Sugar-modified derivatives of cytostatic 6-(het)aryl-7-deazapurine nucleosides: 2′-c-methylribonucleosides, arabinonucleosides and 2′-deoxy-2′-fluoroarabinonucleosides

Sugar-Modified Nucleosides

957

SUGAR-MODIFIED DERIVATIVES OF CYTOSTATIC

6-(HET)ARYL-7-DEAZAPURINE NUCLEOSIDES:

2′-C-METHYLRIBONUCLEOSIDES, ARABINONUCLEOSIDES AND

2′-DEOXY-2′-FLUOROARABINONUCLEOSIDES

1

2

3

4,

Petr NAUŠ , Pavla PERLÍKOVÁ , Radek POHL and Michal HOCEK *

Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i.,

Gilead Sciences & IOCB Research Center, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic;

e-mail: ¹naus@uochb.cas.cz, ²spacilova@uochb.cas.cz, ³pohl@uochb.cas.cz, ⁴hocek@uochb.cas.cz

Received April 20, 2011

Accepted May 31, 2011

Published online July 7, 2011

Dedicated to Professor Antonín Holý on the occasion of his 75th birthday.

A series of novel sugar-modified derivatives of cytostatic 6-hetaryl-7-deazapurine ribonucleo-

sides: 2′-C-methylribonucleosides, arabinonucleosides and 2′-deoxy-2′-fluoroarabinonucleo-

sides bearing an alkyl, aryl and hetaryl group in position 6 were prepared by palladium

catalyzed cross-coupling reactions of corresponding (protected) 6-chloro-(7-fluoro)-

7-deazapurine nucleosides with (het)arylboronic, hetarylstannanes and trimethylaluminium

eventually followed by deprotection. Key intermediate 6-chloro-7-deazapurine 2′-C-methyl-

β-D-ribofuranoside was prepared via a stereoselective nucleobase anion glycosylation with

toluoyl-protected 1,2-anhydro-2-C-methylribofuranose. The 1,2-anhydro sugar was synthe-

sized in 3 steps starting from readily available 2-C-methylribonolactone. The 6-chloro-

7-deazapurine arabinofuranoside intermediate was obtained by epimerization from 3′,5′-

protected 6-chloro-7-deazapurine ribofuranoside via 2′-hydroxyl oxidation followed by re-

duction. None of the prepared compounds showed any considerable cytostatic or antiviral

activity.

Keywords: Nucleosides; Cross-coupling; Antitumor agents; Purines; 7-Deazapurines;

7H-Pyrrolo[2,3-d]pyrimidine; Cytostatic agents.

Biological activity of purine ribonucleosides bearing aryl or hetaryl groups

at position 6 have been a long term topic of our laboratory (Chart 1). The

parent 6-(het)arylpurine ribonucleosides 1 possess¹significant cytostatic

and anti-HCV activities. However, any of the prepared 2- and 8-substituted

derivatives²or 2′-, 3′- and 5′-deoxyribonucleosides³were inactive, whereas

the corresponding L-ribonucleosides⁴showed only moderate anti-HCV ef-

fect. Recently, we found⁵that 6-hetaryl-7-deazapurine 2 and 6-hetaryl-

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

doi:10.1135/cccc2011082

958

Nauš, Perlíková, Pohl, Hocek:

7-fluoro-7-deazapurine ribonucleosides 3 exert even pronounced cytostatic

effect in nanomolar concentrations. However, their cycloSal-phosphate

and ProTide prodrugs⁶were less active due to efflux from the cells. Since

some sugar-modified purine nucleosides (i.e. Fludarabine⁷or Clofarabine⁸)

are clinically used cytostatics and 7-deazaadenine 2′-C-methylribo-

nucleoside⁹is in clinical trials for treatment of HCV, we decided to prepare

and study the biological activity of three types of sugar-modified deri-

vatives of 6-(hetaryl)-7-deazapurine nucleosides: 2′-C-methylribonucleo-

sides (analogues of the anti-HCV drug candidate), arabinosides (analogues

Cytostatic nucleosides from our lab:

X, Y = O, S, NH, N, CH

X

Y

N

X

Y

N

X

Y

N

F

N

HO

N

O

HO

OH

HO

OH

HO

OH

1

2

3

Commercial nucleoside cytostatics:

NH₂

Anti-HCV nucleoside in

NH₂

N

clinical trials:

HO

Cl

NH₂

N

HO

N

F

N

O

N

O

CH₃

OH

HO

OH

HO

F

HO

Clofarabine

Fludarabine

cytostatic

2'-C-Me-7-deazaA

cytostatic

anti-HCV

This work:

X

Y

X

Y

N

HO

N

R

N

O

CH₃

OH

HO

R = OH or F

X, Y = O, S, NH, N, CH

CHART 1

Structures of modified purine and deazapurine cytostatics and antivirals

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

Sugar-Modified Nucleosides

959

of Fludarabine) and 2′-deoxy-2′-fluoroarabinonucleosides (analogue of

Clofarabine).

The synthesis of 2′-C-methylribonucleosides required the preparation of

6-chloro-7-deazapurine 2′-C-methylriboside key intermediate. The corre-

sponding free nucleoside was synthesized by Merck researchers¹⁰by

nucleobase anion glycosylation of 6-chloro-7-deazapurine with 3,5-bis-

O-(2,4-dichlorobenzyl)-2-C-methylribofuranosylbromide followed by ben-

zyl deprotection. The authors later found that actual glycosylating agent

is anomeric α-epoxide¹¹formed from halogenose by internal S_N2 reaction

of bromohydrin unit under basic reaction conditions. The observed clean

stereoselective outcome of nucleosidation (only β anomer formation) was

then explained by S_N2 ring opening of α-epoxide. The starting 2-C-methyl-

ribofuranosylbromide was prepared by lengthy multi-step sequence from

D-ribose. For larger scale preparation of 7-deaza-2′-C-methyladenosine

(Chart 2), potent inhibitor of HCV RNA replication, the authors later devel-

oped a more suitable toluoyl-protected epoxide 4 ¹¹and successfully uti-

lized it in multi-kilogram glycosylation of N-phtalimido-7-deazaadenine.

The epoxide 4 is generated from key diol 5 by mesylation rather than via

halogenose. Although practical and efficient, Merck synthesis of key diol 5

comprises nine steps starting from diacetone glucose and thus is not just

convenient for rapid access to epoxide 4 in laboratory small scale.

NH₂

NPhth

TolO

N

O

OH

HO

N

O

CH₃

N

TolO

CH₃

TolO

OH

H

CH₃

OH

HO

HCV replication

inhibitor

4

5

CHART 2

Retrosynthetic analysis of 7-deazapurine 2′-C-methylribonucleoside

We envisaged 2-C-methyl-D-ribonolactone 6 (Scheme 1) as attractive

starting material for epoxide 4, because it is a product of calcium hydroxide

promoted isomerization of cheap D-fructose¹². Although not high yielding

(ca. 10% after crystallization) this one step process enables access to crystal-

line branched sugar 6 without chromatographic separation. Fleet group has

more recently disclosed a new one-pot procedure¹³to lactone 6 from D-

glucose by similar isomerization of in situ formed Amadori ketose in yields

up to 27%.

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

960

Nauš, Perlíková, Pohl, Hocek:

CH₂OH

O

CH₂NMe₂

CHO

O

H

HO

H

OH

H

HO

CaO

O

Me₂NH

HO

H

HO

H

O

H₂O

9.5%

H₂O

20-27%

OH

AcOH, EtOH

CH₃

H

OH

H

OH

HO

OH

CH₂OH

D-fructose

CH₂OH

Amadori

ketose

CH₂OH

D-glucose

6

SCHEME 1

The lactone 6 was prepared by the published procedure^12,13and then it

was selectively 3,5-diacylated¹⁴(Scheme 2) by the action of 2 equivalents

of p-toluoyl chloride in the mixture of dichloromethane-pyridine (4:1) at

–20 °C affording 3,5-di-O-toluoyl lactone 7 ¹⁵in 82% yield after crystalliza-

tion. Under these conditions the formation of 2,3,5-tri-O-toluoyl derivative

is minimized compared to older procedure¹⁵and this contaminant is easily

discarded from crude product by crystallization. The next step, partial re-

duction of lactone 7 to the desired lactol 5 was complicated by the presence

of free 2-hydroxy group, which precludes reducing reagents susceptible to

alcoholysis (like DIBAH). As the reduction of free lactone 6 to 2-C-methyl-

D-ribose by sodium borohydride in water was reported¹⁶, we attempted the

reduction of more hydrophobic lactone 7 by the treatment with sodium

borohydride in THF/MeOH mixture, but desired diol 5 was isolated in less

then 35% yields whereas overreduction of hemiacetal 5 was prevalent. As

sodium bis(2-methoxyethoxy)aluminumhydride (SMEAH, Red-Al) modified

by the introduction of ethoxy group simply by the addition of one equiva-

lent of absolute ethanol to the Red-Al solution is well established reagent

for partial reduction of lactones to lactols¹⁷, we presumed that free

2-hydroxy group could at least partly play the role of Red-Al modifier in-

stead of ethanol. Thus the lactone 7 was treated with equimolar amount of

Red-Al in toluene at –15 °C and desired diol 5 was isolated in satisfactory

57% yield. Unreacted lactone 7 was recovered in 8% yield and non-isolated

remaining material was the product of overreduction. Crystalline diol 5 was

TolO

HO

TolO

O

a

b

O

OH

c

O

82%

57%

CH₃

TolO

CH₃

HO

OH

TolO

OH

TolO

OH

6

7

5

4

SCHEME 2

(a) TolCl, CH₂Cl₂/Pyridine (4:1), –20 °C; (b) Red-Al, toluene, –15 °C; (c) MsCl, NEt₃,

CH₂Cl₂, r.t.

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

Sugar-Modified Nucleosides

961

then mesylated with methanesulfonyl chloride in the presence of triethyl-

amine in dichloromethane to almost quantitatively afford epoxide 4. In ac-

cord with observations of its inventors¹¹, 1,2-anhydro sugar 4 displayed

enhanced stability towards hydrolysis, uncommon amongst other known

glycal epoxides¹⁸(mainly benzyl or TBS protected).

The glycosylation of 6-chloro-7-deazapurine 8 with epoxide 4 in the pres-

ence of NaH as base in DMF/toluene afforded the desired protected 2′-C-

methyl ribonucleoside intermediate 9 in 58% yield (Scheme 3). Compound

9 was deprotected by the treatment with methanolic ammonia at room

temperature affording free 2′-C-methylriboside 10 in 85% yield.

Cl

N

TolO

N

O

a

b

TolO

HO

N

O

58%

85%

N

TolO

CH₃

H

CH₃

OH

CH₃

OH

10

TolO

HO

8

4

9

SCHEME 3

(a) NaH, DMF-toluene, r.t.; (b) 27 wt.% ammonia in MeOH, r.t.

With the key chlorodeazapurine nucleoside intermediate 10 in hand, the

aqueous Suzuki cross-coupling reactions¹⁹were conducted with a set of

boronic acids affording 6-(het)aryl-7-deazapurine 2′-C-methyl ribosides

11a–11c, 11e and 11f in a single step in good to excellent yields (Scheme 4,

Table I).

An alternative nucleosidation route was used for the synthesis of

7-fluorinated 6-hetaryl-7-deazapurine 2′-C-methylribonucleosides. We an-

ticipated that the corresponding protected 7-fluorinated 6-chloro-7-deaza-

purine 2′-C-methylribonucleoside might be accessible by Silyl–Hilbert–

Johnson reaction, similarly to the synthesis of per-O-benzoyl 7-halogenated

6-chloro-7-deazapurine ribonucleosides by TMSOTf-catalyzed glycosyl-

ation²⁰of 5-halogenated 4-chloro-7H-pyrrolo[2,3-d]pyrimidines with 1-O-

acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose. Thus the reaction of 1,2,3,5-

tetra-O-benzoyl-2-C-methyl-β-D-ribofuranose 12 (Scheme 5) with 4-chloro-

5-fluoropyrrolo[2,3-d]pyrimidine 13 ^20awas performed in the presence of

DBU and TMSOTf in acetonitrile at 70 °C to give the desired 2′-C-methyl-

ribonucleoside 14 in 21% unoptimized yield. This hydrophobic benzoyl-

protected 2′-C-methylribofuranoside 14 was directly reacted with 2-thio-

phene and 2-furane boronic acids under the conditions of aqueous Suzuki–

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

962

Nauš, Perlíková, Pohl, Hocek:

Cl

N

R

N

Pd(OAc)₂, TPPTS

HO

R-B(OH)₂

N

O

Na₂CO₃, H₂O/CH₃CN

CH₃

OH

10

CH₃

OH

11a-11c, 11e, 11f

HO

SCHEME 4

TABLE I

Suzuki–Myiaura reaction of chlorodeazapurine nucleoside 10 with boronic acids

Cross-coupling

product (yield)

Cross-coupling

product (yield)

11

R

11

R

S

a

b

c

11a (73%)

11b (81%)

11c (84%)

e

f

11e (99%)

11f (75%)

N

O

S

Myiaura reaction¹⁹. Although the reaction mixtures were unhomogeneous,

full conversions of starting chloride 14 were reached and only small degree

of acyl deprotection was observed under quite harsh and basic reaction

Cl

F

Cl

N

A

N

F

N

13

12

F

N

a

b

H

BzO

N

+

HO

O

21%

N

BzO

N

O

OBz

CH₃

OBz

CH₃

OBz

CH₃

OH

15a (A=O), 30%

15b (A=S), 31%

BzO

HO

BzO

14

SCHEME 5

(a) DBU, TMSOTf, MeCN, 70 °C; (b) 1. RB(OH)₂, Pd(OAc)₂, TPPTS, Na₂CO₃, H₂O/CH₃CN (2:1),

100 °C; 2. CH₃ONa/CH₃OH, pyridine

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

Sugar-Modified Nucleosides

963

conditions. Crude reaction mixtures were directly deprotected using

methanolic sodium methoxide in pyridine and, after purification by reverse

phase chromatography, the desired 6-hetaryl-7-fluoro-7-deazapurine 2-C-

methylribonucleosides 15a and 15b were obtained in moderate 30 and 31%

overall yields from 14.

A synthetic path to 6-hetaryl-7-deazapurine arabinonucleosides was de-

veloped starting from 3′,5′-O-disiloxane ribonucleoside 16 ²¹(Scheme 6, Ta-

ble II). First, the 2′-hydroxyl group of riboside 16 was oxidized using

Dess–Martin periodinane to ketone 17 in 88% yield. The application of

Dess–Martin oxidation led to higher yield compared to CrO₃oxidation de-

scribed in literature²¹. The follow up reduction of the 2′-oxo group by so-

dium borohydride in ethanol provided arabino-derivative 18

stereoselectively in high 87% yield. Silyl protecting group was cleaved by

TBAF affording the unprotected 6-chloro-7-deazapurine arabinoside 19 in

83% yield. 6-Hetaryl-7-deazapurine arabinonucleosides were prepared by

two different strategies. The first one was the Suzuki cross-coupling reaction

of unprotected 6-chloro-7-deazapurine arabinofuranoside 19 with

hetarylboronic acids using aqueous-phase conditions¹⁹that led to

6-hetaryl-7-deazapurine arabinosides 21d and 21e in good yields after crys-

tallization. Alternatively, 6-hetaryl-7-deazapurine arabinosides were synthe-

sized starting from silyl-protected arabino-derivative 18 using Stille

cross-coupling reaction with hetaryltributylstannanes. By this reaction, de-

rivatives 20b and 20c were prepared in high yields. In the case of reaction

of compound 18 and 2-thienyltributylstannane, concomitant isomeration

of 3′,5′-disiloxane-protected group to 2′,3′ position was observed. This rear-

rangement is known to be acid-catalyzed²². In this particular case the rear-

rangement was catalyzed by PdCl₂(PPh₃)₄as a Lewis acid. Final desilylations

of 20b and 20c using TBAF led to target 6-hetaryl-7-deazapurine

arabinonucleosides 21b and 21c in 72 and 77% yields, respectively.

To get access to the 2′-deoxy-2′-fluoroarabino series, key starting materi-

als: benzoyl-protected 6-chloro-7-deazapurine 2′-deoxy-2′-fluoroarabino-

nucleoside 23 ²³and its 7-fluoro derivative 24 ²⁴were prepared by stereo-

selective S_N2 nucleobase-anion glycosylation with α-bromo sugar 25

(Scheme 7). Compound 23 was obtained in 72% yield by the glycosylation

of 6-chloro-7-deazapurine 8 using Seela’s protocol²⁴(KOH, TDA-1 {TDA-1 =

tris[2-(2-methoxyethoxy)ethyl]amine)}, MeCN) instead of original one²³

(NaH, MeCN). The reaction should be monitored and quenched as soon as

the conversion is completed to avoid concomitant saponification of benzo-

yl groups under strongly basic reaction conditions. This observation was

also noted in a recent related communication²⁵. The bromide 25 ²⁶was

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

964

Nauš, Perlíková, Pohl, Hocek:

Cl

N

Cl

N

Cl

a

b

N

88 %

87 %

N

O

N

O

(iPr)₂Si

O

OH

O

(iPr)₂

O

(iPr)₂

O

Si

(iPr)₂

17

18

16

e

83%

N

c

R

N

R

N

Cl

N

HO

O

d

c

N

O

(iPr)₂Si

O

OH

O

(iPr)₂

Si

HO

OH

21b-21e

HO

OH

20b, 20c

19

SCHEME 6

(a) Dess–Martin periodinane, CH₂Cl₂, 0 °C; (b) NaBH₄/EtOH; (c) TBAF, THF; (d) RB(OH)₂,

Pd(OAc)₂, TPPTS, Na₂CO₃, H₂O/CH₃CN (2:1), 100 °C; (e) RSnBu₃, PdCl₂(PPh₃)₂, DMF, 105 °C

TABLE II

Cross-coupling reactions of chlorodeazapurine nucleosides 18 and 19 with boronic acids or

stannanes

Starting

compound

Cross-coupling

product (yield)

Deprotection

product (yield)

20, 21

R

b

c

18

19

20b (99%)

20c^a(88%)

21d (78%)

21e (68%)

21b (72%)

O

S

21c (77%)

O

d

e

–

S

a

Mixture of 3′,5′-O-protected 20c and 2′,3′-O-protected derivative 22c was obtained.

