺, 14), 149 (3), 133 (3). ¹H NMR (400 MHz, CD₃OD): 3.79 (dd, 1

H, J_gem= 12.3, J_5′b,4′= 3.4, H-5′b); 3.90 (dd, 1 H, J_gem= 12.3, J_5′a,4′= 3.1, H-5′a); 4.15 (q, 1 H,

J_4′,3′= 4.0, J_4′,5′= 3.4, 3.1, H-4′); 4.36 (dd, 1 H, J_3′,2′= 5.2, J_3′,4′= 4.0, H-3′); 4.68 (t, 1 H,

J_2′,1′= 5.3, J_2′,3′= 5.2, H-2′); 5.04 (s, 2 H, CH₂-OH); 6.10 (d, 1 H, J_1′,2′= 5.3, H-1′); 8.75 (s,

1 H, H-8). ¹³C NMR (100.6 MHz, CD₃OD): 61.55 (CH₂-O); 62.76 (CH₂-5′); 71.93 (CH-3′);

75.86 (CH-2′); 87.86 (CH-4′); 90.56 (CH-1′); 132.01 (C-5); 146.76 (CH-8); 153.93 (C-4);

155.07 (C-2); 163.37 (C-6). IR (KBr): 3391, 1594, 1499, 1387, 1327, 1211, 1083, 1054, 637.

2-Chloro-9-(2-deoxy-β-D-erythro-pentofuranosyl)-6-(hydroxymethyl)purine (20g). Yield 87% of

wh ite (h ygroscopic) solid (m .p. 99–101 °C), wh ich was crystallized from 2-propan ol/h eptan e,

[α ]²_D⁰+51.8 (c 0.28, MeOH). For C₁₁H₁₃ClN₄O₄(300.7) calculated: 43.94% C, 4.36% H,

11.79% Cl, 18.63% N; foun d: 43.61% C, 4.41% H, 11.43% Cl, 18.32% N. Exact m ass (FAB

HR MS) calculated for C₁₁H₁₄ClN₄O₄: 301.0704, foun d: 301.0717. FAB MS, m/z (%): 301

(MH⁺, 35), 185 (100), 167 (8), 117 (19). ¹H NMR (400 MHz, CD₃OD): 2.50 (ddd, 1 H, J_gem

=

13.6, J_2′b,1′= 6.4, J_2′b,3′= 3.8, H-2′b); 2.82 (ddd, 1 H, J_gem= 13.6, J_2′a,1′= 6.9, J_2′a,3′= 6.1,

H-2′a); 3.75 (dd, 1 H, J_gem= 12.1, J_5′b,4′= 4.2, H-5′b); 3.84 (dd, 1 H, J_gem= 12.1, J_5′a,4′= 3.6,

H-5′a); 4.05 (q, 1 H, J_4′,5′= 4.2, 3.6, J_4′,3′= 3.3, H-4′); 4.60 (dt, 1 H, J_3′,2′= 6.1, 3.8, J_3′,4′= 3.3,

H-3′); 5.03 (s, 2 H, CH₂-O); 6.50 (t, 1 H, J_1′2′= 6.9, 6.4, H-1′); 8.71 (s, 1 H, H-8). ¹³C NMR

(100.6 MHz, CD₃OD): 41.28 (CH₂-2′); 61.49 (CH₂-O); 63.11 (CH₂-5′); 72.46 (CH-3′); 86.46

(CH-1′); 89.62 (CH-4′); 131.93 (C-5); 146.66 (CH-8); 153.72 (C-4); 154.98 (C-2); 163.17 (C-6).

IR (KBr): 3492, 1593, 1498, 1387, 1327, 1211, 1093, 1056, 642.