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

Sugar-Modified Nucleosides

965

obtained by treatment of 2-deoxy-2-fluoro-1,3,5-tri-O-benzoyl-α-D-arabino-

furanose 26 with 30% HBr in acetic acid.

Cl

R

BzO

N

O

OBz

Br

23, R = H

24, R = F

BzO

a

b

N

F

N

O

BzO

F

BzO

F

26

25

BzO

SCHEME 7

(a) HBr, AcOH; (b) 8 or 13, KOH, TDA-1, MeCN

Palladium catalyzed cross-coupling reactions of chloride 23 (Scheme 8,

Table III) with the corresponding (het)arylboronic acids, stannanes and

trimethylaluminium provided the desired 6-substituted benzoyl-protected

2-deoxy-2-fluoroarabinonucleosides 27a–27e, 27g, 27h, which after depro-

tection by NaOMe in MeOH afforded final free 6-substituted 7-deazapurine

2′-deoxy-2′-fluoroarabinonucleosides 28a–28e, 28g, 28h.

Similarly, analogous 7-fluoro-6-hetaryl-7-deazapurine 2′-deoxy-2′-fluoro-

arabinonucleosides 30b–30e (Scheme 9, Table IV) were prepared by cross-

couplings of protected 6-chloro nucleoside 24 followed by deprotection of

benzoylated intermediates 29b–29e.

In summary, five types of sugar-modified 6-(het)aryl-7-deazapurine nu-

cleosides were prepared: five examples of 6-(het)aryl-7-deazapurine

2′-C-methyl ribosides 11a–11c, 11e, 11f, two examples of 6-hetaryl-

7-fluoro-7-deazapurine 2′-C-methylribonucleosides 15a, 15b, four examples

of 6-hetaryl-7-deazapurine arabinonucleosides 21b–21e, seven examples of

6-substituted 7-deazapurine 2′-deoxy-2′-fluoroarabinonucleosides 28a–28e,

28g, 28h and four examples of 7-fluoro-6-hetaryl-7-deazapurine

2′-deoxy-2′-fluoroarabinonucleosides 30b–30e. All of them were tested for

in vitro cytostatic (HL60, HeLa S3, CCRF-CEM, A549, NCI-H23, Du145,

PC3, HCT-116, HCT-15, Hs-578 and BT-549 cell-lines)⁵and for anti-HCV ⁴

activity. None of them showed any considerable activity in any of these

assays indicating that the cytostatic activity of 6-hetaryl-7-deazapurine

nucleosides is only limited to ribonucleosides. Also the introduction of the

2′-C-methyl did not lead to selectivity toward inhibition of RNA-depending

RNA polymerase of HCV.

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

966

Nauš, Perlíková, Pohl, Hocek:

Cl

N

R

N

R

N

R-M

MeONa

BzO

HO

N

F

N

F

N

F

N

O

Pd cat.

MeOH

BzO

HO

23

27a-27e, 27g, 27h

28a-28e, 28g, 28h

SCHEME 8

TABLE III

Cross-couplings of 23 and deprotections

Cross-coupling

product (yield)

Deprotection

product (yield)

27, 28

R

M

a

b

c

B(OH)₂

SnBu₃

27a (95%)

27b (97%)

27c (91%)

27d (97%)

27e (95%)

28a (92%)

28b (90%)

28c (85%)

28d (86%)

28e (89%)

O

S

SnBu₃

O

d

e

B(OH)₂

S

g

SnBu₃

AlMe₂

27g (81%)

27h (99%)

28g (69%)

28h (85%)

N

h

Me

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

Sugar-Modified Nucleosides

967

Cl

R

N

R

N

F

N

R-M

MeONa

MeOH

BzO

HO

N

O

Pd cat.

BzO

F

BzO

F

HO

F

24

29b-29e

30b-30e

SCHEME 9

TABLE IV

Cross-coupling of 24 and deprotections

Cross-coupling

product (yield)

Deprotection

product (yield)

27, 28

R

M

b

c

SnBu₃

B(OH)₂

29b (88%)

29c (89%)

29d (91%)

29e (88%)

30b (94%)

O

30c (91%)

30d (93%)

30e (90%)

S

O

d

e

S

EXPERIMENTAL

Melting points were determined on a Kofler block and are uncorrected. Optical rotations

20

were measured at 25 °C, [α]_Dvalues are given in 10^–1deg cm²g^–1. NMR spectra were mea-

sured at 400.1 MHz for ¹H and 100.6 MHz for ¹³C nuclei, or at 499.8 MHz for ¹H and

125.7 MHz for ¹³C, or at 600.1 MHz for ¹H and 150.9 MHz for ¹³C in CDCl₃(TMS was used

as internal standard), MeOH-d₄(referenced to the residual solvent signal), DMSO-d₆(refer-

enced to the residual solvent signal), D₂O (methanol as internal standard, referenced to

CH₃OH singlet 3.34 ppm and to CH₃OH signal 49.5 ppm). ¹⁹F NMR spectra were recorded at

470.3 MHz. Chemical shifts are given in ppm (δ-scale), coupling constants (J) in Hz. Com-

plete assignment of all NMR signals was performed using a combination of H,H-COSY,

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

968

Nauš, Perlíková, Pohl, Hocek:

H,H-ROESY, H,C-HSQC and H,C-HMBC experiments. High resolution mass spectra were

measured using electrospray ionization. Reverse phase high performance flash chromatog-

raphy (HPFC) purifications were performed with Biotage SP1 apparatus on KP-C18-HS

columns. 6-Chloro-7-deazapurine (4-chloro-7H-pyrrolo[2,3-d]pyrimidine) 8 and 2-deoxy-

2-fluoro-1,3,5-tri-O-benzoyl-α-D-arabinofuranose 26 and 1,2,3,5-tetra-O-benzoyl-2-C-methyl-

β-D-ribofuranose 12 were purchased from Nucleo Chemisty Co. (Shenzhen, China).

2-C-Methyl-3,5-di-O-(4-methylbenzoyl)-D-ribono-1,4-lactone (7)

Finely powdered 2-C-methylribonolactone 6 ^12,13(20 g, 0.123 mol) was nearly fully dissolved

in dichloromethane (400 ml)/pyridine (100 ml) by vigorous stirring at r.t., the mixture was

cooled to –20 °C (bath temperature) and p-toluoyl chloride (34 ml, 0.257 mol) was dropwise

added. The mixture was stirred at –20 °C for 2 h and then was left stand overnight at 5 °C

(refrigerator). The volatiles were evaporated in vacuo and the residue was partitioned be-

tween AcOEt (500 ml) and aq. hydrochloric acid (3 M, 200 ml). Aqueous phase was re-

extracted with AcOEt (2 × 100 ml) and combined organic phases were washed with water

(200 ml) and aq. NaHCO₃(sat., 100 ml), dried over MgSO₄and evaporated. The crude prod-

uct was recrystallized from heptane–AcOEt (ca. 400 ml/80 ml) affording 7 (40.4 g, 82%) as

white fine needles. M.p. 123–125 °C (heptane–AcOEt), lit.¹⁵123 °C (diisopropylether); [α]_D

–81.5 (c 0.254, DMSO). ¹H NMR (400.1 MHz, CDCl₃): 1.65 (s, 3 H, CH₃-2); 2.39, 2.41 (2 × s,

2 × 3 H, CH₃-Tol); 2.95 (s, 1 H, OH); 4.56 (dd, 1 H, J_gem= 12.5, J_5b,4= 5.7, H-5b); 4.68 (dd,

1 H, J_gem= 12.5, J_5a,4= 3.8, H-5a); 4.93 (ddd, 1 H, J_4,3= 5.7, J_4,5= 5.7, 3.8, H-4); 5.38 (d,

1 H, J_3,4= 5.7, H-3); 7.20, 7.24 (2 × m, 2 × 2 H, H-m-Tol); 7.88, 7.94 (2 × m, 2 × 2 H,

H-o-Tol). ¹³C NMR (100.6 MHz, CDCl₃): 21.66, 21.72 (CH₃-Tol); 23.17 (CH₃-2); 62.74

(CH₂-5); 72.69 (C-2); 74.07 (CH-3); 78.24 (CH-4); 125.56, 126.295 (C-i-Tol); 129.17, 129.32

(CH-m-Tol); 129.75, 130.00 (CH-o-Tol); 144.24, 144.90 (C-p-Tol); 165.49, 165.97 (CO);

174.63 (CO-1). MS (ESI) m/z: 421 (M + Na). HRMS (ESI) for C₂₂H₂₂O₇Na [M + Na] calculated:

421.1258; found: 421.1255.

2-C-Methyl-3,5-di-O-(4-methylbenzoyl)-α,β-D-ribofuranose (5)

To a stirred solution of lactone 7 (8.81 g, 22.1 mmol) in toluene (150 ml) was dropwise

added sodium bis(2-methoxyethoxy)aluminum hydride (Red-Al) (65 wt.% in toluene, 7 ml,

22.9 mmol) at –15 °C during 10 min. The mixture was stirred while the temperature (bath)

was gradually increased to 0 °C within 3 h. The reaction was quenched by the addition of

aq. hydrochloric acid (3 M, 100 ml) at 0 °C [Caution! Exothermic]. The mixture was filtered

through celite, phases separated and aqueous phase was re-extracted with toluene (2 × 50 ml).

Combined organics were washed with brine (100 ml), dried over MgSO₄and evaporated.

Column chromatography of the residue on silica (hexanes–AcOEt, 6:1→2:1) afforded

unreacted starting material 7 (714 mg, 8%) and diol 5 (5.09 g, 57%) as a colorless oil which

solidified on standing. The α/β ratio according to ¹H NMR in CDCl₃solution is ca. 4.5:1.

Compound can be crystallized from heptane–AcOEt. M.p. 116–118 °C. α anomer: ¹H NMR

(499.8 MHz, CDCl₃): 1.47 (s, 3 H, CH₃-2); 2.38 and 2.40 (2 × s, 2 × 3 H, CH₃-Tol); 3.12 (s,

1 H, OH-2); 4.05 (bd, 1 H, J_OH,1= 5.5, OH-1); 4.48 (dd, 1 H, J_gem= 11.4, J_5b,4= 4.8, H-5b);

4.63 (m, 1 H, H-4); 4.64 (dd, 1 H, J_gem= 11.4, J_5a,4= 3.6, H-5a); 5.10 (d, 1 H, J_3,4= 5.4, H-3);

5.13 (bd, 1 H, J_1,OH= 5.5, H-1); 7.18 and 7.22 (2 × m, 2 × 2 H, H-m-Tol); 7.90 and 7.94 (2 ×

m, 2 × 2 H, H-o-Tol). ¹³C NMR (125.7 MHz, CDCl₃): 21.61 and 21.66 (CH₃-Tol); 23.43

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Sugar-Modified Nucleosides

969

(CH₃-2); 64.00 (CH₂-5); 76.34 (CH-3); 76.39 (C-2); 79.16 (CH-4); 100.67 (CH-1); 126.40 and

126.81 (C-i-Tol); 129.06 and 129.18 (CH-m-Tol); 129.70 and 129.83 (CH-o-Tol); 143.85 and

144.31 (C-p-Tol); 165.91 and 166.35 (CO). β anomer: ¹H NMR (499.8 MHz, CDCl₃): 1.42 (s,

3 H, CH₃-2); 2.35 and 2.41 (2 × s, 2 × 3 H, CH₃-Tol); 2.43 (s, 1 H, OH-2); 3.72 (bd, 1 H,

J_OH,1= 3.1, OH-1); 4.50 (m, 1 H, H-4); 4.54 (dd, 1 H, J_gem= 15.4, J_5b,4= 6.2, H-5b); 4.63 (dd,

1 H, J_gem= 15.4, J_5a,4= 3.6, H-5a); 5.22 (bd, 1 H, J_1,OH= 3.1, H-1); 5.52 (d, 1 H, J_3,4= 6.9,

H-3); 7.13 and 7.24 (2 × m, 2 × 2 H, H-m-Tol); 7.88 and 7.94 (2 × m, 2 × 2 H, H-o-Tol).

¹³C NMR (125.7 MHz, CDCl₃): 19.89 (CH₃-2); 21.59 and 21.66 (CH₃-Tol); 65.53 (CH₂-5);

76.87 (CH-3); 78.57 (CH-4); 79.71 (C-2); 102.87 (CH-1); 126.18 and 126.91 (C-i-Tol); 129.00

and 129.25 (CH-m-Tol); 129.70 and 129.83 (CH-o-Tol); 143.74 and 144.53 (C-p-Tol); 165.70

and 166.59 (CO). MS (ESI) m/z: 423 (M + Na). HRMS (ESI) for C₂₂H₂₄O₇Na [M + Na] calcu-

lated: 423.1414; found: 423.1413.

1,2-Anhydro-2-C-methyl-3,5-di-O-(4-methylbenzoyl)-α-D-ribofuranose (4)

To a stirred solution of diol 5 (2.00 g, 5 mmol) and triethylamine (1.74 ml, 12.5 mmol) in

dichloromethane (20 ml) was dropwise added mesyl chloride (465 µl, 6 mmol) within

20 min at r.t.. The mixture was stirred for 1 h and then diluted with toluene (100 ml) and

washed with phosphate buffer (pH 7; 75 ml). Aqueous phase was re-extracted with toluene

(25 ml), combined organics (cloudy) were dried over Na₂SO₄and evaporated in vacuo pro-

viding epoxide 1 as a colorless oil which was directly used in next. NMR spectra of epoxide

4 were recorded in “common” undried NMR grade CDCl₃(stabilized with silver wire); ¹H

spectrum revealed the presence of only single clean compound. ¹H NMR (499.8 MHz,

CDCl₃): 1.56 (s, 3 H, CH₃-2); 2.39, 2.43 (2 × s, 2 × 3 H, CH₃-Tol); 4.25 (ddd, 1 H, J_4,3= 6.5,

J_4,5= 5.1, 3.4, H-4); 4.46 (dd, 1 H, J_gem= 12.1, J_5b,4= 5.1, H-5b); 4.62 (dd, 1 H, J_gem= 12.1,

J_5a,4= 3.4, H-5a); 5.15 (s, 1 H, H-1); 5.54 (d, 1 H, J_3,4= 6.5, H-3); 7.18, 7.26 (2 × m, 2 × 2 H,

H-m-Tol); 7.88, 7.99 (2 × m, 2 × 2 H, H-o-Tol). ¹³C NMR (125.7 MHz, CDCl₃): 14.08 (CH₃-2);

21.64, 21.71 (CH₃-Tol); 63.12 (CH₂-5); 63.68 (C-2); 75.87 (CH-3); 78.16 (CH-4); 85.90

(CH-1); 126.15, 126.87 (C-i-Tol); 129.06, 129.19 (CH-m-Tol); 129.68, 130.01 (CH-o-Tol);

143.83, 144.46 (C-p-Tol); 166.07, 166.28 (CO). MS (ESI) m/z: 383 (M + H). HRMS (ESI) for

C

₂₂H₂₃O₆[M + H] calculated: 383.1489; found: 383.1486.

4-Chloro-7-[2-C-methyl-3,5-di-O-(4-methylbenzoyl)-β-D-ribofuranosyl]-

7H-pyrrolo[2,3-d]pyrimidine (9)

6-Chloro-7-deazapurine 8 (691 mg, 4.5 mmol) was added to a stirred mixture of NaH (50%

suspension in oil, 98 mg, 2.25 mmol) in dry DMF (10 ml) under argon at 0 °C. The mixture

was stirred for 15 min, followed by the addition of a solution of epoxide 4 (prepared from

5 mmol of diol 5) in toluene (20 ml). The mixture was stirred for 18 h at r.t. and then di-

luted with AcOEt (100 ml) and washed with aq. KH₂PO₄(0.3 M, 75 ml). Organic phase was

washed with 5% brine (3 × 50 ml), dried over MgSO₄, concentrated in vacuo and final chro-

matography on the column of silica (hexanes–AcOEt, 6:1) afforded protected nucleoside 9 as

a colorless foam (1.41 g, 58%). ¹H NMR (400.1 MHz, CDCl₃): 1.08 (s, 3 H, CH₃-2′); 2.42 and

2.44 (2 × s, 2 × 3 H, CH₃-Tol); 3.21 (s, 1 H, OH-2′); 4.66 (dd, 1 H, J_gem= 12.1, J_5′b,4′= 4.8,

H-5′b); 4.73 (ddd, 1 H, J_4′,3′= 7.3, J_4′,5′= 4.8, 3.3, H-4′); 4.85 (dd, 1 H, J_gem= 12.1, J_5′a,4′

=

3.3, H-5′a); 5.65 (d, J_3′,4′= 7.3, H-3′); 6.44 (s, 1 H, H-1′); 6.61 (d, 1 H, J_5,6= 3.8, H-5); 7.23,

7.27 (2 × m, 2 × 2 H, H-m-Tol); 7.53 (d, 1 H, J_6,5= 3.8, H-6); 7.92–8.00 (m, 4 H, H-o-Tol);

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970

Nauš, Perlíková, Pohl, Hocek:

8.65 (s, 1 H, H-2). ¹³C NMR (100.6 MHz, CDCl₃): 21.08 (CH₃-2); 21.67 and 21.71 (CH₃-Tol);

63.06 (CH₂-5′); 75.51 (CH-3′); 78.46 (CH-4′); 79.34 (C-2′); 91.62 (CH-1′); 100.62 (CH₂-5);

118.24 (C-4a); 125.92 (C-i-Tol); 126.65 (CH-6); 126.79 (C-i-Tol); 129.22, 129.30 (CH-m-Tol);

129.69, 129.93 (CH-o-Tol); 144.10, 144.75 (C-p-Tol); 150.67 (C-4); 150.85 (CH-2); 152.58

(C-7a); 165.58, 166.25 (CO). MS (ESI) m/z: 536 (M + H), 558 (M + Na). HRMS (ESI) for

C

₂₈H₂₇N₃O₆Cl [M + H] calculated: 536.1583; found: 536.1573.

4-Chloro-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (10)

Protected nucleoside 9 (281 mg, 0.52 mmol) was treated with methanolic ammonia (27 wt.%,

6 ml) at r.t. for 24 h. Volatiles were removed under reduced pressure and the residue was

co-evaporated with silica and chromatographed on the column of silica (3% MeOH in

CHCl₃) affording free chloro nucleoside 10 (133 mg, 85%) as a colorless oil which solidified

on standing. Compound was recrystallized from water as colorless prisms. M.p. 158–160 °C.

[α]_D–8.6 (c 0.360, DMSO). ¹H NMR (400.1 MHz, D₂O): 0.65 (s, 3 H, CH₃-2′); 3.90 (dd, J_gem

=

13.1, J_5′b,4= 3.8, H-5′b); 4.02–4.13 (m, 3 H, H-5′a, H-4′, H-3′); 6.20 (s, 1 H, H-1′); 6.46 (d,

1 H, J_5,6= 3.8, H-5); 7.61 (d, 1 H, J_6,5= 3.8, H-6); 8.32 (s, 1 H, H-2). ¹³C NMR (100.6 MHz,

D₂O): 19.12 (CH₃-2′); 60.63 (CH₂-5′); 73.06 (CH-3′); 80.00 (C-2′); 82.45 (CH-4′); 91.65

(CH-1′); 101.36 (CH-5); 118.20 (C-4a); 128.20 (CH-6); 150.22 (C-4); 150.37 (CH-2); 152.11

(C-7a). MS (ESI) m/z: 300 (M + H), 322 (M + Na). HRMS (ESI) for C₁₂H₁₄N₃O₄ClNa [M + Na]

calculated: 322.0565; found: 322.0567. For C₁₂H₁₄N₃O₄Cl calculated: 48.09% C, 4.71% H,

14.02% N; found: 48.05% C, 4.63% H, 13.78% N.

7-(2-C-Methyl-β-D-ribofuranosyl)-4-(phenyl)-7H-pyrrolo[2,3-d]pyrimidine (11a)

An argon purged mixture of compound 10 (157 mg, 0.52 mmol), phenylboronic acid (95 mg,

0.78 mmol), Na₂CO₃(167 mg, 1.57 mmol), Pd(OAc)₂(5.9 mg, 0.026 mmol) and TPPTS

(37 mg, 0.065 mmol) in water–MeCN (2:1, 3 ml) was stirred at 100 °C for 3 h. After cooling

the mixture was neutralized by the addition of aq. HCl (3 M), volatiles were removed in

vacuo and purification of the residue by reverse phase HPFC on C-18 (0→100% MeOH in

water) afforded product 11a (129 mg, 73%) as an amorphous tan solid. M.p. 177–179 °C.

[α]_D–26.3 (c 0.353, DMSO). ¹H NMR (499.8 MHz, DMSO-d₆): 0.71 (s, 3 H, CH₃); 3.70 (ddd,

1 H, J_gem= 12.3, J_5′b,OH= 5.0, J_5′b,4′= 3.2, H-5′b); 3.87 (ddd, 1 H, J_gem= 12.3, J_5′a,OH= 5.0,

J_5′a,4′= 2.1, H-5′b); 3.92 (ddd, 1 H, J_4′,3′= 9.2, J_4′,5′= 3.2, 2.1, H-4′); 4.02 (dd, 1 H, J_3′,4′= 9.2,

J_3′,OH= 7.0, H-3′); 5.207 (t, 1 H, J_OH,3′= 5.0, OH-5′); 5.210 (d, 1 H, J_OH,3′= 7.0, OH-3′); 5.23

(s, 1 H, OH-2′); 6.37 (s, 1 H, H-1′); 6.99 (d, 1 H, J_5,6= 3.8, H-5); 7.56 (m, 1 H, H-p-Ph); 7.59

(m, 2 H, H-m-Ph); 8.09 (d, 1 H, J_6,5= 3.8, H-6); 8.17 (m, 2 H, H-o-Ph); 8.89 (s, 1 H, H-2).

¹³C NMR (125.7 MHz, DMSO-d₆): 19.90 (CH₃); 59.75 (CH₂-5′); 72.15 (CH-3′); 79.00 (C-2′);

82.60 (CH-4′); 90.73 (CH-1′); 100.96 (CH-5); 115.24 (C-4a); 127.89 (CH-6); 128.91 (CH-o-Ph);

129.19 (CH-m-Ph); 130.56 (CH-p-Ph); 137.74 (C-i-Ph); 151.25 (CH-2); 151.59 (C-7a); 156.34

(C-4). MS (ESI) m/z: 364 (M + Na). HRMS (ESI) for C₁₈H₂₀N₃O₄[M + H] calculated: 342.1448;

found: 342.1448. HRMS (ESI) for C₁₈H₁₉N₃O₄Na [M + Na] calculated: 364.1268; found:

364.1267. For C₁₈H₁₉N₃O₄·0.7CH₄O calculated: 61.74% C, 6.04% H, 11.55% N; found:

62.01% C, 5.79% H, 11.06% N.

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Sugar-Modified Nucleosides

971

4-(Furan-2-yl)-7-(2-C-methyl-β-D-ribofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (11b)

Compound 11b was prepared as described for 11a by the reaction of compound 10 (257 mg,

0.86 mg) and furane-2-boronic acid. Yield 230 mg (81%). Compound crystallized from

MeOH as yellowish needles. M.p. 183–184 °C. [α]_D–26.9 (c 0.309, DMSO). ¹H NMR

(499.8 MHz, DMSO-d₆): 0.68 (s, 3 H, CH₃); 3.70 (ddd, 1 H, J_gem= 12.3, J_5′b,OH= 5.0, J_5′b,4′

=

3.2, H-5′b); 3.86 (ddd, 1 H, J_gem= 12.3, J_5′a,OH= 5.0, J_5′a,4′= 2.1, H-5′b); 3.91 (ddd, 1 H,

J_4′,3′= 9.1, J_4′,5′= 3.2, 2.1, H-4′); 4.01 (dd, 1 H, J_3′,4′= 9.1, J_3′,OH= 7.0, H-3′); 5.17 (d, 1 H,

J_OH,3′= 7.0, OH-3′); 5.18 (t, 1 H, J_OH,3′= 5.0, OH-5′); 5.19 (s, 1 H, OH-2′); 6.33 (s, 1 H, H-1′);

6.79 (dd, 1 H, J_4,3= 3.5, J_4,5= 1.8, H-4-furyl); 7.04 (d, 1 H, J_5,6= 3.8, H-5); 7.47 (dd, 1 H,

J_3,4= 3.5, J_3,5= 0.8, H-3-furyl); 8.057 (dd, 1 H, J_5,4= 1.8, J_5,3= 0.8, H-5-furyl); 8.062 (d, 1 H,

J_6,5= 3.8, H-6); 8.78 (s, 1 H, H-2). ¹³C NMR (125.7 MHz, DMSO-d₆): 19.74 (CH₃); 59.66

(CH₂-5′); 72.05 (CH-3′); 78.88 (C-2′); 82.52 (CH-4′); 90.56 (CH-1′); 101.09 (CH-5); 112.37

(C-4a); 112.84 (CH-4-furyl); 113.41 (CH-3-furyl); 127.74 (CH-6); 146.49 (CH-5-furyl); 146.58

(C-4); 151.15 (CH-2); 151.59 (C-7a); 152.65 (C-2-furyl). MS (ESI) m/z: 354 (M + Na). HRMS

(ESI) for C₁₆H₁₈N₃O₅[M + H] calculated: 332.1241; found: 332.1241. HRMS (ESI) for

C

₁₆H₁₇N₃O₅Na [M + Na] calculated: 354.1060; found: 354.1060. For C₁₆H₁₇N₃O₅calculated:

58.00% C, 5.17% H, 12.68% N; found: 57.97% C, 4.95% H, 12.46% N.

7-(2-C-Methyl-β-D-ribofuranosyl)-4-(thiophen-2-yl)-7H-pyrrolo[2,3-d]pyrimidine (11c)

Compound 11c was prepared as described for 11a by the reaction of compound 10 (133 mg,

0.44 mmol) and thiophene-2-boronic acid as a white powder. Yield 129 mg (84%). Com-

pound was recrystallized from MeOH. M.p. 180–181 °C. [α]_D–15.2 (c 0.309, DMSO).

¹H NMR (499.8 MHz, DMSO-d₆): 0.69 (s, 3 H, CH₃); 3.70 (ddd, 1 H, J_gem= 12.4, J_5′b,OH= 5.0,

J_5′b,4′= 3.1, H-5′b); 3.87 (ddd, 1 H, J_gem= 12.4, J_5′a,OH= 5.0, J_5′a,4′= 2.1, H-5′b); 3.92 (ddd,

1 H, J_4′,3′= 9.1, J_4′,5′= 3.1, 2.1, H-4′); 4.02 (dd, 1 H, J_3′,4′= 9.1, J_3′,OH= 7.0, H-3′); 5.22 (d,

1 H, J_OH,3′= 7.0, OH-3′); 5.226 (s, 1 H, OH-2′); 5.231 (t, 1 H, J_OH,3′= 5.0, OH-5′); 6.33 (s,

1 H, H-1′); 7.15 (dd, 1 H, J_5,6= 3.8, J = 0.3, H-5); 7.30 (dd, 1 H, J_4,5= 5.0, J_4,3= 3.8,

H-4-thienyl); 7.84 (dd, 1 H, J_5,4= 5.0, J_5,3= 1.1, H-5-thienyl); 8.09 (d, 1 H, J_6,5= 3.8, H-6);

8.16 (dd, 1 H, J_3,4= 3.8, J_3,5= 1.1, H-3-thienyl); 8.75 (s, 1 H, H-2). ¹³C NMR (125.7 MHz,

DMSO-d₆): 19.87 (CH₃); 59.74 (CH₂-5′); 72.13 (CH-3′); 79.04 (C-2′); 82.64 (CH-4′); 90.74

(CH-1′); 100.86 (CH-5); 112.80 (C-4a); 128.05 (CH-6); 129.40 (CH-4-thienyl); 129.87

(CH-3-thienyl); 131.03 (CH-5-thienyl); 142.68 (C-2-thienyl); 150.37 (C-4); 151.03 (CH-2);

151.64 (C-7a). MS (ESI) m/z: 348 (M + H), 370 (M + Na). HRMS (ESI) for C₁₆H₁₈N₃O₄S

[M + H] calculated: 348.1012; found: 348.1013. HRMS (ESI) for C₁₆H₁₇N₃O₄SNa [M + Na]

calculated: 370.0832; found: 370.0831. For C₁₆H₁₇N₃O₄S calculated: 55.32% C, 4.93% H,

12.10% N; found: 55.14% C, 4.72% H, 11.84% N.

7-(2-C-Methyl-β-D-ribofuranosyl)-4-(thiophen-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (11e)

Compound 11e was prepared as described for 11a by the reaction of compound 10 (150 mg,

0.5 mmol) and thiophene-3-boronic acid as an off-white foamy solid. Yield 172 mg (99%).

M.p. 154–156 °C. [α]_D–24.0 (c 0.329, DMSO). ¹H NMR (499.8 MHz, DMSO-d₆): 0.69 (s, 3 H,

CH₃); 3.71 (ddd, 1 H, J_gem= 12.4, J_5′b,OH= 5.0, J_5′b,4′= 3.1, H-5′b); 3.87 (ddd, 1 H, J_gem

=

12.4, J_5′a,OH= 5.0, J_5′a,4′= 2.1, H-5′b); 3.92 (ddd, 1 H, J_4′,3′= 9.1, J_4′,5′= 3.1, 2.1, H-4′); 4.02

(dd, 1 H, J_3′,4′= 9.1, J_3′,OH= 7.0, H-3′); 5.195 (d, 1 H, J_OH,3′= 7.0, OH-3′); 5.21 (s, 1 H,

OH-2′); 5.22 (t, 1 H, J_OH,3′= 5.0, OH-5′); 6.35 (s, 1 H, H-1′); 7.12 (d, 1 H, J_5,6= 3.8, H-5);

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972

Nauš, Perlíková, Pohl, Hocek:

7.74 (dd, 1 H, J_5,4= 5.1, J_5,2= 2.9, H-5-thienyl); 7.95 (dd, 1 H, J_4,5= 5.1, J_4,2= 1.3,

H-4-thienyl); 8.08 (d, 1 H, J_6,5= 3.8, H-6); 8.53 (dd, 1 H, J_2,5= 2.9, J_2,4= 1.3, H-2-thienyl);

8.82 (s, 1 H, H-2). ¹³C NMR (125.7 MHz, DMSO-d₆): 19.84 (CH₃); 59.72 (CH₂-5′); 72.12

(CH-3′); 78.98 (C-2′); 82.58 (CH-4′); 90.66 (CH-1′); 100.96 (CH-5); 114.30 (C-4a); 128.05

(CH-6); 127.38 (CH-5-thienyl); 127.65 (CH-4-thienyl); 127.68 (CH-6); 128.78 (CH-2-thienyl);

140.13 (C-3-thienyl); 151.15 (CH-2); 151.62, 151.66 (C-4,7a). MS (ESI) m/z: 348 (M + H), 370

(M + Na). HRMS (ESI) for C₁₆H₁₈N₃O₄S [M + H] calculated: 348.10125; found: 348.10125.

HRMS (ESI) for C₁₆H₁₇N₃O₄SNa [M + Na] calculated: 370.0832; found: 370.0832. For

C₁₆H₁₇N₃O₄S calculated: 55.32% C, 4.93% H, 12.10% N; found: 55.27% C, 4.78% H, 11.80% N.

7-(2-C-Methyl-β-D-ribofuranosyl)-4-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (11f)

Compound 11f was prepared as described for 11a by the reaction of compound 10 (157 mg,

0.52 mmol) and pyridine-3-boronic acid. Yield 134 mg (75%). Compound crystallized from

MeOH tan solid. M.p. 191–193 °C. [α]_D–20.3 (c 0.310, DMSO). ¹H NMR (499.8 MHz,

DMSO-d₆): 0.71 (s, 3 H, CH₃); 3.71 (ddd, 1 H, J_gem= 12.4, J_5′b,OH= 5.0, J_5′b,4′= 3.2, H-5′b);

3.87 (ddd, 1 H, J_gem= 12.4, J_5′a,OH= 5.0, J_5′a,4′= 2.1, H-5′b); 3.93 (ddd, 1 H, J_4′,3′= 9.1, J_4′,5′

3.2, 2.1, H-4′); 4.03 (dd, 1 H, J_3′,4′= 9.1, J_3′,OH= 7.0, H-3′); 5.23 (t, 1 H, J_OH,3′= 5.0, OH-5′);

5.24 (d, 1 H, J_OH,3′= 7.0, OH-3′); 5.25 (s, 1 H, OH-2′); 6.37 (s, 1 H, H-1′); 7.05 (d, 1 H, J_5,6

=

3.8, H-5); 7.62 (dd, 1 H, J_5,4= 8.0, J_5,6= 4.8, H-5-py); 8.13 (d, 1 H, J_6,5= 3.8, H-6); 8.52 (ddd,

1 H, J_4,5= 8.0, J_4,2= 2.3, J_4,6= 1.7, H-4-py); 8.74 (bd, 1 H, J_6,5= 4.8, H-6-py); 8.93 (s, 1 H,

H-2); 9.32 (bs, 1 H, H-2-py). ¹³C NMR (125.7 MHz, DMSO-d₆): 19.94 (CH₃); 59.78 (CH₂-5′);

72.18 (CH-3′); 79.05 (C-2′); 82.68 (CH-4′); 90.81 (CH-1′); 100.76 (CH-5); 115.58 (C-4a);

124.42 (CH-5-py); 128.49 (CH-6); 133.44 (C-3-py); 136.43 (CH-4-py); 149.52 (CH-2-py);

151.23 (CH-6-py); 151.36 (CH-2); 151.56 (C-7a); 153.91 (C-4). MS (ESI) m/z: 365 (M + Na).

HRMS (ESI) for C₁₇H₁₉N₄O₄[M + H] calculated: 343.1401; found: 343.1401. HRMS (ESI) for

C

₁₇H₁₈N₄O₄Na [M + Na] calculated: 365.12203; found: 365.12200. For C₁₇H₁₈N₄O₄·0.2H₂O

calculated: 59.02% C, 5.36% H, 16.19% N; found: 58.92% C, 5.11% H, 15.96% N.

4-Chloro-5-fluoro-7-(2,3,5-tri-O-benzoyl-2-C-methyl-β-D-ribofuranosyl)-

7H-pyrrolo[2,3-d]pyrimidine (14)

To a mixture of 6-chloro-7-fluoro-7-deazapurine 13 ^20a(577 mg, 3.36 mmol) and per-

O-benzoyl-2-C-methylribofuranose 12 (1.68 g, 2.90 mmol) and DBU (1.3 ml, 8.71 mmol) in

dry CH₃CN (20 ml) was dropwise added TMSOTf (2.1 ml, 11.63 mmol). The mixture was

stirred at 70 °C for 24 h, cooled to r.t. diluted with CHCl₃(50 ml) and washed with aq.