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

1692

Šilhár, Pohl, Votruba, Hocek:

2-Ch loro-6-(h ydroxym eth yl)-9H-purin e (20e)

Yield 84%, prepared from 20b with Dowex 50X8 (H⁺) in eth an ol (96%). Th e reaction m ix-

ture was stirred at 70–75 °C for 2 h , filtered, th e resin was wash ed with eth an olic am m on ia

an d th e collected solution was evaporated to dryn ess. Th e crude product was ch rom atog-

raph ed (eth yl acetate/m eth an ol 8:2) afforded wh ite solid, wh ich was crystallized from

eth an ol/h eptan e (m .p. 213–214 °C). For C₆H₅ClN₄O (184.6) calculated: 39.04% C, 2.73% H,

19.21% Cl, 30.35% N; foun d: 38.61% C, 2.82% H, 18.78% Cl, 29.83% N. Exact m ass

(FAB HR MS) calculated for C₆H₆ClN₄O: 185.0230, foun d: 185.0227. FAB MS, m/z (%): 185

(MH⁺, 100), 151 (6). ¹H NMR (400 MHz, DMSO-d₆+ CF₃COOD): 4.86 (s, 2 H, 6-CH₂-O); 8.64

(s, 1 H, H-8). ¹³C NMR (100.6 MHz, DMSO-d₆+ CF₃COOD): 62.11 (6-CH₂-O); 123.54 (C-5);

146.57 (CH-8); 152.28 (C-2); 159.15 (C-6); 160.57 (C-4). IR (KBr): 3382, 3003, 1613, 1563,

1473, 1376, 1301, 1233, 1078, 623.

Gen eral Procedure for Deacylation Reaction s of 17

A 1 M m eth an olic MeONa (0.1 m l, 0.1 m m ol) was added to a solution of a protected purin es

or n ucleosides 17 (0.5 m m ol) in m eth an ol (20 m l) an d th e m ixture was stirred at am bien t

tem perature. After com plete deprotection , th e solven t was evaporated an d th e residue was

ch rom atograph ed.

9-Benzyl-2,6-bis(hydroxymethyl)purine (21a). Yield 87%, wh ite solid, m .p. 76–77 °C. For

C

₁₄H₁₄N₄O₂(270.3) calculated: 62.21% C, 5.22% H, 20.73% N; foun d: 61.83% C, 5.43% H,

20.36% N. Exact m ass (FAB HR MS) calculated for C₁₄H₁₅N₄O₂: 271.1195, foun d: 271.1184.

FAB MS, m/z (%): 271 (MH⁺, 100), 181 (4), 163 (3), 91 (82). ¹H NMR (500 MHz, DMSO-d₆):

4.69 (d, 2 H, J_vic= 5.9, CH₂-O-2); 4.90 (d, 2 H, J_vic= 5.7, CH₂-O-6); 5.27 (t, 1 H, J_vic= 5.9,

OH-2); 5.40 (t, 1 H, J_vic= 5.7, OH-6); 5.51 (s, 2 H, CH₂-N); 7.26–7.37 (m , 5 H, Ph ); 8.63

(s, 1 H, H-8). ¹³C NMR (125.8 MHz, DMSO-d₆): 46.37 (CH₂-N); 60.16 (CH₂-O-6); 65.08

(CH₂-O-2); 127.65 (CH-o-Ph ); 128.07 (CH-p-Ph ); 128.96 (CH-m-Ph ); 129.61 (C-5); 136.89

(C-i-Ph ); 146.06 (CH-8); 151.69 (C-4); 159.33 (C-6); 163.17 (C-2). IR (CHCl₃): 3472, 3070,

1599, 1505, 1456, 1409, 1360, 1315, 1247, 1072, 649.

2,6-Bis(hydroxymethyl)-9-(tetrahydropyran-2-yl)purine (21b ). Yield 89%, wh ite solid, m .p.

100–101 °C. Exact m ass (FAB HR MS) calculated for C₁₂H₁₇N₄O₃: 265.1301, foun d: 265.1312.