NaHCO₃(sat., 50 ml). Aqueous phase was re-extracted with CHCl₃(2 × 10 ml), combined

organics were dried over MgSO₄and evaporated. The residue was purified twice by column

chromatography on silica (hexanes–AcOEt, 10:1) affording product 14 as a colorless foam

(380 mg, 21%). ¹H NMR (499.8 MHz, CDCl₃): 1.60 (s, 3 H, CH₃); 4.70 (td, 1 H, J_4′,3′= 5.7,

J_4′,5′= 5.7, 3.5, H-4′); 4.87 (dd, 1 H, J_gem= 12.3, J_5′b,4′= 5.7, H-5′b); 4.93 (dd, 1 H, J_gem

=

12.3, J_5′a,4′= 3.5, H-5′a); 5.975 (d, 1 H, J_3′,4′= 5.7, H-3′); 6.97 (d, 1 H, J_H,F= 0.9, H-1′); 7.33

(m, 2 H, H-m-Bz); 7.36 (d, 1 H, J_H,F= 2.4, H-6); 7.46 (m, 4 H, H-m-Bz); 7.54, 7.59, 7.61 (3 ×

m, 3 × 1 H, H-p-Bz); 7.95, 8.10, 8.11 (3 × m, 3 × 2 H, H-o-Bz); 8.76 (s, 1 H, H-2). ¹³C NMR

(125.7 MHz, CDCl₃): 17.80 (CH₃); 63.28 (CH₂-5′); 75.48 (CH-3′); 80.09 (CH-4′); 84.83 (C-2′);

88.39 (CH-1′); 107.96 (d, J_C,F= 13.8, C-4a); 110.58 (d, J_C,F= 27.1, CH-6); 128.49, 128.54,

128.57 (CH-m-Bz); 128.65, 129.49, 129.61 (C-i-Bz); 129.74, 129.83, 129.93 (CH-o-Bz); 133.41,

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Sugar-Modified Nucleosides

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133.65, 133.72 (CH-p-Bz); 141.39 (d, J_C,F= 254.2, C-5); 146.82 (C-7a); 151.02 (d, J_C,F= 3.9,

C-4); 151.83 (CH-2); 165.05, 165.34, 166.31 (CO). MS (ESI) m/z: 630 (M + H), 652 (M + Na).

HRMS (ESI) for C₃₃H₂₅ClFN₃O₇Na [M + Na] calculated: 652.1263; found: 652.1260.

5-Fluoro-4-(furan-2-yl)-7-(2-C-methyl-β-D-ribofuranosyl)-

7H-pyrrolo[2,3-d]pyrimidine (15a)

To an argon purged mixture of compound 14 (185 mg, 0.29 mmol), furane-2-boronic acid

(41 mg, 0.37 mmol), Na₂CO₃(94 mg, 0.89 mmol) was added a pre-prepared solution of

Pd(OAc)₂(3 mg, 0.013 mmol) and TPPTS (21 mg, 0.037 mmol) in water/CH₃CN (2:1, 2.5

ml). The reaction mixture was stirred at 100 °C for 3 h. The volatiles were removed under

reduced pressure and the residue was twice co-evaporated with absolute ethanol, dissolved

in pyridine (2 ml), followed by addition of MeONa (1 M in MeOH, 0.9 ml, 0.9 mmol). After

15 min the the mixture was desalted with Dowex 50 (pyridinium form) and after removal of

volatiles final reverse phase chromatography on C-18 (0→100% MeOH in water) afforded

product 15a as a colorless solid (31 mg, 30%). M.p. 222–224 °C. [α]_D–16.7 (c 0.132, DMSO).

¹H NMR (600.1 MHz, CD₃OD): 0.86 (s, 3 H, CH₃); 3.86 (m, 1 H, H-5′b); 4.01–4.05 (m, 2 H,

H-4′,5′a); 4.13 (d, 1 H, J_3′,4′= 8.9, H-3′); 6.51 (d, 1 H, J_H,F= 1.7, H-1′); 6.73 (dd, 1 H, J_4,3

3.6, J_4,5= 1.7, H-4-furyl); 7.54 (dd, 1 H, J_3,4= 3.6, J_3,5= 0.8, H-3-furyl); 7.87 (dd, 1 H, J_5,4

=

1.7, J_5,3= 0.8, H-5-furyl); 7.96 (d, 1 H, J_H,F= 2.0, H-6); 8.73 (s, 1 H, H-2). ¹³C NMR

(150.9 MHz, CD₃OD): 19.84 (CH₃); 60.92 (CH₂-5′); 73.41 (CH-3′); 80.51 (C-2′); 83.94

(CH-4′); 91.97 (CH-1′); 103.55 (d, J_C,F= 15.7, C-4a); 111.52 (d, J_C,F= 31.4, CH-6); 113.82

(CH-4-furyl); 116.50 (d, J_C,F= 9.6, CH-3-furyl); 143.31 (d, J_C,F= 249.9, C-5); 147.54

(CH-5-furyl); 147.73 (d, J_C,F= 3.8, C-4); 148.34 (d, J_C,F= 3.2, C-7a); 151.87 (C-2-furyl);

152.37 (CH-2). ¹⁹F NMR (470.3 MHz, DMSO-d₆): –162.07. MS (ESI) m/z: 350 (M + H), 372

(M + Na). HRMS (ESI) for C₁₆H₁₆FN₃O₅Na [M + Na] calculated: 372.0971; found: 372.0965.

5-Fluoro-7-(2-C-methyl-β-D-ribofuranosyl)-4-(thiophen-2-yl)-

7H-pyrrolo[2,3-d]pyrimidine (15b)

Compound 15b was prepared as described for 15a from compound 14 (182 mg, 0.29 mmol)

and thiophene-2-boronic acid. Yield 33 mg (31%). Colorless solid. M.p. 146–148 °C.

¹H NMR (600.1 MHz, CD₃OD): 0.87 (s, 3 H, CH₃); 3.86 (m, 1 H, H-5′b); 4.01–4.05 (m, 2 H,

H-4′,5′a); 4.13 (d, 1 H, J_3′,4′= 9.0, H-3′); 6.51 (d, 1 H, J_H,F= 1.9, H-1′); 7.25 (dd, 1 H, J_4,5

=

5.0, J_4,3= 3.8, H-4-thienyl); 7.73 (dd, 1 H, J_5,4= 5.0, J_5,3= 1.0, H-5-thienyl); 7.96 (d, 1 H,

J_H,F= 1.9, H-6); 8.13 (dd, 1 H, J_3,4= 3.8, J_3,5= 1.0, H-3-thienyl); 8.69 (s, 1 H, H-2). ¹³C NMR

(150.9 MHz, CD₃OD): 19.86 (CH₃); 60.94 (CH₂-5′); 73.42 (CH-3′); 80.51 (C-2′); 83.92

(CH-4′); 92.02 (CH-1′); 103.95 (d, J_C,F= 15.4, C-4a); 111.16 (d, J_C,F= 32.1, 3.4, CH-6); 129.74

(d, J_C,F= 2.3, CH-4-thienyl); 131.65 (d, J_C,F= 16.5, CH-3-thienyl); 132.12 (CH-5-thienyl);

143.00 (d, J_C,F= 1.1, C-2-thienyl); 143.36 (d, J_C,F= 247.5, C-5); 148.39 (d, J_C,F= 3.1, C-7a);

152.45 (d, J_C,F= 3.9, C-4); 152.46 (CH-2). ¹⁹F NMR (470.3 MHz, DMSO-d₆): –161.16. MS (ESI)

m/z: 366 (M + H), 388 (M + Na). HRMS (ESI) for C₁₆H₁₆FN₃O₄SNa [M + Na] calculated:

388.0743; found 388.0736.

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974

Nauš, Perlíková, Pohl, Hocek:

4-Chloro-7-[3,5-O-(tetraisopropyldisiloxan-1,3-diyl)-β-D-erythro-pentofuran-2-ulosyl]-

7H-pyrrolo[2,3-d]pyrimidine (17)

Dess–Martin periodinane (3.61 g, 8.51 mmol) was dissolved in anhydrous dichloromethane

(20 ml) and the solution was cooled to 0 °C. Then the solution of compound 16 (1.50 g,

2.83 mmol) in anhydrous dichloromethane (10 ml) was added. The reaction mixture was

stirred at 0 °C for 5 min and then was allowed to warm to r.t. and stirred overnight. Then

the reaction mixture was diluted with chloroform (50 ml) and the solution of Na₂S₂O₃·5H₂O

(19.20 g) in aq. NaHCO₃(sat., 150 ml) was added. The organic phase was extracted with

water, dried over MgSO₄and evaporated under reduced pressure. The crude product was

purified by column chromatography on silica (hexane–EtOAc, 10:1) to give the ketone 17

(1.31 g, 88%) as a white solid. ¹H NMR (500.0 MHz, CDCl₃): 1.05–1.22 (m, 28 H,

(CH₃)₂CHSi); 4.03 (dt, 1 H, J_4′,3′= 9.8, J_4′,5′= 2.9, H-4′); 4.14, 4.20 (2 × dd, 2 × 1 H, J_gem

=

13.1, J_5′,4′= 2.9, H-5′); 5.52 (d, 1 H, J_3′,4′= 9.8, H-3′); 5.74 (d, 1 H, J_1′,3′= 0.6, H-1′); 6.65 (d,

1 H, J_5,6= 3.7, H-5); 7.26 (d, 1 H, J_6,5= 3.7, H-6); 8.49 (s, 1 H, H-2). ¹³C NMR (125.7 MHz,

CDCl₃): 12.44, 12.54, 12.94, 13.47 ((CH₃)₂CHSi); 16.75, 16.78, 16.82, 16.90, 17.20, 17.27,

17.29, 17.32 ((CH₃)₂CHSi); 60.94 (CH₂-5′); 72.50 (CH-3′); 78.60 (CH-4′); 82.43 (CH-1′);

101.23 (CH-5); 118.54 (C-4a); 129.17 (CH-6); 150.81 (C-7a); 150.90 (CH-2); 152.69 (C-4);

206.07 (C-2′). MS (ESI) m/z: 548 [M + Na], 550 [M + 2 + Na], 558 [M + H + MeOH], 560 [M +

H

+ MeOH], 580 [M + Na + MeOH], 582 [M + 2 Na + MeOH]. HRMS (ESI) for

C

₂₃H₃₆O₅N₃ClNaSi₂[M + Na] calculated: 548.1774; found: 548.1772.

4-Chloro-7-[3,5-O-(tetraisopropyldisiloxan-1,3-diyl)-β-D-arabinofuranosyl]-

7H-pyrrolo[2,3-d]pyrimidine (18)

A solution of sodium borohydride (173 mg, 4.58 mmol) in ethanol (99%, 30 ml) was slowly

added to a solution of ketone 17 (1.20 g, 2.28 mmol) in ethanol (99%, 50 ml) at 0 °C. The

reaction mixture was stirred at r.t. for 1 h. The reaction was quenched with aq. NH₄Cl (sat.,

15 ml). The reaction mixture was extracted with EtOAc (100 ml). The organic phase was

washed with water, dried over MgSO₄and evaporated under reduced pressure. The crude

product was purified by column chromatography on silica (hexane–EtOAc, 10:1) to give the

arabino-derivative 18 (1.05 g, 87%) as a white solid. ¹H NMR (500.0 MHz, CDCl₃): 0.97–1.17

(m, 28 H, (CH₃)₂CHSi); 2.96 (bs, 1 H, OH-2′); 3.85 (dt, 1 H, J_4′,3′= 8.4, J_4′,5′= 3.0, H-4′); 4.05,

4.11 (2 × dd, 2 × 1 H, J_gem= 13.0, J_5′,4′= 3.0, H-5′); 4.54 (dd, 1 H, J_3′,4′= 8.4, J_3′,2′= 7.8,

H-3′); 4.66 (dd, 1 H, J_2′,3′= 7.8, J_2′,1′= 6.3, H-2′); 6.43 (d, 1 H, J_1′,2′= 6.3, H-1′); 6.63 (d, 1 H,

J_5,6= 3.7, H-5); 7.70 (d, 1 H, J_6,5= 3.7, H-6); 8.57 (s, 1 H, H-2). ¹³C NMR (125.7 MHz,

CDCl₃): 12.42, 13.00, 13.01, 13.49 ((CH₃)₂CHSi); 16.86, 16.90, 16.94, 17.04, 17.31, 17.33,

17.37, 17.49 ((CH₃)₂CHSi); 60.01 (CH₂-5′); 73.68 (CH-3′); 76.98 (CH-2′); 80.85 (CH-4′); 83.80

(CH-1′); 100.03 (CH-5); 118.47 (C-4a); 128.34 (CH-6); 150.40 (CH-2); 150.85 (C-7a); 152.37

(C-4). MS (ESI) m/z: 528 [M + H], 530 [M + 2 + H], 550 [M + Na], 552 [M + 2 + Na]. HRMS

(ESI) for C₂₃H₃₉O₅N₃ClSi₂[M + H] calculated: 528.2111; found: 528.2112.

4-Chloro-7-(β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (19)

Compound 18 (363 mg, 0.69 mmol) was dissolved in anhydrous THF (10 ml) and cooled to

0 °C. Then, the solution of tetrabutylammonium fluoride (433 mg, 1.37 mmol) in an-

hydrous THF (1.4 ml) was slowly added. The reaction mixture was stirred at r.t. for 2 h. The

reaction mixture was evaporated under reduced pressure and purified by column chromatog-

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Sugar-Modified Nucleosides

975

raphy on silica (4% MeOH in CHCl₃) to give the free nucleoside 19 (163 mg, 83%) as a

white solid. M.p. 163–165 °C. ¹H NMR (500.0 MHz, DMSO-d₆): 3.64 (dt, 1 H, J_gem= 11.8,

J_5′b,OH= J_5′b,4′= 5.3, H-5′b); 3.71 (ddd, 1 H, J_gem= 11.8, J_5′a,OH= 5.3, J_5′a,4′= 3.9, H-5′a); 3.79

(ddd, 1 H, J_4′,5′= 5.3, 3.9, J_4′,3′= 4.7, H-4′); 4.11 (dt, 1 H, J_3′,2′= 5.0, J_3′,OH= J_3′,4′= 4.7, H-3′);

4.19 (ddd, 1 H, J_2′,OH= 5.5, J_2′,1′= 5.2, J_2′,3′= 5.0, H-2′); 5.08 (t, 1 H, J_OH,5′= 5.3, OH-5′); 5.50

(d, 1 H, J_OH,2′= 5.5, OH-2′); 5.52 (d, 1 H, J_OH,3′= 4.7, OH-3′); 6.55 (d, 1 H, J_1′,2′= 5.2, H-1′);

6.67 (dd, 1 H, J_5,6= 3.7, ⁵J = 0.4, H-5); 7.88 (d, 1 H, J_6,5= 3.7, H-6); 8.64 (s, 1 H, H-2).

¹³C NMR (125.7 MHz, DMSO-d₆): 60.85 (CH₂-5′); 74.83 (CH-3′); 76.15 (CH-2′); 83.97, 83.98

(CH-1′,4′); 98.61 (CH-5); 117.14 (C-4a); 130.66 (CH-6); 150.40 (CH-2); 150.53 (C-4); 150.97

(C-7a). MS (ESI) m/z: 284 [M–H], 286 [M + 2 – H]. HRMS (ESI) for C₁₁H₁₁O₄N₃Cl [M – H] cal-

culated: 284.0444; found: 284.0444.

4-(Furan-2-yl)-7-[3,5-O-(tetraisopropyldisiloxan-1,3-diyl)-β-D-arabinofuranosyl]-

7H-pyrrolo[2,3-d]pyrimidine (20b)

An argon purged mixture of compound 18 (220 mg, 0.42 mmol), 2-(tributylstannyl)furane

(230 mg, 0.64 mmol) and PdCl₂(PPh₃)₂(15 mg, 0.021 mmol) in DMF (2 ml) was stirred at

100 °C for 2 h. After cooling volatiles were removed in vacuo and the residue was several

times co-evaporated with toluene. Column chromatography on silica (hexanes–AcOEt,

10:1→3:1) afforded product 20b (230 mg, 99%) as a colorless oil. ¹H NMR (400.0 MHz,

CDCl₃): 0.97–1.15 (m, 28 H, (CH₃)₂CHSi); 3.62 (bs, 1 H, OH-2′); 3.84 (dt, 1 H, J_4′,3′= 8.0,

J_4′,5′= 3.2, H-4′); 4.04–4.05 (m, 2 H, H-5′); 4.60–4.70 (m, 2 H, H-2′, H-3′); 6.40 (d, 1 H, J_1′,2′

=

6.4, H-1′); 6.63 (dd, 1 H, J = 3.6, J = 2.0, H-4-furyl); 7.03 (d, 1 H, J_5,6= 3.6, H-5); 7.44 (m,

1 H, H-3-furyl); 7.64 (d, 1 H, J_6,5= 3.6, H-6); 7.71 (m, 1 H, H-5-furyl); 8.74 (s, 1 H, H-2). MS

(ESI) m/z: 560 [M + H], 582 [M + Na]. HRMS (ESI) for C₂₇H₄₂O₆N₃Si₂[M + H] calculated:

560.2607; found: 560.2608.

4-(Thiophene-2-yl)-7-[3,5-O-(tetraisopropyldisiloxan-1,3-diyl)-β-D-arabinofuranosyl]-

7H-pyrrolo[2,3-d]pyrimidine (20c) and 4-(Thiophene-2-yl)-7-[2,3-O-

(tetraisopropyldisiloxan-1,3-diyl)-β-D-arabinofuranosyl]-7H-pyrrolo[2,3-d]pyrimidine (22c)

An argon purged mixture of compound 18 (220 mg, 0.42 mmol), 2-(tributylstannyl)-

thiophene (240 mg, 0.64 mmol) and PdCl₂(PPh₃)₂(15 mg, 0.021 mmol) in DMF (2 ml) was

stirred at 100 °C for 2 h. After cooling volatiles were removed in vacuo and the residue was

several times co-evaporated with toluene. HPFC of the residue on silica (0→100% EtOAc in

hexane) afforded product 20c (32 mg, 13%) as a colourless oil, product 22c (32 mg, 13%) as

a colourless oil and the mixture of compounds 20c and 22c (146 mg, 61%). The overall

yield of the cross-coupling products 20c and 22c is 210 mg (88%).

20c: ¹H NMR (400.0 MHz, CDCl₃): 1.00–1.15 (m, 28 H, (CH₃)₂CHSi); 3.55 (bs, 1 H,

OH-2′); 3.83 (dt, 1 H, J_4′,3′= 7.6, J_4′,5′= 3.2, H-4′); 4.01–4.10 (m, 2 H, H-5′); 4.28–4.70 (m,

2 H, H-2′, H-3′); 6.41 (d, 1 H, J_1′,2′= 6.0, H-1′); 7.89 (d, 1 H, J_5,6= 3.6, H-5); 7.22 (dd, 1 H,

J = 5.2, J = 3.6, H-4-thienyl); 7.57 (dd, 1 H, J = 5.2, J = 1.2, H-3-thienyl); 7.67 (d, 1 H, J_5,6

=

4.0, H-6); 7.98 (d, 1 H, J = 3.2, H-3-thienyl); 8.74 (s, 1 H, H-2). MS (ESI) m/z: 576 [M + H],

598 [M + Na]. HRMS (ESI) for C₂₇H₄₂O₅N₃SSi₂[M + H] calculated: 576.2378; found:

576.2379.

22c: ¹H NMR (400.0 MHz, CDCl₃): 0.92–1.10 (m, 28 H, (CH₃)₂CHSi); 3.74 (bs, 1 H,

OH-5′); 3.87 (bd, 1 H, J_5′a,5′b= 12.4, H-5′a); 3.96 (dt, 1 H, J_4′,3′= 8.8, J_4′,5′= 2.0, H-4′);

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976

Nauš, Perlíková, Pohl, Hocek:

4.08 (dd, 1 H, J_5′a,5′b= 12.0, J_4′,5′= 2.0, H-5′b); 4.70 (dd, 1 H, J_4′,3′= 8.0, J_2′,3′= 7.6, H-2′);

4.85 (t, 1 H, J_1′,2′= J_2′,3′= 7.6, H-3′); 6.54 (d, 1 H, J_1′,2′= 7.2, H-1′); 6.85 (d, 1 H, J_5,6= 3.6,

H-5); 7.22 (dd, 1 H, J = 5.2, J = 3.6, H-4-thienyl); 7.42 (d, 1 H, J_5,6= 3.6, H-6); 7.56 (dd, 1 H,

J = 4.8, J = 0.8, H-5-thienyl); 7.96 (bs, 1 H, H-3-thienyl); 8.78 (s, 1 H, H-2). MS (ESI) m/z: 576

[M + H], 598 [M + Na]. HRMS (ESI) for C₂₇H₄₂O₅N₃SSi₂[M + H] calculated: 576.2378; found:

576.2378.

4-(Furan-2-yl)-7-(β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (21b)

Deprotection of nucleoside 20b (200 mg, 0.36 mmol) was performed as described for

compound 19. White crystalline solid (82 mg, 72%). Compound was recrystallized (H₂O–

20

methanol, 2:1). M.p. 228–230 °C. [α]_D–19.6 (c 0.204, DMSO). IR (ATR): 3509, 1601, 1572,

1466, 1249, 1069, 1018 cm^{–1 1}H NMR (500.0 MHz, DMSO-d₆): 3.64 (dt, 1 H, J_gem= 11.6,

.

J_5′b,OH= J_5′b,4′= 5.3, H-5′b); 3.71 (ddd, 1 H, J_gem= 11.6, J_5′a,OH= 5.3, J_5′a,4′= 4.1, H-5′a);

3.79 (ddd, 1 H, J_4′,5′= 5.3, 4.1, J_4′,3′= 4.7, H-4′); 4.12 (q, 1 H, J_3′,2′= J_3′,OH= J_3′,4′= 4.7, H-3′);

4.17 (ddd, 1 H, J_2′,OH= 5.6, J_2′,1′= 5.3, J_2′,3′= 4.7, H-2′); 5.07 (t, 1 H, J_OH,5′= 5.3, OH-5′);

5.51 (d, 1 H, J_OH,2′= 5.6, OH-2′); 5.52 (d, 1 H, J_OH,3′= 4.7, OH-3′); 6.60 (d, 1 H, J_1′,2′= 5.1,

H-1′); 6.78 (dd, 1 H, J_4,3= 3.5, J_4,5= 1.7, H-4-furyl); 7.00 (d, 1 H, J_5,6= 3.7, H-5); 7.45 (dd,

1 H, J_3,4= 3.5, J_3,5= 0.8, H-3-furyl); 7.81 (d, 1 H, J_6,5= 3.8, H-6); 8.06 (dd, 1 H, J_5,4= 1.7,

J_5,3= 0.8, H-5-furyl); 8.75 (s, 1 H, H-2). ¹³C NMR (125.7 MHz, DMSO-d₆): 61.15 (CH₂-5′);

75.35 (CH-3′); 76.17 (CH-2′); 83.34 (CH-1′); 83.94 (CH-4′); 100.11 (CH-5); 112.44 (C-4a);

112.78 (CH-4-furyl); 113.17 (CH-3-furyl); 130.17 (CH-6); 146.18 (C-4); 146.35 (CH-5-furyl);

150.88 (CH-2); 151.91 (C-7a); 152.79 (C-2-furyl). MS (ESI) m/z: 318 [M + H], 340 [M + Na].

HRMS (ESI) for

C₁₅H₁₅O₅N₃Na [M + Na] calculated: 340.0904; found: 340.0904.

For C₁₅H₁₅O₅N₃calculated: 56.78% C, 4.76% H, 13.24% N; found: 56.45% C, 4.75% H,

12.82% N.

4-(Thiophene-2-yl)-7-(β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (21c)

Deprotection of the 20c and 22c mixture (180 mg, 0.31 mmol) was performed as described

for compound 19. Pale yellow needles (80 mg, 77%). Compound was recrystallized (H₂O–

20

methanol, 2:1). M.p. 225–227 °C. [α]_D–15.7 (c 0.172, DMSO). IR (ATR): 3126, 1567, 1439,

1072, 1023 cm^{–1 1}H NMR (499.8 MHz, DMSO-d₆): 3.65 (dt, 1 H, J_gem= 11.7, J_5′b,OH= J_5′b,4′

. =

5.3, H-5′b); 3.72 (ddd, 1 H, J_gem= 11.7, J_5′a,OH= 5.3, J_5′a,4′= 4.3, H-5′a); 3.79 (ddd, 1 H,

J_4′,5′= 5.3, 4.3, J_4′,3′= 4.6, H-4′); 4.13 (dt, 1 H, J_3′,2′= 5.1, J_3′,OH= J_3′,4′= 4.6, H-3′); 4.19 (dt,

1 H, J_2′,OH= 6.0, J_2′,1′= J_2′,3′= 5.1, H-2′); 5.09 (t, 1 H, J_OH,5′= 5.3, OH-5′); 5.522 (d, 1 H,

J_OH,2′= 6.0, OH-2′); 5.523 (d, 1 H, J_OH,3′= 4.6, OH-3′); 6.61 (d, 1 H, J_1′,2′= 5.1, H-1′); 7.10 (d,

1 H, J_5,6= 3.8, H-5); 7.31 (dd, 1 H, J_4,5= 5.0, J_4,3= 3.8, H-4-thienyl); 7.84 (d, 1 H, J_6,5= 3.8,

H-6); 7.85 (dd, 1 H, J_5,4= 5.0, J_5,3= 1.0, H-5-thienyl); 8.15 (dd, 1 H, J_3,4= 3.8, J_3,5= 1.0,

H-3-thienyl); 8.73 (s, 1 H, H-2). ¹³C NMR (125.7 MHz, DMSO-d₆): 61.07 (CH₂-5′); 75.21

(CH-3′); 76.19 (CH-2′); 83.43 (CH-1′); 83.91 (CH-4′); 99.72 (CH-5); 112.74 (C-4a); 129.21

(CH-4-thienyl); 129.49 (CH-3-thienyl); 130.33 (CH-6); 130.69 (CH-5-thienyl); 142.76

(C-2-thienyl); 149.82 (C-4); 150.66 (CH-2); 151.85 (C-7a). MS (ESI) m/z: 334 [M + H]. HRMS

(ESI) for C₁₅H₁₆O₄N₃S [M + H] calculated: 334.0856; found: 334.0856. For C₁₅H₁₅O₄N₃S·

1.5H₂O calculated: 49.99% C, 5.03% H, 11.66% N; found: 50.30% C, 4.98% H, 11.45% N.

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

Sugar-Modified Nucleosides

977

4-(Furan-3-yl)-7-(β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (21d)

An argon purged mixture of compound 19 (130 mg, 0.45 mmol), furane-2-boronic acid (63 mg,

0.56 mmol), Na₂CO₃(144 mg, 1.36 mmol), Pd(OAc)₂(5.1 mg, 0.023 mmol) and TPPTS

(39 mg, 0.069 mmol) in water–MeCN (2:1, 2 ml) was stirred at 100 °C for 3 h. After cooling

the mixture was neutralized by the addition of aq. HCl (3 M), volatiles were removed in

vacuo and purification of the residue by reverse phase HPFC on C-18 (0→100% MeOH in

water) and crystallization (H₂O–methanol, 2:1) afforded product 21d (112 mg, 78%) as a

20

white crystalline solid. M.p. 212–214 °C. [α]_D–13.9 (c 0.245, DMSO). IR (ATR): 3494, 1579,

1461, 1165, 1074, 1022 cm^{–1 1}H NMR (499.8 MHz, DMSO-d₆): 3.64, 3.71 (2 × dt, 2 × 1 H,

.

J_gem= 11.8, J_5′,OH= J_5′,4′= 5.3, H-5′); 3.78 (td, 1 H, J_4′,5′= 5.3, J_4′,3′= 4.3, H-4′); 4.13 (ddd,

1 H, J_3′,2′= 5.0, J_3′,OH= 4.7, J_3′,4′= 4.3, H-3′); 4.18 (ddd, 1 H, J_2′,OH= 6.1, J_2′,1′= 5.3, J_2′,3′

=

5.0, H-2′); 5.08 (t, 1 H, J_OH,5′= 5.3, OH-5′); 5.50 (d, 1 H, J_OH,2′= 6.1, OH-2′); 5.51 (d, 1 H,

J_OH,3′= 4.7, OH-3′); 6.60 (d, 1 H, J_1′,2′= 5.3, H-1′); 7.02 (d, 1 H, J_5,6= 3.8, H-5); 7.25 (bs, 1 H,

H-4-furyl); 7.79 (d, 1 H, J_6,5= 3.8, H-6); 7.90 (bs, 1 H, H-5-furyl); 8.71 (bs, 1 H, H-2-furyl);

8.76 (s, 1 H, H-2). ¹³C NMR (125.7 MHz, DMSO-d₆): 61.08 (CH₂-5′); 75.23 (CH-3′); 76.19

(CH-2′); 83.33 (CH-1′); 83.86 (CH-4′); 99.65 (CH-5); 109.58 (CH-4-furyl); 114.25 (C-4a);

125.32 (C-3-furyl); 129.65 (CH-6); 144.73 (CH-5-furyl); 144.87 (CH-2-furyl); 149.70 (C-4);

150.88 (CH-2); 151.42 (C-7a). MS (ESI) m/z: 318 [M + H]. HRMS (ESI) for C₁₅H₁₆O₅N₃[M + H]

calculated: 318.10845; found: 318.10838. For C₁₅H₁₅O₅N₃calculated: 56.7% C, 4.76% H,

13.24% N; found: 56.28% C, 4.7% H, 12.82% N.

4-(Thiophene-3-yl)-7-(β-D-arabinofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine (21e)

Compound 21e was prepared as described for compound 21d from compound 19 (155 mg,

0.54 mmol) and 3-thienylboronic acid. Compound 21e (123 mg, 68%) was obtained as an

off-white crystalline solid after recrystallization (H₂O–MeOH, 2:1). M.p. 215–217 °C.

20

[α]_D–9.5 (c 0.211, DMSO). IR (ATR): 3520, 1578, 1461, 1248, 1076, 1026 cm^{–1 1}H NMR

.

(499.8 MHz, DMSO-d₆): 3.65 (ddd, 1 H, J_gem= 11.7, J_5′b,OH= 5.4, J_5′b,4′= 4.8, H-5′b); 3.72

(ddd, 1 H, J_gem= 11.7, J_5′a,OH= 5.4, J_5′a,4′= 4.2, H-5′a); 3.79 (ddd, 1 H, J_4′,3′= 5.0, J_4′,5′= 4.8,

4.2, H-4′); 4.13 (dt, 1 H, J_3′,4′= 5.0, J_3′,OH= 4.4, J_3′,2′= 4.2, H-3′); 4.18 (ddd, 1 H, J_2′,OH= 5.9,

J_2′,1′= 5.1, J_2′,3′= 4.2, H-2′); 5.08 (t, 1 H, J_OH,5′= 5.4, OH-5′); 5.516 (d, 1 H, J_OH,2′= 5.9,

OH-2′); 5.518 (d, 1 H, J_OH,3′= 4.4, OH-3′); 6.62 (d, 1 H, J_1′,2′= 5.1, H-1′); 7.07 (d, 1 H, J_5,6

=

3.8, H-5); 7.74 (dd, 1 H, J_5,4= 5.0, J_5,2= 2.9, H-5-thienyl); 7.83 (d, 1 H, J_6,5= 3.8, H-6); 7.95

(dd, 1 H, J_4,5= 5.0, J_4,2= 1.2, H-4-thienyl); 8.53 (dd, 1 H, J_2,5= 2.9, J_2,4= 1.2, H-2-thienyl);

8.79 (s, 1 H, H-2). ¹³C NMR (125.7 MHz, DMSO-d₆): 61.10 (CH₂-5′); 75.28 (CH-3′); 76.18

(CH-2′); 83.37 (CH-1′); 83.89 (CH-4′); 99.87 (CH-5); 114.27 (C-4a); 127.27 (CH-5-thienyl);

127.59 (CH-4-thienyl); 128.47 (CH-2-thienyl); 129.99 (CH-6); 140.23 (C-3-thienyl); 150.83

(CH-2); 151.17 (C-4); 151.85 (C-7a). MS (ESI) m/z: 334 [M + H]. HRMS (ESI) for C₁₅H₁₆O₄N₃S

[M + H] calculated: 334.0856; found: 334.0856. For C₁₅H₁₅O₄N₃S calculated: 54.04% C,

4.54% H, 12.60% N; found: 54.05% C, 4.51% H, 12.42% N.

4-Chloro-7-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-

7H-pyrrolo[2,3-d]pyrimidine (23)

A mixture of powdered KOH (840 mg, 85%, 12.75 mmol), TDA-1 (0.26 ml, 0.81 mmol) in

dry MeCN (40 ml) was stirred at r.t. for 10 min before 6-chloro-7-deazapurine 8 (768 mg,

5 mmol) was added. Stirring was continued for another 15 min and then 2-deoxy-2-fluoro-

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

978

Nauš, Perlíková, Pohl, Hocek:

3,5-di-O-benzoyl-β-D-arabinofuranosyl bromide 25 ²⁶(2.12 g, 5 mmol, prepared from 26) in

MeCN (40 ml) was added and the mixture was stirred at r.t. for 10 min. The mixture was

neutralized by the addition of AcOH, evaporated to dryness and the residue was co-

evaporated with silica. Column chromatography (hexanes–AcOEt, 6:1) afforded chloro

nucleoside 23 (1.79 g, 72%) as a colorless solid. Analytical data of compound 23 are as de-

scribed²³

.

7-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-4-phenyl-

7H-pyrrolo[2,3-d]pyrimidine (27a)

An argon purged mixture of 4-chloro-7-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabino-

furanosyl)-7H-pyrrolo[2,3-d]pyrimidine 23 (414 mg, 0.83 mmol), phenylboronic acid

(153 mg, 1.25 mmol), K₂CO₃(230 mg, 1.67 mmol) and Pd(PPh₃)₄(48 mg, 0.04 mmol) in

toluene (5 ml) was stirred at 100 °C for 3 h. After cooling the solids were filtered off and

the filtrate was co-evaporated with silica and chromatography on silica (hexanes–AcOEt, 6:1)

afforded product 27a (426 mg, 95%) as a colorless foam. ¹H NMR (400.1 MHz, CDCl₃): 4.59

(dt, 1 H, J_4′,5′= 4.7, 4.7, J_4′,3′= 2.9, H-4′); 4.82 (m, 2 H, H-5′a and 5′b); 5.38 (ddd, 1 H, J_H,F

=

50.1, J_2′,1′= 2.9, J_2′,3′= 0.9, H-2′); 5.78 (ddd, 1 H, J_H,F= 17.3, J_3′,4′= 3.0, J_3′,2′= 0.8, H-3′);

6.89 (d, 1 H, J_5,6= 3.9, H-5); 6.99 (dd, 1 H, J_H,F= 23.2, J_1′,2′= 2.8, H-1′); 7.43–7.69 (m, 10 H,

H-m-Bz, H-6, H-p-Bz); 8.09–8.16 (m, 6 H, H-o-Bz); 8.98 (s, 1 H, H-2). MS (ESI) m/z: 538 (M +

H), 560 (M + Na). HRMS (ESI) for C₃₁H₂₅N₃O₅F [M + H] calculated: 538.1773; found

538.1771.