FAB MS, m/z (%): 265 (MH⁺, 18), 181 (84), 165 (11), 149 (14), 85 (64). ¹H NMR (500 MHz,

DMSO-d₆): 1.55–1.67, 1.76, 1.95–2.03 an d 2.33 (4 × m , 6 H, CH₂-THP); 3.72 (m , 1 H, J =

11.5, 9.6, 4.8 an d 3.6, bCH₂-O-THP); 4.02 (ddt, 1 H, J = 11.5, 3.9 an d 2.4, aCH₂-O-THP);

4.70 (d, 2 H, J_vic= 5.4, CH₂-O-2); 4.90 (d, 2 H, J_vic= 5.4, CH₂-O-6); 5.28 (t, 1 H, J_vic= 5.4,

OH-2); 5.40 (t, 1 H, J_vic= 5.4, OH-6); 5.79 (dd, 1 H, J = 11.0 an d 2.2, CH-O-THP); 8.73 (s,

1 H, H-8). ¹³C NMR (125.8 MHz, DMSO-d₆): 22.57, 24.66 an d 30.17 (CH₂-THP); 60.15

(CH₂-O-6); 65.05 (CH₂-O-2); 67.94 (CH₂-O-THP); 80.97 (CH-O-THP); 129.65 (C-5); 143.99

(CH-8); 151.13 (C-4); 159.46 (C-6); 163.22 (C-2). IR (KBr): 3414, 3325, 1600, 1505, 1453,

1398, 1352, 1212, 1087, 1075, 1047, 644.

2,6-Bis(hydroxymethyl)-9-(β-D-ribofuranosyl)purine (21f). Yield 80% of wh ite h ygroscopic

solid (m .p. 120–123 °C), wh ich was crystallized from 2-propan ol/h eptan e, [α ]²_D⁰–17.7 (c 0.36,

MeOH). For C₁₂H₁₆N₄O₆·1/2H₂O (321.3) calculated: 44.86% C, 5.33% H, 17.44% N; foun d:

44.78% C, 4.96% H, 17.10% N. Exact m ass (FAB HR MS) calculated for C₁₂H₁₇N₄O₆:

313.1148, foun d: 313.1150. FAB MS, m/z (%): 313 (MH⁺, 80), 279 (9), 181 (97), 163 (17), 149

(10), 133 (8). ¹H NMR (400 MHz, CD₃OD): 3.78 an d 3.91 (2 × dd, 2 H, J_gem= 12.4, J_5′,4′

=

3.2, H-5′); 4.16 (q, 1 H, J_4′,3′= 3.7, J_4′,5′= 3.2, H-4′); 4.37 (dd, 1 H, J_3′,2′= 5.2, J_3′,4′= 3.7,

Collect. Czech. Chem. Commun. (Vol. 70) (2005)

2-Substituted 6-(Hydroxymethyl)purine Bases

1693

H-3′); 4.72 (t, 1 H, J_2′,1′= 5.6, J_2′,3′= 5.2, H-2′); 4.86 (s, 2 H, 2-CH₂-OH); 5.10 (s, 2 H,

6-CH₂-OH); 6.15 (d, 1 H, J_1′,2′= 5.6, H-1′); 8.70 (s, 1 H, H-8). ¹³C NMR (100.6 MHz, CD₃OD):

61.53 (6-CH₂-O); 62.90 (CH₂-5′); 65.97 (2-CH₂-O); 72.06 (CH-3′); 75.81 (CH-2′); 87.53

(CH-4′); 90.64 (CH-1′); 131.32 (C-5); 146.05 (CH-8); 152.57 (C-4); 160.86 (C-6); 164.37 (C-2).

IR (KBr): 3401, 1598, 1505, 1402, 1350, 1219, 1084, 638.