7-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-4-(furan-2-yl)-

7H-pyrrolo[2,3-d]pyrimidine (27b)

An argon purged mixture of compound 23 (496 mg, 1 mmol), 2-(tributylstannyl)furane

(411 µl, 1.30 mmol) and PdCl₂(PPh₃)₂(35 mg, 0.05 mmol) in DMF (5 ml) was stirred at

100 °C for 1 h. After cooling volatiles were removed in vacuo and the residue was several

times co-evaporated with toluene. Column chromatography on silica (hexanes–AcOEt,

20:1→6:1) afforded product 27b (511 mg, 97%) as a colorless foam. ¹H NMR (400.1 MHz,

CDCl₃): 4.57 (dt, 1 H, J_4′,5′= 4.7, 4.7, J_4′,3′= 2.9, H-4′); 4.81 (m, 2 H, H-5′a and 5′b); 5.36

(ddd, 1 H, J_H,F= 50.1, J_2′,1′= 2.8, J_2′,3′= 0.9, H-2′); 5.76 (ddd, 1 H, J_H,F= 17.2, J_3′,4′= 2.9,

J_3′,2′= 0.8, H-3′); 6.63 (dd, 1 H, J_4,3= 3.5, J_4,5= 1.8, H-4-furyl); 6.94 (dd, 1 H, J_H,F= 23.2,

J_1′,2′= 2.8, H-1′); 7.08 (d, 1 H, J_5,6= 3.9, H-5); 7.42–7.67 (m, 8 H, H-m-Bz, H-6, H-3-furyl,

H-p-Bz); 7.71 (dd, 1 H, J_5,4= 1.8, J_5,3= 0.8, H-5-furyl); 8.11 (m, 4 H, H-o-Bz); 8.86 (s, 1 H,

H-2). MS (ESI) m/z: 528 (M + H), 550 (M + Na). HRMS (ESI) for C₂₉H₂₃N₃O₆F [M + H] calcu-

lated: 528.1565; found 528.1562.

7-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-4-(thiophen-2-yl)-

7H-pyrrolo[2,3-d]pyrimidine (27c)

Compound 27c was prepared as described for 27b by the reaction of compound 23 (496 mg,

1 mmol) and 2-(tributylstannyl)thiophene. Yield 495 mg (91%). Colorless foam. ¹H NMR

(400.1 MHz, CDCl₃): 4.58 (dt, 1 H, J_4′,5′= 4.7, 4.7, J_4′,3′= 2.9, H-4′); 4.81 (m, 2 H, H-5′a and

5′b); 5.37 (ddd, 1 H, J_H,F= 50.0, J_2′,1′= 2.8, J_2′,3′= 0.9, H-2′); 5.77 (ddd, 1 H, J_H,F= 17.2,

J_3′,4′= 2.9, J_3′,2′= 0.9, H-3′); 6.94 (d, 1 H, J_5,6= 3.9, H-5); 6.96 (dd, 1 H, J_H,F= 23.2, J_1′,2′

=

2.8, H-1′); 7.23 (dd, 1 H, J_4,5= 5.1, J_4,3= 3.8, H-4-thienyl); 7.46, 7.51 (2 × m, 2 × 2 H,

Collect. Czech. Chem. Commun. 2011, Vol. 76, No. 8, pp. 957–988

Sugar-Modified Nucleosides

979

H-m-Bz); 7.55–7.61 (m, 1 H, H-6); 7.57 (dd, 1 H, J_5,4= 5.2, J_5,3= 1.2, H-5-thienyl); 7.62, 7.65

(2 × m, 2 × 1 H, H-p-Bz); 7.98 (dd, 1 H, J_3,4= 3.8, J_3,5= 1.2, H-3-thienyl); 8.11 (m, 4 H,

H-o-Bz); 8.86 (s, 1 H, H-2). MS (ESI) m/z: 544 (M + H), 566 (M + Na). HRMS (ESI) for

C

₂₉H₂₃N₃O₅FS [M + H] calculated: 544.1337; found 544.1334.

7-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-4-(furan-3-yl)-

7H-pyrrolo[2,3-d]pyrimidine (27d)

Compound 27d was prepared as described for 27a by the reaction of compound 23 (372 mg,

0.75 mmol) and furane-3-boronic acid. Yield 384 mg (97%). Colorless foam. ¹H NMR

(400.1 MHz, CDCl₃): 4.58 (dt, 1 H, J_4′,5′= 4.7, 4.7, J_4′,3′= 2.9, H-4′); 4.81 (m, 2 H, H-5′a and

5′b); 5.37 (ddd, 1 H, J_H,F= 50.1, J_2′,1′= 2.8, J_2′,3′= 0.8, H-2′); 5.76 (ddd, 1 H, J_H,F= 17.2,

J_3′,4′= 3.0, J_3′,2′= 0.8, H-3′); 6.75 (d, 1 H, J_5,6= 3.9, H-5); 6.95 (dd, 1 H, J_H,F= 23.2, J_1′,2′

=

2.8, H-1′); 7.14 (dd, 1 H, J_4,5= 1.9, J_4,2= 0.9, H-4-furyl); 7.41–7.68 (m, 8 H, H-m-Bz, H-6,

H-5-furyl, H-p-Bz); 8.27 (dd, 1 H, J_2,5= 1.5, J_2,4= 0.9, H-2-furyl); 8.08–8.14 (m, 4 H, H-o-Bz);

8.87 (s, 1 H, H-2). MS (ESI) m/z: 528 (M + H), 550 (M + Na). HRMS (ESI) for C₂₉H₂₃N₃O₆F

[M + H] calculated: 528.1565; found 528.1564.

7-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-4-(thiophen-3-yl)-

7H-pyrrolo[2,3-d]pyrimidine (27e)

Compound 27e was prepared as described for 27a by the reaction of compound 23 (621 mg,

1.25 mmol) and thiophene-3-boronic acid. Yield 645 mg (95%). Colorless foam. ¹H NMR

(400.1 MHz, CDCl₃): 4.58 (dt, 1 H, J_4′,5′= 4.7, 4.7, J_4′,3′= 3.0, H-4′); 4.81 (m, 2 H, H-5′a and

5′b); 5.37 (ddd, 1 H, J_H,F= 50.1, J_2′,1′= 2.8, J_2′,3′= 0.9, H-2′); 5.77 (ddd, 1 H, J_H,F= 17.2,

J_3′,4′= 2.9, J_3′,2′= 0.9, H-3′); 6.88 (d, 1 H, J_5,6= 3.9, H-5); 6.97 (dd, 1 H, J_H,F= 23.2, J_1′,2′

=

2.8, H-1′); 7.43–7.69 (m, 8 H, H-m-Bz, H-6, H-5-thienyl, H-p-Bz); 7.89 (dd, 1 H, J_4,5= 5.1,

J_4,2= 1.3, H-4-thienyl); 8.09-8.16 (m, 4 H, H-o-Bz); 8.20 (dd, 1 H, J_2,5= 3.0, J_2,4= 1.3,

H-2-thienyl); 8.91 (s, 1 H, H-2). MS (ESI) m/z: 544 (M + H), 566 (M + Na). HRMS (ESI) for

C

₂₉H₂₃N₃O₅FS [M + H] calculated: 544.1337; found 544.1334.

7-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-4-(thiazol-2-yl)-

7H-pyrrolo[2,3-d]pyrimidine (27g)

Compound 27g was prepared as described for 27b by the reaction of compound 23 (337 mg,

0.68 mmol) and 2-(tributylstannyl)thiazole. Reaction time 18 h. Yield 300 mg (81%).

Yellowish oil. ¹H NMR (400.1 MHz, CDCl₃): 4.59 (dt, 1 H, J_4′,5′= 4.7, 4.7, J_4′,3′= 3.0, H-4′);

4.82 (m, 2 H, H-5′a and 5′b); 5.37 (ddd, 1 H, J_H,F= 50.1, J_2′,1′= 2.9, J_2′,3′= 0.9, H-2′); 5.77

(ddd, 1 H, J_H,F= 17.2, J_3′,4′= 3.0, J_3′,2′= 0.9, H-3′); 6.97 (dd, 1 H, J_H,F= 23.0, J_1′,2′= 2.9, H-1′);

7.43–7.70 (m,

9 H, H-5-thiazolyl, H-5, H-m-Bz, H-6, H-p-Bz); 8.09–8.15 (m, 5 H,

H-4-thiazolyl, H-o-Bz); 8.91 (s, 1 H, H-2). MS (ESI) m/z: 545 (M + H), 567 (M + Na).

7-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-4-methyl-

7H-pyrrolo[2,3-d]pyrimidine (27h)

An argon purged mixture of compound 23 (337 mg, 0.68 mmol), trimethylaluminium (2 M

in toluene, 680 µl, 1.36 mmol) and Pd(PPh₃)₄(39 mg, 0.034 mmol) in THF (3 ml) was

stirred at 100 °C for 6 h. The mixture was diluted with CHCl₃(20 ml) and treated with aq.

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980

Nauš, Perlíková, Pohl, Hocek:

NH₄Cl (sat., 20 ml). The slurry was filtered through cellite and after phase separation, aque-

ous phase was re-extracted with CHCl₃(2 × 10 ml). Combined organics were dried over

MgSO₄, evaporated and the residue was chromatographed on silica (hexanes–AcOEt, 2:1) af-

fording compound 27h (320 mg, 99%) as a colorless oil. ¹H NMR (400.1 MHz, CDCl₃): 2.76

(s, 3 H, CH₃); 4.56 (dt, 1 H, J_4′,5′= 4.7, 4.7, J_4′,3′= 3.0, H-4′); 4.79 (m, 2 H, H-5′a and 5′b);

5.34 (ddd, 1 H, J_H,F= 50.1, J_2′,1′= 2.8, J_2′,3′= 1.0, H-2′); 5.76 (ddd, 1 H, J_H,F= 17.3, J_3′,4′= 2.9,

J_3′,2′= 1.0, H-3′); 6.62 (d, 1 H, J_5,6= 3.8, H-5); 6.91 (dd, 1 H, J_H,F= 23.2, J_1′,2′= 2.9, H-1′);

7.45 (m, 2 H, H-m-Bz); 7.48–7.55 (m, 3 H, H-m-Bz and H-6); 7.58, 7.66 (2 × m, 2 × 1 H,

H-p-Bz); 8.11 (m, 4 H, H-o-Bz); 8.78 (s, 1 H, H-2). MS (ESI) m/z: 476 (M + H). HRMS (ESI) for

C

₂₆H₂₃N₃O₅F [M + H] calculated: 476.1616; found 476.1607.

7-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-4-phenyl-

7H-pyrrolo[2,3-d]pyrimidine (28a)

Compound 27a (400 mg, 0.74 mmol) was treated with NaOMe (1 M in MeOH, 200 µl,

0.2 mmol) in MeOH (5 ml) for 12 h at r.t.. The mixture was co-evaporated with silica and

chromatographed on a column of silica (2.5% MeOH in CHCl₃) affording product 28a

(225 mg, 92%) as a colorless foamy solid. M.p. 72–76 °C. [α]_D+44.2 (c 0.339, DMSO).

¹¹H NMR (400.1 MHz, DMSO-d₆): 3.66 (dtd, 1 H, J_gem= 11.9, J_5′b,OH= J_5′b,4′= 5.7, J_H,F= 0.9,

H-5′b); 3.725 (dddd, 1 H, J_gem= 11.9, J_5′a,OH= 5.7, J_5′a,4′= 4.3, J_H,F= 1.4, H-5′a); 3.88 (dddd,

1 H, J_4′,5′= 5.7, 4.3, J_4′,3′= 5.1, J_H,F= 0.5, H-4′); 4.45 (dtd, 1 H, J_H,F= 19.0, J_3′,4′= J_3′,OH= 5.1,

J_3′,2′= 3.8, H-3′); 5.13 (t, 1 H, J_OH,5′= 5.7, OH-5′); 5.24 (ddd, 1 H, J_H,F= 52.7, J_2′,1′= 4.6,

J_2′,3′= 3.8, H-2′); 5.99 (d, 1 H, J_OH,3′= 5.0, OH-3′); 6.80 (dd, 1 H, J_H,F= 15.1, J_1′,2′= 4.6, H-1′);

7.02 (d, 1 H, J_5,6= 3.8, H-5); 7.54–7.63 (m, 3 H, H-m,p-Ph); 7.85 (dd, 1 H, J_6,5= 3.8, J_H,F

=

2.2, H-6); 8.17 (m, 2 H, H-o-Ph); 8.92 (s, 1 H, H-2). ¹³C NMR (100.6 MHz, DMSO-d₆): 60.62

(CH₂-5′); 73.07 (d, J_C,F= 23.3, CH-3′); 81.40 (d, J_C,F= 16.8, CH-1′); 83.41 (d, J_C,F= 5.0,

CH-4′); 96.02 (d, J_C,F= 191.7, CH-2′); 101.05 (CH-5); 115.13 (C-4a); 128.78 (CH-o-Ph);

129.05 (CH-m-Ph); 129.09 (d, J_C,F= 3.9, CH-6); 130.45 (CH-p-Ph); 137.56 (C-i-Ph); 151.30

(CH-2); 151.72 (C-7a); 156.31 (C-4). ¹⁹F NMR (470.3 MHz, DMSO-d₆): -197.90. MS (ESI) m/z:

330 (M + H), 352 (M + Na). HRMS (ESI) for C₁₇H₁₇N₃O₃F [M + H] calculated: 330.1249;

found: 330.1248. HRMS (ESI) for C₁₇H₁₆N₃O₃FNa [M + Na] calculated: 352.1068; found:

352.1067. For C₁₇H₁₆N₃O₃F·0.3H₂O calculated: 61.00% C, 5.00% H, 12.55% N; found:

61.28% C, 4.97% H, 12.28% N.

7-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-4-(furan-2-yl)-

7H-pyrrolo[2,3-d]pyrimidine (28b).

Deprotection of 27b (495 mg, 0.94 mmol) as described for 28a gave compound 28b as a

beige foam. Yield 270 mg (90%). Compound 28b crystallized from MeOH(trace)–AcOEt–

hexanes as a beige microcrystalline solid. M.p. 185–187 °C. [α]_D+39.9 (c 0.321, DMSO).

¹H NMR (600.1 MHz, DMSO-d₆): 3.65 (dddd, 1 H, J_gem= 11.8, J_5′b,OH= 5.7, J_5′b,4′= 5.3, J_H,F

=

0.9, H-5′b); 3.71 (dddd, 1 H, J_gem= 11.8, J_5′a,OH= 5.7, J_5′a,4′= 4.3, J_H,F= 1.6, H-5′a); 3.86 (tdd,

1 H, J_4′,5′= 5.3, 4.3, J_4′,3′= 5.3, J_H,F= 0.8, H-4′); 4.42 (dddd, 1 H, J_H,F= 19.0, J_3′,4′= 5.3,

J_3′,OH= 5.0, J_3′,2′= 3.7, H-3′); 5.13 (t, 1 H, J_OH,5′= 5.7, OH-5′); 5.22 (ddd, 1 H, J_H,F= 52.6,

J_2′,1′= 4.6, J_2′,3′= 3.7, H-2′); 5.98 (d, 1 H, J_OH,3′= 5.0, OH-3′); 6.74 (dd, 1 H, J_H,F= 15.2, J_1′,2′

=

4.6, H-1′); 6.79 (dd, 1 H, J_4,3= 3.5, J_4,5= 1.8, H-4-furyl); 7.07 (d, 1 H, J_5,6= 3.8, H-5); 7.49

(dd, 1 H, J_3,4= 3.5, J_3,5= 0.8, H-3-furyl); 7.81 (dd, 1 H, J_6,5= 3.8, J_H,F= 2.3, H-6); 8.07 (dd,

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Sugar-Modified Nucleosides

981

1 H, J_5,4= 1.8, J_5,3= 0.8, H-5-furyl); 8.79 (s, 1 H, H-2). ¹³C NMR (150.9 MHz, DMSO-d₆):

60.63 (CH₂-5′); 73.01 (d, J_C,F= 23.2, CH-3′); 81.22 (d, J_C,F= 16.8, CH-1′); 83.35 (d, J_C,F= 5.2,

CH-4′); 96.05 (d, J_C,F= 191.6, CH-2′); 101.41 (CH-5); 112.34 (C-4a); 112.92 (CH-4-furyl);

113.60 (CH-3-furyl); 129.16 (d, J_C,F= 3.6, CH-6); 146.62 (C-4); 146.64 (CH-5-furyl); 151.37

(CH-2); 151.86 (C-7a); 152.59 (C-2-furyl). ¹⁹F NMR (470.3 MHz, DMSO-d₆): –194.35. MS (ESI)

m/z: 320 (M + H), 342 (M + Na). HRMS (ESI) for C₁₅H₁₅N₃O₄F [M + H] calculated: 320.1041;

found: 320.1041. HRMS (ESI) for C₁₅H₁₄N₃O₄FNa [M + Na] calculated: 342.0861; found:

342.0860. For C₁₅H₁₄N₃O₄F calculated: 56.43% C, 4.42%% H, 13.16% N; found: 56.12% C,

4.53% H, 12.87% N.