9-(2-Deoxy-β-D-erythro-pentofuranosyl)-2,6-bis(hydroxymethyl)purine (21g). Yield 90% of

wh ite h ygroscopic solid (m .p. 78–80 °C), wh ich was crystallized from 2-propan ol/h eptan e,

[α ]²_D⁰+49.5 (c 0.37, MeOH). For C₁₂H₁₆N₄O₅·H₂O (314.3) calculated: 45.86% C, 5.77% H,

17.83% N; foun d: 46.23% C, 5.41% H, 17.62% N. Exact m ass (FAB HR MS) calculated for

C

₁₂H₁₇N₄O₅: 297.1199, foun d: 297.1196. FAB MS, m/z (%): 297 (MH⁺, 27), 181 (44), 163 (7),

117 (7). ¹H NMR (400 MHz, CD₃OD): 2.48 (ddd, 1 H, J_gem= 13.5, J_2′b,1′= 6.3, J_2′b,3′= 3.4,

H-2′b); 2.85 (ddd, 1 H, J_gem= 13.5, J_2′a,1′= 7.3, J_2′a,3′= 6.0, H-2′a); 3.76 (dd, 1 H, J_gem= 12.1,

J_5′b,4′= 3.9, H-5′b); 3.84 (dd, 1 H, J_gem= 12.1, J_5′a,4′= 3.4, H-5′a); 4.06 (q, 1 H, J_4′,5′= 3.9,

3.4, J_4′,3′= 3.1, H-4′); 4.61 (dt, 1 H, J_3′,2′= 6.0, 3.4, J_3′,4′= 3.1, H-3′); 4.86 (s, 2 H, 2-CH₂-O);

5.09 (s, 2 H, 6-CH₂-O); 6.59 (dd, 1 H, J_1′2′= 7.3, 6.3, H-1′); 8.68 (s, 1 H, H-8). ¹³C NMR

(100.6 MHz, CD₃OD): 41.40 (CH₂-2′); 61.51 (6-CH₂-O); 63.26 (CH₂-5′); 66.02 (2-CH₂-O);

72.67 (CH-3′); 86.45 (CH-1′); 89.62 (CH-4′); 131.19 (C-5); 145.94 (CH-8); 152.41 (C-4);

160.65 (C-6); 164.26 (C-2). IR (KBr): 3413, 1599, 1502, 1396, 1320, 1217, 1092, 1057, 644.

2,6-Bis(h ydroxym eth yl)-9H-purin e (21e)

Yield 74%, prepared from 21b with Dowex 50X8 (H⁺) in 96% eth an ol. Reaction m ixture was

stirred at 70–75 °C for 2 h , filtered, th e resin was wash ed with eth an olic am m on ia an d th e

collected solution was evaporated to dryn ess. Crude product was ch rom atograph ed (eth yl

acetate/m eth an ol 2:1) to give wh ite solid, wh ich was crystallized from m eth an ol/eth yl

acetate (m .p. > 300 °C). For C₇H₈N₄O₂·1/2H₂O (189.2) calculated: 44.44% C, 4.80% H,

29.62% N; foun d: 44.29% C, 4.39% H, 29.28% N. Exact m ass (FAB HR MS) calculated for

C₇H₉N₄O₂: 181.0726, foun d: 181.0729. FAB MS, m/z (%): 181 (MH⁺, 44), 165 (6), 149 (10).

¹H NMR (400 MHz, DMSO-d₆): 4.64 (s, 2 H, 2-CH₂-O); 4.88 (s, 2 H, 6-CH₂-O); 8.51 (s, 1 H,

H-8). ¹³C NMR (100.6 MHz, DMSO-d₆): 62.06 (6-CH₂-O); 65.15 (2-CH₂-O); 123.94 (C-5);

146.51 (CH-8); 156.43 (C-6); 158.18 (C-4); 162.39 (C-2). IR (KBr): 3392, 1598, 1390, 1317,

1230, 1082, 1038, 638.

This work is a part of the research project Z4 055 0506. It was supported by the Grant Agency of

the Czech Republic (grant No. 203/03/0035) by the Centre for New Antivirals and Antineoplastics

(1M0508), by the Programme of Targeted Projects of Academy of Sciences of the Czech Republic

(1QS400550501) and by Sumitomo Chemical, Inc. (Osaka, Japan).

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Collect. Czech. Chem. Commun. (Vol. 70) (2005)

Article Doi

Synthesis of 2-substituted 6-(hydroxymethyl)purine bases and nucleosides

DOI: 10.1135/cccc20051669

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