7-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-4-(thiophen-2-yl)-

7H-pyrrolo[2,3-d]pyrimidine (28c)

Deprotection of 27c (470 mg, 0.86 mmol) as described for 28a gave compound 28c as an

amorphous yellow solid. Yield 247 mg (85%). Compound 28c was recrystallized from EtOH

as an yellow crystalline solid. M.p. 144–146 °C. [α]_D+39.8 (c 0.587, DMSO). ¹H NMR

(499.8 MHz, DMSO-d₆): 3.66 (dddd, 1 H, J_gem= 11.8, J_5′b,OH= 5.7, J_5′b,4′= 5.3, J_H,F= 0.8,

H-5′b); 3.72 (dddd, 1 H, J_gem= 11.8, J_5′a,OH= 5.7, J_5′a,4′= 4.3, J_H,F= 1.6, H-5′a); 3.86 (tdd,

1 H, J_4′,5′= 5.3, 4.3, J_4′,3′= 5.3, J_H,F= 0.7, H-4′); 4.44 (dddd, 1 H, J_H,F= 19.0, J_3′,4′= 5.3,

J_3′,OH= 5.0, J_3′,2′= 3.9, H-3′); 5.15 (t, 1 H, J_OH,5′= 5.7, OH-5′); 5.23 (ddd, 1 H, J_H,F= 52.8,

J_2′,1′= 4.6, J_2′,3′= 3.9, H-2′); 5.99 (d, 1 H, J_OH,3′= 5.0, OH-3′); 6.75 (dd, 1 H, J_H,F= 14.5, J_1′,2′

=

4.6, H-1′); 7.19 (d, 1 H, J_5,6= 3.9, H-5); 7.31 (dd, 1 H, J_4,5= 5.1, J_4,3= 3.8, H-4-thienyl); 7.85

(dd, 1 H, J_6,5= 3.9, J_H,F= 2.3, H-6); 7.87 (dd, 1 H, J_5,4= 5.1, J_5,3= 1.1, H-5-thienyl); 8.18 (dd,

1 H, J_3,4= 3.8, J_3,5= 1.1, H-3-thienyl); 8.78 (s, 1 H, H-2). ¹³C NMR (125.7 MHz, DMSO-d₆):

60.58 (CH₂-5′); 72.91 (d, J_C,F= 23.2, CH-3′); 81.30 (d, J_C,F= 16.8, CH-1′); 83.31 (d, J_C,F= 5.4,

CH-4′); 96.06 (d, J_C,F= 191.7, CH-2′); 101.04 (CH-5); 112.68 (C-4a); 129.32 (d, J_C,F= 3.6,

CH-6); 129.35 (CH-4-thienyl); 129.91 (CH-3-thienyl); 131.08 (CH-5-thienyl); 142.50

(C-2-thienyl); 150.34 (C-4); 151.15 (CH-2); 151.79 (C-7a). ¹⁹F NMR (470.3 MHz, DMSO-d₆):

-194.43. MS (ESI) m/z: 336 (M + H), 358 (M + Na). HRMS (ESI) for C₁₅H₁₅N₃O₃FS [M + H]

calculated: 336.0813; found: 336.0813. HRMS (ESI) for C₁₅H₁₄N₃O₃FSNa [M + Na] calculated:

358.0632; found: 358.0632. For C₁₅H₁₄N₃O₃FS calculated: 53.72% C, 4.21% H, 12.53% N;

found: 53.47% C, 4.38% H, 12.24% N.

7-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-4-(furan-3-yl)-

7H-pyrrolo[2,3-d]pyrimidine (28d)

Deprotection of 27d (370 mg, 0.70 mmol) as described for 28a gave compound 28d as a

white foam. Yield 193 mg (86%). Compound 28d crystallized from MeOH–water as white

leaves. M.p. 112–114 °C. [α]_D+38.7 (c 0.336, DMSO). ¹H NMR (400.1 MHz, DMSO-d₆): 3.66

(dt, 1 H, J_gem= 12.0, J_5′b,OH= J_5′b,4′= 5.6, H-5′b); 3.72 (dddd, 1 H, J_gem= 12.0, J_5′a,OH= 5.6,

J_5′a,4′= 4.3, J_H,F= 1.5, H-5′a); 3.87 (ddd, 1 H, J_4′,5′= 5.6, 4.3, J_4′,3′= 5.3, H-4′); 4.44 (dddd,

1 H, J_H,F= 19.2, J_3′,4′= 5.3, J_3′,OH= 5.0, J_3′,2′= 3.9, H-3′); 5.12 (t, 1 H, J_OH,5′= 5.6, OH-5′);

5.22 (ddd, 1 H, J_H,F= 52.7, J_2′,1′= 4.6, J_2′,3′= 3.9, H-2′); 5.97 (d, 1 H, J_OH,3′= 5.0, OH-3′); 6.75

(dd, 1 H, J_H,F= 14.7, J_1′,2′= 4.6, H-1′); 7.11 (d, 1 H, J_5,6= 3.8, H-5); 7.26 (dd, 1 H, J_4,5= 1.9,

J_4,2= 0.8, H-4-furyl); 7.80 (dd, 1 H, J_6,5= 3.8, J_H,F= 2.2, H-6); 7.90 (dd, 1 H, J_5,4= 1.9, J_5,2

=

1.4, H-5-furyl); 8.74 (dd, 1 H, J_2,5= 1.4, J_2,4= 0.8, H-2-furyl); 8.81 (s, 1 H, H-2). ¹³C NMR

(100.6 MHz, DMSO-d₆): 60.59 (CH₂-5′); 73.00 (d, J_C,F= 23.3, CH-3′); 81.26 (d, J_C,F= 16.9,

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Nauš, Perlíková, Pohl, Hocek:

CH-1′); 83.31 (d, J_C,F= 5.1, CH-4′); 96.02 (d, J_C,F= 191.7, CH-2′); 100.84 (CH-5); 109.51

(CH-4-furyl); 114.16 (C-4a); 125.11 (C-3-furyl); 128.58 (d, J_C,F= 3.6, CH-6); 144.73

(CH-5-furyl); 145.02 (CH-2-furyl); 150.21 (C-4); 151.26 (CH-2); 151.32 (C-7a). ¹⁹F NMR

(470.3 MHz, DMSO-d₆): –198.01. MS (ESI) m/z: 320 (M + H), 342 (M + Na). HRMS (ESI) for

C

₁₅H₁₅N₃O₄F [M

+

H] calculated: 320.1041; found: 320.1041. HRMS (ESI) for

₁₅H₁₄N₃O₄FNa [M + Na] calculated: 342.0861; found: 342.0860. For C₁₅H₁₄N₃O₄F·0.5H₂O

calculated: 54.88% C, 4.61% H, 12.80% N; found: 55.10% C, 4.61% H, 12.48% N.

7-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-4-(thiophen-3-yl)-

7H-pyrrolo[2,3-d]pyrimidine (28e)

Deprotection of 27e (620 mg, 1.14 mmol) as described for 28a gave compound 28e as a

brownish foamy solid after evaporation from MeOH. Yield 340 mg (89%). M.p. 71–73 °C.

[α]_D+41.6 (c 0.375, DMSO). ¹H NMR (499.8 MHz, DMSO-d₆): 3.66 (ddd, 1 H, J_gem= 12.0,

J_5′b,4′= 5.1, J_H,F= 0.8, H-5′b); 3.72 (ddd, 1 H, J_gem= 12.0, J_5′a,4′= 4.3, J_H,F= 1.5, H-5′a); 3.87

(dddd, 1 H, J_4′,3′= 5.4, J_4′,5′= 5.1, 4.3, J_H,F= 0.8, H-4′); 4.44 (ddd, 1 H, J_H,F= 19.1, J_3′,4′= 5.4,

J_3′,2′= 3.8, H-3′); 5.10 (bs, 1 H, OH-5′); 5.22 (ddd, 1 H, J_H,F= 52.7, J_2′,1′= 4.6, J_2′,3′= 3.8,

H-2′); 5.98 (bs, 1 H, OH-3′); 6.77 (dd, 1 H, J_H,F= 14.9, J_1′,2′= 4.6, H-1′); 7.15 (dd, 1 H, J_5,6

=

3.9, J_H,F= 0.3, H-5); 7.75 (dd, 1 H, J_5,4= 5.0, J_5,2= 2.9, H-5-thienyl); 7.83 (dd, 1 H, J_6,5= 3.9,

J_H,F= 2.2, H-6); 7.96 (dd, 1 H, J_4,5= 5.0, J_4,2= 1.3, H-4-thienyl); 8.55 (dd, 1 H, J_2,5= 2.9,

J_2,4= 1.3, H-2-thienyl); 8.84 (s, 1 H, H-2). ¹³C NMR (125.7 MHz, DMSO-d₆): 60.63 (CH₂-5′);

73.01 (d, J_C,F= 23.1, CH-3′); 81.32 (d, J_C,F= 16.9, CH-1′); 83.34 (d, J_C,F= 5.2, CH-4′); 96.07

(d, J_C,F= 191.7, CH-2′); 101.20 (CH-5); 114.24 (C-4a); 127.42 (CH-5-thienyl); 127.62

(CH-4-thienyl); 128.91 (CH-2-thienyl); 129.02 (d, J_C,F= 3.5, CH-6); 139.93 (C-3-thienyl);

151.25 (CH-2); 151.65 (C-4); 151.80 (C-7a). ¹⁹F NMR (470.3 MHz, DMSO-d₆): –197.97.

MS (ESI) m/z: 336 (M + H), 358 (M + Na). HRMS (ESI) for C₁₅H₁₅N₃O₃FS [M + H] calculated:

336.0813; found: 336.0813. HRMS (ESI) for C₁₅H₁₄N₃O₃FSNa [M + Na] calculated: 358.0632;

found: 358.0632. For C₁₅H₁₄N₃O₃FS calculated: 53.72% C, 4.21% H, 12.53% N; found:

53.61% C, 4.47% H, 12.15% N.

7-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-4-(thiazol-2-yl)-

7H-pyrrolo[2,3-d]pyrimidine (28g)

Deprotection of 27g (290 mg, 0.53 mmol) as described for 28a gave compound 28g as a

yellowish foamy solid after evaporation from diethylether. Yield 123 mg (69%). M.p.

150–152 °C. [α]_D+39.5 (c 0.324, DMSO). ¹H NMR (499.8 MHz, DMSO-d₆): 3.66 (dd, 1 H,

J_gem= 11.9, J_5′b,4′= 5.1, H-5′b); 3.72 (ddd, 1 H, J_gem= 11.9, J_5′a,4′= 4.1, J_H,F= 1.3, H-5′a); 3.87

(dddd, 1 H, J_4′,3′= 5.6, J_4′,5′= 5.1, 4.1, J_H,F= 0.8, H-4′); 4.43 (dddd, 1 H, J_H,F= 18.7, J_3′,4′

5.6, J_3′,OH= 4.4, J_3′,2′= 3.8, H-3′); 5.13 (bs, 1 H, OH-5′); 5.24 (ddd, 1 H, J_H,F= 52.7, J_2′,1′

=

4.6, J_2′,3′= 3.8, H-2′); 5.99 (bd, 1 H, J_OH,3′= 4.4, OH-3′); 6.77 (dd, 1 H, J_H,F= 14.9, J_1′,2′= 4.6,

H-1′); 7.31 (dd, 1 H, J_5,6= 3.7, J_H,F= 0.4, H-5); 7.91 (dd, 1 H, J_6,5= 3.7, J_H,F= 2.2, H-6); 8.05

(d, 1 H, J_5,4= 3.1, H-5-thiazolyl); 8.21 (d, 1 H, J_4,5= 3.1, H-4-thiazolyl); 8.90 (s, 1 H, H-2).

¹³C NMR (125.7 MHz, DMSO-d₆): 60.61 (CH₂-5′); 72.98 (d, J_C,F= 23.2, CH-3′); 81.38 (d,

J_C,F= 16.8, CH-1′); 83.41 (d, J_C,F= 5.3, CH-4′); 96.07 (d, J_C,F= 191.7, CH-2′); 102.16 (CH-5);

113.41 (C-4a); 124.31 (CH-5-thiazolyl); 130.73 (d, J_C,F= 3.6, CH-6); 145.78 (CH-4-thiazolyl);

148.27 (C-4); 151.19 (CH-2); 152.41 (C-7a); 167.33 (C-2-thiazolyl). ¹⁹F NMR (470.3 MHz,

DMSO-d₆): –197.98. MS (ESI) m/z: 337 (M + H), 359 (M + Na). HRMS (ESI) for C₁₄H₁₄N₄O₃FS

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Sugar-Modified Nucleosides

983

[M + H] calculated: 337.0765; found: 337.0765. HRMS (ESI) for C₁₄H₁₃N₄O₃FSNa [M + Na]

calculated: 359.0585; found: 359.0584. For C₁₄H₁₃N₄O₃FS·0.45C₄H₁₀O calculated: 51.33% C,

4.77% H, 15.15% N; found: 51.59% C, 4.53% H, 15.06% N.

7-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-4-(methyl)-

7H-pyrrolo[2,3-d]pyrimidine (28h)

Deprotection of 27h (300 mg, 0.63 mmol) as described for 28a gave compound 28h as a

white solid. Yield 143 mg (85%). Column chromatography (4% MeOH in CHCl₃). Com-

pound 28h was recrystallized from water as white prisms. M.p. 175–177 °C. [α]_D+32.2

(c 0.317, DMSO). ¹H NMR (499.8 MHz, DMSO-d₆): 2.66 (s, 3 H, CH₃); 3.63 (ddd, 1 H, J_gem

=

12.0, J_5′b,OH= 5.7, J_5′b,4′= 5.2, J_H,F= 0.8, H-5′b); 3.69 (dddd, 1 H, J_gem= 12.0, J_5′a,OH= 5.7,

J_5′a,4′= 4.3, J_H,F= 1.5, H-5′a); 3.84 (dddd, 1 H, J_4′,5′= 5.2, 4.3, J_4′,3′= 5.0, J_H,F= 0.9, H-4′);

4.40 (dtd, 1 H, J_H,F= 19.1, J_3′,4′= J_3′,OH= 5.0, J_3′,2′= 3.8, H-3′); 5.08 (t, 1 H, J_OH,5′= 5.7,

OH-5′); 5.18 (ddd, 1 H, J_H,F= 52.7, J_2′,1′= 4.6, J_2′,3′= 3.8, H-2′); 5.93 (d, 1 H, J_OH,3′= 5.0,

OH-3′); 6.69 (dd, 1 H, J_H,F= 15.0, J_1′,2′= 4.6, H-1′); 6.76 (dd, 1 H, J_5,6= 3.8, J_H,F= 0.4, H-5);

7.67 (dd, 1 H, J_6,5= 3.8, J_H,F= 2.2, H-6); 8.67 (s, 1 H, H-2). ¹³C NMR (125.7 MHz, DMSO-d₆):

21.33 (CH₃); 60.62 (CH₂-5′); 72.98 (d, J_C,F= 23.2, CH-3′); 81.20 (d, J_C,F= 16.9, CH-1′); 83.21

(d, J_C,F= 5.3, CH-4′); 96.02 (d, J_C,F= 191.7, CH-2′); 100.29 (CH-5); 117.58 (C-4a); 127.46 (d,

J_C,F= 3.6, CH-6); 150.09 (C-7a); 151.11 (CH-2); 159.21 (C-4). ¹⁹F NMR (470.3 MHz,

DMSO-d₆): –198.03. MS (ESI) m/z: 268 (M + H), 290 (M + Na). HRMS (ESI) for C₁₂H₁₅N₃O₃F

[M + H] calculated: 268.1092; found: 268.1092. HRMS (ESI) for C₁₂H₁₄N₃O₃FNa [M + Na]

calculated: 290.0911; found: 290.0912. For C₁₂H₁₄N₃O₃F calculated: 53.93% C, 5.28% H,

15.72% N; found: 53.87% C, 5.25% H, 15.63% N.

7-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluoro-4-(furan-2-yl)-

7H-pyrrolo[2,3-d]pyrimidine (29b)

Compound 29b was prepared as described for 27b by the reaction of compound 24 (514 mg,

1 mmol) and 2-(tributylstannyl)furane. Yield 480 mg (88%). Yellowish oil. ¹H NMR

(400.1 MHz, CDCl₃): 4.56 (dt, 1 H, J_4′,5′= 4.7, 4.7, J_4′,3′= 2.9, H-4′); 4.79 (m, 2 H, H-5′a and

5′b); 5.35 (ddd, 1 H, J_H,F= 50.1, J_2′,1′= 2.9, J_2′,3′= 0.9, H-2′); 5.74 (ddd, 1 H, J_H,F= 17.3,

J_3′,4′= 2.9, J_3′,2′= 0.9, H-3′); 6.65 (dd, 1 H, J_4,3= 3.6, J_4,5= 1.7, H-4-furyl); 6.99 (ddd, 1 H,

J_H,F= 22.8, 1.7, J_1′,2′= 2.9, H-1′); 7.39 (dd, 1 H, J_H,F= 2.8, 2.3, H-6); 7.43–7.70 (m, 7 H,

H-m-Bz, H-3-furyl, H-p-Bz); 7.74 (dd, 1 H, J_5,4= 1.8, J_5,3= 0.8, H-5-furyl); 8.11 (m, 4 H,

H-o-Bz); 8.88 (s, 1 H, H-2). MS (ESI) m/z: 546 (M + H), 568 (M + Na). HRMS (ESI) for

C

₂₉H₂₂N₃O₆F₂[M + H] calculated: 546.1471; found: 546.1468.

7-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluoro-4-(thiophen-2-yl)-

7H-pyrrolo[2,3-d]pyrimidine (29c)

Compound 29c was prepared as described for 27b by the reaction of compound 24 (514 mg,

1 mmol) and 2-(tributylstannyl)thiophene. Yield 500 mg (89%). Yellowish oil. ¹H NMR

(400.1 MHz, CDCl₃): 4.56 (dt, 1 H, J_4′,5′= 4.7, 4.7, J_4′,3′= 3.0, H-4′); 4.80 (m, 2 H, H-5′a and

5′b); 5.35 (ddd, 1 H, J_H,F= 50.1, J_2′,1′= 2.9, J_2′,3′= 0.8, H-2′); 5.74 (ddd, 1 H, J_H,F= 17.2,

J_3′,4′= 2.9, J_3′,2′= 0.7, H-3′); 6.99 (ddd, 1 H, J_H,F= 23.2, 1.8, J_1′,2′= 2.8, H-1′); 7.23 (dd, 1 H,

J_4,5= 5.1, J_4,3= 3.9, H-4-thienyl); 7.39 (dd, 1 H, J_H,F= 3.0, 2.2, H-6); 7.43–7.69 (m, 7 H,

H-m-Bz, H-5-thienyl, H-p-Bz); 8.12 (m, 4 H, H-o-Bz); 8.17 (dd, 1 H, J_3,4= 3.9, J_3,5= 1.1,

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H-3-thienyl); 8.81 (s, 1 H, H-2). MS (ESI) m/z: 562 (M + H), 584 (M + Na). HRMS (ESI) for

C

₂₉H₂₂N₃O₅F₂S [M + H] calculated: 562.1243; found: 562.1240. HRMS (ESI) for

₂₉H₂₁N₃O₅F₂SNa [M + Na] calculated: 584.1062; found: 584.1060.

7-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluoro-4-(furan-3-yl)-

7H-pyrrolo[2,3-d]pyrimidine (29d)

Compound 29d was prepared as described for 27a by the reaction of compound 24 (514 mg,

1 mmol) and furane-3-boronic acid. Yield 496 mg (91%). Colorless foam. ¹H NMR

(400.1 MHz, CDCl₃): 4.56 (dt, 1 H, J_4′,5′= 4.8, 4.8, J_4′,3′= 3.0, H-4′); 4.79 (m, 2 H, H-5′a and

5′b); 5.35 (ddd, 1 H, J_H,F= 50.1, J_2′,1′= 2.9, J_2′,3′= 0.8, H-2′); 5.74 (ddd, 1 H, J_H,F= 17.4,

J_3′,4′= 2.7, J_3′,2′= 0.7, H-3′); 6.99 (ddd, 1 H, J_H,F= 23.2, 1.8, J_1′,2′= 2.8, H-1′); 7.25 (m, 1 H,

H-4-furyl); 7.37 (t, 1 H, J_H,F= 2.6, H-6); 7.42–7.70 (m, 7 H, H-m-Bz, H-5-furyl, H-p-Bz); 8.11

(m, 4 H, H-o-Bz); 8.41 (dd, 1 H, J_2,5= 1.5, J_2,4= 0.8, H-2-furyl); 8.86 (s, 1 H, H-2). MS (ESI)

m/z: 546 (M + H), 568 (M + Na). HRMS (ESI) for C₂₉H₂₂N₃O₆F₂[M + H] calculated: 546.1471;

found: 546.1467.

7-(3,5-Di-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluoro-4-(thiophen-3-yl)-

7H-pyrrolo[2,3-d]pyrimidine (29e)

Compound 29e was prepared as described for 27a by the reaction of compound 24 (514 mg,

1 mmol) and thiophene-3-boronic acid. Yield 494 mg (88%). Yellowish foam. ¹H NMR

(400.1 MHz, CDCl₃): 4.56 (dt, 1 H, J_4′,5′= 4.7, 4.7, J_4′,3′= 2.8, H-4′); 4.80 (m, 2 H, H-5′a and

5′b); 5.36 (ddd, 1 H, J_H,F= 50.1, J_2′,1′= 2.9, J_2′,3′= 0.9, H-2′); 5.74 (ddd, 1 H, J_H,F= 17.3,

J_3′,4′= 3.0, J_3′,2′= 0.9, H-3′); 7.01 (ddd, 1 H, J_H,F= 23.2, 2.0, J_1′,2′= 2.9, H-1′); 7.38 (dd, 1 H,

J_H,F= 3.0, 2.2, H-6); 7.42–7.69 (m, 7 H, H-m-Bz, H-5-thienyl, H-p-Bz); 7.93 (dd, 1 H, J_4,5

=

5.1, J_4,2= 1.0, H-4-thienyl); 8.12 (m, 4 H, H-o-Bz); 8.30 (dd, 1 H, J_2,5= 3.0, J_2,4= 0.9,

H-2-thienyl); 8.88 (s, 1 H, H-2). MS (ESI) m/z: 562 (M + H), 584 (M + Na). HRMS (ESI) for

C

₂₉H₂₂N₃O₅F₂S [M + H] calculated: 562.1243; found: 562.1240.

7-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluoro-4-(furan-2-yl)-

7H-pyrrolo[2,3-d]pyrimidine (30b)

Deprotection of 29b (465 mg, 0.85 mmol) as described for 28a gave compound 30b as a

yellowish oil which solidified on standing. Yield 270 mg (94%). Compound 30b was

recrystallized from MeOH. M.p. 187–188 °C. [α]_D+46.9 (c 0.460, DMSO). ¹H NMR (499.8 MHz,

DMSO-d₆): 3.64 (dddd, 1 H, J_gem= 12.0, J_5′b,OH= 5.6, J_5′b,4′= 4.7, J_H,F= 0.6, H-5′b); 3.71

(dddd, 1 H, J_gem= 12.0, J_5′a,OH= 5.6, J_5′a,4′= 4.0, J_H,F= 1.6, H-5′a); 3.85 (dddd, 1 H, J_4′,3′

5.5, J_4′,5′= 4.7, 4.0, J_H,F= 0.8, H-4′); 4.41 (ddd, 1 H, J_H,F= 19.2, J_3′,4′= 5.5, J_3′,OH= 5.1, J_3′,2′

=

4.3, H-3′); 5.13 (t, 1 H, J_OH,5′= 5.6, OH-5′); 5.23 (ddd, 1 H, J_H,F= 52.8, J_2′,1′= 4.7, J_2′,3′= 4.3,

H-2′); 5.95 (t, 1 H, J_OH,3′= 5.1, OH-3′); 6.80 (ddd, 1 H, J_H,F= 13.3, 1.7, J_1′,2′= 4.7, H-1′); 6.81

(dd, 1 H, J_4,3= 3.5, J_4,5= 1.7, H-4-furyl); 7.49 (dd, 1 H, J_3,4= 3.5, J_3,5= 0.8, H-3-furyl); 7.85

(t, 1 H, J_H,F= 1.9, H-6); 8.08 (dd, 1 H, J_5,4= 1.7, J_5,3= 0.8, H-5-furyl); 8.82 (s, 1 H, H-2).

¹³C NMR (125.7 MHz, DMSO-d₆): 60.42 (CH₂-5′); 72.51 (d, J_C,F= 23.0, CH-3′); 80.75 (d,

J_C,F= 16.9, CH-1′); 83.17 (d, J_C,F= 5.9, CH-4′); 95.98 (d, J_C,F= 192.0, CH-2′); 101.90 (d, J_C,F

=

15.9, C-4a); 111.85 (dd, J_C,F= 30.7, 3.4, CH-6); 113.13 (CH-4-furyl); 115.02 (d, J_C,F= 5.8,

CH-3-furyl); 141.33 (d, J_C,F= 249.0, C-5); 146.06 (d, J_C,F= 3.7, C-4); 147.08 (CH-5-furyl);

147.26 (d, J_C,F= 3.1, C-7a); 150.99 (d, J_C,F= 1.6, C-2-furyl); 151.88 (CH-2). ¹⁹F NMR

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Sugar-Modified Nucleosides

985

(470.3 MHz, DMSO-d₆): –198.80 (ddd, J_F,H= 52.8, 19.2, 13.3); –161.19 (s). MS (ESI) m/z: 338

(M + H), 360 (M + Na). HRMS (ESI) for C₁₅H₁₄N₃O₄F₂[M + H] calculated: 338.0947; found:

338.0947. HRMS (ESI) for C₁₅H₁₃N₃O₄F₂Na [M + Na] calculated: 360.0766; found: 360.0766.

For C₁₅H₁₃N₃O₄F₂calculated: 53.42% C, 3.88% H, 12.46% N; found: 53.40% C, 4.12% H,

12.07% N.

7-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluoro-4-(thiophen-2-yl)-

7H-pyrrolo[2,3-d]pyrimidine (30c)

Deprotection of 29c (485 mg, 0.86 mmol) as described for 28a gave compound 30c as a yel-

low foamy solid. Yield 278 mg (91%). Compound 30c was crystallized from MeOH–water as

off white needles. M.p. 104–106 °C. [α]_D+43.8 (c 0.653, DMSO). ¹H NMR (499.8 MHz,

DMSO-d₆): 3.65 (ddd, 1 H, J_gem= 12.1, J_5′b,4′= 5.0, J_H,F= 0.7, H-5′b); 3.72 (ddd, 1 H, J_gem

=

12.0, J_5′a,4′= 4.1, J_H,F= 1.6, H-5′a); 3.85 (dddd, 1 H, J_4′,3′= 5.7, J_4′,5′= 5.0, 4.1, J_H,F= 0.9,

H-4′); 4.42 (ddd, 1 H, J_H,F= 19.1, J_3′,4′= 5.7, J_3′,2′= 4.2, H-3′); 5.24 (ddd, 1 H, J_H,F= 52.8,

J_2′,1′= 4.8, J_2′,3′= 4.2, H-2′); 6.80 (ddd, 1 H, J_H,F= 13.2, 1.9, J_1′,2′= 4.8, H-1′); 7.305 (dd, 1 H,

J_4,5= 5.0, J_4,3= 3.8, H-4-thienyl); 7.88 (t, 1 H, J_H,F= 1.9, H-6); 7.89 (dd, 1 H, J_5,4= 5.0, J_5,3

=

1.1, H-5-thienyl); 8.07 (dd, 1 H, J_3,4= 3.8, J_3,5= 1.1, H-3-thienyl); 8.78 (s, 1 H, H-2).

¹³C NMR (125.7 MHz, DMSO-d₆): 60.48 (CH₂-5′); 72.56 (d, J_C,F= 23.0, CH-3′); 80.93 (d,

J_C,F= 16.9, CH-1′); 83.26 (d, J_C,F= 5.9, CH-4′); 96.02 (d, J_C,F= 192.1, CH-2′); 102.30 (d, J_C,F

=

15.4, C-4a); 111.84 (dd, J_C,F= 31.7, 3.2, CH-6); 129.42 (d, J_C,F= 2.4, CH-4-thienyl); 130.45

(d, J_C,F= 16.2, CH-3-thienyl); 132.10 (CH-5-thienyl); 141.48 (d, J_C,F= 246.1, C-5); 141.85 (d,

J_C,F= 1.4, C-2-thienyl); 147.25 (d, J_C,F= 3.5, C-7a); 150.35 (d, J_C,F= 3.9, C-4); 151.82 (CH-2).

¹⁹F NMR (470.3 MHz, DMSO-d₆): –198.76 (ddd, J_F,H= 52.8, 19.1, 13.2); –160.20 (s). MS (ESI)

m/z: 354 (M + H), 376 (M + Na). HRMS (ESI) for C₁₅H₁₄N₃O₃F₂S [M + H] calculated:

354.0718; found: 354.0718. HRMS (ESI) for C₁₅H₁₃N₃O₃F₂SNa [M + Na] calculated: 376.0538;

found: 376.0537. For C₁₅H₁₃N₃O₃F₂S·0.2H₂O·0.6CH₄O calculated: 49.81% C, 4.23% H,

11.17% N; found: 49.90% C, 4.12% H, 11.05% N.

7-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluoro-4-(furan-3-yl)-

7H-pyrrolo[2,3-d]pyrimidine (30d)

Deprotection of 29d (480 mg, 0.88 mmol) as described for 28a gave compound 30d as a

yellow foamy solid. Yield 276 mg (93%). Compound 30d was crystallized from MeOH–

diethylether as a ochry solid. M.p. 77–79 °C. [α]_D+32.8 (c 0.445, DMSO). ¹H NMR

(600.1 MHz, DMSO-d₆): 3.65 (ddd, 1 H, J_gem= 12.0, J_5′b,4′= 4.9, J_H,F= 0.7, H-5′b); 3.71 (ddd,

1 H, J_gem= 12.0, J_5′a,4′= 4.0, J_H,F= 1.5, H-5′a); 3.84 (dddd, 1 H, J_4′,3′= 5.7, J_4′,5′= 4.9, 4.0,

J_H,F= 0.9, H-4′); 4.41 (ddd, 1 H, J_H,F= 19.3, J_3′,4′= 5.7, J_3′,2′= 4.2, H-3′); 5.12 (bs, 1 H,

OH-5′); 5.23 (ddd, 1 H, J_H,F= 52.8, J_2′,1′= 4.8, J_2′,3′= 4.2, H-2′); 5.96 (bs, 1 H, OH-3′); 6.80

(ddd, 1 H, J_H,F= 13.2, 1.9, J_1′,2′= 4.8, H-1′); 7.17 (dt, 1 H, J_4,5= 1.8, J_4,2= J_H,F= 0.7,

H-4-furyl); 7.83 (t, 1 H, J_H,F= 1.9, H-6); 7.90 (dd, 1 H, J_5,4= 1.8, J_5,2= 1.5, H-5-furyl); 8.48

(dt, 1 H, J_2,5= 1.5, J_2,4= J_H,F= 0.7, H-5-furyl); 8.84 (s, 1 H, H-2). ¹³C NMR (150.9 MHz,

DMSO-d₆): 60.45 (CH₂-5′); 72.53 (d, J_C,F= 23.0, CH-3′); 80.78 (d, J_C,F= 16.9, CH-1′); 83.18

(d, J_C,F= 5.9, CH-4′); 95.99 (d, J_C,F= 192.1, CH-2′); 103.82 (d, J_C,F= 15.6, C-4a); 109.91 (d,

J_C,F= 6.3, CH-4-furyl); 111.39 (dd, J_C,F= 30.8, 3.2, CH-6); 124.42 (d, J_C,F= 1.0, C-3-furyl);

141.42 (d, J_C,F= 246.0, C-5); 144.90 (d, J_C,F= 0.9, CH-5-furyl); 145.55 (d, J_C,F= 13.3,

CH-2-furyl); 146.92 (d, J_C,F= 3.4, C-7a); 149.74 (d, J_C,F= 3.7, C-4); 152.09 (CH-2). ¹⁹F NMR

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986

Nauš, Perlíková, Pohl, Hocek:

(470.3 MHz, DMSO-d₆): –198.79 (ddd, J_F,H= 52.8, 19.3, 13.2); –162.57 (s). MS (ESI) m/z: 338

(M + H), 360 (M + Na). HRMS (ESI) for C₁₅H₁₄N₃O₄F₂[M + H] calculated: 338.0947; found:

338.0947. HRMS (ESI) for C₁₅H₁₃N₃O₄F₂Na [M + Na] calculated: 360.0766; found: 360.0766.

For C₁₅H₁₃N₃O₄F₂·0.7H₂O·0.2C₄H₁₀O calculated: 52.03% C, 4.53% H, 11.52% N; found:

52.04% C, 4.48% H, 11.46% N.

7-(2-Deoxy-2-fluoro-β-D-arabinofuranosyl)-5-fluoro-4-(thiophen-3-yl)-

7H-pyrrolo[2,3-d]pyrimidine (30e)

Deprotection of 29e (478 mg, 0.85 mmol) as described for 28a gave compound 30e as a yel-

lowish foamy solid. Yield 271 mg (90%). Compound 30e was crystallized from MeOH–water

as ochry plates. M.p. 90–92 °C. [α]_D+42.5 (c 0.442, DMSO). ¹H NMR (499.8 MHz, DMSO-d₆):

3.65 (ddd, 1 H, J_gem= 12.0, J_5′b,4′= 5.0, J_H,F= 0.7, H-5′b); 3.72 (ddd, 1 H, J_gem= 12.0, J_5′a,4′

=

4.0, J_H,F= 1.6, H-5′a); 3.85 (dddd, 1 H, J_4′,3′= 5.7, J_4′,5′= 5.0, 4.0, J_H,F= 0.9, H-4′); 4.42 (ddd,

1 H, J_H,F= 19.1, J_3′,4′= 5.7, J_3′,2′= 4.2, H-3′); 5.24 (ddd, 1 H, J_H,F= 52.8, J_2′,1′= 4.8, J_2′,3′= 4.2,

H-2′); 6.82 (ddd, 1 H, J_H,F= 13.3, 1.8, J_1′,2′= 4.8, H-1′); 7.74 (dd, 1 H, J_5,4= 5.1, J_5,2= 2.9,

H-5-thienyl); 7.83 (ddd, 1 H, J_4,5= 5.1, J_4,2= 1.3, J_H,F= 0.9, H-4-thienyl); 7.865 (t, 1 H, J_H,F

=

1.9, H-6); 8.37 (ddd, 1 H, J_2,5= 2.9, J_2,4= 1.3, J_H,F= 0.7, H-2-thienyl); 8.87 (s, 1 H, H-2).

¹³C NMR (125.7 MHz, DMSO-d₆): 60.48 (CH₂-5′); 72.57 (d, J_C,F= 23.0, CH-3′); 80.86 (d,

J_C,F= 17.0, CH-1′); 83.22 (d, J_C,F= 5.9, CH-4′); 96.03 (d, J_C,F= 192.0, CH-2′); 103.99 (d, J_C,F

15.0, C-4a); 111.64 (dd, J_C,F= 31.1, 3.3, CH-6); 127.36 (CH-5-thienyl); 128.02 (d, J_C,F= 10.8,

CH-4-thienyl); 129.77 (d, J_C,F= 10.8, CH-2-thienyl); 138.88 (C-3-thienyl); 141.52 (d, J_C,F

=

246.7, C-5); 147.23 (d, J_C,F= 3.3, C-7a); 151.75 (d, J_C,F= 4.0, C-4); 151.98 (CH-2). ¹⁹F NMR

(470.3 MHz, DMSO-d₆): –198.73 (ddd, J_F,H= 52.8, 19.1, 13.3); –160.48 (s). MS (ESI) m/z:

354 (M + H), 376 (M + Na). HRMS (ESI) for C₁₅H₁₄N₃O₃F₂S [M + H] calculated: 354.0718;

found: 354.0718. HRMS (ESI) for C₁₅H₁₃N₃O₃F₂SNa [M + Na] calculated: 376.0538; found:

376.0537. For C₁₅H₁₃N₃O₃F₂S·0.2H₂O·0.55CH₄O calculated: 49.86% C, 4.20% H, 11.22% N;

found: 49.92% C, 4.15% H, 11.16% N.

This work is a part of the research project Z4 055 0506 from the Academy of Sciences of

the Czech Republic. It was supported by the the Czech Science Foundation (P207/11/0344) and by

Gilead Sciences, Inc. The authors thank Dr. I. Votruba (IOCB) and Dr. T. Cihlar, Dr. G. Birkus and

Dr. R. Mackman (Gilead) for cytostatic and antiviral screening.

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Sugar-modified derivatives of cytostatic 6-(het)aryl-7-deazapurine nucleosides: 2′-c-methylribonucleosides, arabinonucleosides and 2′-deoxy-2′-fluoroarabinonucleosides

DOI: 10.1135/cccc2011082

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Article abstract of DOI:10.1135/cccc2011082

Full text of DOI:10.1135/cccc2011082

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